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News Article | April 27, 2017
Site: www.eurekalert.org

Researchers from the transformation and metastasis group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Eva González-Suárez, have been able to recreate and characterize the process of acquisition of resistance to chemotherapy in orthotopic animal models of breast cancer, unveiling the possibility of reversing this resistance after a period of rest from the treatment. Basic and clinical researchers from IDIBELL and other centers such as VHIO, IDIBAPS and IRB Barcelona have collaborated in the paper, published by Stem Cell Reports. Taxane chemotherapy is one of the most common therapeutic options in breast cancer; however, its effectiveness usually decreases progressively until it reaches a point where the treatment must be modified. Working in animal models, the researchers observed that breast tumors that do not express hormone receptors - called triple negatives -- are more sensitive to taxane chemotherapy than luminal tumors, which are generally more resistant. As seen in clinical practice, after multiple rounds of treatment, triple negative tumors acquired resistance to the drug; this resistance, once present, remained even if the treatment was not supplied. "However, when we kept these models for long periods in absence of the drug, we saw that sensitivity was restored," says Dr. Eva González-Suárez, last author of the study. It is a process known as "drug holidays", that is, sensitive tumors that have developed resistance are able to partially reverse this process after a long period not being in contact with the drug. Based on these results, the main hypothesis researchers are working with is the existence of different cellular populations in the tumor, some more sensitive and some more resistant, whose balance can be modified based on the presence or absence of treatment and its duration. In fact, results show that resistance to taxanes in triple negative tumors is associated with the dynamics of a CD49f+ cell population, which has a greater capacity for tumor initiation and can therefore lead to relapses after chemotherapy. "We wanted to know if those resistant tumor cells that we see in greater proportion in resistant tumors (CD49f+) have appeared de novo or by selection of cell populations", explains Dr. González-Suárez. To do so, they treated sensitive tumors with taxanes and found that these resistant cells already existed in the tumors and their proportion to the sensitive cells increased in the residual disease precisely because of its chemoresistance capacity. "The results suggest that the CD49f+ population is associated with resistance to docetaxel in most of triple negative tumors, which is notorious considering the great heterogeneity of this subtype", adds the IDIBELL researcher. In cancer patients, once resistance develops one treatment is switched to another, so it is not known whether this drug holiday period would work. "Given that breast cancer relapses happen after a long time - about 10-20 years in luminal tumors and 3-5 in the triple negative ones-, perhaps this time window would be enough to return to taxane therapies even when the patient had previously developed resistance to them, especially considering that these therapies are the only treatments currently available for this disease", says the doctor. In order to carry out this work, IDIBELL researchers have developed PDX animal models, also known as ortoxenografts, placing samples of breast cancer patients in immunodepressed mice. "It's not an easy process, and efficiency is very low," says Eva Gonzalez-Suarez. "However, unlike other studies, performed on cell lines or patient samples that are very difficult to obtain, working with PDX models allows for enough paired samples that are sensitive and resistant to a particular drug." These sensitive / resistant paired models have led to the identification, in collaboration with the group of Dr. Aleix Prat in IDIBAPS, of a genetic signature associated with resistance in triple negative disease, that is, in those tumors that do not disappear after treatment with chemotherapy. "This signature can help us predict whether patients will respond to chemotherapy or not in a personalized way," concludes Gonzalez-Suarez.


Hyafil A.,Idibaps
Journal of Neurophysiology | Year: 2017

Cross-frequency phase coupling (PPC) may play an important role in neural processing and cognition. However, a new study unveils a statistical bias in how PPC is detected in neural recordings, questions prior evidence for PPC in hippocampus, and shows PPC tests are dramatically flawed by their confounds with oscillation harmonics. © 2017 the American Physiological Society.


Mattia M.,Instituto Superiore Of Sanita | Sanchez-Vives M.V.,IDIBAPS | Sanchez-Vives M.V.,Catalan Institution for Research and Advanced Studies
Cognitive Neurodynamics | Year: 2012

Rhythms at slow (<1 Hz) frequency of alternating Up and Down states occur during slow-wave sleep states, under deep anaesthesia and in cortical slices of mammals maintained in vitro. Such spontaneous oscillations result from the interplay between network reverberations nonlinearly sustained by a strong synaptic coupling and a fatigue mechanism inhibiting the neurons firing in an activity-dependent manner. Varying pharmacologically the excitability level of brain slices we exploit the network dynamics underlying slow rhythms, uncovering an intrinsic anticorrelation between Up and Down state durations. Besides, a non-monotonic change of Down state duration is also observed, which shrinks the distribution of the accessible frequencies of the slow rhythms. Attractor dynamics with activity-dependent self-inhibition predicts a similar trend even when the system excitability is reduced, because of a stability loss of Up and Down states. Hence, such cortical rhythms tend to display a maximal size of the distribution of Up/Down frequencies, envisaging the location of the system dynamics on a critical boundary of the parameter space. This would be an optimal solution for the system in order to display a wide spectrum of dynamical regimes and timescales. © Springer Science+Business Media B.V. 2012.


News Article | November 14, 2016
Site: globenewswire.com

SAN DIEGO , Nov. 14, 2016 (GLOBE NEWSWIRE) -- Conatus Pharmaceuticals Inc. (NASDAQ:CNAT) announced today the presentation of four posters – two addressing clinical results and two addressing preclinical results with the company’s pan-caspase inhibitor, emricasan – at The Liver Meeting®, the annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston November 11-15, 2016. Poster #2095, “Emricasan (IDN-6556) Orally for 6 Months in Patients with Cirrhosis and Elevated MELD Score Improves Liver Function,” will be presented by Catherine Frenette, M.D., Medical Director of Liver Transplantation at Scripps Clinic, La Jolla, CA, and a principal investigator in the company’s multicenter Phase 2 Liver Cirrhosis clinical trial of emricasan. Poster #2099, “Emricasan (IDN-6556) Orally for 6 Months in Patients with Non-alcoholic Steatohepatitis (NASH) Cirrhosis Decreases the Progression of MELD Score and Improves Liver Function,” also will be presented by Dr. Frenette. “We were highly encouraged by the results from our Phase 2 Liver Cirrhosis trial after the first three months of treatment, which showed improvement using two clinically relevant measures of liver function and prognosis – MELD and Child Pugh scores – in the high baseline MELD score subgroup, and decreased progression using the same two measures in the NASH subgroup regardless of baseline MELD score,” said David T. Hagerty, M.D., Executive Vice President of Clinical Development at Conatus. “The continued directional improvements after six months of treatment support continued development in patients with NASH cirrhosis, and directly inform the design of our upcoming ENCORE-LF trial.” Poster #2097, “The pan caspase inhibitor Emricasan improves the hepatic microcirculatory dysfunction of CCl -cirrhotic rats leading to portal hypertension amelioration and cirrhosis regression,” will be presented by Jordi Gracia-Sancho, Ph.D., Ramón y Cajal Researcher in Biomedicine at Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute & CIBEREHD, Barcelona, Spain. Poster #2098, “Circulating microparticles carry apoptosis markers CK-18 and caspase-3/7 which are reduced by treatment with Emricasan in subjects with chronic liver diseases,” will be presented by Akiko Eguchi, Ph.D., Project Scientist in the Department of Pediatrics, University of California San Diego, La Jolla, CA. “Thanks to the continuing efforts of our independent research collaborators, we continue to expand our understanding of emricasan’s multiple mechanisms of action,” said Alfred P. Spada, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Conatus. “The cirrhotic rat portal hypertension study demonstrated that emricasan improved microvascular dysfunction in the liver and drove related improvements in fibrosis, portal hypertension and liver function. The detailed analysis of serum samples from our hepatic impairment trial showed that subjects with severe hepatic injury have elevated levels of circulating microparticle-encapsulated cCK-18 and active caspase-3/7, and that emricasan can reduce these elevated levels. These results support continued development in patients with NASH cirrhosis.” Both poster #2095 and poster #2097 were accepted as “Presidential Posters of Distinction,” indicating review scores that place them within the top 10 percent of all posters submitted. All four posters will be displayed in Hall C on Level 2 of the Hynes Convention Center in Poster Session IV on Monday, November 14, from 8:00 a.m. to 5:30 p.m. EST, with authors available for discussion at the posters from 12:30 p.m. to 2:00 p.m. EST. Copies of the posters are available in the Data section of the Conatus website at www.conatuspharma.com. About Conatus Pharmaceuticals Conatus is a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease. Conatus is developing its lead compound, emricasan, for the treatment of patients with chronic liver disease. Emricasan is a first-in-class, orally active pan-caspase inhibitor designed to reduce the activity of enzymes that mediate inflammation and apoptosis. Conatus believes that by reducing the activity of these enzymes, emricasan has the potential to interrupt the disease progression across the spectrum of liver disease. For additional information, please visit www.conatuspharma.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward looking statements, including statements regarding:  the Liver Cirrhosis trial results and preclinical results as support for continued development of emricasan in patients with NASH cirrhosis; and emricasan’s potential to reduce caspase activity and interrupt disease progression across the spectrum of liver disease. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including: Conatus’ ability to initiate and successfully complete current and future clinical trials; the risk that the preclinical results may not be predictive of future clinical results; the uncertainty of the U.S. Food and Drug Administration’s and other regulatory agencies’ approval processes and other regulatory requirements; and those risks described in Conatus’ prior press releases and in the periodic reports it files with the Securities and Exchange Commission. The events and circumstances reflected in Conatus’ forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, Conatus does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.


News Article | November 9, 2016
Site: www.sciencedaily.com

Huntington's disease is a neurodegenerative disease that is presently incurable. Scientists around the world are researching its causes and molecular processes in the attempt to find a treatment. The research just published by a group of scientists from the Centre for Genomic Regulation (CRG) led by Eulàlia Martí, in cooperation with researchers from the University of Barcelona (UB) and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), has brought to light new information on the molecular mechanisms that cause Huntington's disease, and defines new pathways to therapy discovery. The results of the study are published in the November issue of the Journal of Clinical Investigation. Eulàlia Martí is the lead author, while Laura Rué and Mónica Bañez are its first authors. Huntington's disease is caused by the excessive repetition of a nucleotide triplet (CAG) in the Huntingtin gene. The number of CAG repetitions varies from person to person. Healthy individuals can have up to 36 repetitions. Nevertheless, as of 36 repetitions, Huntington's disease develops. The direct consequence of this excess of repetitions is the synthesis of a mutated protein-different from what would be obtained without the additional CAG repetitions-which has been considered the main cause of the disease for the past 20 years. "What we have observed in our study is that the mutated fragment acting as a conveyor-the so-called messenger RNA-is key in the pathogenesis," says Dr. Eulàlia Martí, lead author of the research project, together with Xavier Estivill, and acting group leader of the Genes and Disease laboratory at the Centre for Genomic Regulation. "The research on this disease being done by most groups around the world seeking new therapeutic strategies focuses on trying to prevent expression of the mutated protein. Our work suggests that blocking the activity of messenger RNA (the "conveyor"), would be enough to revert the alterations associated with Huntington's disease. We hope this will contribute to improving the strategies in place to find a cure," states the researcher. Going deeper in molecular mechanisms enables progress to future applications This work underscores the importance of rethinking the mechanisms behind illnesses in order to find new treatments. The work of scientists at the CRG has helped explore the molecular mechanisms that cause the disease. Now, their results will contribute to better delimit research efforts towards a cure. As opposed to most other research groups, Eulàlia Martí's team has sought to identify whether the problem resided in the messenger RNA -- which would be the copy responsible for manufacturing the protein -- or in the resulting protein. Prior work indicated that mRNA produced, in addition to defective protein, other damages. This previous work was the starting point for Martí and her fellow researchers, who have finally demonstrated that mRNA has a key role in the pathogenesis of Huntington's chorea. "The research we have just published points to RNA's clear role in Huntington's disease. This information is very important in translational research to take on new treatments," says the researcher. More in-depth studies on these mechanisms are yet to be done. For example, research must explore whether it will be possible to revert the effects of Huntington's disease in patients, just as researchers have demonstrated in mouse models. It also remains to be seen whether the proposal of the CRG researchers can be used in a preventive way, as the disease does not generally appear until after 40 years of age (in humans). Despite the remaining gaps, the published work makes for a key step in knowledge of the mechanisms of this neurodegenerative disease that, as of today, remains incurable.


News Article | November 8, 2016
Site: www.eurekalert.org

Huntington's disease is a neurodegenerative disease that is presently incurable. Scientists around the world are researching its causes and molecular processes in the attempt to find a treatment. The research just published by a group of scientists from the Centre for Genomic Regulation (CRG) led by Eulàlia Martí, in cooperation with researchers from the University of Barcelona (UB) and August Pi i Sunyer Biomedical Research Institute (IDIBAPS), has brought to light new information on the molecular mechanisms that cause Huntington's disease, and defines new pathways to therapy discovery. The results of the study are published in the November issue of the Journal of Clinical Investigation. Eulàlia Martí is the lead author, while Laura Rué and Mónica Bañez are its first authors. Huntington's disease is caused by the excessive repetition of a nucleotide triplet (CAG) in the Huntingtin gene. The number of CAG repetitions varies from person to person. Healthy individuals can have up to 36 repetitions. Nevertheless, as of 36 repetitions, Huntington's disease develops. The direct consequence of this excess of repetitions is the synthesis of a mutated protein-different from what would be obtained without the additional CAG repetitions-which has been considered the main cause of the disease for the past 20 years. "What we have observed in our study is that the mutated fragment acting as a conveyor-the so-called messenger RNA-is key in the pathogenesis," says Dr. Eulàlia Martí, lead author of the research project, together with Xavier Estivill, and acting group leader of the Genes and Disease laboratory at the Centre for Genomic Regulation. "The research on this disease being done by most groups around the world seeking new therapeutic strategies focuses on trying to prevent expression of the mutated protein. Our work suggests that blocking the activity of messenger RNA (the "conveyor"), would be enough to revert the alterations associated with Huntington's disease. We hope this will contribute to improving the strategies in place to find a cure," states the researcher. Going deeper in molecular mechanisms enables progress to future applications This work underscores the importance of rethinking the mechanisms behind illnesses in order to find new treatments. The work of scientists at the CRG has helped explore the molecular mechanisms that cause the disease. Now, their results will contribute to better delimit research efforts towards a cure. As opposed to most other research groups, Eulàlia Martí's team has sought to identify whether the problem resided in the messenger RNA - which would be the copy responsible for manufacturing the protein - or in the resulting protein. Prior work indicated that mRNA produced, in addition to defective protein, other damages. This previous work was the starting point for Martí and her fellow researchers, who have finally demonstrated that mRNA has a key role in the pathogenesis of Huntington's chorea. "The research we have just published points to RNA's clear role in Huntington's disease. This information is very important in translational research to take on new treatments," says the researcher. More in-depth studies on these mechanisms are yet to be done. For example, research must explore whether it will be possible to revert the effects of Huntington's disease in patients, just as researchers have demonstrated in mouse models. It also remains to be seen whether the proposal of the CRG researchers can be used in a preventive way, as the disease does not generally appear until after 40 years of age (in humans). Despite the remaining gaps, the published work makes for a key step in knowledge of the mechanisms of this neurodegenerative disease that, as of today, remains incurable.


News Article | November 28, 2016
Site: www.eurekalert.org

A team of scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), led by Prof. Francisco Sánchez-Madrid, has characterized a cell signal that impedes intercellular communication and could play a central role in biomedical strategies such as gene therapy, vaccine design, and immunotherapy. The study, published today in Nature Communications, characterizes a signal that impedes the secretion of nanovesicles called exosomes. Cells secrete exosomes as a means of intercellular communication; however, certain viruses can use exosomes as "Trojan horses" to facilitate their propagation and entry into neighboring cells. The signal, called ISGylation, has in the past been viewed mainly as an antiviral signal, although some studies show that it can also be activated by other stimuli such as a lack of oxygen, aging, or cancer. "In these situations, the secretion of exosomes, and therefore communication between cells, can be affected by this modification," explains Dr. Carolina Villarroya. The research team is dedicated to decoding the processes that control exosome secretion and exploring potential biomedical applications. As Dr. Sánchez-Madrid explains, "as well as acting as messengers in intercellular communication, exosomes are potential tools for gene therapy, vaccine design, and immunotherapy." Several clinical trials are underway to assess new treatments using this approach. The Nature Communications article describes how an antiviral signal activates the programmed degradation of proteins involved in exosome degradation. According to Villarroya, this signal "marks specific proteins located in endosomes, the place where exosomes are formed. This mark redirects these proteins toward the degradation pathway and impedes exosome secretion." Sánchez-Madrid points out that this newly identified mechanism, through which cells defend themselves against infection by activating the degradation of their own proteins, "could also be exploited by external agents for their propagation." The study was carried out by CNIC-UAM scientists Carolina Villarroya, Francesc Baixauli, Irene Fernández, María Mittelbrunn, Daniel Torralba, and Olga Moreno, in collaboration with Susana Guerra (UAM) and Carles Enrich (IDIBAPS).


News Article | February 15, 2017
Site: www.prweb.com

Voxeleron announced today that it has been awarded a Phase I Small Business Innovation Research (SBIR) grant for $222,991 from the National Institutes of Health’s (NIH) National Center for the Advancement of Translational Sciences (NCATS) to further develop device-independent retinal image analysis software. This grant will significantly expand and enhance Voxeleron’s Orion image analysis software for studying optical coherence tomography (OCT) images of the human retina. This platform will provide the first device-independent and commercially available software that can perform analyses, static or longitudinal, on the thicknesses of the layers of the retina directly associated with photoreceptor and neuronal degeneration. Voxeleron will collaborate with Professor Pablo Villoslada of UCSF/IDIBAPS and Dr. Pearse Keane of Moorfields Eye Hospital to validate the algorithms and ensure clinical utility. “Ocular and neurodegenerative diseases affect millions of Americans each year,” said Daniel Russakoff, Ph.D., Voxeleron’s co-founder and the principal investigator of this grant. “There is a dire need for advanced, device-independent tools for ophthalmic OCT analysis - a need we will address directly with this award.” This technology is poised to facilitate the development of new and robust clinical biomarkers for the diagnosis and monitoring of diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, Alzheimer’s, Parkinson’s, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). By validating segmentation algorithms across devices and time this work is poised to accelerate the pace of discovery and understanding for both ocular and neurodegenerative diseases. Pearse Keane, MD, FRCOphth, is an NIHR clinician scientist at the Institute of Ophthalmology, UCL, and an honorary consultant ophthalmologist at Moorfields Eye Hospital. Professor Pablo Villoslada is an adjunct professor at UCSF and the Director of the Visual Pathway Lab at IDIBAPS in Barcelona. About Voxeleron Voxeleron LLC is based in Pleasanton, CA, and was co-founded in 2010 by Daniel Russakoff and Jonathan Oakley to develop state-of-the-art software in the field of computer vision and machine learning. Voxeleron’s mission is to be the leader in delivering advanced image analysis solutions for applications in medicine, biology, and beyond. For more information, please contact Voxeleron at contact(at)voxeleron(dot)com.


Ruiz-Mejias M.,IDIBAPS | Ciria-Suarez L.,IDIBAPS | Mattia M.,Instituto Superiore Of Sanita | Sanchez-Vives M.V.,IDIBAPS | Sanchez-Vives M.V.,Catalan Institution for Research and Advanced Studies
Journal of Neurophysiology | Year: 2011

A characterization of the oscillatory activity in the cerebral cortex of the mouse was realized under ketamine anesthesia. Bilateral recordings were obtained from deep layers of primary visual, somatosensory, motor, and medial prefrontal cortex. A slow oscillatory activity consisting of up and down states was detected, the average frequency being 0.97 Hz in all areas. Different parameters of the oscillation were estimated across cortical areas, including duration of up and down states and their variability, speed of state transitions, and population firing rate. Similar values were obtained for all areas except for prefrontal cortex, which showed significant faster down-to-up state transitions, higher firing rate during up states, and more regular cycles. The wave propagation patterns in the anteroposterior axis in motor cortex and the mediolateral axis in visual cortex were studied with multielectrode recordings, yielding speed values between 8 and 93 mm/s. The firing of single units was analyzed with respect to the population activity. The most common pattern was that of neurons firing in >90% of the up states with 1-6 spikes. Finally, fast rhythms (beta, low gamma, and high gamma) were analyzed, all of them showing significantly larger power during up states than in down states. Prefrontal cortex exhibited significantly larger power in both beta and gamma bands (up to 1 order of magnitude larger in the case of high gamma) than the rest of the cortical areas. This study allows us to carry out interareal comparisons and provides a baseline to compare against cortical emerging activity from genetically altered animals. © 2011 the American Physiological Society.


Esposito K.,The Second University of Naples | Maiorino M.I.,The Second University of Naples | Ceriello A.,IDIBAPS | Giugliano D.,The Second University of Naples
Diabetes Research and Clinical Practice | Year: 2010

We conducted a systematic review of the available studies that assessed the effect of a Mediterranean diet in type 2 diabetes. We searched publications up to 30 November 2009. Seventeen studies were included. Two large prospective studies report a substantially lower risk (83% and 35%, respectively) of type 2 diabetes in healthy people or in post-infarct patients with the highest adherence to a Mediterranean diet. Five randomized controlled trials have evaluated the effects of a Mediterranean diet, as compared with other commonly used diets, on indices of glycaemic control in subjects with type 2 diabetes. Improvement of fasting glucose and HbA1c levels was greater with a Mediterranean diet and ranged from 7 to 40. mg/dl for fasting glucose, and from 0.1 to 0.6% for HbA1c. No trial reported worsening of glycaemic control with a Mediterranean diet. Two controlled trials in a secondary prevention setting demonstrated that post-infarct patients, including diabetic patients, had cardiovascular benefits from a Mediterranean diet. The evidence so far accumulated suggests that adopting a Mediterranean diet may help prevent type 2 diabetes, and also improve glycaemic control and cardiovascular risk in persons with established diabetes. © 2010 Elsevier Ireland Ltd.

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