Researchers identify genetic mutations associated with diseases of the esophagus

ScienceDaily (July 26, 2011) — Mutations in three genes have been identified that are more prevalent in patients with esophageal cancer and Barrett esophagus, a premalignant metaplasia (change in cells or tissue) caused by chronic gastroesophageal reflux disease (GERD), according to preliminary research reported in the July 27 issue of JAMA.See Also:Health & MedicineGenesBrain TumorParkinson's ResearchDiseases and ConditionsGastrointestinal ProblemsPersonalized MedicineReferenceTumor suppressor geneBRCA1BRCA2Tumor

The incidence of esophageal adenocarcinoma (EAC) in the United States and Europe has increased 350 percent since 1970, with the cause uncertain. Esophageal adenocarcinoma is believed to be preceded by Barrett esophagus (BE), according to background information in the article. Barrett esophagus is common, estimated to occur in 1 percent to 10 percent of the general population. "Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management," the authors write.

Charis Eng, M.D., Ph.D., of the Cleveland Clinic, and colleagues conducted a study to identify a gene or genes associated with BE/EAC predisposition. The research included an analyses of 21 concordant (both)-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). The study also included data from 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010). Data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis. Genes that showed mutations in cases but not in controls were further screened in 58 cases.

Analyses indicated that three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC. Mutational analyses of the 12 priority candidate genes in BE/EAC cases found mutations in these three genes in 13 of 116 patients (11.2 percent), with the most frequently mutated being MSR1 (approximately 7 percent), followed by ASCCl and CTHRC1. "Findings of germline

How the modular structure of proteins permits evolution to move forward

ScienceDaily (July 26, 2011) — Changes in a short protein domain can alter a whole signaling network involved in organ development- this is the key result of a comparative study of the development of the egg laying organ in two species of nematodes. However, the outward appearance of the organ remains the same in both species. The study provides support for the theory of developmental systems drift -- a theory maintaining that, over the course of evolution, analogous organs of different species can retain the same shape and function while the regulative mechanisms underlying their development can change considerably.See Also:Plants & AnimalsEvolutionary BiologyGeneticsMolecular BiologyBiologyDevelopmental BiologyBiotechnologyReferenceDevelopmental biologyRoundwormHuman biologyMorphogenesis

The new results, published July 26 in the online, open-access journal PLoS Biology, raise the question of whether the modular structure of proteins creates space for evolutionary development, even in otherwise highly conserved structures of organs and signaling pathways.

The nematode Caenorhabditis elegans (C. elegans) is a model organism of genetics. The worm is only about one millimeter long, and its genome has been completely sequenced, so scientists can trace the fate of every one of its 959 cells. In research lasting more than a decade, Ralf Sommer, Director of the Department for Evolutionary Biology at the Max Planck Institute for Developmental Biology in Tübingen, Germany, has established as a comparative model organism, a second nematode, Pristionchus pacificus (P. pacificus). At first sight, this species resembles C. elegans, but it belongs to another family. The last common ancestor of the two species lived 250 to 420 million years ago, well before the zenith of the dinosaurs. "For

Scientists induce hibernation at will: Discovery puts scientists closer to human application

ScienceDaily (July 26, 2011) — Hibernation is an essential survival strategy for some animals and scientists have long thought it could also hold promise for human survival. But how hibernation works is largely unknown. Scientists at the University of Alaska Fairbanks have successfully induced hibernation at will, showing how the process is initiated. Their research is published in the July 26 issue of The Journal of Neuroscience.See Also:Health & MedicineInsomnia ResearchControlled SubstancesHuman BiologyPlants & AnimalsBiologyAnimalsNatureStrange ScienceReferenceParasympathetic nervous systemExcitotoxicity and cell damageNeurotransmitterAntifreeze protein

A hibernating animal has a reduced heart rate and blood flow similar to a person in cardiac arrest, yet the hibernator doesn't suffer the brain damage that can occur in people. "Understanding the neuroprotective qualities of hibernating animals may lead to development of a drug or therapy to save people's lives after a stroke or heart attack," said Kelly Drew, senior author and UAF professor of chemistry and biochemistry in the Institute of Arctic Biology.

Hibernating animals survive by severely reducing their metabolism, a condition called torpor, in which oxygen consumption can fall to as low as one percent of resting metabolic rate and core body temperature to near or below freezing temperatures.

Arctic ground squirrels, like all animals and people, produce a molecule called adenosine that slows nerve cell activity. "When a squirrel begins to hibernate and when you feel drowsy it's because adenosine molecules have attached themselves to receptors in your brain," said Tulasi Jinka, lead author and IAB post-doctoral fellow in Drew's lab.

The receptors can be regulated by a simple cup of coffee. A caffeine molecule is similar enough in structure to adenosine that it binds to the receptors and effectively stops or reverses the onset of drowsiness. Jinka and Drew wanted to know what substances trip the squirrels' switch to start to hibernate.

"We devised an experiment in which non-hibernating arctic ground squirrels were given a substance that stimulated adenosine receptors in their brains. We expected the substance to induce hibernation," Drew said. "We also gave a substance similar to caffeine to arouse hibernating ground squirrels."

The non-hibernating squirrels were tested three times during one year. They were tested during the summer when they were not hibernating, again early in their hibernation season and a third time mid-way through the hibernation season. If animals were hibernating before the test Jinka woke them up to see if the substance would cause them to go back into hibernation. To ensure that his expectations did not influence the results he delivered a placebo in the same manner as the drug and did not know which solution contained the active substance when he conducted the experiments.

Torpor was induced in all six of the squirrels awoken during mid-hibernation season, but in only two of the six from the early hibernation season group and in none during the summer season. The caffeine-like substance reversed torpor in all of the hibernating squirrels.

"We show for the first time that activation of the adenosine receptors is sufficient to induce torpor in arctic ground squirrels during their hibernation season," Jinka said, who conducted this experiment while he was a graduate student.

What Jinka and Drew don't yet know is how season causes the receptors to become increasingly sensitive to adenosine as the time of hibernation progresses.

Jinka and Drew are expanding their adenosine research to rats, which more closely resemble the physiology of humans. "Rats allow us to move toward being able to apply this research to humans," Jinka said.

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To help doctors and patients, researchers are developing a 'vocabulary of pain'

ScienceDaily (July 26, 2011) — All over the world, patients with chronic pain struggle to express how they feel to the doctors and health-care providers who are trying to understand and treat them.See Also:Health & MedicinePain ControlWorkplace HealthFibromyalgiaMind & BrainCaregivingPTSDBrain InjuryReferenceChronic painBack painTension headacheGate control theory of pain

Now, a University at Buffalo psychiatrist is attempting to help patients suffering from chronic pain and their doctors by drawing on ontology, the branch of philosophy concerned with the nature of being or existence.

The research will be discussed during a tutorial he will give at the International Conference on Biomedical Ontology, sponsored by UB, that will be held in Buffalo July 26-30.

"Pain research is very difficult because nothing allows the physician to see the patient's pain directly," says Werner Ceusters, MD, professor of psychiatry in UB's School of Medicine and Biomedical Sciences, and principal investigator on a new National Institutes of Health grant, An Ontology for Pain and Related Disability, Mental Health and Quality of Life.

"The patient has to describe what he or she is feeling."

That is a serious shortcoming, Ceusters says, because each patient's subjective experience of pain is different. Descriptions of pain therefore lack the precision and specificity that is taken for granted with other disorders, where biomarkers or physiological indicators reveal what health-care providers need in order to assess the severity of a particular disorder.

"If we want to more effectively help people suffering from chronic pain, we need to study a population that is consistent, patients who have features in common," Ceusters says. "The problem with pain is, it's very hard to build up a group with the same sort of pain. People don't have the same vocabulary or linguistic capabilities or even the same cultural backgrounds. It's something pain researchers have struggled with for decades," Ceusters says. "We need to develop a vocabulary of pain."

That's where ontology comes in.

"The philosophical definition of ontology is the study of things that exist and how they relate to each other," says Ceusters, who also is director of the Ontology Research Group of UB's New York State Center of Excellence in Bioinformatics and Life Sciences. "I am a person and you are a person so we share something. Suppose I drop dead. What lies on the floor? Is that still a person? If it is no longer a person, is it still the very same thing that was sitting here as a person but now is a corpse?"

Ceusters says that in much the same way, definitions of pain and especially of chronic pain need to be much more precise; ontology provides methods of distinguishing among categories and describing data in uniform and formal ways.

While the philosophical approach to ontology naturally has its roots in ancient Greece, a computational approach to ontology began in the latter part of the 20th century, when computer scientists interested in artificial intelligence wanted to create software programs that perform reasoning they way humans do. To do so, they began to draw on ontology.

"Here at the University at Buffalo, we excel at combining the two approaches; we have a very strong foundation in the philosophical approach to ontology with Barry Smith, who is a pioneer in contemporary ontology, especially related to biomedical applications," says Ceusters, "while we also have a very strong presence in computational approaches, especially to biomedical ontology. These computational approaches allow us to devise systems of communication in which there is a consistent meaning for terms used in different language systems and conceptual frameworks."

With the $793,571 NIH grant, Ceusters and colleagues will study data gathered from thousands of patients in the U.S., the United Kingdom, Sweden, Israel and Germany who suffer from oral and facial pain, including temporomandibular disorder (TMD).

Ceusters will work with his colleagues, including Richard Ohrbach, DDS, PhD, associate professor of oral diagnostic sciences in the UB School of Dental Medicine, to develop an ontology that allows the data to be described in a much more uniform way.

"The goal is to integrate the data together so that we have a large pool of data that will allow us to obtain better insight into the complexity of pain disorders, specifically the assessment of pain disorders and how they impact mental health and a patients' quality of life," Ceusters says.

The grant will build on past work that Ceusters conducted with a grant from the Oishei Foundation related to improving the classification, diagnosis and treatment of psychiatric conditions.

Ceusters, who has degrees in knowledge engineering and information science as well as in neuropsychiatry, says that the current effort grew out of his work on that grant and also from a meeting with pain researchers that he attended in 2009.

"At that meeting, we discussed how we might build an ontology so that it could represent what pain is and how it relates to body parts and their activities and functions," he says. "Our goal is to create a software program that will allow all pain specialists to express themselves in crystal clear terms," he says, "We will create a symptom checklist that can be understood by computers. We have to define the terminology of pain. This can only be solved by the kind of ontology we are doing here at the University at Buffalo."

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Eliminating protein in specific brain cells blocks nicotine reward

ScienceDaily (July 26, 2011) — Removing a protein from cells located in the brain's reward center blocks the anxiety-reducing and rewarding effects of nicotine, according to a new animal study in the July 27 issue of The Journal of Neuroscience. The findings may help researchers better understand how nicotine affects the brain.See Also:Health & MedicineSmokingBrain TumorPsychology ResearchMind & BrainSmoking AddictionAddictionAnxietyReferenceNicotineAddictionDrug addictionDopamine hypothesis of schizophrenia

Nicotine works by binding to proteins called nicotinic receptors on the surface of brain cells. In the new study, researchers led by Tresa McGranahan, Stephen Heinemann, PhD, and T. K. Booker, PhD, of the Salk Institute for Biological Studies, found that removing a specific type of nicotinic receptor from brain cells that produce dopamine -- a chemical released in response to reward -- makes mice less likely to seek out nicotine. The mice also did not show reductions in anxiety-like behaviors normally seen after nicotine treatment. Smokers commonly report anxiety relief as a key factor in continued smoking or relapse.

"These findings show that the rewarding and anxiety-reducing properties of nicotine, thought to play a key role in the development of tobacco addiction, are related to actions at a single set of brain cells," said Paul Kenny, PhD, an expert on drug addiction at Scripps Research Institute, who was unaffiliated with the study.

Previous studies showed blocking the alpha4 nicotinic receptor within the ventral tegmental area (VTA) -- a brain region important in motivation, emotion, and addiction -- decreases the rewarding properties of nicotine. Because alpha4 receptors are present on several cell types in the VTA, it was unclear how nicotine produced pleasurable feelings.

To zero in on the circuit important in the brain's response to nicotine, researchers developed mice with a mutation that left them unable to produce the alpha4 receptor, but only on dopamine brain cells. Mice lacking alpha4 receptors in these cells spent less time looking to obtain nicotine compared with normal mice, suggesting the alpha4 receptors are required for the rewarding effects of nicotine. Nicotine also failed to reduce anxiety-like behaviors in the mutant mice, as it normally does in healthy mice.

"Identification of the type of nicotinic receptors necessary for two key features of nicotine addiction -- reward and anxiety -- may help us better understand the pathway that leads to nicotine dependence, and potential treatment for the one billion cigarette smokers worldwide," McGranahan said. Diseases from tobacco use remain a major killer throughout the world, causing more than 5 million deaths per year.

The findings could guide researchers to a better understanding of the mechanisms of tobacco addiction and assist in the development of new drugs to treat tobacco addiction and provide relief from anxiety disorders, Kenny added.

The research was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse.

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Vitamin D relieves joint, muscle pain for breast cancer patients

ScienceDaily (July 26, 2011) — High-dose vitamin D relieves joint and muscle pain for many breast cancer patients taking estrogen-lowering drugs, according to a new study from Washington University School of Medicine in St. Louis.See Also:Health & MedicineVitaminVitamin DPain ControlOsteoporosisBreast CancerDietary SupplementReferenceCOX-2 inhibitorBreast cancerHysterectomyHormone replacement therapy

The drugs, known as aromatase inhibitors, are commonly prescribed to shrink breast tumors fueled by the hormone estrogen and help prevent cancer recurrence. They are less toxic than chemotherapy, but for many patients, the drugs may cause severe musculoskeletal discomfort, including pain and stiffness in the hands, wrists, knees, hips, lower back, shoulders and feet.

"About half of patients can experience these symptoms," says Antonella L. Rastelli, MD, assistant professor of medicine and first author of the study published online in the journal Breast Cancer Research and Treatment. "We don't know exactly why the pain occurs, but it can be very debilitating -- to the point that patients decide to stop taking aromatase inhibitors."

Because the drugs reduce cancer recurrence, finding a way to help patients stay on them is important for long-term, relapse-free survival, according to Rastelli. Aromatase inhibitors are prescribed to post-menopausal women for at least five years and often longer after a breast cancer diagnosis. There is some evidence that patients who experience the drugs' side effects are less likely to see their cancer return, providing even more incentive to help these patients continue taking them.

It was Rastelli's colleague, Marie E. Taylor, MD, assistant professor of radiation oncology, who first noticed that patients on aromatase inhibitors who experienced this pain found some relief from high doses of vitamin D.

So Rastelli's group recruited 60 patients who reported pain and discomfort associated with anastrozole, one of three FDA-approved aromatase inhibitors. The patients they studied also had low vitamin D levels. Half the group was randomly assigned to receive the recommended daily dose of vitamin D (400 international units) plus a 50,000-unit vitamin D capsule once a week. The other half received the daily dose of 400 units of vitamin D plus a weekly placebo. All subjects received 1,000 milligrams of calcium daily throughout the study.

Patients in the study reported any pain they experienced through three different questionnaires. They were asked to quantify their pain intensity, as well as report how much the pain altered their mood, affected their work and interfered with relationships and daily activities. The results show that patients receiving high-dose vitamin D every week reported significantly less musculoskeletal pain and also were less likely to experience pain that interfered with daily living.

"High-dose vitamin D seems to be really effective in reducing the musculoskeletal pain caused by aromatase inhibitors," Rastelli says. "Patients who get the vitamin D weekly feel better because their pain is reduced and sometimes goes away completely. This makes the drugs much more tolerable. Millions of women worldwide take aromatase inhibitor therapy, and we may have another 'tool' to help them remain on it longer."

Like anastrozole used in this study, the other two FDA-approved aromatase inhibitors, letrozole and exemestane, also cause musculoskeletal pain. Given the similar side effects, Rastelli says patients on these drugs may also benefit from high-dose vitamin D.

The vitamin used in this study is a plant-derived type called vitamin D2. Rastelli says it achieves the best results when given weekly because the body metabolizes it within seven to 10 days. Rastelli and her colleagues did not use high-dose vitamin D3, which remains in the body longer.

"This was a very carefully conducted study, and the placebo control makes the findings quite compelling," says Matthew J. Ellis, MD, PhD, the study's senior author and director of the Breast Cancer Program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. "We should follow up these findings further to determine the most efficacious and safe approach to vitamin D supplementation in our breast cancer patients."

Since vitamin D helps the body absorb calcium, too much of it can cause high levels of calcium in the urine, which may increase the risk of kidney stones. Such possible side effects emphasize the importance of tracking patients' urine calcium levels while taking high-dose vitamin D.

"It's important to monitor the patients, but overall it appears to be very safe," Rastelli says. "Because vitamin D2 is eliminated from the body so quickly, it's very hard to overdose."

In addition to relieving pain, the group wanted to examine whether vitamin D could protect against the bone loss often seen in patients taking aromatase inhibitors. The researchers measured each patient's bone density at the beginning of the study and again after six months.

Perhaps because of its role in calcium absorption, high-dose vitamin D did appear to help maintain bone density at the neck of the femur, the top of the thighbone near the hip joint. Although the result did not reach statistical significance, Rastelli calls the result promising and worth further studies.

"It's great that we have something as simple as vitamin D to help patients alleviate some of this pain," Rastelli says. "It's not toxic -- it doesn't cause major side effects. And if it is actually protecting against bone loss, that's even better."

The study was supported by Astra-Zeneca, which makes the aromatase inhibitor anastrozole under the brand name Arimidex.

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Seeing the wood for the trees: New study shows sheep in tree-ring records

ScienceDaily (July 26, 2011) — Nibbling by herbivores can have a greater impact on the width of tree rings than climate, new research has found. The study, published this week in the British Ecological Society's journal Functional Ecology, could help increase the accuracy of the tree ring record as a way of estimating past climatic conditions.See Also:Plants & AnimalsTreesBotanyNatureEarth & ClimateForestClimateGlobal WarmingReferenceGrowth ringTemperature recordPetrified woodClimate changes of 535 to 536

Many factors in addition to climate are known to affect the tree ring record, including attack from parasites and herbivores, but determining how important these other factors have been in the past is difficult.

Working high in the mountains of southern Norway, midway between Oslo and Bergen, a team from Norway and Scotland fenced off a large area of mountainside and divided it into different sections into each of which a set density of domestic sheep was released every summer.

After nine summers, cross sections of 206 birch trees were taken and tree ring widths were measured. Comparing these with local temperature and the numbers of sheep at the location where the tree was growing allowed the team to disentangle the relationship between temperature and browsing by sheep and the width of tree rings.

According to lead author Dr James Speed of the NTNU Museum of Natural History and Archaeology: "We found tree ring widths were more affected by sheep than the ambient temperature at the site, although temperatures were still visible in the tree ring records. This shows that the density of herbivores affects the tree ring record, at least in places with slow-growing trees."

The impact of large herbivores on tree rings has, until now, been largely unknown, so these findings could help increase the accuracy of the tree ring record as a way of estimating past climatic conditions, says Dr Speed: "Our study highlights that other factors interact with climate to affect tree rings, and that to increase the accuracy of the tree ring record to estimate past climatic conditions, you need to take into account the history of wild and domestic herbivores. The good news is that past densities of herbivores can be estimated from historic records, and from the fossilised remains of spores from fungi that live on dung."

"This study does not mean that using tree rings to infer past climate is flawed as we can still see the effect of temperatures on the rings, and in lowland regions tree rings are less likely to have been affected by herbivores because they can grow out of reach faster," he explains.

Tree rings give us a window into the past, and have been widely used as climate recorders since the early 1900s. The growth rings are visible in tree trunk cross sections, and are formed in seasonal environments as the wood is laid down faster in summer than winter. In years with better growing conditions (in cool locations this usually means warmer) tree rings are wider, and because trees can be very long-lived and wood is easily preserved, for example in bogs and lakes, this allows very long time-series to be established, and climatic conditions to be estimated from the ring widths.

The study was funded by the Norwegian Research Council and the Norwegian Directorate for Nature Management.

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