Category Archives: Transhuman News

PUBLIC RELEASE DATE:

10-Nov-2014

Contact: Elizabeth Dowling newsmedia@mssm.edu 212-241-9200 The Mount Sinai Hospital / Mount Sinai School of Medicine @mountsinainyc

Regulation of a single, specific gene in a brain region related to drug addiction and depression is sufficient to reduce drug and stress responses, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published October 27 online in the journal Nature Neuroscience.

The Mount Sinai study focuses on epigenetics, the study of changes in the action of human genes caused, not by changes in DNA code we inherit from our parents, but instead by molecules that regulate when, where and to what degree our genetic material is activated.

Previous research has found links between epigenetic regulation and the diseases of drug addiction and depression, in both human patients and animal models. Such regulation derives, in part, from the function of transcription factors, specialized proteins that bind to specific DNA sequences and either encourage or shut down the expression of a given gene.

Using mouse models of human depression, stress and addiction, the current research team introduced synthetic- transcription factors into a brain region called the nucleus accumbens at a single gene called FosB, which has been linked by past studies to both addiction and depression. They found that changes to this single gene brought on by the transcription factors made the study mice more resilient to stress and less likely to become addicted to cocaine.

Found in every cell of the body, DNA contains genes and the instructions needed for an organism to develop and survive. To carry out these functions, DNA sequences are converted into messages that "tell" cells which proteins to make, dictating the specific function of a given cell. While all cells contain the DNA that codes for every gene, most genes are not activated at all times. The expression of a given gene depends on the action of transcription factors, proteins that regulate the structure of DNA within the cell, allowing some genes to be active and others to be repressed. Transcription factors act by epigenetic mechanisms: chemically modifying either the DNA itself, or the histone proteins packaged around DNA that change shape given the right signal to make stretches of DNA available to the protein building machinery.

"Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression," says Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, who led the study. "But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease."

To directly address this issue, Elizabeth A Heller, PhD, lead author on the paper, developed an innovative method to control epigenetic regulation of FosB. Dr. Heller introduced synthetic transcription factors called Zinc Finger Proteins (ZFPs), designed to target only a single gene out of 20,000, by incorporating them into a virus and injecting that virus into the reward-related brain region. Study results indicate that upon binding to that one gene, the FosB-ZFPs modified histones in the vicinity of the FosB gene, in order to either activate (turn on) or repress (turn off) expression.

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Changes in a single gene's action can control addiction and depression-related behaviors

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Newswise PHILADELPHIA Oncology researchers studying gene mutations in the childhood cancer neuroblastoma are refining their diagnostic tools to predict which patients are more likely to respond to drugs called ALK inhibitors that target such mutations. Removing some of the guesswork in diagnosis and treatment, the researchers say, may lead to more successful outcomes for children with this often-deadly cancer.

Some mutations are more important than others, said Yal P. Moss, MD, a pediatric oncologist at The Childrens Hospital of Philadelphia, and a co-leader of the new study published online today in the journal Cancer Cell. By integrating biochemistry into our clinical strategies, we can better match a patients specific ALK-mutation profile with an optimum treatment. Moss is also an assistant professor of Pediatrics in the Perelman School of Medicine, University of Pennsylvania.

Understanding the specific mutations that trigger signals in cell receptors to stimulate cell growth will help us identify biomarkers for specific subtypes of neuroblastoma, said study co-leader Mark A. Lemmon, PhD, professor and chair of Biochemistry and Biophysics at Penn. Lemmons research focuses on cell receptors in cancer.

Moss, Lemmon and their computational collaborator Ravi Radhakrishnan, PhD, an associate professor in the department of Bioengineering at Penn, say their new findings will provide crucial data for a pivotal phase 3 study for patients with ALK-driven high-risk neuroblastoma. This trial will be conducted through the Childrens Oncology Group (COG), a cooperative research organization encompassing over 250 pediatric cancer programs in North America. The COG is supported by the National Cancer Institute.

A solid tumor of the peripheral nervous system, often appearing in the chest or abdomen, neuroblastoma is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children, with cure rates lagging behind those for other pediatric cancers.

The current study concentrates on various mutations in ALK, the anaplastic lymphoma kinase gene. Moss led a team that first discovered in 2008 that an ALK mutation caused a hereditary form of neuroblastoma, and also identified ALK mutations implicated in some non-hereditary neuroblastoma.

Moss was subsequently able to expedite a phase 1 pediatric trial for neuroblastoma and other ALK-dependent childhood cancers using an existing drug called crizotinib, a molecule that inhibits the ALK protein when it is switched on by some ALK gene mutations. Crizotinib had a stronger anticancer effect against some ALK mutations than in others. In later collaboration with Lemmon, the investigators analyzed the biochemistry of how the two most common ALK mutations responded to crizotinib. The results strongly suggested that higher doses of the drug would be necessary for children with one mutation compared to the otherand that this knowledge could help oncologists define the correct dosage before an initial treatment.

Neuroblastoma is complex, with many subtypes of the disease. The current study explored the full spectrum of neuroblastoma, analyzing DNA from a COG tumor bank drawn from nearly 1,600 patients. The team discovered ALK mutations in 8 percent of the tumors, with a higher rate among tumors from older patients and those with high-risk neuroblastoma. The researchers also investigated which ALK mutations were more sensitive to crizotinib in cell cultures.

See more here:
Classification of Gene Mutations in a Children's Cancer May Point to Improved Treatments