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Archive - Jan 26, 2014

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.