Cancer
Geneticists verify link between cholesterol and cancer. University of Rochester Medical Center scientists have discovered new genetic evidence linking cholesterol and cancer, raising the possibility that cholesterol medications could be useful for cancer prevention. Data published in the online journal Cell Reports suggest that individuals who take cholesterol-lowering drugs may have a reduced risk of cancer and conversely that individuals with the highest levels of cholesterol seem to have an elevated risk.
A cholesterol lipid panel, consisting of total cholesterol, HDL, LDL, and triglycerides, is routinely ordered for serum cholesterol, which is bound to proteins. However, cholesterol also hides inside cells. While locked inside cell membranes before it is eventually exported, cholesterol has an impact on cell growth and survival. The gene ABCA1 is at the crossroads of the process that shuttles intracellular cholesterol outbound.
Research published a few years ago identified a network of approximately 100 so-called “cooperation response genes” that mediate the action of cancer genes.ABCA1, found among these genes, is frequently turned off in presence of other mutant cancer genes. In the latest investigation, researchers found that defective cholesterol exportation appears to be a key component in a variety of cancers. If ABCA1 function is lost in cancer cells, cholesterol builds up in the cells’ mitochondria, making their membranes more rigid. This in turn inhibits the function of cell-death triggers that normally become activated in response to cell stresses, including cancer gene activation. Therefore, when functioning properly, ABCA1 may have anti-cancer activity: by keeping mitochondrial cholesterol low, it may protect the functioning of cellular stress response systems and act as a barrier to tumor formation and progression.
The clinical implications of the new insights are to be determined. But by re-establishing the cholesterol export function in human colon cancer cells, researchers inhibited the cells’ ability to grow as cancers when grafted onto mice.
Stroke
Canadian lab study for stroke drug predicts outcomes in human clinical trials. Scientists at the Krembil Neuroscience Centre at the Toronto Western Hospital have developed the first lab study to accurately predict the outcomes of a human clinical trial for a drug that protects the brain against the damaging effects of stroke. The study, “A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic non-human primates,” published online in Science Translational Medicine, was conducted concurrently with a human trial called ENACT. The purpose of the animal study was to test whether the Toronto team could predict benefits of the stroke drug Tat-NR2B9c in a larger, multi-center trial conducted in humans. This study builds on work published in the journal Nature earlier this year, which showed the ability of this drug to reduce brain damage caused by stroke.
Several previous attempts at developing stroke drugs have suggested that certain drugs were effective in reducing stroke damage in small animals such as rats. However, none have shown efficacy in humans suffering from stroke, leaving an unexplained gap between results of studies in animals and those in humans. The research may be an early first step toward enabling researchers to predict whether or not a drug may work in humans. The UHN scientific team ran a trial in the lab that mimicked the design of a human clinical trial, which was conducted across Canada and the U.S.
Both studies evaluated the effectiveness of Tat-NR2B9c when it was administered after the onset of embolic strokes. The laboratory study replicated in animals the small strokes that are incurred by patients who undergo neurointerventional procedures to repair brain aneurysms. In the research lab, animals were randomized to receive either Tat-NR2B9c or placebo. Those treated with Tat-NR2B9c showed a marked reduction in both the numbers and the volumes of strokes when compared with the placebo group. Says Michael Tymianski, MD, PhD, the study’s lead author, “Our work provides a method to predict whether a stroke drug may be effective in humans.”
Influenza
Nasal spray for flu may be on the horizon. In an advance toward the development of a nasal spray that protects against infection with influenza and spread of the disease, scientists are reporting identification of a substance that activates the first-line defense system against infection inside the nose. They describe the effects of a synthetic form of a natural substance found in bacterial cell walls in the American Chemical Society’s journal Molecular Pharmaceutics.
David C. Jackson, PhD, and colleagues explain that the body’s so-called innate immune system forms a first-line defense system against respiratory diseases such as influenza A, which causes up to one billion infections and 500,000 deaths worldwide during seasonal epidemics. Those defenses swing into action almost immediately when viruses enter the nose and begin launching an infection. Scientists have been looking for ways to jump-start those defenses during flu outbreaks, and Jackson’s team turned to Pam2Cys. That synthetic lipoprotein, a substance consisting of a fat and a protein, has shown significant promise in activating the innate immune system.
The team found in laboratory tests that using Pam2Cys as a nasal spray primes the body’s immune system to fight infections. Importantly, researchers showed that the compound encourages but does not replace a normal immune response, which has been a concern about some antiviral medicines. Because Pam2Cys stimulates the immune system against a wide spectrum of viral and bacterial attacks, the authors suggest that it may be a particularly useful agent against pandemics and emerging viral strains.
Guidelines
CLSI releases new guideline for error grids. The Clinical and Laboratory Standards Institute (CLSI) has published a new document called How to Construct and Interpret an Error Grid for Diagnostic Assays; Approved Guideline. Document EP27-A provides guidance on constructing error grids, locating the error grid zones, and estimating proportions of differences in results. It contains illustrated examples of these concepts.
An error grid demonstrates the relationship between results obtained by one quantitative test to those obtained by a second one, while considering the diagnostic or therapeutic implications of the magnitude of the difference between the two results. Error grids inform users about the performance required to prevent potential patient harm. Once constructed, error grids can be populated with data from a measurement procedure comparison experiment. Then, one can calculate the proportion of data in each error grid zone as well as confidence intervals. The focus of this document is to improve error grid methodologies by keeping the patient in mind. It is intended for use by developers of measurement procedures, including laboratory-developed tests, and by clinical laboratories, and can be purchased through the CLSI website. You can preview sample pages at http://www.clsi.org/source/orders/free/EP27AE_sample.pdf.
New Studies
NIH researchers provide detailed view of brain protein structure. Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs). The new understanding of how the peptide binds to its receptor may help scientists design more effective drugs for neurological disorders.
Binding of neurotensin initiates a series of reactions in nerve cells. Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth. Researchers used X-ray crystallography, a technique in which X-rays are shot at crystallized molecules to determine the molecules’ shape and structure, to show what the receptor looks like in atomic detail when it is bound to neurotensin. The results provide the most direct and detailed views describing this interaction which may change the way scientists develop drugs targeting similar neuropeptide receptors.
The results are the first X-ray crystallography studies showing how a neuropeptide agonist binds to neuropeptide GPCRs. Nonetheless, researchers note that more work is needed to fully understand the detailed signaling mechanism of this GPCR.
Biomarker for mesothelioma may have been found. Researchers at NYU School of Medicine have discovered the protein product of a little-known gene may prove useful in identifying and monitoring the development of mesothelioma in early stages. “This gene produces a protein, fibulin-3, that is present in levels four to five times higher in the plasma of patients with mesothelioma compared to levels in asbestos-exposed patients or patients with several other conditions that cause tumors in the chest,” says lead investigator Harvey I. Pass, MD, the Stephen E. Banner Professor of Thoracic Oncology, vice chair of research for the Department of Cardiothoracic Surgery and division chief of General Thoracic Surgery at NYU Langone Medical Center.
Fibulin-3 is a protein that floats outside cells, coating the cells and free floating in blood plasma and extracellular fluid. The research team compared levels of fibulin-3 in two separate cohorts of patients who were exposed to asbestos through their jobs: a group of iron workers and other asbestos-exposed individuals in Detroit, and a group of insulators in New York. Both cohorts included individuals who had been exposed to asbestos but did not develop mesothelioma, as well as individuals with a confirmed mesothelioma diagnosis. The researchers found that fibulin-3 expression was markedly elevated in the plasma of the patients with mesothelioma compared with the plasma of patients without mesothelioma.
To test how specific the over-expression of fibulin-3 is to mesothelioma, they compared levels of the protein in the plasma of patients with mesothelioma to the plasma levels of the protein in patients afflicted by a variety of different types of cancer resulting in chest tumors. They found that fibulin-3 also discriminated between non-mesothelioma patients with different kinds of chest-tumor cancers and patients with mesothelioma, confirming high specificity.
Genomics
Gene variant linked to lung cancer risk A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44% reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with data on a different sample collection from NCI’s genome-wide association studies (GWAS), lung cancer risk was still estimated to be lower, but only by 21%. While this variation of gene NFKB1 had not previously been linked to lung cancer risk, a protein produced by the NFKB1 gene has been associated with several important roles in immunity, inflammation, and cell proliferation. These findings, by Meredith Shiels, PhD, and Anil Chaturvedi, PhD, NCI Division of Cancer Epidemiology and Genetics, and their colleagues, were published in the journal Cancer.
In the samples derived from the prevention study, 1,429 variants in inflammation or immunity related genes were investigated. The investigators found a significant link between lung cancer and 81 single nucleotide polymorphisms (SNPs) located in 44 genes in innate immunity and inflammation pathways. SNPs are the most common type of changes in DNA. They occur when a single nucleotide—a building block of DNA—is replaced with another of the four nucleotides (T, C, G or A) that comprise DNA. The investigators then compared their results with data from four recently completed GWAS that included 5,739 lung cancer cases and 5,848 controls. Of the 81 SNPs identified, the rs4648127 SNP, which is located within the NFKB1 gene, was associated with lung cancer in both analyses. This association between the NFKB1 gene variant and lung cancer risk underscores the role of inflammation and immunity in lung cancer development, according to the investigators.
