Featured Research

Unprecedented interception of pain: Relief from chronic pain is a major priority for the 1,000,000 US residents that suffer from spinal cord injury (SCI). Ching-Yi Lin, PhD, Department of Neurosciences in Cleveland Clinic's Lerner Research Institute, is the lead and corresponding author of a new study published in the Journal of Neurotrauma, showing that a single injection of fibronectin, a naturally occurring protein, leads to an unprecedented inhibition of chronic SCI pain for over eight months in an experimental model. This is a collaborative project between Dr. Lin and Yu-Shang Lee, PhD, Department of Neurosciences; Vernon Lin, MD, PhD, Department of Physical Medicine and Rehabilitation, Cleveland Clinic; and Jerry Silver, PhD, Department of Neurosciences, Case Western Reserve University.

Fibronectin is known to support the survival and growth of neurons in the brain and spinal cord. The researchers discovered, through the use of fibronectin fragments and competitive inhibitors, that the pain-curbing results depended upon a short, 8-amino acid segment of fibronectin, which activated specific cellular signaling pathways.

It is known that spinal cord injury increases the permeability of the blood-spinal cord barrier, causing secondary pathogenesis and chronic pain due to exposure of the spinal cord to inflammatory cells. Results show that fibronectin not only maintained the integrity of the blood-spinal cord barrier, but also suppressed the inflammatory response. Researchers found that fibronectin reversed spinal cord injury-induced decreases in serotonin, a neurotransmitter that plays an important role in pain perception.

Researchers are hopeful regarding the implications of this study on therapeutic development, and Dr. Lin was invited to present the research in the “pain-relief press conference” at the annual meeting of Society for Neuroscience 2011, Washington DC, the premier venue for neuroscientists from around the world to debut cutting-edge research on the brain and nervous system.

See Fibronectin inhibits chronic pain development after spinal cord injury. Lin CY, Lee YS, Lin VW, Silver J. J Neurotrauma 2011 Oct 24. [Epub ahead of print].

New study defines markers that distinguish a subset of colon cancers: Genome-wide research confirms that a subset of colon cancers are characterized by a process called “DNA methylation” of specific genes. DNA methylation, a type of heritable change in gene expression caused by factors beyond the genetic code, is shown to set “CIMP” colon cancers apart from others. These tumors were shown to bear CIMP tumor-specific methylation sites, namely in regions called “CpG islands” of the DNA, and more extensive methylation of regions commonly methylated in colon cancer.

Although CIMP stands for “CpG island methylator phenotype,” it has been controversial whether this was applicable to colon cancers. With no standardized characterization of CIMP colon cancers, prognostic value and clinical relevance have remained inconclusive.

Genome Research reports that researchers at Cleveland Clinic’s Genomic Medicine Institute of the Lerner Research Institute, led by Angela Ting, PhD, GMI, used strict guidelines to characterize CIMP colon tumors (hypermethylated at CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS; microsatellite unstable; mutant BRAF) versus non-CIMP colon tumors (not hypermethylated at those five loci, microsatellite stable; mutant BRAF). They suggest that this definition may rectify the usefulness of CIMP status as a prognostic indicator.

Dr. Ting’s group used state-of-the-art “massively parallel” DNA sequencing technology to discover that not only do CIMP tumors exhibit increased methylation, but also that 80% of the areas of hypermethylation unique to CIMP tumors occur in regions known as CpG islands, thus verifying their name.

Methylation is a strategy cancer uses to prevent the expression of genes the body would use against the cancer. Dr. Ting’s study shows that the hypermethylation noted in CIMP tumors has a functional consequence: all 12 core cancer signaling pathways were affected.

The research, which gives a detailed catalog of differentially methylated sites, will assist further studies into what causes DNA methylation in colon cancer, and candidate players in this process were identified. New therapeutic targets are expected to emerge from this investigation.