Scientists could soon better predict a man’s risk of getting prostate cancer after a worldwide team of researchers carried out the largest-ever analysis of the cancer’s genetic biomarkers.
QUT Institute of Health and Biomedical Innovation’s Dr Jyotsna Batra and Distinguished Professor Judith Clements, who led the Australian researchers in the large consortia of research hubs around the world, said the teams analysed more than 10 million genetic markers in 80,000 men.
‘It’s the largest analysis of genetic biomarkers ever done. We found another 23 new prostate cancer risk loci (sites) on the genome in addition to the 76 identified previously,’ Dr Batra said.
‘We now have 100 genetic regions and no other cancer has had this many loci identified to be associated with it. What we are looking for is the combination effect of how these loci work together and how much they can explain the heritability of prostate cancer.
‘The indications are that these genetic variants explain 33 per cent of the familial risk of the disease.

‘These are low-risk gene variants but what we have learnt is you can’t rely on just one gene to predict risk. You have to look at the total of the 100.
‘The top one per cent of men with these variants have a 5.7-fold relative risk compared with the population average.’
Dr Batra said that, in addition to family history, incorporating information regarding carrier status of these 100 risk variants could be valuable in defining risk levels in targeted screening and prevention programs for prostate cancer.
She said the multi-ethnic analysis of 80,000 individuals with prostate cancer found some risk variants were more common in different ethnic populations.
‘The aggressive form is prevalent in Africa and we found some risk genes specific to African populations,’ she said.
‘Of the 23 new variants we found 15 were in men of European ancestry and seven in the multi-ethnic analyses.’
Dr Batra said the sufferers of the non-aggressive form of prostate cancer outnumbered those with the aggressive form in the sample of 80,000 men.
‘Only 10 per cent of prostate cancers were the aggressive form in the current analysis,’ she said.
‘So far, we haven’t identified the loci for the aggressive form of the disease – research is ongoing on this. The next sample set will have more than 100,000 people with prostate cancer,’ she said.
‘Being able to predict the aggressive form before it goes on to spread is a goal of the future research because even after the prostate is removed a few cells can go on to kill the person.’ Queensland University of Technology

Researchers have identified a genetic/molecular network that fuels a high-risk and aggressive form of Acute Myeloid Leukaemia (AML) and its precursor disease Myelodysplastic Syndrome (MDS) – providing a possible therapeutic strategy for an essentially untreatable form of the blood cancer.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signalling network involving several components of NF-kB, one of which involved a protein called p62 – a critical regulator of cell metabolism, cellular remodelling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signalling network. This fuelled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signalling network.
The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukaemia and in human cells.  The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukaemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment. Cincinnati Children’s Hospital Medical Center

The first assay to meet the new CLSI H59-A* standards for exclusion of pulmonary embolism

03/09/2014 – Stago has received approval from the US Food and Drug Administration (FDA) for the reagent STA^® _–Liatest^® D-Di, in the exclusion of pulmonary embolism (PE) in patients with low or moderate risk, presenting at an emergency unit.
FDA requirements for D-dimer assays for exclusion are now based on the new and more restrictive standards established and published by the Clinical Laboratory Standards Institute (CLSI, H59-A). Stago’s rapid, automated and highly sensitive D-Dimer is thus the first test to comply with these new requirements.

In order to comply with the new CLSI guidelines, Stago performed a 2-years international prospective study similar to clinical studies performed in the pharmaceutical field (9 sites, 5 countries, more than 1100 patients, including evaluation of clinical pretest probability, imaging and 3 months of follow-up): a first in the field of Haemostasis diagnostics.

As its coordinator Prof. Gilles Pernod (Grenoble University Hospital, France) pointed out: 
“As well as providing the results required to validate this test for the exclusion of PE, this study brought to light some significant evolutions in clinical practice and shifts in prevalence. In fact, these findings will be presented in some interesting upcoming publications”.

This study also confirmed the excellent diagnostic performance of the STA^® -Liatest^® D-Di assay, with a very high negative predictive value (NPV) for the exclusion of PE, far exceeding FDA requirements (>99.7% versus 97%), and excellent sensitivity (>97% versus 95%).

The second part of this international clinical study, concerning deep vein thrombosis (DVT), is underway and due to be completed in the next few months. Let us hope that it provides the scientific community with as much relevant data as this first essential phase.

A study led by University of North Carolina at Chapel Hill researchers represents an important step forward in the accurate diagnosis of people who are experiencing the earliest stages of psychosis.

Psychosis includes hallucinations or delusions that define the development of severe mental disorders such as schizophrenia. Schizophrenia emerges in late adolescence and early adulthood and affects about 1 in every 100 people. In severe cases, the impact on a young person can be a life compromised, and the burden on family members can be almost as severe.

The study reports preliminary results showing that a blood test, when used in psychiatric patients experiencing symptoms that are considered to be indicators of a high risk for psychosis, identifies those who later went on to develop psychosis.

“The blood test included a selection of 15 measures of immune and hormonal system imbalances as well as evidence of oxidative stress,” said Diana O. Perkins, MD, MPH, professor of psychiatry in the UNC School of Medicine and corresponding author of the study. She is also medical director of UNC’s Outreach and Support Intervention Services (OASIS) program for schizophrenia.

“While further research is required before this blood test could be clinically available, these results provide evidence regarding the fundamental nature of schizophrenia, and point towards novel pathways that could be targets for preventative interventions,” Perkins said.

Clark D. Jeffries, PhD, bioinformatics scientist at the UNC-based Renaissance Computing Institute (RENCI), is a co-author of the study, which was conducted as part of the North American Prodrome Longitudinal Study (NAPLS), an international effort to understand risk factors and mechanisms for development of psychotic disorders.

“Modern, computer-based methods can readily discover seemingly clear patterns from nonsensical data,” said Jeffries. “Added to that, scientific results from studies of  complex disorders like schizophrenia can be confounded by many hidden dependencies. Thus, stringent testing is necessary to build a useful classifier. We did that.”

The study concludes that the multiplex blood assay, if independently replicated and if integrated with studies of other classes of biomarkers, has the potential to be of high value in the clinical setting. University of North Carolina at Chapel Hill

University of Adelaide psychiatry researchers have developed a model that could help to predict a patient’s likelihood of a good outcome from treatment – from their very first psychotic episode.

The model is based on a range of factors, including clinical symptoms, cognitive abilities, MRI scans of the brain’s structure, and biomarkers in the patient’s blood.

Speaking in the lead up to Mental Health Week, the University’s Head of Psychiatry, Professor Bernhard Baune, says the model is a revolutionary idea for psychiatric care, and is aimed at improving treatment for people suffering from mental illnesses such as schizophrenia. He says the model is applicable to other types of mental illnesses as well.

‘Being able to predict the trajectory of psychotic illness is a kind of ‘holy grail’ in psychiatric medicine,’ says Professor Baune, who is corresponding author of a paper on the new model.

‘There is no doubt that our model will be challenging for many in the profession. However, we believe this will improve our understanding of the course of an illness, and lead to a more personalised and specialised approach to the assessment and treatment of people presenting with their first psychotic episode.’

Professor Baune says the model builds on a decade of research in this field, and a review and reinterpretation of the relevant studies to date. ‘Individual illness progression is dependent on a wide range of factors, including sociodemographic, clinical, psychological and biological. These are complex issues, and data on all of them is required in order to model the trajectory of the illness,’ he says.

‘Our model shows that the probability of achieving long-term favourable or unfavourable outcomes can differ significantly depending on the information we have within the first six months of the onset of the disease.’

Professor Baune says the use of such a model raises a number of ethical dilemmas: ‘Should a patient be offered a rigorous treatment right away at the beginning of the disease that, according to current treatment guidelines, is only offered at later stages after years of disease progression? Or should certain treatments be denied if evidence suggests that the course of the illness will be mild or that they will do little for the patient’s outcome? These are just some of the questions this work raises, which should be discussed and debated by the profession. University of Adelaide