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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quarta-feira, 19.08.15

link between smaller hippocampal brain volume and marijuana use

Scientists reveal link between smaller hippocampal brain volume and marijuana use

Published on August 19, 2015 at 6:15 AM ·

How scientists study the effects of marijuana on the brain is changing. Until recently marijuana research largely excluded tobacco users from its participant pool, but scientists at the Center for BrainHealth at The University of Texas at Dallas have found reason to abandon this practice, uncovering significant differences in the brains of individuals who use both tobacco and marijuana and the brains of those who only use marijuana.

In a study that appears online in the journal Behavioural Brain Research, scientists report an association between smaller hippocampal brain volume and marijuana use. Although the size of the hippocampus, an area of the brain associated with memory and learning, is significantly smaller in both the marijuana group and marijuana plus tobacco group compared to non-using controls and individuals who use tobacco exclusively, the relationship to memory performance is unique.

Hippocampal size of nonusers reflects a direct relationship to memory function; the smaller the hippocampus, the poorer the memory function. Individuals who use marijuana and tobacco show an inverse relationship, i.e., the smaller the hippocampus size, the greater memory the function. Furthermore the number of nicotine cigarettes smoked per day in the marijuana and nicotine using group appears to be related to the severity of hippocampal shrinkage. The greater the number of cigarettes smoked per day, the smaller the hippocampal volume and the greater the memory performance. There were no significant associations between hippocampal size and memory performance in individuals who only use tobacco or only use marijuana.

"Approximately 70% of individuals who use marijuana also use tobacco," explained Francesca Filbey, Ph.D., the study's principal investigator and Director of Cognitive Neuroscience of Addictive Behaviors at the Center for BrainHealth. "Our findings exemplify why the effects of marijuana on the brain may not generalize to the vast majority of the marijuana using population, because most studies do not account for tobacco use. This study is one of the first to tease apart the unique effects of each substance on the brain as well as their combined effects."

Dr. Filbey's research team used magnetic resonance imaging (MRI) to examine the hippocampus; an area of the brain that is know to have altered size and shape in association with chronic marijuana use. Participants completed a substance use history assessment and neuropsychological tests three days prior to an MRI head scan. The team compared four groups: nonusers (individuals who have not had any marijuana or tobacco in the past three months), chronic marijuana users (individuals who use marijuana at least four times per week), frequent nicotine users (10 or more times daily) and chronic marijuana plus frequent nicotine users (at least four marijuana uses per week and 10 or more nicotine uses per day).

"We have always known that each substance is associated with effects on the brain and hypothesized that their interaction may not simply be a linear relationship. Our findings confirm that the interaction between marijuana and nicotine is indeed much more complicated due to the different mechanisms at play," said Filbey. "Future studies need to address these compounding effects of substances."

She continued, "The combined use of marijuana and tobacco is highly prevalent. For instance, a 'blunt' is wrapped in tobacco leaf. A 'spliff' is a joint rolled with tobacco. We really need to understand how the combined use changes the brain to really understand its effects on memory function and behavior."

Source:

Center for BrainHealth

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por cyto às 12:15

Quarta-feira, 19.08.15

special brain mechanism that can retrieve unconscious memories

 

Scientists discover special brain mechanism that can retrieve unconscious memories

Published on August 18, 2015 at 8:46 AM ·

Some stressful experiences - such as chronic childhood abuse - are so overwhelming and traumatic, the memories hide like a shadow in the brain.

At first, hidden memories that can't be consciously accessed may protect the individual from the emotional pain of recalling the event. But eventually those suppressed memories can cause debilitating psychological problems, such as anxiety, depression, post-traumatic stress disorder or dissociative disorders.

A process known as state-dependent learning is believed to contribute to the formation of memories that are inaccessible to normal consciousness. Thus, memories formed in a particular mood, arousal or drug-induced state can best be retrieved when the brain is back in that state.

In a new study with mice, Northwestern Medicine scientists have discovered for the first time the mechanism by which state-dependent learning renders stressful fear-related memories consciously inaccessible.

"The findings show there are multiple pathways to storage of fear-inducing memories, and we identified an important one for fear-related memories," said principal investigator Dr. Jelena Radulovic, the Dunbar Professor in Bipolar Disease at Northwestern University Feinberg School of Medicine. "This could eventually lead to new treatments for patients with psychiatric disorders for whom conscious access to their traumatic memories is needed if they are to recover."

It's difficult for therapists to help these patients, Radulovic said, because the patients themselves can't remember their traumatic experiences that are the root cause of their symptoms.

The best way to access the memories in this system is to return the brain to the same state of consciousness as when the memory was encoded, the study showed.

The study will be published August 17 in Nature Neuroscience.

Changing the Brain's Radio Frequencies

Two amino acids, glutamate and GABA, are the yin and yang of the brain, directing its emotional tides and controlling whether nerve cells are excited or inhibited (calm). Under normal conditions the system is balanced. But when we are hyper-aroused and vigilant, glutamate surges. Glutamate is also the primary chemical that helps store memories in our neuronal networks in a way that they are easy to remember.

GABA, on the other hand, calms us and helps us sleep, blocking the action of the excitable glutamate. The most commonly used tranquilizing drug, benzodiazepine, activates GABA receptors in our brains.

There are two kinds of GABA receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.

The other population, extra-synaptic GABA receptors, are independent agents. They ignore the peppy glutamate. Instead, their job is internally focused, adjusting brain waves and mental states according to the levels of internal chemicals, such as GABA, sex hormones and micro RNAs. Extra-synaptic GABA receptors change the brain's state to make us aroused, sleepy, alert, sedated, inebriated or even psychotic. However, Northwestern scientists discovered another critical role; these receptors also help encode memories of a fear-inducing event and then store them away, hidden from consciousness.

"The brain functions in different states, much like a radio operates at AM and FM frequency bands," Radulovic said. "It's as if the brain is normally tuned to FM stations to access memories, but needs to be tuned to AM stations to access subconscious memories. If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again, essentially tuning the brain into the AM stations."

Retrieving Stressful Memories in Mice

In the experiment, scientists infused the hippocampus of mice with gaboxadol, a drug that stimulates extra-synaptic GABA receptors. "It's like we got them a little inebriated, just enough to change their brain state," Radulovic said.

Then the mice were put in a box and given a brief, mild electric shock. When the mice were returned to the same box the next day, they moved about freely and weren't afraid, indicating they didn't recall the earlier shock in the space. However, when scientists put the mice back on the drug and returned them to the box, they froze, fearfully anticipating another shock.

"This establishes when the mice were returned to the same brain state created by the drug, they remembered the stressful experience of the shock," Radulovic said.

The experiment showed when the extra-synaptic GABA receptors were activated with the drug, they changed the way the stressful event was encoded. In the drug-induced state, the brain used completely different molecular pathways and neuronal circuits to store the memory.

"It's an entirely different system even at the genetic and molecular level than the one that encodes normal memories," said lead study author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic's lab.

This different system is regulated by a small microRNA, miR-33, and may be the brain's protective mechanism when an experience is overwhelmingly stressful.

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.

Traumatic Memories Rerouted and Hidden Away

Memories are usually stored in distributed brain networks including the cortex, and can thus be readily accessed to consciously remember an event. But when the mice were in a different brain state induced by gaboxadol, the stressful event primarily activated subcortical memory regions of the brain. The drug rerouted the processing of stress-related memories within the brain circuits so that they couldn't be consciously accessed.

Source:

Northwestern University

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por cyto às 11:42

Quarta-feira, 19.08.15

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

GLIOBASTOMA GBM

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

Published on August 13, 2015 at 8:32 AM ·

ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) announced today that it has reached agreement with the US Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the phase 3 registrational trial of its cancer immunotherapy ICT-107 to treat patients with newly diagnosed glioblastoma.

The phase 3 trial is designed as a randomized, double-blind, placebo-controlled study of about 400 HLA-A2 positive subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups. Patient enrollment is anticipated to begin in the late third quarter or early fourth quarter of 2015.

A Special Protocol Assessment is a written agreement between the sponsor company and the FDA on the design, clinical endpoints, size and statistical design of a clinical trial intended to form the primary basis of an efficacy claim in the marketing application, such as a biologic licensing application (BLA) or a new drug application (NDA). Final marketing approval depends upon the safety and efficacy results demonstrated in the phase 3 clinical program.

Andrew Gengos, ImmunoCellular's Chief Executive Officer Commented: "We are pleased to have achieved this important milestone, and think that successful completion of the SPA process adds meaningful validation to the ICT-107 phase 3 program and design, especially the use of the gold standard primary endpoint of overall survival. With this SPA in place, we think that ICT-107 is uniquely positioned in the field of immuno-oncology approaches being tested in glioblastoma. We are making significant progress toward establishing our clinical site network and obtaining the necessary institutional review board approvals. We are confident that we are on track to begin patient enrollment in the late third quarter or early fourth quarter of this year."

Source:

ImmunoCellular Therapeutics, Ltd.

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por cyto às 11:37

Quarta-feira, 29.07.15

Brain - Reaching the right size

 

Brain - Reaching the right size

Mutations in a protein involved in neuronal proliferation and survival cause extreme brain malformations and atrophy

Published online 29 July 2015

Magnetic resonance image of the brain of an individual with the brain formation disorder microlissencephaly.

Reprinted from Ref. 1, Copyright 2014, with permission from Elsevier.

A gene responsible for a severe form of the brain formation disorder microlissencephaly has been identified by A*STAR scientists through a collaboration with researchers in seven countries1.

Microlissencephaly is a neuronal development disorder characterized by smaller brains having fewer neurons than normally developed brains (see image). Researchers, including Bruno Reversade from the A*STAR Institute of Medical Biology, identified three Middle Eastern families with children affected by the disorder who did not have mutations in any of the genes already known to cause microlissencephaly. Because some of the families had a history of marriages between closely related individuals, such as first cousins, the causative gene was believed to be passed on by both parents. By sequencing regions that were identical in the affected individuals of a particular family, the researchers were able to home in on mutations in the KATNB1 gene, as these mutations were absent in unaffected individuals in other populations.

The protein encoded by KATNB1 is part of a complex responsible for severing structural proteins in the cell called microtubules. A structure called the centrosome is known to play a central role in organizing microtubules in the cell, and many centrosomal proteins have previously been linked to patients with microlissencephaly.

To determine the function of KATNB1 during development, Reversade and his colleagues generated mice and fish lacking the Katnb1 gene — the mouse and fish analogue of KATNB1. The animal models showed defective proliferation of neuronal progenitor cells, loss of many cell types that rely on normal cell division, enhanced cell death and thinner brains. Also, cells derived from humans with microlissencephaly showed many abnormalities in cell division, such as centromeres that were abnormally placed, chromosomes that did not line up properly and cells with too many chromosomes.

Centromeres are made up of paired structures called centrioles and play a key role in forming hair-like extensions of the cell called cilia. The researchers found that cells from mice lackingKatnb1 contained many more centrioles than normal cells and that these centrioles were often unpaired. Moreover, the cells lacking this gene contained many more cilia than normal, which the researchers argue could mean that signaling regulated by cilia is defective. These dysfunctional processes probably contribute to the abnormal neuronal development observed in organisms lacking KATNB1.

“Our discovery of the causative gene for this disease will benefit families as we are now able to provide premarital and prenatal diagnosis for parents,” explains Reversade.

 

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Institute of Molecular and Cellular Biology. More information about the group’s research can be found at theHuman Genetics and Embryology Group webpage.

 

Related Links

Developmental biology: How a protein collaboration builds the brain

Molecular biology: Fragile interactions and brain function

Cell biology: Taking advantage of defects in splicing

 

 

Reference

  1. Hu, W. F., Pomp, O., Ben-Omran, T., Kodani, A. & Henke, K. et al. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron 84, 1240–1257 (2014). | article

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por cyto às 11:41

Terça-feira, 21.07.15

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

 

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

Published on July 8, 2015 at 11:50 PM 

Ludwig Cancer Research (Ludwig) and the Cancer Research Institute (CRI) have launched clinical trials evaluating an immunotherapy for the treatment of the brain cancer glioblastoma multiforme (GBM), and a combination of immunotherapies for a variety of solid tumors.

The trials are being conducted through the CVC Clinical Trials Network in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca. The CVC Clinical Trials Network -- jointly managed by Ludwig and CRI -- is a coordinated global network of basic and clinical immunologists with expertise in devising and developing immunotherapies for the treatment of cancer. The CVC Clinical Trials Network is led by Jedd Wolchok, Ludwig member and director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, as well as associate director of the CRI Scientific Advisory Council.

The GBM trial is a nonrandomized, multicenter Phase 2 trial testing the effects of MedImmune's checkpoint blockade antibody durvalumab (MEDI4736) in patients with GBM, which is the most aggressive and deadly type of adult brain cancer. The study will be conducted using three cohorts of patients - newly diagnosed, recurrent patients and those with tumors which have become unresponsive to standard treatment of care.

"GBM is an inevitably lethal cancer that has so far eluded every therapy in the pharmaceutical arsenal," said Jonathan Skipper, Ludwig's executive director of technology development. "We are hopeful that adding a promising immunotherapy to the treatment regimen for this brain cancer will yield significant benefits for patients who today have a median life expectancy of roughly 15 months, even with the best treatment available."

Durvalumab is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor's immune-evading tactics. The antibody belongs to an emerging class of immunotherapies commonly referred to as checkpoint inhibitors because they remove checks the body places on immune activation.

"Checkpoint inhibitors have deservedly stirred considerable excitement in the oncology community as their application yields notable results against a growing variety of cancers," said Adam Kolom, managing director of CRI's venture fund and Clinical Accelerator, which organizes and provides philanthropic funding and clinical resources for this and other promising immunotherapy trials. "This will be the first time the immunotherapeutic agent will be tested against this difficult-to-treat cancer, and its outcomes are eagerly anticipated by the GBM patient community."

The other trial, which Ludwig and CRI launched in 2013, is a Phase 1 nonrandomized multicenter trial evaluating the combination of durvalumab with another checkpoint blockade therapy (tremelimumab, anti-CTLA-4) for the treatment of a variety of advanced solid tumors including ovarian cancer, non-small cell lung cancer, colorectal cancer, head and neck cancer, cervical cancer and kidney cancer.

Both clinical trials, which are now under way, are part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs. All of the studies will include collection of genetic and immunologic data derived from clinical samples obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.

Source:

Ludwig Institute for Cancer Research

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por cyto às 18:12

Terça-feira, 21.07.15

Patients' own genetically engineered immune cells show significant success against multiple myeloma

 

Patients' own genetically engineered immune cells show significant success against multiple myeloma

Published on July 21, 2015 at 2:37 AM 

In recent years, immunotherapy has emerged as a promising treatment for certain cancers. Now this strategy, which uses patients' own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable. The results appeared in a study published online today in Nature Medicine.

Patients received an infusion of altered immune cells known as T-cells - roughly 2.4 billion of them - after undergoing a stem cell transplantation of their own stem cells. In 16 of 20 patients with advanced disease, there was a significant clinical response. The scientists found that the T-cell therapy was generally well-tolerated and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are found, and showed a long-term ability to fight the tumors. Relapse was generally associated with a loss of the engineered T-cells.

"This study suggests that treatment with engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," says first author Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine. "Our findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better results for our patients."

The trial is the first published use of genetically modified T-cells for treating patients with multiple myeloma. The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

More than 77,000 people in the United States have multiple myeloma, with about 24,000 new cases diagnosed each year. Patients are treated with chemotherapy and in many cases an autologous stem cell transplant, but long-term response rates are low, and median survival is three to five years.

"The majority of patients who participated in this trial had a meaningful degree of clinical benefit," Dr. Rapoport notes. "Even patients who later relapsed after achieving a complete response to treatment or didn't have a complete response had periods of disease control that I believe they would not have otherwise experienced. Some patients are still in remission after nearly three years."

The research is a collaboration between the University of Maryland School of Medicine, the Perelman School of Medicine at the University of Pennsylvania and Adaptimmune, a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study. Dr. Rapoport and co-authors Edward A. Stadtmauer, MD, of the University of Pennsylvania Abramson Cancer Center, and Gwendolyn K. Binder-Scholl, PhD, of Adaptimmune, contributed equally to the research. Dr. Rapoport is the study's principal investigator.

In the clinical study, patients' T-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen, or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1 and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1, which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is the first published study of lentiviral vector mediated TCR gene expression in humans.

Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment. Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment. Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center. Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant. In addition, patients did not experience side effects which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.

The study was originally developed by Carl H. June, MD, of the University of Pennsylvania Abramson Cancer Center, and Dr. Rapoport, who have been research collaborators for 18 years.

"Multiple myeloma is a treatable but largely incurable cancer. This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body's ability to attack the cancer and provide patients with better treatments and control of their disease," says E. Albert Reece, MD., PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "This trial is also an excellent example of significant scientific advances that result from collaborations between academic medical institutions and private industry."

Source:

University of Maryland Medical Center

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por cyto às 18:10

Sábado, 04.07.15

effect of pioglitazone and other antidiabetics on dementia

Pioglitazone drug significantly decreases risk of dementia

Published on June 23, 2015 at 2:03 PM 

Patients with type 2 diabetes have a dysfunctional sugar metabolism because the essential hormone insulin does not work effectively. Once the disease reaches an advanced stage, the body stops producing insulin altogether, which means that it has to be administered externally. Type 2 diabetes most commonly occurs in late adulthood, and it has long been known that it can affect the patient's mental health: Patients have a greater risk of developing dementia than non-diabetics. However, how does antidiabetic medication influence this risk? Neurologist Michael Heneka and the demographers Anne Fink and Gabriele Doblhammer investigated this issue in the current study. Their work is based on data from the years 2004 to 2010 provided by the German public health insurance company AOK. These data set comprises information about diseases and medication related to more than 145,000 men and women aged 60 and over.

Long-term treatment reduced dementia risk

The analysis confirmed previous findings that diabetics have an increased risk of developing dementia. However, it was also found that this risk can significantly be modified by pioglitazone. This drug is taken as tablets. It is applied in short-term as well as in long-term treatment of diabetes as long as the body is still capable of producing its own insulin.

"Treatment with pioglitazone showed a remarkable side benefit. It was able to significantly decrease the risk of dementia," says Doblhammer. "The longer the treatment, the lower the risk." Risk reduction was most noticeable when the drug was administered for at least two years. Diabetics given this treatment developed dementia less often than non-diabetics. Doblhammer: "The risk of developing dementia was around 47 percent lower than in non-diabetics, i.e. only about half as large."

Metformin - another frequently prescribed antidiabetic drug - also lowered the risk of developing dementia. However, the effect was lower than that of pioglitazone.

Protection against nerve cell damage

Pioglitazone improves the effect of the body's own insulin. Moreover, laboratory tests have long indicated that it also protects the nerve cells. The current results are therefore no surprise to neuroscientist Michael Heneka. "Pioglitazone is an anti-inflammatory drug that also inhibits the deposition of harmful proteins in the brain," he says.

However, Heneka emphasizes that the exact mechanisms are not yet understood: "Our study suggests that pioglitazone has a preventive effect. This happens when the drug is taken before symptoms of dementia manifest. Thus, it protects in particular against Alzheimer's, the most common form of dementia. The causes for this, whether pioglitazone only has this protective effect in diabetics or if it would also work in non-diabetics - all these questions have yet to be answered. The next logical step would therefore be clinical studies. These studies would specifically investigate the effect of pioglitazone and other antidiabetics on dementia."

Source:

DZNE - German Center for Neurodegenerative Diseases

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por cyto às 11:54

Sábado, 04.07.15

gene mutation linked to anaplastic oligodendroglioma

Scientists identify gene mutation linked to anaplastic oligodendroglioma

Published on June 12, 2015 at 9:23 AM · 

Scientists have identified a gene mutation linked to the development of an aggressive form of brain cancer.

Researchers found that errors in a gene known as TCF12 - which plays a key role in the formation of the embryonic brain are associated with more aggressive forms of a disease called anaplastic oligodendroglioma.

The new research is the largest ever genetic study of oligodendrogliomas, and provides important insights into their causes - and how they might be treated.

Oligodendrogliomas are fast-growing cancers that account for around 5-10 per cent of all tumours of the brain and central nervous system, and typically have a very poor prognosis.

Researchers at The Institute of Cancer Research, London, in collaboration with laboratories in France and Canada, compared the genetic sequence of 134 of these brain tumours with the DNA of healthy cells.

The study was largely funded by Investissements d'avenir and Génome Québec, with support from Cancer Research UK, and was published in the journal Nature Communications.

Researchers identified mutations in the TCF12 gene in 7.5 per cent of anaplastic oligodendrogliomas. They found that this subset of cancers grew more rapidly, and in other ways seemed more aggressive, than those where the gene was intact.

TCF12 is the genetic code for a protein that binds to DNA and controls the activity of other genes. The researchers found that mutations in TCF12 rendered the protein less able to bind to DNA, and this in turn led to a reduction in activity of other key genes - including one already associated with cancer spread, known as CHD1.

The researchers initially read the DNA sequence of 51 tumours and went on to look for TCF12 mutations in an additional group of 83.

The researchers also discovered errors in the gene IDH1 in 78 per cent of the tumours, confirming the findings of an initial scan of the data.

Finding out more about what genetic faults cause anaplastic oligodendrogliomas will allow scientists and clinicians to develop new personalised therapies that target a range of the mutations driving the disease.

Professor Richard Houlston, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, said:

"Our in-depth study has set out many of the genetic defects that cause this rare but highly aggressive form of brain cancer - including identifying a gene mutation that appears in particularly fast-growing forms.

"Anaplastic oligodendrogliomas are difficult to remove by surgery and don't respond well to other forms of treatment. We hope this new information might be used to discover new targeted therapies, offering patients a better chance at survival from this aggressive cancer."

Source:

Institute of Cancer Research

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por cyto às 11:46

Sábado, 04.07.15

Fibromyalgia now considered as a lifelong central nervous system disorder

Fibromyalgia now considered as a lifelong central nervous system disorder

Published on May 18, 2015 at 6:10 AM ·

Fibromyalgia is the second most common rheumatic disorder behind osteoarthritis and, though still widely misunderstood, is now considered to be a lifelong central nervous system disorder, which is responsible for amplified pain that shoots through the body in those who suffer from it. Daniel Clauw, M.D., professor of anesthesiology, University of Michigan, analyzed the neurological basis for fibromyalgia in a plenary session address today at the American Pain Society Annual Scientific Meeting.

"Fibromyalgia can be thought of both as a discreet disease and also as a final common pathway of pain centralization and chronification. Most people with this condition have lifelong histories of chronic pain throughout their bodies," said Clauw. "The condition can be hard to diagnose if one isn't familiar with classic symptoms because there isn't a single cause and no outward signs."

Clauw explained that fibromyalgia pain comes more from the brain and spinal cord than from areas of the body in which someone may experience peripheral pain. The condition is believed to be associated with disturbances in how the brain processes pain and other sensory information. He said physicians should suspect fibromyalgia in patients with multifocal (mostly musculoskeletal) pain that is not fully explained by injury or inflammation.

"Because pain pathways throughout the body are amplified in fibromyalgia patients, pain can occur anywhere, so chronic headaches, visceral pain and sensory hyper-responsiveness are common in people with this painful condition," said Clauw.

"This does not imply that peripheral nociceptive input does not contribute to pain experienced by fibromyalgia patients, but they do feel more pain than normally would be expected from the degree of peripheral input. Persons with fibromyalgia and other pain states characterized by sensitization will experience pain from what those without the condition would describe as touch," Clauw added.

Due to the central nervous system origins of fibromyalgia pain, Clauw said treatments with opioids or other narcotic analgesics usually are not effective because they do not reduce the activity of neurotransmitters in the brain. "These drugs have never been shown to be effective in fibromyalgia patients, and there is evidence that opioids might even worsen fibromyalgia and other centralized pain states," he said.

Clauw advises clinicians to integrate pharmacological treatments, such as gabapentinoids, trycyclics and serotonoin reuptake inhibitors, with nonpharmacological approaches like cognitive behavioral therapy, exercise and stress reduction.

"Sometimes the magnitude of treatment response for simple and inexpensive non-drug therapies exceeds that for pharmaceuticals," said Clauw. "The greatest benefit is improved function, which should be the main treatment goal for any chronic pain condition. The majority of patients with fibromyalgia can see improvement in their symptoms and lead normal lives with the right medications and extensive use of non-drug therapies."

Source:

American Pain Society (APS)

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por cyto às 11:40

Sábado, 04.07.15

new protein that affects growth of secondary breast tumours in the brain

Scientists identify new protein that affects growth of secondary breast tumours in the brain

Published on July 1, 2015 at 7:19 AM 

Scientists from the University of Leeds and The Institute of Cancer Research, London, have discovered a new protein which triggers the growth of blood vessels in breast cancer tumours which have spread to the brain, a common location which breast cancer can spread to.

Dr Georgia Mavria's team in the School of Medicine at Leeds found that by withholding the DOCK4 protein in mouse models, a particular part of the blood vessel did not form as quickly, meaning tumours grew at a slower rate.

Dr Mavria said: "We want to understand how these tumours form and grow, but we still need to do more research to stop these tumours growing altogether.

"The finding gives an important indicator of how the protein affects the growth of secondary breast tumours in the brain. The discovery could also enable experts to predict which patients might be at risk of their breast cancer spreading, and develop drugs to prevent the growth of secondary tumours."

Working with Professor Chris Marshall, Professor of Cell Biology at The Institute of Cancer Research, London and the late Dr Tony Pawson at the Lunenfeld-Tanenbaum Research Institute in Toronto, researchers found that a complex of two related proteins, DOCK4 and DOCK9, is critical in the formation of the lumen, the interior space of a vessel through which blood flows.

By impeding the speed at which the lumen forms, tumours are not fed as effectively by blood vessels.

Normally, when breast cancer spreads to other parts of the body, it forces new blood vessels to form to supply it with nutrients and oxygen to help it to grow, resulting in tumours that are very difficult to treat.

Professor Marshall said: "Our study reveals new insights into how the complex process of forming blood vessels is controlled. This knowledge could lead to new approaches to preventing the blood supply to tumours and metastases. If we can find new ways to reduce the blood supply to tumours, we might be able to find new ways to slow cancer growth in future."

The research, which has been published in Nature Communications, was funded by Breast Cancer Now, Yorkshire Cancer Research and Cancer Research UK.

Dr Matthew Lam, Senior Research Communications Officer at Breast Cancer Now, said: "These findings could one day help us better identify and treat patients that might be at risk of their breast cancer spreading to the brain, a particularly common site for metastasis.

"12,000 women have their lives cut short by breast cancer in the UK each year. An understanding of what is happening on a molecular level - such as the role played by DOCK proteins - will be essential if we are to find ways to prevent secondary tumours and finally stop women dying from the disease."

Kathryn Scott, Head of Research and Innovation at Yorkshire Cancer Research, said: "Tumours need blood vessels to grow, but these blood vessels could be the cancer's weakest link because it is believed that they are less able to become resistant to drugs than the cancer cells themselves. Targeting drugs to the blood vessels that are serving the tumour rather than the tumour itself is an exciting new area of research and we are supporting a number of projects in Yorkshire which are investigating this approach."

Dr Aine McCarthy, Science Information Officer at Cancer Research UK, said: "This research shows for the first time that a molecule called DOCK4 is a key player in tumour blood vessel development and blocking it could slow tumour growth by starving the cancer cells. But the study was carried out in mice, so more research is needed to see if drugs can be developed that target the molecule and whether this approach would be safe and effective in people with cancer."

Source:

University of Leeds

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