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News Article | May 3, 2017
Site: phys.org

The cover image of the MCB journal. Credit: IDIBELL Researchers from the Cell death group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Cristina Muñoz-Pinedo, have characterized the cell death process due to starvation, in which the endoplasmic reticulum plays a leading role. Their work, chosen as the cover of the latest Molecular and Cellular Biology journal, was carried out within TRAIN-ERs, a European collaborative action that studies diseases associated with this cellular organelle. "Usually, programmed cell death—also called apoptosis—follows a biochemical pathway related to the permeabilization of mitochondria; However, we observed that in cases of cell death due to lack of glucose, cells die in an unexpected way, following a process similar to what we would expect from an immune response", explains Dr. Cristina Muñoz-Pinedo, last author of the study. In cell-death-related treatments such as chemotherapy, the mitochondrial pathway is activated. Instead, when starved, cells activate the so-called "death receptors" on their membrane, which are normally used by the lymphocytes of the immune system to attack and destroy infected cells. IDIBELL researchers have been able to relate the activation of these membrane receptors to the endoplasmic reticulum, a cellular organelle involved in protein synthesis and lipid metabolism, as well as intracellular transport. "Feeling the stress produced by the lack of nutrients, the reticulum send an alarm signal that triggers the appearance of death receptors in the membrane", says Dr. Muñoz-Pinedo. "According to our in vitro results, we assume that this is how the tumor cells located in the center of a tumor—the so-called necrotic core—die, because there are never enough nutrients in those areas", adds the IDIBELL researcher. "On the other hand, in ischemia, besides the lack of oxygen there is also cell death due to lack of glucose, so this process could also be related to the activity of the endoplasmic reticulum at a biochemical level". More information: Raffaella Iurlaro et al, Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors, Molecular and Cellular Biology (2017). DOI: 10.1128/MCB.00479-16


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.


News Article | December 20, 2016
Site: www.eurekalert.org

Researchers of the TGF-beta and Cancer group of Bellvitge Biomedical Research Institute (IDIBELL), in collaboration with King's College London, have unveiled the role of NADPH oxidase NOX4 as an inhibitor of the epithelial-amoeboid transition, a process that contributes to the migration and invasion of tumor cells. The study has just been published in the journal Oncogene. In previous studies, the researchers suggested that NOX4 acts as a tumor suppressor in the liver, through inhibiting cell proliferation. "In this work, we proved that NOX4 also is an important inhibitor of the invasion and metastasis of liver tumor cells," explains Dr. Isabel Fabregat, leader of the IDIBELL research group. In vitro studies indicate that NOX4 silencing in liver tumor cells induces a migratory movement known as amoeboid. The amoeboid movement, related to cell contractility, is regulated by the Rho family of proteins; increased expression of these proteins results in this type of movement, associated with aggressive metastases. In the study in hepatocellular carcinoma patients, it was observed that a significant number of cases present NOX4 deletions; in addition, those patients with a low expression of NOX4 and a high expression of Rho proteins had a much worse prognosis. "This gives to our in vitro study a translational relevance, since it brings forward new prognostic biomarkers for this type of cancer", the IDIBELL researcher comments. NOX4 is regulated at the transcriptional level by the TGF-beta cytokine, which has been studied by the research group for more than 15 years. It is known that TGF-beta acts as a tumor suppressor in early stages, but it becomes an inductor in late ones. According to previous studies of the group, when the expression level of NOX4 is high, TGF-beta behaves like a suppressor so the use of drugs inhibiting TGF-beta would be counterproductive. The present study suggests that when the expression levels of NOX4 are low and those of Rho proteins are high, patients could be ideal candidates for this type of drug. "Thus, low expression of NOX4 could not only be used as a marker of poor prognosis but also as a marker for the use of TGF-beta inhibitory drugs," concludes Dr. Fabregat. The work, whose main author is Eva Crosas-Molist, was co-directed by Victoria Sanz Moreno, from King's College, and Isabel Fabregat from IDIBELL. These findings have redirected the research line of the IDIBELL group, which will now focus on in-depth study of the molecular mechanisms regulated by NOX4 in liver cancer.


News Article | February 16, 2017
Site: www.eurekalert.org

Researchers of the Cancer Virotherapy Research Group of Bellvitge Biomedicine Research Institute (IDIBELL), led by Dr. Ramon Alemany, have developed an oncolytic virus capable of redirecting the patient's immune system against their tumor cells. Their work, published in the Cancer Research journal, may lead to the development of new therapeutic strategies for several types of cancer. "We work with oncolytic adenoviruses, viruses that are modified to exclusively attack cancer cells without attacking normal tissue, like a targeted therapy", explains Carlos Fajardo, lead author of the study. Adenoviruses are a family of viruses that can cause colds, conjunctivitis or gastroenteritis. However, these viruses, once modified to acquire selectivity towards tumor cells, have great potential to be used as cancer therapy. There are several limitations in this field; one of them is our own immune system, which recognizes the virus as a pathogen and therefore attacks it. "What we are trying to do is redirect the immune system to attack the cancer cells instead of the virus. In this way, we not only prevent the virus from being eliminated from the organism too soon, but complement its action by adding that of T lymphocytes", says Fajardo. To achieve this, the researchers used the newly developed BiTE antibodies (bispecific T-cell engager antibodies). These antibodies are capable of specifically connecting T lymphocytes with some proteins expressed on the surface of cancer cells; this connection activates the T cell, which then attacks and destroys the tumor cell. "We modified the virus so that when it infects the tumor cell, it secretes a specific BiTE against the EGFR protein, which is overexpressed in many types of cancer". In in vitro studies, the research team found that these BiTEs were able to capture the T lymphocytes present in the medium to attack adjacent cancer cells. In addition, mouse studies demonstrated that the virus armed with BiTE were able to increase the presence of T lymphocytes in tumors, resulting in improved antitumor efficacy. At the moment virotherapy in cancer is a very active field in research thanks to the advances in immunotherapy developed in recent years. "With these results, we will try to attract the interest of the companies that develop BiTEs to establish collaboration agreements for the clinical development of viruses armed with BiTEs," added Dr. Alemany, the last author of the study. "We are also exploring the development of viruses that target T lymphocytes against tumor stroma fibroblasts to eliminate them".


News Article | December 1, 2016
Site: www.eurekalert.org

Researchers of the Sarcoma research group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Òscar Martínez-Tirado, have first described the methylation profile of Ewing's sarcoma (ES), a cancer of bone and soft tissues that mainly affects children and teenagers. Their analysis has unveiled the potential of the PTRF gene as a prognostic marker of the disease and as a possible future therapeutic target in conjunction with the new genomic editing tools available. "This is the first time that the methylation profile of Ewing's sarcoma has been described," explains Dr. Òscar Martínez-Tirado, lead author of the study. DNA methylation is a type of epigenetic modification capable of controlling gene expression, that is, it can activate or deactivate genes that enhance to or block characteristics and processes in individuals, including the development of tumors. Using bioinformatic tools, the research team looked for common elements that allowed them to relate the set of differentially hypomethylated or hypermethylated genes they found in the tumor samples. The researchers identified a group of 12 genes related to the structure of the cell membrane; Among them, the precursor of the protein PTRF particularly called their attention by its relation with the caveolae, small invaginations that are present in the membrane of some cells; the IDIBELL group has extensive experience in the study of these structures and their relationship with ES. The team correlated the presence of PTRF in samples from 67 patients. "Initially, we saw that those patients who express PTRF have a better survival, therefore, we could consider this protein as a potential marker of prognosis of the disease," concludes Martinez-Tirado. Normal cells with caveolae express both the PTRF protein and caveolin-1 (CAV1), another protein related to caveolae formation. In contrast, tumor cells in ES do not have caveolae, nor express PTRF. "This made us think about the possibility of exogenously reintroducing the precursor gene PTRF into the study cell lines", explains the researcher. "In those that also expressed CAV1, the reintroduction of PTRF triggered caveolae formation. For tumor cells, this modification of the structure is so stressful that it destroys them". In addition, researchers have shown that the formation of the caveolae in these cells activates a known cell death signaling pathway promoted by the p53 protein. Current epigenetic drugs are rather nonspecific, but new CRISPR genomic editing tools have the potential to be used to demethylate specific genes from a tumor cell in the future. "If we are able to specifically act on the PTRF promoter gene so that the protein is expressed at normal levels, we would induce cell death and therefore we would have a promising new personalized therapeutic option for ES." This has been a highly collaborative work, both at the research level, as researchers by two groups from IDIBELL's epigenetics and cancer biology program, Germans Trias Institute, Institute of biomedicine of Seville, University Hospital la Paz, Children's University Hospital Niño Jesús, San Juan de Dios Hospital, Vall d'Hebron University Hospital and Virgen del Rocío University Hospital have collaborated, as well as at a financial level level, given that the project is funded by the Carlos III Health Institute, the AECC and the Alba Pérez Foundation.


News Article | November 10, 2016
Site: www.sciencedaily.com

A new study by researchers at the Bellvitge Biomedical Research Institute (IDIBELL) has found a cause of multiple resistance in cancer chemotherapy. The work, published in the Proceedings of the National Academy of Sciences (PNAS) journal, has been carried out by the research group of Dr. Manel Esteller, Director of Epigenetics and Cancer Biology Program (PEBC) of IDIBELL, ICREA Researcher and Professor of Genetics at the University of Barcelona. The introduction of cancer chemotherapy was a revolution for the treatment of this disease in those cases in which the cure is no longer possible only with the mere extirpation of the tumor. Chemotherapy has been shown to be effective in a wide range of patients, but one of its main problems is the emergence of resistance against the anti-tumor drug used. However, it has been known for decades that there are tumors that display cross-resistance against different drugs since its inception, when they have not yet been treated. "We have found that 10% of colon and stomach tumors present the loss of a molecule called TP53TG1, whose function in healthy cells is to prevent activation of YBX1 protein. Without surveillance of TP53TG1 in these gastrointestinal tumors, YBX1 goes to the nucleus of the cell and is responsible for the activation of hundreds of oncogenes that will prevent the death of malignant cells that antitumor drugs induce," says Dr. Manel Esteller. The spectrum of resistances induced by this mechanism is extensive and includes drugs commonly used in the treatment of these cancers, such as as 5-fluorouracil, oxyplatinum or irinotecan, but also drugs targeting recent molecular targets such as kinase inhibitors. After publishing their results in PNAS, Dr. Esteller explains, "we want to study if there is any drug that escapes this mechanism of multiple chemoresistance and also to explore whether returning the activity of the molecule TP53TG1 would mean regaining the sensitivity of these tumors to the drugs analyzed, which would represent a clinical benefit for these patients."


News Article | November 7, 2016
Site: www.eurekalert.org

A new study by researchers at the Bellvitge Biomedical Research Institute (IDIBELL) has found a cause of multiple resistance in cancer chemotherapy. The work, published today in the Proceedings of the National Academy of Sciences (PNAS) journal, the organ of expression of the United States Academy of Sciences, has been carried out by the research group of Dr. Manel Esteller, Director of Epigenetics and Cancer Biology Program (PEBC) of IDIBELL, ICREA Researcher and Professor of Genetics at the University of Barcelona. The introduction of cancer chemotherapy was a revolution for the treatment of this disease in those cases in which the cure is no longer possible only with the mere extirpation of the tumor. Chemotherapy has been shown to be effective in a wide range of patients, but one of its main problems is the emergence of resistance against the anti-tumor drug used. However, it has been known for decades that there are tumors that display cross-resistance against different drugs since its inception, when they have not yet been treated. "We have found that 10% of colon and stomach tumors present the loss of a molecule called TP53TG1, whose function in healthy cells is to prevent activation of YBX1 protein. Without surveillance of TP53TG1 in these gastrointestinal tumors, YBX1 goes to the nucleus of the cell and is responsible for the activation of hundreds of oncogenes that will prevent the death of malignant cells that antitumor drugs induce", says Dr. Manel Esteller. The spectrum of resistances induced by this mechanism is extensive and includes drugs commonly used in the treatment of these cancers, such as as 5-fluorouracil, oxyplatinum or irinotecan, but also drugs targeting recent molecular targets such as kinase inhibitors. After publishing their results in PNAS, Dr. Esteller explains, "we want to study if there is any drug that escapes this mechanism of multiple chemoresistance and also to explore whether returning the activity of the molecule TP53TG1 would mean regaining the sensitivity of these tumors to the drugs analyzed, which would represent a clinical benefit for these patients."


News Article | November 17, 2016
Site: www.eurekalert.org

Researchers from the Cognition and Cerebral Plasticity group of the Bellvitge Biomedical Research Institute and the University of Barcelona (IDIBELL-UB), in collaboration with researchers from the University of McGill (Montreal), have published a new study in which brain mechanisms associated to the lack of sensitivity to music are explained. The study, published by PNAS journal, gives clues about the importance of music at an evolutionary level based on the connection between the auditory and emotional areas of the brain. Although listening to music is considered a rewarding activity on a universal scale, about 3-5% of the healthy population does not experience pleasurable feelings in response to any type of music. This condition is known by the specific name of musical anhedonia. "Anhedonic people do not have problems correctly perceiving and processing the information contained in a melody (such as intervals or rhythms) and present a normal pleasure response to other pleasant stimuli (such as money), but do not enjoy musical stimuli", explains Noelia Martínez-Molina, researcher at the IDIBELL-UB group and lead author of the study. Although the existence of this phenomenon has been known for some years, it was not known why or how it was produced. In their work, researchers analyzed 45 healthy volunteers using functional magnetic resonance imaging (fMRI). Participants were divided into three groups according to the score obtained in a questionnaire developed by the same research group, the Barcelona Music Reward Questionnaire (BMRQ, available online at http://www. ). During the fMRI session, participants had to listen to snippets of classic genre songs and provide pleasure values on a scale from 1 to 4 in real time. To control the brain response to other types of rewards, participants also had to play a monetary wagering task in which they could win or lose real money. The results showed that the decrease of pleasant response to music shown by participants with musical anhedonia is related to a reduction in the activity of the nucleus accumbens, a key subcortical structure of the reward system. However, the activity of this structure is maintained when other reinforcers, such the money gained in the task of betting, are in place. "It is interesting to consider the evolutionary importance of the connection between the auditory areas, cortical, and the more primitive system of emotional evaluation, subcortical", says the researcher. This connection is very clear in hedonic musical people - those who enjoy music - but diminishes in anhedonics. "The link between areas ensures that music is experienced as very rewarding, while stressing its importance at an evolutionary level, even when it does not seem obvious what the biological gain of this cultural production is."


News Article | November 19, 2016
Site: www.sciencedaily.com

Researchers from the Cognition and Cerebral Plasticity group of the Bellvitge Biomedical Research Institute and the University of Barcelona (IDIBELL-UB), in collaboration with researchers from the University of McGill (Montreal), have published a new study in which brain mechanisms associated to the lack of sensitivity to music are explained. The study, published by PNAS journal, gives clues about the importance of music at an evolutionary level based on the connection between the auditory and emotional areas of the brain. Although listening to music is considered a rewarding activity on a universal scale, about 3-5% of the healthy population does not experience pleasurable feelings in response to any type of music. This condition is known by the specific name of musical anhedonia. "Anhedonic people do not have problems correctly perceiving and processing the information contained in a melody (such as intervals or rhythms) and present a normal pleasure response to other pleasant stimuli (such as money), but do not enjoy musical stimuli," explains Noelia Martínez-Molina, researcher at the IDIBELL-UB group and lead author of the study. Although the existence of this phenomenon has been known for some years, it was not known why or how it was produced. In their work, researchers analyzed 45 healthy volunteers using functional magnetic resonance imaging (fMRI). Participants were divided into three groups according to the score obtained in a questionnaire developed by the same research group, the Barcelona Music Reward Questionnaire (BMRQ, available online at http://www.brainvitge.org/bmrq.php). During the fMRI session, participants had to listen to snippets of classic genre songs and provide pleasure values on a scale from 1 to 4 in real time. To control the brain response to other types of rewards, participants also had to play a monetary wagering task in which they could win or lose real money. The results showed that the decrease of pleasant response to music shown by participants with musical anhedonia is related to a reduction in the activity of the nucleus accumbens, a key subcortical structure of the reward system. However, the activity of this structure is maintained when other reinforcers, such the money gained in the task of betting, are in place. "It is interesting to consider the evolutionary importance of the connection between the auditory areas, cortical, and the more primitive system of emotional evaluation, subcortical," says the researcher. This connection is very clear in hedonic musical people -- those who enjoy music -- but diminishes in anhedonics. "The link between areas ensures that music is experienced as very rewarding, while stressing its importance at an evolutionary level, even when it does not seem obvious what the biological gain of this cultural production is."


News Article | November 22, 2016
Site: www.eurekalert.org

More than 2 million people got infected by human immunodeficiency virus (HIV) in 2015, being sexual transmission the main channel of infection. Researchers from the Infections of the Respiratory Tract and in Immunocompromised Patients group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Daniel Podzamczer, have evaluated the speed at which a new antiretroviral drug, Dolutegravir, is able to reduce the viral load in semen, an area of the body considered to be a reservoir of the virus and where access for drugs is more difficult. The results, published in Journal of Infectious Diseases, show the potential of these new treatments to reduce the chances of sexual transmission of the virus. Current antiretroviral treatments are able to decrease blood viral load and make it undetectable in most patients within six to nine months of starting treatment, although it is estimated that about 5-25% of patients maintain detectable levels of virus in their semen after this time due to several factors, which are not always known. "Therefore, in the case of serodiscordant couples, in which only one of the members is carrying the virus, in addition to condoms it is recommended that the seronegative person also takes antiretroviral drugs as prophylaxis while the viral load of their partner decreases in both blood and reservoirs", says Dr. Podzamczer. However, there are new drugs, known as integrase inhibitors, which can act much faster. "In this study we have focused on evaluating the rate of viral load drop in patients receiving these new treatments, namely Dolutegravir", explains Dr. Arkaitz Imaz, first author of the study. "We have measured the viral load in blood and semen before starting treatment, at 3 days, at 7, at 14, at one month, at three months, and at six months. We know that viral load drop goes quick during the first few days/weeks, then slower and it finally stabilizes. Adapting a complex mathematical-statistical model to our data and to the characteristics of our patients, we have been able to obtain a kinetic model of the specific viral load drop for each compartment, blood and semen, with this treatment regimen". The researchers observed that while the rate at which viral load falls during the first few days is significantly higher in blood than in semen, it is equal during the second phase of fall. However, despite the speed difference, viral load becomes undetectable faster in semen than in blood because the base values are much higher in blood, ie there are many more viruses to eliminate. "These results suggest the possibility of reducing the time of previous antiretroviral prophylaxis when using these new treatments," the researchers note. On the other hand, the fall pattern is much more homogeneous in blood than in semen; This heterogeneity demonstrates the differential and more unpredictable nature of semen as a reservoir of the virus. In this sense, it is interesting to note that there is no clear correlation between the concentration of drug in semen and the decrease in viral load: "the concentration of dolutegravir in semen is more than enough to ensure viral load drop in this reservoir", explains Dr. Podzamczer, "because even though only 7-8% of the drug in the blood reaches the semen, the proportion of active drug is much higher than what the observed in blood. This was something that we did not know until now ". Integrase inhibitors are currently recommended by all clinical guidelines as the first line of treatment. "Our study reinforces this decision, especially in light of the current HIV transmission landscape. If we reduce the time of viral load drop we clearly reduce the possibility of transmission, especially in groups at risk", argues Dr. Imaz. In the editorial that Journal of Infectious Diseases dedicates to the article, it is pointed out the need to replicate this study with other new drugs currently under development, namely long-term antiretrovirals, to evaluate the potential of these new therapies and their activity in this viral reservoir. The work was carried out in collaboration with Dr. Jordi Niubó, also a member of the Infections of the Respiratory Tract and in Immunocompromised Patients group of IDIBELL and with the research groups of Dr. Angela D Kashuba of the UNC Center for AIDS Research of North Carolina, and Dr. Javier Martínez-Picado of IrsiCaixa AIDS Research Institute.

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