Think of bacteria eating rock. Now think of bacteria eating rock below the ocean floor. How about experimenting on bacteria in that rock 15,000 feet underwater?

With a $3.9 million grant from the Gordon and Betty Moore Foundation, USC researcher Katrina Edwards will lead a first-of-its-kind drilling expedition to study subseafloor life.

Recently discovered subseafloor microbes, which live on chemical reactions with rock and water, may affect ocean chemistry, the marine food web and global climate.

That’s because the entire volume of Earth’s oceans appears to circulate through the seabed every 200,000 years – lightning fast, by geologic standards.

“The ocean crust is more like fractured hard sponge cake than what we think of as truly solid,” Edwards explained.

Yet scientists know little about this “deep biosphere,” so Edwards and more than 30 colleagues have pushed for an observatory and at least a decade of research, which the Moore Foundation grant helps make possible.

“Dr. Edwards is pursuing one of the most fascinating problems in science,” said David Kingsbury, chief program officer of science at the Moore Foundation, based in San Francisco.

“With the recognition that the subseafloor ocean may teem with microbial life comes new, fundamental questions about the evolution and distribution of life and the operation of the carbon cycle,” he added.

The grant will fund complex engineering and instrumentation needed for long-term experiments at and below the seafloor. The drilling will occur under the auspices of the Integrated Ocean Drilling Program, an international marine research program funded by the National Science Foundation and Asian government agencies. Shallow drilling is expected to begin in 2009, and deeper drilling in 2010.

The undertaking will further bridge the earth and life sciences, a key goal in the emerging field of geobiology, described by Edwards as the co-evolution of Earth and life.

The deep biosphere is uniquely suited for a geobiological approach, Edwards said, since a proper understanding requires genomics, analysis of microbe-rock chemical interactions and a timescale in the millions of years.

Edwards and colleagues will drill at a site near Bermuda through sediments that have accumulated over 7 million years. In addition, they will drill into the basalt below and then conduct long-term experiments in both rock types.

The observatory is expected to uncover new details about the microbes – details impossible to obtain using only rock samples, lab cultures and other traditional methods.

In addition, the unique site – with its deep bed of sediments enclosed by basalt – will allow researchers to understand where the bacteria came from.

“The bacteria could have ‘swum’ up into the sediments from below or they could have floated down from above,” Edwards explained.

Genetic and metabolic pathway data will help the scientists understand how bacteria at different depths in the sediment are related to each other and to other known species.

This in turn could offer clues about how the bacteria evolved, perhaps shedding light on the origin of life.

Still, the scientists are unsure of what they will ultimately discover.

“No one has ever done a project like this before, so we really don’t know,” Edwards said.

ABOUT GEOBIOLOGY AT USC

Geobiology at USC draws strength from diverse disciplines – from paleontology to genomics – and focuses on how the geosphere and biosphere interact chemically, how this works on a molecular level and how these systems evolve through time.

The USC Wrigley Institute for Environmental Studies brings together established and emerging scholars in the field during symposia and a summer geobiology course on Catalina Island funded this year by the National Science Foundation.

Edwards holds a doctorate in geomicrobiology – the first degree in the field awarded by the University of Wisconsin – and was formerly with the Woods Hole Oceanographic Institution.

She was among seven scientists with multidisciplinary interests related to geobiology to join USC in its 2006 “cluster hire.” The six others are John Heidelberg, Karla Heidelberg, David Hutchins, James Moffett, Sergio Sanudo-Wilhelmy and Eric Webb.

ABOUT THE GORDON AND BETTY MOORE FOUNDATION

The Gordon and Betty Moore Foundation, established in 2000, seeks to advance environmental conservation and cutting-edge scientific research around the world and improve the quality of life in the San Francisco Bay Area. For more information, visit moore/.

Source: Terah DeJong

University of Southern California Read the rest of this entry »

The validation of a test, based on gene expression and predicting the tumours that will metastasize in lymph nodes of head & neck cancers, was presented today at the 3rd International Conference on innovative approaches in Head and Neck Oncology (ICHNO), in Barcelona.

Dr Robert Takes, from the Radboud University Nijmegen Medical Centre, the Netherlands, reported results of a study involving 222 cases of oral or oropharyngeal cancer. The study was jointly led by scientists from Nijmegen and the University Medical Center Utrecht, and involved all eight head and neck oncological centres of the Netherlands.

“Today, it is impossible with current diagnostic tools to detect small lymph node metastasis in patients with head and neck squamous cell carcinoma and therefore it is common practice to operate on the neck even if no metastases have been detected,” said Dr Takes. “The majority of these operations is unnecessary because, in most cases, no metastases are present.”

If the chance of metastasis could be predicted more accurately, the number of operations could be reduced. “In our study, determining gene expression changes in the primary tumour improved the distinction between tumours that do metastasize from those that don’t,” continued Dr Takes.

With an array containing a set of 825 relevant genes, identified in a prior study and suitable for clinical application, distinction between metastasizing and non-metastasizing tumours was possible. The test correctly predicted the absence of metastasis in 89% of the cases.

“This is the first biological test that was able to obtain a high level of accuracy and has been validated in multiple centres on a large cohort of patients,” said Dr Takes.

“The possible reduction of unnecessary neck treatments in case of a negative test may result in decreased morbidity without deterioration of oncological outcomes. Also, in the remaining cases that still develop metastasis in the neck, salvage treatment is still possible,” added Dr Takes.

This signature is an additional method to already existing means to assess the neck, like imaging techniques and sentinel node procedures. “One important message arising from the study is that the combination of biological (gene signature) and clinical factors did better than either alone,” commented Prof Adrian Begg from the Netherlands Cancer Institute (NKI). “It thus appears that this signature is a useful addition which can help the decision on treatment policy.”

“Treatment is usually mainly selected based on the anatomical extent of the primary tumour and its metastasis. Additional biological information on the behaviour of each individual tumour could result in a more tailored treatment resulting in better survival,” said Dr Takes.

“Takes and colleagues have carried out an important and essential step in all studies on gene signatures,” concluded Prof Begg, “namely to move on from the initial finding of potential prognostic or predictive significance to validation in an independent clinical series.”

“We look forward to further validation and refinement of this approach which opens promising developments. In such studies it would still be useful to look at genome-wide expression, which would provide the opportunity to not only validate the present signature but also to look for even better ones.”

Source:
Cecile Hardon-Villard

European Society for Medical Oncology Read the rest of this entry »

New data, generated by Peter Lichter and colleagues, at the German Cancer Research Center, Heidelberg, have characterized a molecular pathway underlying low-grade forms of a type of brain tumor known as an astrocytoma. The authors therefore suggest that therapeutics targeting this pathway might provide a new approach to treating individuals with low-grade atrocytomas.

Analysis of the DNA of astrocytomas from a large number of children revealed that the most common genetic mutation was the duplication of a region of DNA containing the BRAF gene. Tumors with this genetic mutation showed signs of increased BRAF protein activity. Consistent with the idea that increased BRAF activity had a role in the development of the tumors, mutations in the BRAF gene that caused increased BRAF protein activity were detected in tumors that did not exhibit duplication of the region of DNA containing the BRAF gene. As pharmacologic and genetic silencing of the BRAF signaling pathway and the BRAF gene, respectively, prevented tumor cells from low-grade gliomas growing in culture, it was suggested that inhibiting the signaling pathway downstream of BRAF might be beneficial for individuals with low-grade atrocytomas.

TITLE: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

AUTHOR CONTACT:

Peter Lichter
German Cancer Research Center, Heidelberg, Germany.

View the PDF of this article at: the-jci/article.php?id=33656

Source:
Karen Honey
Journal of Clinical Investigation Read the rest of this entry »

Tokyo, (JCN) – The National Institute of Agrobiological Sciences (NIAS) has developed a DNA profiling method for poultry in collaboration with the Aichi-ken Agricultural Research Center.

The new method, which amplifies five microsatellite markers of the chicken DNA with PCR (polymerase chain reaction) and examines their lengths, can differentiate Nagoya Cochin, a well-received breed of chicken, from other chicken breeds such as broilers.

The method is effective when used with processed poultry.

The two partners jointly filed a patent for the new method on March 9. NIAS expects that the latest DNA profiling method will prevent the mislabeling of poultry while increasing the brand value of local chicken breeds like Nagoya Cochin as well as consumer confidence.

By Aki Tsukioka, JCN Staff Writer

Copyright © 2006 JCN. All rights reserved. A division of Japan Corporate News Network KK. Read the rest of this entry »

A genetic variant implicated in several cancers by genome-wide association studies (GWAS) has been found to drive increased expression of a known oncogene in the prostate.

The study, published July 13th in Genome Research, showcases a new protocol for studying the activity of cancer-risk variants suggested by GWAS studies. The results also underscore the dramatic consequences of small genetic changes even in the vast stretches of DNA, known as “gene deserts,” that do not code for proteins.

“This paper shows a way to follow-up on GWAS leads that pointed to these barren areas of the genome,” said senior author Marcelo Nobrega, MD, PhD, assistant professor of human genetics and member of the University of Chicago Comprehensive Cancer Center at the University of Chicago Medical Center.

Since the completion of the Human Genome Project in 2000, GWAS projects seeking genetic risk factors for disease have become a popular scientific tool. A population of people with a particular disease is compared to controls without the disease, uncovering genetic variants correlated with increased disease risk.

But the hope that such genetic variants would provide easy targets for novel therapies was initially deflated by an unexpected result. Most of the variants, called single nucleotide polymorphisms or SNPs, associated with disease risk were found not in the sequences encoding proteins, but in the other 98 percent of the genome where the biological role is less clear.

Attention has since turned to short regulatory sequences lying undiscovered as of yet in the “gene deserts.” With the power to control expression of faraway genes including when and where they are expressed these regulators could exert dramatic effects.

“There are all kinds of functional DNA sequences that have important biological roles that are not protein-encoding sequences,” Nobrega said. “There’s every reason to believe that mutations in these non-coding sequences may lead to disease or increase the risk of disease.”

But finding those non-coding sequences, much less determining their function, is a challenge. Regulatory sequences are typically around 500 base pairs in length, Nobrega said, dispersed in regions that are millions of base pairs long.

With colleagues Nora Wasserman and Ivy Aneas, Nobrega devised a method of quickly testing gene deserts to find biologically relevant sequences. A gene desert upstream of a known oncogene called MYC was chosen because of several GWAS results implicating the region in different cancers, including prostate. “This is one of strongest genetic signals to prostate cancer that has been identified so far,” Nobrega said.

Three artificial chromosomes were created that reproduced partial, overlapping segments of that gene desert, plus a gene called lacZ that produces a blue color in the cell when expressed. After introducing the chromosomes into a strain of mouse, the researchers measured where blue dye appeared reflecting organs where MYC expression was under the control of regulatory sequences present in each of the artificial chromosomes. Because two of the three chromosomes promoted expression in the prostate, the team was able to narrow down the relevant sequence to a 5,000 base pair segment.

That segment included a SNP called rs6983267, which had previously been associated through GWAS studies with increased risk of prostate and colorectal cancer. A second phase of experiments tested the “risk allele” version of that SNP against the non-risk allele different by only a single nucleotide.

Such a small difference produced dramatically different expression patterns, the study found. Transgenic mice carrying the risk allele exhibited robust blue staining in their prostate, while mice given the non-risk allele showed little to no detectable gene expression in the organ.

“Perhaps what this is telling us is that by inheriting the risk allele here, you may drive the overexpression of MYC,” Nobrega said. “It’s not going to cause prostate cancer, but it could increase the risk for prostate cancer.”

The differences in prostate expression between risk allele and non-risk allele are also apparent as early as embryonic stages, suggesting that the predisposition toward prostate cancer is set long before the disease actually appears.

“The mechanistic link between MYC expression levels and prostate may be much earlier than the cancer itself,” Nobrega said. “It could potentially prime the system for cancer and then, depending on either secondary mutations or environmental injuries, it might or might not develop.”

A next step would be to determine why the risk allele is capable of enhancing prostate expression with only a single nucleotide change. Nobrega suggested that an intermediary protein that binds to the enhancer sequence may be a promising target for preventive therapy in those carrying the risk allele.

But most importantly, the results confirm that the small genetic variants turned up by GWAS analyses are not artifacts, but highly relevant biological differences.

“This is a convincing demonstration in vivo that these noncoding SNPs that have been associated with complex diseases do lead to phenotypic differences,” Nobrega said. “It strongly suggests that this is a way to follow up on these associations for all kinds of disease; not only for cancer but for diabetes, obesity, and other conditions.”

The paper, “An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer,” appears in the July 13, 2010 issue of Genome Research. The research was funded by the National Human Genome Research Institute and the Department of Defense.

Source: University of Chicago Medical Center Read the rest of this entry »

Bits of movable DNA called transposable elements or TEs fill up the genomes of plants and animals, but it has remained unclear how a genome can survive a rapid burst of hundreds, even thousands of new TE insertions.

Now, for the first time, research led by plant biologists at the University of Georgia have documented the impact of such a burst in a rice strain that is accumulating more than 40 new TE insertions per plant per generation of an element called mPing.

The big surprise of their study is that the impact on the host seems to be modest. Not only that, the research shows that the genetic diversity created by massive and rapid TE insertions can actually benefit the plant in entirely unexpected ways.

“What we discovered was brand new and really stunning,” said Susan Wessler, UGA Foundation Chair in the Biological Sciences and leader of the research. “We found that the TE we studied avoids insertion sites in exons [sequences of DNA that code information for protein synthesis that is transcribed to messenger RNA]. But even more important may be that this shows that for rice and other `selfing’ plants [ones that essentially pollinate themselves], TE bursts may be one of the critical solutions to rapidly generate genetic diversity in the face of an ever-changing environment.”

The research was published online in the journal Nature. Other authors of the paper include Ken Naito, Feng Zhang, Nathan Hancock and Aaron Richardson of Wessler’s lab at UGA, and Takuji Tsukiyama, Hiroki Saito, Yukata Okumoto and Takatoshi Taniska of Kyoto University. Wessler and her lab are part of the department of plant biology, which is in the Franklin College of Arts and Sciences at UGA.

Transposable elements have been known to science for more than six decades. Despite making up half of the human genome and more than 90 percent of some plant genomes, the reasons for their success has remained elusive. Several things came together, however, to make the new research possible.

First, the complete rice genome sequence is now available including the location of most of its roughly 30,000 genes. Using this resource, Wessler and co-workers were able to decipher the precise sites for almost 2,000 new mPing insertions using a new high-throughput DNA sequencing method.

Next, they used DNA chip technology to determine the effect of most of these insertions on rice gene expression. And third but not least, the team demonstrated that a large subset of new alleles (different forms of a gene) that contain mPing “may actually benefit the host by creating potentially useful . . . and novel, stress-induced regulatory networks.” The stresses tested that demonstrate this were drought and salt-tolerance.

“One thing to remember is that for virtually all plants and animals characterized to date, most of their TEs were inserted hundreds of thousands to millions of years ago,” said Wessler, “so being able to observe the effects of their rapid increase in a well-characterized genome like rice gives us tremendous insights into these critical early events and permits us to glimpse how they alter the host organism.”

Demonstration that a rapid burst of TE insertions generate new regulatory networks is consistent with the ideas of Barbara McClintock, the scientist who discovered transposable elements and who was the first to propose that they were tools of evolutionary change.

It appears, the team said, that the ability of mPing to target its insertion sites helps to mitigate the effects of sudden rapid bursts of large-scale TE insertions – something one might think could be detrimental to the health of the host.

“Catching” a TE in the act of actual amplification, as the team did, brings important new insights into insertions that happened in the distant past and may finally help unravel why these ubiquitous bits of DNA comprise the majority of the genomes of plants and animals.

Source:
Phil Williams

University of Georgia Read the rest of this entry »

Thousands of the world’s top scientists and clinicians in the human genetics field will convene to present their latest research findings at the American Society of Human Genetics (ASHG) 60th Annual Meeting, on November 2-6, 2010, in Washington, D.C.

A number of the scientific papers presented at the ASHG 2010 meeting will provide information about important new research findings in statistical genetics and genetic epidemiology. One such research abstract of interest on these topics titled, “Mitochondrial Haplogroup X is Associated with Successful Aging in the Amish,” will be featured in a platform session that will take place on Friday, November 5, 2010, from 1:30-4:00 p.m. at the Walter E. Washington Convention Center. A brief summary of the research findings from this abstract is included in the section below:

Mitochondrial Haplogroup X is Associated with Successful Aging in the Amish

Avoiding disease, maintaining physical and cognitive function, and continuing social engagement in late life are considered to be key factors associated with what some gerontologists call “successful aging.” While conducting studies of Amish families in Indiana and Ohio, a group of researchers led by William K. Scott, PhD, Professor of Human Genetics at the University of Miami Miller School of Medicine, began to notice that a significant number of people over age 80 in these communities demonstrated the three main factors associated with successful aging. In the current study, Scott and his colleagues investigated the genetic differences between Amish individuals who had successfully aged compared with individuals from the general population to see what genetic factors are keeping them healthier and happier well into their later years.

A total of 263 volunteers, age 80 and older, were enrolled in a population-based door-to-door survey of Amish communities in Indiana and Ohio. The researchers studied this particular Amish population because they have fairly large families with well-documented genealogies. Furthermore, because they live relatively homogeneous lives, non-genetic factors such as environment and diet would have a smaller effect on successful aging, as compared to the general population. Study participants who scored in the top third of the sample for lower limb function, required little assistance with self-care tasks, had no symptoms of depression, and expressed a high level of life satisfaction were considered to be ‘successfully aged’ (73 participants in total). The remaining 190 study participants were retained as controls.

Researchers have theorized for some time that mitochondria – the organelles that produce energy in human cells – may play a role in aging. There is evidence that people who age successfully have genetically different mitochondria when compared to the general population. Furthermore, mitochondrial lineages described by patterns of common genetic variants (or “haplogroups”) have also been shown to be associated with increased longevity in different populations. To better understand these underlying genetic factors, Dr. Scott and his colleagues studied the influence of mitochondrial haplogroups on successful aging and sought to identify the common genetic variations in the mitochondrial genome that are potentially associated with successful aging in a sample of Amish individuals age 80 and older.

The common variations in the mitochondrial genome define distinct ‘haplogroups that are found in specific geographic regions around the world. For this study, Scott’s research team looked at the nine most common European haplogroups, since the Amish are descendants of individuals from Europe.

The current research results indicate that one fairly rare mitochondrial haplogroup found in only 2% of all Europeans – which is known as ‘haplogroup X’ – was found in 15% of the successfully aged Amish population (versus only 3% of the controls) and had a significant positive association with successful aging. On the other hand, the researchers also reported that another mitochondrial haplogroup called ‘haplogroup J’ which is typically found in about 10-25% of Southern Europeans, was found in only 5% of the Amish population and had a negative association with successful aging factors.

Thus, a significant positive association with successful aging was found with mitochondrial haplogroup X (which was more prevalent among the successfully aged Amish population), while a negative association was found with haplogroup J (which is more prevalent in European populations than the Amish). All positively associated alleles were found together on haplogroup X, while all negatively associated alleles fell in haplogroup J. All positively associated alleles were found together on haplogroup X (1719A), while all negatively associated alleles fell in haplogroup J (rs2854122, rs3135030, and 10398G). These data represent a novel association of mitochondrial haplogroup X with successful aging that conflicts with previous positive associations of haplogroup J with longevity in other populations.

“In this study, we focused on looking for genes that may have an influence on keeping people healthy, rather than identifying genes associated with disease,” said William Scott, PhD, the senior author of the research abstract presented at the ASHG 2010 Annual Meeting. “Our research results support the idea that mitochondria play an important role in aging, and our findings also suggest a specific subset of genetic variants that might influence successful aging in this group of people.”

“In our future research, it is important that we attempt to broadly associate this mitochondrial variation to aging in this population, figure out what it does biologically, and then see if we can reproduce it in other samples,” said Scott. “Furthermore, we will also need to look more closely at the mitochondrial genome for specific variants that influence aging.”

Source:
Kristen Long
American Society of Human Genetics Read the rest of this entry »

A California Institute of Technology (Caltech)-led team of researchers and clinicians has published the first proof that a targeted nanoparticle – used as an experimental therapeutic and injected directly into a patient’s bloodstream – can traffic into tumors, deliver double-stranded small interfering RNAs (siRNAs), and turn off an important cancer gene using a mechanism known as RNA interference (RNAi). Moreover, the team provided the first demonstration that this new type of therapy, infused into the bloodstream, can make its way to human tumors in a dose-dependent fashion – i.e., a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumor cells.

These results, published in the March 21 advance online edition of the journal Nature, demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future “game-changing” therapeutics that attack cancer and other diseases at the genetic level, says Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, and the research team’s leader.

The discovery of RNA interference, the mechanism by which double strands of RNA silence genes, won researchers Andrew Fire and Craig Mello the 2006 Nobel Prize in Physiology or Medicine. The scientists first reported finding this novel mechanism in worms in a 1998 Nature paper. Since then, the potential for this type of gene inhibition to lead to new therapies for diseases like cancer has been highly touted.

“RNAi is a new way to stop the production of proteins,” says Davis. What makes it such a potentially powerful tool, he adds, is the fact that its target is not a protein. The vulnerable areas of a protein may be hidden within its three-dimensional folds, making it difficult for many therapeutics to reach them. In contrast, RNA interference targets the messenger RNA (mRNA) that encodes the information needed to make a protein in the first place.

“In principle,” says Davis, “that means every protein now is druggable because its inhibition is accomplished by destroying the mRNA. And we can go after mRNAs in a very designed way given all the genomic data that are and will become available.”

Still, there have been numerous potential roadblocks to the application of RNAi technology as therapy in humans. One of the most problematic has been finding a way to ferry the therapeutics, which are made up of fragile siRNAs, into tumor cells after direct injection into the bloodstream. Davis, however, had a solution. Even before the discovery of RNAi, he and his team had begun working on ways to deliver nucleic acids into cells via systemic administration. They eventually created a four-component system – featuring a unique polymer – that can self-assemble into a targeted, siRNA-containing nanoparticle. The siRNA delivery system is under clinical development by Calando Pharmaceuticals, Inc., a Pasadena-based nanobiotech company.

“These nanoparticles are able to take the siRNAs to the targeted site within the body,” says Davis. Once they reach their target – in this case, the cancer cells within tumors – the nanoparticles enter the cells and release the siRNAs.

The scientific results described in the Nature paper are from a Phase I clinical trial of these nanoparticles that began treating patients in May 2008. Phase I trials are, by definition, safety trials; the idea is to see if and at what level the drug or other therapy turns harmful or toxic. These trials can also provide an in-human scientific proof of concept – which is exactly what is being reported in the Nature paper.

Using a new technique developed at Caltech, the team was able to detect and image nanoparticles inside cells biopsied from the tumors of several of the trial’s participants. In addition, Davis and his colleagues were able to show that the higher the nanoparticle dose administered to the patient, the higher the number of particles found inside the tumor cells – the first example of this kind of dose-dependent response using targeted nanoparticles.

Even better, Davis says, the evidence showed the siRNAs had done their job. In the tumor cells analyzed by the researchers, the mRNA encoding the cell-growth protein ribonucleotide reductase had been degraded. This degradation, in turn, led to a loss of the protein.

More to the point, the mRNA fragments found were exactly the length and sequence they should be if they’d been cleaved in the spot targeted by the siRNA, notes Davis. “It’s the first time anyone has found an RNA fragment from a patient’s cells showing the mRNA was cut at exactly the right base via the RNAi mechanism,” he says. “It proves that the RNAi mechanism can happen using siRNA in a human.”

“There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive,” says Antoni Ribas, associate professor of medicine and surgery at UCLA’s Jonsson Comprehensive Cancer Center. “This is because many of these targets are not amenable to be blocked by traditionally designed anti-cancer drugs. This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles. We can start thinking about targeting the untargetable.”

“Although these data are very early and more research is needed, this is a promising study of a novel cancer agent, and we are proud of our contribution to the initial clinical development of siRNA for the treatment of cancer,” says Anthony Tolcher, director of clinical research at South Texas Accelerated Research Therapeutics (START).

“Promising data from the clinical trials validates our years of research at City of Hope into ribonucleotide reductase as a target for novel gene-based therapies for cancer,” adds coauthor Yun Yen, associate director for translational research at City of Hope. “We are seeing for the first time the utility of siRNA as a cancer therapy and how nanotechnology can target cancer cells specifically.”

The Phase I trial – sponsored by Calando Pharmaceuticals – is proceeding at START and UCLA’s Jonsson Comprehensive Cancer Center, and the clinical results of the trial will be presented at a later time. “At the very least, we’ve proven that the RNAi mechanism can be used in humans for therapy and that the targeted delivery of siRNA allows for systemic administration,” Davis says. “It is a very exciting time.”

In addition to Davis, Ribas, Tolcher, and Yen, the coauthors on the Nature paper, “Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles,” are Caltech graduate students Jonathan Zuckerman (an MD/PhD student doing his MD work at UCLA) and Chung Hang Choi; former Caltech graduate student Christopher Alabi, now a postdoctoral scholar at the Massachusetts Institute of Technology; David Seligson, director of the UCLA Tissue Array Core Facility at the David Geffen School of Medicine; and Jeremy Heidel, who is currently a consultant for Calando Pharmaceuticals.

The work described in the paper was supported in part by the National Cancer Institute and the Daljit S. and Elaine Sarkaria Biomarker Laboratories. Caltech, Davis, and Heidel have a financial interest in Calando Pharmaceuticals.

Source:
Jon Weiner
California Institute of Technology Read the rest of this entry »

Researchers at the University of Pennsylvania have demonstrated that gene therapy used to restore retinal activity to the blind also restores function to the brain’s visual center, a critical component of seeing. The multi-institutional study led by Geoffrey K. Aguirre, assistant professor of neurology in Penn’s School of Medicine, shows that gene therapy can improve retinal, visual-pathway and visual-cortex responses in animals born blind and has the potential to do the same in humans.

“The retina of the eye captures light, but the brain is where vision is experienced,” Aguirre said. “The traditional view is that blindness in infancy permanently alters the structure and function of the brain, leaving it unable to process visual information if sight is restored. We’ve now challenged that view.”

The results support the potential for human benefit from retinal therapies aimed at restoring vision to those with genetic retinal disease. Researchers used functional MRI to measure brain activity in blind dogs born with a mutation in gene RPE65, an essential molecule in the retinoid-visual cycle. The same mutation causes a blindness in humans called Leber congenital amaurosis, or LCA. It is the first human eye-retinal disorder slated for gene therapy.

Gene therapy, performed by introducing a working copy of RPE65 into the retina, restored eye function in canines. Yet, it was previously unclear if the brain could ‘receive’ the restored sight.

The team found that gene therapy to the eye dramatically increased responses to light within the visual cortex of the canine brain. The recovery of visual brain function occurred in a canine that had been blind for the first four years of its life, and recovery was found to persist in another dog for at least two-and-a-half years after therapy, suggesting a level of permanence to the treatment.

Penn scientists then studied the structure and function of the visual brain of human patients with the same form of blindness. Young adults with blindness from RPE65 mutation had intact visual brain pathways with nearly normal structure. The Penn team also found that, while the visual cortex of these patients with LCA did not respond to dim lights, the brain’s reaction to brighter lights was comparable to that of individuals with normal sight.

“It seems these patients have the necessary brain pathways ready to go if their eyes start working again,” Aguirre said.

The results of the current study are critical to these human clinical trials, led at Penn’s Scheie Eye Institute by Samuel G. Jacobson, professor of ophthalmology, and Artur V. Cideciyan, research associate professor of ophthalmology.

“Existence of functional potential both in the eye and brain are prerequisites for successful gene therapy in all forms of LCA,” Cideciyan said. “In the RPE65 form of the disease, we now have evidence for both, and treatment at the retinal level has the hope of recovery of useful vision in patients.”

Findings of the study were reported in the journal PLoS Medicine.

The study was conducted by Aguirre and Marc Korczykowski of the Department of Neurology in Penn’s School of Medicine; Cideciyan, Tomas S. Alem’n, Alejandro J. Roman and Samuel G. Jacobson of the Department of Ophthamology; Brian B. Avants and James C. Gee of the Department of Radiology; David H. Brainard of the Department of Psychology in Penn’s School of Arts and Sciences; Andr’s M. Kom’romy and Gustavo D. Aguirre of Penn’s School of Veterinary Medicine; Gregory M. Acland of the Baker Institute of the College of Veterinary Medicine at Cornell University; and William W. Hauswirth of the University of Florida’s Department of Ophthalmology, who created the vector used for the gene therapy.

The research was supported by the National Institutes of Health, the Foundation Fighting Blindness, the Macula Vision Research Foundation, The Chatlos Foundation, the Alcon Research Institute, the Ruth and Milton Steinbach Fund, the The ONCE International Prize for Research and Development in Biomedicine and New Technologies for the Blind, the Macular Disease Foundation and the Burroughs-Wellcome Fund.

Contact: Jordan Reese

University of Pennsylvania Read the rest of this entry »

Pluronic surfactants are synthetic copolymers based on ethylene oxide and propylene oxide. It has been reported that a nonionic L-81, effectively inhibits absorption of dietary lipids from the intestine and secretion of VLDL and LDL from the liver. Although L-81 is a potent anti-obesity drug, its potential in alleviating obesity-induced insulin resistance and type 2 diabetes has not been fully explored.

A research article published in the World Journal of Gastroenterology addresses this question. The research group led by Prof. Lin from the Department of Chemistry of the University of Hong Kong constructed db/db mice to investigate the potential anti-diabetic activity of L-81. In addition to exploration of the underlying molecular mechanism, they examined the effects of L-81 on apolipoprotein B (apoB) secretion and the mRNA level of the MTP gene.

In their study, Genetically diabetic (db /db ) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db /db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apoB secretion and mRNA level of the MTP gene were assessed.

The results revealed that L-81 significantly corrected the body weight, hyperphagia and polydipsia of db/db mice, and remarkably decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. With the effective dosage, little toxicity was observed. Treatment on HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter.

Their study L-81 is a promising candidate in the development of a selective insulin-mimetic molecule and an anti-diabetic agent.

Reference: Au WS, Lu LW, Tam S, Ko OKH, Chow BKC, He ML, Ng SS, Yeung CM, Liu CC, Kung HF, Lin MC. Pluronic L-81 ameliorates diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein. World J Gastroenterol 2009; 15(24): 2987-2994

Source:
Lai-Fu Li

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