Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide, especially in developed countries, and there is currently no known treatment or cure or for the vast majority of AMD patients. New research published in BioMed Central's open access journal Genome Medicine has identified genes whose expression levels can identify people with AMD, as well as tell apart AMD subtypes.
It is estimated that 6.5% of people over age 40 in the US currently have AMD. There is an inheritable genetic risk factor but risk is also increased for smokers and with exposure to UV light. Genome-wide studies have indicated that genes involved in the innate immune system and fat metabolism are involved in this disease. However none of these prior studies examined gene expression differences between AMD and normal eyes.
In order to address this question, researchers at the University of California Santa Barbara, the University of Utah John Moran Eye Center, and the University of Iowa combined forces and used a human donor eye repository to identify genes up-regulated in AMD. The ability of these genes to recognize AMD was tested on a separate set of samples.
The team discovered over 50 genes that have higher than normal levels in AMD, the top 20 of which were able to 'predict' a clinical AMD diagnosis. Genes over-expressed in the RPE-choroid (a tissue complex located beneath the retina) included components of inflammatory responses, while in the retina, the researchers found genes involved in wound healing and the complement cascade, a part of the innate immune system. They found retinal genes with expression levels that matched the disease severity for advanced stages of AMD.
Dr. Monte Radeke, one of the project leaders, explained, "Not only are these genes able to identify people with clinically recognized AMD and distinguish between different advanced types - some of these genes appear to be associated with pre-clinical stages of AMD. This suggests that they may be involved in key processes that drive the disease. Now that we know the identity and function of many of the genes involved in the disease, we can start to look among them to develop new diagnostic methods, and for new targets for the development of treatments for all forms of AMD."
Saturday, February 25, 2012
Citrus Fruits May Help Women Reduce Risk Of Stroke
Eating citrus fruits, especially oranges and grapefruit, because of the flavonone they contain, may lower women's risk of developing clot-associated or ischemicstroke, according to a new study led by Norwich Medical School of the University of East Anglia in the UK that was published online in Stroke: Journal of the American Heart Association on Thursday.
The researchers wanted to examine more closely how consumption of foods containing different classes of flavonoids affected the risk of stroke.
Flavonoids are a group of compounds found in fruits, vegetables, dark chocolate and red wine.
Study lead author and professor of nutrition at Norwich Medical School, Dr AedÃn Cassidy, told the press:
"Studies have shown higher fruit, vegetable and specifically vitamin C intake is associated with reduced stroke risk."
A stroke is where part of the brain shuts down because of loss of blood supply, caused either by a blockage or embolism that stops the blood flow (ischemia), or due to leakage caused by a hemorrhage.
Cassidy said flavonoids are thought to provide some protection against stroke by improving blood vessel function and reducing inflammation, among other things.
For their study, Cassidy and colleagues examined data from the Nurse's Health Study. Based in the US, this is one of the largest and longest running investigations of factors that influence women's health. It started in 1976 and expanded in 1989.
The researchers looked at 14 years of follow-up data completed by 69,622 female participants who every four years had reported their dietary intake, including details of the fruits and vegetables they consumed.
They looked for links between the six major subclasses of flavonoids commonly present in the American diet and risk of ischemic, hemorrhagic and total stroke.
The six major subclasses they examined were: flavonones, anthocyanins, flavon-3-ols, flavonoid polymers, flavonols and flavones.
Since we already know that each subclass has a different biological effect, the researchers did not expect to find any strong beneficial links between total flavonoid consumption and stroke risk.
But they did find a strong link between high consumption of flavonones in citrus fruits and reduced stroke risk: women who consumed the most showed a 19% lower risk of ischemic stroke compared to women who ate the least amounts of flavonones in citrus fruits.
In this study, oranges and orange juice (82%) and grapefruit and grapefruit juice (14%) had the highest amounts of flavonones. But the researchers said if you are looking to increase your intake, then go for the fruit rather than the juice, because the latter tends to be accompanied by high amounts of sugar.
While previous studies have shown links between various foods and protection against both kinds of stroke, and this study further informs the field, the researchers said we still need to get a better understanding about why the link occurs, and that has to come from further research.
Funds from the National Institutes of Health helped pay for the research.
The researchers wanted to examine more closely how consumption of foods containing different classes of flavonoids affected the risk of stroke.
Flavonoids are a group of compounds found in fruits, vegetables, dark chocolate and red wine.
Study lead author and professor of nutrition at Norwich Medical School, Dr AedÃn Cassidy, told the press:
"Studies have shown higher fruit, vegetable and specifically vitamin C intake is associated with reduced stroke risk."
A stroke is where part of the brain shuts down because of loss of blood supply, caused either by a blockage or embolism that stops the blood flow (ischemia), or due to leakage caused by a hemorrhage.
Cassidy said flavonoids are thought to provide some protection against stroke by improving blood vessel function and reducing inflammation, among other things.
For their study, Cassidy and colleagues examined data from the Nurse's Health Study. Based in the US, this is one of the largest and longest running investigations of factors that influence women's health. It started in 1976 and expanded in 1989.
The researchers looked at 14 years of follow-up data completed by 69,622 female participants who every four years had reported their dietary intake, including details of the fruits and vegetables they consumed.
They looked for links between the six major subclasses of flavonoids commonly present in the American diet and risk of ischemic, hemorrhagic and total stroke.
The six major subclasses they examined were: flavonones, anthocyanins, flavon-3-ols, flavonoid polymers, flavonols and flavones.
Since we already know that each subclass has a different biological effect, the researchers did not expect to find any strong beneficial links between total flavonoid consumption and stroke risk.
But they did find a strong link between high consumption of flavonones in citrus fruits and reduced stroke risk: women who consumed the most showed a 19% lower risk of ischemic stroke compared to women who ate the least amounts of flavonones in citrus fruits.
In this study, oranges and orange juice (82%) and grapefruit and grapefruit juice (14%) had the highest amounts of flavonones. But the researchers said if you are looking to increase your intake, then go for the fruit rather than the juice, because the latter tends to be accompanied by high amounts of sugar.
While previous studies have shown links between various foods and protection against both kinds of stroke, and this study further informs the field, the researchers said we still need to get a better understanding about why the link occurs, and that has to come from further research.
Funds from the National Institutes of Health helped pay for the research.
Detecting Down Syndrome Risk - Noninvasive Method Efficient and Accurate
Two studies published online, ahead of the April issue of the American Journal of Obstetrics & Gynecology (AJOG), show that the risk of a fetus having chromosomal abnormalities that cause Down syndrome, and a genetic disorder known as Edwards syndrome, can now be almost precisely be identified by using a noninvasive test on maternal blood that involves a novel biochemical assay and a new algorithm for analysis.
Apart from being more scalable, compared with other recently developed genetic screening tests, this test is also able to potentially reduce unnecessary amniocentesis or CVS.
Diagnosing fetal chromosomal abnormalities, or aneuploidies, requires invasive tests that consist of chorionic villous sampling or amniocentesis in pregnancies that are known to be of high-risk, and even though these tests are accurate, they are costly and carry a risk of miscarriage.
Massively parallel shotgun sequencing (MPSS), a technique that examines cell-free DNA (cfDNA) from the mother's plasma for fetal conditions has been used to identify trisomy 21 (T21) pregnancies, i.e. pregnancies with an extra copy of chromosome 21, which leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. Although MPSS can accurately detect these conditions by analyzing the entire genome, it requires DNA sequencing large amounts and therefore its clinical usefulness is limited.
A novel assay, called Digital Analysis of Selected Regions (DANSR™), has recently been developed by scientists at Aria Diagnostics in San Jose, CA, which sequences loci from only those chromosomes under investigation, which requires 10 times less DNA sequencing as compared with MPSS.
The current study describes a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which takes age-related risks and the percentage of fetal DNA in the sample into account, in order to provide an individualized risk score for trisomy. Lead researcher Dr. Ken Song, MD, explains:
Dr. Song and his team set out to assess 123 normal pregnancies, 36 T21, and 8 T18 pregnancies to assess the performance of the DANSR/FORTE assay. They referenced all samples for FORTE odd scores of chromosome 18 and chromosome 21 and discovered in a blinded analysis that the combination of DANSR and FORTE managed to correctly identify all 36 cases of T21 and 8 cases of T18 as having a risk of more than 99% for each trisomy. The separations in risk score between trisomic and disomic samples were at least a 1,000-fold magnitude.
In an associated study, researchers from the Harris Birthright Research Centre for Fetal Medicine at Kings College Hospital in London and the University College London Hospital provided 400 maternal plasma samples to Aria for a DANSR analysis with the FORTE algorithm. All subjects were at risk for aneuploidies and had been tested by chorionic villous sampling.
According to the analysis results, all cases of T21 and 98% of T18 cases from euploid pregnancies were identified, showing that all cases of T21 had an estimated risk for this aneuploidy of ≥ 99%, whilst all normal pregnancies and those with T18 had a risk score for T21 of ≤ 0.01%.
Dr. Song explains:
Lead researcher Kypros H. Nicolaides, MD, of the University of London study believes that fetal trisomy evaluation with cfDNA testing will be introduced into clinical practice sooner or later, saying:
Dr. Nicolaides highlights that the plasma samples were taken from high-risk pregnancies that showed some evidence of impaired placental function, and adds that it would require further tests to confirm that the observed accuracy with cfDNA testing from the investigation of pregnancies at high-risk for aneuploidies also applies to the general population, in which prevalence of fetal trisomy 21 is significantly lower.
He concludes:
Apart from being more scalable, compared with other recently developed genetic screening tests, this test is also able to potentially reduce unnecessary amniocentesis or CVS.
Diagnosing fetal chromosomal abnormalities, or aneuploidies, requires invasive tests that consist of chorionic villous sampling or amniocentesis in pregnancies that are known to be of high-risk, and even though these tests are accurate, they are costly and carry a risk of miscarriage.
Massively parallel shotgun sequencing (MPSS), a technique that examines cell-free DNA (cfDNA) from the mother's plasma for fetal conditions has been used to identify trisomy 21 (T21) pregnancies, i.e. pregnancies with an extra copy of chromosome 21, which leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. Although MPSS can accurately detect these conditions by analyzing the entire genome, it requires DNA sequencing large amounts and therefore its clinical usefulness is limited.
A novel assay, called Digital Analysis of Selected Regions (DANSR™), has recently been developed by scientists at Aria Diagnostics in San Jose, CA, which sequences loci from only those chromosomes under investigation, which requires 10 times less DNA sequencing as compared with MPSS.
The current study describes a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which takes age-related risks and the percentage of fetal DNA in the sample into account, in order to provide an individualized risk score for trisomy. Lead researcher Dr. Ken Song, MD, explains:
"The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk."
Dr. Song and his team set out to assess 123 normal pregnancies, 36 T21, and 8 T18 pregnancies to assess the performance of the DANSR/FORTE assay. They referenced all samples for FORTE odd scores of chromosome 18 and chromosome 21 and discovered in a blinded analysis that the combination of DANSR and FORTE managed to correctly identify all 36 cases of T21 and 8 cases of T18 as having a risk of more than 99% for each trisomy. The separations in risk score between trisomic and disomic samples were at least a 1,000-fold magnitude.
In an associated study, researchers from the Harris Birthright Research Centre for Fetal Medicine at Kings College Hospital in London and the University College London Hospital provided 400 maternal plasma samples to Aria for a DANSR analysis with the FORTE algorithm. All subjects were at risk for aneuploidies and had been tested by chorionic villous sampling.
According to the analysis results, all cases of T21 and 98% of T18 cases from euploid pregnancies were identified, showing that all cases of T21 had an estimated risk for this aneuploidy of ≥ 99%, whilst all normal pregnancies and those with T18 had a risk score for T21 of ≤ 0.01%.
Dr. Song explains:
"Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk. Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation."
Lead researcher Kypros H. Nicolaides, MD, of the University of London study believes that fetal trisomy evaluation with cfDNA testing will be introduced into clinical practice sooner or later, saying:
"It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing."
Dr. Nicolaides highlights that the plasma samples were taken from high-risk pregnancies that showed some evidence of impaired placental function, and adds that it would require further tests to confirm that the observed accuracy with cfDNA testing from the investigation of pregnancies at high-risk for aneuploidies also applies to the general population, in which prevalence of fetal trisomy 21 is significantly lower.
He concludes:
"This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population."
Survival Circuits In Animal Brains: What Can They Tell Us About Human Emotion?
New York University neuroscientist Joseph LeDoux, author of "The Emotional Brain", has come up with a new theory called "the survival circuit concept" that he outlines in Wednesday's issue of the journal Neuron. He suggests that instead of asking whether the feelings and emotions we humans experience are also present in other animals, we should ask to what extent the survival circuits present in other animals are also present in humans, and then consider how they contribute to emotions.
The basis for his reasoning, drawn from twenty years researching emotion and memory in the brain, is the neurological common ground that exists between humans and other animals: we both have brain functions used for survival, these include "circuits" responsible for defense, managing energy and nutrition, fluid balance, regulating heat, and reproduction.
LeDoux, a professor in New York University's Center for Neuroscience and Department of Psychology, says in a press statement released earlier this week that while the functions of these "survival circuits" are not causally related to emotional feelings, they will contribute to them indirectly.
"The survival circuit concept integrates ideas about emotion, motivation, reinforcement, and arousal in the effort to understand how organisms survive and thrive by detecting and responding to challenges and opportunities in daily life," he explains.
LeDoux, who is also director of the Emotional Brain Institute, part of the Nathan S. Kline Institute for Psychiatric Research, is fully aware of the difficulty of researching feelings and emotions. It is not easy, he says, because you can't measure them directly, you have to rely on "outward expression of emotional responses, or on verbal declarations by the person experiencing the feeling, as ways of assessing what that person is feeling".
"This is true both when scientists do research on emotions and when people judge emotions in their social interactions with one another," he adds.
As if that is not complicated enough, we are even more limited when we try to interpret the emotions and feelings of animals.
LeDoux says we tend to ascribe human subjective feelings to explain what we see when animals behave in ways we can relate to:
"When a deer freezes to the sound of a shotgun we say it is afraid, and when a kitten purrs or a dog wags its tail, we say it is happy."
Although LeDoux accepts that we may probably never know what animals truly "feel", he thinks we could improve the way we try to understand and interpret their emotions. One way to do this is to look at the brain, and he suggests:
"If we can find neural correlates of conscious feelings in humans -- and distinguish them from correlates of unconscious emotional computations in survival circuits -- and show that similar correlates exists in homologous brain regions in animals, then some basis for speculating about animal feelings and their nature would exist."
LeDoux has done a lot of work on fear, and his research shows we can respond to danger before we even "know" consciously what we are responding to. He has also discovered a lot about how we form and store emotional memories in the brain.
His research has helped us to map the brain's neural circuits for fear and fear memory, to the point of identifying cells, synapses and molecules that make emotional learning and memory possible.
The basis for his reasoning, drawn from twenty years researching emotion and memory in the brain, is the neurological common ground that exists between humans and other animals: we both have brain functions used for survival, these include "circuits" responsible for defense, managing energy and nutrition, fluid balance, regulating heat, and reproduction.
LeDoux, a professor in New York University's Center for Neuroscience and Department of Psychology, says in a press statement released earlier this week that while the functions of these "survival circuits" are not causally related to emotional feelings, they will contribute to them indirectly.
"The survival circuit concept integrates ideas about emotion, motivation, reinforcement, and arousal in the effort to understand how organisms survive and thrive by detecting and responding to challenges and opportunities in daily life," he explains.
LeDoux, who is also director of the Emotional Brain Institute, part of the Nathan S. Kline Institute for Psychiatric Research, is fully aware of the difficulty of researching feelings and emotions. It is not easy, he says, because you can't measure them directly, you have to rely on "outward expression of emotional responses, or on verbal declarations by the person experiencing the feeling, as ways of assessing what that person is feeling".
"This is true both when scientists do research on emotions and when people judge emotions in their social interactions with one another," he adds.
As if that is not complicated enough, we are even more limited when we try to interpret the emotions and feelings of animals.
LeDoux says we tend to ascribe human subjective feelings to explain what we see when animals behave in ways we can relate to:
"When a deer freezes to the sound of a shotgun we say it is afraid, and when a kitten purrs or a dog wags its tail, we say it is happy."
Although LeDoux accepts that we may probably never know what animals truly "feel", he thinks we could improve the way we try to understand and interpret their emotions. One way to do this is to look at the brain, and he suggests:
"If we can find neural correlates of conscious feelings in humans -- and distinguish them from correlates of unconscious emotional computations in survival circuits -- and show that similar correlates exists in homologous brain regions in animals, then some basis for speculating about animal feelings and their nature would exist."
LeDoux has done a lot of work on fear, and his research shows we can respond to danger before we even "know" consciously what we are responding to. He has also discovered a lot about how we form and store emotional memories in the brain.
His research has helped us to map the brain's neural circuits for fear and fear memory, to the point of identifying cells, synapses and molecules that make emotional learning and memory possible.
Thursday, February 23, 2012
New Approach To Fighting Cancer - New Combo Of Chemo And Malaria Drug Delivers Double Punch To Tumors
Blocking autophagy - the process of "self-eating" within cells -- is turning out to be a viable way to enhance the effectiveness of a wide variety of cancer treatments.
Specifically, blocking the action of an acidic inner cell part, which acts like a stomach and chews up proteins for recycling, is the main attack strategy, says Ravi K. Amaravadi, MD, an assistant professor of Medicine at the Perelman School of Medicine and Abramson Cancer Center at the University of Pennsylvania. Amaravadi gave a presentation on the role of autophagy in fighting cancer at the annual American Association for Advancement of Science meeting in Vancouver, British Columbia.
His lab and others have demonstrated that adding hydroxychloroquine (HCQ) - an FDA-approved drug used commonly for malaria and rheumatoid arthritis - to many cancer therapies, including chemotherapy, targeted therapy, radiation, and immunotherapy, can enhance the antitumor activity of these drugs in laboratory models of treatment-resistant cancers, and ongoing clinical trials.
Autophagy is increased in cancer cells. Normally, it is a survival pathway allowing a cell to recycle damaged proteins when it's under stress and reuse the damaged parts to fuel further growth.
Cancer cells might be addicted to autophagy, since this innate response may be a critical means by which the cells survive nutrient limitation and lack of oxygen commonly found within tumors. And, it is likely to explain how some cancer cells evade chemotherapies by using, essentially, a work around.
Nearly 30 phase I and Phase II clinical trials involving HCQ have been launched or are in planning stages in many different malignancies, including melanoma, multiple myeloma, renal cell carcinoma, colon cancer, prostate cancer, breast cancer, and others.
Preliminary results for most of the trials are encouraging. "Our assays performed on human blood and tissue samples indicate that high doses of HCQ are required to block autophagy in patients, and in some cases, such as in a brain tumor trial, these high doses, in combination with specific anticancer agents, can lead to toxicity for the tumor," says Amaravadi. "As the first phase I trials of HCQ are being completed, it is clear that in most cases the high-dose HCQ, in combination with existing cancer therapy, is well tolerated."
Randomized controlled trials using HCQ combinations to truly determine the effectiveness of the approach are planned. While these are being considered, the team will conduct additional laboratory experiments to identify more potent and specific inhibitors of autophagy and to identify biomarkers that can predict which patients are most likely to respond to this approach. To that end, the Amaravadi lab has identified a compound called Lys05, which is 10-fold more potent than HCQ at blocking the cell from giving the cancer cell a source of raw energy.
"While our knowledge of the role of autophagy in cancer is still in its infancy, the opportunity to learn about autophagy, both at the bench and the bedside, could accelerate the translation of basic advances in this field into clinical benefit for patients with cancer," says Amaravadi.
Specifically, blocking the action of an acidic inner cell part, which acts like a stomach and chews up proteins for recycling, is the main attack strategy, says Ravi K. Amaravadi, MD, an assistant professor of Medicine at the Perelman School of Medicine and Abramson Cancer Center at the University of Pennsylvania. Amaravadi gave a presentation on the role of autophagy in fighting cancer at the annual American Association for Advancement of Science meeting in Vancouver, British Columbia.
His lab and others have demonstrated that adding hydroxychloroquine (HCQ) - an FDA-approved drug used commonly for malaria and rheumatoid arthritis - to many cancer therapies, including chemotherapy, targeted therapy, radiation, and immunotherapy, can enhance the antitumor activity of these drugs in laboratory models of treatment-resistant cancers, and ongoing clinical trials.
Autophagy is increased in cancer cells. Normally, it is a survival pathway allowing a cell to recycle damaged proteins when it's under stress and reuse the damaged parts to fuel further growth.
Cancer cells might be addicted to autophagy, since this innate response may be a critical means by which the cells survive nutrient limitation and lack of oxygen commonly found within tumors. And, it is likely to explain how some cancer cells evade chemotherapies by using, essentially, a work around.
Nearly 30 phase I and Phase II clinical trials involving HCQ have been launched or are in planning stages in many different malignancies, including melanoma, multiple myeloma, renal cell carcinoma, colon cancer, prostate cancer, breast cancer, and others.
Preliminary results for most of the trials are encouraging. "Our assays performed on human blood and tissue samples indicate that high doses of HCQ are required to block autophagy in patients, and in some cases, such as in a brain tumor trial, these high doses, in combination with specific anticancer agents, can lead to toxicity for the tumor," says Amaravadi. "As the first phase I trials of HCQ are being completed, it is clear that in most cases the high-dose HCQ, in combination with existing cancer therapy, is well tolerated."
Randomized controlled trials using HCQ combinations to truly determine the effectiveness of the approach are planned. While these are being considered, the team will conduct additional laboratory experiments to identify more potent and specific inhibitors of autophagy and to identify biomarkers that can predict which patients are most likely to respond to this approach. To that end, the Amaravadi lab has identified a compound called Lys05, which is 10-fold more potent than HCQ at blocking the cell from giving the cancer cell a source of raw energy.
"While our knowledge of the role of autophagy in cancer is still in its infancy, the opportunity to learn about autophagy, both at the bench and the bedside, could accelerate the translation of basic advances in this field into clinical benefit for patients with cancer," says Amaravadi.
Subscribe to:
Posts (Atom)