Most prostate cancer (Pca) is diagnosed through a blood test, serum PSA testing. The well appreciated down-side of PSA testing is the diagnosis of a considerable proportion of indolent cancers that are highly unlikely to progress to clinically significant, lethal disease. Our limited ability to accurately identify men destined to suffer and die from the disease from the majority of indolent cases is a major concern and contributes to the dilemma regarding Pca screening and its genetic testing. There is therefore an unmet need to develop genetic tests that can predict whether a man specifically is highly susceptible to the aggressive form of prostate cancer. In some other cancers, such as breast and ovarian cancer, certain predictors of aggressiveness (e.g. BRCA gene mutations) have proven effective in identifying subsets of patients for specific interventions. In prostate cancer, genetic testing to predict the individual risk to Pca is not performed routinely because of the absence of a marker which accurately identifies aggressive prostate cancer. In a new study, Dr. Alex Zlotta and colleagues identified a new region within the Kallikrein gene, the Kallikrein 6 gene region, detectable in the blood, that is strongly associated with aggressive prostate cancer (defined as Gleason Score ?8) in a cohort of 1858 men from three continents. The team developed a blood test at the Lunenfeld-Tanenbaum Research Institute which detects variants of this Kallikrein 6 gene. The test was validated in three independent cohorts including unique cohorts from large international screening studies for prostate cancer. The Kallikrein 6 gene variants identified also independently predicted treatment failure after surgery or radiation for prostate cancer in a fourth independent cohort. The frequency of the gene variants varied from 6 to 14% in the population and the increased risk of aggressive prostate cancer was multiplied by almost 3 times in men who harboured the mutations. Most studies to date have focused on the risk of prostate cancer, not the specific risk of aggressive lethal prostate cancer. The demonstration that germline variants of a new gene, Kallikrein 6, are strongly associated with aggressive prostate cancer, may be of high value in the management of the most common cancer in men.
Lunenfeld-Tanenbaum Research Institute research.lunenfeld.ca/rssnews/?page=2165
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An overactive molecular signal pathway in the brain region of the amygdala can lead to obsessive-compulsive disorder (OCD). A research team from Würzburg has established this connection. Some people have an extreme fear of dirt or bacteria. As a result, they may develop a habit of compulsive washing and repeatedly cleaning their hands or body. They are trapped in a vicious circle, as the fear of new contamination returns quickly after washing. Sufferers see no way out. They are even incapable of changing their behaviour when the excessive washing has led to skin irritation or damage. Around two percent of the general population suffer from some kind of obsessive-compulsive disorder (OCD) at least once in their life. The disorder is characterised by persistent intrusive thoughts which the sufferers try to compensate for by repetitive ritualized behaviour. Like depression, eating disorders and other mental diseases, OCD is treated with antidepressants. However, the drugs are non-specific, that is they are not tailored to the respective disease. Therefore, scientists have been looking for new and better targeted therapies that have fewer side effects. Professor Kai Schuh from the Institute of Physiology at the Julius-Maximilians-Universität (JMU) Würzburg (Germany) and his team explore the underlying causes of obsessive-compulsive disorder in collaboration with the JMU’s Departments of Psychiatry and Neurology. "We were able to show in mouse models that the absence of the protein SPRED2 alone can trigger an excessive grooming behaviour," Schuh says. He believes that this finding is crucial as no clear trigger for this type of disorder has been identified until now. Previous research pointed to multiple factors being responsible for developing OCD. Occurring in all cells of the body, the protein SPRED2 is found in particularly high concentrations in regions of the brain, namely in the basal ganglia and the amygdala. Normally, the protein inhibits an important signal pathway of the cell, the so-called Ras/ERK-MAP kinase cascade. When it is missing, this signal pathway is more active than usual. "It is primarily the brain-specific initiator of the signal pathway, the receptor tyrosine kinase TrkB, that is excessively active and causes the overshooting reaction of the downstream components", biologist Dr. Melanie Ullrich explains. Administering an inhibitor to attenuate the overactive signal cascade in the animal model improves the obsessive-compulsive symptoms. Moreover, the JMU research team was able to treat the OCD with an antidepressant, similarly to standard therapy in humans. "Our study delivers a valuable new model that allows the disease mechanisms to be investigated and new therapy options for obsessive-compulsive disorders to be tested," Professor Schuh says. The recently discovered link between OCDs and the Ras/ERK-MAP kinase cascade also opens up new targets for therapy. Drugs that inhibit this cascade are already available and some of them are approved for human treatment. According to Melanie Ullrich, these are cancer drugs, as overactivation of the Ras/ERK-MAP kinase cascade is also a frequent trigger of cancer: "So we are wondering whether such drugs could also be effective in the treatment of obsessive-compulsive disorders and whether they are beneficial in terms of side effects."
University of Würzburg www.uni-wuerzburg.de/en/sonstiges/meldungen/detail/artikel/ursache-fuer-zwangsstoerungen-entdeckt-1/
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A new Tel Aviv University study identified a gene coding for a protein that turns off neurotransmission signalling, which contributes to Alzheimer’s disease (AD).
The gene, called RGS2 (Regulator of Protein Signalling 2), has never before been implicated in AD. The researchers report that lower RGS2 expression in AD patient cells increases their sensitivity to toxic effects of amyloid-ß. The study may lead to new avenues for diagnosing Alzheimer’s disease — possibly a blood test — and new therapies to halt the progression of the disease.
The research was led by Dr. David Gurwitz of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Sackler School of Medicine; and a member of TAU’s Adams Super Center for Brain Studies and TAU’s Sagol School of Neuroscience.
“Alzheimer’s researchers have until now zeroed in on two specific pathological hallmarks of the chronic neurodegenerative disease: deposits of misfolded amyloid-ß (Aß) peptide plaques, and phosphorylated tau protein neurofibrillary tangles found in diseased brains,” Dr. Gurwitz said. “But recent studies suggest amyloid-? plaques are also a common feature of healthy older brains. This raises questions about the central role of A? peptides in Alzheimer’s disease pathology.”
The researchers pinpointed a common suspect — the RGS2 gene — by combining genome-wide gene expression profiling of Alzheimer’s disease blood-derived cell lines with data-mining of previously published gene expression datasets. They found a reduced expression of RGS2 in Alzheimer’s disease blood-derived cell lines, then validated the observation by examining datasets derived from blood samples and post-mortem brain tissue samples from Alzheimer’s patients.
“Several genes and their protein products are already known to be implicated in Alzheimer’s disease pathology, but RGS2 has never been studied in this context,” Dr. Gurwitz said. “We now propose that whether or not Aß is a primary culprit in Alzheimer’s disease, neuroprotective mechanisms activated during early disease phases lead to reduced RGS2 expression.”
The new TAU study furthermore proposes that reduced RGS2 expression increases the susceptibility of brain neurons to the potentially damaging effects of Aß.
“We found that reduced expression of RGS2 is already noticeable in blood cells during mild cognitive impairment, the earliest phase of Alzheimer’s,” Dr. Gurwitz observed. “This supported our theory that the reduced RGS2 expression represents a ‘protective mechanism’ triggered by ongoing brain neurodegeneration.”
The team further found that the reduced expression of RGS2 was correlated with increased Aß neurotoxicity. It acted like a double-edged sword, allowing the diseased brain to function with fewer neurons, while increasing damage to it by accumulating misfolded Aß.
“Our new observations must now be corroborated by other research groups,” Dr. Gurwitz concluded. “The next step will be to design early blood diagnostics and novel therapeutics to offset the negative effects of reduced expression of the RGS2 protein in the brain.”
American Friends of Tel Aviv University
http://tinyurl.com/h6nz7pf
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Prostate-specific antigen (PSA) and other biomarkers are essential tools for diagnosing and monitoring prostate cancer. However, biomarkers to selectively identify patients with high risk of recurrence, those who might benefit from intervention, and those who can safely choose active surveillance, are lacking. A report describes a biomarker, PITX2 DNA methylation, which is capable of distinguishing cancerous tissue from non-cancerous tissue and predicting the risk of cancer recurrence using only small amounts of tissue obtained from core needle biopsies.
“Previous studies have shown that aberrant PITX2 methylation is a strong prognostic marker for disease progression in breast and lung cancer. In prostate cancer, several studies have demonstrated that PITX2 hypermethylation is an independent prognosticator of biochemical recurrence following radical prostatectomy. However, none of these studies were conducted on presurgical biopsies,” explained Glen Kristiansen, MD, of the Institute of Pathology at the University Hospital Bonn (Germany). This is the first study to determine whether PITX2 methylation can be used for individualized risk assessment of prostate cancer using core biopsy tissue.
Investigators measured PITX2 methylation biomarker levels using a quantitative real-time PCR assay in 24 tumour samples, 24 normal adjacent prostate tissue, and 22 samples with benign prostatic hyperplasia. PITX2 promoter methylation was found to be significantly higher in cancer samples compared to matched normal and benign prostatic hypertrophy tissues. “These findings demonstrate that the PITX2 biomarker discriminates between prostate cancer and non-cancerous tissue,” noted Dr. Kristiansen.
Researchers then examined whether PITX2 methylation could predict biochemical recurrence (two consecutive rises of serum PSA > 0.2 ng/mL) within a group of 300 prostate cancer patients who had undergone radical prostatectomy. They found that patients with high PITX2 methylation were at significantly increased risk for recurrence.
Subsequently, the biomarker was applied to the core biopsies of 32 patients with prostate cancer and 31 patients with benign prostatic disease. The core needle biopsy, the most common type of prostate biopsy, is performed by inserting a needle into the prostate to remove a small cylinder of tissue. Investigators found that 95% of 753 biopsy cores from 63 patients could be analysed. PITX2 methylation was significantly higher in tumour-positive biopsies and strongly correlated with prostate cancer severity as indicated by the International Society of Urological Pathology grading system.
Whether a patient with prostate cancer detected by elevated PSA should be treated pharmacologically, radiotherapeutically, or surgically is controversial, especially because of concerns about side effects and in light of recent data that intervention may not affect mortality within the first ten years. “This study not only confirms the prognostic value of PITX2 methylation in prostate cancer, but it also demonstrates its applicability to prostate biopsies. This enables us to plan further studies that may finally translate this biomarker into clinical practice with the aim of further individualizing treatment strategies,” commented Dr. Kristiansen.
EurekAlert
http://tinyurl.com/hob7dal
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Researchers at Lund and Malmö universities in Sweden have measured a biomarker in cell-free blood plasma which can be linked to an overactive stress system in suicidal individuals. This biomarker can hopefully be used in future psychiatric studies.
“We don’t expect the marker to be able to predict who will try to commit suicide, but it may serve as a biological marker indicating greater stress exposure in vulnerable people suffering from various psychiatric conditions such as anxiety and depression. We would like to test the marker in future psychiatric studies and see how it is affected by, for example, lifestyle interventions, psychotherapy and pharmacological treatment”, says Daniel Lindqvist, associate professor of experimental psychiatry at Lund University and psychiatry resident at Psykiatri Skåne.
The researchers compared 37 patients who had been hospitalized at a psychiatric clinic after attempting suicide with an equal number of healthy control subjects. About 70 per cent of both groups were female, and the average age of the patients was approximately 40.
Compared to the healthy control subjects, the suicidal patients had strikingly increased levels of mitochondrial DNA in their cell-free blood plasma.
The researchers also found that the large amount of mitochondrial DNA in the plasma was linked to higher levels of cortisol in the blood. Cortisol is an important hormone in the body’s stress system and high levels of cortisol, which have been found in depressed and suicidal patients in previous studies, are a sign of an overactive stress system.
Previous studies have shown that depressed individuals have an increased level of mitochondrial DNA in their immune cells and that this is linked to stressful life events. Furthermore, studies on animals have shown that increased stress and cortisol levels are linked to higher mitochondrial DNA, but this is the first study to be tested on psychiatric patients.
“We believe the increased levels in suicidal patients are due to their exposure to severe stress for longer periods than the healthy subjects we compared them to. An increased level of cortisol can cause the body’s cells to malfunction, which in turn contributes to increased levels of cell-free mitochondrial DNA in the blood”, says Lars Ohlsson, senior lecturer at Malmö University.
“The amount of mitochondrial DNA in cell-free plasma is a new and interesting marker of stress that can be used in future psychiatric studies, but the results have to be replicated in other groups of patients as well. A key question will be how the biomarker changes over time in connection with the patient’s symptoms improving or deteriorating”, says Åsa Westrin, associate professor of clinical psychiatry at Lund University and senior physician at Psykiatri Skåne.
Lund University
http://tinyurl.com/zrjeo9o
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Researchers cracked the complete genetic code of individual cells in healthy and diseased human lung tissues to find potential new molecular targets for diagnosing and treating the lethal lung disease Idiopathic Pulmonary Fibrosis (IPF).
A team of scientists from Cincinnati Children’s Hospital Medical Center, in collaboration with investigators at Cedars-Sinai Medical Center in Los Angeles, have published their findings.
“This paper identifies a number of novel targets and molecular pathways for IPF, for which there are pharmaceutical approaches,” said Jeffrey Whitsett, MD, lead investigator and co-director of the Perinatal Institute at Cincinnati Children’s. “Airway cells can be obtained by brushing the airway or biopsy, and marker genes can be tested to make a diagnosis or monitor treatment.”
IPF is a common and lethal interstitial lung disease in adults, which means it inflames, scars and reconfigures lung tissues. This causes loss of alveoli, where oxygen and carbon dioxide are normally exchanged. Similar losses of lung function can occur earlier in life, especially in children with diseases caused by mutations in genes critical for surfactant and maintenance of the lung saccules.
Biological processes controlling the formation and function of the lung’s alveolar region require precisely orchestrated interactions between diverse epithelial, stromal and immune cells, according to study authors. Despite many years of extensive laboratory studies of whole tissue samples – trying to identify genetic, cellular and molecular processes that fuel lung ailments like IPF – the precise biology has remained elusive.
To overcome this, Whitsett and colleagues – including first author and bioinformatician Yan Xu, PhD of Cincinnati Children’s – conducted what they believe to be the first-ever single-cell RNA sequence analysis of normal and diseased human lung tissues (all donated with prior informed consent). This provided the authors with a detailed genetic blueprint of all the different epithelial cell types involved in IPF progression and a window to identify aberrant biological processes driving inflammation and fibrosis.
Analysis of normal lung epithelial cells found gene patterns linked to fully formed alveolar type 2 lung cells (AT2 cells), which are important for the production of surfactant, a substance containing a complex of proteins critical to breathing.
Analysis of diseased IPF cells found genetic markers for lung cells that were in indeterminate states of formation, the authors report. IPF cells had lost the normal genetic control systems needed to guide their functions. This study identifies abnormalities in gene expression that can be targeted for therapy of chronic lung diseases like IPF.
Leukemia researchers at Princess Margaret Cancer Centre have developed a 17-gene signature derived from leukemia stem cells that can predict at diagnosis if patients with acute myeloid leukemia (AML) will respond to standard treatment.
The findings could potentially transform patient care in AML by giving clinicians a risk scoring tool that within a day or two of diagnosis can predict individual response and help guide treatment decisions, says co-principal investigator Dr. Jean Wang, Affiliate Scientist at the Princess Margaret, University Health Network (UHN). Dr. Wang is also an assistant professor, Faculty of Medicine, University of Toronto and a hematologist at Toronto General Hospital, UHN.
The new biomarker is named the LSC17 score as it comes from the leukemia stem cells that drive disease and relapse. These dormant stem cells have properties that allow them to resist standard chemotherapy, which is designed to defeat rapidly dividing cancer cells. The persistence of these stem cells is the reason the cancer comes back in patients despite being in remission following treatment. AML is one of the most deadly types of leukemia and the most common type of acute leukemia in adults; it increases in frequency as we age. In Canada, there are more than 1,200 new cases each year. The five-year survival ranges between 20 per cent to 30 per cent and is lower in older people.
The study authors write that using the LSC17 score to single out high-risk patients predicted to have resistant disease “provides clinicians with a rapid and powerful tool to identify AML patients who are less likely to be cured by standard therapy and who could be enrolled in trials evaluating novel upfront or post-remission strategies.”
The researchers identified the LSC17 score by sampling the leukemia stem cell properties of blood or bone marrow samples from 78 AML patients from the cancer centre combined with molecular profiling technology that measures gene expression. Stanley W. K. Ng, a senior PhD candidate in the lab of Dr. Peter Zandstra at the Institute for Biomaterials and Biomedical Engineering, University of Toronto and co-lead author of the paper, used rigorous statistical approaches to develop and test the new “stemness score”, using AML patient data provided by the Princess Margaret leukemia clinic and collaborators in the United States and Europe.
“We identified the minimal set of genes that were most critical for predicting survival in these other groups of AML patients, regardless of where they were treated. With this core 17-gene score, we have shown we can rapidly measure risk in newly diagnosed AML patients,” says Dr. Wang.
In the study, analysis of patient samples demonstrated that high LSC17 scores meant poor outcomes with current standard treatment, even for patients who had undergone allogeneic stem cell transplantation. A low score indicated a patient would respond well to standard treatment and have a long-term remission.
The test to measure the LSC17 score has been adapted to a technology platform called NanoString. As the research team and international collaborators continue to validate the stemness risk score, plans are under way to test the score in a clinical trial at the Princess Margaret, which now has the NanoString system in its molecular diagnostic laboratory.
Princess Margaret Cancer Centre
http://tinyurl.com/jcba4tq
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Researchers at VIB and Ghent University have developed a tool to diagnose Familial Mediterranean Fever (FMF). Particularly common among Mediterranean populations, this genetic disease is characterized by inflammation, fever and severe pain. Because of its complex diagnosis, patients often remain untreated for many years, which can eventually lead to kidney failure. In collaboration with Ghent University Hospital and Antwerp University Hospital, VIB and Ghent University are now planning clinical trials to further validate immunodiagnosis of FMF.
In the Mediterranean basin, including the Middle East and Caucasus, FMF has a prevalence between 1 and 2 per 1,000 inhabitants. FMF is usually diagnosed during childhood, after which a daily, lifelong treatment is necessary. However, accurate diagnosis is complicated by a number of factors: other auto-inflammatory diseases show similar symptoms, the clinical picture is often incomplete in young children, atypical signs may occur, and a suggestive family history is sometimes lacking. Wrong or late diagnosis often even leads to unnecessary surgery and, ultimately, kidney failure.
The lab of professor Mohamed Lamkanfi (VIB-Ghent University) developed an alternative for today’s inadequate diagnosis, efficiently segregating FMF patients from people suffering from other auto-inflammatory diseases and healthy individuals. The tool detects changes in the body’s immune reaction to pyrin, a protein that is usually mutated in FMF. Following successful tests on mice, the tool has been validated in 13 patients in collaboration with physicians from Belgium and Italy.
Prof. Mohamed Lamkanfi (VIB-Ghent University): “As next steps, we are setting up clinical trials in Belgium for which we are actively seeking volunteers – both FMF patients and people suffering from related inflammatory disorders. These trials are funded by, among other parties, the European Research Council and FWO (Research Foundation – Flanders). In addition, labs from the Netherlands and Italy have already expressed interest. We are also exploring possible collaborations with industrial partners in order to make our method available as a diagnostic kit.”
VIB
http://tinyurl.com/zpa6s88
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Chemistry researchers develop a simple diagnostic test that can identify the level of cocaine in a person’s urine or oral fluid. The new test offers a low cost, quick method that could be used for testing at the roadside, in the workplace or in prisons
Current commercially available portable testing kits can give false positive results and cannot tell how much cocaine a person has ingested
For the first time, the researchers have been able to prove that it is possible to confidently detect levels of cocaine and their metabolites using a compact ‘mass spectrometer’ (a chemical-based analytical technique). The test uses chromatography to separate cocaine from other compounds and can not only detect the presence of cocaine but also give quantitative data about the amount of cocaine a person has ingested.
The test was found to offer a level of sensitivity below the cut-off level normally used for oral fluid drug testing, meaning that it can detect even low levels of cocaine in a person’s urine or oral fluid. The technique potentially offers an effective solution for scenarios where a rapid test is required. This could include roadside testing by police of motorists, and also drug testing in the workplace and in prisons.
While there are a number of portable tests for cocaine commercially available, these are mainly based on antibody reagents, which cannot offer quantitative data and – since the cocaine antibody can bind to something that is not cocaine – can give false positive results.
The research paper’s lead author, Mahado Ismail of the University of Surrey, explained, “Surface mass spectrometry is used in a wide range of disciplines to obtain chemical information from the surface of a sample. However until now it has not been possible to translate this method to low cost, portable testing.
“This new method, which extracts analytes from a surface and separates them using chromatography, has been shown to provide a sensitive, accurate result. Our next step will be to test the efficacy of the system for monitoring other drugs of abuse, while we are also looking for follow-on funding to further develop the test.”
University of Surrey
http://tinyurl.com/z65q5du
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Genetic differences in the FADS1 gene determine the risk for many different diseases. The ability to produce polyunsaturated fats like omega-3 and omega-6 differs between individuals and this affects the risk for disturbed metabolism, inflammatory diseases and several types of cancer.
Scientists at Uppsala University and SciLifeLab in Sweden have clarified this in detail.
“After detailed experiments we now know exactly which mutation in the region that is functional and directly involved in FADS1 regulation,” says Gang Pan at the Department of Immunology, Genetics and Pathology, Uppsala University and one of the authors of the article.
In this new study the scientists show that the gene region which controls FADS1 appeared 6 million years ago and is present in human and chimpanzee but not in other species. Since increased production of omega-3 and omega-6 is favourable to brain development this event may have contributed to human evolution. A mutation happened 300,000 years ago which further increased the capacity of the gene to produce both omega-3 and omega-6 fatty acids. This mutation constituted an evolutionary advantage that has led to the more active variant of FADS1 being the common one in major parts of the world.
In historical times people ate equal amounts of omega-3, coming from fish and vegetables, and omega-6 coming from meat and egg.
“Since we now live longer and have changed our diet radically – modern food in the Western world has drastic excess of omega-6 – what was an advantage in historical times may have turned against us and become an increased risk for many diseases,” says Gang Pan.
The genetic difference at FADS1 affects levels of LDL- and HDL-cholesterol, several other important fats, blood sugar and the metabolic syndrome, as well as how well we respond to treatment to control blood fat. It affects the risk for allergies and inflammatory diseases like rheumatism and inflammatory bowel disease. In addition it influences the risk for colon cancer and other types of cancer, as well as the heart rate.
“Polyunsaturated fats are involved in a surprising number of processes and the hope is that the new knowledge will make it possible to treat some of these diseases in a targeted way,” says Claes Wadelius, Professor of Medical Genetics at Uppsala University/SciLIfeLab, Sweden and the main author of the study.
Uppsala University
http://tinyurl.com/jc8xek6
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New insights into predicting the most aggressive forms of prostate cancer
, /in E-News /by 3wmediaMost prostate cancer (Pca) is diagnosed through a blood test, serum PSA testing. The well appreciated down-side of PSA testing is the diagnosis of a considerable proportion of indolent cancers that are highly unlikely to progress to clinically significant, lethal disease. Our limited ability to accurately identify men destined to suffer and die from the disease from the majority of indolent cases is a major concern and contributes to the dilemma regarding Pca screening and its genetic testing. There is therefore an unmet need to develop genetic tests that can predict whether a man specifically is highly susceptible to the aggressive form of prostate cancer. In some other cancers, such as breast and ovarian cancer, certain predictors of aggressiveness (e.g. BRCA gene mutations) have proven effective in identifying subsets of patients for specific interventions.
In prostate cancer, genetic testing to predict the individual risk to Pca is not performed routinely because of the absence of a marker which accurately identifies aggressive prostate cancer. In a new study, Dr. Alex Zlotta and colleagues identified a new region within the Kallikrein gene, the Kallikrein 6 gene region, detectable in the blood, that is strongly associated with aggressive prostate cancer (defined as Gleason Score ?8) in a cohort of 1858 men from three continents. The team developed a blood test at the Lunenfeld-Tanenbaum Research Institute which detects variants of this Kallikrein 6 gene. The test was validated in three independent cohorts including unique cohorts from large international screening studies for prostate cancer.
The Kallikrein 6 gene variants identified also independently predicted treatment failure after surgery or radiation for prostate cancer in a fourth independent cohort. The frequency of the gene variants varied from 6 to 14% in the population and the increased risk of aggressive prostate cancer was multiplied by almost 3 times in men who harboured the mutations.
Most studies to date have focused on the risk of prostate cancer, not the specific risk of aggressive lethal prostate cancer. The demonstration that germline variants of a new gene, Kallikrein 6, are strongly associated with aggressive prostate cancer, may be of high value in the management of the most common cancer in men.
Lunenfeld-Tanenbaum Research Institute
research.lunenfeld.ca/rssnews/?page=2165
Cause of obsessive-compulsive disorder discovered
, /in E-News /by 3wmediaAn overactive molecular signal pathway in the brain region of the amygdala can lead to obsessive-compulsive disorder (OCD). A research team from Würzburg has established this connection.
Some people have an extreme fear of dirt or bacteria. As a result, they may develop a habit of compulsive washing and repeatedly cleaning their hands or body. They are trapped in a vicious circle, as the fear of new contamination returns quickly after washing. Sufferers see no way out. They are even incapable of changing their behaviour when the excessive washing has led to skin irritation or damage.
Around two percent of the general population suffer from some kind of obsessive-compulsive disorder (OCD) at least once in their life. The disorder is characterised by persistent intrusive thoughts which the sufferers try to compensate for by repetitive ritualized behaviour.
Like depression, eating disorders and other mental diseases, OCD is treated with antidepressants. However, the drugs are non-specific, that is they are not tailored to the respective disease. Therefore, scientists have been looking for new and better targeted therapies that have fewer side effects.
Professor Kai Schuh from the Institute of Physiology at the Julius-Maximilians-Universität (JMU) Würzburg (Germany) and his team explore the underlying causes of obsessive-compulsive disorder in collaboration with the JMU’s Departments of Psychiatry and Neurology.
"We were able to show in mouse models that the absence of the protein SPRED2 alone can trigger an excessive grooming behaviour," Schuh says. He believes that this finding is crucial as no clear trigger for this type of disorder has been identified until now. Previous research pointed to multiple factors being responsible for developing OCD.
Occurring in all cells of the body, the protein SPRED2 is found in particularly high concentrations in regions of the brain, namely in the basal ganglia and the amygdala. Normally, the protein inhibits an important signal pathway of the cell, the so-called Ras/ERK-MAP kinase cascade. When it is missing, this signal pathway is more active than usual.
"It is primarily the brain-specific initiator of the signal pathway, the receptor tyrosine kinase TrkB, that is excessively active and causes the overshooting reaction of the downstream components", biologist Dr. Melanie Ullrich explains.
Administering an inhibitor to attenuate the overactive signal cascade in the animal model improves the obsessive-compulsive symptoms. Moreover, the JMU research team was able to treat the OCD with an antidepressant, similarly to standard therapy in humans.
"Our study delivers a valuable new model that allows the disease mechanisms to be investigated and new therapy options for obsessive-compulsive disorders to be tested," Professor Schuh says.
The recently discovered link between OCDs and the Ras/ERK-MAP kinase cascade also opens up new targets for therapy. Drugs that inhibit this cascade are already available and some of them are approved for human treatment.
According to Melanie Ullrich, these are cancer drugs, as overactivation of the Ras/ERK-MAP kinase cascade is also a frequent trigger of cancer: "So we are wondering whether such drugs could also be effective in the treatment of obsessive-compulsive disorders and whether they are beneficial in terms of side effects."
University of Würzburg
www.uni-wuerzburg.de/en/sonstiges/meldungen/detail/artikel/ursache-fuer-zwangsstoerungen-entdeckt-1/
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