August 7, 2009

Aliquots — research highlights from VUMC laboratories

Watching cancer’s retreat

Predicting which patients will respond to targeted cancer therapies is a critical step in personalizing cancer treatment. In the July 15 issue of Clinical Cancer Research, H. Charles Manning, Ph.D., and colleagues report that molecular imaging might offer a noninvasive way to gauge early response to trastuzumab, a targeted therapy for breast cancers that overexpress the HER2 oncogene.

Using noninvasive molecular imaging methods, the researchers assessed programmed cell death (apoptosis), glucose uptake and cellular proliferation in two mouse models of HER2-positive breast cancer. They found that molecular imaging of apoptosis predicts response of HER2-positive tumors to trastuzumab; increases in the apoptosis marker (Annexin V) were inversely proportional to the decrease in tumor size following trastuzumab treatment.

However, molecular imaging of cellular proliferation predicted response in only one tumor model, while glucose uptake did not predict response in either model. The investigators suggest that molecular imaging of apoptosis should be further explored clinically as a noninvasive biomarker for tumor response to such drugs.
Melissa Marino


Protein ‘SOCS’ it to inflammation

Cytokines – molecular mediators of inflammation – have to be kept in check. If they run amok, they can cause blood poisoning known as sepsis, acute respiratory distress syndrome (ARDS), and chronic disorders such as inflammatory bowel disease and rheumatoid arthritis. Our own proteins called suppressors of cytokine signaling (SOCS) act inside cells to counteract inflammation.

The idea of replenishing these physiologic SOCS proteins to combat inflammatory signals propelled Jacek Hawiger, M.D., Ph.D., Antonio DiGiandomenico, Ph.D., and Lukasz Wylezinski to engineer a cell-penetrating SOCS1 protein (CP-SOCS1) for anti-inflammatory use.

They report July 21 in Science Signaling that CP-SOCS1 gains access to the interior of isolated immune cells and blocks pro-inflammatory signaling, thereby suppressing mediators of inflammation. The studies demonstrate the feasibility of using intracellular delivery of SOCS1 to suppress pro-inflammatory signals and provide a starting point for the development of new therapeutics for acute inflammatory syndromes, such as sepsis, ARDS, and kidney and liver failure.

Leigh MacMillan


Blood clotting balancing act

The complex process of coagulation (blood clotting) halts uncontrolled bleeding and helps initiate repair of damaged tissue. The process depends on a series of plasma proteins (clotting factors) that operate in a cascade leading to the formation of fibrin, a fibrous protein component of clots.

In this cascade, tissue damage activates factor XII (fXII), which then activates factor XI (fXI). While fXI deficiency is associated with bleeding disorders, fXII deficiency does not lead to abnormal bleeding, suggesting that some other mechanism can activate fXI to maintain normal clotting in the absence of fXII.

In the July 9 issue of Blood, David Gailani, M.D., and colleagues demonstrate that the key coagulation enzyme alpha-thrombin can fill this role, mediating fXI activation in the absence of fXII in plasma. The results confirm the presence of alternate mechanisms for the activation of fXI, and provide a better understanding of how this complex process may be regulated in the body.

Melissa Marino


This is your brain on Ecstasy

MDMA – known as Ecstasy – is a widely used recreational drug. It is also being evaluated in clinical trials for anxiety in severe post-traumatic stress disorder and in advanced stage cancer. Studies of the effects of MDMA on brain neurophysiology are essential for guiding public policy related to the potential risks and benefits of the drug.

John Karageorgiou, Ronald Cowan, M.D., Ph.D., and colleagues used functional magnetic resonance imaging to assess brain activation associated with a motor task (finger tapping) in 14 MDMA users and 10 controls. The two groups did not differ in motor reaction time, but MDMA users had higher activation in the right supplementary motor area of the brain. Lifetime exposure to MDMA (dose) was positively associated with signal magnitude in several brain regions.

The increased brain activity (for the same motor task) suggests that MDMA may have reduced the efficiency of brain motor functions. The findings, reported in the July 1 issue of NeuroImage, raise concern about the long-lasting effects of recreational MDMA use on brain neurophysiology.

Leigh MacMillan


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012