A newborn’s first stool can signal the child may struggle with persistent cognitive problems, according to Case Western Reserve University Project Newborn researchers.
In particular, high levels of fatty acid ethyl esters (FAEE) found in the meconium (a newborn’s first stool) from a mother’s alcohol use during pregnancy can alert doctors that a child is at risk for problems with intelligence and reasoning.
Left untreated, such problems persist into the teen years, the research team from the Jack, Joseph and Morton Mandel School of Applied Social Sciences found.
“We wanted to see if there was a connection between FAEE level and their cognitive development during childhood and adolescence—and there was,” said Meeyoung O. Min, PhD, research assistant professor at the Mandel School and the study’s lead researcher. “FAEE can serve as a marker for foetal alcohol exposure and developmental issues ahead.”
Detecting prenatal exposure to alcohol at birth could lead to early interventions that help reduce the effects later, Min said.
For this study, researchers analysed the meconium of 216 subjects for levels of FAEE. (FAEE are composed of a group of products from metabolizing alcohol; this study examined ethyl myristate, ethyl oleate ethyl linoleate and ethyl linolenate.) They then gave intelligence tests at ages 9, 11 and 15.
The conclusion: There was a link between those with high levels of FAEE at birth and lower IQ scores.
“Although we already knew a mother’s alcohol use during her pregnancy may cause cognitive deficits, what is significant is that the early marker, not previously available, predicted this, establishing the predictive validity of FAEEs for determining alcohol exposure in utero” Min said.
Case Western Reserve University
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While the overall rate of colorectal cancer (CRC) is declining, CRC specifically among young patients is increasing. Previous studies have shown that CRC in patients younger than 50 years old tends to be more aggressive than CRC in older patients. A University of Colorado Cancer Center study offers early evidence of genetic differences between CRC in young and old patients, possibly pointing toward different treatments and strategies in combating the young form of the disease.
“We saw differences in two important gene signalling pathways, PPAR and IGF1R, which are involved in regulating cell development, metabolism, and growth,” says Christopher Lieu, MD, investigator at the CU Cancer Center and assistant professor of medical oncology at the University of Colorado School of Medicine.
Alterations in these signalling pathways have been implicated in the development of several types of cancer.
The study compared the genetics of 5 colorectal cancer tumours from younger patients (median age 31) to 6 tumours from older patients (median age 73), sequencing 45 million “reads” from each tumour. The group then explored the data for significant differences between groups. In addition to the pathways PPAR and IGF1R, the study showed that younger CRC tumour samples were enriched for pathways responsible for metabolizing drugs.
“Chemotherapies challenge cancer cells and younger people may metabolize these chemotherapies differently than older patients. This may explain why our traditional chemotherapy treatments may be less effective for younger patients with metastatic colorectal cancer,” says Todd Pitts, MS, research instructor in the Developmental Therapeutics Program at the CU Cancer Center, and the study’s lead author. (Pitts notes that this hypothesis will require additional exploration.)
The group plans to validate the finding of these differences in a larger patient population. Then, if PPAR and/or IGF1R prove to in fact be important drivers of CRC in young patients, the group hopes to explore trials of drugs targeting these potential tumour drivers. Toward this goal, the group has gathered the important resource of tumour samples grown from the tissues of young CRC patients, allowing further preclinical genetic and drug testing.
University of Colorado Cancer Centre
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Innovative gastric cancer-detection technology can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology.
Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the oesophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.
The new technology, developed by Prof. Hossam Haick of the Technion Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.
The research, published as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.
The first sample from each participant was analysed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.
The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.
The findings:
Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
The new technology accurately distinguishes between the various pre-malignant stages.
The new technology can be used to identify persons at risk for developing gastric cancer.
The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.
In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumours.
Technion
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Nobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.
The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.
The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.
Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”
Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli.
Rockefeller Hospital
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A new test developed by UBC researchers allows physicians to measure the effects of gene silencing therapy in Huntington’s disease and will support the first human clinical trial of a drug that targets the genetic cause of the disease.
The gene silencing therapy being tested by UBC researchers aims to reduce the levels of a toxic protein in the brain that causes Huntington’s disease.
The test was developed by Amber Southwell, Michael Hayden, and Blair Leavitt of UBC’s Centre for Molecular Medicine and Therapeutics and the Centre for Huntington Disease in collaboration with colleagues from Mayo Clinic.
“This is an important breakthrough for several promising gene silencing therapies in Huntington’s disease that are now moving from the bench to the bedside,” said Leavitt. “We can move forward with these clinical trials and accurately measure whether our treatments are working.”
Huntington’s disease is a genetic disorder but symptoms generally don’t appear until later in life. It affects the brain and gradually worsens, causing problems with coordination and movement, mental decline and psychiatric issues.
The genetic mutation responsible for Huntington’s produces a toxic form of a protein called huntingtin, which progressively injures brain cells. Reducing brain levels of this toxic protein should prevent or delay the onset of symptoms. Several huntingtin-lowering therapies have already shown great promise in animal models of Huntington’s disease and are rapidly approaching trials in humans.
The UBC research team found that they could accurately measure the levels of mutant huntingtin protein in the brain by collecting cerebrospinal fluid from a spinal tap. The ultrasensitive test detects small amounts of the toxic protein and can be used to follow changes in brain levels of the protein over time in response to new therapies.
This study enables Leavitt to initiate a new clinical trial of a huntingtin gene-silencing therapy for patients at the Centre for Huntington Disease at the Djavad Mowafaghian Centre for Brain Health, a partnership between UBC and Vancouver Coastal Health. This trial will test the safety of a novel gene-silencing treatment in patients and is already in the process of screening patient candidates. The trial will be the first human study of a drug targeting mutant huntingtin.
University of British Columbia
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The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that sticky aggregations or plaques of amyloid-beta peptides accumulate over time in the brain, triggering a series of events that ultimately result in the full-blown neurodegenerative disorder. The hypothesis has been a major driver of AD research for more than 20 years.
However, in a new study researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System suggest the picture is not so clear-cut, reporting that early indicators or biomarkers of AD development are not fixed in a specific sequence.
“Our current ability to identify early stages of AD is limited by the focus on amyloid accumulation and the expectation that biomarkers follow the same timeline for all individuals,” said Emily C. Edmonds, PhD, a senior postdoctoral fellow in the Department of Psychiatry and first author of the study.
But, Edmonds said, “AD is complex in the sense that there may be different neurobiological pathways leading to expression of the disease. Our findings suggest that the number of abnormal biomarkers and cognitive markers an individual possesses, without regard to the temporal sequence, is most predictive of future decline.”
“Preclinical AD” is a very early stage of AD prior to the appearance of diagnosable symptoms. Current National Institute of Aging-Alzheimer’s Association (NIA-AA) criteria for preclinical AD describe a disease progression that begins with accumulation of amyloid-beta, leading to neurodegeneration, cognitive decline and, eventually, diagnosable AD.
In their study, researchers classified 570 cognitively normal participants in the Alzheimer’s Disease Neuroimaging Initiative according to NIA-AA criteria, and then separately examined the participants based upon the presence and number of abnormal biological and cognitive markers associated with preclinical AD. They found that neurodegeneration alone was 2.5 times more common than amyloid accumulation alone at baseline measurements.
They then examined only those participants who progressed to a diagnosis of mild cognitive impairment, which is an at-risk cognitive state of AD. They found that it was most common to show neurodegeneration as the first sign of early AD, and equally common to show amyloid accumulation or subtle cognitive decline as the first sign.
Edmonds said that the findings underscore the need to improve identification of persons at risk for AD through the use of multiple, diverse assessment tools. This includes sensitive learning and memory tests capable of reliably identifying cognitive changes at the earliest stages.
“At present, it is much more common for assessment of cognition to be based on insensitive screening measures or reports of cognitive problems by patients or their family members,” said Edmonds. “These blunt screening tools can be very unreliable, which might explain why cognitive decline has traditionally been viewed as occurring later in the disease process. The integration of sensitive neuropsychological measures with assessment of biomarkers of AD can enhance our ability to more accurately identify individuals who are at risk for future progression to AD.”
University of California – San Diego
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Researchers discovered a new mechanism of how fluorescent proteins can change colour. It enables the microscopic visualization of individual cells in their three-dimensional environment in living organisms.
Researchers at ETH Zurich’s Department of Biosystems Science and Engineering in Basel have developed a new microscopy technique that enables for the first time to selectively visualize individual cells within the complex, three-dimensional tissue of a living organism. The researchers have thus succeeded in capturing spectacular microscopic images, such as in the nervous system of a zebrafish larva, a preferred model organism for research. Motor neurons in the spinal cord can be seen in the researchers’ images; at the same time, a single neuron with all its extensions is highlighted in another colour.
An observation by William Dempsey, post-doc in the group of ETH professor Periklis Pantazis, led to the new application. He worked with a special class of fluorescent proteins that change colour when irradiated with laser light of a specific wavelength. One such ‘chameleon protein’ is called Dendra 2, which normally emits green light when illuminated with blue light. The emission of Dendra 2 is however shifted into the red when it is irradiated by intensive violet or ultraviolet (UV) laser light.
Dempsey and Pantazis specifically discovered that when Dendra 2 is irradiated by both a blue and a red laser at the same time, the protein’s colour can also change to red. For this dual-colour illumination low intensity laser light is sufficient. In contrast to high intensity violet or UV irradiation it does not damage living cells.
ETH professor Pantazis and his colleagues then had an idea of how this finding could be deployed in light microscopy. Fluorescent proteins can be used to make whole cells, precise cell structures or single molecules visible. For the first time, the ETH researcher’s discovery permits a single cell or group of molecules located within a desirable part of a living organism to be highlighted with one colour, while all the other cells or molecules remain visible with another colour.
The research group showed that when used individually, two different laser beams cannot change a chameleon protein’s colour. But when the two beams are combined and directed in a way that they meet at a certain point on the object, then the proteins in focus change colour. In contrast, the proteins that are not activated at the same time by the two lasers retain their original colour.
The researchers have developed a simple and inexpensive colour filter, which can be used with the conventional confocal laser microscopes that are found in many biomedical research institutes. When mounted between the laser source and object, the filter divides the laser light into separate blue and red beams that are directed on to a small focal point on the object.
In the case of the zebrafish larva, which is transparent and therefore well suited for microscopy, the ETH researchers used Dendra 2 to colour neurons. They then focused the combined laser beam’s focal point on the cell body of a single neuron in a live, anesthetized zebrafish. The local Dendra 2 molecules became red, spread throughout the entire cell and dyed the cell extensions. All other cells, even in the immediate vicinity of the targeted cell, remained green.
The ability to make individual neurons visible could be of great importance, for example, in the precise mapping of the brain, according to Pantazis. Since the method is suitable for individual cell targeting in living organisms, it could also be used to examine dynamic processes; for example, what happens to individual cells or a group of molecules when researchers treat an organism with active pharmaceutical ingredients. Embryo development could also be examined in more detail. “Our method allows for a three-dimensional analysis in an elegant manner,” explains Pantazis. “This is a very nice example of how you can take a result from basic research and use it to provide a solution for a technically challenging issue.” Pantazis hopes the technique will be used more broadly in biomedical research in the future and is in talks with microscope manufacturers to implement this technology.
wavelength of light.
ETH Zurich
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Scientists of the Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München have identified a new mechanism which contributes to the development of idiopathic pulmonary fibrosis (IPF). They showed that the pathological changes of lung tissue are accompanied by an increase in protein turnover by the central protein degradation machinery of the cell – the proteasome.
Idiopathic pulmonary fibrosis is a very aggressive form of pulmonary fibrosis and has a particularly poor prognosis. This fatal disease, for which so far no causal therapies exist, is characterized by a massive deposition of connective and scar tissue in the lung, which leads to a progressive loss of lung function and ultimately death. Connective tissue is mainly produced by myofibroblasts. The research group led by PD Dr. Silke Meiners of the Institute of Lung Biology and the CPC showed now for the first time that the activation of these myofibroblasts depends on increased protein turnover by the 26S proteasome.
In the recently published study, the Helmholtz scientists were able to demonstrate an activation of the 26S proteasome during the transformation of normal fibroblasts into myofibroblasts both in vitro and in vivo using two different experimental models of pulmonary fibrosis. Moreover, increased protein turnover was also detected in fibrotic lung tissue of IPF patients. “Conversely, we were able to show that targeted inhibition of the 26S proteasome prevents the differentiation of primary human lung fibroblasts into myofibroblasts, confirming the essential role of enhanced proteasomal protein degradation for this pathological process,” said Silke Meiners.
“Understanding the mechanisms that lead to a disease such as IPF helps us identify innovative approaches that allow therapeutic intervention,” comments Professor Oliver Eickelberg, director of the Institute of Lung Biology and scientific director of the CPC. In further studies, the Helmholtz scientists want to test the therapeutic use of substances which specifically inhibit the 26S proteasome, but do not affect other proteasome complexes in the cell.
Helmholtz Zentrum München
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New research by an international team including Keck Medicine of USC scientists is bringing the origins of ovarian cancer into sharper focus.
The study highlights the discovery of three genetic variants associated with mucinous ovarian carcinomas (MOCs), offering the first evidence of genetic susceptibility in this type of ovarian cancer. The research also suggests a link between common pathways of development between MOCs and colorectal cancer and for the first time identifies a gene called HOXD9, which turns genes on and off, and provides clues about the development of MOCs.
‘It remains a mystery where these cancers come from,’ said Simon Gayther, Ph.D., professor in preventive medicine, Keck School of Medicine of USC, corresponding author of the international genome-wide association study (GWAS). ‘By finding these genetic markers, we begin to understand more about the biology of the disease itself. This study tells us more about the biology of ovarian cancer from the early development stage than most research has.’
Ovarian cancer is the fourth leading cause of cancer in American women and seventh most common cancer in women throughout the world (World Health Organization). In 2015, more than 14,000 American women will die of ovarian cancer, according to the American Cancer Society.
Most ovarian cancers have low survival rates, typically because of the misunderstanding of symptoms and discovery of the cancer in later, less treatable stages. ‘Although MOCs are a less common type of ovarian cancer with generally good prognosis when diagnosed in early stages, they are twice as likely to be resistant to treatment at later stages,’ said Andrew Berchuck, M.D., director of gynecologic oncology at Duke University Cancer Institute, and senior author of the study. ‘Our results will contribute to the identification of women at greatest risk of developing the disease with the long-term goal of prevention.’
The association analysis was based on 1,644 women diagnosed with MOC and more than 21,000 women without ovarian cancer. The research was conducted as part of the Collaborative Oncological Gene-environment Study (COGS), launched in 2009 with the goal of determining risks of breast, ovarian and prostate cancer.
EurekAlert
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With more than 200 million global users of statins, these medications are the very definition of ‘blockbuster.’ By stopping a substance the body uses to make cholesterol, statins can help stave off heart attacks and strokes — the top two causes of death worldwide. But in a significant percent of patients — up to 30 percent by some reports — statins can also eat away muscle tissue, causing weakness, muscle pain and in rare cases, potentially deadly kidney and liver damage.
And the problem could grow larger. Under the most recent heart disease prevention guidelines issued by the American Heart Association and American College of Cardiology, the potential number of candidates for statin therapy in the US jumped from 43 million to 56 million.
‘As doctors follow the current guidelines, we expect that nearly half of Americans ages 40 to 75 and most men over 60 may be prescribed a statin,’ said Joseph Kitzmiller, MD, PhD an associate director of the Center for Pharmacogenomics at The Ohio State University Wexner Medical Center. ‘We currently have a limited ability to predict clinical outcomes and potential side effects for any of those individual patients — many of whom will be on a statin for the rest of their lives. In general and for most patients, statins are largely beneficial. Unfortunately, not all patients benefit and some are harmed by statins.’
Kitzmiller, who has devoted his career to untangling the many ways that genetics influence how patients respond to their medications, thinks that statin dosage recommendations need also to consider common genetic variants the affect drug exposure.
‘The muscle toxicity associated with statins is largely about exposure, and exposure is significantly affected by a patient’s genetics,’ Kitzmiller explained. ‘If you give two people 20 milligrams of a statin, and one of them has a polymorphism, or gene variation that changes the way the body processes that statin, it may be as though you’ve given them two or three times as much medication.’
Kitzmiller is team, which is primarily studying simvastatin, have already identified a gene variation that decreases statin metabolism — making people more susceptible to adverse events.
‘For our patients carrying this genetic variant, simvastatin doesn’t break down as much in the liver. This means more of the drug is in their bloodstream, increasing their exposure and potential for muscle toxicity,’ said Kitzmiller. ‘For these people, a lower dose of simvastatin could potentially deliver the same benefits while causing fewer side effects.’
Kitzmiller also found that a patient’s likelihood for carrying a genetic polymorphism depends on their race. Recent work by his research team suggests that the effect size also varies significantly across racial groups. One genetic variant resulted in a nearly 3-fold increase in simvastatin concentrations for African-Americans but only a modest increase for Caucasians.
‘That can have incredible clinical significance, especially since African-Americans often suffer higher rates of drug adverse outcomes and higher disease mortality rates despite receiving similar or even identical treatment,’ said Kitzmiller, who is also an associate professor in the Department of Pharmacology at Ohio State’s College of Medicine.
His team has also recently developed a blood test that can simultaneously measure the quantities of three different types of statins and their metabolites, which indicates how much of a medication the body has metabolized. This type of tool is essential to help scientists establish connections between genetic profiles and the variation in how statins are absorbed, transported, distributed and excreted. Kitzmiller is in the process of developing a multigene test that could tell clinicians if their patients have any of the genetic culprits that are likely to lead to muscle problems or other side effects from statins. He hopes to bring this test to clinical trials later this year.
Science Daily
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