Aliquots - highlights from VUMC laboratories

10/23/2009 - Targeting Hedgehog in brain tumors

Malignant gliomas are brain tumors that are particularly resistant to current therapies. There are many subtypes of malignant glioma, and some patient specimens show activity of the Hedgehog (Hh) signaling pathway, indicating that this pathway may play a role in tumor growth and, thus, could be a target for treating these tumors.

To study Hh’s role, Michael Cooper, M.D., and colleagues generated a primary xenograft model by transplanting human glioma cells on the day of surgical resection directly into the brains of mice. They report, in the Oct. 1 issue of Oncogene that a primary xenograft model differentiated Hh-responsive from unresponsive malignant glioma subtypes. They also demonstrated that in Hh-responsive gliomas, pathway activity is confined to cancer stem cells and that inhibiting the pathway with a drug called cyclopamine conferred a significant survival benefit. The results suggest that Hh signaling regulates the growth of certain malignant gliomas, and that drugs like cyclopamine may represent one component of more effective therapies.

— Melissa Marino

Modified histones add stability

In the cell nucleus, DNA wraps around groups of eight histone proteins to form nucleosomes, the basic subunits of chromatin (the complex of DNA and protein that makes up chromosomes). Modifications of the histones, without changes in the DNA sequence, can be inherited and have been shown in some cases to activate oncogenes and contribute to tumorigenesis.

Zu-Wen Sun, Ph.D., and colleagues are exploring histone modifications – and how they affect chromatin structure and gene expression – using the budding yeast S. cerevisiae as a model. In a study reported in the Sept. 29 Proceedings of the National Academy of Sciences, they investigated the role of H2Bub1 (histone 2B modified by the addition of a small protein, ubiquitin) in regulating chromatin structure. They showed that, contrary to some models, H2Bub1 does not function simply as a “wedge” to non-specifically unfold chromatin, but that it instead stabilizes nucleosomes. The results suggest that H2Bub1 modulates nucleosomal dynamics during gene expression by regulating nucleosome stability.

— Leigh MacMillan

Brain training for sensory processing

How do our brains recognize that the person moving his or her lips is the same person we hear talking? If two stimuli – a sight and a sound – appear close in time, the brain “binds” the stimuli, concluding that they result from a single event. While the size of this “temporal window” – the time interval between incoming sensory stimuli – has been explored, it is not known whether it is possible to enlarge or contract this window.

To investigate how the temporal window might be altered, Mark Wallace, Ph.D., and graduate student Albert Powers put subjects through two types of perceptual “training” in which they were rewarded for correctly determining if a tone and a shape on a computer screen were simultaneous. They found these training paradigms resulted in a significant and long-lasting narrowing of the temporal window. The results, published in the Sept. 30 Journal of Neuroscience, suggest that perceptual training may be beneficial in interventions for conditions in which multisensory temporal processing is disrupted, such as dyslexia, autism and schizophrenia.

— Melissa Marino

HIV therapy better during pregnancy

For HIV-infected women receiving highly active antiretroviral therapy (HAART), pregnancy has been associated with a lower risk of HIV disease progression. It’s not clear if the timing of HAART initiation relative to pregnancy affects the mother’s virologic, immunologic and clinical outcomes.

Vlada Melekhin, M.D., M.P.H., and colleagues conducted a retrospective study of 112 HIV-infected pregnant women who started HAART before, during or after pregnancy. The researchers evaluated changes in HIV-1 RNA (virologic response) and CD4+ lymphocytes (immunologic response), and subsequent HIV disease progression. They report in the September issue of PLoS ONE that women initiating HAART during pregnancy had better HIV-1 RNA and CD4+ changes than those who started HAART after pregnancy. There were no statistical differences in the rates of HIV disease progression between the groups. The improved virologic and immunologic responses among women starting HAART during pregnancy suggest that larger studies with longer follow-up periods are needed to assess differences in clinical outcomes.

— Leigh MacMillan

Past Aliquots

Nov. 20, 2009
Nov. 6, 2009
Oct. 23, 2009
Oct. 9, 2009
Sept. 18, 2009
Sept. 4, 2009
Aug. 21, 2009
©2009 Vanderbilt Medical Center
Editorial tool created by Vanderbilt Medical Center Web Development