An imbalance of female sex hormones among men in Western nations may be contributing to high levels of male obesity, according to new research from the University of Adelaide.
In a paper researchers from the University’s School of Medical Sciences suggest that obesity among Western men could be linked with exposure to substances containing the female sex hormone oestrogen – substances that are more often found in affluent societies, such as soy products and plastics.
The research was conducted by University of Adelaide medical student James Grantham and co-authored by Professor Maciej Henneberg, Wood Jones Professor of Anthropological and Comparative Anatomy.
Mr Grantham compared obesity rates among men and women from around the world with measures such as Gross Domestic Product to determine the impact of affluence on obesity. He found that while it was normal for women in the developing world to have significantly greater levels of obesity than men, the developed world offers quite a different picture.
‘Hormonally driven weight gain occurs more significantly in females than in males, and this is very clear when we look at the rates of obesity in the developing world,’ Mr Grantham says.
‘However, in the Western world, such as in the United States, Europe and Australia, the rates of obesity between men and women are much closer. In some Western nations, male obesity is greater than female obesity.
‘While poor diet is no doubt to blame, we believe there is more to it than simply a high caloric intake,’ Mr Grantham says.
Professor Henneberg says: ‘Exposure to oestrogen is known to cause weight gain, primarily through thyroid inhibition and modulation of the hypothalamus. Soy products contain xenoestrogens, and we are concerned that in societies with a high dietary saturation of soy, such as the United States, this could be working to ‘feminise’ the males. This would allow men in those communities to artificially imitate the female pattern of weight gain.
‘Another well-established source of xenoestrogen is polyvinyl chloride, known as PVC. This product is in prominent use in most wealthy countries, from plastic medical devices to piping for our water supplies.’
Professor Henneberg says micro-evolutionary changes may be occurring within Western societies that could also be leading to changes in testosterone and oestrogen in men. ‘This would certainly explain the various concerns about sperm count reductions among men in developed nations,’ he says.
Professor Henneberg and Mr Grantham say further research is needed to better understand whether or not environmental factors are leading to a ‘feminisation’ of men in the Western world.
University of Adelaide
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A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found.
Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. ‘Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,’ Chen said.
The research behind those drugs had targeted the long-recognised feature of Alzheimer’s patients’ brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die.
‘The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,’ Chen explained.
‘We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients,’ Chen said.
He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called ‘reactive astrocytes’ in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.
Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped ‘astrocyte’ cells which, in a healthy individual, surround and support individual neurons in the brain. ‘Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,’ Chen said.
Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice).
‘Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,’ Chen said.
His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.
Importantly, Chen said, ‘After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.’
Penn State University
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Different mechanisms of response could explain poor treatment response in rheumatoid factor positive patients
Data demonstrate the possibility of using biomarkers (developed from whole blood gene expression profiles) in children with juvenile idiopathic arthritis (JIA) to predict the status of their disease at 12 months. The long-term disease status at 12 months was accurately predicted only after treatment had been initiated, in newly diagnosed patients.
JIA is the most common childhood chronic rheumatic disease, affecting 16-150 children in every 100,000. As indicated by the name, the cause of JIA is largely unknown.3
‘By predicting disease progression in these young children we can better understand the course of the disease and how best to treat the individual,’ said lead author of the study Professor James Jarvis, from the Department of Paediatrics, University at Buffalo, Buffalo, New York.
Blood gene expression profiling has led to major advances in the field of rheumatology over the last decade but to date it has only been possible to predict therapeutic outcome at 6 months.
‘The challenge was to test the feasibility of using these prognostic biomarkers from whole blood gene expression profiles in children with newly diagnosed JIA to predict disease status at one year,’ explained Professor Jarvis. ‘Baseline expression profiles that could predict disease status at six months could not predict status at 12 months. However, using four month data (the earliest point at which samples were collected from children on treatment) we were able to determine strong predictive properties for disease status at 12 months. Thus, after children had initiated therapy longer term outcome was predictable,’ Professor Jarvis said.
In this study, researchers also discovered the appearance of different mechanisms of response in Rheumatoid Factor (RF) positive and RF negative patients after four months of therapy, a finding that could explain the relative refractoriness of RF positive patients to otherwise effective therapies.
Whole blood expression profiles were studied from children enrolled in the TREAT study, an NIH-funded clinical trial comparing methotrexate (MTX) with MTX + etanercept in children with newly-diagnosed JIA. Gene expression profiles were examined to determine those genes whose expression levels best predicted outcome (active vs. inactive disease) at 12 months.
Researchers have described seven types of JIA, which are distinguished by their signs and symptoms, the number of joints affected, the results of laboratory tests, and the family history. In general, symptoms include joint pain, swelling, tenderness and stiffness that last for more than six continuous weeks; the condition can also affect the eyes and lymph nodes.
EurekAlert
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An Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.
Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.
Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.
‘As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away,’ said Dr. Picketts. ‘Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six.’
The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.
‘These epigenetic regulators are known to affect memory, behaviour and learning,’ said Dr. Picketts. ‘Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal.’
There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it ‘is certainly possible and an interesting avenue to explore.’
In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum.
Ottawa Hospital Research Institute
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The Children’s Medical Center Research Institute at UT Southwestern (CRI) has identified a biomarker that enables researchers to accurately characterise the properties and function of mesenchymal stem cells (MSCs) in the body. MSCs are the focus of nearly 200 active clinical trials registered with the National Institutes of Health, targeting conditions such as bone fractures, cartilage injury, degenerative disc disease, and osteoarthritis.
The finding, published in the journal Cell Stem Cell on June 19, significantly advances the field of MSC biology, and if the same biomarker identified in CRI’s studies with mice works in humans, the outlook for clinical trials that use MSCs will be improved by the ability to better identify and characterize the relevant cells.
“There has been an increasing amount of clinical interest in MSCs, but advances have been slow because researchers to date have been unable to identify MSCs and study their normal physiological function in the body,” said Dr. Sean Morrison, Director of the Children’s Research Institute, Professor of Paediatrics at UT Southwestern Medical Center, and a Howard Hughes Medical Institute Investigator. “We found that a protein known as leptin receptor can serve as a biomarker to accurately identify MSCs in adult bone marrow in vivo, and that those MSCs are the primary source of new bone formation and bone repair after injury.”
In the course of their investigation, the CRI researchers found that leptin receptor-positive MSCs are also the main source of factors that promote the maintenance of blood-forming stem cells in the bone marrow.
“Unfortunately, many clinical trials that are testing potential therapies using MSCs have been hampered by the use of poorly characterized and impure collections of cultured cells,” said Dr. Morrison, senior author of the study and holder of the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern. “If this finding is duplicated in our studies with human MSCs, then it will improve the characterization of MSCs that are used clinically and could increase the probability of success for well-designed clinical trials using MSCs.”
Children’s Medical Center Research Institute at UT Southwestern
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The discovery of a new therapeutic target for certain kinds of myeloproliferative disease is, without doubt, good news. This is precisely the discovery made by the Stem Cell Physiopathology group at the CNIC (the Spanish National Cardiovascular Research Center), led by Dr. Simón Méndez–Ferrer. The team has shown that the microenvironment that controls hematopoietic stem cells can be targeted for the treatment of a set of disorders called myeloproliferative neoplasias, the most prominent of which are chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myelogenous leukemia (CML).
The findings, published today in Nature, demonstrate that these myeloproliferative neoplasias only appear after damage to the microenvironment that sustains and controls the hematopoietic stem cells—the cells that produce the cells of the blood and the immune system. Protecting this microenvironment, or niche, has thus emerged as a new route for the treatment of these diseases, for which there is currently no fully effective treatment.
‘In normal conditions, the microenvironment is able to control the proliferation, differentiation and migration of the hematopoietic stem cell. A specific genetic mutation in these cells results in inflammatory injury to the microenvironment and this control breaks down. What our work shows is that this damage can be prevented or reversed by treatments that target the niche,’ explained Dr. Méndez-Ferrer.
Indeed, the same team of researchers has demonstrated the efficacy of a possible new treatment, which has been patented through the CNIC. The treatment involves an innovative use of clinically approved treatments for other diseases, so that, according to the authors, ‘it shouldn’t be associated with adverse side effects’. The new treatment route has been tested in animals and has received financial backing for a multicenter phase II clinical trial. ‘This study has a very strong translational and clinical potential’, emphasized study first author Dr. Lorena Arranz, who added that ‘current treatment for myeloproliferative neoplasias is largely symptomatic and directed at preventing thrombosis and fatal cardiovascular events’.
The only real cure available today is a bone marrow transplant, which is not advisable in patients over 50 years old. ‘This makes it important to identify new therapeutic targets for the development of effective treatments,’ the investigators conclude.
EurekAlert
www.eurekalert.org/pub_releases/2014-06/cndi-moh062014.php
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UCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.
Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.
The study collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.
Adult stem cells in lung airways are present specifically to repair the airways after injury or disease caused by smoking, pollution, viruses or other factors. Gomperts and her team found that this reparative process is tightly regulated by molecules called reactive oxygen species, or ROS.
Recent research has shown that low levels of ROS are important for signalling the stem cells to perform important functions — such as repairing tissue damage — while high levels of ROS can cause stem cells to die. But the level of ROS needed for repair to be initiated has remained a subject of debate among researchers.
The UCLA study found that the dynamic flux of ROS from low to moderate levels in the airway stem cells is what drives the repair process, and that the increase in ROS levels in the repairing cell is quickly reduced to low levels to prevent excessive cell proliferation.
Gomperts’ lab found that disrupting this normal regulation of ROS back to low levels is equivalent to pulling the brakes off of the stem cells: They will continue to make too many of themselves, which causes the cells not to mature and instead become precancerous lesions. Subsequent progressive genetic changes to the cells in these lesions over time can eventually allow cancerous tumours to form.
‘Low ROS is what keeps stem cells primed so that your body is poised and ready to respond to injury and repair,’ said Gomperts, who also is an associate professor in the department of paediatrics at UCLA. ‘Loss of this ROS regulation leads to precancerous lesions. Now, with this precancerous model in place, we can begin looking for what we call ‘driver mutations,’ or those specific changes that take the precancerous lesions to full-blown cancer.’
Gomperts said that because many different factors — including cigarette smoke, smog and inflammation — could potentially trigger an increase in ROS in the airway stem cells, researchers might eventually be able to customize treatments based on the cause. ‘There are likely multiple ways for a person to get to a precancerous lesion, so the process could be different among different groups of people. Imagine a personalized way to identify what pathways have gone wrong in a patient, so that we could target a therapy to that individual.’
The research’s ultimate goal is to develop a targeted strategy to prevent pre-malignant lesions from forming by targeting the biology of these lesions and
University of California – Los Angeles
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A team of scientists, led by principal investigator David D. Schlaepfer, PhD, professor in the Department of Reproductive Medicine at the University of California, San Diego School of Medicine report that small molecule inhibitors to a protein called focal adhesion kinase (FAK) selectively prevent the growth of ovarian cancer cells as tumour spheroids.
Ovarian cancer is a leading cause of female cancer death in the United States. On average, more than 21,000 women are diagnosed with ovarian cancer each year and 14,270 die. Many women achieve remission, but cancer recurrence rates exceed 75 percent, prompting the need for new treatments.
“Ovarian cancer spreads within a women’s peritoneal space through a unique mechanism that involves the survival of small clusters of tumour cells termed spheroids,” said Schlaepfer. “Our studies show that FAK signalling functions at the centre of a tumour cell survival signalling network.”
In the first study, published in Gynecologic Oncology, first author Nina Shah, MD, a gynaecological oncology fellow in the Department of Reproductive Medicine, found that ovarian tumour cells with low levels of a tumour suppressor protein, called merlin, displayed heightened sensitivity to FAK inhibitor growth cessation.
“With FAK inhibitor clinical trials already testing a similar linkage in mesothelioma (a rare cancer that affects the protective lining of many internal organs), our results support the hypothesis that protein biomarkers such as merlin may identify those patients who may best respond to FAK inhibitor therapy,” said Schlaepfer.
In the second study in Molecular Cancer Therapeutics, first author Isabelle Tancioni PhD, an assistant project scientist at UC San Diego Moores Cancer Center discovered that a network of signals generated by osteopontin – a beta-5 integrin receptor used in cell-to-cell signalling – and FAK control ovarian cancer spheroid growth. High levels of beta-5 integrin and FAK expression are associated with a poor prognosis for some ovarian cancer patients. “Thus, high levels of beta-5 integrin may serve as a novel biomarker for ovarian carcinoma cells that possess active FAK signalling,” said Schlaepfer.
Schlaepfer noted that tumour recurrence and metastasis are responsible for the majority of ovarian cancer-related deaths and said the new findings support on going clinical trials of FAK inhibitors as new agents in the fight to prevent ovarian cancer progression.
University of California – San Diego
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Researchers at the University of California, San Diego School of Medicine have identified a new biomarker that predicts whether glioblastoma – the most common form of primary brain cancer – will respond to chemotherapy.
“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”
To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase or MGMT. This protein dampens the cancer-killing effect of temozolomide. Tumours with high levels of MGMT are associated with a poor response to temozolomide therapy.
The scientists systematically tested every microRNA in the human genome to identify those that suppressed MGMT expression, with the expectation that high-levels of these microRNAs in the tumour would predict improved therapeutic response to temozolomide.
“We showed that a signature of the MGMT-regulating microRNAs predicted temozolomide response in a cohort of glioblastoma patients. Validation of these results should lead to diagnostic tools to enable us to determine which patients will benefit most from temozolomide therapy,” said Chen.
In the study, the scientists also discovered that injection of the MGMT-regulating microRNAs into glioblastoma cells increased tumour sensitivity to temozolomide treatment.
“These findings establish the foundation for microRNAs-based therapies to increase the efficacy of temozolomide in glioblastoma patients,” said lead author, Valya Ramakrishnan, PhD, postdoctoral researcher, UC San Diego School of Medicine.
University of California – San Diego
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Researchers led by geneticists at the Miller School have discovered a new gene mutation that causes hearing loss. Their study, which focused on a large Turkish family in which six individuals have been affected by hereditary deafness, identified a mutated form of the gene FAM65B as a cause of sensorineural hearing loss.
The research also demonstrates that FAM65B is a previously unrecognized component of the inner ear that is required for hearing.
“Hearing loss is the most common human sensory problem,” said Tekin. “We hope that identifying a new genetic cause of this disorder will lead to a better understanding of the molecular components of normal hearing.”
Hearing loss, which affects approximately 1 in 500 newborns, most often results from mutations of single genes that perform specific functions in the inner ear, where sound waves are converted to electrical signals. This process originates in the stereocilia — “hairs” projecting from cochlear hair cells that interconnect to form the hair bundle. Most of the approximately 50 previously identified hair bundle proteins are the products of genes that, when mutated, lead to hearing loss.
Researchers in this study, who conducted a genetic analysis of the subject family, identified a mutated form of FAM65B — a protein previously unassociated with hearing — as the cause. Further characterization of the protein product of FAM65B in rodents and zebrafish has confirmed the findings of the family study.
Miller School of Medicine
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Are female hormones playing a key role in obesity epidemic?
, /in E-News /by 3wmediaAn imbalance of female sex hormones among men in Western nations may be contributing to high levels of male obesity, according to new research from the University of Adelaide.
In a paper researchers from the University’s School of Medical Sciences suggest that obesity among Western men could be linked with exposure to substances containing the female sex hormone oestrogen – substances that are more often found in affluent societies, such as soy products and plastics.
The research was conducted by University of Adelaide medical student James Grantham and co-authored by Professor Maciej Henneberg, Wood Jones Professor of Anthropological and Comparative Anatomy.
Mr Grantham compared obesity rates among men and women from around the world with measures such as Gross Domestic Product to determine the impact of affluence on obesity. He found that while it was normal for women in the developing world to have significantly greater levels of obesity than men, the developed world offers quite a different picture.
‘Hormonally driven weight gain occurs more significantly in females than in males, and this is very clear when we look at the rates of obesity in the developing world,’ Mr Grantham says.
‘However, in the Western world, such as in the United States, Europe and Australia, the rates of obesity between men and women are much closer. In some Western nations, male obesity is greater than female obesity.
‘While poor diet is no doubt to blame, we believe there is more to it than simply a high caloric intake,’ Mr Grantham says.
Professor Henneberg says: ‘Exposure to oestrogen is known to cause weight gain, primarily through thyroid inhibition and modulation of the hypothalamus. Soy products contain xenoestrogens, and we are concerned that in societies with a high dietary saturation of soy, such as the United States, this could be working to ‘feminise’ the males. This would allow men in those communities to artificially imitate the female pattern of weight gain.
‘Another well-established source of xenoestrogen is polyvinyl chloride, known as PVC. This product is in prominent use in most wealthy countries, from plastic medical devices to piping for our water supplies.’
Professor Henneberg says micro-evolutionary changes may be occurring within Western societies that could also be leading to changes in testosterone and oestrogen in men. ‘This would certainly explain the various concerns about sperm count reductions among men in developed nations,’ he says.
Professor Henneberg and Mr Grantham say further research is needed to better understand whether or not environmental factors are leading to a ‘feminisation’ of men in the Western world. University of Adelaide
Discovery may lead to improvements in diagnosing, treating Alzheimer’s disease
, /in E-News /by 3wmediaA new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found.
Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. ‘Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,’ Chen said.
The research behind those drugs had targeted the long-recognised feature of Alzheimer’s patients’ brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die.
‘The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,’ Chen explained.
‘We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients,’ Chen said.
He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called ‘reactive astrocytes’ in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.
Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped ‘astrocyte’ cells which, in a healthy individual, surround and support individual neurons in the brain. ‘Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,’ Chen said.
Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice).
‘Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,’ Chen said.
His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.
Importantly, Chen said, ‘After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.’ Penn State University
Biomarkers predict long-term outcomes in juvenile idiopathic arthritis
, /in E-News /by 3wmediaDifferent mechanisms of response could explain poor treatment response in rheumatoid factor positive patients
Data demonstrate the possibility of using biomarkers (developed from whole blood gene expression profiles) in children with juvenile idiopathic arthritis (JIA) to predict the status of their disease at 12 months. The long-term disease status at 12 months was accurately predicted only after treatment had been initiated, in newly diagnosed patients.
JIA is the most common childhood chronic rheumatic disease, affecting 16-150 children in every 100,000. As indicated by the name, the cause of JIA is largely unknown.3
‘By predicting disease progression in these young children we can better understand the course of the disease and how best to treat the individual,’ said lead author of the study Professor James Jarvis, from the Department of Paediatrics, University at Buffalo, Buffalo, New York.
Blood gene expression profiling has led to major advances in the field of rheumatology over the last decade but to date it has only been possible to predict therapeutic outcome at 6 months.
‘The challenge was to test the feasibility of using these prognostic biomarkers from whole blood gene expression profiles in children with newly diagnosed JIA to predict disease status at one year,’ explained Professor Jarvis. ‘Baseline expression profiles that could predict disease status at six months could not predict status at 12 months. However, using four month data (the earliest point at which samples were collected from children on treatment) we were able to determine strong predictive properties for disease status at 12 months. Thus, after children had initiated therapy longer term outcome was predictable,’ Professor Jarvis said.
In this study, researchers also discovered the appearance of different mechanisms of response in Rheumatoid Factor (RF) positive and RF negative patients after four months of therapy, a finding that could explain the relative refractoriness of RF positive patients to otherwise effective therapies.
Whole blood expression profiles were studied from children enrolled in the TREAT study, an NIH-funded clinical trial comparing methotrexate (MTX) with MTX + etanercept in children with newly-diagnosed JIA. Gene expression profiles were examined to determine those genes whose expression levels best predicted outcome (active vs. inactive disease) at 12 months.
Researchers have described seven types of JIA, which are distinguished by their signs and symptoms, the number of joints affected, the results of laboratory tests, and the family history. In general, symptoms include joint pain, swelling, tenderness and stiffness that last for more than six continuous weeks; the condition can also affect the eyes and lymph nodes. EurekAlert
Researchers find gene critical for development of brain motor centre
, /in E-News /by 3wmediaAn Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.
Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.
Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.
‘As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away,’ said Dr. Picketts. ‘Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six.’
The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.
‘These epigenetic regulators are known to affect memory, behaviour and learning,’ said Dr. Picketts. ‘Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal.’
There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it ‘is certainly possible and an interesting avenue to explore.’
In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum. Ottawa Hospital Research Institute
Key to identifying, enriching mesenchymal stem cells
, /in E-News /by 3wmediaThe Children’s Medical Center Research Institute at UT Southwestern (CRI) has identified a biomarker that enables researchers to accurately characterise the properties and function of mesenchymal stem cells (MSCs) in the body. MSCs are the focus of nearly 200 active clinical trials registered with the National Institutes of Health, targeting conditions such as bone fractures, cartilage injury, degenerative disc disease, and osteoarthritis.
The finding, published in the journal Cell Stem Cell on June 19, significantly advances the field of MSC biology, and if the same biomarker identified in CRI’s studies with mice works in humans, the outlook for clinical trials that use MSCs will be improved by the ability to better identify and characterize the relevant cells.
“There has been an increasing amount of clinical interest in MSCs, but advances have been slow because researchers to date have been unable to identify MSCs and study their normal physiological function in the body,” said Dr. Sean Morrison, Director of the Children’s Research Institute, Professor of Paediatrics at UT Southwestern Medical Center, and a Howard Hughes Medical Institute Investigator. “We found that a protein known as leptin receptor can serve as a biomarker to accurately identify MSCs in adult bone marrow in vivo, and that those MSCs are the primary source of new bone formation and bone repair after injury.”
In the course of their investigation, the CRI researchers found that leptin receptor-positive MSCs are also the main source of factors that promote the maintenance of blood-forming stem cells in the bone marrow.
“Unfortunately, many clinical trials that are testing potential therapies using MSCs have been hampered by the use of poorly characterized and impure collections of cultured cells,” said Dr. Morrison, senior author of the study and holder of the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern. “If this finding is duplicated in our studies with human MSCs, then it will improve the characterization of MSCs that are used clinically and could increase the probability of success for well-designed clinical trials using MSCs.” Children’s Medical Center Research Institute at UT Southwestern
Microenvironment of haematopoietic stem cells can be a target for myeloproliferative disorders
, /in E-News /by 3wmediaThe discovery of a new therapeutic target for certain kinds of myeloproliferative disease is, without doubt, good news. This is precisely the discovery made by the Stem Cell Physiopathology group at the CNIC (the Spanish National Cardiovascular Research Center), led by Dr. Simón Méndez–Ferrer. The team has shown that the microenvironment that controls hematopoietic stem cells can be targeted for the treatment of a set of disorders called myeloproliferative neoplasias, the most prominent of which are chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myelogenous leukemia (CML).
The findings, published today in Nature, demonstrate that these myeloproliferative neoplasias only appear after damage to the microenvironment that sustains and controls the hematopoietic stem cells—the cells that produce the cells of the blood and the immune system. Protecting this microenvironment, or niche, has thus emerged as a new route for the treatment of these diseases, for which there is currently no fully effective treatment.
‘In normal conditions, the microenvironment is able to control the proliferation, differentiation and migration of the hematopoietic stem cell. A specific genetic mutation in these cells results in inflammatory injury to the microenvironment and this control breaks down. What our work shows is that this damage can be prevented or reversed by treatments that target the niche,’ explained Dr. Méndez-Ferrer.
Indeed, the same team of researchers has demonstrated the efficacy of a possible new treatment, which has been patented through the CNIC. The treatment involves an innovative use of clinically approved treatments for other diseases, so that, according to the authors, ‘it shouldn’t be associated with adverse side effects’. The new treatment route has been tested in animals and has received financial backing for a multicenter phase II clinical trial. ‘This study has a very strong translational and clinical potential’, emphasized study first author Dr. Lorena Arranz, who added that ‘current treatment for myeloproliferative neoplasias is largely symptomatic and directed at preventing thrombosis and fatal cardiovascular events’.
The only real cure available today is a bone marrow transplant, which is not advisable in patients over 50 years old. ‘This makes it important to identify new therapeutic targets for the development of effective treatments,’ the investigators conclude.
EurekAlert
www.eurekalert.org/pub_releases/2014-06/cndi-moh062014.php
Link between stem cell regulation and the development of lung cancer
, /in E-News /by 3wmediaUCLA researchers led by Dr. Brigitte Gomperts have discovered the inner workings of the process thought to be the first stage in the development of lung cancer. Their study explains how factors that regulate the growth of adult stem cells that repair tissue in the lungs can lead to the formation of precancerous lesions.
Findings from the three-year study could eventually lead to new personalized treatments for lung cancer, which is responsible for an estimated 29 percent of U.S. cancer deaths, making it the deadliest form of the disease.
The study collaborated with Manash Paul and Bharti Bisht, postdoctoral scholars and co-lead authors of the study.
Adult stem cells in lung airways are present specifically to repair the airways after injury or disease caused by smoking, pollution, viruses or other factors. Gomperts and her team found that this reparative process is tightly regulated by molecules called reactive oxygen species, or ROS.
Recent research has shown that low levels of ROS are important for signalling the stem cells to perform important functions — such as repairing tissue damage — while high levels of ROS can cause stem cells to die. But the level of ROS needed for repair to be initiated has remained a subject of debate among researchers.
The UCLA study found that the dynamic flux of ROS from low to moderate levels in the airway stem cells is what drives the repair process, and that the increase in ROS levels in the repairing cell is quickly reduced to low levels to prevent excessive cell proliferation.
Gomperts’ lab found that disrupting this normal regulation of ROS back to low levels is equivalent to pulling the brakes off of the stem cells: They will continue to make too many of themselves, which causes the cells not to mature and instead become precancerous lesions. Subsequent progressive genetic changes to the cells in these lesions over time can eventually allow cancerous tumours to form.
‘Low ROS is what keeps stem cells primed so that your body is poised and ready to respond to injury and repair,’ said Gomperts, who also is an associate professor in the department of paediatrics at UCLA. ‘Loss of this ROS regulation leads to precancerous lesions. Now, with this precancerous model in place, we can begin looking for what we call ‘driver mutations,’ or those specific changes that take the precancerous lesions to full-blown cancer.’
Gomperts said that because many different factors — including cigarette smoke, smog and inflammation — could potentially trigger an increase in ROS in the airway stem cells, researchers might eventually be able to customize treatments based on the cause. ‘There are likely multiple ways for a person to get to a precancerous lesion, so the process could be different among different groups of people. Imagine a personalized way to identify what pathways have gone wrong in a patient, so that we could target a therapy to that individual.’
The research’s ultimate goal is to develop a targeted strategy to prevent pre-malignant lesions from forming by targeting the biology of these lesions and University of California – Los Angeles
Finding the Achilles’ heel of ovarian tumour growth
, /in E-News /by 3wmediaA team of scientists, led by principal investigator David D. Schlaepfer, PhD, professor in the Department of Reproductive Medicine at the University of California, San Diego School of Medicine report that small molecule inhibitors to a protein called focal adhesion kinase (FAK) selectively prevent the growth of ovarian cancer cells as tumour spheroids.
Ovarian cancer is a leading cause of female cancer death in the United States. On average, more than 21,000 women are diagnosed with ovarian cancer each year and 14,270 die. Many women achieve remission, but cancer recurrence rates exceed 75 percent, prompting the need for new treatments.
“Ovarian cancer spreads within a women’s peritoneal space through a unique mechanism that involves the survival of small clusters of tumour cells termed spheroids,” said Schlaepfer. “Our studies show that FAK signalling functions at the centre of a tumour cell survival signalling network.”
In the first study, published in Gynecologic Oncology, first author Nina Shah, MD, a gynaecological oncology fellow in the Department of Reproductive Medicine, found that ovarian tumour cells with low levels of a tumour suppressor protein, called merlin, displayed heightened sensitivity to FAK inhibitor growth cessation.
“With FAK inhibitor clinical trials already testing a similar linkage in mesothelioma (a rare cancer that affects the protective lining of many internal organs), our results support the hypothesis that protein biomarkers such as merlin may identify those patients who may best respond to FAK inhibitor therapy,” said Schlaepfer.
In the second study in Molecular Cancer Therapeutics, first author Isabelle Tancioni PhD, an assistant project scientist at UC San Diego Moores Cancer Center discovered that a network of signals generated by osteopontin – a beta-5 integrin receptor used in cell-to-cell signalling – and FAK control ovarian cancer spheroid growth. High levels of beta-5 integrin and FAK expression are associated with a poor prognosis for some ovarian cancer patients. “Thus, high levels of beta-5 integrin may serve as a novel biomarker for ovarian carcinoma cells that possess active FAK signalling,” said Schlaepfer.
Schlaepfer noted that tumour recurrence and metastasis are responsible for the majority of ovarian cancer-related deaths and said the new findings support on going clinical trials of FAK inhibitors as new agents in the fight to prevent ovarian cancer progression. University of California – San Diego
Biomarker predicts effectiveness of brain cancer treatment
, /in E-News /by 3wmediaResearchers at the University of California, San Diego School of Medicine have identified a new biomarker that predicts whether glioblastoma – the most common form of primary brain cancer – will respond to chemotherapy.
“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”
To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase or MGMT. This protein dampens the cancer-killing effect of temozolomide. Tumours with high levels of MGMT are associated with a poor response to temozolomide therapy.
The scientists systematically tested every microRNA in the human genome to identify those that suppressed MGMT expression, with the expectation that high-levels of these microRNAs in the tumour would predict improved therapeutic response to temozolomide.
“We showed that a signature of the MGMT-regulating microRNAs predicted temozolomide response in a cohort of glioblastoma patients. Validation of these results should lead to diagnostic tools to enable us to determine which patients will benefit most from temozolomide therapy,” said Chen.
In the study, the scientists also discovered that injection of the MGMT-regulating microRNAs into glioblastoma cells increased tumour sensitivity to temozolomide treatment.
“These findings establish the foundation for microRNAs-based therapies to increase the efficacy of temozolomide in glioblastoma patients,” said lead author, Valya Ramakrishnan, PhD, postdoctoral researcher, UC San Diego School of Medicine. University of California – San Diego
Newly discovered gene mutation is linked to hereditary deafness
, /in E-News /by 3wmediaResearchers led by geneticists at the Miller School have discovered a new gene mutation that causes hearing loss. Their study, which focused on a large Turkish family in which six individuals have been affected by hereditary deafness, identified a mutated form of the gene FAM65B as a cause of sensorineural hearing loss.
The research also demonstrates that FAM65B is a previously unrecognized component of the inner ear that is required for hearing.
“Hearing loss is the most common human sensory problem,” said Tekin. “We hope that identifying a new genetic cause of this disorder will lead to a better understanding of the molecular components of normal hearing.”
Hearing loss, which affects approximately 1 in 500 newborns, most often results from mutations of single genes that perform specific functions in the inner ear, where sound waves are converted to electrical signals. This process originates in the stereocilia — “hairs” projecting from cochlear hair cells that interconnect to form the hair bundle. Most of the approximately 50 previously identified hair bundle proteins are the products of genes that, when mutated, lead to hearing loss.
Researchers in this study, who conducted a genetic analysis of the subject family, identified a mutated form of FAM65B — a protein previously unassociated with hearing — as the cause. Further characterization of the protein product of FAM65B in rodents and zebrafish has confirmed the findings of the family study. Miller School of Medicine