Scientists have tracked down and quantified the diverse origins of cells that drive fibrosis, the incurable, runaway wound-healing that scars and ultimately destroys organs such as the lungs, liver and kidneys.
Findings are from research conducted at Beth Israel Deaconess Medical Center, Harvard Medical School and Massachusetts Institute of Technology in Boston and continued at The University of Texas MD Anderson Cancer Center.
‘Answering a fundamental question about the origin of these cells by identifying four separate pathways involved in their formation allows us to look at ways to block those pathways to treat fibrosis,’ said senior author Raghu Kalluri, Ph.D., M.D., MD Anderson chair and professor of Cancer Biology. ‘It’s highly unlikely that a single drug will work.’
‘In addition to being lethal in its own right, fibrosis is a precursor for the development of cancer and plays a role in progression, metastasis and treatment resistance,’ Kalluri said. ‘In some cancers, such as pancreatic cancer, up to 95 percent of tumours consist of fibrotic stroma.’
Working in genetic mouse models of kidney fibrosis, Kalluri and colleagues identified four sources of cells called myofibroblasts, the dominant producers of collagen. Collagen normally connects damaged tissue and serves as scaffolding for wound-healing. As healing occurs, myofibroblasts and collagen usually diminish or disappear.
In fibrosis, collagen production marches on. While inflammation-inhibiting drugs can sometimes slow its progress, fibrosis now is treatable only by organ transplant.
The researchers employed a fate-mapping strategy to track cells on their way to becoming myofibroblasts. In fate mapping, the promoter of a protein expresses a colour inside a cell that remains with the cell no matter what happens to it until it dies, Kalluri said.
This was particularly important because two of the four sources of myofibroblasts start out as another cell type and differentiate into the collagen-producing cells.
Their experiments showed:
Half of all myofibroblasts are produced by the proliferation of pre-existing resting fibroblasts.
Another 35 percent are produced by mesenchymal stem cells that originate in the bone marrow, migrate to the ‘wound’ site, and then differentiate into myofibroblasts.
An additional 10 percent are the products of endothelial to mesenchymal transition (EndMT), in which blood vessel cells change into mesenchymal cells, then become myofibroblasts.
The final 5 percent come from epithelial to mesenchymal transition (EMT), in which functional cells of an organ sometimes behave like mesenchymal cells and myofibroblasts.
‘These differentiation pathways provide leads for drug targets,’ Kalluri said. ‘Combining an antiproliferation drug with therapies that block one or more differentiation pathways could provide a double hit to control fibrosis. We hope to synergise these pathways for the most effective therapeutic response.’
MD Anderson Cancer Center
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Sensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognised as a distinct disease.
In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders.
One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.
‘Until now, SPD hasn’t had a known biological underpinning,’ said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. ‘Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,’ Mukherjee said.
Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out. The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers.
‘Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,’ said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey.
‘Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,’ said Marco, who treats affected children in her cognitive and behavioural neurology clinic.
‘If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,’ she said.
University of California – San Francisco
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Researchers from Boston University School of Medicine (BUSM) and George Washington University (GWU) have developed a method to rapidly identify pathogenic species and strains causing illnesses, such as pneumonia, that could help lead to earlier detection of disease outbreaks and pinpoint effective treatments more quickly.
Emerging sequencing technologies have revolutionised the collection of genomic data for bioforensics, biosurveillance and for use in clinical settings. However, new approaches are being developed to analyse these large volumes of genetic data. Principal investigator Evan Johnson, PhD, assistant professor of medicine at BUSM, and Keith Crandall, PhD, director of the Computational Biology Institute at GWU, have created a statistical framework called Pathoscope to identify pathogenic genetic sequences from infected tissue samples.
This unique approach can accurately discriminate between closely related strains of the same species with little coverage of the pathogenic genome. The method also can determine the complete composition of known pathogenic and benign organisms in a biological sample. No other method can accurately identify multiple species or substrains in such a direct and automatic way. Current methods, such as the standard polymerase chain reaction detection or microscope observation, are often imperfect and time-consuming.
‘Pathoscope is like completing a complex jigsaw puzzle. Instead of manually assembling the puzzle, which can take days or weeks of tedious effort, we use a statistical algorithm that can determine how the picture should look without actually putting it together,’ said Johnson. ‘Our method can characterise a biological sample faster, more accurately and in a more automated fashion than any other approach out there.’
This work will be relevant in a broad range of scenarios. For example, in hospitals, this sequencing method will allow for rapid screening of thousands of infectious pathogens simultaneously, while being sensitive enough to monitor disease outbreaks caused by specific pathogenic strains. Veterinarians can even apply the method in their practices. This research is also applicable outside of clinical settings, allowing officials to quickly identify agents of bioterrorism (e.g. in a tainted letter) and harmful pathogens on hard surfaces, soil, water or in food products.
‘This approach has the ability to drastically change the process for identifying and combating pathogens, whether they’re in a hospital, veterinarian’s office or salmon stream,’ Crandall said. Researchers plan to conduct more studies to further verify the efficacy of their approach, and will soon begin to work with the aquaculture industry, helping fishermen with water-quality surveillance.
Boston University School of Medicine
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An international team of researchers has discovered why people with a variation of the FTO gene that affects one in six of the population are 70 per cent more likely to become obese.
A new study led by scientists at UCL, the Medical Research Council (MRC) and King’s College London Institute of Psychiatry shows that people with the obesity-risk FTO variant have higher circulating levels of the ‘hunger hormone’, ghrelin, in their blood. This means they start to feel hungry again soon after eating a meal.
Real-time brain imaging reveals that the FTO gene variation also changes the way the brain responds to ghrelin, and to images of food, in the regions linked with the control of eating and reward.
Together these findings explain for the first time why people with the obesity-risk variant of the FTO gene eat more and prefer higher calorie foods compared with those with the low-risk version, even before they become overweight.
Individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more. Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food – it’s a double hit.
Previous studies have revealed that single ‘letter’ variations in the genetic code of the FTO gene are linked with an increased risk of obesity, and this behaviour is present even in pre-school children.
Using a unique study design, scientists led by Dr Rachel Batterham (UCL Metabolism and Experimental Therapeutics) recruited 359 healthy male volunteers to examine the ‘real life’ effects of the FTO variation in humans.
They studied two groups of participants – those with two copies of the high obesity-risk FTO variant (AA group) and those with the low obesity-risk version (TT group). They matched the volunteers perfectly for body weight, fat distribution and social factors such as educational level to ensure that any differences they saw were linked to FTO, and not to other physical or psychological characteristics.
A group of 20 participants (10 AA and 10 TT) were asked to rate their hunger before and after a standard meal, while blood samples were taken to test levels of ghrelin – a hormone released by cells in the stomach that stimulates appetite.
Normally ghrelin levels rise before meals and fall after eating, but in this study men with the AA variation had much higher circulating ghrelin levels and felt hungrier after the meal than the TT group. This suggests that the obesity-risk variant (AA) group do not suppress ghrelin in a normal way after a meal.
The researchers then used functional magnetic resonance imaging (fMRI) in a different group of 24 participants to measure how the brain responds to pictures of high-calorie and low-calorie food images, and non-food items, before and after a meal. Again they took blood samples and asked the participants to rate on a scale how appealing the images were.
Individuals with the obesity-risk FTO variant rated pictures of high-calorie foods as more appealing after a meal than the low-risk group. In addition, the fMRI study results revealed that the brains of the two groups responded differently to food images (before and after a meal) and to circulating levels of ghrelin. The differences were most pronounced in the brain’s reward regions (known to respond to alcohol and recreational drugs) and in the hypothalamus – a non-conscious part of the brain that controls appetite.
Finally, the scientists looked at mouse and human cells to uncover what causes increased ghrelin production at a molecular level. They over-expressed the FTO gene and found that this altered the chemical make-up of ghrelin mRNA (the template for the ghrelin protein) leading to higher levels of ghrelin itself. Blood cells taken from the obesity-risk group also had higher levels of FTO gene expression and more ghrelin mRNA than the low-risk group.
Dr Rachel Batterham from UCL and University College London Hospitals, who led the study, said: ‘We’ve known for a while that variations in the FTO gene are strongly linked with obesity, but until now we didn’t know why. What this study shows us is that individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more. Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food – it’s a double hit.
University College London
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A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there’s nothing of which to be afraid. In a study, researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in a human’s genetic code as well as on that of mice.
Prior research has found an association between deficiencies of these enzymes in humans and developmental disabilities along the autism spectrum, such as clinical perseverance, the inability to change or modulate actions along with social context. ‘These mice may serve as an interesting model to develop interventions to these neuropsychiatric disorders,’ said University Professor and senior author Jean Shih, Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. ‘The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages.’
Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviours as aggression and anxiety. In this latest study, Shih and her co-investigators — including lead author Chanpreet Singh, a USC doctoral student at the time of the research who is now at the California Institute of Technology (Caltech), and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences — expanded their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine. Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear. But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalised their phobia to other contexts — their fear spilled over onto places where they should have no reason to be afraid. ‘The neural substrates processing fear in the brain is very different in these mice,’ Singh said. ‘Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things.’
The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes. Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, ‘but in their ability to learn an emotional event, the [MAO A/B knockout mice] are very different than wild types,’ Singh said. He continued: ‘When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity — a measure of learning — and to behavior that is quite similar to what we see along the autism spectrum.’
University of Southern California
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The trajectory of amyloid plaque build-up—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. ‘Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,’ said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.
Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
‘It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,’ Dr. Davatzikos said. ‘This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.’
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analysed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analysing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).
Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.
A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.
‘This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,’ said Dr Davatzikos. ‘The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.’
Perelman School of Medicine at the University of Pennsylvania
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Scientists at the National Cancer Institute (NCI) have generated a data set of cancer-specific genetic variations and are making these data available to the research community.
This will help cancer researchers better understand drug response and resistance to cancer treatments.
‘To date, this is the largest database worldwide, containing 6 billion data points that connect drugs with genomic variants for the whole human genome across cell lines from nine tissues of origin, including breast, ovary, prostate, colon, lung, kidney, brain, blood, and skin,’ said Yves Pommier, M.D., Ph.D., chief of the Laboratory of Molecular Pharmacology at the NCI in Bethesda, Md., in an interview. ‘We are making this data set public for the greater community to use and analyse.
‘Opening this extensive data set to researchers will expand our knowledge and understanding of tumorigenesis [the process by which normal cells are transformed into cancer], as more and more cancer-related gene aberrations are discovered,’ Pommier added. ‘This comes at a great time, because genomic medicine is becoming a reality, and I am very hopeful this valuable information will change the way we use drugs for precision medicine.’
Pommier and colleagues conducted whole-exome sequencing of the NCI-60 human cancer cell line panel, which is a collection of 60 human cancer cell lines, and generated a comprehensive list of cancer-specific genetic variations. Preliminary studies conducted by the researchers indicate that the extensive data set has the potential to dramatically enhance understanding of the relationships between specific cancer-related genetic variations and drug response, which will accelerate the drug development process.
The NCI-60 human cancer cell line panel is used extensively by cancer researchers to discover novel anti-cancer drugs. To conduct whole-exome sequencing, Pommier and his NCI team extracted DNA from the 60 different cell lines, which represent cancers of the lung, colon, brain, ovary, breast, prostate, and kidney, as well as leukaemia and melanoma, and catalogued the genetic coding variants for the entire human genome. The genetic variations identified were of two types: type I variants corresponding to variants found in the normal population, and type II variants, which are cancer-specific.
The researchers then used the Super Learner algorithm to predict the sensitivity of cells harboring type II variants to 103 anti-cancer drugs approved by the FDA and an additional 207 investigational new drugs. They were able to study the correlations between key cancer-related genes and clinically relevant anti-cancer drugs, and predict the outcome.
The data generated in this study provide means to identify new determinants of response and mechanisms of resistance to drugs, and offer opportunities to target genomic defects and overcome acquired resistance, according to Pommier. To enable this, the researchers are making these data available to all researchers via two database portals, called the CellMiner database and the Ingenuity systems database.
American Association for Cancer Research
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Knowing what type of lung cancer a patient has is critical to determine which drug will work best and which therapies are safest in the era of personalised medicine. Key to making that judgement is an adequate tumour specimen for the pathologist to determine the tumour’s histology, a molecular description of a tumour based on the appearance of cells under a microscope. But not all specimens are perfect, and are sometimes so complex that a definitive diagnosis presents a challenge.
Scientists at the Universities of North Carolina and Utah have developed a histology expression predictor for the most common types of lung cancer: adenocarcinoma, carcinoid, small cell carcinoma and squamous cell carcinoma. This predictor can confirm histologic diagnosis in routinely collected paraffin samples of patients’ tumours and can complement and corroborate pathologists’ findings.
Neil Hayes, MD, MPH, associate professor of medicine and corresponding author of the study says, ‘As we learn more about the genetics of lung cancer, we can use that understanding to tailor therapies to the individual’s tumour. Gene expression profiling has great potential for improving the accuracy of the histologic diagnosis. Historically, gene expression analysis has required fresh tumour tissue that is usually not possible in routine clinical care. We desperately needed to extend the analysis of genes (aka RNA) to paraffin samples that are routinely generated in clinical care, rather than fresh frozen tissue. That is the major accomplishment of the current study and one of the first large scale endeavours in lung cancer to show this is possible.
‘Our predictor identifies the major histologic types of lung cancer in paraffin-embedded tissue specimens which is immediately useful in confirming the histologic diagnosis in difficult tissue biopsy specimens.’ Dr. Hayes is a member of UNC Lineberger Comprehensive Cancer Center.
The scientists used 442 samples of formalin-fixed paraffin-embedded specimens from lung cancer patients at UNC and the University of Utah Health Sciences Center as they developed their predictor.
First author Matthew Wilkerson, PhD, explains, ‘Our question was, ‘Can histology be predicted accurately by gene expression?’ We had lung cancer genes we already knew were differentially expressed in the different tumour types, so we measured them in tumour paraffin specimens. Next we developed a predictor in an independent set of tumour samples. We then compared the predictor to the actual clinical diagnosis and had additional pathologists review the samples. We showed accuracy as least as good as the pathologist. Our predictor exhibited a mean accuracy of 84 percent, and when compared with pathologist diagnoses, yielded similar accuracy and precision as the pathologists.’
Dr. Hayes summarizes, ‘Going beyond meeting a current need of increasing the accuracy of histologic diagnosis is expected to be the ultimate benefit of this technology. There are many additional characteristics of tumours that could be leveraged for clinical purposes once the world of gene expression analysis from paraffin is efficient from clinical samples. We anticipate additional uses such as predicting responses to additional therapies and prognostication as near term additions.’
University of North Carolina Health Care
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It turns out the love hormone oxytocin is two-faced. Oxytocin has long been known as the warm, fuzzy hormone that promotes feelings of love, social bonding and well-being. It’s even being tested as an anti-anxiety drug. But new Northwestern Medicine research shows oxytocin also can cause emotional pain, an entirely new, darker identity for the hormone.
Oxytocin appears to be the reason stressful social situations, perhaps being bullied at school or tormented by a boss, reverberate long past the event and can trigger fear and anxiety in the future.
That’s because the hormone actually strengthens social memory in one specific region of the brain, Northwestern scientists discovered.
If a social experience is negative or stressful, the hormone activates a part of the brain that intensifies the memory. Oxytocin also increases the susceptibility to feeling fearful and anxious during stressful events going forward.
(Presumably, oxytocin also intensifies positive social memories and, thereby, increases feelings of well being, but that research is ongoing.)
The findings are important because chronic social stress is one of the leading causes of anxiety and depression, while positive social interactions enhance emotional health. The research, which was done in mice, is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.
‘By understanding the oxytocin system’s dual role in triggering or reducing anxiety, depending on the social context, we can optimise oxytocin treatments that improve well-being instead of triggering negative reactions,’ said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University Feinberg School of Medicine.
This is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. Northwestern scientists also discovered the brain region responsible for these effects — the lateral septum – and the pathway or route oxytocin uses in this area to amplify fear and anxiety.
The scientists discovered that oxytocin strengthens negative social memory and future anxiety by triggering an important signalling molecule — ERK (extracellular signal regulated kinases) — that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, Radulovic believes, by stimulating the brain’s fear pathways, many of which pass through the lateral septum. The region is involved in emotional and stress responses.
Northwestern University
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Researchers have developed a reliable way to use a finger-stick blood sample to detect fibromyalgia syndrome, a complicated pain disorder that often is difficult to diagnose.
If it were someday made available to primary care physicians, the test could knock up to five years off of the wait for a diagnosis, researchers predict.
In a pilot study, the scientists used a high-powered and specialized microscope to detect the presence of small molecules in blood-spot samples from patients known to have fibromyalgia.
By ‘training’ the equipment to recognise that molecular pattern, the researchers then showed that the microscope could tell the difference between fibromyalgia and two types of arthritis that share some of the same symptoms.
Though more analysis is needed to identify exactly which molecules are related to development of the disorder itself, the researchers say their pilot data are promising.
‘We’ve got really good evidence of a test that could be an important aid in the diagnosis of fibromyalgia patients,’ said Tony Buffington, professor of veterinary clinical sciences at The Ohio State University and senior author of the study. ‘We would like this to lead to an objective test for primary care doctors to use, which could produce a diagnosis as much as five years before it usually occurs.’
Patients with fibromyalgia are often desperate by the time they receive treatment because of the lengthy process required to make a diagnosis. The main symptoms, persistent pain and fatigue, mimic many other conditions, so physicians tend to rule out other potential causes before diagnosing fibromyalgia. Additional symptoms include disrupted sleep and memory or thought problems. An estimated 5 million American adults have the disorder, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
‘The importance of producing a faster diagnosis cannot be overstated, because patients experience tremendous stress during the diagnostic process. Just getting the diagnosis actually makes patients feel better and lowers costs because of reductions in anxiety,’ said Kevin Hackshaw, associate professor of medicine, division of rheumatology and immunology, at Ohio State’s Wexner Medical Center and lead author of the study.
The technology used in this work is infrared microspectroscopy, which identifies the biochemical content of a blood sample based on where peaks of molecules appear in the infrared spectrum. The technology offers hints at the molecules present in the samples based on how molecular bonds vibrate when they are struck by light.
The spectroscopy works on dried blood, so just a few drops from a finger stick produce enough blood to run this test.
Researchers first obtained blood samples from patients diagnosed with fibromyalgia (14), rheumatoid arthritis (15) and osteoarthritis (12). These other conditions were chosen for comparison because they produce similar symptoms as fibromyalgia, but are easier to diagnose.
The scientists analysed each sample with the infrared microspectroscopy to identify the molecular patterns associated with each disease. This functioned as a ‘training’ phase of the study.
When the researchers then entered blinded blood samples into the same machinery, each condition was accurately identified based on its molecular patterns.
‘It separated them completely, with no misclassifications,’ Buffington said. ‘That’s very important. It never mistook a patient with fibromyalgia for a patient with arthritis. Clearly we need more numbers, but this showed the technique is quite effective.’
The researchers also analyzed some of the potential chemicals that could someday function as biomarkers in the fibromyalgia blood samples, but further studies are needed to identify the molecules responsible for the spectral patterns, he said.
EurekAlert
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Researchers pinpoint sources of fibrosis-promoting cells that ravage organs
, /in E-News /by 3wmediaScientists have tracked down and quantified the diverse origins of cells that drive fibrosis, the incurable, runaway wound-healing that scars and ultimately destroys organs such as the lungs, liver and kidneys.
Findings are from research conducted at Beth Israel Deaconess Medical Center, Harvard Medical School and Massachusetts Institute of Technology in Boston and continued at The University of Texas MD Anderson Cancer Center.
‘Answering a fundamental question about the origin of these cells by identifying four separate pathways involved in their formation allows us to look at ways to block those pathways to treat fibrosis,’ said senior author Raghu Kalluri, Ph.D., M.D., MD Anderson chair and professor of Cancer Biology. ‘It’s highly unlikely that a single drug will work.’
‘In addition to being lethal in its own right, fibrosis is a precursor for the development of cancer and plays a role in progression, metastasis and treatment resistance,’ Kalluri said. ‘In some cancers, such as pancreatic cancer, up to 95 percent of tumours consist of fibrotic stroma.’
Working in genetic mouse models of kidney fibrosis, Kalluri and colleagues identified four sources of cells called myofibroblasts, the dominant producers of collagen. Collagen normally connects damaged tissue and serves as scaffolding for wound-healing. As healing occurs, myofibroblasts and collagen usually diminish or disappear.
In fibrosis, collagen production marches on. While inflammation-inhibiting drugs can sometimes slow its progress, fibrosis now is treatable only by organ transplant.
The researchers employed a fate-mapping strategy to track cells on their way to becoming myofibroblasts. In fate mapping, the promoter of a protein expresses a colour inside a cell that remains with the cell no matter what happens to it until it dies, Kalluri said.
This was particularly important because two of the four sources of myofibroblasts start out as another cell type and differentiate into the collagen-producing cells.
Their experiments showed:
Half of all myofibroblasts are produced by the proliferation of pre-existing resting fibroblasts.
Another 35 percent are produced by mesenchymal stem cells that originate in the bone marrow, migrate to the ‘wound’ site, and then differentiate into myofibroblasts.
An additional 10 percent are the products of endothelial to mesenchymal transition (EndMT), in which blood vessel cells change into mesenchymal cells, then become myofibroblasts.
The final 5 percent come from epithelial to mesenchymal transition (EMT), in which functional cells of an organ sometimes behave like mesenchymal cells and myofibroblasts.
‘These differentiation pathways provide leads for drug targets,’ Kalluri said. ‘Combining an antiproliferation drug with therapies that block one or more differentiation pathways could provide a double hit to control fibrosis. We hope to synergise these pathways for the most effective therapeutic response.’ MD Anderson Cancer Center
Study reveals biological basis for sensory processing disorders in kids
, /in E-News /by 3wmediaSensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognised as a distinct disease.
In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders.
One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.
‘Until now, SPD hasn’t had a known biological underpinning,’ said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. ‘Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,’ Mukherjee said.
Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out. The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers.
‘Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,’ said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey.
‘Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,’ said Marco, who treats affected children in her cognitive and behavioural neurology clinic.
‘If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,’ she said. University of California – San Francisco
Method to rapidly identify specific strains of illness
, /in E-News /by 3wmediaResearchers from Boston University School of Medicine (BUSM) and George Washington University (GWU) have developed a method to rapidly identify pathogenic species and strains causing illnesses, such as pneumonia, that could help lead to earlier detection of disease outbreaks and pinpoint effective treatments more quickly.
Emerging sequencing technologies have revolutionised the collection of genomic data for bioforensics, biosurveillance and for use in clinical settings. However, new approaches are being developed to analyse these large volumes of genetic data. Principal investigator Evan Johnson, PhD, assistant professor of medicine at BUSM, and Keith Crandall, PhD, director of the Computational Biology Institute at GWU, have created a statistical framework called Pathoscope to identify pathogenic genetic sequences from infected tissue samples.
This unique approach can accurately discriminate between closely related strains of the same species with little coverage of the pathogenic genome. The method also can determine the complete composition of known pathogenic and benign organisms in a biological sample. No other method can accurately identify multiple species or substrains in such a direct and automatic way. Current methods, such as the standard polymerase chain reaction detection or microscope observation, are often imperfect and time-consuming.
‘Pathoscope is like completing a complex jigsaw puzzle. Instead of manually assembling the puzzle, which can take days or weeks of tedious effort, we use a statistical algorithm that can determine how the picture should look without actually putting it together,’ said Johnson. ‘Our method can characterise a biological sample faster, more accurately and in a more automated fashion than any other approach out there.’
This work will be relevant in a broad range of scenarios. For example, in hospitals, this sequencing method will allow for rapid screening of thousands of infectious pathogens simultaneously, while being sensitive enough to monitor disease outbreaks caused by specific pathogenic strains. Veterinarians can even apply the method in their practices. This research is also applicable outside of clinical settings, allowing officials to quickly identify agents of bioterrorism (e.g. in a tainted letter) and harmful pathogens on hard surfaces, soil, water or in food products.
Boston University School of Medicine‘This approach has the ability to drastically change the process for identifying and combating pathogens, whether they’re in a hospital, veterinarian’s office or salmon stream,’ Crandall said. Researchers plan to conduct more studies to further verify the efficacy of their approach, and will soon begin to work with the aquaculture industry, helping fishermen with water-quality surveillance.
How ‘obesity gene’ triggers weight gain
, /in E-News /by 3wmediaAn international team of researchers has discovered why people with a variation of the FTO gene that affects one in six of the population are 70 per cent more likely to become obese.
A new study led by scientists at UCL, the Medical Research Council (MRC) and King’s College London Institute of Psychiatry shows that people with the obesity-risk FTO variant have higher circulating levels of the ‘hunger hormone’, ghrelin, in their blood. This means they start to feel hungry again soon after eating a meal.
Real-time brain imaging reveals that the FTO gene variation also changes the way the brain responds to ghrelin, and to images of food, in the regions linked with the control of eating and reward.
Together these findings explain for the first time why people with the obesity-risk variant of the FTO gene eat more and prefer higher calorie foods compared with those with the low-risk version, even before they become overweight.
Individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more. Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food – it’s a double hit.
Previous studies have revealed that single ‘letter’ variations in the genetic code of the FTO gene are linked with an increased risk of obesity, and this behaviour is present even in pre-school children.
Using a unique study design, scientists led by Dr Rachel Batterham (UCL Metabolism and Experimental Therapeutics) recruited 359 healthy male volunteers to examine the ‘real life’ effects of the FTO variation in humans.
They studied two groups of participants – those with two copies of the high obesity-risk FTO variant (AA group) and those with the low obesity-risk version (TT group). They matched the volunteers perfectly for body weight, fat distribution and social factors such as educational level to ensure that any differences they saw were linked to FTO, and not to other physical or psychological characteristics.
A group of 20 participants (10 AA and 10 TT) were asked to rate their hunger before and after a standard meal, while blood samples were taken to test levels of ghrelin – a hormone released by cells in the stomach that stimulates appetite.
Normally ghrelin levels rise before meals and fall after eating, but in this study men with the AA variation had much higher circulating ghrelin levels and felt hungrier after the meal than the TT group. This suggests that the obesity-risk variant (AA) group do not suppress ghrelin in a normal way after a meal.
The researchers then used functional magnetic resonance imaging (fMRI) in a different group of 24 participants to measure how the brain responds to pictures of high-calorie and low-calorie food images, and non-food items, before and after a meal. Again they took blood samples and asked the participants to rate on a scale how appealing the images were.
Individuals with the obesity-risk FTO variant rated pictures of high-calorie foods as more appealing after a meal than the low-risk group. In addition, the fMRI study results revealed that the brains of the two groups responded differently to food images (before and after a meal) and to circulating levels of ghrelin. The differences were most pronounced in the brain’s reward regions (known to respond to alcohol and recreational drugs) and in the hypothalamus – a non-conscious part of the brain that controls appetite.
Finally, the scientists looked at mouse and human cells to uncover what causes increased ghrelin production at a molecular level. They over-expressed the FTO gene and found that this altered the chemical make-up of ghrelin mRNA (the template for the ghrelin protein) leading to higher levels of ghrelin itself. Blood cells taken from the obesity-risk group also had higher levels of FTO gene expression and more ghrelin mRNA than the low-risk group.
Dr Rachel Batterham from UCL and University College London Hospitals, who led the study, said: ‘We’ve known for a while that variations in the FTO gene are strongly linked with obesity, but until now we didn’t know why. What this study shows us is that individuals with two copies of the obesity-risk FTO variant are biologically programmed to eat more. Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food – it’s a double hit. University College London
When fear factors in
, /in E-News /by 3wmediaA little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there’s nothing of which to be afraid. In a study, researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in a human’s genetic code as well as on that of mice.
Prior research has found an association between deficiencies of these enzymes in humans and developmental disabilities along the autism spectrum, such as clinical perseverance, the inability to change or modulate actions along with social context. ‘These mice may serve as an interesting model to develop interventions to these neuropsychiatric disorders,’ said University Professor and senior author Jean Shih, Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. ‘The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages.’
Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviours as aggression and anxiety. In this latest study, Shih and her co-investigators — including lead author Chanpreet Singh, a USC doctoral student at the time of the research who is now at the California Institute of Technology (Caltech), and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences — expanded their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine. Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear. But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalised their phobia to other contexts — their fear spilled over onto places where they should have no reason to be afraid. ‘The neural substrates processing fear in the brain is very different in these mice,’ Singh said. ‘Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things.’
The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes. Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, ‘but in their ability to learn an emotional event, the [MAO A/B knockout mice] are very different than wild types,’ Singh said. He continued: ‘When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity — a measure of learning — and to behavior that is quite similar to what we see along the autism spectrum.’ University of Southern California
Path of plaque build-up in brain shows promise as early biomarker for Alzheimer’s Disease
, /in E-News /by 3wmediaThe trajectory of amyloid plaque build-up—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. ‘Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,’ said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.
Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
‘It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,’ Dr. Davatzikos said. ‘This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.’
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analysed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analysing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).
Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.
A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.
‘This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,’ said Dr Davatzikos. ‘The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.’ Perelman School of Medicine at the University of Pennsylvania
NCI generate largest data set of cancer-related genetic variations
, /in E-News /by 3wmediaScientists at the National Cancer Institute (NCI) have generated a data set of cancer-specific genetic variations and are making these data available to the research community.
This will help cancer researchers better understand drug response and resistance to cancer treatments.
‘To date, this is the largest database worldwide, containing 6 billion data points that connect drugs with genomic variants for the whole human genome across cell lines from nine tissues of origin, including breast, ovary, prostate, colon, lung, kidney, brain, blood, and skin,’ said Yves Pommier, M.D., Ph.D., chief of the Laboratory of Molecular Pharmacology at the NCI in Bethesda, Md., in an interview. ‘We are making this data set public for the greater community to use and analyse.
‘Opening this extensive data set to researchers will expand our knowledge and understanding of tumorigenesis [the process by which normal cells are transformed into cancer], as more and more cancer-related gene aberrations are discovered,’ Pommier added. ‘This comes at a great time, because genomic medicine is becoming a reality, and I am very hopeful this valuable information will change the way we use drugs for precision medicine.’
Pommier and colleagues conducted whole-exome sequencing of the NCI-60 human cancer cell line panel, which is a collection of 60 human cancer cell lines, and generated a comprehensive list of cancer-specific genetic variations. Preliminary studies conducted by the researchers indicate that the extensive data set has the potential to dramatically enhance understanding of the relationships between specific cancer-related genetic variations and drug response, which will accelerate the drug development process.
The NCI-60 human cancer cell line panel is used extensively by cancer researchers to discover novel anti-cancer drugs. To conduct whole-exome sequencing, Pommier and his NCI team extracted DNA from the 60 different cell lines, which represent cancers of the lung, colon, brain, ovary, breast, prostate, and kidney, as well as leukaemia and melanoma, and catalogued the genetic coding variants for the entire human genome. The genetic variations identified were of two types: type I variants corresponding to variants found in the normal population, and type II variants, which are cancer-specific.
The researchers then used the Super Learner algorithm to predict the sensitivity of cells harboring type II variants to 103 anti-cancer drugs approved by the FDA and an additional 207 investigational new drugs. They were able to study the correlations between key cancer-related genes and clinically relevant anti-cancer drugs, and predict the outcome.
The data generated in this study provide means to identify new determinants of response and mechanisms of resistance to drugs, and offer opportunities to target genomic defects and overcome acquired resistance, according to Pommier. To enable this, the researchers are making these data available to all researchers via two database portals, called the CellMiner database and the Ingenuity systems database. American Association for Cancer Research
RNA diagnostic test from paraffin improves lung cancer diagnosis over routine microscopic evaluation alone
, /in E-News /by 3wmediaKnowing what type of lung cancer a patient has is critical to determine which drug will work best and which therapies are safest in the era of personalised medicine. Key to making that judgement is an adequate tumour specimen for the pathologist to determine the tumour’s histology, a molecular description of a tumour based on the appearance of cells under a microscope. But not all specimens are perfect, and are sometimes so complex that a definitive diagnosis presents a challenge.
Scientists at the Universities of North Carolina and Utah have developed a histology expression predictor for the most common types of lung cancer: adenocarcinoma, carcinoid, small cell carcinoma and squamous cell carcinoma. This predictor can confirm histologic diagnosis in routinely collected paraffin samples of patients’ tumours and can complement and corroborate pathologists’ findings.
Neil Hayes, MD, MPH, associate professor of medicine and corresponding author of the study says, ‘As we learn more about the genetics of lung cancer, we can use that understanding to tailor therapies to the individual’s tumour. Gene expression profiling has great potential for improving the accuracy of the histologic diagnosis. Historically, gene expression analysis has required fresh tumour tissue that is usually not possible in routine clinical care. We desperately needed to extend the analysis of genes (aka RNA) to paraffin samples that are routinely generated in clinical care, rather than fresh frozen tissue. That is the major accomplishment of the current study and one of the first large scale endeavours in lung cancer to show this is possible.
‘Our predictor identifies the major histologic types of lung cancer in paraffin-embedded tissue specimens which is immediately useful in confirming the histologic diagnosis in difficult tissue biopsy specimens.’ Dr. Hayes is a member of UNC Lineberger Comprehensive Cancer Center.
The scientists used 442 samples of formalin-fixed paraffin-embedded specimens from lung cancer patients at UNC and the University of Utah Health Sciences Center as they developed their predictor.
First author Matthew Wilkerson, PhD, explains, ‘Our question was, ‘Can histology be predicted accurately by gene expression?’ We had lung cancer genes we already knew were differentially expressed in the different tumour types, so we measured them in tumour paraffin specimens. Next we developed a predictor in an independent set of tumour samples. We then compared the predictor to the actual clinical diagnosis and had additional pathologists review the samples. We showed accuracy as least as good as the pathologist. Our predictor exhibited a mean accuracy of 84 percent, and when compared with pathologist diagnoses, yielded similar accuracy and precision as the pathologists.’
Dr. Hayes summarizes, ‘Going beyond meeting a current need of increasing the accuracy of histologic diagnosis is expected to be the ultimate benefit of this technology. There are many additional characteristics of tumours that could be leveraged for clinical purposes once the world of gene expression analysis from paraffin is efficient from clinical samples. We anticipate additional uses such as predicting responses to additional therapies and prognostication as near term additions.’ University of North Carolina Health Care
The love hormone is two-faced
, /in E-News /by 3wmediaIt turns out the love hormone oxytocin is two-faced. Oxytocin has long been known as the warm, fuzzy hormone that promotes feelings of love, social bonding and well-being. It’s even being tested as an anti-anxiety drug. But new Northwestern Medicine research shows oxytocin also can cause emotional pain, an entirely new, darker identity for the hormone.
Oxytocin appears to be the reason stressful social situations, perhaps being bullied at school or tormented by a boss, reverberate long past the event and can trigger fear and anxiety in the future.
That’s because the hormone actually strengthens social memory in one specific region of the brain, Northwestern scientists discovered.
If a social experience is negative or stressful, the hormone activates a part of the brain that intensifies the memory. Oxytocin also increases the susceptibility to feeling fearful and anxious during stressful events going forward.
(Presumably, oxytocin also intensifies positive social memories and, thereby, increases feelings of well being, but that research is ongoing.)
The findings are important because chronic social stress is one of the leading causes of anxiety and depression, while positive social interactions enhance emotional health. The research, which was done in mice, is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.
‘By understanding the oxytocin system’s dual role in triggering or reducing anxiety, depending on the social context, we can optimise oxytocin treatments that improve well-being instead of triggering negative reactions,’ said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University Feinberg School of Medicine.
This is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. Northwestern scientists also discovered the brain region responsible for these effects — the lateral septum – and the pathway or route oxytocin uses in this area to amplify fear and anxiety.
The scientists discovered that oxytocin strengthens negative social memory and future anxiety by triggering an important signalling molecule — ERK (extracellular signal regulated kinases) — that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, Radulovic believes, by stimulating the brain’s fear pathways, many of which pass through the lateral septum. The region is involved in emotional and stress responses. Northwestern University
Faster, simpler diagnosis for fibromyalgia may be on the horizon
, /in E-News /by 3wmediaResearchers have developed a reliable way to use a finger-stick blood sample to detect fibromyalgia syndrome, a complicated pain disorder that often is difficult to diagnose.
If it were someday made available to primary care physicians, the test could knock up to five years off of the wait for a diagnosis, researchers predict.
In a pilot study, the scientists used a high-powered and specialized microscope to detect the presence of small molecules in blood-spot samples from patients known to have fibromyalgia.
By ‘training’ the equipment to recognise that molecular pattern, the researchers then showed that the microscope could tell the difference between fibromyalgia and two types of arthritis that share some of the same symptoms.
Though more analysis is needed to identify exactly which molecules are related to development of the disorder itself, the researchers say their pilot data are promising.
‘We’ve got really good evidence of a test that could be an important aid in the diagnosis of fibromyalgia patients,’ said Tony Buffington, professor of veterinary clinical sciences at The Ohio State University and senior author of the study. ‘We would like this to lead to an objective test for primary care doctors to use, which could produce a diagnosis as much as five years before it usually occurs.’
Patients with fibromyalgia are often desperate by the time they receive treatment because of the lengthy process required to make a diagnosis. The main symptoms, persistent pain and fatigue, mimic many other conditions, so physicians tend to rule out other potential causes before diagnosing fibromyalgia. Additional symptoms include disrupted sleep and memory or thought problems. An estimated 5 million American adults have the disorder, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
‘The importance of producing a faster diagnosis cannot be overstated, because patients experience tremendous stress during the diagnostic process. Just getting the diagnosis actually makes patients feel better and lowers costs because of reductions in anxiety,’ said Kevin Hackshaw, associate professor of medicine, division of rheumatology and immunology, at Ohio State’s Wexner Medical Center and lead author of the study.
The technology used in this work is infrared microspectroscopy, which identifies the biochemical content of a blood sample based on where peaks of molecules appear in the infrared spectrum. The technology offers hints at the molecules present in the samples based on how molecular bonds vibrate when they are struck by light.
The spectroscopy works on dried blood, so just a few drops from a finger stick produce enough blood to run this test.
Researchers first obtained blood samples from patients diagnosed with fibromyalgia (14), rheumatoid arthritis (15) and osteoarthritis (12). These other conditions were chosen for comparison because they produce similar symptoms as fibromyalgia, but are easier to diagnose.
The scientists analysed each sample with the infrared microspectroscopy to identify the molecular patterns associated with each disease. This functioned as a ‘training’ phase of the study.
When the researchers then entered blinded blood samples into the same machinery, each condition was accurately identified based on its molecular patterns.
‘It separated them completely, with no misclassifications,’ Buffington said. ‘That’s very important. It never mistook a patient with fibromyalgia for a patient with arthritis. Clearly we need more numbers, but this showed the technique is quite effective.’
The researchers also analyzed some of the potential chemicals that could someday function as biomarkers in the fibromyalgia blood samples, but further studies are needed to identify the molecules responsible for the spectral patterns, he said. EurekAlert