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Archive - Dec 19, 2019

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Cryo-EM & Supercomputer Analyses Reveal Asymmetry in Active Sites of B-Raf Kinases; Possible Key Clue to Solving Melanoma Mystery

It starts off small, just a skin blemish. The most common moles stay just that way -- harmless clusters of skin cells called melanocytes, which give us pigment. In rare cases, what begins as a mole can turn into melanoma, the most serious type of human skin cancer because it can spread throughout the body. Scientists are using powerful supercomputers to uncover the mechanism that activates cell mutations found in about 50 percent of melanomas. The scientists say they're hopeful their study can help lead to a better understanding of skin cancer and to the design of better drugs. In 2002, scientists found a link between skin cancer and mutations of B-Raf (Rapidly Accelerated Fibrosarcoma) kinase (image), a protein that's part of the signal chain that starts outside the cell and goes inside to direct cell growth. This signal pathway, called the Ras/Raf/Mek/Erk kinase pathway, is important for cancer research, which seeks to understand out-of-control cell growth. According to the study, approximately 50 percent of melanomas have a specific single mutation on B-Raf, known as the valine 600 residue to glutamate (V600E). B-Raf V600E thus became an important drug target, and specific inhibitors of the mutant were developed in the following years. The drugs inhibited the mutant, but something strange happened. Paradoxically, quieting the mutant had a down side. It activated the un-mutated, wild-type B-Raf protein kinases, which again triggered melanoma. "With this background, we worked on studying the structure of this important protein, B-Raf," said Yasushi Kondo, PhD, a postdoctoral researcher in the John Kuriyan Lab at UC Berkeley. Dr.

Large-Scale Generation of Functional mRNA-Encapsulating Exosomes Achieved by Nanoporation; Advance May Enable New Gene Therapy Strategies; Initial Study Done on Gliomas

Scientists have developed a new gene-therapy technique by transforming human cells into mass producers of tiny nano-sized particles full of genetic material that has the potential to reverse disease processes. Though the research was intended as a proof of concept, the experimental therapy slowed tumor growth and prolonged survival in mice with gliomas, which constitute about 80 percent of malignant brain tumors in humans. The technique takes advantage of exosomes, fluid-filled subcellular vesicles that cells release as a way to communicate with other cells. While exosomes are gaining ground as biologically friendly carriers of therapeutic materials – because there are a lot of them and they don’t elicit an immune response – the trick with gene therapy is finding a way to fit those comparatively large genetic instructions inside the tiny exosomes on a scale that will have a therapeutic effect. This new method relies on patented technology that prompts donated human cells such as adult stem cells to release millions of exosomes that, after being collected and purified, function as nanocarriers containing a drug. When they are injected into the bloodstream, these exosomes know exactly where in the body to find their target – even if it’s in the brain. “Think of them like Christmas gifts: The gift is inside a wrapped container that is postage-paid and ready to go,” said senior study author L. James Lee, Phd, Professor Emeritus of Chemical and Biomolecular Engineering at The Ohio State University. And they are gifts that keep on giving, Dr. Lee noted: “This is a Mother Nature-induced therapeutic nanoparticle.” The new study was published online on December 16, 2019 in Nature Biomedical Engineering. The article is titled “Large-Scale Generation of Functional mRNA-Encapsulating Exosomes Via Cellular Nanoporation.”