RESEARCHERS IDENTIFY THE LINK BETWEEN INHERITED DNA SEQUENCES AND HEART DISEASE.

A study to examine recessively inherited genome-wide DNA sequences has for the first time discovered a potential link with Britain’s biggest killer, Coronary Artery Disease (CAD).  The research led by a team from the University of Leicester is the first time that recessively inherited DNA sequences in the whole genome called Runs of homozygosity were examined for a connection to the disease.  The team state the findings show that having more stretches of DNA containing the same version of a gene, one inherited from each parent, is associated with increased heart disease risk.  The opensource study appears in the American Journal of Human Genetics.

Previous studies show that CAD is a terminal clinical manifestation of cardiovascular disease and is the leading cause of death worldwide as well as being the UK’s single biggest killer. Nearly one in six men and one in ten women die from CAD. CAD is a complex, multifactorial disorder originating from a complicated interplay of multiple genetic and environmental factors.

The lab are at the cutting-edge of genetic research to understand the key genes that increase a person’s risk of premature coronary heart disease, which can lead to a sudden heart attack. Earlier studies from the team have found over 40 such genes.

The team explain that Runs of homozygosity are regions of the genome with identical copies inherited from parents and traced back to a common ancestor.  They go on to add that to their knowledge there is no study that has examined whether genome-wide homozygosity levels are a risk factor for CAD and whether Runs of homozygosity might play a role in regulation of gene expression within cells of key importance to atherosclerosis.

Previous to the current study contributions of Runs of homozygosity to the genetic architecture of CAD are not known. Therefore the researchers’ primary goal was a comprehensive analysis of association between genome-wide homozygosity measures and CAD in individuals of white European ancestry. A secondary aim was to explore the association of Runs of homozygosity and gene expression in human monocytes and macrophages.

To investigate this the current study analysed 24,320 individuals from 11 populations of white European ethnicity. This revealed statistically significant differences in homozygosity levels between individuals with CAD and control subjects.  The data findings showed that on average, individuals with CAD had 0.63 Runs of homozygosity more than control subjects. The results also showed that the average total length of Runs of homozygosity was approximately 1046.92 kb greater in individuals with CAD than control subjects.

The current study qualified a measure of genome-wide homozygosity levels in relation to CAD with an estimated 13% increase in CAD per 1 standard deviation increase in the proportion of the autosomal genome covered by Runs of homozygosity.  They go on to add that individual Runs of homozygosity showed significant associations with monocyte and macrophage expression of genes located nearby.

The researchers note that the findings are important because they provide evidence for an excess of Runs of homozygosity as a potential contributor to CAD and therefore support a theory on the role of recessive component in the genetic architecture of CAD.  They also stress that additional work is needed to unravel the exact synergistic role of multiple recessive variants, homozygosity levels and their association to CAD.

The team conclude that research to improve the understanding of how a person’s genes can increase their risk of a heart attack is helping the medical community to find new ways to target the effects of those genes, which could lead to new drugs to prevent these deadly events.

Source:  University of Leicester

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RESEARCHERS DEVELOP WORLD’S MOST SENSITIVE UNIVERSAL DIAGNOSTIC TEST FOR ALL DISEASE.

July 13, 2015

Infectious diseases such as hepatitis C and some of the world’s deadliest superbugs, C. difficileand MRSA among them, could soon be detected much earlier by a unique diagnostic test, designed to easily and quickly identify dangerous pathogens.  Researchers at McMaster University have developed a new way to detect the smallest traces of metabolites, proteins or fragments of DNA. In essence, the new method can pick up any compound that might signal the presence of infectious disease, be it respiratory or gastrointestinal.  The team state that the method allows the medical community to detect targets at levels that are unprecedented. This study is published in the journal Angewandte Chemie International Edition.

The researchers explain that the test has the best sensitivity ever reported for a detection system of this kind, adding that it is as much as 10,000 times more sensitive than other detection systems.  Using sophisticated techniques, the current study developed a molecular device made of DNA that can be switched ‘on’ by a specific molecule of their choice, such as a certain type of disease indicator or DNA molecule representing a genome of a virus, an action that leads to a massive, amplified signal which can be easily spotted.

Another important advantage of the new test, state the team, is that the method does not require complicated equipment so tests can be run at room temperature under ordinary conditions.  They go on to add that this will be the foundation for the medical community to create future diagnostic tests.

The researchers note that this invention will allow the medical community to detect anything they might be interested in, bacterial contamination or perhaps a protein molecule such as a cancer marker. They state that the method can sensitively detect all of them, and it can do so in a relatively short period of time.

For the future the researchers are currently working to move the test onto a paper surface to create a portable point-of-care test, which would completely eliminate the need for lab instruments, allowing users, such as family physicians, or health workers in the field to run the test.

Source:  McMaster’s Biointerfaces Institute

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FECAL MICROBIOTA TRANSPLANTATION IN HUMANS WITH ULCERATIVE COLITIS.

FIRST EVER TRIAL OF FECAL MICROBIOTA TRANSPLANTATION IN HUMANS WITH ULCERATIVE COLITIS SUCCESSFUL.

There is currently great interest in treating ulcerative colitis with fecal microbiota transplantation (FMT), which involves transplanting gut fecal bacteria from healthy people into patients with ulcerative colitis.  Now, two new studies, one animal and the other human, by researchers from McMaster University show that transplantation of fecal matter may be a useful tool in the fight against ulcerative colitis.

Previous studies show that ulcerative colitis is a chronic, debilitating inflammatory bowel condition characterized by symptoms including bloody stools, diarrhea, abdominal pain, weight loss and malnutrition. It results from the development of abnormal immune responses to the normal bacteria in the digestive tract. It is difficult to treat and standard therapy doesn’t always work.

The first new study from the team uses an animal model and is published in the journalInflammatory Bowel Diseases.  The data findings showed that ulcerative colitis can be controlled by the type of bacteria that inhabits the gut. The team state that the animal research provides insight that selected bacterial groups, involved in gut health, are important for protecting the colon against injury and inflammation.

The second new study from the team is a clinical human trial published in the journalGastroenterology.  The team explored the safety and efficacy of FMT by conducting a placebo-controlled, randomized trial. The results showed that FMT induces remission in a significantly greater percentage of patients with active UC than placebo.

The researchers state that to their knowledge the current study in patients with ulcerative colitis is the first randomized trial of fecal microbiota transplantation in adults with ulcerative colitis.  On top of this the data findings also show that this therapy may work.  They go on to add that the effect of fecal transplant seems to be dependent on the sort of bacteria that is in the donor stool, which fits with the observations of the animal study.

In the animal study, mice were given gut bacteria from patients with severe ulcerative colitis and the effects were compared to those produced in mice that were given bacteria from a healthy person. The results identified a reduced amount of the bacterial families that are important for gut health in the feces of patients with severe colitis.

The results showed that when mice were given these bacteria and then exposed to a toxin that causes gut injury, the resulting inflammation was higher in the mice with ulcerative colitis bacteria than in mice with bacteria from the healthy person, in whom the beneficial bacterial groups were abundant.  The data findings also showed that the same protective effect could be achieved using the fecal material from the healthy person as with specific groups of bacteria that were isolated from the ‘healthy’ fecal matter.  The team ssuggest that specific combinations of beneficial bacteria extracted from healthy people could be tested in future clinical fecal transplantation studies, and could potentially replace fecal matter.

The team state that the implications of the animal study relate to the selection of healthy donors for fecal transplantation. The researchers note that in addition to screening for infections and disease, donors that harbour an abundance of the beneficial bacterial groups identified in the animal study could be selected to increase the chances of success of transplantation.

This was validated in the human study which recruited 75 patients with a flare up of their ulcerative colitis.  The patients were randomized to fecal transplant therapy given as an enema derived from stool donated by an anonymous healthy donor once per week for six weeks, or a placebo consisting of a water enema. The results showed that 24 per cent were in remission in the fecal transplant group compared to five per cent in the placebo group.

The researchers note that out of two main healthy donors, donor A and donor B, one of which was the healthy donor from the animal study, the benefit seemed to be mostly related to those that received stool from donor B. The effect was also greater in those that had recently been diagnosed with ulcerative colitis.

The team surmise that many questions remain, however their studies provide interesting data suggesting that altering the gut microbial flora may be promising for treating ulcerative colitis.  They conclude that their data also suggests more research is needed using the FMT approach.

Source:  Farncombe Family Digestive Health Research Institute at McMaster University

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STUDY SUCCESSFULLY TARGETS NERVE ENDINGS TO CURB ALLERGIC ASTHMA IN ANIMAL MODEL.

Current asthma medications, which work by suppressing inflammatory signaling by immune cells or by dilating the airways, can stop working over time. Now, a new study from Boston Children’s Hospital, Brigham and Women’s Hospital, and Harvard Medical School supports a highly innovative approach to controlling asthma; by targeting certain sensory nerve endings in the lungs that help drive allergic inflammation.  The opensource study is published in the journal Neuron.

Previous studies show that nociceptors in the lungs connect to the brainstem and trigger the cough reflex when they detect potential harms like dust particles, chemical irritants or allergens. Nociceptor nerve endings are known to be more plentiful and more readily activated in people with asthma, but a role in driving allergic inflammation had not previously been suspected.  The team state that an attractive aspect of targeting nociceptors is that this approach would be most effective when inflammation is already present and should accelerate its resolution.

The current study shows that nociceptors are not only activated by allergic inflammation, but also exacerbate the allergic immune response. When these neurons were selectively silenced in mouse models of acute and chronic asthma, both inflammation and bronchial twitchiness were reduced.  The researchers explain that current asthma treatments can help to control symptoms and dampen airway inflammation; however, therapies are not available to promote the resolution of asthma.  A treatment to interrupt the vicious cycle of neuro-immune signaling holds promise as a disease-modifying therapy and is mechanistically distinct from any of the currently available asthma therapies.

The researchers tested a strategy for selectively blocking nociceptor activity in mice using a drug called QX-314.  The team explain that QX-314 is chemically related to the local anesthetic lidocaine, modified in such a way that it specifically targets inflammation-activated nociceptors (including those in the lung) and stays inside cells for prolonged periods without getting into the bloodstream. The researchers believe these properties will increase the drug’s duration of action in the lung and limit side effects.

They go on to note that QX-314 is not able to get into nerve cells normally, however it can enter cells by passing through the large pores of TRP-family ion channels, which are expressed selectively in nociceptors and are activated during inflammation.  This limits the action of QX-314 to just the neurons activated by inflammation.  The researchers stress that people have tried to use lidocaine itself to target asthma, however, it works nonspecifically on all neurons, posing a risk of impaired swallowing.  It can also spread to and act on the heart and brain.

In the current study the lab induced asthma in mice by exposing them to dust mites or another allergen, ovalbumin, then administered QX-314 via nebulizer to silence the nociceptors.

The data findings show that when stimulated, nociceptors release chemicals (neuropeptides) that cause immune cells to infiltrate the lungs and become more active.  IL-5, an inflammatory molecule produced by the immune cells, in turn activates the nociceptors to produce a neuropeptide called vasoactive intestinal peptide (VIP).  VIP further stimulates the inflammatory response, creating a neuro-immune feedback loop that inflames the lungs and escalates asthma symptoms.  When asthmatic mice had their nociceptors silenced, either genetically or with QX-314, they had much less airway inflammation and less bronchial twitchiness.

The researchers conclude that nociceptors both react to and drive inflammatory immune responses in the lung, and that silencing these cells interrupts this feedback loop, helping relieve allergic airway inflammation and bronchospasm.

The team are now working on new, more potent versions of QX-314 that would enhance its safety but preserve and even increase its beneficial properties.  They go on to add that they are sufficiently encouraged by the strong relief of lung inflammation and airway constriction to actively embark on a major drug development program, with the aim of clinically testing this strategy for multiple allergic conditions.

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RESEARCHERS IDENTIFY GENE RESPONSIBLE FOR OBESITY AND DIABETES IN OLD AGE.

July 14, 2015

Practically everyone gets fatter as they get older, however, according to a new study from researchers at Duke University some people can blame their genes for the extra padding. The new findings show that two different mutations in a gene called ankyrin-B causes cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity.  The team state that the results, which were generated in mice, could help identify at-risk individuals who might be able to tip the scales back in their favour by eating better and exercising more.  The opensource study is published in the Journal of Clinical Investigation.

Previous studies show that the more severe of the two mutations, called R1788W, is carried by nearly one million Americans. The milder mutation, known as L1622I, is shared by seven percent of the African American population and is about as common as the trait for sickle cell anemia.

The researchers discovered ankyrin-B more than thirty years ago. Earlier studies from the team found that ankyrin-B acts as a kind of protein anchor, tethering important proteins to the inside of the cell’s plasma membrane. Since this initial discovery the lab have implicated defects in ankyrin-B in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.

Diabetes is quickly becoming one of the greatest threats to public health, according to previous studies, as waistlines expand around the world. If the current trends continue, one in three Americans will have diabetes by 2050. Patients with type 1 diabetes do not make enough insulin, the hormone that helps process the glucose that builds up in the bloodstream after a meal. Patients with type 2 diabetes, the form linked to obesity, make insulin but become resistant to its effects.

The team state that this is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle.  They go on to explain that as the obesity epidemic really took off in the 1980’s, when sugary sodas and French fries became popular. They stress that it’s not like humans suddenly changed genetically in 1980, however rather people have carried susceptibility genes that were exacerbated by this new diet. The researchers hypothesize that the findings are just the beginning, and that there are going to be many genes like this.

Several years ago the team found evidence that ankyrin-B mutations might play a role in insulin secretion and metabolism. Since then, several studies have uncovered rare ankyrin-B variants that are associated with type 2 diabetes. One mutation, called R1788W, was more common in Caucasians and Hispanics. Another, called L1622I, was found exclusively in African-Americans, a group known to be at a particularly high risk of diabetes. However, it was still unclear how these changes in the genetic code could set a course for diabetes.

To get at that answer the current study used mouse models which carried these same human genetic variants. The data findings showed that animals with two copies of the R1788W mutation made less insulin than normal mice. The results also showed that despite this shortcoming, their blood glucose levels were normal. The researchers then performed the rodent equivalent of a glucose tolerance test, commonly used to screen for type 2 diabetes in people, to determine how quickly glucose was cleared from the bloodstream in the mutant mice. To their surprise, the mutant mice metabolized glucose more quickly than normal mice.

The lab explain that glucose doesn’t enter cells and tissues all on its own, and instead has to rely on a second molecule, called GLUT4 transporter to gain access. They go on to add that normally GLUT4 hangs out in the cell and when insulin is present it alerts GLUT4 to spring into action to transport glucose into the cell. When insulin goes away the GLUT4 transporters close the channels and return into the middle of the cell.

However,the current study found that this wasn’t the case with the mutant mice. The results showed that the mice had lots of GLUT4 on the surface of their muscle and fat cells even when there wasn’t any insulin around. That meant that glucose could flow in without necessarily having to bother with the doorbell.  The team state that this was an advantage when they were young, because it protected the animals from low insulin levels. However, when the mice got older or switched to a particularly high-fat diet, it made the mice fatter and eventually led them to become insulin resistant.

The researchers believe that long ago, the R1788W mutation, and the milder L1622I mutation, may have provided an evolutionary advantage. They hypothesize that aging hunter-gatherer types, who weren’t as effective at chasing down their next meal, needed to gain as much fat as possible to avoid starvation. Now that high-fat, high-calorie foods are plentiful in much of the world, these variants put people at increased risk for modern afflictions like obesity and diabetes.

The team surmise that if people with these mutations are detected early enough, they become prime candidates for intervention with precision medicine therapies.  They that might involve specific strategies to manage their deficits in insulin secretion, as well as adhering to a normal diet and an active lifestyle, with the hope that they can avoid the metabolic diseases that could severely impair their quality of life.

Next, the researchers would like to explore whether the effects they observed in mice hold true in humans. They plan to genotype people in the general population, identify families with ankyrin mutations, and then perform family histories as well as glucose metabolism tests to assess the consequences of these genetic variants at a cellular level.

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Source:   Duke University School of Medicine 

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UCLA researchers identify new mechanism that delivers glucose to cancer cells

UCLA scientists have identified a new mechanism that delivers a key substance that fuels the growth of pancreatic and prostate cancer cells, a finding that offers new hope in the fight against two of the deadliest forms of the disease.

Cancer cells require high amounts of the sugar glucose to survive and grow, and long-standing research has established passive glucose transporters, known as GLUTS, as the primary method the body uses to deliver glucose to tumors.

UCLA

Ernest Wright

But the results of a three-year study by UCLA researchers, demonstrated that pancreatic and prostate cancer cells also utilize glucose from sodium-dependent glucose transporters known as SGLTs, specifically SGLT2.The findings in the study, which waspublished online today in the journal PNAS, provide the first promising evidence that positron emission tomography (PET) imaging techniques and SGLT2 inhibitors could be used to better diagnose and treat pancreatic and prostate cancers , said Ernest Wright, professor of physiology in the David Geffen School of Medicine at UCLA and lead author of the three-year study.

“This is exciting because it provides strong evidence that SGLT2 inhibitors, such as those currently approved by the FDA to treat diabetes, could potentially block glucose uptake and reduce tumor growth and increase survival in pancreatic and prostate cancers,” said Wright, who is also a member of the UCLA Jonsson Comprehensive Cancer Center.

Wright, Jorge Barrio, Dr. Claudio Scafoglio and colleagues first mapped the distribution of sodium-dependent glucose transporters in human cancer tumors, then measured glucose uptake in fresh tumors using a glucose analog specifically transported by SGLTs. They observed that SGLT2 was present in pancreatic and prostate andenocarcinomas and that it assisted in delivering the glucose that is vital to cancer growth and survival, Wright said.

The team then measured sodium-dependent glucose transporter activity in a mouse cancer model using a radioactive imaging probe for sodium-dependent glucose transporters. This measuring procedure is based on PET imaging techniques pioneered at UCLA. The results confirmed that SGLT2 is actively involved in glucose uptake and the growth of these tumors.

UCLA

Jorge Barrio

Passive glucose transporters serve as the basis for current clinical methods to detect and stage cancer tumors using PET imaging techniques, but this type of imaging is not effective for pancreatic and prostate cancers, Barrio noted.

“The specific radioactive imaging probe we have developed for SGLTs on these tumors holds tremendous promise to diagnose, stage and monitor SGLT-based therapeutic interventions in pancreatic and prostate cancers, and potentially other cancers,” said Barrio, a distinguished professor of molecular and medical pharmacology.

Pancreatic cancer is the fourth-leading cause of cancer-related death in the United States behind only lung, colon and breast cancers, and overall five-year survival rates hover at 7 percent. Prostate cancer, though generally more treatable and with improved survival rates is still the second-leading cause of cancer-related deaths in men.

Wright and Barrio will next begin a clinical study to further investigate the importance of sodium-dependent glucose transporters in glucose delivery. They hope that these findings will lead to the potential use of current Food and Drug Administration-approved SGLT2 inhibitors to reduce the viability of pancreatic and prostate cancer cells and increase patient survival.

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