Team finds a new way to inhibit blood clotting and inflammation

Scientists have identified a group of small molecules that interfere with the activity of a compound that initiates multiple steps in blood clotting, including those that lead to the obstruction of veins or arteries, a condition called thrombosis. Blocking the activity of this compound, polyphosphate, could treat thrombosis with fewer bleeding side effects than the drugs that are currently on the market.
Their findings appear in the journal Blood.
Blood clots are formed at the site of an injured blood vessel to prevent blood loss. Sometimes, however, blood clots completely clog an artery or vein and the surrounding tissues are damaged. The U.S. Centers for Disease Control and Prevention reports that annually, 300,000 to 600,000 Americans are afflicted with deep vein thrombosis or pulmonary embolism, a blocked lung artery that often results from thrombosis, and 60,000 to 100,000 people die each year as a result of these conditions.There are two pathways that trigger blood clotting. The tissue factor pathway helps stop bleeding if a person is injured. If any of the proteins of this pathway are missing, a bleeding problem will develop. In contrast, the contact pathway is activated when blood comes into contact with some artificial substances. Although this pathway can cause pathological blood clots, humans who lack proteins in this pathway do not have bleeding problems. These two pathways eventually converge to form a common pathway.
In 2006, the researchers found that compounds called polyphosphates can, when released from cell fragments called platelets, activate the contact pathway, said University of Illinois biochemistry professor James H. Morrissey, who led that study and the new analysis.
Because the contact pathway is not essential for normal blood clotting after an injury, interrupting polyphosphate “wouldn’t have the bleeding side effects that touching anything downstream of it in the clotting cascade (would) have,” Morrissey said.
The researchers found a variety of positively charged molecules that can bind to the negatively charged polyphosphate molecule and inhibit its ability to induce blood clotting. By adding these compounds to human blood and plasma isolated from the body, Morrissey and his colleagues were able to measure their effectiveness in inhibiting polyphosphate’s pro-thrombotic and pro-inflammatory activities.
The researchers also tested these inhibitors in mice that were afflicted with venous and arterial thrombosis or inflammation, and found that these inhibitors prevented or reduced these negative effects.
“What this shows is that you could put really potent inhibitors of polyphosphate in and interrupt the clotting system by decreasing thrombotic risk, but probably not increasing (a person’s) bleeding risk,” Morrissey said. “This is the proof of principle that it works.”
Although the compounds identified would not, by themselves, be good drug candidates, Morrissey said, the new study offers clues for developing more suitable drugs to target polyphosphates.
“I think that the work going forward would be to identify compounds that would be better drug candidates,” he said.
The study team also included researchers from the Medical College of Wisconsin. The National Heart, Lung and Blood Institute at the National Institutes of Health supported this research.
Source:Journal Blood

Cannabis Users At High Risk Of Developing Schizophrenia

Use of cannabis can cause a temporary cognitive breakdown among non-psychotic individuals, leading to long-term psychosis, according to researchers. In an fMRI study, researchers found a different brain activity pattern in schizophrenia patients with previous cannabis use than in schizophrenic patients without prior cannabis use.
 The results reinforce the researchers' model where cannabis users suffering from schizophrenia actually may have higher cognitive abilities than non-cannabis using schizophrenics. This difference may indicate that the cannabis-user group did not have the same mental propensity for psychosis. 
"While brain activity for both groups was similar, there are subtle differences between schizophrenia sufferers with a history of cannabis use and those who have never used cannabis. These differences lead us to believe that the cognitive weakness leading to schizophrenia is imitated by the effects of cannabis in otherwise non-psychotic people," explained Else-Marie Loeberg, lead author on the article and associate professor of Psychology at the University of Bergen, Norway. 
The 26 patients involved in the study attempted difficult cognitive tasks while in the fMRI machine. They were asked to listen to different syllables in each ear and try to say which syllable was spoken when instructed to concentrate on either the left or right ear-a difficult task for anyone but particularly difficult for schizophrenia patients who often have impaired attention, limited executive functioning and difficulty in processing verbal cues. 
The study showed that schizophrenia sufferers with previous cannabis use had consistently higher levels of brain activity while undergoing these tests as well as a higher number of correct answers. 
These results are in line with previous conclusions from the Bergen researchers who support the idea that cannabis users with schizophrenic characteristics do not appear to suffer from the same neuro-cognitive weaknesses as other patients with schizophrenia. 
This implies that it is the cannabis use itself that leads otherwise non-psychotic individuals down the nightmarish path towards schizophrenia by imitating the cognitive weakness that is the main risk factor for developing the psychological condition. 
They published their finding this week in Frontiers in Psychiatry.
Source-ANI

 

1000 Genomes Study Sheds Light on How Genes Vary

Researchers can now interpret the genetic changes in people with disease thanks to a landmark project that has sequenced 1,092 human genomes from individuals around the world. The first study to break the '1000 genomes barrier' will enable scientists to begin to examine genetic variations at the scale of the populations of individual countries, as well as guiding them in their search for the rare genetic variations related to many diseases.The vast majority of genetic variation is shared with populations around the world but it is thought that a lot of the contribution to disease may come from rare variants of genes, found in 1 in 100 people or fewer. Researchers need to find these rare variants to see who has them and work out how they might contribute to a range of conditions from multiple sclerosis to heart disease and cancer. 
The international team behind the 1000 Genomes Project found that rare gene variants tend to be restricted to particular geographic regions, because they typically arise from more recent mutations since humans spread across the world. By, for the first time, drilling down to genetic variants occurring at the scale of 1 in 100 people this study will enable researchers to interpret an individual's genome in the context of the genetic variation found in their own national population: identifying differences between genomes from 14 countries from Europe (including the UK) the Americas, East Asia and Africa. 
A report of the research is published this week in the journal Nature. 
'We are all walking natural experiments; some of our genes are switched off, some are active, whilst others are overactive,' said Professor Gil McVean of Oxford University, the lead author for the study. 'Our research has found that each apparently healthy person carries hundreds of rare variants of genes that have a significant impact on how genes work, and a handful (from two to five) of rare changes that have been identified as contributing to disease in other people. 
The study has been designed so that, as well as the genome data, researchers have access to living cells (cell lines) from all 1,092 of the individuals whose genomes have been sequenced. Scientists can now study how differences in the biology of these cells correlate with genetic differences. 
'There are variations that jump out from the data as looking 'a bit bad for you', for example mutations in regions that regulate genes are likely to be 'bad news' – possibly doing something dramatic to how cells behave,' said Dr Richard Durbin from the Wellcome Trust Sanger Institute, co-chair of the 1000 Genomes Project. 'Using our data you can now look to see if natural selection has been getting rid of such mutations – giving you a clue as to how harmful these variants might be.' 
The team's work is already being used to screen cancer genomes for mutations that might identify therapeutic pathways, to interpret the genomes of children with developmental disorders and to pin-point variation that leads to increased risk for complex diseases such as heart disease or multiple sclerosis. 
Professor Gil McVean of Oxford University said: 'Our research shows that you can take localism much further: for example, even just within the UK, Orkney islanders will have different variations from mainlanders, and will be different again from those from other nearby islands. In the future we would like to reach the scale of having a grid of individuals giving us a different genome every couple of square kilometres but there is a long way to go before we can make this a reality.' 
Sir Mark Walport, Director of the Wellcome Trust who part-funded the study, said: 'It is quite remarkable that we have gone from completion of the first human genome sequence in 2003 to being able to sequence more than a 1000 human genomes for a single study in 2012. This study is an important contribution to our understanding of human genetic variation in health and disease and the DNA sequences are freely available for analysis and use by researchers.' 
Source:Journal Nature
 
 

First gene therapy study in human salivary gland shows promise

Treatment proves safe and effective, helps cancer survivors with chronic dry mouth

Gene therapy can be performed safely in the human salivary gland, according to scientists at the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health.
This finding comes from the first-ever safety, or Phase I, clinical study of gene therapy in a human salivary gland. Its results, published this week in the Proceedings of the National Academy of Sciences, also show that the transferred gene, Aquaporin-1, has great potential to help head and neck cancer survivors who battle with chronic dry mouth. Aquaporin-1 encodes a protein that naturally forms pore-like water channels in the membranes of cells to help move fluid, such as occurs when salivary gland cells secrete saliva into the mouth.
These initial results clear the way for additional gene therapy studies in the salivary glands. Although sometimes overlooked, salivary glands present an ideal target for gene therapy. They are easily accessible and, once a gene is introduced, it has no obvious escape route into the bloodstream, where it can have unintended consequences.
"You cannot imagine how fulfilling it is to jot down an idea on a napkin in 1991 and then see it enter a clinical trial and help people.," said Bruce Baum, D.M.D., Ph.D., lead author on the study and recently retired NIDCR scientist who spent the last 21 years moving gene therapy in the salivary glands from the research bench to the clinic. "Can a scientist ask for anything better?"
Baum's interest in helping head and neck cancer survivors dates to the early 1980s. While attending to patients in the NIDCR's Dry Mouth Clinic, Baum encountered numerous people with head and neck cancer who had received radiation therapy to shrink their tumors. The radiation, while effective in treating cancer, had inadvertently damaged nearby salivary glands, compromising their ability to secrete saliva into the mouth.
Baum said he was thoroughly frustrated at the time because he had no effective moisture-restoring treatments to offer most patients. They had beaten cancer, but the radiation had left them with a permanent parched sensation in their mouths that diminished their quality of life and often led to chronic oral problems, such as difficulty swallowing, inflammation, infection, bad breath, and pain.
In the early 1990s, as the first gene-therapy studies entered research clinics, Baum saw an opportunity to make a difference. An initial napkin sketch of the procedure and 15 years of research later, Baum and his colleagues had assembled a compelling scientific case in animal studies that the transferred Aquaporin-1 gene, once expressed, will create new water channels in the impermeable salivary gland cells and allow water to flow through them. After rigorous reviews by NIH and the U. S. Food and Drug Administration, the Phase I protocol was launched and the first patients treated in 2008.
The scientists gave 11 head and neck cancer survivors a single-dose injection of the Aquaporin-1 gene directly into one of their two parotid salivary glands, the largest of the major salivary glands. The gene was packaged in a disabled, non-replicating adenovirus, the cause of the common cold when intact but incapable of causing a cold in this case. As is standard in gene therapy studies, the virus served as the vector, or Trojan horse, to deliver the gene into the cells lining the salivary gland.
The scientists found that five participants had increased levels of saliva secretion, as well as a renewed sense of moisture and lubrication in their mouths, within the study's first 42 days, the period covered in this report. Of the six who didn't benefit from gene therapy, none had serious side effects. The most common side effect was a transient and relatively minor immune response against the disabled adenovirus.
"It is time to evaluate a different vector to deliver the Aquaporin-1 gene, one that will cause only a minimal immune response," said Baum. "But these data will serve as stepping stones for other scientists to improve on this first attempt in the years ahead. The future for applications of gene therapy in the salivary gland is bright. "

Source:NIH/National Institute of Dental and Craniofacial Research 

Inhibition of enzyme NOX4 prevents liver fibrosis

Researchers at the Bellvitge Biomedical Research Institute (IDIBELL) have led a study published in PLoS One showing that the inhibition of a family member of NADPH oxidase enzyme, NOX4, plays an important role in liver fibrosis.

The researchers studied the function of a cytokine called transforming growth factor-beta (TGF-beta) in the pathophysiology of the liver, which is one of the main research lines of the Biological Clues of the Invasive and Metastatic Phenotype research group at the IDIBELL, leaded by Isabel Fabregat.

 This paper is related with the processes of liver fibrosis, an illness caused by the overproduction of extracellular matrix proteins in the liver tissue. During fibrosis, levels of TGF-beta are increased, and there is an activation of the extracellular matrix producing the activation of protecting cells of the extracellular matrix and other possible events leading to the death of hepatocytes.

 Two sides

 The TGF-beta is a complex cytokine. It is a prominent tumor suppressor in early stages of tumor formation, but, in advanced stages, the cells adapt to escape from the growth inhibitory signals and, under these conditions, the TGF-beta is able to potentiate tumor progression contributing to metastasis.

 The study published in PLoS One is a collaboration between IDIBELL and the research group of Wolfgang Mikulits, coauthor of the study, at the Cancer Research Institute of the Medical University of Vienna (Austria), that have provided cellular and animal models. The analysis in patient samples has been possible thanks to the collaboration with the University Hospital Alcorcon Foundation and the Complutense University of Madrid.

 The aim of the study was to analyze routes below TGF-beta, i.e. the cytokine-induced pathways that may be responsible for the process leading to the occurrence of fibrosis, cell activation and production of extracellular matrix and the hepatocytes death.

 Previous studies have demonstrated in vitro and in vivo that it would be possible to inhibit the TGF-beta to reduce fibrosis. However, the TGF-beta is a tumor suppressor. Giving an anti-TGF-beta to people who are undergoing a process of liver fibrosis is a risk factor to eliminate a potential tumor suppressor, "and this is very important in the process of fibrosis, which can induce a chronic damage to the liver and it can lead to liver carcinoma. Therefore, in this situation, the administration of a drug that is an inhibitor of a suppressor factor may contribute to increase the probability of develop tumors", explained Dr. Fabregat.

 Several laboratories are studying the routes below the TGF-beta that mediate the fibrotic process to maintain other processes induced by TGF-beta to inhibit the tumor formation. The research group has demonstrated that a family member of the enzymes involved in oxidation, the NOX4, which acts in the TGF-beta pathway, plays an important role in fibrosis in both in vivo in fibrotic experimental models mouse, and in vitro with culture cells. "Cancelling NOX4 prevents both activation of extracellular matrix producing cells and hepatocyte death", concluded the IDIBELL researcher.

 Medical Applications

 The study also shows that NOX4 levels are very high in samples from patients at different stages of fibrosis caused by infection with hepatitis C virus. Currently there are some NOX4 inhibitors drugs, so the study indicates its clinical potential and explains how they might act if they are used as a treatment in patients with hepatic fibrosis.

 Article reference

 Sancho P, Mainez J, Crosas-Molist E, Roncero C, Fernández-Rodriguez CM, Pinedo F, Huber H, Eferl R, Mikulits W, Fabregat I.NADPH Oxidase NOX4 Mediates Stellate Cell Activation and Hepatocyte Cell Death during Liver Fibrosis Development. PLoS One. 2012; 7(9):e45285. doi: 10.1371/journal.pone.0045285. Epub 2012 Sep 26.

HIV and AIDS Prevention—Progress and the Challenges Ahead

At least 2 million people worldwide will be infected with HIV this year, driving the need for better HIV prevention strategies to slow the global pandemic. A better understanding of how to prevent HIV transmission using antiviral drugs led to approval of the first oral pill for HIV prevention, and microbicides delivered as topical gels or via intravaginal rings are in clinical testing and have yielded both positive and negative results. The complex factors involved in the sexual transmission of HIV, the urgent need for new preventive approaches, and the most promising methods currently in development are examined in a special issue of AIDS Research and Human Retroviruses, a peer-reviewed journal published by Mary Ann Liebert, Inc, publishers. The entire issue is available free on the AIDS Research and Human Retroviruses website.Guest Editor Patrick Kiser, University of Utah, Salt Lake City, and coauthors Pedro Mesquita andBetsy Herold, Albert Einstein College of Medicine, New York, NY, provide an overview of the scientific and developmental gaps in the field of drug discovery, formulation, and delivery to prevent sexual transmission of HIV. In the article "A Perspective on Progress and Gaps in HIV Prevention Science," they review the prophylactic agents in development and their advantages and limitations, and they present recommendations for future research directions. "The advances we are seeing today are exciting and justify a continued focus on the science and technologies that can make a difference in this public health crisis," says Dr. Kiser.Peter Anton and coauthors, David Geffen School of Medicine at UCLA and the School of Public Health (Los Angeles, CA), University of Pittsburgh and Medical School (PA), University of North Carolina, Chapel Hill, Johns Hopkins University School of Medicine (Baltimore, MD), Alpha StatConsult (Damascus, MD), Columbia University (New York, NY), and CONRAD (Arlington, VA), compared the oral and topical administration of the microbicide tenofovir, given as a pill or rectal gel. A mucosal tissue sample was removed from each participant and exposed to HIV to assess if treatment prevented infection. While the patients preferred the oral drug, one-time rectal exposure to the microbicide led to 6-10 times greater drug concentrations in the sampled tissue, and this correlates with reduced infectibility.The methods and materials used to administer microbicidal drugs can affect whether or not they will be effective. Meropi Aravantinou et al. (Population Council and Rockefeller University, New York, NY; Tulane University, Covington, LA; National Cancer Institute, Frederick, MD) demonstrate this in the article "The Nonnucleoside Reverse Transcription Inhibitor MIV-160 Delivered from an Intravaginal Ring, But Not from a Carrageenan Gel, Protects Against Simian/Human Immunodeficiency Virus-RT Infection."Line Vibholm and colleagues from Aarhus University and Aarhus University Hospital, Denmark, present the results of a study designed to evaluate in a female mouse model the effects of a topical gel containing 1% tenofovir, a microbicide previously shown to reduce substantially the transmission of both HIV and herpes simplex virus (HSV). In "Antiviral and Immunological Effects of Tenofovir Microbicide in Vaginal Herpes Simplex Virus 2 Infection," the authors provide data to support the suitability of this model for testing future microbicidal drug candidates.“It is currently an exciting time in HIV prevention science research, with progress on multiple fronts," says Thomas Hope, PhD, Editor-in-Chief of AIDS Research and Human Retroviruses and Professor of Cell and Molecular Biology at the Feinberg School of Medicine, Northwestern University, Chicago, IL. "We are proud to feature this work in the special issue and, in the future, to report critical advances to bring the field closer to the goal of decreasing the rate of HIV transmission around the world.”

Source:AIDS Research and Human Retroviruses Journal is published monthly in print and online. It contains papers, reviews, and case studies documenting the latest developments and research advances in the molecular biology of HIV and SIV and innovative approaches to HIV vaccine and therapeutic drug research, including the development of antiretroviral agents and immune-restorative therapies. The content also explores the molecular and cellular basis of HIV pathogenesis and HIV/HTLV epidemiology. The Journal features rapid publication of emerging sequence information and reports on clinical trials of emerging HIV therapies. Tables of content and a sample issue may be viewed on the AIDS Research and Human Retroviruses website.

How Full We Feel by Eating a Food Item can be Influenced by Altering Its Flavor and Texture

Manipulating the texture and flavor of the food could make us believe that it is filling, regardless of the amount of calories present, according to a new study published in the journal Flavor.
New research published in BioMed Central's open access journal Flavour shows that subtle manipulations of texture and creamy flavour can increase the expectation that a fruit yoghurt drink will be filling and suppress hunger regardless of actual calorific content.There is a currently a debate about satiety, how full low calorie foods and drinks make people feel and for how long, and whether or not they actually make people eat or drink more because the body is expecting more calories than are actually provided. Researchers from the University of Sussex designed an experiment to first see whether or not adding a thickening agent (tara gum) increased the sensation of thickness, stickiness and creaminess of a yoghurt drink, and then looked at how these affected expected fullness and expected satiety.The results showed that even people who are not trained in food tasting were able to accurately pick up subtle differences in drink texture even though the taste remained the same. In the second phase of the experiment subjects rated how filling they expected a drink to be by selecting a portion of pasta that they thought would have the same effect on their hunger as drinking a bottle of yoghurt. On average the thick drinks and the creamy drinks were expected to be more filling than the thin or non-creamy versions, and enhancing the creamy flavour of a thick drink further increased expected fullness. However their contributions to expected satiety were not equal - only thickness (and not creaminess) had an effect on the expectation that a drink would suppress hunger over time.Keri McCrickerd, who led this study, explained, "Hunger and fullness are complicated issues because it is not just the calories in a food or drink that make it filling. Signals from the stomach are important but so too is how the drink feels in the mouth. In our study both creamy flavour and texture affected expected fullness, but only thickness seemed to affect whether hunger was expected to be satisfied. This may be because thick texture is a characteristic of food that we associate with being full. Consumer expectations are important and our study shows that consumers are sensitive to subtle changes in oral sensory characteristics of a drink, and that thick texture and creamy flavour can be manipulated to enhance expectations of fullness and satiety regardless of calories." 
 Source: journal Flavour s