Ribonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.
A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.
The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.
In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.
It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.
Tohoku University
www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html
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In a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.
In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.
Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.
The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.
The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.
Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.
“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.
“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.
“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.
“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”
Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.
“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.
“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”
“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”
Garvan Institute
www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk
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A research team at the Krembil Research Institute has discovered a pair of tissue biomarkers that directly contribute to the harmful joint degeneration associated with spine osteoarthritis.
The study is the first to show that elevated levels of both of these biomarkers cause inflammation, cartilage destruction and collagen depletion.
‘These biomarkers are actively involved in increasing inflammation and destructive activities in spine cartilage and assist in its destruction,’ says principal investigator Dr. Mohit Kapoor, Senior Scientist at the Krembil Research Institute and Associate Professor in the Department of Surgery and the Department of Laboratory Medicine and Pathobiology at the University of Toronto. Dr. Kapoor specializes in arthritis research.
Osteoarthritis affects about three million Canadians and is characterized by a breakdown of the protective cartilage found in the body’s spine, hand, knee and hip joints. There is no known cure.
The study involved tissue biopsies from 55 patients undergoing decompression or discectomy at the Krembil Neuroscience Centre at Toronto Western Hospital. As part of the study, the research team – led by Dr. Kapoor and comprising Dr. Akihiro Nakamura, a post-doctoral fellow, and Dr. Y. Raja Rampersaud, a clinical expert and spine surgeon – explored the role, function and signaling mechanisms of two tissue biomarkers: microRNA-181a-5p and microRNA-4454.
The study screened 2,100 microRNAs and found that measuring the levels of these two specific biomarkers can help clinicians determine the stage to which the disease has progressed, and provide a tool for determining the degree of cartilage destruction.
‘These are biologically active molecules. By detecting them in the tissue biopsies, we have a tool for determining the stage of spine osteoarthritis,’ says Dr. Kapoor. ‘What is really significant, however, is we have discovered that these biomarkers are actively involved in destroying cartilage and increasing inflammation. Furthermore, they promote cartilage cells to die and deplete the most important component of your cartilage, which is your collagen.’
The discovery represents the end of the first stage of research. The team is now investigating whether these biomarkers can be detected in the blood – which would help clinicians more simply determine the stage of spine osteoarthritis – and whether further studying the biomarkers will allow researchers to halt and reverse spine degeneration.
‘The most critical aspect of this discovery is that we have found that they are active. Now that we know what they are, we are currently looking at blocking them and restoring the joint,’ says Dr. Kapoor.
Krembil Research Institute
www.uhn.ca/corporate/News/PressReleases/Pages/research_team_discovers_two_biomarkers_that_contribute_to_spine_osteoarthritis.aspx
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Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.
“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.
Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.
The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.
Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.
After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.
The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.
In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.
In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.
University of Pittsburgh School of Medicine
www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx
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Researchers from the National Institutes of Health and their colleagues identified the genetic cause and a possible therapeutic target for a rare form of paediatric progressive neuropathy. Neuropathy, damage or disease affecting the peripheral nervous system, can range from rare conditions linked to a patient’s exome to more common causes like diabetes and viral infections. Neuropathies can affect both motor and sensory neurons, producing muscle weakness, numbness, pain, and a wide range of symptoms.
These types of discoveries underscore the importance of the families who volunteer to participate in clinical research. “This case superbly illustrates how the intensive study of children with very rare neurological disorders can lead quickly to a deep knowledge of a specific genetic condition, as well as uncover mysteries of the nervous system relevant to a wide spectrum of disorders,” said Walter J. Koroshetz, M.D., director of NINDS.
In their report, researchers examined a 10-year-old child with early onset, progressive neuropathy primarily affecting his ability to walk, grasp, and perform fine motor skills. When the patient’s complete genetic makeup, or genome, was analysed, a mutation was found in the gene associated with the protein KCC3. This protein is important for the ability of cells to respond to swelling.
When a neuron swells, KCC3 is involved in the mechanism that drives fluid out, returning the cell to normal. In the absence of this protein (in what is called a loss-of-function mutation), extreme swelling of the neurons can occur, which in turn leads to nerve damage.
In the study, the patient’s mutation affected the ability of KCC3 to turn off once it was no longer needed, leading to the opposite effect—shrunken neurons that also fail to communicate properly. This is referred to as a gain-of-function mutation, causing the affected protein to behave in a new and damaging way.
“This protein, KCC3, has been connected to other forms of neuropathy in the past,” said Carsten G. Bonnemann, M.D., a senior investigator in the Neuromuscular and Neurogenetic Disorders of Childhood Section at NINDS and a senior author of the paper. “What’s unique here is that this is the first time that we have seen a gain-of-function mutation in the KCC3 protein that leads to neuropathy.”
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The leading cause of death in the world remains cardiovascular diseases, which are responsible for more than one third of overall mortality, according to the World Health Organization. Obesity and diet are obvious culprits behind heart disease but, over the past decade, research has also pointed to genetic factors, specifically mutations in cell adhesion components—the forces that bind cells together.
In a new study, scientists from the Florida campus of The Scripps Research Institute offer new molecular insights into how the interaction between specific genetic mutations and a cytoskeletal protein critical for the proper development and maintenance of heart tissue can lead to conditions such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM)—and ultimately heart failure.
The new study, which was led by Associate Professor T. Izard of the Florida campus of TSRI. The new insights could aid in the development of drug therapies to strengthen the hearts of patients suffering from age-related heart failure.
The study focuses on the protein vinculin and a variant form known as metavinculin, which is found only in muscle tissue. Vinculin has been shown to reinforce the myocardial cell cytoskeleton, improving heart muscle contractility and prolonging life, while metavinculin plays an essential role in the development and function of the heart.
Both vinculin and metavinculin regulate cell adhesion and migration by linking the cell’s cytoskeleton to adhesion receptor complexes via a process known as dimerization—the joining of two similar subunits. Control of the dimerization process is crucial for normal protein function in cell adhesion sites.
But mutations in the variant metavinculin, either inherited or spontaneous, corrupt this process, altering dimerization and, the study suggests, producing a decreased ability to stabilize critical cell adhesions, weakening the heart muscle over time.
The researchers found that these mutations—specifically, a mutation known as R975W in metavinculin—dictate the type of interaction during dimerization and can actually block the process. That, in turn, results in heart muscles that are far more susceptible to stress-induced heart disease.
The Scripps Research Institute
www.scripps.edu/news/press/2016/20160811izard.html
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University of Helsinki researchers have previously demonstrated that a point mutation in a gene of serotonin 2B receptor can render the carrier prone to impulsive behaviour, particularly when drunk. Now the research group has established that the same mutation may shield its bearers from obesity and insulin resistance, both of which are associated with type 2 diabetes.
The study focused on the insulin sensitivity, beta cell activity and BMI of 98 Finnish men between the ages of 25 and 30, all of whom had been diagnosed with antisocial personality disorder. The results indicate that carriers of a point mutation in a gene of serotonin 2B receptor had a lower BMI and higher insulin sensitivity than persons without the mutation. Normally, men with low testosterone levels are more susceptible to metabolic disorders, but among carriers of the point mutation, this tendency was reversed – lower levels of testosterone increased insulin sensitivity.
The results also suggest that men in their thirties with antisocial personalities may constitute a risk group for insulin resistance, and consequently type 2 diabetes later in life.
“It is fascinating to think that this receptor mutation which has been passed through the chain of evolution would impact both the brain as impulsive behaviour and energy metabolism,” says psychiatrist, Dr Roope Tikkanen from the University of Helsinki, who led the study.
“We could speculate that the compound effect the mutation and testosterone have on energy metabolism may have been beneficial in the cool, nutrition-poor environment after the Ice Age, particularly for men with a high physiological level of testosterone – they would have survived with a lower calorie intake. Simultaneously, the aggression associated with high levels of testosterone may have helped them compete for food.”
In our modern society with ample food, the carriers of the mutation who have normal or low levels of testosterone may be better protected from metabolic illnesses relating to obesity, such as type 2 diabetes.
“One would assume that the effect would be particularly pronounced in women, who naturally have lower levels of testosterone than men,” Tikkanen points out.
Over 100,000 Finns and more than 1,000 Finnish infants born every year are carriers of the point mutation in the serotonin 2B receptor. The intention is to study the national health implications of the results from the extensive FINRISKI research material through cooperation between Finnish, Swedish and American researchers.
“Our results will further highlight the importance of Finnish diabetes research,’ Tikkanen states.
University of Helsinki
www.helsinki.fi/en/news/aggressive-drunk-gene-may-protect-carriers-from-obesity
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An international research team has linked rare variations in a cell membrane protein to the wide variation in symptom severity that is a hallmark of porphyria, a rare disorder that often affects the skin, liver and nervous system. St. Jude Children’s Research Hospital helped to lead the research.
Porphyrias are a family of diseases usually caused by inherited mutations in one of the eight enzymes involved in assembling heme. Heme is a molecule that plays a critical role in oxygen transport, drug metabolism and other vital physiological processes.
In this study, researchers discovered rare variations in the ABCB6 gene, also called Lan. The variations were associated with the toxic build-up in cells of chemicals produced during heme assembly. Investigators reported that the variants were more common in patients with severe porphyria than in those with less severe symptoms.
“One of the mysteries of this disease has been why some individuals with the same genetic defect have mild symptoms while others have severe symptoms and require hospitalization in the intensive care unit,” said corresponding author John Schuetz, Ph.D., a member of the St. Jude Department of Pharmaceutical Sciences. “Using gene sequencing, biochemical analysis and a new mouse model of the disease, we have identified variations in ABCB6 as an unexpected genetic modifier of porphyria severity.”
The discovery followed DNA sequencing of the protein-coding regions, or exomes, of seven porphyria patients with a history of life-threatening symptoms and hospitalization in the intensive care unit. They were among the 36 porphyria patients treated at the Royal Prince Alfred Hospital in Sydney, Australia, included in the study.
Researchers found that five of the seven patients carried rare versions of ABCB6 and made little or no functional ABCB6 protein. Sixty-two percent of patients with the rare ABCB6 variants were admitted to the intensive care unit compared to about 7 percent of other patients.
ABCB6 is carried on the surface of red blood cells, where 85 percent of heme is produced. The protein is one of several proteins that export porphyrins and related molecules from liver, blood and other cells.
Jann Ingmire
St. Jude Children’s Research Hospital
www.stjude.org/media-resources/news-releases/2016-medicine-science-news/rare-genetic-variations-may-solve-mystery-of-porphyria-severity-in-some-patients.html
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SCIEX University is a new online service launched by SCIEX for its mass spectrometry customers. Designed as a new way to master workflows, SCIEX University is powered by a robust learning management system and features a new look and feel. A personalized dashboard allows the user to see all training records, certifications and enrol in courses for online and instructor-led trainings. Learning programmes are customized for the user and hundreds of interactive courses are provided, enabling the user to participate at his/her own pace. The trainings will be in English initially followed by translations into Chinese and Japanese next year. The user interface on the website, however, can be changed into 24 different languages.
SCIEX University can be freely accessed at https://sciex.com/education
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The International Congress on Quality in Laboratory Medicine will be held at Messukeskus, Expo and Convention Centre Helsinki on 9th-10th of February 2017. The annual congress is one of the largest events in Scandinavia focused on quality and laboratory medicine.
The congress inspires medical doctors, pathologists, clinical chemists, biomedical laboratory scientists, medical laboratory experts, managers, quality managers and point-of-care supervisors from the healthcare sector.
The 2017 Congress themes are Impact of Total Quality Management (TQM) and Evidence-Based Laboratory Medicine (EBLM).
Total Quality Management (TQM) is an already more than 60-year old concept that has steadily become more popular in healthcare settings. The idea is to develop a culture which aims at providing patients and customers with products and services that satisfy their needs. In Total Quality Management both management and employees are involved in the continuous improvement of services. It is a combination of quality and management tools to reduce wasteful processes and to avoid errors. In healthcare TQM outcomes are measured by patient health and customer satisfaction. For healthcare organizations TQM means also a continuous learning process and its base is quantitative, thus being closely related to evidence-based medicine. Labquality Days 2017 will bring distinguished international speakers together who will highlight the importance of management’s involvement in continuous process improvement. The speakers will also show some concrete examples and tools of TQM in smaller healthcare organizations and in large enterprises.
Evidence-Based Laboratory Medicine (EBLM) is the second theme of the 2017 Congress. How important are laboratory results in clinical decision making? Are they as valuable in acute myocardial infarction as for a patient suffering from a common cold? Where is the evidence – and do we have enough data to support better patient outcomes? Choosing the right laboratory test at the right time has become increasingly important particularly in improving and speeding up the diagnostic process and reducing diagnostic errors and costs. The speakers will discuss whether we have enough up-to-date evidence to evaluate the importance of laboratory results, though more controlled well-designed studies are needed.
The International Congress on Quality in Laboratory Medicine will gather leading international speakers and opinion leaders together. The programme consists of scientific lectures and panel discussions. During the congress, participants have the opportunity to meet colleagues, share ideas and experience the extensive clinical laboratory exhibition.
www.labqualitydays.com
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New analytical tool for fluorescence detection of double-stranded RNA
, /in E-News /by 3wmediaRibonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.
A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.
The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.
In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.
It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.
Tohoku University www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html
Researchers uncover complex genetic secrets of cancer risk
, /in E-News /by 3wmediaIn a landmark multi-country study, Australian researchers have transformed our understanding of the genes that affect our risk of cancer. The researchers uncovered numerous new genetic risk factors for the bone and soft-tissue cancer, sarcoma – and, in a world first for any cancer, they showed that carrying several of these genetic mutations markedly increases an individual’s cancer risk. The findings have immediate implications for how sarcomas and other cancers are treated.
In a landmark study of over 1000 sarcoma patients, the researchers uncovered numerous new genetic risk factors for the cancer – and, in a world first for any cancer type, they showed that carrying two or more of these rare mutations increases an individual’s cancer risk.
Sarcomas are cancers of connective tissues that disproportionately affect the young. They are one of the three leading causes of disease-related death among children and young adults in Australia, and sarcoma survivors are at higher risk of developing a second cancer.
The new findings relating to cancer risk were uncovered through the International Sarcoma Kindred Study (ISKS), an Australian-led international consortium that is exploring the genetic basis of sarcoma in over 1000 individuals – the largest study ever conducted in this disease.
The ISKS team used a ‘gene panel’ of 72 genes to detect mutations in each study participant. They identified mutations in a number of new genes that significantly increase the risk of developing sarcoma, including in the genes ERCC2, ATR, BRCA2 and ATM.
Importantly, in individuals carrying mutations in two genes, the risk of developing sarcoma was measurably higher than in those with a mutation in only one gene. And in carriers of three or more mutations, the risk was greater still.
“This is the first time – in any cancer – that anyone has quantified the effect of multiple rare genetic mutations on cancer risk,” says Professor David Thomas (Head of The Kinghorn Cancer Centre and the Cancer Division of the Garvan Institute of Medical Research), who led the study.
“Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means their breast cancer risk is higher, or that their risk of sarcoma and other cancers is higher if they’ve got a particular mutation in the p53 gene.
“The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer.
“These previously invisible effects are at least as large as the impact of mutations in the p53 gene itself, which is currently the strongest known genetic cause of sarcoma.”
Dr Mandy Ballinger (Garvan), who co-ordinates the ISKS globally, says the study will radically change how sarcoma risk is understood.
“It’s well accepted for a few cancers – like breast cancer and bowel cancer – that cancer risk is substantially determined by the genes we inherit from our parents. Our study brings sarcoma into that select group.
“About half the study participants carried at least one of these apparently cancer-promoting mutations, and almost a quarter carried more than one, which really underscores that sarcoma risk is inherited to a large extent from one’s parents.”
“We’ve never been able to identify these at-risk individuals, and their families, before. Now we can,” adds Prof Thomas. “That means we can manage risk better, and help those people to get the care they need, when they need it.”
Garvan Institute www.garvan.org.au/news/news/beyond-single-gene-thinking-garvan-researchers-uncover-complex-genetic-secrets-of-cancer-risk
Two biomarkers that contribute to spine osteoarthritis
, /in E-News /by 3wmediaA research team at the Krembil Research Institute has discovered a pair of tissue biomarkers that directly contribute to the harmful joint degeneration associated with spine osteoarthritis.
The study is the first to show that elevated levels of both of these biomarkers cause inflammation, cartilage destruction and collagen depletion.
‘These biomarkers are actively involved in increasing inflammation and destructive activities in spine cartilage and assist in its destruction,’ says principal investigator Dr. Mohit Kapoor, Senior Scientist at the Krembil Research Institute and Associate Professor in the Department of Surgery and the Department of Laboratory Medicine and Pathobiology at the University of Toronto. Dr. Kapoor specializes in arthritis research.
Osteoarthritis affects about three million Canadians and is characterized by a breakdown of the protective cartilage found in the body’s spine, hand, knee and hip joints. There is no known cure.
The study involved tissue biopsies from 55 patients undergoing decompression or discectomy at the Krembil Neuroscience Centre at Toronto Western Hospital. As part of the study, the research team – led by Dr. Kapoor and comprising Dr. Akihiro Nakamura, a post-doctoral fellow, and Dr. Y. Raja Rampersaud, a clinical expert and spine surgeon – explored the role, function and signaling mechanisms of two tissue biomarkers: microRNA-181a-5p and microRNA-4454.
The study screened 2,100 microRNAs and found that measuring the levels of these two specific biomarkers can help clinicians determine the stage to which the disease has progressed, and provide a tool for determining the degree of cartilage destruction.
‘These are biologically active molecules. By detecting them in the tissue biopsies, we have a tool for determining the stage of spine osteoarthritis,’ says Dr. Kapoor. ‘What is really significant, however, is we have discovered that these biomarkers are actively involved in destroying cartilage and increasing inflammation. Furthermore, they promote cartilage cells to die and deplete the most important component of your cartilage, which is your collagen.’
The discovery represents the end of the first stage of research. The team is now investigating whether these biomarkers can be detected in the blood – which would help clinicians more simply determine the stage of spine osteoarthritis – and whether further studying the biomarkers will allow researchers to halt and reverse spine degeneration.
‘The most critical aspect of this discovery is that we have found that they are active. Now that we know what they are, we are currently looking at blocking them and restoring the joint,’ says Dr. Kapoor.
Krembil Research Institute www.uhn.ca/corporate/News/PressReleases/Pages/research_team_discovers_two_biomarkers_that_contribute_to_spine_osteoarthritis.aspx
Correcting metabolic deficiencies may improve depression symptoms
, /in E-News /by 3wmediaIdentifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine.
“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, M.D., Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.
Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, M.D., professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.
The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, M.D., Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.
Searching for answers, Dr. Pan contacted Jerry Vockley, M.D., Ph.D., chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, M.D., professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signalling chemicals called neurotransmitters.
After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.
The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.
In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.
In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.
University of Pittsburgh School of Medicine www.upmc.com/media/NewsReleases/2016/Pages/l-pan.aspx
Novel genetic mutation may lead to the progressive loss of motor function
, /in E-News /by 3wmediaResearchers from the National Institutes of Health and their colleagues identified the genetic cause and a possible therapeutic target for a rare form of paediatric progressive neuropathy. Neuropathy, damage or disease affecting the peripheral nervous system, can range from rare conditions linked to a patient’s exome to more common causes like diabetes and viral infections. Neuropathies can affect both motor and sensory neurons, producing muscle weakness, numbness, pain, and a wide range of symptoms.
These types of discoveries underscore the importance of the families who volunteer to participate in clinical research. “This case superbly illustrates how the intensive study of children with very rare neurological disorders can lead quickly to a deep knowledge of a specific genetic condition, as well as uncover mysteries of the nervous system relevant to a wide spectrum of disorders,” said Walter J. Koroshetz, M.D., director of NINDS.
In their report, researchers examined a 10-year-old child with early onset, progressive neuropathy primarily affecting his ability to walk, grasp, and perform fine motor skills. When the patient’s complete genetic makeup, or genome, was analysed, a mutation was found in the gene associated with the protein KCC3. This protein is important for the ability of cells to respond to swelling.
When a neuron swells, KCC3 is involved in the mechanism that drives fluid out, returning the cell to normal. In the absence of this protein (in what is called a loss-of-function mutation), extreme swelling of the neurons can occur, which in turn leads to nerve damage.
In the study, the patient’s mutation affected the ability of KCC3 to turn off once it was no longer needed, leading to the opposite effect—shrunken neurons that also fail to communicate properly. This is referred to as a gain-of-function mutation, causing the affected protein to behave in a new and damaging way.
“This protein, KCC3, has been connected to other forms of neuropathy in the past,” said Carsten G. Bonnemann, M.D., a senior investigator in the Neuromuscular and Neurogenetic Disorders of Childhood Section at NINDS and a senior author of the paper. “What’s unique here is that this is the first time that we have seen a gain-of-function mutation in the KCC3 protein that leads to neuropathy.”
NIH www.nih.gov/news-events/news-releases/novel-genetic-mutation-may-lead-progressive-loss-motor-function
Mutations responsible for debilitating heart conditions
, /in E-News /by 3wmediaThe leading cause of death in the world remains cardiovascular diseases, which are responsible for more than one third of overall mortality, according to the World Health Organization. Obesity and diet are obvious culprits behind heart disease but, over the past decade, research has also pointed to genetic factors, specifically mutations in cell adhesion components—the forces that bind cells together.
In a new study, scientists from the Florida campus of The Scripps Research Institute offer new molecular insights into how the interaction between specific genetic mutations and a cytoskeletal protein critical for the proper development and maintenance of heart tissue can lead to conditions such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM)—and ultimately heart failure.
The new study, which was led by Associate Professor T. Izard of the Florida campus of TSRI. The new insights could aid in the development of drug therapies to strengthen the hearts of patients suffering from age-related heart failure.
The study focuses on the protein vinculin and a variant form known as metavinculin, which is found only in muscle tissue. Vinculin has been shown to reinforce the myocardial cell cytoskeleton, improving heart muscle contractility and prolonging life, while metavinculin plays an essential role in the development and function of the heart.
Both vinculin and metavinculin regulate cell adhesion and migration by linking the cell’s cytoskeleton to adhesion receptor complexes via a process known as dimerization—the joining of two similar subunits. Control of the dimerization process is crucial for normal protein function in cell adhesion sites.
But mutations in the variant metavinculin, either inherited or spontaneous, corrupt this process, altering dimerization and, the study suggests, producing a decreased ability to stabilize critical cell adhesions, weakening the heart muscle over time.
The researchers found that these mutations—specifically, a mutation known as R975W in metavinculin—dictate the type of interaction during dimerization and can actually block the process. That, in turn, results in heart muscles that are far more susceptible to stress-induced heart disease.
The Scripps Research Institute www.scripps.edu/news/press/2016/20160811izard.html
Mutation makes its bearers prone to behave impulsively while intoxicated
, /in E-News /by 3wmediaUniversity of Helsinki researchers have previously demonstrated that a point mutation in a gene of serotonin 2B receptor can render the carrier prone to impulsive behaviour, particularly when drunk. Now the research group has established that the same mutation may shield its bearers from obesity and insulin resistance, both of which are associated with type 2 diabetes.
The study focused on the insulin sensitivity, beta cell activity and BMI of 98 Finnish men between the ages of 25 and 30, all of whom had been diagnosed with antisocial personality disorder. The results indicate that carriers of a point mutation in a gene of serotonin 2B receptor had a lower BMI and higher insulin sensitivity than persons without the mutation. Normally, men with low testosterone levels are more susceptible to metabolic disorders, but among carriers of the point mutation, this tendency was reversed – lower levels of testosterone increased insulin sensitivity.
The results also suggest that men in their thirties with antisocial personalities may constitute a risk group for insulin resistance, and consequently type 2 diabetes later in life.
“It is fascinating to think that this receptor mutation which has been passed through the chain of evolution would impact both the brain as impulsive behaviour and energy metabolism,” says psychiatrist, Dr Roope Tikkanen from the University of Helsinki, who led the study.
“We could speculate that the compound effect the mutation and testosterone have on energy metabolism may have been beneficial in the cool, nutrition-poor environment after the Ice Age, particularly for men with a high physiological level of testosterone – they would have survived with a lower calorie intake. Simultaneously, the aggression associated with high levels of testosterone may have helped them compete for food.”
In our modern society with ample food, the carriers of the mutation who have normal or low levels of testosterone may be better protected from metabolic illnesses relating to obesity, such as type 2 diabetes.
“One would assume that the effect would be particularly pronounced in women, who naturally have lower levels of testosterone than men,” Tikkanen points out.
Over 100,000 Finns and more than 1,000 Finnish infants born every year are carriers of the point mutation in the serotonin 2B receptor. The intention is to study the national health implications of the results from the extensive FINRISKI research material through cooperation between Finnish, Swedish and American researchers.
“Our results will further highlight the importance of Finnish diabetes research,’ Tikkanen states.
University of Helsinki www.helsinki.fi/en/news/aggressive-drunk-gene-may-protect-carriers-from-obesity
Rare genetic variations may solve mystery of porphyria severity in some patients
, /in E-News /by 3wmediaAn international research team has linked rare variations in a cell membrane protein to the wide variation in symptom severity that is a hallmark of porphyria, a rare disorder that often affects the skin, liver and nervous system. St. Jude Children’s Research Hospital helped to lead the research.
Porphyrias are a family of diseases usually caused by inherited mutations in one of the eight enzymes involved in assembling heme. Heme is a molecule that plays a critical role in oxygen transport, drug metabolism and other vital physiological processes.
In this study, researchers discovered rare variations in the ABCB6 gene, also called Lan. The variations were associated with the toxic build-up in cells of chemicals produced during heme assembly. Investigators reported that the variants were more common in patients with severe porphyria than in those with less severe symptoms.
“One of the mysteries of this disease has been why some individuals with the same genetic defect have mild symptoms while others have severe symptoms and require hospitalization in the intensive care unit,” said corresponding author John Schuetz, Ph.D., a member of the St. Jude Department of Pharmaceutical Sciences. “Using gene sequencing, biochemical analysis and a new mouse model of the disease, we have identified variations in ABCB6 as an unexpected genetic modifier of porphyria severity.”
The discovery followed DNA sequencing of the protein-coding regions, or exomes, of seven porphyria patients with a history of life-threatening symptoms and hospitalization in the intensive care unit. They were among the 36 porphyria patients treated at the Royal Prince Alfred Hospital in Sydney, Australia, included in the study.
Researchers found that five of the seven patients carried rare versions of ABCB6 and made little or no functional ABCB6 protein. Sixty-two percent of patients with the rare ABCB6 variants were admitted to the intensive care unit compared to about 7 percent of other patients.
ABCB6 is carried on the surface of red blood cells, where 85 percent of heme is produced. The protein is one of several proteins that export porphyrins and related molecules from liver, blood and other cells.
Jann Ingmire
St. Jude Children’s Research Hospital www.stjude.org/media-resources/news-releases/2016-medicine-science-news/rare-genetic-variations-may-solve-mystery-of-porphyria-severity-in-some-patients.html
SCIEX University accessible online for MS users
, /in E-News /by 3wmediaSCIEX University is a new online service launched by SCIEX for its mass spectrometry customers. Designed as a new way to master workflows, SCIEX University is powered by a robust learning management system and features a new look and feel. A personalized dashboard allows the user to see all training records, certifications and enrol in courses for online and instructor-led trainings. Learning programmes are customized for the user and hundreds of interactive courses are provided, enabling the user to participate at his/her own pace. The trainings will be in English initially followed by translations into Chinese and Japanese next year. The user interface on the website, however, can be changed into 24 different languages.
SCIEX University can be freely accessed at https://sciex.com/education
Labquality Days 2017
, /in E-News /by 3wmediaThe International Congress on Quality in Laboratory Medicine will be held at Messukeskus, Expo and Convention Centre Helsinki on 9th-10th of February 2017. The annual congress is one of the largest events in Scandinavia focused on quality and laboratory medicine.
The congress inspires medical doctors, pathologists, clinical chemists, biomedical laboratory scientists, medical laboratory experts, managers, quality managers and point-of-care supervisors from the healthcare sector.
The 2017 Congress themes are Impact of Total Quality Management (TQM) and Evidence-Based Laboratory Medicine (EBLM).
Total Quality Management (TQM) is an already more than 60-year old concept that has steadily become more popular in healthcare settings. The idea is to develop a culture which aims at providing patients and customers with products and services that satisfy their needs. In Total Quality Management both management and employees are involved in the continuous improvement of services. It is a combination of quality and management tools to reduce wasteful processes and to avoid errors. In healthcare TQM outcomes are measured by patient health and customer satisfaction.
For healthcare organizations TQM means also a continuous learning process and its base is quantitative, thus being closely related to evidence-based medicine.
Labquality Days 2017 will bring distinguished international speakers together who will highlight the importance of management’s involvement in continuous process improvement. The speakers will also show some concrete examples and tools of TQM in smaller healthcare organizations and in large enterprises.
Evidence-Based Laboratory Medicine (EBLM) is the second theme of the 2017 Congress.
How important are laboratory results in clinical decision making? Are they as valuable in acute myocardial infarction as for a patient suffering from a common cold? Where is the evidence – and do we have enough data to support better patient outcomes?
Choosing the right laboratory test at the right time has become increasingly important particularly in improving and speeding up the diagnostic process and reducing diagnostic errors and costs. The speakers will discuss whether we have enough up-to-date evidence to evaluate the importance of laboratory results, though more controlled well-designed studies are needed.
The International Congress on Quality in Laboratory Medicine will gather leading international speakers and opinion leaders together. The programme consists of scientific lectures and panel discussions. During the congress, participants have the opportunity to meet colleagues, share ideas and experience the extensive clinical laboratory exhibition.
www.labqualitydays.com