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Archive for the ‘Interesting Studies’ Category

Bioinformatics approach helps researchers find new uses for old drug

 :: Posted by American Biotechnologist on 05-05-2014

Developing and testing a new anti-cancer drug can cost billions of dollars and take many years of research. Finding an effective anti-cancer medication from the pool of drugs already approved for the treatment of other medical conditions could cut a considerable amount of time and money from the process.

Now, using a novel bioinformatics approach, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that the approved antimicrobial drug pentamidine may help in the treatment of patients with advanced kidney cancer. Described online in the journal Molecular Cancer Therapeutics, the discovery reveals how linking cancer gene expression patterns with drug activity might help advance cancer care.

“The strategy of repurposing drugs that are currently being used for other indications is of significant interest to the medical community as well as the pharmaceutical and biotech industries,” says senior author Towia Libermann, PhD, Director of the Genomics, Proteomics, Bioinformatics and Systems Biology Center at BIDMC and Associate Professor of Medicine at Harvard Medical School. “Our results demonstrate that bioinformatics approaches involving the analysis and matching of cancer and drug gene signatures can indeed help us identify new candidate cancer therapeutics.”

Renal cell cancer consists of multiple subtypes that are likely caused by different genetic mutations. Over the years, Libermann has been working to identify new disease markers and therapeutic targets through gene expression signatures of renal cell cancer that distinguish these different cancer subtypes from each other, as well as from healthy individuals. In this new paper, he and his colleagues were looking for drugs that might be effective against clear cell renal cancer, the most common and highly malignant subtype of kidney cancer. Although patients with early stage disease can often be successfully treated through surgery, up to 30 percent of patients with renal cell cancer present with advanced stages of disease at the time of their diagnosis.

To pursue this search, they made use of the Connectivity Map (C-MAP) database, a collection of gene expression data from human cancer cells treated with hundreds of small molecule drugs.

“C-MAP uses pattern-matching algorithms to enable investigators to make connections between drugs, genes and diseases through common, but inverse, changes in gene expression,” says Libermann. “It provided us with an exciting opportunity to use our renal cell cancer gene signatures and a new bioinformatics strategy to match kidney cancer gene expression profiles from individual patients with gene expression changes inducted by various commonly used drugs.”

After identifying drugs that may reverse the gene expression changes associated with renal cell cancer, the investigators used assays to measure the effect of the selected drugs on cells. This led to the identification of a small number of FDA-approved drugs that induced cell death in multiple kidney cancer cell lines. The investigators then tested three of these drugs in an animal model of renal cell cancer and demonstrated that the antimicrobial agent pentamidine (primarily used for the treatment of pneumonia) reduced tumor growth and enhanced survival. Gene expression experiments using microarrays also identified the genes in renal cell cancer that were counteracted by pentamidine.

“One of the main challenges in treating cancer is the identification of the right drug for the right individual,” explains first author Luiz Fernando Zerbini, PhD, of the International Center for Genetic Engineering and Biotechnology in Cape Town, South Africa, adding that this bioinformatics approach could be a particularly valuable lower-cost model in developing countries.

The authors say their next step will be to evaluate the potential of pentamidine in combination with the current standard-of-care therapies to treat kidney cancer. “Since the drugs we are evaluating are already FDA-approved, successful studies in preclinical animal models may enable us to rapidly move these drugs into clinical trials,” adds Libermann.

Thanks to Beth Israel Deaconess Medical Center for contributing this story.

Much-needed tool for neuroscience emerges after years of work

 :: Posted by American Biotechnologist on 04-24-2014

Nearly a decade ago, the era of optogenetics was ushered in with the development of channelrhodopsins, light-activated ion channels that can, with the flick of a switch, instantaneously turn on neurons in which they are genetically expressed. What has lagged behind, however, is the ability to use light to inactivate neurons with an equal level of reliability and efficiency. Now, Howard Hughes Medical Institute (HHMI) scientists have used an analysis of channelrhodopsin’s molecular structure to guide a series of genetic mutations to the ion channel that grant the power to silence neurons with an unprecedented level of control.

The new structurally engineered channel at last gives neuroscientists the tools to both activate and inactivate neurons in deep brain structures using dim pulses of externally projected light. Deisseroth and his colleagues published their findings April 25, 2014 in the journal Science. “We’re excited about this increased light sensitivity of inhibition in part because we think it will greatly enhance work in large-brained organisms like rats and primates,” he says.

First discovered in unicellular green algae in 2002, channelrhodopsins function as photoreceptors that guide the microorganisms’ movements in response to light. In a landmark 2005 study, Deisseroth and his colleagues described a method for expressing the light-sensitive proteins in mouse neurons. By shining a pulse of blue light on those neurons, the researchers showed they could reliably induce the ion channel at channelrhodopsin’s core to open up, allowing positively charged ions to rush into the cell and trigger action potentials. Channelrhodopsins have since been used in hundreds of research projects investigating the neurobiology of everything from cell dynamics to cognitive functions.

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Why Geneticists May Have to Learn Yet Another Language

 :: Posted by American Biotechnologist on 04-17-2014

When talking about genetic abnormalities at the DNA level that occur when chromosomes swap, delete or add parts, there is an evolving communication gap both in the science and medical worlds, leading to inconsistencies in clinical and research reports.
Now a study by researchers at Brigham and Women’s Hospital (BWH) proposes a new classification system that may standardize how structural chromosomal rearrangements are described. Known as Next-Gen Cytogenetic Nomenclature, it is a major contribution to the classification system to potentially revolutionize how cytogeneticists worldwide translate and communicate chromosomal abnormalities. The study will be published online April 17, 2014 in The American Journal of Human Genetics.

“As scientists we are moving the field of cytogenetics forward in the clinical space,” said Cynthia Morton, PhD, BWH director of Cytogenetics, senior study author. “We will be able to define chromosomal abnormalities and report them in a way that is integral to molecular methods entering clinical practice.”

According to the researchers, advances in next-generation sequencing methods and results from BWH’s Developmental Genome Anatomy Project (DGAP) revealed an assortment of genes disrupted and dysregulated in human development in over 100 cases. Given the wide variety of chromosomal abnormalities, the researchers recognized that more accurate and full descriptions of structural chromosomal rearrangements were needed.

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Scarless Wound Healing

 :: Posted by American Biotechnologist on 04-10-2014

In early fetal development, skin wounds undergo regeneration and healing without scar formation. This mechanism of wound healing later disappears, but by studying the fetal stem cells capable of this scarless wound healing, researchers may be able to apply these mechanisms to develop cell-based approaches able to minimize scarring in adult wounds, as described in a Critical Review article published in Advances in Wound Care, a monthly publication from Mary Ann Liebert, Inc., publishers and an Official Journal of the Wound Healing Society. The article is available free on the Advances in Wound Care website.

Michael Longaker, Peter Lorenz, and co-authors from Stanford University School of Medicine and John A. Burns School of Medicine, University of Hawaii, Honolulu, describe a new stem cell that has been identified in fetal skin and blood that may have a role in scarless wound healing. In the article “The Role of Stem Cells During Scarless Skin Wound Healing,” the authors propose future directions for research to characterize the differences in wound healing mechanisms between fetal and adult skin-specific stem cells.

“This work comes from the pioneers in the field and delineates the opportunities towards scarless healing in adults,” says Editor-in-Chief Chandan K. Sen, PhD, Professor of Surgery and Director of the Comprehensive Wound Center and the Center for Regenerative Medicine and Cell-Based Therapies at The Ohio State University Wexner Medical Center, Columbus, OH.

Directing the World With Your Imagination

 :: Posted by American Biotechnologist on 04-07-2014