New research from Queen Mary, University of London has uncovered a gene which plays a key role in the development of oesophageal cancer (cancer of the gullet).
The researchers studied families who suffer a rare inherited condition making them highly susceptible to the disease and found that a fault in a single gene was responsible. Initial studies suggest that the gene could play a role in the more common, non-inherited form of the disease, revealing a new target for treating this aggressive type of cancer.
Oesophageal cancer affects more than 8,000 people each year in the UK and rates are rising. It is more common in the UK than anywhere else in Europe.
Survival rates are poor compared to other types of cancer with only eight per cent of people alive five years after diagnosis. Scientists know little about how oesophageal cancer develops and very few drugs for targeting the disease are currently available.
The new study was led by Professor David Kelsell from Barts and the London Medical School, Queen Mary, University of London with collaborators from the University of Dundee and the University of Liverpool.
The research concentrated on three families with a hereditary condition called tylosis with oesophageal cancer. This condition affects the skin and mouth and sufferers have a 95 per cent chance of developing oesophageal cancer by the age of 65.
The research revealed that all three families carried a faulty version of a gene called RHBDF2.
Experiments showed that this gene plays an important role in how cells that line the oesophagus, and cells in the skin, respond to injury. When the gene is functioning normally it ensures that cells grow and divide in a controlled fashion to help heal a wound.
However, in tylosis patients’ cells, and in cells from oesophageal cancers, the gene malfunctions. This allows cells to divide and grow uncontrollably, causing cancer.
Professor Kelsell explains: ‘In studying this relatively rare condition, we have made an important discovery about a cancer that is all too common. Finding a genetic cause for this aggressive cancer, and understanding what that gene is doing, is an enormous step forward.
‘By analysing the complex biology which causes a particular type of cancer we begin to understand which treatments might be effective and also which treatments are unlikely to help.’
Queen Mary University of London
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Regular cervical screening saves lives not only by discovering pre-cursors to cervical cancer before they become invasive – but also by improving the chances of successful treatment in cases where invasive cancer could not be prevented.
‘We found that women who die of cervical cancer have usually not been screened for a long time,’ says research leader Professor Pär Sparén of the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet. ‘This is important to know for women who are hesitant about screening and for the sake of future changes to screening programmes.’
Around 450 women develop cervical cancer every year in Sweden, of whom about 140 die. Less than twenty of the vast majority of women (about 80 per cent) who undergo cervical screening every three years develop incurable and fatal cervical cancer. Moreover, of the cases discovered during routine screening before symptoms appear fewer than five every year are incurable.
In this present study, the researchers examined all new cases (a total of 1,230) of cervical cancer in Sweden over three years (1999-2001) using data from the National Quality Register for Cervical Screening. The project is part of the ACCES (Advancing Cervical Cancer Eradication Strategies) project, which was set up to monitor and evaluate the long-term effects of the cervical screening programme and vaccination programme against human papillomavirus (HPV), which causes cervical cancer.
The results of the study show, that women with symptom-discovered cervical cancer have a much better chance of being cured if they have previously had regular smear tests than if they have not taken part in any screening programme. About 92 per cent of the women with cervical cancer discovered through screening (i.e. before the appearance of symptoms), are cured from their cancer, even those who undergo screening for the first time.
‘This clearly shows that the positive results for cervical cancer after the introduction of screening have nothing to do with the over-diagnosis of benign cancers,’ says lead author Bengt Andrae, consultant at Gävle Hospital’s gynaecological clinic and researcher at Karolinska Institutet. ‘What it does show is that early diagnosis significantly improves the chance of successful treatment. This is a powerful argument for taking a Pap smear when invited to cervical screening, even if you feel healthy.’
Karolinska Institute
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Today, heterosexuals in Europe are at particular risk of carrying HIV for so long that they remain undiagnosed until their immune system starts to fail and they become ill.
An international study under the leadership of the HIV in Europe initiative has now revealed that a number of diseases, including herpes zoster and certain forms of cancer, should be on the list of indicators for having HIV – and thus serve to prompt health care professionals to suggest an HIV-test to their patients.
The new results and guidelines are to be debated at a major international HIV conference in Copenhagen on 19th-20th March.
‘At the HIV in Europe conference we will be discussing how to disseminate knowledge of the new HIV indicator diseases to non-HIV doctors and health care professionals across Europe,’ says Jens Lundgren, Co-chair of the HIV in Europe initiative.
He’s also a Professor of Viral Diseases at Rigshospitalet and the Faculty of Health and Medical Sciences at the University of Copenhagen, where he heads the Copenhagen HIV Programme, one of the leading HIV/AIDS centres in the world.
Half of all people living with HIV are diagnosed very late in the course of their chronic HIV infection. People infected through heterosexual transmission now comprise 42 per cent of these late presenters, as a study of 90,000 Europeans tested HIV positive since 2.000 shows.
UNAIDS has estimated that 2,5 million Europeans carry an HIV infection, and as many as 900 000 of these, are still unaware of this. Inside EU the numbers are 800.000 infected with 250.000 undiagnosed.
Ton Coenen, co-chair of the HIV in Europe initiative, Director of Aids Funds and Soa AIDS Nederland suggests that since the HIV/AIDS issue is no longer high on the agenda in many European countries, and since people have to actively choose to be HIV-tested, many perhaps no longer consider going for a test if they have had unsafe sex.
However, the sooner HIV-infected individuals receive a diagnosis and start therapy, the greater are their chances of survival and their quality of life. And new research also shows therapy lowers the risk of passing the infection on to someone else.
‘The currently situation shows that we need more effective testing strategies and guidelines,’ Ton Coenen continues. ‘More than 300 doctors, health care professionals, NGOs and health politicians from 40 European countries will be discussing this need at the conference on 19th and 20th of March, so we have the ideal forum for it.’
‘We already have a list of Aids defining diseases, the vast majority of which indicate a weak immune system. This is a symptom of HIV and should lead to an immediate HIV test,’ Professor Lundgren explains. ‘We nned to find people living with HIV sooner than is currently the case, but to do so requires that doctors and other health care professionals offer tests to people presenting with diseases indicative of a hidden and undiagnosed HIV infection earlier in the course of the disease.’
The HIV in Europe initiative took up this challenge in 2009 and started the HIDES study (HIV Indicator Diseases Across Europe), which investigated eight new diseases and how often they proved to be signs of an undiagnosed HIV infection among the 3588 patients in the study.
‘We could see that if an adult had a sexually transmitted infection, malignant lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B or C, ongoing mononucleosis-like illness, inexplicable, persistent decline in the number of circulating white blood cells, or seborrheic dermatitis/exanthema, the risk of HIV infection was so high that it would be cost-effectiveness for society to routinely offer them a test,’ Professor Lundgren says. He also emphasises that the new indicator diseases do not necessarily mean that the patient has HIV.
‘But the incidence of HIV is greater for these eight indicator diseases and they should encourage health care professionals to offer the patient an HIV test. Draft guidelines on how to ensure this throughout Europe are one of the topics we need to debate and decide on, before they can be implemented.’
University of Copenhagen
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Scientists have successfully completed an initial trial of a new, potentially more reliable, technique for screening breast cancer using ultrasound. The team at the National Physical Laboratory (NPL), the UK’s National Measurement Institute, working with the University Hospitals Bristol NHS Foundation Trust, are now looking to develop the technique into a clinical device.
Annually, 46,000 women are diagnosed with breast cancer in the UK, using state-of-the-art breast screening methods, based on X-ray mammography. Only about 30% of suspicious lesions turn out to be malignant. Each lesion must be confirmed by invasive biopsies, estimated to cost the NHS £35 million per year. Ionising radiation also has the potential to cause cancer, which limits the use of X-rays to single screenings of at risk groups, such as women over 50 through the National Breast Screening Programme.
There is a compelling need to develop improved, ideally non-ionising, methods of detecting breast lesions and solid masses. Improved diagnosis would reduce unnecessary biopsies and consequent patient trauma from being wrongly diagnosed.
Ultrasound ticks many of the boxes: it is safe, low cost, and already extensively used in trusted applications such as foetal scanning. However the quality of the images is not yet good enough for reliable diagnoses.
Part of the problem lies with the current detectors used. Different biological tissues have different sound speeds, and this affects the time taken for sound waves to arrive at the detector. This can distort the arriving waves, in extreme cases causing them to cancel each other out. This results in imaging errors, such as suggesting abnormal inclusions where there may be none.
The new method works by detecting the intensity of ultrasonic waves. Intensity is converted to heat that is then sensed by a thin membrane of pyroelectric film, which generates a voltage output dependant on the temperature rise. Imaging detectors based on this new principle should be much less susceptible to the effects caused by the uneven sound speed in tissues.
This technique, when used in a Computed Tomography (CT) configuration, should produce more accurate images of tissue properties and so provide better identification of breast tissue abnormalities. The aim of tomography is to produce a cross-section map of the tissue, which describes how the acoustic properties vary across the tissue. Using this map, it is possible to identify abnormal inclusions.
An initial feasibility project has proved the concept by testing single detectors using purpose-built artefacts. These artefacts were designed to include well-defined structures, enabling the new imaging method to be compared with more conventional techniques. The results confirmed that the new detectors generated more reliable maps of the internal structure of the artefacts than existing techniques.
Having received positive results and proven the potential of the project, NPL is now seeking funding to develop the work further. They hope to produce a demonstrator using a full array of 20 sensors, which should allow more rapid scanning and move the idea towards a system which might eventually be used clinically. It is hoped that this will provide both a suitable resolution and fast enough scanning to become a viable replacement for current clinical scanners. Following successful completion of the demonstrator, NPL and partners will look to work with a manufacturer to commercialise the technology.
EurekAlert
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UT Southwestern Medical Center cardiologists have uncovered how a specific protein’s previously unsuspected role contributes to the deterioration of heart muscle in patients with diabetes. Investigators in the mouse study also have found a way to reverse the damage caused by this protein.
Dr. Joseph HillThe new research was carried out in the laboratory of Dr. Joseph Hill, director of the Harry S. Moss Heart Center at UT Southwestern.
‘If we can protect the heart of diabetic patients, it would be a significant breakthrough,’ said Dr. Hill, the study’s senior author who also serves as chief of cardiology at the medical center. ‘These are fundamental research findings that can be applied to a patient’s bedside.’
Cardiovascular disease is the leading cause of illness and death in patients with diabetes, which affects more than 180 million people around the world, according to the American Heart Association. Diabetes puts additional stress on the heart – above and beyond that provoked by risk factors such as high blood pressure or coronary artery disease, Dr. Hill said.
‘Elevated glucose and the insulin-resistant diabetic state are both toxic to the heart,’ he said.
Dr. Hill and his colleagues in this study were able to maintain heart function in mice exposed to a high fat diet by inactivating a protein called FoxO1. Previous investigations from Dr. Hill’s laboratory demonstrated that FoxO proteins, a class of proteins that govern gene expression and regulate cell size, viability and metabolism, are tightly linked to the development of heart disease in mice with type 2 diabetes.
‘If you eliminate FoxO1, the heart is protected from the stress of diabetes and continues to function normally,’ Dr. Hill said. ‘If we can prevent FoxO1 from being overactive, then there is a chance that we can protect the hearts of patients with diabetes.’
UT Southwestern Medical Center
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Researchers at Winship Cancer Institute have identified a new function for a gene that normally prevents the development of cancer.
Scientists had known that the gene, which encodes a protein called p14 ARF, works inside the cell to control proliferation and division. A team led by Erwin Van Meir, PhD, discovered that p14 ARF also regulates tumour-induced angiogenesis, the process by which growing cancers attract new blood vessels.
The findings provide insight into how cancers form and progress, communicate with surrounding vascular cells and could guide the development of new therapies to fight tumours whose growth is driven by loss of p14 ARF.
Van Meir is professor of neurosurgery and haematology & medical oncology at Emory University School of Medicine, and director of the Laboratory for Molecular Neuro-Oncology at Winship Cancer Institute. Abdessamad Zerrouqi, PhD, research associate, is the first author of the paper.
Pinning down the new function for p14 ARF was a several-year detective investigation for Zerrouqi. The gene was a slippery target because growing cells in culture tend to lose or silence it, he says. P14 ARF is not turned on in most tissues of the body, but is activated in response to aberrant growth signals.
The gene encoding p14 ARF is mutated or silenced in many types of cancers, including most gliomas, the most common brain cancer in adults. People who inherit mutations affecting this gene develop ‘melanoma-astrocytoma syndrome,’ with increased occurrence of both types of tumours. ARF stands for ‘alternate reading frame’ because the DNA sequence overlaps with another protein that is read out of step in comparison to ARF. Previous research had linked the function of p14 ARF to another gene, p53, which is also frequently mutated in cancers. P53 is known as ‘guardian of the genome’ because it shuts down cell division in response to DNA damage.
Zerrouqi says several clues pointed to a separate function for p14 ARF. P14 ARF is often lost when astrocytoma progresses to glioblastoma, a more deadly form of brain cancer.
‘These tumours are bigger, more infiltrative and more vascularised,’ he says. ‘Yet p53 is usually lost at an early stage, before this transition takes place. This suggested that p14 ARF has a function that is independent of p53.’
Zerrouqi could show that restoring p14 ARF in cells from a tumour that had lost it interfered with the tumour’s ability to stimulate blood vessel growth. P14 ARF induces brain cancer cells to secrete a protein called TIMP3, which inhibits vascular cell migration, he found.
Zerrouqi and Van Meir’s findings are applicable to brain cancers as well as several other cancer types. TIMP3 itself has been found to be silenced in brain, kidney, colon, breast and lung cancers, suggesting that it is an obstacle to their growth.
Emory University School of Medicine
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Roche Accu-Chek® Inform II test strips chosen by CEGA Air Ambulance requirements for accuracy and ease-of-use
CEGA Air Ambulance has recently upgraded its blood glucose monitoring system to use the advanced Accu-Chek Inform II test strips from Roche. Ensuring accurate and reliable results across a wide range of glucose levels, these easy to use blood glucose test strips provide the performance criteria necessary for monitoring critically ill patients prior to, during and after emergency flight transfers.
“We require a reliable, easy to use, professional tool for blood glucose measurement,” comments CEGA Senior Flight Nurse, Stuart Cox. “After reviewing all the kits that are available on the market, we felt that the Roche Accu-Chek Inform II test strips best met our requirements for high quality patient care in the air ambulance environment. The user interface is very simple and straightforward to use anywhere and by any of our trained staff. In addition, the strips have a very good range compared to other systems, giving accurate results at both high and low glucose levels, which is essential for patient safety.”
Stress-induced insulin resistance and hyperglycaemia is common in critically ill patients [1,2,3] and so close monitoring of blood glucose levels is an important part of their care. Studies have shown that maintenance of appropriate glycaemic control in such patients improves morbidity and mortality [1,4,5].
“Providing international medical assistance, including the transportation of critical care patients around Europe, we use the Accu-Chek Inform II glucose strips to assess patients prior to the flight to make sure they are stable; during the transfer to monitor them and guide any necessary treatment; and then after the flight to assess their status before handing them over to the next medical team. The accuracy of the Accu-Chek Inform II strips ensures that patients get the right care at the right time, and we can have confidence in the results.”
The Accu-Chek Inform II test strips have undergone extensive evaluation, including studies at over 30 external sites as well as thorough internal testing [6]. The results of these evaluations demonstrate that the Accu‑Chek Inform II strips provide accurate and reliable blood glucose measurements under a variety conditions, including wide haematocrit and environmental ranges and in presence of maltose. Furthermore, the strips require a minimal sample volume of just 0.6µl and deliver accurate results from alternative sampling sites, such as the palm and forearm.
“The Accu-Chek Inform II strips mirror our needs for air ambulance work,” concludes Stuart. “They are well researched, with evidence-based performance. We also value the after sales and technical support we have received from Roche, which has been invaluable in the training of our staff.”
www.roche.co.ukwww.cega-air-ambulance.com.
1. Van den Berghe, G., Wouters, P., Weekers, F. et al (2001) N Engl. J. Med. 345: 1359-67 2. Van den Berghe, G. (2004) J. Clin. Invest. 114: 1187-1195 3. Mizock, B.A. Best Pract. Res. Clin. Endocrinol. Metab. 2001,15(4): 533 – 551. 4. Krinsley, J.S. (2004) Mayo Clin. Proc. 79:992-1000 5. Insulin in Intensive Care – The Leuven Protocol. Intensive Care Society website: http://www.ics.ac.uk/icmprof/pubsother.asp?menuid=86. Information available on request, Roche Diagnostics, Burgess Hill, UK.
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Researchers have identified a genetic signature for a severe, often painful food allergy – eosinophilic esophagitis – that could lead to improved diagnosis and treatment for children unable to eat a wide variety of foods.
The scientists, from Cincinnati Children’s Hospital Medical Center that they have pinpointed a dysregulated microRNA signature for eosinophilic esophagitis (EoE), a disease that also may cause weight loss, vomiting, heartburn and swallowing difficulties.
Interestingly, the dysregulated microRNA was reversible with steroid treatment, according to the study’s senior investigator, Marc E. Rothenberg, MD, PhD, director of Allergy and Immunology and the Center for Eosinophilic Disorders at Cincinnati Children’s. MicroRNAs are short segments of RNA that can regulate whether genetic messengers (mRNAs) are degraded or translated into protein.
‘The identification of biomarkers specific to EoE is a significant advancement for both the diagnosis and treatment of the disease,’ explains Rothenberg. ‘The microRNA signature provides an opportunity for more precise analysis of oesophageal biopsies.’
Rothenberg said children with EoE now undergo anaesthesia and invasive endoscopy to diagnose and monitor the allergy. The ability to determine the presence and status of EoE with a non-invasive method, such as blood test that measures microRNAs, would have a positive impact on individuals and families.
In the current study, investigators analyzed esophageal microRNA expression of patients with active EoE, steroid-induced EoE remission, patients with chronic (non-eosinophilic) esophagitis and of healthy individuals. Additionally, they assessed plasma microRNA expression of patients with active EoE, remission of EoE remission and of healthy individuals.
The researchers found that EoE was associated with 32 differentially regulated microRNAs and distinguishable from the non-eosinophilic forms of esophagitis (such as reflux disease). Esophageal eosinophil levels correlated significantly with expression of the most increased microRNAs, miR-21 and miR-223, and most decreased, miR-375. MiR-223 was also one of the most increased microRNAs in the plasma, along with miR-146a and miR-146b.
Notably, the expression of microRNAs dysregulated in patients with active EoE was normalised in patients with EoE who responded to steroid treatment. This suggests a significantly specific microRNA signature for disease activity points to its promise for use as a biomarker for EoE.
EurekAlert
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Charles Eberhart, M.D., Ph.D. Johns Hopkins scientists have published laboratory data refuting studies that suggest blood vessels that form within brain cancers are largely made up of cancer cells. The theory of cancer-based blood vessels calls into question the use and value of anticancer drugs that target these blood vessels, including bevacizumab (Avastin).
‘We don’t question whether brain cancer cells have the potential to express blood vessel markers and may occasionally find their way into blood vessels, but we do question the extent to which this happens,’ says Charles Eberhart, M.D., Ph.D., chief of neuropathology at the Johns Hopkins University School of Medicine. ‘In general, we find no evidence in our study that these vessels contain substantial amounts of cancer cells.’
Eberhart, professor of pathology, ophthalmology and oncology at Johns Hopkins, said he first encountered claims about the cancerous nature of tumour blood vessels about a year ago when he was invited to join students at a journal club meeting, a forum for discussing studies published in medical journals. ‘My first reaction to this research was ‘How could this be true?’’ says Eberhart. ‘Our clinical experience examining tissue from brain cancers does not support it.’
Studies have long demonstrated that malignant brain tumours contain large numbers of blood vessels to feed their growing demand for nutrients. The blood vessels are formed when tumours pump out growth factors that increase vessel production. Such studies opened the door to treatment strategies that specifically targeted blood-vessel growth and the vessel cells themselves.
More recently, scientists in Italy and the Memorial Sloan Kettering Cancer Center in New York published results of studies suggesting that these tumour blood vessels are made by primitive types of brain cancer cells that are a form of stem cells. In their studies, they found tumour markers on blood vessel cells in 20 to 90 percent of their brain cancer samples. The U.S./Italian research teams said their findings also suggested that the cancer-like blood vessels were more prone to drug resistance, potentially explaining why drugs like bevacizumab yield tumour-shrinking responses, but only for short periods. Bevacizumab is currently approved by the U.S. Food and Drug Administration for use in patients with colorectal, lung, kidney and brain cancers.
Eberhart said pathologists, including those who work on brain tissue, use certain tissue-based techniques to distinguish cancer cells from normal ones. When evaluating specimens of brain tissue removed during surgery for suspected cancer, he said, most pathologists agree that blood vessel cells in these specimens consistently lack the molecular changes associated with cancer cells, according to Eberhart. In fact, they often use these blood vessel cells as ‘normal controls’ to compare with potentially cancerous ones.
After the journal club experience, Eberhart teamed up with fellow neuropathologist Fausto Rodriguez, M.D., and colleagues at the Dana Farber Cancer Institute and Harvard Medical School in Boston to look more closely at the molecular features of blood vessel cells in brain cancer samples. They tested more than 100 samples from patients at Johns Hopkins and Dana Farber for EGFR and IDH1 markers, two common genes altered in brain cancer.
‘We also used a marker called CD34 to differentiate vascular [blood vessel] cells from other types of cells,’ says Rodriguez, assistant professor of pathology at Johns Hopkins. The research teams found no more than 10 percent of their samples contained vascular cells with EGFR or IDH1 cancer markers, and in those rare tumour samples, only a few cells exhibited those markers. The Johns Hopkins-Dana Farber-Harvard team tested all parts of the vessel walls for presence of the cancer markers.
Although the two groups used different markers to identify vessel cells, Rodriguez says ‘there is no marker that is absolute for each cell.’
Johns Hopkins Medical Institutions
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Researchers at Oregon State University have tapped into the extraordinary power of carbon ‘nanotubes’ to increase the speed of biological sensors, a technology that might one day allow a doctor to routinely perform lab tests in minutes, speeding diagnosis and treatment while reducing costs.
The new findings have almost tripled the speed of prototype nano-biosensors, and should find applications not only in medicine but in toxicology, environmental monitoring, new drug development and other fields.
More refinements are necessary before the systems are ready for commercial production, scientists say, but they hold great potential.
‘With these types of sensors, it should be possible to do many medical lab tests in minutes, allowing the doctor to make a diagnosis during a single office visit,’ said Ethan Minot, an OSU assistant professor of physics. ‘Many existing tests take days, cost quite a bit and require trained laboratory technicians.
‘This approach should accomplish the same thing with a hand-held sensor, and might cut the cost of an existing $50 lab test to about $1,’ he said.
The key to the new technology, the researchers say, is the unusual capability of carbon nanotubes. An outgrowth of nanotechnology, which deals with extraordinarily small particles near the molecular level, these nanotubes are long, hollow structures that have unique mechanical, optical and electronic properties, and are finding many applications.
In this case, carbon nanotubes can be used to detect a protein on the surface of a sensor. The nanotubes change their electrical resistance when a protein lands on them, and the extent of this change can be measured to determine the presence of a particular protein – such as serum and ductal protein biomarkers that may be indicators of breast cancer.
The newest advance was the creation of a way to keep proteins from sticking to other surfaces, like fluid sticking to the wall of a pipe. By finding a way to essentially ‘grease the pipe,’ OSU researchers were able to speed the sensing process by 2.5 times.
Further work is needed to improve the selective binding of proteins, the scientists said, before it is ready to develop into commercial biosensors.
‘Electronic detection of blood-borne biomarker proteins offers the exciting possibility of point-of-care medical diagnostics,’ the researchers wrote in their study. ‘Ideally such electronic biosensor devices would be low-cost and would quantify multiple biomarkers within a few minutes.’
Oregon State University
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High risk oesophageal cancer gene discovered
, /in E-News /by 3wmediaNew research from Queen Mary, University of London has uncovered a gene which plays a key role in the development of oesophageal cancer (cancer of the gullet).
The researchers studied families who suffer a rare inherited condition making them highly susceptible to the disease and found that a fault in a single gene was responsible. Initial studies suggest that the gene could play a role in the more common, non-inherited form of the disease, revealing a new target for treating this aggressive type of cancer.
Oesophageal cancer affects more than 8,000 people each year in the UK and rates are rising. It is more common in the UK than anywhere else in Europe.
Survival rates are poor compared to other types of cancer with only eight per cent of people alive five years after diagnosis. Scientists know little about how oesophageal cancer develops and very few drugs for targeting the disease are currently available.
The new study was led by Professor David Kelsell from Barts and the London Medical School, Queen Mary, University of London with collaborators from the University of Dundee and the University of Liverpool.
The research concentrated on three families with a hereditary condition called tylosis with oesophageal cancer. This condition affects the skin and mouth and sufferers have a 95 per cent chance of developing oesophageal cancer by the age of 65.
The research revealed that all three families carried a faulty version of a gene called RHBDF2.
Experiments showed that this gene plays an important role in how cells that line the oesophagus, and cells in the skin, respond to injury. When the gene is functioning normally it ensures that cells grow and divide in a controlled fashion to help heal a wound.
However, in tylosis patients’ cells, and in cells from oesophageal cancers, the gene malfunctions. This allows cells to divide and grow uncontrollably, causing cancer.
Professor Kelsell explains: ‘In studying this relatively rare condition, we have made an important discovery about a cancer that is all too common. Finding a genetic cause for this aggressive cancer, and understanding what that gene is doing, is an enormous step forward.
‘By analysing the complex biology which causes a particular type of cancer we begin to understand which treatments might be effective and also which treatments are unlikely to help.’ Queen Mary University of London
Cervical screening programme saves lives in more ways than one
, /in E-News /by 3wmediaRegular cervical screening saves lives not only by discovering pre-cursors to cervical cancer before they become invasive – but also by improving the chances of successful treatment in cases where invasive cancer could not be prevented.
‘We found that women who die of cervical cancer have usually not been screened for a long time,’ says research leader Professor Pär Sparén of the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet. ‘This is important to know for women who are hesitant about screening and for the sake of future changes to screening programmes.’
Around 450 women develop cervical cancer every year in Sweden, of whom about 140 die. Less than twenty of the vast majority of women (about 80 per cent) who undergo cervical screening every three years develop incurable and fatal cervical cancer. Moreover, of the cases discovered during routine screening before symptoms appear fewer than five every year are incurable.
In this present study, the researchers examined all new cases (a total of 1,230) of cervical cancer in Sweden over three years (1999-2001) using data from the National Quality Register for Cervical Screening. The project is part of the ACCES (Advancing Cervical Cancer Eradication Strategies) project, which was set up to monitor and evaluate the long-term effects of the cervical screening programme and vaccination programme against human papillomavirus (HPV), which causes cervical cancer.
The results of the study show, that women with symptom-discovered cervical cancer have a much better chance of being cured if they have previously had regular smear tests than if they have not taken part in any screening programme. About 92 per cent of the women with cervical cancer discovered through screening (i.e. before the appearance of symptoms), are cured from their cancer, even those who undergo screening for the first time.
‘This clearly shows that the positive results for cervical cancer after the introduction of screening have nothing to do with the over-diagnosis of benign cancers,’ says lead author Bengt Andrae, consultant at Gävle Hospital’s gynaecological clinic and researcher at Karolinska Institutet. ‘What it does show is that early diagnosis significantly improves the chance of successful treatment. This is a powerful argument for taking a Pap smear when invited to cervical screening, even if you feel healthy.’ Karolinska Institute
New indicator diseases reveal hidden HIV
, /in E-News /by 3wmediaToday, heterosexuals in Europe are at particular risk of carrying HIV for so long that they remain undiagnosed until their immune system starts to fail and they become ill.
An international study under the leadership of the HIV in Europe initiative has now revealed that a number of diseases, including herpes zoster and certain forms of cancer, should be on the list of indicators for having HIV – and thus serve to prompt health care professionals to suggest an HIV-test to their patients.
The new results and guidelines are to be debated at a major international HIV conference in Copenhagen on 19th-20th March.
‘At the HIV in Europe conference we will be discussing how to disseminate knowledge of the new HIV indicator diseases to non-HIV doctors and health care professionals across Europe,’ says Jens Lundgren, Co-chair of the HIV in Europe initiative.
He’s also a Professor of Viral Diseases at Rigshospitalet and the Faculty of Health and Medical Sciences at the University of Copenhagen, where he heads the Copenhagen HIV Programme, one of the leading HIV/AIDS centres in the world.
Half of all people living with HIV are diagnosed very late in the course of their chronic HIV infection. People infected through heterosexual transmission now comprise 42 per cent of these late presenters, as a study of 90,000 Europeans tested HIV positive since 2.000 shows.
UNAIDS has estimated that 2,5 million Europeans carry an HIV infection, and as many as 900 000 of these, are still unaware of this. Inside EU the numbers are 800.000 infected with 250.000 undiagnosed.
Ton Coenen, co-chair of the HIV in Europe initiative, Director of Aids Funds and Soa AIDS Nederland suggests that since the HIV/AIDS issue is no longer high on the agenda in many European countries, and since people have to actively choose to be HIV-tested, many perhaps no longer consider going for a test if they have had unsafe sex.
However, the sooner HIV-infected individuals receive a diagnosis and start therapy, the greater are their chances of survival and their quality of life. And new research also shows therapy lowers the risk of passing the infection on to someone else.
‘The currently situation shows that we need more effective testing strategies and guidelines,’ Ton Coenen continues. ‘More than 300 doctors, health care professionals, NGOs and health politicians from 40 European countries will be discussing this need at the conference on 19th and 20th of March, so we have the ideal forum for it.’
‘We already have a list of Aids defining diseases, the vast majority of which indicate a weak immune system. This is a symptom of HIV and should lead to an immediate HIV test,’ Professor Lundgren explains. ‘We nned to find people living with HIV sooner than is currently the case, but to do so requires that doctors and other health care professionals offer tests to people presenting with diseases indicative of a hidden and undiagnosed HIV infection earlier in the course of the disease.’
The HIV in Europe initiative took up this challenge in 2009 and started the HIDES study (HIV Indicator Diseases Across Europe), which investigated eight new diseases and how often they proved to be signs of an undiagnosed HIV infection among the 3588 patients in the study.
‘We could see that if an adult had a sexually transmitted infection, malignant lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B or C, ongoing mononucleosis-like illness, inexplicable, persistent decline in the number of circulating white blood cells, or seborrheic dermatitis/exanthema, the risk of HIV infection was so high that it would be cost-effectiveness for society to routinely offer them a test,’ Professor Lundgren says. He also emphasises that the new indicator diseases do not necessarily mean that the patient has HIV.
‘But the incidence of HIV is greater for these eight indicator diseases and they should encourage health care professionals to offer the patient an HIV test. Draft guidelines on how to ensure this throughout Europe are one of the topics we need to debate and decide on, before they can be implemented.’ University of Copenhagen
New screening technique could provide more reliable breast cancer detection
, /in E-News /by 3wmediaScientists have successfully completed an initial trial of a new, potentially more reliable, technique for screening breast cancer using ultrasound. The team at the National Physical Laboratory (NPL), the UK’s National Measurement Institute, working with the University Hospitals Bristol NHS Foundation Trust, are now looking to develop the technique into a clinical device.
Annually, 46,000 women are diagnosed with breast cancer in the UK, using state-of-the-art breast screening methods, based on X-ray mammography. Only about 30% of suspicious lesions turn out to be malignant. Each lesion must be confirmed by invasive biopsies, estimated to cost the NHS £35 million per year. Ionising radiation also has the potential to cause cancer, which limits the use of X-rays to single screenings of at risk groups, such as women over 50 through the National Breast Screening Programme.
There is a compelling need to develop improved, ideally non-ionising, methods of detecting breast lesions and solid masses. Improved diagnosis would reduce unnecessary biopsies and consequent patient trauma from being wrongly diagnosed.
Ultrasound ticks many of the boxes: it is safe, low cost, and already extensively used in trusted applications such as foetal scanning. However the quality of the images is not yet good enough for reliable diagnoses.
Part of the problem lies with the current detectors used. Different biological tissues have different sound speeds, and this affects the time taken for sound waves to arrive at the detector. This can distort the arriving waves, in extreme cases causing them to cancel each other out. This results in imaging errors, such as suggesting abnormal inclusions where there may be none.
The new method works by detecting the intensity of ultrasonic waves. Intensity is converted to heat that is then sensed by a thin membrane of pyroelectric film, which generates a voltage output dependant on the temperature rise. Imaging detectors based on this new principle should be much less susceptible to the effects caused by the uneven sound speed in tissues.
This technique, when used in a Computed Tomography (CT) configuration, should produce more accurate images of tissue properties and so provide better identification of breast tissue abnormalities. The aim of tomography is to produce a cross-section map of the tissue, which describes how the acoustic properties vary across the tissue. Using this map, it is possible to identify abnormal inclusions.
An initial feasibility project has proved the concept by testing single detectors using purpose-built artefacts. These artefacts were designed to include well-defined structures, enabling the new imaging method to be compared with more conventional techniques. The results confirmed that the new detectors generated more reliable maps of the internal structure of the artefacts than existing techniques.
Having received positive results and proven the potential of the project, NPL is now seeking funding to develop the work further. They hope to produce a demonstrator using a full array of 20 sensors, which should allow more rapid scanning and move the idea towards a system which might eventually be used clinically. It is hoped that this will provide both a suitable resolution and fast enough scanning to become a viable replacement for current clinical scanners. Following successful completion of the demonstrator, NPL and partners will look to work with a manufacturer to commercialise the technology. EurekAlert
Cardiologists identify mechanism that makes heart disease worse in diabetics
, /in E-News /by 3wmediaUT Southwestern Medical Center cardiologists have uncovered how a specific protein’s previously unsuspected role contributes to the deterioration of heart muscle in patients with diabetes. Investigators in the mouse study also have found a way to reverse the damage caused by this protein.
Dr. Joseph HillThe new research was carried out in the laboratory of Dr. Joseph Hill, director of the Harry S. Moss Heart Center at UT Southwestern.
‘If we can protect the heart of diabetic patients, it would be a significant breakthrough,’ said Dr. Hill, the study’s senior author who also serves as chief of cardiology at the medical center. ‘These are fundamental research findings that can be applied to a patient’s bedside.’
Cardiovascular disease is the leading cause of illness and death in patients with diabetes, which affects more than 180 million people around the world, according to the American Heart Association. Diabetes puts additional stress on the heart – above and beyond that provoked by risk factors such as high blood pressure or coronary artery disease, Dr. Hill said.
‘Elevated glucose and the insulin-resistant diabetic state are both toxic to the heart,’ he said.
Dr. Hill and his colleagues in this study were able to maintain heart function in mice exposed to a high fat diet by inactivating a protein called FoxO1. Previous investigations from Dr. Hill’s laboratory demonstrated that FoxO proteins, a class of proteins that govern gene expression and regulate cell size, viability and metabolism, are tightly linked to the development of heart disease in mice with type 2 diabetes.
‘If you eliminate FoxO1, the heart is protected from the stress of diabetes and continues to function normally,’ Dr. Hill said. ‘If we can prevent FoxO1 from being overactive, then there is a chance that we can protect the hearts of patients with diabetes.’ UT Southwestern Medical Center
New pathway for regulation of blood vessel growth in cancer
, /in E-News /by 3wmediaResearchers at Winship Cancer Institute have identified a new function for a gene that normally prevents the development of cancer.
Scientists had known that the gene, which encodes a protein called p14 ARF, works inside the cell to control proliferation and division. A team led by Erwin Van Meir, PhD, discovered that p14 ARF also regulates tumour-induced angiogenesis, the process by which growing cancers attract new blood vessels.
The findings provide insight into how cancers form and progress, communicate with surrounding vascular cells and could guide the development of new therapies to fight tumours whose growth is driven by loss of p14 ARF.
Van Meir is professor of neurosurgery and haematology & medical oncology at Emory University School of Medicine, and director of the Laboratory for Molecular Neuro-Oncology at Winship Cancer Institute. Abdessamad Zerrouqi, PhD, research associate, is the first author of the paper.
Pinning down the new function for p14 ARF was a several-year detective investigation for Zerrouqi. The gene was a slippery target because growing cells in culture tend to lose or silence it, he says. P14 ARF is not turned on in most tissues of the body, but is activated in response to aberrant growth signals.
The gene encoding p14 ARF is mutated or silenced in many types of cancers, including most gliomas, the most common brain cancer in adults. People who inherit mutations affecting this gene develop ‘melanoma-astrocytoma syndrome,’ with increased occurrence of both types of tumours. ARF stands for ‘alternate reading frame’ because the DNA sequence overlaps with another protein that is read out of step in comparison to ARF. Previous research had linked the function of p14 ARF to another gene, p53, which is also frequently mutated in cancers. P53 is known as ‘guardian of the genome’ because it shuts down cell division in response to DNA damage.
Zerrouqi says several clues pointed to a separate function for p14 ARF. P14 ARF is often lost when astrocytoma progresses to glioblastoma, a more deadly form of brain cancer.
‘These tumours are bigger, more infiltrative and more vascularised,’ he says. ‘Yet p53 is usually lost at an early stage, before this transition takes place. This suggested that p14 ARF has a function that is independent of p53.’
Zerrouqi could show that restoring p14 ARF in cells from a tumour that had lost it interfered with the tumour’s ability to stimulate blood vessel growth. P14 ARF induces brain cancer cells to secrete a protein called TIMP3, which inhibits vascular cell migration, he found.
Zerrouqi and Van Meir’s findings are applicable to brain cancers as well as several other cancer types. TIMP3 itself has been found to be silenced in brain, kidney, colon, breast and lung cancers, suggesting that it is an obstacle to their growth. Emory University School of Medicine
Advanced blood glucose monitoring system provides superior patient safety during emergency flight transfer
, /in E-News /by 3wmediaRoche Accu-Chek® Inform II test strips chosen by CEGA Air Ambulance requirements for accuracy and ease-of-use
CEGA Air Ambulance has recently upgraded its blood glucose monitoring system to use the advanced Accu-Chek Inform II test strips from Roche. Ensuring accurate and reliable results across a wide range of glucose levels, these easy to use blood glucose test strips provide the performance criteria necessary for monitoring critically ill patients prior to, during and after emergency flight transfers.
“We require a reliable, easy to use, professional tool for blood glucose measurement,” comments CEGA Senior Flight Nurse, Stuart Cox. “After reviewing all the kits that are available on the market, we felt that the Roche Accu-Chek Inform II test strips best met our requirements for high quality patient care in the air ambulance environment. The user interface is very simple and straightforward to use anywhere and by any of our trained staff. In addition, the strips have a very good range compared to other systems, giving accurate results at both high and low glucose levels, which is essential for patient safety.”
Stress-induced insulin resistance and hyperglycaemia is common in critically ill patients [1,2,3] and so close monitoring of blood glucose levels is an important part of their care. Studies have shown that maintenance of appropriate glycaemic control in such patients improves morbidity and mortality [1,4,5].
“Providing international medical assistance, including the transportation of critical care patients around Europe, we use the Accu-Chek Inform II glucose strips to assess patients prior to the flight to make sure they are stable; during the transfer to monitor them and guide any necessary treatment; and then after the flight to assess their status before handing them over to the next medical team. The accuracy of the Accu-Chek Inform II strips ensures that patients get the right care at the right time, and we can have confidence in the results.”
The Accu-Chek Inform II test strips have undergone extensive evaluation, including studies at over 30 external sites as well as thorough internal testing [6]. The results of these evaluations demonstrate that the Accu‑Chek Inform II strips provide accurate and reliable blood glucose measurements under a variety conditions, including wide haematocrit and environmental ranges and in presence of maltose. Furthermore, the strips require a minimal sample volume of just 0.6µl and deliver accurate results from alternative sampling sites, such as the palm and forearm.
“The Accu-Chek Inform II strips mirror our needs for air ambulance work,” concludes Stuart. “They are well researched, with evidence-based performance. We also value the after sales and technical support we have received from Roche, which has been invaluable in the training of our staff.” www.roche.co.ukwww.cega-air-ambulance.com.
1. Van den Berghe, G., Wouters, P., Weekers, F. et al (2001) N Engl. J. Med. 345: 1359-67
2. Van den Berghe, G. (2004) J. Clin. Invest. 114: 1187-1195
3. Mizock, B.A. Best Pract. Res. Clin. Endocrinol. Metab. 2001,15(4): 533 – 551.
4. Krinsley, J.S. (2004) Mayo Clin. Proc. 79:992-1000
5. Insulin in Intensive Care – The Leuven Protocol. Intensive Care Society website: http://www.ics.ac.uk/icmprof/pubsother.asp?menuid=86. Information available on request, Roche Diagnostics, Burgess Hill, UK.
Genetic marker for painful food allergy points to improved diagnosis, treatment
, /in E-News /by 3wmediaResearchers have identified a genetic signature for a severe, often painful food allergy – eosinophilic esophagitis – that could lead to improved diagnosis and treatment for children unable to eat a wide variety of foods.
The scientists, from Cincinnati Children’s Hospital Medical Center that they have pinpointed a dysregulated microRNA signature for eosinophilic esophagitis (EoE), a disease that also may cause weight loss, vomiting, heartburn and swallowing difficulties.
Interestingly, the dysregulated microRNA was reversible with steroid treatment, according to the study’s senior investigator, Marc E. Rothenberg, MD, PhD, director of Allergy and Immunology and the Center for Eosinophilic Disorders at Cincinnati Children’s. MicroRNAs are short segments of RNA that can regulate whether genetic messengers (mRNAs) are degraded or translated into protein.
‘The identification of biomarkers specific to EoE is a significant advancement for both the diagnosis and treatment of the disease,’ explains Rothenberg. ‘The microRNA signature provides an opportunity for more precise analysis of oesophageal biopsies.’
Rothenberg said children with EoE now undergo anaesthesia and invasive endoscopy to diagnose and monitor the allergy. The ability to determine the presence and status of EoE with a non-invasive method, such as blood test that measures microRNAs, would have a positive impact on individuals and families.
In the current study, investigators analyzed esophageal microRNA expression of patients with active EoE, steroid-induced EoE remission, patients with chronic (non-eosinophilic) esophagitis and of healthy individuals. Additionally, they assessed plasma microRNA expression of patients with active EoE, remission of EoE remission and of healthy individuals.
The researchers found that EoE was associated with 32 differentially regulated microRNAs and distinguishable from the non-eosinophilic forms of esophagitis (such as reflux disease). Esophageal eosinophil levels correlated significantly with expression of the most increased microRNAs, miR-21 and miR-223, and most decreased, miR-375. MiR-223 was also one of the most increased microRNAs in the plasma, along with miR-146a and miR-146b.
Notably, the expression of microRNAs dysregulated in patients with active EoE was normalised in patients with EoE who responded to steroid treatment. This suggests a significantly specific microRNA signature for disease activity points to its promise for use as a biomarker for EoE. EurekAlert
Study refutes research claims that call into question use of vessel-targeting, anticancer drugs
, /in E-News /by 3wmediaCharles Eberhart, M.D., Ph.D. Johns Hopkins scientists have published laboratory data refuting studies that suggest blood vessels that form within brain cancers are largely made up of cancer cells. The theory of cancer-based blood vessels calls into question the use and value of anticancer drugs that target these blood vessels, including bevacizumab (Avastin).
‘We don’t question whether brain cancer cells have the potential to express blood vessel markers and may occasionally find their way into blood vessels, but we do question the extent to which this happens,’ says Charles Eberhart, M.D., Ph.D., chief of neuropathology at the Johns Hopkins University School of Medicine. ‘In general, we find no evidence in our study that these vessels contain substantial amounts of cancer cells.’
Eberhart, professor of pathology, ophthalmology and oncology at Johns Hopkins, said he first encountered claims about the cancerous nature of tumour blood vessels about a year ago when he was invited to join students at a journal club meeting, a forum for discussing studies published in medical journals. ‘My first reaction to this research was ‘How could this be true?’’ says Eberhart. ‘Our clinical experience examining tissue from brain cancers does not support it.’
Studies have long demonstrated that malignant brain tumours contain large numbers of blood vessels to feed their growing demand for nutrients. The blood vessels are formed when tumours pump out growth factors that increase vessel production. Such studies opened the door to treatment strategies that specifically targeted blood-vessel growth and the vessel cells themselves.
More recently, scientists in Italy and the Memorial Sloan Kettering Cancer Center in New York published results of studies suggesting that these tumour blood vessels are made by primitive types of brain cancer cells that are a form of stem cells. In their studies, they found tumour markers on blood vessel cells in 20 to 90 percent of their brain cancer samples. The U.S./Italian research teams said their findings also suggested that the cancer-like blood vessels were more prone to drug resistance, potentially explaining why drugs like bevacizumab yield tumour-shrinking responses, but only for short periods. Bevacizumab is currently approved by the U.S. Food and Drug Administration for use in patients with colorectal, lung, kidney and brain cancers.
Eberhart said pathologists, including those who work on brain tissue, use certain tissue-based techniques to distinguish cancer cells from normal ones. When evaluating specimens of brain tissue removed during surgery for suspected cancer, he said, most pathologists agree that blood vessel cells in these specimens consistently lack the molecular changes associated with cancer cells, according to Eberhart. In fact, they often use these blood vessel cells as ‘normal controls’ to compare with potentially cancerous ones.
After the journal club experience, Eberhart teamed up with fellow neuropathologist Fausto Rodriguez, M.D., and colleagues at the Dana Farber Cancer Institute and Harvard Medical School in Boston to look more closely at the molecular features of blood vessel cells in brain cancer samples. They tested more than 100 samples from patients at Johns Hopkins and Dana Farber for EGFR and IDH1 markers, two common genes altered in brain cancer.
‘We also used a marker called CD34 to differentiate vascular [blood vessel] cells from other types of cells,’ says Rodriguez, assistant professor of pathology at Johns Hopkins. The research teams found no more than 10 percent of their samples contained vascular cells with EGFR or IDH1 cancer markers, and in those rare tumour samples, only a few cells exhibited those markers. The Johns Hopkins-Dana Farber-Harvard team tested all parts of the vessel walls for presence of the cancer markers.
Although the two groups used different markers to identify vessel cells, Rodriguez says ‘there is no marker that is absolute for each cell.’ Johns Hopkins Medical Institutions
Nanotube technology leading to fast, lower-cost medical diagnostics
, /in E-News /by 3wmediaResearchers at Oregon State University have tapped into the extraordinary power of carbon ‘nanotubes’ to increase the speed of biological sensors, a technology that might one day allow a doctor to routinely perform lab tests in minutes, speeding diagnosis and treatment while reducing costs.
The new findings have almost tripled the speed of prototype nano-biosensors, and should find applications not only in medicine but in toxicology, environmental monitoring, new drug development and other fields.
More refinements are necessary before the systems are ready for commercial production, scientists say, but they hold great potential.
‘With these types of sensors, it should be possible to do many medical lab tests in minutes, allowing the doctor to make a diagnosis during a single office visit,’ said Ethan Minot, an OSU assistant professor of physics. ‘Many existing tests take days, cost quite a bit and require trained laboratory technicians.
‘This approach should accomplish the same thing with a hand-held sensor, and might cut the cost of an existing $50 lab test to about $1,’ he said.
The key to the new technology, the researchers say, is the unusual capability of carbon nanotubes. An outgrowth of nanotechnology, which deals with extraordinarily small particles near the molecular level, these nanotubes are long, hollow structures that have unique mechanical, optical and electronic properties, and are finding many applications.
In this case, carbon nanotubes can be used to detect a protein on the surface of a sensor. The nanotubes change their electrical resistance when a protein lands on them, and the extent of this change can be measured to determine the presence of a particular protein – such as serum and ductal protein biomarkers that may be indicators of breast cancer.
The newest advance was the creation of a way to keep proteins from sticking to other surfaces, like fluid sticking to the wall of a pipe. By finding a way to essentially ‘grease the pipe,’ OSU researchers were able to speed the sensing process by 2.5 times.
Further work is needed to improve the selective binding of proteins, the scientists said, before it is ready to develop into commercial biosensors.
‘Electronic detection of blood-borne biomarker proteins offers the exciting possibility of point-of-care medical diagnostics,’ the researchers wrote in their study. ‘Ideally such electronic biosensor devices would be low-cost and would quantify multiple biomarkers within a few minutes.’ Oregon State University