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Archive - 2014

January 28th

GWAS Study Identifies 11 New Genetic Associations for Asthma-with-Hay Fever

23andMe, a California-based personal genetics company, has participated in the first-ever genome-wide association study (GWAS) of the combined asthma-with-hay fever phenotype. Led by researchers at the QIMR Berghofer Medical Research Institute in Australia, the study identified 11 independent genetic markers associated with the development of asthma-with-hay fever, including two associations reaching a level of significance with allergic disease for the first time. Through these findings, 23andMe aims to substantially improve the ability to detect genetic risk factors shared between both diseases. Previous research has shown that both asthma and hay fever share 50-90 percent of their genetic susceptibility and 20-50 percent of their environmental susceptibility. 23andMe has collected information on both conditions through its asthma symptoms survey, and, in this analysis, used data contributed by 15,072 of its customers. Data was also collected from three additional studies conducted in Australia and the United Kingdom, with cases defined as persons who reported a physician diagnosis of asthma and also hay fever (total N=6,685). This group was compared to a control group of individuals who reported neither a diagnosis of asthma or hay fever (total N=14,091). “While previous analyses provided evidence of a stronger genetic association of this combined phenotype, there has not been a genome-wide association study exploring the connection in further detail,” said David Hinds, Ph.D., study author and 23andMe principal scientist in statistical genetics.

January 27th

Hopkins Study Suggests Non-CpG Methylation Is Reversible System of Gene Regulation That May Contribute to Rett Syndrome

In normal development, all cells turn off genes they don't need, often by attaching a chemical methyl group to the DNA, a process called methylation. Historically, scientists believed methyl groups could only stick to a particular DNA sequence: a cytosine followed by a guanine, called CpG. But in recent years, methyl groups have been found on other sequences, and so-called non-CpG methylation has been found in stem cells, and in neurons in the brain. Now, a team of researchers at Johns Hopkins has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation. In a study that was published online on December 23, 2013 in Nature Neuroscience, the Hopkins team describes this new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication. The research team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons, a finding that surprised the team, because this wasn't found in any other cells other than stem cells. By looking at what genes were being transcribed in neurons, he and his colleagues found that, like the form of methylation scientists had seen in stem cells, non-CpG methylation stops genes from being expressed. They also mapped the genome to find where non-CpG methylation happens, and found that it carves out its own niche, and the sites are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Dr. Song says.

Study Casts Doubt on Theory That Retired NFL Football Players Suffer Chronic Traumatic Encephalopathy (CTE)

The media have widely reported that a debilitating neurological condition called chronic traumatic encephalopathy (CTE) is a well-established disease in retired athletes who played football and other contact sports. But a study by a Loyola University Medical Center neuropsychologist has found little evidence that CTE actually exists. "There has not yet been one controlled epidemiological study looking at the risk of late-life cognitive impairment in any collision sport, including boxing, American football, or other sports involving repetitive head trauma," Christopher Randolph, Ph.D., reports in an open-access article in the January-February 2014 peer-reviewed journal Current Sports Medicine Reports. The author declares no conflict of interest and has no financial disclosures. CTE is said to be the cause of behavioral symptoms such as anger, aggression and suicidality, and cognitive symptoms such as impaired learning and memory problems. CTE is thought to be linked to concussions and characterized by the build-up of abnormal substances in the brain called tau proteins. A 2005 study, co-authored by Dr. Randolph, reported that rates of mild cognitive impairment among retired National Football League (NFL) players seemed to be higher than that of the general population, but Dr. Randolph noted there were no controls in this study, and results may have been subject to reporting biasb A more recent study of retired NFL players found that rates of Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) were higher than that of the general population. But this may be due to the fact that the NFL players had lower overall mortality rates from heart disease and other causes. Because they lived longer, the players naturally would be more likely to get age-related diseases such as Alzheimer's disease.

DNA-Glued Gold Nanostructures Safely Target and Image Cancerous Tumors

A team of researchers at the University of Toronto has discovered a method of assembling "building blocks" of gold nanoparticles as the vehicle to deliver cancer medications or cancer-identifying markers directly into cancerous tumors. The study, led by Dr. Warren Chan, Professor at the Institute of Biomaterials & Biomedical Engineering (IBBME) and the Donnelly Centre for Cellular & Biomolecular Research (CCBR), appears in an article published online on January 27, 2014 in Nature Nanotechnology. "To get materials into a tumor they need to be a certain size," explains Dr. Chan. "Tumors are characterized by leaky vessels with holes roughly 50 – 500 nanometers in size, depending on the tumor type and stage. The goal is to deliver particles small enough to get through the holes and 'hang out' in the tumor's space for the particles to treat or image the cancer. If a particle is too large, it can't get in, but if the particle is too small, it leaves the tumor very quickly." Dr. Chan and his fellow researchers solved this problem by creating modular structures 'glued' together with DNA. "We're using a 'molecular assembly' model - taking pieces of materials that we can now fabricate accurately and organizing them into precise architectures, like putting LEGO blocks together," comments Leo Chou, a 5th year Ph.D. student at IBBME and first author of the paper. Dr. Chou was awarded a 2012-13 Canadian Breast Cancer Foundation Ontario Region Fellowship for his work with nanotechnology. "The major advantage of this design strategy is that it is highly modular, which allows you to 'swap' components in and out. This makes it very easy to create systems with multiple functions, or screen a large library of nanostructures for desirable biological behaviors," he states.

January 26th

Computer Modeling Identifies Gene-Inhibiting Drug to Potentially Halt Breast Cancer Metastasis

Researchers at Cardiff University are developing a novel compound known to reverse the spread of malignant breast cancer cells. The vast majority of deaths from cancer result from its progressive spread to vital organs, known as metastasis. In breast cancer, up to 12,000 patients a year develop this form of the disease, often several years after initial diagnosis of a breast lump. In a recent series of studies, researchers identified a previously unknown critical role for a potential cancer-causing gene, Bcl3, in metastatic breast cancer. "We showed that suppressing this gene reduced the spread of cancer by more than 80%," said Dr Richard Clarkson from Cardiff University's European Cancer Stem Cell Research Institute. "Our next goal was to then find a way to suppress Bcl3 pharmacologically. Despite great improvements in therapy of early-stage breast cancer, the current therapeutic options for patients with late-stage metastatic disease are limited. There is therefore a clear unmet clinical need to identify new drugs to reverse or at least to slow down disease progression," he added. Dr. Clarkson and his team joined up with researchers Dr. Andrea Brancale and Dr. Andrew Westwell from the Cardiff University School of Pharmacy and Pharmaceutical Sciences, to develop small chemical inhibitors of the Bcl3 gene. Computer-aided modeling of how the Bcl3 gene functions inside the cell allowed the group to identify a pocket on the surface of Bcl3 essential for its function. By screening a virtual compound library for chemicals that could fit inside this pocket, using state-of-the-art computer software, they identified a drug candidate that potently inhibits Bcl3. The compound was then trialed on mice with metastatic disease.

Research Sheds Light on How Brain Creates Behavioral Sequences

When you learn how to play the piano, first you have to learn notes, scales, and chords, and only then will you be able to play a piece of music. The same principle applies to speech and to reading, where instead of scales you have to learn the alphabet and the rules of grammar. But how do separate small elements come together to become a unique and meaningful sequence. It has been shown that a specific area of the brain, the basal ganglia, is implicated in a mechanism called chunking, which allows the brain to efficiently organize memories and actions. Until now little was known about how this mechanism is implemented in the brain. In an article published online on January 26, 2014 in Nature Neuroscience, neuroscientist Dr. Rui Costa, and his postdoctoral fellow, Dr. Fatuel Tecuapetla, both working at the Champalimaud Neuroscience Programme (CNP) in Lisbon, Portugal, and Dr. Xin Jin, an investigator at the Salk Institute, in San Diego, California, reveal that neurons in the basal ganglia can signal the concatenation of individual elements into a behavioral sequence. "We trained mice to perform gradually faster sequences of lever presses, similar to a person who is learning to play a piano piece at an increasingly fast pace," explains Dr. Costa. "By recording the neural activity in the basal ganglia during this task, we found neurons that seem to treat a whole sequence of actions as a single behavior." The basal ganglia encompass two major pathways, the direct and the indirect pathways. The authors found that although activity in these pathways was similar during the initiation of movement, it was rather different during the execution of a behavioral sequence. "The basal ganglia and these pathways are absolutely crucial for the execution of actions.

Shortening Guide RNA Markedly Improves Specificity of CRISPR-Cas Nucleases

A simple adjustment to a powerful gene-editing tool may be able to improve its specificity. In a report published online on January 26, 2014 in Nature Biotechnology, Massachusetts General Hospital (MGH) investigators describe how adjusting the length of the the guide RNA (gRNA) component of the synthetic enzymes called CRISPR-Cas RNA-guided nucleases (RGNs) can substantially reduce the occurrence of DNA mutations at sites other than the intended target, a limitation the team had previously described just last year. "Simply by shortening the length of the gRNA targeting region, we saw reductions in the frequencies of unwanted mutations at all of the previously known off-target sites we examined," says J. Keith Joung, MD, PhD, associate chief for Research in the MGH Department of Pathology and senior author of the report. "Some sites showed decreases in mutation frequency of 5,000-fold or more, compared with full-length gRNAs, and importantly, these truncated gRNAs - which we call tru-gRNAs - are just as efficient as full-length gRNAs at reaching their intended target DNA segments." CRISPR-Cas RGNs combine a gene-cutting enzyme called Cas9 with a short RNA segment and are used to induce breaks in a complementary DNA segment in order to introduce genetic changes. Last year, r. Joung's team reported finding that, in human cells, CRISPR-Cas RGNs could also cause mutations in DNA sequences with differences of up to five nucleotides from the target, which could seriously limit the proteins' clinical usefulness. The team followed up those findings by investigating a hypothesis that could seem counterintuitive, that shortening the gRNA segment might reduce off-target mutations.

Breast Stem Cells Have Much Longer Lifespan Than Previously Thought, Implications for Breast Cancer

Researchers from Melbourne's Walter and Eliza Hall Institute in Australia have discovered that breast stem cells and their 'daughters' have a much longer lifespan than previously thought, and are active in puberty and throughout life. The longevity of breast stem cells and their daughters means that they could harbor genetic defects or damage that can progress to cancer decades later, potentially shifting back the timeline of breast cancer development. The finding is also integral to identifying the 'cells of origin' of breast cancer and the ongoing quest to develop new treatments and diagnostics for breast cancer. Breast stem cells were isolated in 2006 by Professors Jane Visvader and Geoff Lindeman and their colleagues at the Walter and Eliza Hall Institute. Now, in a project led by Dr. Anne Rios and Dr. Nai Yang Fu that tracked normal breast stem cells and their development, the team has discovered that breast stem cells actively maintain breast tissue for most of the life of the individual and contribute to all major stages of breast development. The research was published online on January 26, 2014 in Nature. Professor Lindeman, who is also an oncologist at The Royal Melbourne Hospital, said discovering the long lifespan and programming of breast stem cells would have implications for identifying the cells of origin of breast cancers. Professor Visvader said understanding the hierarchy and development of breast cells was critical to identifying the cells that give rise to breast cancer, and to understanding how and why these cells become cancerous. "Without knowing the precise cell types in which breast cancer originates, we will continue to struggle in our efforts to develop new diagnostics and treatments for breast cancer, or developing preventive strategies," Professor Visvader said.

January 25th

New Computer Model May Aid Personalized Cancer Care

Dana-Farber Cancer Institute scientists in Boston and colleagues have developed a mathematical model to predict how a patient's tumor is likely to behave and which of several possible treatments is most likely to be effective. Reporting online on January 23, 2014 in an open-access article in the journal Cell Reports, researchers combined several types of data from pre- and post-treatment biopsies of breast tumors to obtain a molecular picture of how the cancer evolved as a result of chemotherapy. "Better understanding of tumor evolution is key to improving the design of cancer therapies and for truly individualized cancer treatment," said Kornelia Polyak, M.D., Ph.D., a breast cancer researcher in the Susan F. Smith Center for Women's Cancers at Dana-Farber. The model was developed by Dr. Polyak and Franziska Michor, Ph.D., a computational biologist at Dana-Farber. The study analyzed breast cancer samples from 47 patients who underwent pre-operative chemotherapy to shrink the tumor so it could be removed more easily. The biopsy samples, representing the major types of breast cancer, included specimens taken at diagnosis and again after the chemotherapy was completed. As has been increasingly recognized, a tumor contains a varied mix of cancer cells and the mix is constantly changing. This is known as tumor heterogeneity. The cells may have different sets of genes turned on and off – phenotypic heterogeneity – or have different numbers of genes and chromosomes – genetic heterogeneity. These characteristics, and the location of different types of cells with the tumor, shape how the cancer evolves and are a factor in the patient's outcome. In generating their predictive model, Drs.

Study Identifies New Potential Targets for Eczema Treatment

A recent study reports the development of a new mouse model for atopic dermatitis, an inflammatory skin disorder commonly known as eczema. The findings, published online on January 9, 2014 in an open-access article in Cell Reports, suggest that mast cells (image), a type of immune cell, are critical for both spontaneous and allergen-induced eczema. The study, led by researchers at the La Jolla Institute for Allergy and Immunology in the United States and including researchers from the Laboratory for Allergic Disease at the RIKEN Center for Integrative Medicine in Japan and other institutions, was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health. Eczema is estimated to affect approximately one in five infants and one in fifty adults in the United States. The causes underlying the disorder are unclear. Previous research has suggested a role for imbalanced immune responses and impaired skin defenses, as well as overproduction of thymic stromal lymphopoietin (TSLP), a protein that promotes inflammation. While different mouse models for eczema have been developed, research examining how they are linked to human disease is still ongoing. In the current study, researchers show that mice lacking phospholipase C-beta3 (PLC- beta3), an enzyme that helps regulate inflammation, develop a skin disorder similar to human eczema, with high levels of TSLP. In this model, disease progression depends on the accumulation of mast cells and the activity of a signaling protein called Stat5. This role for mast cells and Stat5 in eczema was not previously known. The researchers also examined skin lesions of eczema patients and found that some had accumulation of mast cells expressing active Stat5.