Personalised prognostic tools and gene-based therapies may improve the survival and quality of life of patients suffering from glioblastoma, an aggressive and deadly form of brain cancer, reports a new University of Illinois study funded by the NIH National Cancer Institute.
‘We confirmed known biomarkers of glioblastoma survival and discovered new general and clinical-dependent gene profiles,’ said Nicola Serao, a U of I Ph.D. candidate in animal sciences with a focus in statistical genomics. ‘We were able to compare biomarkers across three glioblastoma phases that helped us gain insight into the roles of genes associated with cancer survival.’
Glioblastoma is a complex, multifactorial disease that has swift and devastating consequences, Serao said. Although some genes have been associated with the presence of glioblastoma, few have been identified as prognostic biomarkers of glioblastoma survival and fewer have been confirmed in independent reports.
‘You can’t just find one gene that is related to this cancer and fix it,’ he said. ‘This is one of the aspects of our research that makes it unique. We were able to look at several genes at the same time and relate our findings to this cancer.’
Using genomic information from more than 22,000 genes, Serao took this huge piece of information and began slicing away at it, one gene at a time, until he ended up with a group of genes related to brain cancer.
He studied different survival variables, including length of survival from birth to death, from diagnosis to death, and from diagnosis to progression of the cancer.
‘We studied different variables, but they were complementary, and allowed us to learn more about those genes,’ he said. ‘We understand that some genes have much more impact in cancer than others. And we also discovered that some genes only appeared in one variable, so they were specific for a given phase of cancer.’
This study not only evaluated genes influencing survival, but also took into consideration clinical factors such as age, race and gender.
‘Our research suggests you can’t treat all patients the same,’ Serao said. ‘For example, we found gene expression patterns that have different, and sometimes opposite, relationships with survival in males and females and concluded that treatments affecting these genes will not be equally effective. Personalised therapy dependent on gender, race and age is something that is possible today with our advanced genomic tools.’
Recognising that genes seldom act alone, this team of researchers took several genes into consideration at the same time and uncovered networks of genes related to glioblastoma survival.
Sandra Rodriguez Zas, co-researcher and U of I professor of animal science and bioinformatics, said they looked at commonalities between the genes linked to glioblastoma survival and progression, too.
‘If a large number of genes linked to survival belong to a particular pathway, this pathway is considered enriched,’ Rodriguez Zas said. ‘Depending on whether the pathway and genes have tumour suppressor or oncogenic characteristics, we should be able to use that information to support or attack that pathway with targeted therapies.’
Gaining a deeper understanding of the biological meaning, or roles, for these genes will provide researchers with even more ammunition to fight this deadly form of brain cancer.
‘Because of the innovative approach we used, we believe we can more confidently predict whether a patient will have a shorter or longer survival rate and select the most adequate therapies,’ she said.
Illinois. University of Illinois College of Agricultural, Consumer and Environmental Sciences

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson’s disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson’s and could lead to a blood test for the disease. The study was based mainly on analysis of human brain tissue.
Studies of rare, familial (heritable) forms of Parkinson’s show that a protein called alpha-synuclein plays a role in the development of the disease. People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson’s. Another key feature of Parkinson’s is the presence of excess alpha-synuclein aggregates in the brain.
As the vast majority of patients with Parkinson’s do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson’s nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.
Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson’s. ‘It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits,’ said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and neurology at CUMC. ‘Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson’s. In our study, we show that people with ‘bad’ variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain.’
‘An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models,’ said Dr. Abeliovich. ‘In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don’t really get Parkinson’s, which underscores the importance of including the analysis of human brain tissue.’
‘Furthermore, we found that exposure to toxins associated with Parkinson’s can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease,’ said Dr. Abeliovich.
The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson’s. The CUMC team is currently searching for drug candidates and has identified several possibilities.
The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson’s, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. ‘There is a tremendous need for a biomarker for Parkinson’s, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups,’ said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug’s effectiveness. Columbia University Medical Center

When a patient is diagnosed with type 2 diabetes, the disease has usually already progressed over several years and damage to areas such as blood vessels and eyes has already taken place. To find a test that indicates who is at risk at an early stage would be valuable, as it would enable preventive treatment to be put in place. Researchers at Lund University have now identified a promising candidate for a test of this kind
‘We have shown that individuals who have above-average levels of a protein called SFRP4 in the blood are five times more likely to develop diabetes in the next few years than those with below-average levels’, says Anders Rosengren, a researcher at the Lund University Diabetes Centre (LUDC), who has led the work on the risk marker.
It is the first time a link has been established between the protein SFRP4, which plays a role in inflammatory processes in the body, and the risk of type 2 diabetes.
Studies at LUDC, in which donated insulin-producing beta cells from diabetic individuals and non-diabetic individuals have been compared, show that cells from diabetics have significantly higher levels of the protein.
It is also the first time the link between inflammation in beta cells and diabetes has been proven.
‘The theory has been that low-grade chronic inflammation weakens the beta cells so that they are no longer able to secrete sufficient insulin. There are no doubt multiple reasons for the weakness, but the SFRP4 protein is one of them’, says Taman Mahdi, main author of the study and one of the researchers in Anders Rosengren’s group.
The level of the protein SFRP4 in the blood of non-diabetics was measured three times at intervals of three years. Thirty-seven per cent of those who had higher than average levels developed diabetes during the period of the study. Among those with a lower than average level, only nine per cent developed the condition.
‘This makes it a strong risk marker that is present several years before diagnosis. We have also identified the mechanism for how SFRP4 impairs the secretion of insulin. The marker therefore reflects not only an increased risk, but also an ongoing disease process’, says Anders Rosengren.
The marker works independently of other known risk factors for type 2 diabetes, for example obesity and age.
Motivation for lifestyle changes
‘If we can point to an increased risk of diabetes in a middle-aged individual of normal weight using a simple blood test, up to ten years before the disease develops, this could provide strong motivation to them to improve their lifestyle to reduce the risk’, says Anders Rosengren, adding:
‘In the long term, our findings could also lead to new methods of treating type 2 diabetes by developing ways of blocking the protein SFRP4 in the insulin-producing beta cells and reducing inflammation, thereby protecting the cells.’ Lund University

About 10 percent of kids born with kidney defects have large alterations in their genomes known to be linked with neuro-developmental delay and mental illness, a new study by Columbia University Medical Center (CUMC) researchers has shown.
Congenital defects of the kidney and urinary tract account for nearly 25 percent of all birth defects in the US and are present in about 1 in every 200 births. Eventually, an evaluation for genomic alterations will be part of the standard clinical workup. Patients with congenital kidney disease—who are currently lumped into one category—will be placed in subgroups based on their genetic mutations and receive a more precise diagnosis.
‘This changes the way we should handle these kids,’ said kidney specialist Ali Gharavi, MD, associate professor of medicine at CUMC, associate director of the Division of Nephrology, and an internist and nephrologist at NewYork-Presbyterian Hospital.’
‘If a physician sees a child with a kidney malformation, that is a warning sign that the child has a genomic disorder that should be looked at immediately because of the risk of neuro-developmental delay or mental illness later in life,’ he said. ‘This is a major opportunity for personalising medical care. As we learn which therapies work best for each subgroup, the underlying genetic defect of the patient will dictate what approach to take.’
The current study was the result of a large collaborative effort of CUMC and other medical centers in the US, Italy, Poland, Croatia, Macedonia, and the Czech Republic. It was led by Dr. Gharavi and his colleague Simone Sanna-Cherchi, MD, an associate research scientist in CUMC’s Department of Medicine.
Until now, no studies have linked congenital kidney disease with neuro-developmental disorders.
‘If you talk to clinicians, they tell you that some of these kids behave differently,’ Dr. Sanna-Cherchi said. ‘There has been a general assumption, though, that behavioural or cognitive issues in children with chronic illnesses such as kidney disease stem from the child’s difficulty in coping with the illness. Our study suggests that in some cases, neuro-developmental issues may be attributable to an underlying genomic disorder, not the kidney disease.’
The mutations discovered by Drs. Gharavi and Sanna-Cherchi and their colleagues belong to a class of mutations called copy number variations (CNVs). CNVs are extra copies or deletions of DNA just large enough to contain several genes. When CNVs are present, the ‘dose’ of the affected genes is either lower or higher than normal, potentially leading to a health disorder.
Until the mid-2000s, when effective techniques for detecting CNVs were developed, scientists thought that CNVs caused only a small number of health disorders. Today, tens of thousands of different CNVs have been discovered and linked to several disorders—including autism, schizophrenia, and Parkinson’s disease.
To see if CNVs are involved in congenital kidney defects, Drs. Gharavi and Sanna-Cherchi scanned the genomes of 522 individuals with small and malformed kidneys from medical centres in Europe and United States. About 17 percent of the patients carried a CNV that appeared to contribute to their kidney disorder.
In studies of children with previously discovered CNVs, most of the CNVs had been linked to developmental delays or mental illness. In the current study, about 1 in 10 children had a CNV linked to developmental delays or mental illness.
Though it remains unclear why kidney malformations and neurodevelopment are linked in some cases, it is possible that the same genes involved in kidney development are involved in brain development, Dr. Gharavi said. University of Columbia

In a comparison of novel cardiovascular risk markers, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history were independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors, with coronary artery calcium providing superior discrimination and risk reclassification compared with other risk markers, according to a study.
‘Current trends in primary prevention of cardiovascular disease (CVD) emphasise the need to treat individuals based on their global cardiovascular risk. Accordingly, practice guidelines recommend approaches to classify individuals as high, intermediate, or low risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models. However, there is increasing recognition of the imprecision of these classifications such that the intermediate-risk group actually represents a composite of higher-risk individuals for whom more aggressive (i.e., drug) therapy might be indicated. The intermediate-risk group also contains lower-risk individuals in whom CVD might be managed with lifestyle measures alone. This recognition has motivated researchers to identify markers that could offer greater discrimination of higher- and lower-risk patients within the intermediate-risk group,’ according to background information in the article.
‘Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort,’ the authors write.
Joseph Yeboah, M.D., M.S., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues assessed the improvements in CHD/CVD prediction accuracy and reclassification to high- and low-risk categories using CIMT, CAC, FMD, ABI, high-sensitivity CRP, and family history of CHD in asymptomatic adults classified as intermediate risk who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 6,814 MESA participants from 6 U.S. field centres, 1,330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Analysis was conducted to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Incident CHD was defined as heart attack, angina followed by revascularisation, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.
After a median (midpoint) follow-up of 7.6 years, 94 participants (7.1 percent) experienced a CHD event and 123 (9.2 percent) experienced a CVD event. After analyses, the researchers found that each of the novel risk markers was associated with incident CHD; however, after adjusting for confounders, the associations with CIMT and FMD were no longer significant. Among all of the risk markers, CAC had the strongest association. Similarly, for incident CVD, each of the markers was associated with events except high-sensitivity CRP. However, after adjusting for confounders, the associations between CIMT and FMD were no longer significant. CAC also had the strongest association in the multivariable models for CVD.
‘The current study shows that among 6 of the most promising novel risk markers, CAC provides the highest improvement in discrimination over the FRS and Reynolds score (RS) in individuals classified as intermediate risk. The present study provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk by the FRS or the RS,’ the authors write. ‘Additional research is warranted to explore further both the costs and benefits of CAC screening in intermediate-risk individuals.’
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