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Thursday, December 8, 2011

Predicting early breast cancer recurrence vs. late hormone receptor-positive breast cancer

by Biomechanism “Molecular differences may be used to predict breast cancer recurrence in early vs. late hormone receptor-positive breast cancer”

Researchers may have discovered a series of genes that will help predict whether or not a woman with hormone receptor-positive invasive breast cancer will experience early, late or no recurrence of her disease.

Minetta C. Liu, M.D., associate professor of medicine and oncology and director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center, presented the findings at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 6-10, 2011.

“There are clear biological differences within the supposedly unified group of hormone receptor (HR)-positive breast cancers, and these differences distinguish subtypes relative to the time at which they recur,” Liu said. “Understanding what drives these distinctions will allow us to tailor treatment and improve patient outcomes.”

Women with HR-positive breast cancer are frequently treated with tamoxifen, which is credited with saving the lives of hundreds of thousands of women. Although tamoxifen prevents or delays cancer recurrence in many women, some will recur 10 years or more from their original diagnosis. Until now, the molecular basis for this recurrence pattern was unknown.

In collaboration with investigators from the University of Edinburgh, Liu and colleagues evaluated high-quality frozen tumor samples obtained at the time of breast cancer diagnosis. These tissue samples were linked to data on treatment and clinical outcomes, allowing researchers to analyze gene expression patterns present before the initiation of any systemic therapy.

Together with engineers at Virginia Polytechnic Institute, Liu and colleagues identified significant gene expression patterns among the tumor samples. These patterns correlated strongly with the development of distant metastatic disease.

“We confirmed what many have already suspected,” said Liu. “There are biological drivers that define — at the time of tumor development — whether or not breast cancer will recur early, late or not at all. Now we need to validate these findings and take our knowledge to the next step.”

Liu hopes that this research can be used to help personalize treatment in day-to-day clinical practice. “Endocrine therapy and chemotherapy are not without toxicity,” she said. “The ability to predict which patients will recur early in their treatment course can lead to more appropriate recommendations for adjuvant chemotherapy. It might also identify those women who would benefit most from studies using investigational agents to enhance the effects of tamoxifen or aromatase inhibitors.”

She added: “At the other extreme are those patients with HR-positive tumors who recur long after completing five years of endocrine therapy. These are the patients for whom extended endocrine therapy and its related side effects are really worth it.”

The team’s next step is to validate their predictive model for the timing of recurrences on tamoxifen so that physicians and patients can make more informed decisions about the potential added benefits of adjuvant chemotherapy, extended endocrine therapy and involvement in clinical trials. They will also investigate combinations of molecular targets with the ultimate goal of delaying or preventing the development of metastatic breast cancer, Liu said.

Why aren't we smarter already? Evolutionary limits on cognition

(Medical Xpress) -- We put a lot of energy into improving our memory, intelligence, and attention. There are even drugs that make us sharper, such as Ritalin and caffeine. But maybe smarter isn’t really all that better. A new paper published in Current Directions in Psychological Science, a journal of the Association for Psychological Science, warns that there are limits on how smart humans can get, and any increases in thinking ability are likely to come with problems.

The authors looked to evolution to understand about why humans are only as smart as we are and not any smarter. “A lot of people are interested in drugs that can enhance cognition in various ways,” says Thomas Hills of the University of Warwick, who cowrote the article with Ralph Hertwig of the University of Basel. “But it seems natural to ask, why aren’t we smarter already?”

Tradeoffs are common in evolution. It might be nice to be eight feet tall, but most hearts couldn’t handle getting blood up that high. So most humans top out under six feet. Just as there are evolutionary tradeoffs for physical traits, Hills says, there are tradeoffs for intelligence. A baby’s brain size is thought to be limited by, among other things, the size of the mother’s pelvis; bigger brains could mean more deaths in childbirth, and the pelvis can’t change substantially without changing the way we stand and walk.

Drugs like Ritalin and amphetamines help people pay better attention. But they often only help people with lower baseline abilities; people who don’t have trouble paying attention in the first place can actually perform worse when they take attention-enhancing drugs. That suggests there is some kind of upper limit to how much people can or should pay attention. “This makes sense if you think about a focused task like driving,” Hills says, “where you have to pay attention, but to the right things—which may be changing all the time. If your attention is focused on a shiny billboard or changing the channel on the radio, you’re going to have problems.”

It may seem like a good thing to have a better memory, but people with excessively vivid memories have a difficult life. “Memory is a double-edged sword,” Hills says. In post-traumatic stress disorder, for example, a person can’t stop remembering some awful episode. “If something bad happens, you want to be able to forget it, to move on.”

Even increasing general intelligence can cause problems. Hills and Hertwig cite a study of Ashkenazi Jews, who have an average IQ much higher than the general European population. This is apparently because of evolutionary selection for intelligence in the last 2,000 years. But, at the same time, Ashkenazi Jews have been plagued by inherited diseases like Tay-Sachs disease that affect the nervous system. It may be that the increase in brain power has caused an increase in disease.

Given all of these tradeoffs that emerge when you make people better at thinking, Hills says, it’s unlikely that there will ever be a supermind. “If you have a specific task that requires more memory or more speed or more accuracy or whatever, then you could potentially take an enhancer that increases your capacity for that task,” he says. “But it would be wrong to think that this is going to improve your abilities all across the board.”

More information: The DOI for this paper is 10.1177/0963721411418300

Provided by Association for Psychological Science

"Why aren't we smarter already? Evolutionary limits on cognition." December 7th, 2011. http://medicalxpress.com/news/2011-12-arent-smarter-evolutionary-limits-cognition.html

Posted by
Robert Karl Stonjek

Psychopathy: A misunderstood personality disorder

Psychopathic personalities are some of the most memorable characters portrayed in popular media today. These characters, like Patrick Bateman from American Psycho, Frank Abagnale Jr. from Catch Me If You Can and Alex from A Clockwork Orange, are typically depicted as charming, intriguing, dishonest, guiltless, and in some cases, downright terrifying. But scientific research suggests that psychopathy is a personality disorder that is widely misunderstood.

"Psychopathy tends to be used as a label for people we do not like, cannot understand, or construe as evil," notes Jennifer Skeem, Professor of Psychology and Social Behavior at the University of California, Irvine. Skeem, Devon Polaschek of Victoria University of Wellington, Christopher Patrick of Florida State University, and Scott Lilienfeld of Emory University are the authors of a new monograph focused on understanding the psychopathic personality that will appear in the December issue of Psychological Science in the Public Interest, a journal of the Association for Psychological Science.

In the course of their research, the authors reviewed many scientific findings that seemed to contradict one another. "Psychopathy has long been assumed to be a single personality disorder. However, there is increasing evidence that it is a confluence of several different personality traits," Skeem says. The authors of the monograph argue that rather than being "one thing" as often assumed, psychopathy appears to be a complex, multifaceted condition marked by blends of personality traits reflecting differing levels of disinhibition, boldness, and meanness. And scientific findings also suggest that a sizable subgroup of juvenile and adult offenders labeled as psychopathic are actually more emotionally disturbed than emotionally detached, showing signs of anxiety and dysphoria.

According to Skeem, these important distinctions have long escaped the attention of psychologists and policy-makers. As a result, she and her co-authors set about to try to dispel some of the myths and assumptions that people often make about psychopathy. Although many people might assume that psychopaths are 'born,' not 'made,' the authors stress that psychopathy is not just a matter of genes – it appears to have multiple constitutional causes that can be shaped by environmental factors. Many psychologists also assume that psychopathy is inalterable – once a psychopath, always a psychopath. However, there is currently scant scientific evidence to support this claim. Recent empirical work suggests that youth and adults with high scores on measures of psychopathy can show reduced violent and other criminal behavior after intensive treatment.

Along with challenging the assumption that psychopathy is a monolithic entity, perhaps the other most important myth that the authors hope to dispel is that psychopathy is synonymous with violence. Skeem points out that psychopathic individuals often have no history of violent behaviour or criminal convictions. "Psychopathy cannot be equated with extreme violence or serial killing. In fact, "psychopaths" do not appear different in kind from other people, or inalterably dangerous," she observes. Nor is it clear that psychopathy predicts violence much better than a past history of violent and other criminal behavior – or general antisocial traits.

Effectively dispelling these myths is important, the authors argue, because accurate policy recommendations hinge on which personality traits – and which groups of people – associated with psychopathy one is examining. "Decisions about juvenile and adult offenders that are based on faulty assumptions about violence risk, etiology, and treatment amenability have adverse consequences, both for individual offenders and the public," Skeem says.

In clarifying the personality traits that characterize psychopathy, scientists can contribute to prevention and treatment strategies that improve public health and safety. "In short, research on psychopathy has evolved to a level that it can greatly improve on the current, 'one size fits all' policy approach," concludes Skeem.

Provided by Association for Psychological Science

"Psychopathy: A misunderstood personality disorder." December 7th, 2011. http://medicalxpress.com/news/2011-12-psychopathy-misunderstood-personality-disorder.html

Posted by
Robert Karl Stonjek

Scientists create first realistic 3D reconstruction of a brain circuit

Researchers from the lab of Nobel laureate Bert Sakmann, MD, PhD at the Max Planck Florida Institute (MPFI) are reporting that, using a conceptually new approach and state-of-the-art research tools, they have created the first realistic three-dimensional diagram of a thalamocortical column in the rodent brain. A vertically organized series of connected neurons forming a brain circuit, the cortical column is considered the elementary building block of the cortex, the part of the brain responsible for many of its higher functions.

This achievement is the first step toward creating a complete computer model of the brain and may lead to an understanding of how the brain computes and how it goes awry in neurological, neurodevelopmental and psychiatric disorders. The study is published online in the journal Cerebral Cortex.

"This is the first complete 3D reconstruction of a realistic model of a cortical column," said Marcel Oberlaender, PhD, first author of the paper. "This is the first time we have been able to relate the structure and function of individual neurons in a live, awake animal, using complete 3D reconstructions of axons and dendrites. By creating this model, we hope to begin understanding how the brain processes sensory information and how this leads to specific behaviours."

The electrically excitable axon extends from the body of the neuron (brain cell) and often gives rise to many smaller branches before ending at nerve terminals. Dendrites extend from the neuron cell body and receive messages from other neurons.

In addition to recreating the structure of the cortical column, the study also sheds significant light on the function of its constituent neurons and the relationship between their functionality and structure. In looking at neurons' response to sensory stimulation, the researchers discovered that sensory-evoked activity in some of the cells can be directly correlated with their structure and connectivity, which marks a first step toward understanding the basic organizational principles of the brain.

Working with awake and anaesthetized rats and examining stained brain slices, the neuroscientists used sophisticated new light microscopy and custom-designed tools to examine 15,000 neurons of nine identified cell types. Using a painstaking, six-step process, the researchers identified and reconstructed the column's constituent parts using sophisticated software and a range of other new state-of-the-art tools and processes.

As described in a related paper co-authored by Drs. Sakmann and Oberlaender, these new methods, which were developed in part at the Max Planck Florida Institute, allow researchers, for the first time, to simulate electrical signalling in a computer model at subcellular and millisecond resolution.

"We can now quantify the number of neurons of each cell type, their three-dimensional structure, connectivity within these networks, and response to sensory stimulation, in both an anesthetized and awake animal," said Dr. Oberlaender. "Such a quantitative assessment of cortical structure and function is unprecedented and marks a milestone for future studies on mechanistic principles that may underlie signal flow in the brain, during such functions as decision making."

Provided by Max Planck Florida Institute

"Scientists create first realistic 3D reconstruction of a brain circuit." December 7th, 2011. http://medicalxpress.com/news/2011-12-scientists-realistic-3d-reconstruction-brain.html

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Robert Karl Stonjek

The big picture: Long-term imaging reveals intriguing patterns of human brain maturation

Neuroimaging has provided fascinating insight into the dynamic nature of human brain maturation. However, most studies of developmental changes in brain anatomy have considered individual locations in relative isolation from all others and have not characterized relationships between structural changes in different parts of the developing brain. Now, new research describes the first comprehensive study of coordinated anatomical maturation within the developing human brain. The study, published by Cell Press in the December 8 issue of the journal Neuron, reveals that functionally connected brain regions mature together and uncovers fascinating sex-specific differences in brain development.

"Understanding patterns of structural change in the developing human brain is a challenge because the types of change that we can detect using neuroimaging unfold rather slowly," explains lead study author, Dr. Armin Raznahan, from the National Institutes of Mental Health in Bethesda, Maryland. "So, we drew from the largest and longest-running longitudinal neuroimaging study of human brain maturation, where brain changes were tracked for over several years in the same set of individuals, to analyze patterns of correlated anatomical change across the sensitive developmental window of late childhood, adolescence, and early adulthood."

Dr. Raznahan and colleagues examined the thickness of the cortex because it can be reliably measured and its developmental changes have been described in detail. The cortex is a sheet of neural tissue that covers the surface of the brain and plays a key role in thought, language, memory and consciousness.

The researchers discovered that rates of structural maturation were highly coordinated in the cortex and that regions which were functionally connected to each other also exhibited tightly coupled patterns of maturation. Interestingly, the researchers also observed that maturational coupling within the brain regions crucial for complex decision making differed between males and females.

"Our study represents the first ever investigation of correlated anatomical maturation in the developing human brain and shows that rates of structural cortical development in different cortical regions are highly organized with respect to one another," concludes Dr. Raznahan. "By providing the first link between cortical connectivity and the coordination of cortical development, we reveal a previously unseen property of healthy brain maturation, which may represent a target for neurodevelopmental disease processes and a substrate for sexually dimorphic behavior in adolescence."

Provided by Cell Press

"The big picture: Long-term imaging reveals intriguing patterns of human brain maturation." December 7th, 2011.http://medicalxpress.com/news/2011-12-big-picture-long-term-imaging-reveals.html

Posted by
Robert Karl Stonjek

How our brains keep us focused

In a new study to appear in Neuron, scientists at the RIKEN Brain Science Institute (BSI) have uncovered mechanisms that help our brain to focus by efficiently routing only relevant information to perceptual brain regions. The results provide valuable insights on how our brains achieve such focus and on how this focus can be disrupted, suggesting new ways of presenting information that augment the brain's natural focal capabilities.

Focus on what I am about to tell you! Our complex modern world is filled with so many distractions – flashing images on a television screen, blinking lights, blaring horns – that our ability to concentrate on one thing at a time is of critical importance. How does our brain achieve this ability to focus attention?

The answer is believed to lie in two distinct processes, referred to as "sensitivity enhancement" and "efficient selection". Sensitivity enhancement corresponds to improvements in how neurons in the cortex represent sensory information like sounds and lights, similar to the volume control or reception control on a television set. Efficient selection is more like a filter, routing important sensory information to higher-order perceptual areas of the brain while suppressing disruptions from irrelevant information.

With their research in Neuron, Justin Gardner and colleagues at the RIKEN BSI set out to put these hypotheses to the test and determine which of them plays a dominant role in perception. To do so, they measured brain activity using functional magnetic resonance imaging (fMRI) while human subjects either focused their attention on a single visual location, or distributed their attention across multiple locations. To evaluate results, they used computational models about how brain signals should change based on how well subjects were able to focus their attention.

What they found was that the computational model that best captured the brain activity in the human subjects was the one in which sensory signals were efficiently selected. The model also made a prediction about what kind of stimuli are particularly disruptive to our ability to focus, suggesting that signals which evoke high neural activity are preferentially passed on to perceptual areas of the brain: stimuli with high contrast that evoke large sensory responses, such as flashing lights or loud noises, can thus disrupt our ability to focus. While shedding light on the origins of perception, the results also hint at new ways of presenting information that capitalize on increasing neural activity to help our brains focus, promising applications in the development of critical information display technologies. The findings also offer insights into the causes of common attention-related disorders such as attention deficit hyperactivity disorder (ADHD).

Provided by RIKEN

"How our brains keep us focused." December 7th, 2011. http://medicalxpress.com/news/2011-12-brains-focused.html

Posted by

Robert Karl Stonjek

Drug reverses aging-associated changes in brain cells

Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study in the December 7 issue of The Journal of Neuroscience. The findings could one day aid in the development of new drugs that enhance cognitive function in older adults.

Aging-related memory loss is associated with the gradual deterioration of the structure and function of synapses (the connections between brain cells) in brain regions critical to learning and memory, such as the hippocampus. Recent studies suggested that histone acetylation, a chemical process that controls whether genes are turned on, affects this process. Specifically, it affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory.

In the current study, Cui-Wei Xie, PhD, of the University of California, Los Angeles, and colleagues found that compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) — a protein that promotes synaptic plasticity — and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals.

"These findings shed light on why synapses become less efficient and more vulnerable to impairment during aging," said Xie, who led the study. "Such knowledge could help develop new drugs for cognitive aging and aging-related neurodegenerative diseases, such as Alzheimer's disease," she added.

The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats. Because histone acetylation is important in many functions throughout the body, these findings offer a potential pathway to treat aging-related synaptic plasticity deficits without interfering with histone acetylation.

"It appears that lifelong shifts in gene regulation steadily deprive the brain of a key growth factor and cause a collapse of the 'machinery' supporting memory, cognition, and the viability of neurons," said Gary Lynch, PhD, a synaptic plasticity expert at the University of California, Irvine. "The very good news suggested by this study is that it may be possible to reverse these effects."

More information: http://www.jneurosci.org/

Provided by Society for Neuroscience

"Drug reverses aging-associated changes in brain cells." December 7th, 2011. http://medicalxpress.com/news/2011-12-drug-reverses-aging-associated-brain-cells.html

Posted by
Robert Karl Stonjek

10 STATES WITH HIGHEST PERCENTAGE OF MILLIONAIRE HOUSEHOLDS

Being a millionaire may be more common than you think. Millionaire households are scattered throughout the United States. Find out which states have the highest percentages of millionaire households here!

Success highlights…

Maryland

Percentage of millionaire households: 7.22%
Total millionaire households: 157,779

Hawaii

Percentage of millionaire households: 7.21%
Total millionaire households: 33,461

New Jersey

Percentage of millionaire households: 7.19%
Total millionaire households: 231,456

Connecticut

Percentage of millionaire households: 7.13%
Total millionaire households: 98,392

Massachusetts

Percentage of millionaire households: 6.42%
Total millionaire households: 162,619

Alaska

Percentage of millionaire households: 6.39%
Total millionaire households: 16,239

Virginia

Percentage of millionaire households: 6.26%
Total millionaire households: 195,006

New Hampshire

Percentage of millionaire households: 6.06%
Total millionaire households: 31,159

California

Percentage of millionaire households: 6.01%
Total millionaire households: 750,686

District of Columbia

Percentage of millionaire households: 5.88%
Total millionaire households: 157,603

Get more information from Success!

Brain Evolution at a Distance

Gene expression controlled from afar may have spurred the spurt in brain evolution that led to modern humans.

By Hannah Waters |

Flickr, GreenFlames09

Scientists and philosophers alike have long grasped for the essence that makes humans human, and one answer lies in the brain. Specifically, human brains express genes in different patterns than those of related species, but what causes those changes is unknown. Comparing gene expression in three primate species—human, chimpanzee, and the rhesus macaque—across post-natal development, researchers, publishing today

(December 6) in PLoS Biology, found that the most drastic expression changes are found in genes that are controlled at a distance by transregulators, instead of locally by cis regulators.

“The authors here found a new explanation for how this evolution of the advanced human brain occurred at the molecular level,” said Henrik Kaessmann

, who studies genomic evolution at the University of Lausanne in Switzerland and was not involved in the research. “It’s a very interesting message: that functionally relevant changes tend to be more trans driven.”

Despite the minute genetic differences between human brains and their primate relatives, Homo sapiens cognitive ability is significantly more advanced, enabling us to “make complicated tools, come up with complicated culture and colonize the world,” said lead author Mehmet Somel

, a postdoc studying human evolutionary genomics at the University of California, Berkeley. Because humans spend more than a decade developing into adults and learning, far more than the two or three years of chimpanzee adolescence, researchers have long suspected that developmental genes are involved in human brain evolution. “And the idea that brain gene expression profiles might be different between species was proposed 40 years ago,” Somel added.

To explore both of these ideas, Somel and his colleagues at the Max Planck Institute and the Chinese Academy of Sciences observed gene expression changes throughout postnatal development in humans, chimpanzees, and rhesus macaques. They analyzed the differential expression of around 12,000 genes in two brain regions—the prefrontal cortex and cerebellar cortex, each of which have been put forth as the focal point of human brain evolution. They found significant differences between species, as well as variation among the different aged organisms of a species, but they also found variation in gene expression that couldn’t be simply explained by either of these two factors. It seemed that there were some genes that were not only differentially expressed over the course of development, but also at a different rate by each species.

Looking closer at this group of genes, the researchers found that they were highly conserved, mostly associated with neuronal development or function, and were more frequently upregulated in the human prefrontal cortex, the brain region associated with abstract thinking, as compared with the other primates. But when the researchers searched for parallel expression of nearby genetic regulators that could explain the boost in gene expression, they often came up empty handed.

If the genes weren’t regulated locally by the so-called cis elements that sit right next to the genes they regulate, they must be regulated at a distance by trans elements—such as transcription factors that travel from afar chromosomes to control the expression of specific target genes. Searching the literature for transcription factors and microRNAs that fall into this category, the researchers identified microRNA candidates, and performed molecular experiments on three of them to confirm their involvement in the regulation of the differentially expressed genes.

“The big finding that it is a trans element is in some ways a lot more interesting to me than the specific [microRNAs] that they pulled,” said Eric Vallender

, an evolutionary neurogeneticist at Harvard Medical School who was not involved in the research. The dominance of trans rather thancis regulatory changes is surprising, he said, and “has some fairly important implications for how we pursue these types of questions in the future.”

But while unexpected, the finding makes sense evolutionarily, said Genevieve Konopka

, a genetic neuroscientist at University of Texas Southwestern Medical Center who also did not participate in the study. Adjusting the expression of each gene individually by cis regulators is complex, as cis regulators usually control only a single adjacent gene, while trans regulators can influence a variety of targets. And fewer adjustments that enact broad changes are more likely to occur in evolution than many minute tinkerings. “If you wanted to, for example, build a bigger brain in a faster or in a more complex way, you could manipulate key transcription factors or these microRNAs and regulate a bunch of targets,” said Konopka. “That would be faster…than doing it on a gene-by-gene basis.”

The next steps are to actually identify the functions of some of the trans-regulated genes, but this may be easier said than done, said Vallender. First of all, actually getting hold of such brain tissue, especially from chimpanzees, is very difficult, and nearly impossible for fetal brains, which would be necessary to fully understand expression changes throughout development. Additionally, researchers are limited by what cis and trans sequences are already annotated across all species, potentially leaving out many potential candidates for genes key to human brain evolution.

M. Somel et al., “MicroRNA-driven developmental remodeling in the brain distinguishes humans from other primates,” PLoS Biology, 9: e1001214, 2011.

Source: TheScientist
http://the-scientist.com/2011/12/06/brain-evolution-at-a-distance/

Posted by
Robert Karl Stonjek