Johns Hopkins Kimmel Cancer Center investigators report they have designed a blood test that accurately detects the presence of advanced breast cancer and also holds promise for precisely monitoring response to cancer treatment.
The test, called the cMethDNA assay, accurately detected the presence of cancer DNA in the blood of patients with metastatic breast cancers up to 95 percent of the time in laboratory studies.
Currently, there is no useful laboratory test to monitor patients with early stage breast cancer who are doing well, but could have an asymptomatic recurrence, says Saraswati Sukumar, Ph.D., who is the Barbara B. Rubenstein Professor of Oncology and co-director of the Breast Cancer Program at the Johns Hopkins Kimmel Cancer Center. Generally, radiologic scans and standard blood tests are indicated only if a woman complains of symptoms, such as bone aches, shortness of breath, pain, or worrisome clinical exam findings. Otherwise, routine blood tests or scans in asymptomatic patients often produce false positives, leading to additional unnecessary tests and biopsies, and have not been shown to improve survival outcomes in patients with early stage breast cancer who develop a recurrence.
Sukumar, also a professor of pathology at Johns Hopkins, says that the current approach to monitoring for recurrence is not ideal, and that ‘the goal is to develop a test that could be administered routinely to alert the physician and patient as soon as possible of a return of the original cancer in a distant spot. With the development of cMethDNA, we’ve taken a first big step toward achieving this goal.’
To design the test, Sukumar and her team scanned the genomes of primary breast cancer patients, as well as DNA from the blood of metastatic cancer patients. They selected 10 genes specifically altered in breast cancers, including newly identified genetic markers AKR1B1, COL6A2, GPX7, HIST1H3C, HOX B4, RASGRF2, as well as TM6SF1, RASSF1, ARHGEF7, and TMEFF2, which Sukumar’s team had previously linked to primary breast cancer.
The test, developed by Sukumar, collaborator Mary Jo Fackler, Ph.D., and other scientists, detects so-called hypermethyation, a type of chemical tag in one or more of the breast cancer-specific genes present in tumour DNA and detectable in cancer patients’ blood samples. Hypermethylation often silences genes that keep runaway cell growth in check, and its appearance in the DNA of breast cancer-related genes shed into the blood indicates that cancer has returned or spread.
In one set of experiments, the researchers tested the assay’s ability to detect methylated tumor DNA in 52 blood samples – 24 from patients with recurrent stage IV breast cancer and 28 from healthy women without breast cancer, and again in blood samples from 60 individuals – 33 from women with all stages of breast cancer and 27 from healthy women. In each case, the blood test was up to 95 percent accurate in distinguishing patients with metastatic breast cancer from healthy women.
The investigators also studied the assay’s potential to monitor response to chemotherapy. They evaluated 58 blood samples from 29 patients with metastatic breast cancer, some taken before the initiation of therapy and some taken 18 to 49 days after starting a new chemotherapy regimen. In as little as two weeks, they report, the test detected a significant decrease in DNA methylation in patients with stable disease or in those who responded to treatment; this decrease was not found in patients whose disease progressed or who did not respond to treatment.
‘Our assay shows great potential for development as a clinical laboratory test for monitoring therapy and disease progression and recurrence,’ Sukumar says. If it’s determined early that a treatment is not working, clinicians can save time and switch to a different therapy, she says.
In addition, the researchers tested the gene panel used in the cMethDNA assay against samples from The Cancer Genome Atlas, a catalog of genes in various cancer types, finding that the gene panel may also be useful in detecting recurrent lung or colorectal cancers but not as accurate in detecting recurrent ovarian, kidney or stomach cancers.
Johns Hopkins Kimmel Cancer Center
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The cause of neuronal death in Parkinson’s disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person’s own immune system, similar to the way autoimmune diseases like type I diabetes, celiac disease, and multiple sclerosis attack the body’s cells.
‘This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,’ said the study’s senior author, David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University College of Physicians & Surgeons.
The new hypothesis about Parkinson’s emerges from other findings in the study that overturn a deep-seated assumption about neurons and the immune system.
For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. Most cells, if infected by virus or bacteria, will display bits of the microbe (antigens) on their outer surface. When the immune system recognises the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were exempt from T-cell attacks.
‘That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,’ Dr. Sulzer says. ‘But, unexpectedly, we found that some types of neurons can display antigens.’
Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer and his postdoc Carolina Cebrián, PhD, first noticed—to their surprise—that MHC-1 proteins were present in two types of neurons. These two types of neurons—one of which is dopamine neurons in a brain region called the substantia nigra—degenerate during Parkinson’s disease.
To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances—including conditions known to occur in Parkinson’s—the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were far more responsive than other neurons to signals that triggered antigen display.
The researchers then confirmed that T cells recognised and attacked neurons displaying specific antigens.
The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea.
Columbia University Medical Center
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Researchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease.
Yale University
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Scientists have identified the first genetic variant specifically associated with the risk of a difficult-to-diagnose cancer sub-type accounting for around 10-15 per cent of all breast cancer cases.
The largest ever study of the breast cancer sub-type, called invasive lobular carcinoma, gives researchers important clues to the genetic causes of this particular kind of breast cancer, which can be missed through screening.
The research was co-led by The Institute of Cancer Research, London, King’s College London, and Queen Mary University of London. It used gene chip technology and complex statistical analysis to compare the DNA of more than 6,500 women with invasive lobular cancer with the DNA of more than 35,000 women without the disease.
The study involved more than 100 research institutions from around the world and was funded by several organisations in the UK including Breast Cancer Campaign, Cancer Research UK, Breakthrough Breast Cancer and the ICR.
A woman with the genetic variant, called rs11977670, was found to have a 13 per cent higher chance of developing invasive lobular cancer than a woman without it. The variant is close to two genes on chromosome 7: BRAF, a known cancer-causing gene, and JHDM1D, which is involved in the activation and deactivation of other genes.
The discovery of the genetic variant, in conjunction with other markers, could help in the development of future genetic screening tools to assess women’s risk of developing invasive lobular cancer, and also gives researchers important new clues about the genetic causes of the disease and a related precursor to cancer called lobular carcinoma in situ.
Invasive lobular carcinoma develops in the lobes of the breast that produce milk and can be particularly difficult to diagnose, because the cancer often does not form a definite lump and may not show up on mammograms. As a result, women with this type of cancer tend to be diagnosed when the cancer is more advanced and more difficult to treat.
As well as looking for new genetic risk factors, the researchers also evaluated 75 variants previously linked with breast cancer overall. They found that most of these were associated with risk of invasive lobular cancer specifically, as well as overall breast cancer risk. The study also showed for the first time that genetic factors for invasive breast cancer can also predispose to lobular carcinoma in situ.
Institute of Cancer Research
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Large sections of the genome that were once referred to as ‘junk’ DNA have been linked to human heart failure, according to research from Washington University School of Medicine in St. Louis.
Molecules now associated with these sections of the genome are called non-coding RNAs. They come in a variety of forms, some more widely studied than others. Of these, about 90 percent are called long non-coding RNAs, and exploration of their roles in health and disease is just beginning.
Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied non-failing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.
‘We took an unbiased approach to investigating which types of RNA might be linked to heart failure,’ said senior author Jeanne M. Nerbonne, PhD, the Alumni Endowed Professor of Molecular Biology and Pharmacology. ‘We were surprised to find that long non-coding RNAs stood out. In fact, the field is evolving so rapidly that when we did a slightly earlier, similar investigation in mice, we didn’t even think to include long non-coding RNAs in the analysis.’
Heart failure refers to a gradual loss of heart function. The left ventricle, the heart’s main pumping chamber, becomes less efficient. Blood flow diminishes, and the body no longer receives the oxygen needed to go about daily tasks. Sometimes the condition develops after an obvious trigger such as a heart attack or infection, but other times the causes are less clear.
In the new study, the investigators found that unlike other RNA molecules, expression patterns of long non-coding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.
‘We don’t know whether these changes in long non-coding RNAs are a cause or an effect of heart failure,’ Nerbonne said. ‘But it seems likely they play some role in co-ordinating the regulation of multiple genes involved in heart function.’
Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and non-failing hearts. But only expression of the long non-coding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (non-ischemic). Similarly, only long non-coding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.
Because of the difficulty in obtaining human heart tissue, the study’s sample size was relatively small, Nerbonne said. Her team analysed eight non-failing hearts, eight hearts in ischemic heart failure and eight hearts in non-ischemic heart failure. Though small, the study is unique because each of the 16 failing hearts was sampled twice, once before and once after LVAD support.
According to Nerbonne, this before-and-after sampling of heart tissue is an unusual feature of this study and one of its strengths. Cardiac surgeons first removed a sample of heart tissue while implanting the LVAD. Then, months later, transplant surgeons sampled the same failing hearts when each patient received a new donor organ. Previous studies comparing heart function before and after implanting a pump used samples taken from different patients.
This double sampling of the same organ is important for understanding what is happening on a molecular level to failing heart tissue when a pump literally takes some of the load off.
‘It’s clear that some patients experience a change in the structure and physiology of the heart tissue following pump support, and in some patients that change results in improved heart function,’ Nerbonne said. ‘One interesting question is whether these long non-coding RNAs could be a measure of whether the failing heart is getting better with an LVAD.’
Indeed, using the non-failing heart samples for comparison, about 10 percent of the long non-coding RNA expression that was disturbed in the failing hearts improved or returned to normal following LVAD support. While 10 percent may seem modest, only about 3 percent, at best, of other types of RNA expression returned to normal after pump support.
Nerbonne also is interested in exploring whether measures of long non-coding RNAs could be an early predictor of the disease, ideally before symptoms of heart failure even develop.
Washington University School of Medicine in St. Louis
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How to diagnose and manage Heparin-Induced Thrombocytopenia (HIT)?
by Pr Yves Gruel – Professor of Hematology, Trousseau Hospital and University Francois Rabelais, Tours (France)
Type II Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated adverse effect of heparin treatment. Although rare, this complication can be serious and possibly life threatening.
Approximately one third of hospitalized patients are exposed to heparins. It is therefore of great importance to know how to:
diagnose HIT in order to identify the patients who will benefit from an alternative anticoagulant treatment
avoid HIT overdiagnosis to minimize the risksof bleedings and the costs associated with the use of alternative anticoagulants
This webinar will focus on HIT pathophysiology, and will outline the necessity of an accurate diagnosis and how it can be achieved. Alternative anticoagulant treatment options will also be discussed.
This 30-minute presentation will be followed by a 15-minute live chat with the speaker.
Pr Gruel is the Head of the Hematology Department at Trousseau University Hospital in Tours and is also leading the Hemophilia Care Center.
Apart from his clinical activity focusing on bleeding and thrombotic disorders, his main research topics are today heparin-induced thrombocytopenia (HIT) and the role of specific coagulation proteins in cancer.
He is currently the President of GEHT (French study Group on Haemostasis and Thrombosis), and Chairman of the ISTH Scientific and Standardization Committee on Platelet Immunology.
Save the date! Friday January 31st 2014 at 4:00 p.m. CET (Central European Time)
To attend this webinar, please register at www.stagowebinars.com.
A new study from researchers at the University of Ottawa Heart Institute (UOHI), sheds light on a mysterious gene that likely influences cardiovascular health. After five years, UOHI researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.
Researchers at the Ruddy Canadian Cardiovascular Genetics Centre had initially identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but its role in multiple health processes made it difficult to tease out how it affects heart disease.
The gene holds instructions for producing a protein called SPG7. This protein resides in mitochondria—the small power plants of cells that produce the energy cells need to function. SPG7’s role is to help break down and recycle other damaged proteins within the mitochondria.
Normally, SPG7 requires a partner protein to activate itself and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can activate itself in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.
‘We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,’ said Dr. Stewart, Principal Investigator in the Ruddy Canadian Cardiovascular Genetics Centre and senior author of the study. ‘Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.’
From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome. Between 13 and 15 per cent of people of European descent possess this variant.
‘The idea of mitochondria contributing to inflammation isn’t new,’ concluded Dr. Stewart. ‘But what is new is that we’ve found one of the switches that regulate this process. We’re excited, because once you know where the switches are, you can start looking for ways to turn them on and off.’
EurekAlert
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A study suggests that tests to grade and stage prostate cancer underestimated the severity of the disease in half of men whose cancers had been classified as ‘slow growing’. This highlights the urgent need for better tests to define how aggressive a prostate cancer is from the outset.
Scientists from the University of Cambridge compared the staging and grading of cancer in over 800 men before and after they had surgery to remove their prostate. They found that of the 415 men whose prostate cancer was classified as slow growing and confined to just the prostate after an initial biopsy, half (209) had cancer which was more aggressive than originally thought when assessed again after surgery and almost a third (131) had cancer that had spread beyond the prostate.
Greg Shaw, one of the study authors at the Cancer Research UK Cambridge Institute and a urological surgeon at Cambridge University Hospitals, said: ‘Our results show that the severity of up to half of men’s prostate cancers may be underestimated when relying on tests before they have surgery. ‘This highlights the urgent need for better tests to define how aggressive a prostate cancer is from the outset, building on diagnostic tests like MRI scans and new biopsy techniques which help to more accurately define the extent of the prostate cancer. This would then enable us to counsel patients with more certainty whether the prostate cancer identified is suitable for active surveillance or not. ‘Whilst active surveillance would seem to be a safe approach for some men, nearly a third will end up needing surgery or radiotherapy within five years.’
Prostate cancer is the most common cancer in men in the UK with around 41,700 new cases diagnosed every year. Last year there were around 10,800 deaths in the UK from prostate cancer. The severity of prostate cancers is assessed using biopsy, MRI and PSA tests. Professor Malcolm Mason, Cancer Research UK’s prostate cancer expert, said: ‘Despite the limitations that this study shows, all evidence so far points to active surveillance being safe provided men are carefully selected. But we need better methods of assigning a grade and stage so that no man has to unnecessarily undergo treatment, while at the same time making sure we detect and treat the cancers that really need it.’
Cambridge University
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A research team lead by Academy Professor Kari Rissanen at the University of Jyväskylä has discovered a new water-soluble fluorescent detection system that is extremely sensitive to pyrophosphate (PPi).
Pyrophosphate has a key role in energy transduction, DNA replication and other metabolic processes that are dysregulated in cancer cells. The discovery might lead to the development of a method for early detection of cancer cells.
The team developed a simple metal complex which shows an intense orange fluorescent colour in the presence of very low concentration of pyrophosphate (PPi) in water. The complex, also called a probe, had almost 1000 times higher level of response than earlier methods and an unprecedented sensitivity to detect PPi at a sub-nanomolar level. The discovery represents the first water-soluble fluorescent sensor that is capable of detecting pyrophosphate at this sensitivity level under physiological conditions.
The highly sensitive probes or sensors that are able to report the PPi level could lead to improved cancer diagnostics, since PPi plays a key role in energy transduction, DNA replication and other metabolic processes that are seriously misbehaving in cancer cells. All earlier PPi-selective sensor molecules or complexes have suffered from poor water solubility and low sensitivity in water. They can reach only micromolar levels and, thus, researchers have had to rely on protein-based probes that have their own limitations.
The researchers were able to show that the probe can image the pyrophosphate in the nuclei of living (HeLa) cells, making it an excellent probe for live cell pyrophosphahe imaging. The HeLa cells, originally from Henrietta Lack’s cervix carcinoma, are the most long-lived human cancer cell line and are often used as a cancer cell model. In addition to their applicability in water, they can easily be formulated into a hydrogel and coated onto paper strips for low-cost pyrophosphate detection.
University of Jyväskylä
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Scientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.
‘What was striking is that these were basically normal animals in terms of behaviour, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,’ said Damon Page, a TSRI biologist who led the study. ‘This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behaviour in general. However, brain circuits relevant to social behaviour are more vulnerable or less able to tolerate this overgrowth.’
Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviours and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.
In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second ‘hit’ to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localised overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviours in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviours including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.
The researchers found that Pten mutant mice showed altered social behaviour, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.
Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.
The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behaviour.
‘Timing is everything,’ Page said. ‘Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behaviour may turn out to be particularly vulnerable to the effects of poorly co-ordinated growth.’
Scripps University
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Experimental blood test spots recurrent breast cancers and monitors response to treatment
, /in E-News /by 3wmediaJohns Hopkins Kimmel Cancer Center investigators report they have designed a blood test that accurately detects the presence of advanced breast cancer and also holds promise for precisely monitoring response to cancer treatment.
The test, called the cMethDNA assay, accurately detected the presence of cancer DNA in the blood of patients with metastatic breast cancers up to 95 percent of the time in laboratory studies.
Currently, there is no useful laboratory test to monitor patients with early stage breast cancer who are doing well, but could have an asymptomatic recurrence, says Saraswati Sukumar, Ph.D., who is the Barbara B. Rubenstein Professor of Oncology and co-director of the Breast Cancer Program at the Johns Hopkins Kimmel Cancer Center. Generally, radiologic scans and standard blood tests are indicated only if a woman complains of symptoms, such as bone aches, shortness of breath, pain, or worrisome clinical exam findings. Otherwise, routine blood tests or scans in asymptomatic patients often produce false positives, leading to additional unnecessary tests and biopsies, and have not been shown to improve survival outcomes in patients with early stage breast cancer who develop a recurrence.
Sukumar, also a professor of pathology at Johns Hopkins, says that the current approach to monitoring for recurrence is not ideal, and that ‘the goal is to develop a test that could be administered routinely to alert the physician and patient as soon as possible of a return of the original cancer in a distant spot. With the development of cMethDNA, we’ve taken a first big step toward achieving this goal.’
To design the test, Sukumar and her team scanned the genomes of primary breast cancer patients, as well as DNA from the blood of metastatic cancer patients. They selected 10 genes specifically altered in breast cancers, including newly identified genetic markers AKR1B1, COL6A2, GPX7, HIST1H3C, HOX B4, RASGRF2, as well as TM6SF1, RASSF1, ARHGEF7, and TMEFF2, which Sukumar’s team had previously linked to primary breast cancer.
The test, developed by Sukumar, collaborator Mary Jo Fackler, Ph.D., and other scientists, detects so-called hypermethyation, a type of chemical tag in one or more of the breast cancer-specific genes present in tumour DNA and detectable in cancer patients’ blood samples. Hypermethylation often silences genes that keep runaway cell growth in check, and its appearance in the DNA of breast cancer-related genes shed into the blood indicates that cancer has returned or spread.
In one set of experiments, the researchers tested the assay’s ability to detect methylated tumor DNA in 52 blood samples – 24 from patients with recurrent stage IV breast cancer and 28 from healthy women without breast cancer, and again in blood samples from 60 individuals – 33 from women with all stages of breast cancer and 27 from healthy women. In each case, the blood test was up to 95 percent accurate in distinguishing patients with metastatic breast cancer from healthy women.
The investigators also studied the assay’s potential to monitor response to chemotherapy. They evaluated 58 blood samples from 29 patients with metastatic breast cancer, some taken before the initiation of therapy and some taken 18 to 49 days after starting a new chemotherapy regimen. In as little as two weeks, they report, the test detected a significant decrease in DNA methylation in patients with stable disease or in those who responded to treatment; this decrease was not found in patients whose disease progressed or who did not respond to treatment.
‘Our assay shows great potential for development as a clinical laboratory test for monitoring therapy and disease progression and recurrence,’ Sukumar says. If it’s determined early that a treatment is not working, clinicians can save time and switch to a different therapy, she says.
In addition, the researchers tested the gene panel used in the cMethDNA assay against samples from The Cancer Genome Atlas, a catalog of genes in various cancer types, finding that the gene panel may also be useful in detecting recurrent lung or colorectal cancers but not as accurate in detecting recurrent ovarian, kidney or stomach cancers. Johns Hopkins Kimmel Cancer Center
Is Parkinson’s an autoimmune disease?
, /in E-News /by 3wmediaThe cause of neuronal death in Parkinson’s disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person’s own immune system, similar to the way autoimmune diseases like type I diabetes, celiac disease, and multiple sclerosis attack the body’s cells.
‘This is a new, and likely controversial, idea in Parkinson’s disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson’s that resemble treatments for autoimmune diseases,’ said the study’s senior author, David Sulzer, PhD, professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University College of Physicians & Surgeons.
The new hypothesis about Parkinson’s emerges from other findings in the study that overturn a deep-seated assumption about neurons and the immune system.
For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. Most cells, if infected by virus or bacteria, will display bits of the microbe (antigens) on their outer surface. When the immune system recognises the foreign antigens, T cells attack and kill the cells. Because scientists thought that neurons did not display antigens, they also thought that the neurons were exempt from T-cell attacks.
‘That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system,’ Dr. Sulzer says. ‘But, unexpectedly, we found that some types of neurons can display antigens.’
Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors, Dr. Sulzer and his postdoc Carolina Cebrián, PhD, first noticed—to their surprise—that MHC-1 proteins were present in two types of neurons. These two types of neurons—one of which is dopamine neurons in a brain region called the substantia nigra—degenerate during Parkinson’s disease.
To see if living neurons use MHC-1 to display antigens (and not for some other purpose), Drs. Sulzer and Cebrián conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances—including conditions known to occur in Parkinson’s—the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson’s were far more responsive than other neurons to signals that triggered antigen display.
The researchers then confirmed that T cells recognised and attacked neurons displaying specific antigens.
The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea. Columbia University Medical Center
Gene variant raises risk for aortic tear and rupture
, /in E-News /by 3wmediaResearchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease. Yale University
First genetic link discovered to difficult-to-diagnose breast cancer sub-type
, /in E-News /by 3wmediaScientists have identified the first genetic variant specifically associated with the risk of a difficult-to-diagnose cancer sub-type accounting for around 10-15 per cent of all breast cancer cases.
The largest ever study of the breast cancer sub-type, called invasive lobular carcinoma, gives researchers important clues to the genetic causes of this particular kind of breast cancer, which can be missed through screening.
The research was co-led by The Institute of Cancer Research, London, King’s College London, and Queen Mary University of London. It used gene chip technology and complex statistical analysis to compare the DNA of more than 6,500 women with invasive lobular cancer with the DNA of more than 35,000 women without the disease.
The study involved more than 100 research institutions from around the world and was funded by several organisations in the UK including Breast Cancer Campaign, Cancer Research UK, Breakthrough Breast Cancer and the ICR.
A woman with the genetic variant, called rs11977670, was found to have a 13 per cent higher chance of developing invasive lobular cancer than a woman without it. The variant is close to two genes on chromosome 7: BRAF, a known cancer-causing gene, and JHDM1D, which is involved in the activation and deactivation of other genes.
The discovery of the genetic variant, in conjunction with other markers, could help in the development of future genetic screening tools to assess women’s risk of developing invasive lobular cancer, and also gives researchers important new clues about the genetic causes of the disease and a related precursor to cancer called lobular carcinoma in situ.
Invasive lobular carcinoma develops in the lobes of the breast that produce milk and can be particularly difficult to diagnose, because the cancer often does not form a definite lump and may not show up on mammograms. As a result, women with this type of cancer tend to be diagnosed when the cancer is more advanced and more difficult to treat.
As well as looking for new genetic risk factors, the researchers also evaluated 75 variants previously linked with breast cancer overall. They found that most of these were associated with risk of invasive lobular cancer specifically, as well as overall breast cancer risk. The study also showed for the first time that genetic factors for invasive breast cancer can also predispose to lobular carcinoma in situ. Institute of Cancer Research
Genome regions once mislabeled ‘junk’ linked to heart failure
, /in E-News /by 3wmediaLarge sections of the genome that were once referred to as ‘junk’ DNA have been linked to human heart failure, according to research from Washington University School of Medicine in St. Louis.
Molecules now associated with these sections of the genome are called non-coding RNAs. They come in a variety of forms, some more widely studied than others. Of these, about 90 percent are called long non-coding RNAs, and exploration of their roles in health and disease is just beginning.
Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied non-failing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.
‘We took an unbiased approach to investigating which types of RNA might be linked to heart failure,’ said senior author Jeanne M. Nerbonne, PhD, the Alumni Endowed Professor of Molecular Biology and Pharmacology. ‘We were surprised to find that long non-coding RNAs stood out. In fact, the field is evolving so rapidly that when we did a slightly earlier, similar investigation in mice, we didn’t even think to include long non-coding RNAs in the analysis.’
Heart failure refers to a gradual loss of heart function. The left ventricle, the heart’s main pumping chamber, becomes less efficient. Blood flow diminishes, and the body no longer receives the oxygen needed to go about daily tasks. Sometimes the condition develops after an obvious trigger such as a heart attack or infection, but other times the causes are less clear.
In the new study, the investigators found that unlike other RNA molecules, expression patterns of long non-coding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.
‘We don’t know whether these changes in long non-coding RNAs are a cause or an effect of heart failure,’ Nerbonne said. ‘But it seems likely they play some role in co-ordinating the regulation of multiple genes involved in heart function.’
Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and non-failing hearts. But only expression of the long non-coding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (non-ischemic). Similarly, only long non-coding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.
Because of the difficulty in obtaining human heart tissue, the study’s sample size was relatively small, Nerbonne said. Her team analysed eight non-failing hearts, eight hearts in ischemic heart failure and eight hearts in non-ischemic heart failure. Though small, the study is unique because each of the 16 failing hearts was sampled twice, once before and once after LVAD support.
According to Nerbonne, this before-and-after sampling of heart tissue is an unusual feature of this study and one of its strengths. Cardiac surgeons first removed a sample of heart tissue while implanting the LVAD. Then, months later, transplant surgeons sampled the same failing hearts when each patient received a new donor organ. Previous studies comparing heart function before and after implanting a pump used samples taken from different patients.
This double sampling of the same organ is important for understanding what is happening on a molecular level to failing heart tissue when a pump literally takes some of the load off.
‘It’s clear that some patients experience a change in the structure and physiology of the heart tissue following pump support, and in some patients that change results in improved heart function,’ Nerbonne said. ‘One interesting question is whether these long non-coding RNAs could be a measure of whether the failing heart is getting better with an LVAD.’
Indeed, using the non-failing heart samples for comparison, about 10 percent of the long non-coding RNA expression that was disturbed in the failing hearts improved or returned to normal following LVAD support. While 10 percent may seem modest, only about 3 percent, at best, of other types of RNA expression returned to normal after pump support.
Nerbonne also is interested in exploring whether measures of long non-coding RNAs could be an early predictor of the disease, ideally before symptoms of heart failure even develop. Washington University School of Medicine in St. Louis
New Stago Webinar announcement
, /in E-News /by 3wmediaHow to diagnose and manage Heparin-Induced Thrombocytopenia (HIT)?
by Pr Yves Gruel – Professor of Hematology, Trousseau Hospital and University Francois Rabelais, Tours (France)
Type II Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated adverse effect of heparin treatment. Although rare, this complication can be serious and possibly life threatening.
Approximately one third of hospitalized patients are exposed to heparins. It is therefore of great importance to know how to:
This webinar will focus on HIT pathophysiology, and will outline the necessity of an accurate diagnosis and how it can be achieved. Alternative anticoagulant treatment options will also be discussed.
This 30-minute presentation will be followed by a 15-minute live chat with the speaker.
Pr Gruel is the Head of the Hematology Department at Trousseau University Hospital in Tours and is also leading the Hemophilia Care Center.
Apart from his clinical activity focusing on bleeding and thrombotic disorders, his main research topics are today heparin-induced thrombocytopenia (HIT) and the role of specific coagulation proteins in cancer.
He is currently the President of GEHT (French study Group on Haemostasis and Thrombosis), and Chairman of the ISTH Scientific and Standardization Committee on Platelet Immunology.
Save the date! Friday January 31st 2014 at 4:00 p.m. CET (Central European Time)
To attend this webinar, please register at www.stagowebinars.com.
Function found for mysterious heart disease gene
, /in E-News /by 3wmediaA new study from researchers at the University of Ottawa Heart Institute (UOHI), sheds light on a mysterious gene that likely influences cardiovascular health. After five years, UOHI researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.
Researchers at the Ruddy Canadian Cardiovascular Genetics Centre had initially identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but its role in multiple health processes made it difficult to tease out how it affects heart disease.
The gene holds instructions for producing a protein called SPG7. This protein resides in mitochondria—the small power plants of cells that produce the energy cells need to function. SPG7’s role is to help break down and recycle other damaged proteins within the mitochondria.
Normally, SPG7 requires a partner protein to activate itself and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can activate itself in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.
‘We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,’ said Dr. Stewart, Principal Investigator in the Ruddy Canadian Cardiovascular Genetics Centre and senior author of the study. ‘Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.’
From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome. Between 13 and 15 per cent of people of European descent possess this variant.
‘The idea of mitochondria contributing to inflammation isn’t new,’ concluded Dr. Stewart. ‘But what is new is that we’ve found one of the switches that regulate this process. We’re excited, because once you know where the switches are, you can start looking for ways to turn them on and off.’ EurekAlert
Study finds prostate cancer tests underestimate disease in half of cases
, /in E-News /by 3wmediaA study suggests that tests to grade and stage prostate cancer underestimated the severity of the disease in half of men whose cancers had been classified as ‘slow growing’. This highlights the urgent need for better tests to define how aggressive a prostate cancer is from the outset.
Scientists from the University of Cambridge compared the staging and grading of cancer in over 800 men before and after they had surgery to remove their prostate. They found that of the 415 men whose prostate cancer was classified as slow growing and confined to just the prostate after an initial biopsy, half (209) had cancer which was more aggressive than originally thought when assessed again after surgery and almost a third (131) had cancer that had spread beyond the prostate.
Greg Shaw, one of the study authors at the Cancer Research UK Cambridge Institute and a urological surgeon at Cambridge University Hospitals, said: ‘Our results show that the severity of up to half of men’s prostate cancers may be underestimated when relying on tests before they have surgery. ‘This highlights the urgent need for better tests to define how aggressive a prostate cancer is from the outset, building on diagnostic tests like MRI scans and new biopsy techniques which help to more accurately define the extent of the prostate cancer. This would then enable us to counsel patients with more certainty whether the prostate cancer identified is suitable for active surveillance or not. ‘Whilst active surveillance would seem to be a safe approach for some men, nearly a third will end up needing surgery or radiotherapy within five years.’
Prostate cancer is the most common cancer in men in the UK with around 41,700 new cases diagnosed every year. Last year there were around 10,800 deaths in the UK from prostate cancer. The severity of prostate cancers is assessed using biopsy, MRI and PSA tests. Professor Malcolm Mason, Cancer Research UK’s prostate cancer expert, said: ‘Despite the limitations that this study shows, all evidence so far points to active surveillance being safe provided men are carefully selected. But we need better methods of assigning a grade and stage so that no man has to unnecessarily undergo treatment, while at the same time making sure we detect and treat the cancers that really need it.’ Cambridge University
New sensor molecules have potential for early cancer detection
, /in E-News /by 3wmediaA research team lead by Academy Professor Kari Rissanen at the University of Jyväskylä has discovered a new water-soluble fluorescent detection system that is extremely sensitive to pyrophosphate (PPi).
Pyrophosphate has a key role in energy transduction, DNA replication and other metabolic processes that are dysregulated in cancer cells. The discovery might lead to the development of a method for early detection of cancer cells.
The team developed a simple metal complex which shows an intense orange fluorescent colour in the presence of very low concentration of pyrophosphate (PPi) in water. The complex, also called a probe, had almost 1000 times higher level of response than earlier methods and an unprecedented sensitivity to detect PPi at a sub-nanomolar level. The discovery represents the first water-soluble fluorescent sensor that is capable of detecting pyrophosphate at this sensitivity level under physiological conditions.
The highly sensitive probes or sensors that are able to report the PPi level could lead to improved cancer diagnostics, since PPi plays a key role in energy transduction, DNA replication and other metabolic processes that are seriously misbehaving in cancer cells. All earlier PPi-selective sensor molecules or complexes have suffered from poor water solubility and low sensitivity in water. They can reach only micromolar levels and, thus, researchers have had to rely on protein-based probes that have their own limitations.
The researchers were able to show that the probe can image the pyrophosphate in the nuclei of living (HeLa) cells, making it an excellent probe for live cell pyrophosphahe imaging. The HeLa cells, originally from Henrietta Lack’s cervix carcinoma, are the most long-lived human cancer cell line and are often used as a cancer cell model. In addition to their applicability in water, they can easily be formulated into a hydrogel and coated onto paper strips for low-cost pyrophosphate detection. University of Jyväskylä
Researchers find connection between gene mutation, key symptoms of autism
, /in E-News /by 3wmediaScientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.
‘What was striking is that these were basically normal animals in terms of behaviour, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,’ said Damon Page, a TSRI biologist who led the study. ‘This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behaviour in general. However, brain circuits relevant to social behaviour are more vulnerable or less able to tolerate this overgrowth.’
Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviours and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.
In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second ‘hit’ to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localised overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviours in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviours including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.
The researchers found that Pten mutant mice showed altered social behaviour, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.
Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.
The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behaviour.
‘Timing is everything,’ Page said. ‘Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behaviour may turn out to be particularly vulnerable to the effects of poorly co-ordinated growth.’ Scripps University