Published in the April issue of Cancer Cell, the researchers used a high-resolution genome topography scan (GTS) algorithm to identify gene copy alterations in human glioblastoma (GBM) primary samples and cell lines. Dozens of alterations were identified, some of which had not been linked previously to GBM. The results were then run through another algorithm in order to determine which alterations were most likely to cause cancer.
“As the Human Cancer Genome Project begins to map the genetic alterations in different kinds of cancer, we need to be able to discriminate between alterations that truly are relevant to the disease and those that are not,” explained the paper’s Senior Author, Lynda Chin. “Using a new algorithm developed in collaboration with Cameron Brennan [Managing Director of Memorial Sloan-Kettering], we were able to identify genes with too many or too few copies in cancer cells.”
One of the highest scoring abnormalities involved the p18INK4C gene. A similar gene, p16INK4A, is known to be missing from a large proportion of cases of GBM; therefore the connection between these two genes was investigated by the group.
“We found that p16 and p18 are part of a feedback loop that keeps the growth of normal glial cells in check,” Chin commented. “When p16 goes out of commission, p18 is signaled to pick up the slack. We demonstrated that the deletion of both genes is required for GBM to develop.”
The group hopes that this novel technique will enable researchers in the field to identify key genetic players in cancers, and therefore focus their work in the right direction in order to develop new therapeutics more rapidly.
“This study also demonstrates that GTS can address one critical need in the development of a functional map of GBM genetic targets: namely, to prioritize those genomic alterations that are likely to be of importance from among those that are more likely to be bystanders of the cancer process,” explained Cameron Brennan, a coauthor of the study. “Downstream functional validation of high probability candidates should yield novel GBM genes and potential targets for therapeutic intervention.”
Source: Wiedemeyer R, Brennan C, Heffernan TP et al. Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development. Cancer Cell 13, 355–364 (2008).
Involvement of vascular system in amyotrophic lateral sclerosis demonstrated
Using mutant mice with a hereditary form of amyotrophic lateral sclerosis (ALS), scientists from the University of Rochester (NY, USA) and the University of California at San Diego (CA, USA) have discovered that a breakdown occurs in the blood–spinal cord barrier, allowing toxins to enter the spinal cord and directly affect neurons.
In mice with a SOD1 mutation, which is estimated to play a role in around a quarter of the approximately 10% of human ALS cases that are hereditary, it was found that the SOD1 mutation reduced the levels of the tight junction proteins ZO-1, occludin and claudin-5 between endothelial cells. This disrupts the blood–spinal cord barrier and allows toxic substances from the blood to cross the barrier into the spinal cord.
“We believe these changes contribute to, or possibly initiate, the onset of ALS,” commented lead author Berislav Zlokovic. “It’s clear that these changes occur before the loss of neurons, and it’s well known that the types of changes we are seeing certainly injure or kill these types of cells, which are extremely sensitive to their biochemical environment.”
Source: Zhong Z, Deane R, Ali Z et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422 (2008).
Researchers study epigenetic changes in alcohol addiction
Published in the April issue of the Journal of Neuroscience, the researchers from University of Illinois at Chicago (IL, USA) and the Jesse Brown Veterans Affairs Medical Center (IL, USA) used a rat model of alcoholism in order to study the epigenetic changes occurring during alcohol withdrawal. The rats were fed a liquid diet containing alcohol. When the alcohol was withdrawn, the rats exhibited increased amounts of anxiety-like behaviors compared with rats on a nonalcohol diet.
“We need new strategies to treat alcoholism that are directed toward the prevention of withdrawal symptoms. Anxiety associated with withdrawal from alcohol abuse is a key factor in the maintenance of alcohol addiction,” Subhash Pandey, lead author of the study explained.
These anxiety-like behaviors were associated with an increase in histone deacetylase (HDAC) activity, and a decrease in histone acetylation and levels of neuropeptide Y (NPY) in the amyg-dala. HDACs decrease gene expression by removing acetyl groups from histones, causing them to wrap more tightly with DNA.
“This is the first time anyone has looked for epigenetic changes related to chromatin remodeling in the brain during alcohol addiction,” commented Pandey.
When a HDAC inhibitor, trichostatin A, was used during alcohol withdrawal, histone acetylation and NPY levels were increased, resulting in a prevention of the development of anxiety-like behaviors.
“This is the first direct evidence implicating the HDAC-induced chromatin remodeling in the amygdala as a major factor in the molecular processes of alcohol addiction, and further suggests that HDAC inhibitors may be potential therapeutic agents in treating alcoholism,” said Pandey.
Source: Pandey SC, Ugale R, Zhang H, Tang L, Prakash A. Brain chromatin remodeling: a novel mechanism of alcoholism. J. Neurosci. 28(14), 3729–3737 (2008).
Hope for early diagnosis of neurodegenerative diseases
Platform: NuroPro
Manufacturer: Power3 Medical Products Inc.
Diagnostic target: Relative level of 59 protein biomarkers to determine neurodegenerative disease
Early diagnosis of neurodegenerative disease may be possible through a blood test. The test, called NuroPro, is due to become available in Europe by this summer and in the USA by the end of this year. The test, developed by Power3 Medical Products Inc. (OK, USA), can also distinguish between Parkinson’s, Alzheimer’s and Lou Gehrig’s (amyotrophic lateral sclerosis [ALS]) diseases. In the absence of other molecular-based tests, clinicians rely on symptoms alone to diagnose neurodegenerative disease. Cheif Executive Officer of Power3 Medical Products Steve Rash commented, “Currently, there is no diagnostic test for any neurodegenerative disease on the market. We will be the first.”
Several blood proteins associated with neurodegenerative disease have been identified and patented by Power3 Medical Products. The NuroPro test measures the relative levels of 59 protein biomarkers in order to indicate whether the patient has a neurodegenerative disease and, if this is the case, to distinguish between Parkinson’s disease, Alzheimer’s disease or ALS. Rash claims the test has a specificity and sensitivity of approximately 95% or more. A different database is used for each disease and biostatistical analysis is applied to each biomarker.
In addition to diagnosing neurodegenerative diseases, NuroPro could potentially be a useful tool in monitoring the progression of disease and assessing the effectiveness of drugs. However, larger studies into the test may be required before it is universally accepted as a method of diagnosing for diseases such as Alzheimer’s. Two clinical validation studies are underway at the Cleo Roberts Center of Clincal Research (AZ, USA) and the Research Institute of Thessaly, Greece. Susan Sorensen from the UK Alzheimer’s Society commented, “It remains unclear which group of proteins gives the definitive signs of Alzheimer’s disease … Some suggest Alzheimer’s, for example, is too complex to be identified in this way.”
Source: www.soci.org
Study finds depression may be perpetuated by insomnia
Study: Project IMPACT
Aim: Compare ‘enhanced care’ with ‘usual care’ for treatment of late-life depression
Participants: 1801 patients aged over 60 years who suffer from major depressive disorder or dysthymia
Parameters: Severity of insomnia at baseline and 3-month time points
Conclusion: Persistant insomnia may perpetuate depressive episode
Published in the April 1 issue of the journal Sleep, researchers from the USA have demonstrated that insomnia might perpetuate depression in elderly patients treated by primary care providers.
Project IMPACT (Improving Mood-Promoting Access to Collaborative Treatment), a study involving 1801 elderly patients aged 60 years or over who suffered from major depressive disorder (MDD) or dysthymia, conducted at 18 primary care clinics in five states, compared ‘enhanced care’ with ‘usual care’ for the treatment of late-life depression.
“In the usual-care group, physicians were free to treat patients as they chose,” explained lead author Wilfred Pigeon, from the University of Rochester Medical Center (NY, USA). “In the ‘enhanced care’ group, patients received ‘stepped care’ by a nurse care manager, who provided … education about depression and brief ‘problem-focused therapy’. Depending on their progress, the nurse could suggest medication changes to the primary care provider or suggest and facilitate a referral to a psychiatrist if there was still no progress.”
Using standard diagnostic criteria based on insomnia scores at baseline and at 3-month time points, the 1801 patients from project IMPACT were categorized depending on whether they suffered from insomnia (and if so how severely). Of the 1801 patients, 207 were found to have persistent insomnia. The majority of patients (1301) suffered from intermediate insomnia, and only 293 patients were found not to suffer from insomnia.
“This study highlights the importance of staying on top of insomnia that (occurs) with depression,” commented Pigeon. “We don’t yet know which patients’ insomnia will dissipate when depression starts to improve, so the most conservative approach would be to treat it when you see it.”
Severe depression at 6 months was present in 44, 29 and 16% of patients with persistent, intermediate and no insomnia, respectively. Subgroup analysis found that there was a statistically significantly greater risk of depression at 6, 8 and 12 months follow-up in patients with persistent compared with those not suffering from insomnia at all. The researchers also found that the association was stronger in patients who received usual care and in those who suffered from MDD compared with dysthymia.
The authors conclude that “in addition to being a risk factor for a depressive episode, persistent insomnia may serve to perpetuate the illness in some elderly patients and especially in those receiving standard care for depression in primary care settings.” They also suggest that “enhanced depression care may partially mitigate the perpetuating effects of insomnia on depression.”
Source: Pigeon WR, Hegel M, Unützer J et al. Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep 31(4), 481–488 (2008).