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Senin, 02 Juli 2012

Role Of FOXO1 Gene In Parkinson's Disease Identified

Role Of FOXO1 Gene In Parkinson's Disease Identified

Main Category: Parkinson's Disease
Article Date: 02 Jul 2012 - 1:00 PDT

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A recent study led by researchers at Boston University School of Medicine (BUSM) revealed that the FOXO1 gene may play an important role in the pathological mechanisms of Parkinson's disease. These findings are published online in PLoS Genetics, a peer-reviewed open-access journal published by the Public Library of Science.

The study was led by Alexandra Dumitriu, PhD, a postdoctoral associate in the department of neurology at BUSM. Richard Myers, PhD, professor of neurology at BUSM, is the study's senior author.

According to the Parkinson's Disease Foundation, 60,000 Americans are diagnosed with Parkinson's disease each year and approximately one million Americans are currently living with the disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by a buildup of proteins in nerve cells that lead to their inability to communicate with one another, causing motor function issues, including tremors and slowness in movement, as well as dementia. The substantia nigra is an area of the midbrain that helps control movement, and previous research has shown that this area of the brain loses neurons as Parkinson's disease progresses.

The researchers analyzed gene expression differences in brain tissue between 27 samples with known Parkinson's disease and 26 samples from neurologically healthy controls. This data set represents the largest number of brain samples used in a whole-genome expression study of Parkinson's disease to date. The novel aspect of this study is represented by the researchers' emphasis on removing possible sources of variation by minimizing the differences among samples. They used only male brain tissue samples that showed no significant marks of Alzheimer's disease pathology, one of the frequently co-occurring neurological diseases in Parkinson's disease patients. The samples also had similar tissue quality and were from the brain's prefrontal cortex, one of the less studied areas for the disease. The prefrontal cortex does not show neuronal death to the same extent as the substantia nigra, although it displays molecular and pathological modifications during the disease process, whil e also being responsible for the dementia present in a large proportion of Parkinson's disease patients.

Results of the expression experiment showed that the gene FOXO1 had increased expression in the brain tissue samples with known Parkinson's disease. FOXO1 is a transcriptional regulator that can modify the expression of other genes. Further examination of the FOXO1 gene showed that two single-nucleotide polymorphisms (SNPs), or DNA sequence variations, were significantly associated with age at onset of Parkinson's disease.

"Our hypothesis is that FOXO1 acts in a protective manner by activating genes and pathways that fight the neurodegeneration processes," said Dumitriu. "If this is correct, there could be potential to explore FOXO1 as a therapeutic drug target for Parkinson's disease."

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Study Identifies Pathway To Enhance Usefulness Of EGFR Inhibitors In Lung Cancer Treatment

Study Identifies Pathway To Enhance Usefulness Of EGFR Inhibitors In Lung Cancer Treatment

Main Category: Lung Cancer
Article Date: 02 Jul 2012 - 1:00 PDT

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Many lung cancers are driven by mutations in the epidermal growth-factor receptor (EGFR), and so it makes sense that many successful modern treatments block EGFR activity. Unfortunately, cancers inevitably evolve around EGFR inhibition, and patients with lung cancers eventually relapse.

A University of Colorado Cancer Center study published in the journal Cancer Research details a signaling pathway, known as 'the canonical Wnt pathway', that lung cancer cells use to escape from EGFR-targeted therapy - and suggests that by disrupting this pathway, we could lengthen the usefulness of existing EGFR inhibition therapies.

"As Billy Crystal as Miracle Max said in The Princess Bride, 'There's a big difference between mostly dead and all dead,' and in lung cancer cells, the Wnt pathway could be that difference," says James DeGregori, PhD, investigator at the CU Cancer Center, co-director of the center's Molecular Oncology Program, and the paper's senior author.

Elaborating on DeGregori's very technical description, Matias CasÃ¡s-Selves, PhD, postdoc in the DeGregori lab and the paper's first author, explains, "The Wnt pathway is an ancient mechanism across species that helps stem cells differentiate into tissue, and maintains stem cells' ability to stay 'stemmy' - to produce subsequent generations of cells that can also continue to produce cells. It also maintains adult lung tissue, and now we've shown that it also maintains cancer cells during targeted therapy."

Imagine a dish filled with millions of lung cancer cells. And imagine the cells' genetic material as a shared book. CasÃ¡s-Selves systematically deleted paragraphs from cells' books to create a population of cells, each with a unique paragraph deleted. Then he treated all the cells with an EGFR inhibitor. Which cells died? Well, a number of paragraphs were responsible for cell death, "But many of the paragraphs missing from the dead cells were within the Wnt chapter," he says.

Break the flow of this Wnt chapter, and you break the ability of cells to withstand EGFR inhibition therapy. EGFR inhibitors currently employed in the clinic include popular drugs like gefitinib, erlotinib and cetuximab. Combining EGFR inhibitors with a hypothetical Wnt inhibitor could make the effects of these useful drugs more durable.

It turns out this Wnt inhibitor may be more than hypothetical.

"Traditionally, the Wnt pathway has been considered to be a hard pathway to drug, since there are not many easily druggable enzymes in it, but we were lucky in that just as we were finding roles for Wnt in lung cancer cell survival, other research teams discovered that a group of enzymes, called tankyrases, are key for the correct functioning of Wnt. Not only that, these groups also designed tankyrase inhibitors which were available for all researchers," CasÃ¡s-Selves says.

And so instead of what could have been a lengthy search for a drug, the idea of Wnt inhibition combined with EGFR inhibition goes straight into the preclinical pipeline.

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Reducing Animal Testing With New Technique

Reducing Animal Testing With New Technique

Main Category: Water - Air Quality / Agriculture
Also Included In: Public Health;Â Â Biology / Biochemistry
Article Date: 02 Jul 2012 - 1:00 PDT

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A new way of testing the safety of natural and synthetic chemicals has been developed by scientists with funding from the Biotechnology and Biological Sciences Research Council (BBSRC). Their research, published in the journal Ecotoxicology, could reduce the number of fish needed to test the toxicity of a range of chemicals including pharmaceuticals and environmental pollutants.

The researchers, led by Professor Awadhesh Jha of Plymouth University, have managed to coax cells from the liver of a rainbow trout to form a ball-shaped structure called a spheroid in a petri dish. This ball of cells behaves much more like normal animal tissue than cells grown in traditional ways in the lab and so can give researchers a more accurate picture of how an animal's body would respond to a chemical in the environment.

Fish are used to test whether both new and existing chemicals like pharmaceuticals can damage wildlife or the environment. Because a large number of spheroids can be produced from a single fish the use of this technique could mean less fish are needed to do these tests.

Professor Jha explains "This is a real breakthrough in our efforts to reduce the numbers of fish needed for toxicology testing. It is very important for the health of people, wildlife and whole ecosystems that we understand the effect of chemicals, both natural and manmade, in the environment, but we must strive to avoid the use of animals wherever possible."

One of the most impressive aspects of the fish spheroids is that they can be maintained in the lab for over a month. Many environmental pollutants cause health problems because they accumulate over time and become more concentrated further up the food chain. Because the fish spheroids can be maintained for longer time periods than normal cell cultures scientists can test the effect of long-term exposure to a potential toxin.

The fish spheroids were produced by a BBSRC-funded CASE student, Matthew Baron, who is being supervised by Professor Jha and his colleagues at Plymouth and AstraZeneca Safety Health and Environment. At present, scientists can use flat layers of fish cells to replace some live animal tests but these break down quickly and do not behave like real tissues. Spheroids are already well established models for testing on mammalian cells but this is the first time that they have been developed from fish cells.

Because the liver filters blood it is often the main organ where potential environmental toxins accumulate and are broken down by the body and so is the most important organ for testing toxicity. The researchers also hope to produce spheroids from fish gill cells, as the gills are another important site of toxin accumulation. By combining these two types of spheroids in a single system the researchers hope to develop a 'virtual fish' which could give a clear picture of how a particular chemical would affect a live animal.

Professor Douglas Kell, BBSRC Chief Executive said "Everyone wants to see fewer animals used in testing so this is great news. The UK has always led the way in efforts to reduce, refine and replace the use of animals in research. Whilst the use of some animals will remain important to ensuring that the medicines and other chemicals are safe to use and won't damage the environment, we are making great strides in the combining of new laboratory techniques and computer modelling to avoid using animals wherever possible."

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Minggu, 01 Juli 2012

Severe Sleep Loss Affects Immune System Like Physical Stress Does

Severe Sleep Loss Affects Immune System Like Physical Stress Does

Editor's Choice
Academic Journal
Main Category: Sleep / Sleep Disorders / Insomnia
Also Included In: Immune System / Vaccines
Article Date: 01 Jul 2012 - 18:00 PDT

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Sleep deprivation and physical stress have similar effects on the immune system of human beings, researchers from the Netherlands and the United Kingdom reported in the journal SLEEP. Both physical stress and severe sleep loss jolt the immune system into action, the authors explained.

The scientists , from Erasmus MC University Medical Center Rotterdam, and the Faculty of Health and Medical Sciences at the University of Surrey, United Kingdom, compared the number of white blood cells in 15 healthy young adult males who were subjected to normal sleep and severe sleep loss.

The greatest impact was on granulocytes - types of white blood cells - which lost their day-to-night time rhythmicity as numbers shot up, especially during nighttime.

Lead author, Katrin Ackermann, PhD, said:

"Future research will reveal the molecular mechanisms behind this immediate stress response and elucidate its role in the development of diseases associated with chronic sleep loss.
If confirmed with more data, this will have implications for clinical practice and for professions associated with long-term sleep loss, such as rotating shift work."

The authors explained that prior studies had found a link between lack of sleep and the development of certain diseases and conditions, such as high blood pressure (hypertension), diabetes and obesity. Other studies have demonstration that adequate sleep helps keep the immune system working properly, and that long-term sleep loss is a major risk factor for immune system problems.

The 15 young men were made to follow a strict routine of eight hours sleep every day for one whole week - their white blood cells were categorized and measured. Within 90 minutes of waking up, they were exposed to 15+ minutes of outdoor light. They were not allowed to consume anything with caffeine in it, they were told not to drink alcohol or take any medications. The aim here was to stabilize their circadian clocks and bring sleep deprivation down to a minimum before the intensive laboratory study.

The scientist compared the participants' white cell counts during their normal sleep/wake cycle week to the count during the second part of the experiment when the subjects were made to spend 29 hours without any sleep at all.

Ackermann said:

"The granulocytes reacted immediately to the physical stress of sleep loss and directly mirrored the body's stress response."

What are ganulocytes?

A granulocyte is a type of white blood cell that is full of microscopic granules - tiny sacs that contain enzymes for digesting microorganisms.

Granulocytes form part of our innate immune system. Experts say they have a broad-based immune activity - they are nonspecific. Granulocytes are not like B-cells and T-cells which respond exclusively to specific antigens.

There are different types of granulocytes, including eosinophils, basophils and neutrophils; they get their names from their staining features in the lab.

Several problems associated with lack of sleep or sleep difficulties

Sleep deprivation and bad food choices - Investigators from the University of California demonstrated how sleep deprivation can undermine regions in the brain which are responsible for making food choices. They explained that their findings might explain why sleep deprivation is linked to a higher risk of becoming obese. (Link to article)

Lack of sleep and stroke risk - Normal weight adults who sleep less than six hours per night have a much greater risk of stroke symptoms during middle-to-older age than normal weight people who sleep more hours, researchers from the University of Alabama reported. (Link to article)

Sleep deprivation and anxiety - Scientists from the Sleep and Neuroimaging Laboratory at the University of California, Berkeley, showed that sleep deprivation considerably exaggerates how much we anticipate impending emotional events, especially among those who are already highly anxious individuals. (Link to article)

Lack of sleep and the appeal of junk food - people who have not had enough sleep and have "tired brains" are more likely to find junk foods appealing, researchers from Columbia University in New York, revealed. (Link to article)

Too many workers not sleeping enough - according to the CDC (Centers for Disease Control and Prevention), about one third of all workers in the USA are sleeping for less than six hours each day, instead of the recommended 7 to 9 hours. People especially at risk of not getting enough sleep included those working in health care, social assistance, transportation and warehousing sectors - many of them on shift-work. (Link to article)

Lack of sleep is becoming a growing problem throughout the world

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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Visitor Opinions (latest shown first)

I agree with theory - Severe Sleep Loss Affects Immune System Like Physical Stress Does

posted by John on 1 Jul 2012 at 7:04 pm

I have suffered from Epilepsy for at least 2 decades. I learned through my own trial and error that 1st. by reducing stress my epilepsy episodes were reduced and than completely eliminated.

This didn't increase my white blood count however until I changed my mattress to a temperpedic and worked diligently to increase my 6 hours of sleep to 8 and 9 hours. Now I find my strength has increased in addition I have not had a seizure in over 3 years. I used to have as many as 5 or 6 a week.

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Study Suggests New Screening Method For Sudden Death In Athletes

Study Suggests New Screening Method For Sudden Death In Athletes

Main Category: Sports Medicine / Fitness
Also Included In: Cardiovascular / Cardiology
Article Date: 01 Jul 2012 - 10:00 PDT

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A new study suggests that echocardiography be included as part of screenings to help identify student athletes with heart problems that could lead to sudden death.

The Cincinnati Children's Hospital Medical Center study, to be presented July 1 at the annual meeting of the American Society of Echocardiography, suggests adding a modified echo to the current practice of taking an EKG, getting a family history and having a physical exam.

"EKG is a good tool, but may not be sensitive enough to catch problems that could lead to sudden death," says Michelle Grenier, MD, a physician at the Cincinnati Children's Heart Institute and one of the investigators of the study. "We found that an abbreviated echo is a fiscally responsible addition that will yield useful information when screening student athletes for structural heart disease and cardiomyopathies - heart muscle diseases that are the major cause of sudden death in athletes."

Screening for risk of sudden death in athletes has long been a topic of controversy, in part because it is expensive and time consuming. Her study, however, indicates that a shortened echo may increase the sensitivity of finding heart defects in competitive athletes.

As part of an ongoing study, Dr. Grenier and colleagues at Cincinnati Children's recruited 85 teen athletes for a screening that included a health questionnaire, physical exam, EKG and a 15-image, modified echo that took nine minutes, on average, to obtain. Echoes that were considered abnormal were referred for a complete echo, where they were read by a cardiologist not involved in the study.

Ten of the participants (12 percent) had abnormal echoes when read in real-time and were referred for further assessment. These 10 participants had a normal history, physical exam and EKG. All preliminary diagnoses were later substantiated. The researchers found no additional heart problems, and all 10 echoes were later confirmed to be abnormal.

"The number of patients with asymptomatic, congenital heart disease was higher than expected, but the rate of cardiomyopathy - the main cause of sudden death in athletes - is probably closer to the published rate," says Dr. Grenier. "Our goal is to provide useful information to care providers, who may then better counsel athletes and their families on full participation in sports.

"The cost-effectiveness and impact on reducing the rate of sudden cardiac death aren't yet known, but the impact on quality of life in reassurance of cardiac health during exercise is priceless," she says.

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