Beckman Coulter, Inc. has obtained a CLIA Certificate of Registration, along with Massachusetts State Licensure, allowing Beckman Coulter Genomics to begin accepting clinical samples for genetic sequencing – the most technically complex CLIA category – and to provide those results to physicians for their use in treating, diagnosing and preventing disease in patients.

This milestone certification paves the way for detection of BRAF exon 11 (codons 439-477) and exon 15 (codons 581-620) for mutations using PCR-based DNA Sanger sequencing, the first clinical molecular diagnostic assay the company has developed. Plans call for Beckman Coulter Genomics to develop further CLIA-certified assays using next-generation sequencing for a number of oncology and infectious disease applications.

‘This certification allows Beckman Coulter to work more closely with physicians to bring the promise of high-quality molecular diagnostics to benefit greater numbers of patients,’ said Joseph Repp, vice president and general manager of Beckman Coulter Genomics. ‘We’re actively working to bring additional assays to physicians and clinical researchers across the country, as well as help all our customers further their understanding of genetic involvement in disease states.’

In recent years it became clear that people with diabetes face an ominous prospect – a far greater risk of developing Alzheimer’s disease. Now researchers at The City College of New York (CCNY) have shed light on one reason why. Biology Professor Chris Li and her colleagues have discovered that a single gene forms a common link between the two diseases.
They found that the gene, known to be present in many Alzheimer’s disease cases, affects the insulin pathway. Disruption of this pathway is a hallmark of diabetes. The finding could point to a therapeutic target for both diseases.
‘People with type 2 diabetes have an increased risk of dementia. The insulin pathways are involved in many metabolic processes, including helping to keep the nervous system healthy,’ said Professor Li, explaining why the link is not far-fetched.
Although the cause of Alzheimer’s is still unclear, one criterion for diagnosis of the disease after death is the presence of sticky plaques of amyloid protein in decimated portions of patients’ brains.
Mutations in the human ‘amyloid precursor protein’ (APP) gene, or in genes that process APP, show up in cases of Alzheimer’s that run in families. In the study, Professor Li and her colleagues scrutinised a protein called APL-1, made by a gene in the worm Caenorhabditis elegans (C. elegans ) that happens to be a perfect stand-in for the human Alzheimer’s disease gene.
‘What we found was that mutations in the worm-equivalent of the APP gene slowed their development, which suggested that some metabolic pathway was disrupted,’ said Professor Li. ‘We began to examine how the worm-equivalent of APP modulated different metabolic pathways and found that the APP equivalent inhibited the insulin pathway.’
This suggested that the human version of the gene likely plays a role in both Alzheimer’s disease and diabetes.
They also found that additional mutations in the insulin pathway reversed the defects of the APP mutation. This helped explain how these genes are functionally linked.
The APL-1 is so important, they found, that ‘when you knock out the worm-equivalent of APP, the animals die,’ Li explained. ‘This tells us that the APP family of proteins is essential in worms, as they are essential in mammals,’ like us.
Professor Li and her colleagues hope that this new insight will help focus research in ways that might lead to new therapies in the treatment of both Alzheimer’s disease and diabetes. The City College of New York.

International Osteoporosis Foundation Working Group provides guidance; urges caution in the diagnosis and treatment of osteoporosis in adults under 50 years of age
Much of the research defining osteoporosis and fracture risk has focused on older adults, i.e. postmenopausal women and men over the age of 50. While older adults are at highest risk of osteoporosis and related fractures, the disease can also affect younger adults between 20 and 50 years of age. However, the diagnosis and management of osteoporosis in young adults is complicated by special challenges, including a complex pathophysiology and the related fact that there is no clear definition of osteoporosis, or of intervention thresholds, in this age group.
An International Osteoporosis Foundation scientific working group has now published a review which outlines the pathophysiology, diagnosis and management of osteoporosis in young adults, providing a clear screening strategy that includes the use of clinical and laboratory exams.
Dr. Serge Ferrari of the University of Geneva and chair of the IOF Working Group on Osteoporosis Pathophysiology, explains the diagnostic challenge faced by clinicians, ‘Low bone mass in this age group may not necessarily represent a pathological condition, but result instead from low peak bone mass in relation to body size, late puberty, or genetic and environmental background.’
On the other hand, there are young adults who may truly have osteoporosis with bone fragility at a young age. This may result from altered bone modelling and/or remodelling during growth or later due to a chronic disorder or a genetic or idiopathic condition. Typical examples would be inflammatory bowel diseases, particularly Crohn’s disease. These diseases impair bone mass gain and/or accelerate bone loss because of mal-absorption and poor nutrient intake. In addition, low levels of physical activity, secondary amenorrhea, and in many cases the effects of corticosteroid treatment, can have an impact on bone mass.
Distinguishing between these two situations can be all the more difficult because up to 30% of young women and 50% of young men have had fractures during childhood and adolescence, usually traumatic. These are not necessarily associated with skeletal fragility.
An apparently low areal bone mineral density (T-score < -2.5 at spine or hip by DXA) must be interpreted with caution in young adults of small body size (constitutionally lean) and/or stunted growth. Inaccurate ‘diagnosis’ of osteoporosis in young subjects can lead to anxiety, unnecessary drug prescriptions, and in some countries potential restrictions of insurance coverage. Individuals with low bone mass, although possibly deserving investigation depending on the context (for instance to rule out vitamin D deficiency) should not automatically be classified as osteoporotic. This diagnosis only applies when there is evidence of skeletal fragility. Nevertheless, a truly low BMD and/or unusual fractures (such as low-trauma, multiple and vertebral) should prompt investigation for secondary causes of osteoporosis. Careful medical history, clinical and laboratory investigations can reveal an underlying disease that requires specific medical intervention, which in turn will improve bone mass. Bisphosphonates may improve BMD in young subjects with osteoporosis due to various disorders, however the evidence is scarce so far and there are no data on their anti-fracture efficacy. In any case, the indications and duration of anti-resorptive treatment in the young should be as restrictive as possible, particularly in the absence of secondary causes, multiple and/or fragility (vertebral) fractures, and high bone turnover accompanied by documented bone loss. Professor Cyrus Cooper, chair of the IOF Committee of Scientific Advisors, concluded, 'This review will be of assistance to clinicians managing this important problem. The clinical relevance of low bone mineral density in young adults is less well understood than is the case in postmenopausal women and older men. Furthermore, many treatment modalities licensed for use in postmenopausal osteoporosis have not been carefully evaluated in younger adults. Clear guidance as to the interpretation of BMD and the appropriate use of treatments is therefore most timely.' International Osteoporosis Foundation

Researchers have identified a potential new pathway in prostate cancer cells by which cancer-driving gene products can be generated, according to a study.
‘Our work shows that cancers have many more tricks than we thought to generate potential cancer-driving genes or gene products,’ said Hui Li, Ph.D., assistant professor of pathology at the University of Virginia in Charlottesville, and a recipient of an Innovative Research Grant from Stand Up To Cancer (SU2C). The AACR is the scientific partner of SU2C.
Gene fusion is a common characteristic of human cancers. In many cases, the protein products of these gene fusions, which are generated via an RNA intermediate, have a key role in the genesis of the cancer. A well-characterised example of this is the protein that drives chronic myeloid leukaemia, BCR-ABL, which is generated via RNA intermediates from a fusion gene formed by chromosomal translocation — an event involving exchange of genomic DNA between two distinct chromosomes.
‘For many years, chromosomal translocation was considered the sole way in which single RNAs consisting of copies of parts of two genes, so-called fusion RNAs, could be generated,’ said Li. ‘We have shown that fusion RNAs can be generated without changes to DNA by a new mechanism that we are calling cis-SAGe [cis-splicing of adjacent genes].’ Recently, a fusion RNA formed from parts of the SLC45A3 and ELK4 genes was identified in prostate cancer cells in the absence of any DNA alterations. Li and his colleagues confirmed in two prostate cancer cells lines that the SLC45A3-ELK4 fusion RNA could be detected even though there was no evidence of genomic DNA rearrangement.
Detailed molecular analysis of the prostate cancer cell lines indicated that the SLC45A3-ELK4 fusion RNA was generated by cis-SAGe. SLC45A3 and ELK4 are neighbouring genes, and cis-SAGe occurred when an RNA that crossed the boundary between the two genes was formed.
The protein CCCTC-binding factor normally acts to insulate SLC45A3 and ELK4 from each other. Li and his colleagues found that levels of this protein at the gene boundary inversely correlated with the amount of SLC45A3-ELK4 fusion RNA generated, providing molecular insight into how the quantity of this fusion RNA could be regulated.
A functional role for the SLC45A3-ELK4 fusion RNA in prostate cancer was suggested by two observations. First, it promoted the growth of the two prostate cancer cell lines in culture. Second, its levels in human prostate samples correlated with prostate cancer disease progression — normal prostate tissue expressed the lowest levels and prostate cancer specimens from men with metastatic disease expressed the highest levels.
‘These data are not sufficient to say that the SLC45A3-ELK4 fusion RNA has a causal role in prostate cancer,’ said Li. ‘But they are highly suggestive, and I am very excited that this high-risk project, which I would not have been able to pursue without the grant from Stand Up To Cancer, has uncovered what seems to be a new way in which cancer can be driven.’ EurekAlert

The use of genome-wide array analysis in parents whose children are suspected of having a genetic disease shows that the parents frequently also have previously undetected genetic abnormalities, a researcher from The Netherlands told the annual conference of the European Society of Human Genetics. Being aware of this is important to parents because it means that their risk of having another affected child is significantly increased.
Dr. Nicole de Leeuw, a clinical laboratory geneticist in the Department of Human Genetics of the Radboud University Nijmegen Medical Centre in Nijmegen, and colleagues performed genome-wide SNP array analysis in 6,500 patients and 1,874 parents. The patients had intellectual disability and/or congenital abnormalities, and the parents of those in whom an aberration was detected were tested in a similar way to determine whether they had the same aberration as their child. Mosaic aberrations, where both genetically normal and abnormal cells are present in an individual, were not only found in one in every 300 patients, but in one in every 270 parents as well. ‘These abnormalities occurred more frequently than we had expected’, said Dr. de Leeuw. ‘Armed with this knowledge, we can try to understand not only why, but also how genetic disease arises in individuals, and this can help us to provide better genetic counselling.’
Analysis of patients’ genomes showed 6.5% de novo (spontaneously arising) genomic imbalances, 9.1% of rare, inherited imbalances, and 0.8% of X-linked abnormalities. Moreover, with the additional data from their SNP array test results, the researchers were able to subsequently find pathogenic mutations in recessive disease genes, uniparental disomies (where a single chromosome is doubled leading to two genetically identical ones), and mosaic aneuploidies (an extra or missing chromosome in some of the cells of the body) in about 30 patients.
‘In at least seven families, these findings meant that what we had thought of as a spontaneously arising, non-inherited genetic abnormality in a child was in fact already present in some form in the parent’, said Dr. de Leeuw. ‘Furthermore, when we tested in different cell lines – for example, DNA from blood and that from a mouth swab – we often found that results varied. This is because mosaic aberrations can occur in cells in some organs and not in others, and underlines the importance of not just relying on one type of cell line for this kind of genetic diagnosis.’
In two cases these tissue-dependent differences changed over time, and the researchers believe that this was due to an attempt by the body to correct and rescue the situation. ‘Such rescue attempts are best known in cases of trisomy, where there are three chromosomes instead of two in a cell, or monosomy, where there is only one. In both these cases, the body may try to correct the situation by respectively deleting or adding (doubling) a chromosome. Such rescue mechanisms may be more common than we expected, and by using genome-wide SNP array analysis it will help us to reveal them. For some patients, it would be particularly interesting if we could test multiple samples of these patients over time’, said Dr. de Leeuw. EurekAlert