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

Psychiatric disorders can be described on many levels, the most traditional of which are subjective descriptions of the experience of being depressed and the use of rating scales that quantify depressive symptoms. Over the past two decades, research has developed other strategies for describing the biological underpinnings of depression, including volumetric brain measurements using magnetic resonance imaging (MRI) and the patterns of gene expression in white blood cells.
During this period, a great deal of research has attempted to characterise the genes that cause depression as reflected in rating scales of mood states, alterations in brain structure and function as measured by MRI, and gene expression patterns in post-mortem brain tissue from people who had depression.
So what would happen if one tried to find the gene or genes that explained the ‘whole picture’ by combining all of the different types of information that one could collect? This is exactly what was attempted by Dr. David Glahn, of Yale University and Hartford Hospital’s Institute of Living, and his colleagues.
‘They have provided a very exciting strategy for uniting the various types of data that we collect in clinical research in studies attempting to identify risk genes,’ said Dr. John Krystal, Editor of Biological Psychiatry.
Their work localised a gene, called RNF123, which may play a role in major depression.
They set out with two clear goals: to describe a new method for ranking measures of brain structure and function on their genetic ‘importance’ for an illness, and then to localise a candidate gene for major depression.
‘We were trying to come up with a way that could generally be used to link biological measurements to (psychiatric) disease risk,’ said Dr. John Blangero, director of the AT&T Genomics Computing Center at the Texas Biomedical Research Institute. ‘And in our first application of this, in relation to major depressive disorder, we’ve actually come up with something quite exciting.’
While RNF123 hasn’t previously been linked to depression, it has been shown to affect a part of the brain called the hippocampus, which is altered in people with major depression.
‘We assume that the biological measures are closer mechanistically to the underlying disease processes in the brain. Yet, ultimately we are interested in the subjective experiences and functional impairment associated with mental illness,’ added Krystal. ‘The approach employed in this study may help to make use of all of this information, hopefully increasing our ability to identify genes that cause depression or might be targeted for its treatment.’
Glahn said, ‘We still have more work before we truly believe this is a home-run gene, but we’ve got a really good candidate. Even that has been tough to do in depression.’ AT&T Genomics Computing Center

After a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease.
A report on the discovery was led by investigators at the University of Michigan Health System and Johns Hopkins University School of Medicine. The research team found that men who inherit this mutation have a 10 to 20 times higher risk of developing prostate cancer.
While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.
‘It’s what we’ve been looking for over the past 20 years,’ adds William B. Isaacs, Ph.D., professor of urology and oncology at the Johns Hopkins University School of Medicine, the study’s other senior author. ‘It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results.’
For this study, the researchers collaborated with John Carpten, Ph.D., at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, who used the latest technology to sequence the DNA of more than 200 genes in a human chromosome region known as 17q21-22. Cooney, working with Ethan Lange, Ph.D., of the University of North Carolina on the U-M Prostate Cancer Genetics Project, was the first to identify 17q21-22 as a region of interest.
Researchers started with samples from the youngest patients with prostate cancer in 94 families who had participated in studies at U-M and Johns Hopkins. Each of those families had multiple cases of the disease among close relatives, such as between fathers and sons or among brothers.
Members of four different families were found to have the same mutation in the HOXB13 gene, which plays an important role in the development of the prostate during the foetal stage and its function later in life. The mutation was carried by all 18 men with prostate cancer in these four families.
The researchers collaborated with Jianfeng Xu, Ph.D., and Lilly Zheng, Ph.D., at Wake Forest University to look for the same HOXB13 gene mutation among 5,100 men who had been treated for prostate cancer at either Johns Hopkins or U-M. The mutation was found in 1.4 percent—or 72 of the men. It turned out that those men were much more likely to have at least one first-degree relative, a father or brother, who also had been diagnosed. The researchers also looked for the mutation in a control group of 1,400 men without prostate cancer, and only one of those men carried the mutation. In addition, the researchers studied men who were specifically enrolled in studies of early-onset or familial prostate cancer.
‘We found that the mutation was significantly more common in men with a family history and early diagnosis compared with men diagnosed later, after age 55, without a family history. The difference was 3.1 percent versus 0.62 percent, Cooney says. University of Michigan Health System

A study of almost 3,800 pregnancies has provided the most accurate and direct evidence to date that malaria infection reduces early foetal growth. Low birth weight is the most important risk factor for neonatal mortality in developing countries. The research highlights the importance of preventing malaria in pregnancy.
According to the World Malaria Report 2011, malaria killed an estimated 655,000 people in 2010. The disease is one of the most common parasitic infections to affect pregnancy. Previous studies have suggested that infection with both P. falciparum and P. vivax malaria during pregnancy reduces birth weight whether or not maternal symptoms are present. However, these studies have been hampered by difficulties in estimating gestational age accurately and diagnosing malaria infection in early pregnancy.
Now researchers at the Shoklo Malaria Research Unit on the border of Thailand and Myanmar, part of the Wellcome Trust-Mahidol University-Oxford University Tropical Medicine Research Programme, have used ultrasound scans to provide the first direct evidence of the effect of malaria on foetal growth in pregnancy. Antenatal ultrasound, which is essential for dating pregnancy accurately, is becoming more widely available in developing countries. The technology also allows the diameter of the foetus’s head to be measured. For infections that occur in early pregnancy, the researchers believe that the size of the head may be the most appropriate indicator of growth restriction.
The ultrasound scans revealed that the diameter of the average foetus’s head was significantly smaller when malaria infection occurred in the first half of pregnancy when compared to pregnancies unaffected by malaria. On average, at the mid-pregnancy ultrasound scan the foetuses’ heads were 2% smaller when affected by malaria. Even a single infection of treated P. falciparum or P. vivax malaria was associated with reduced foetal head diameter, irrespective of whether the woman had shown symptoms or not.
However, although a single early detected and well-treated malaria episode had an effect on foetal head size at mid-trimester, this was not seen at delivery, suggesting that early treatment with effective drugs may allow for growth to recover later in pregnancy.
Strategies to prevent malaria in pregnancy have focused on the second half of pregnancy, when most of the foetal weight gain takes place, but this works suggests that focus should be on the first trimester too. Pregnant woman need to be educated about the risks of malaria in pregnancy and where possible in areas of high risk, offered preventative medication from early pregnancy onwards.

Researchers studying the genetic roots of the most common malignant childhood brain tumour have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.
The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.
‘This study provides new direction for understanding what drives these tumours and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases,’ said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study’s corresponding authors.
The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumours.
‘This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel,’ said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. ‘These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids.’
This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumours from an additional 56 patients for the same alterations.
The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumour genomes of 600 young cancer patients with some of the most challenging tumours. The endeavour has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.
Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.
This study found a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumours develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. ‘It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways,’ said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study’s first authors.
Investigators demonstrated that subtype three and four medulloblastoma often had alterations in genes that impact cell maturation. The genes carry instructions for proteins that add or remove the chemical group methyl to the H3K27 protein. H3K27 is part of the chromatin structure that packages DNA to fit inside cells. That packaging helps determine if genes are switched on or off. The addition of methyl to H3K27 permits less specialised cells to keep dividing and blocks activity of genes that would prompt cells to stop dividing, differentiate and take on more specialised roles.
Some subgroup 3 and 4 tumours were characterised by a gain in EZH2, which adds methyl to H3K27. EZH2 is also associated with adult cancers and the focus of ongoing drug development. St. Jude has begun screening those and other compounds for evidence of effectiveness against medulloblastoma.
In other subtype 3 and 4 tumours a different gene, KDM6A, was inactivated by mutations. KDM6A works to remove methyl groups from H3K27, thus eliminating this gene’s function could keep cells in an immature dividing state. The results suggest the genes possibly work together to promote medulloblastoma development.
The EZH2 and KDM6A alterations were found only in the subgroup three and four tumours, which also had higher levels of H3K27 methylation than other medulloblastoma subtypes. ‘With this research we have ‘lifted the lid’ on the most aggressive and challenging form of medulloblastoma, subtype 3, which was really a black box in terms of our understanding, and revealed a major driver of the disease,’ Gilbertson said.
The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer. St. Jude Children’s Research Hospital