May 8, 2009

Aliquots — research highlights from VUMC laboratories

Booster for cancer radiation therapy

Although intended to destroy cancer, radiation can actually induce pro-survival signaling pathways in tumor blood vessels, leading to radioresistance within these vessels and enhancing their survival and growth. Agents that sensitize these vessels to radiation could therefore improve radiation therapy’s ability to control tumor growth.

Amanda Linkous, Eugenia Yazlovitskaya, Ph.D., and colleagues tested an inhibitor of cytosolic phospholipase A2 (cPLA2) – an enzyme whose activation triggers pro-survival signaling and leads to tumor vasculature radioresistance – in irradiated tumor cells and in mice with implanted lung tumors.

They report in the March 1 issue of Clinical Cancer Research that the inhibitor, called arachidonyltrifluoromethyl ketone, prevented radiation-induced activation of survival pathways in the cultured cells. In the radiation-treated mice, the inhibitor disrupted tumor vasculature, enhanced the destruction of tumor blood vessels, and suppressed tumor growth. The results suggest that cPLA2 is a promising therapeutic target for tumor sensitization to radiotherapy, and that cPLA2 inhibition could be particularly beneficial in treating highly radiation-resistant lung tumors.

Melissa Marino


Text-search spots cardiac risk factor

QT interval prolongation – measured on an electrocardiogram (ECG) – is a known risk factor for sudden cardiac death. Many medications can cause or worsen QT prolongation, making its detection important for clinical decision support.

ECG reports stored in medical record systems include calculated QT intervals provided by the ECG machine and cardiologist-generated notes about the findings. Because machine-calculated QT intervals vary in accuracy, cardiologists’ interpretations remain the gold standard for detecting QT prolongation.

Joshua Denny, M.D., and colleagues used a natural language processing (NLP) system to identify QT prolongation within the cardiologists’ text in a set of 44,318 ECGs from hospitalized patients. They report in the International Journal of Medical Informatics that NLP analysis of the ECG-related text was much more accurate at identifying QT prolongation than machine-reported intervals. They suggest that NLP analysis could enable large-scale research on drug adverse events and the development of new decision support tools to improve cardiovascular medication safety.

Leigh MacMillan


Detecting a potential MS “bug”

While some studies have detected the presence of the bacterium Chlamydophila pneumoniae in cerebrospinal fluid of patients with multiple sclerosis (MS), other studies have failed to find such an association. Culturing this pathogen is difficult, and the lack of a standardized protocol for molecular detection of C. pneumoniae could be responsible for the inconsistent previous findings.

Yi-Wei Tang, M.D., Ph.D., and colleagues developed and validated two PCR (polymerase chain reaction)-based methods for detection of C. pneumoniae from cerebrospinal fluid – a qualitative PCR-EIA assay and a quantitative real-time PCR assay. In PLoS ONE, they report that the qualitative PCR-EIA could detect a minimum of 25 copies of bacterial DNA per milliliter of spinal fluid and was as sensitive as the easily contaminated nested-PCR method and more sensitive than the commonly used real-time PCR assay. The results suggest that the PCR-EIA assay may provide a much-needed method for C. pneumoniae detection from clinical samples, which would allow investigators to better evaluate the potential relationship between C. pneumoniae and MS.

Melissa Marino


Designer protein reins in excess signals

G protein-coupled receptors (GPCRs) – the largest family of cell signaling proteins – are targets for the majority of pharmaceuticals. GPCR signaling is “turned off” in a two-step process: receptor phosphorylation followed by binding of a protein called arrestin. Excessive signaling by GPCR mutants that cannot be phosphorylated results in a variety of diseases, from retinal degeneration to cancer.

Rod cells in the eye are full of the light-sensitive GPCR rhodopsin, and defects in rhodopsin shutoff result in cell death. Vsevolod Gurevich, Ph.D., and colleagues tested whether an engineered enhanced arrestin could shut off uncontrolled signaling by unphosphorylated rhodopsin. They report in the April 28 issue of Current Biology that a designer arrestin protein can suppress aberrant rhodopsin signaling and promote rod cell survival and function. The findings show that it’s possible to redesign the GPCR shutoff machinery in living animals and pave the way for correcting genetic defects associated with excessive receptor signaling.

Leigh MacMillan

Past Aliquots

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