A novel study by the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) found that an increase in a gene known as Leo1 affects other genes that are directly implicated in acute myelogenous leukaemia (AML), increasing the incidence of cancer.

Led by Associate Professor Chng Wee Joo, Deputy Director and Senior Principal Investigator at CSI Singapore and Director of the National University Cancer Institute, Singapore, the scientists discovered that inhibition of Leo1 and Leo1 downstream signalling pathways provide an avenue for targeted treatment of AML.

In addition, this is the first study to suggest that the protein PRL-3 plays a role in the regulation of ribonucleic acid (RNA) related processes, a finding which advances the understanding of how the protein contributes to cancer progression. The team’s work represents the first large-scale quantitative survey of proteins regulated by PRL-3 in leukaemia.

The elevated expression of PRL-3 has been implicated in the progression and metastasis of an array of cancer types, including gastric, ovarian, cervical, lung, liver, and breast. In particular, the protein PRL-3 is overexpressed in about half of AML patients and associated with poor survival. Assoc Prof Chng and his team were the first to report that elevated PRL-3 protein expression occurs in about 47 per cent of AML cases while being absent from normal myeloid cells in bone marrow. As a result, PRL-3 is deemed as an attractive therapeutic target that spares normal tissues.

Previously, knowledge of the mechanisms of PRL-3 was limited. In this study, the researchers used a new, advanced SILAC-based mass spectrometry to identify all the protein changes induced by PRL-3 in a comprehensive manner. Using this approach, they discovered that the gene Leo1 serves as a novel target of PRL-3 phosphatase, and inhibition of Leo1 as well as Leo1 downstream signalling pathways provide an avenue for PRL-3 targeted therapy for AML patients.

In the next phase of research, the team is validating several important proteins directly downstream of Leo1 that can possibly be used as biomarkers and drug targets to improve treatment for leukaemia with PRL-3 overexpression.

Assoc Prof Chng said, ‘Our previous studies showed that PRL-3 is clinical and biologically important in acute myelogenous leukaemia, and may therefore be a useful treatment target. In the current study, we have taken the work further by understanding how PRL-3 confers cancer properties to the leukaemia cells. This now provides a framework for rational design of a treatment based on mechanistic understanding. In the process, we will also develop biomarkers to better select patients for the treatment and hence, progress towards personalising treatment for leukaemia patients.’ EurekAlert

Targeted therapies are a growing and ground-breaking field in cancer care in which drugs or other substances are designed to interfere with genes or molecules that control the growth and survival of cancer cells. Now, scientists at Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumour, malignant glioma.

In a study, a team of scientists led by Luni Emdad, M.B.B.S., Ph.D., and Paul B. Fisher, M.Ph., Ph.D., provided the first evidence of an important link between a specific microRNA, miR-184, and a cancer promoting gene, SND1, in the regulation of malignant glioma. miR-184 is known to suppress tumour development by regulating a variety of genes involved in cancer growth, while SND1 has been shown to play a significant role in the development of breast, colon, prostate and liver cancers. Through a variety of preclinical experiments, the team demonstrated that increasing the expression of miR-184 slows the growth and invasive characteristics of glioma cells through direct regulation of SND1. Additionally, they showed that reduced levels of SND1 led to reduced levels of STAT3, a gene that has been shown to promote the most lethal characteristics of brain cancer.

‘Patients suffering from brain tumours are in desperate need of improved therapies,’ says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. ‘We’re hopeful that this new understanding of the relationship between miR-184 and SND1 ultimately will lead to the development of new drugs that reduce SND1 expression and improve patient outcomes.’

Prior studies have shown that levels of miR-184 are unusually low in tissue samples from patients with malignant gliomas. Using advanced computer analysis techniques designed to study and process biological data, the researchers identified SND1 among a handful of other genes that miR-184 helps regulate. Knowing SND1 is implicated in a variety of cancers and having previously defined its role in liver cancer, Emdad, Fisher and their colleagues explored this relationship further. They confirmed low levels of miR-184 expression in human glioma tissue samples and cultured cell lines as well as an increase in the expression of SND1 compared to normal brain tissue. Using data from a large public brain tumour database called REMBRANDT, the researchers confirmed that patients with lower levels of SND1 survived longer than those with elevated SND1 expression.

‘We still have a long way to go and many challenges to overcome before we will have therapies that are ready for clinical use, but this is a significant first step in the process,’ says Emdad, member of the Cancer Molecular Genetics research program at Massey, assistant professor in the VCU Department of Human and Molecular Genetics and member of the VIMM. ‘Future studies will aim to explore the relationship between SND1 and STAT3, identify additional microRNAs that may be relevant to malignant glioma and explore the effects of drugs that block SND1 expression in more advanced preclinical models.’ EurekAlert

Investigators at Nationwide Children’s Hospital have developed an analysis “pipeline” that slashes the time it takes to search a person’s genome for disease-causing variations from weeks to hours.

“It took around 13 years and $3 billion to sequence the first human genome,” says Peter White, PhD, principal investigator and director of the Biomedical Genomics Core at Nationwide Children’s and the study’s senior author. “Now, even the smallest research groups can complete genomic sequencing in a matter of days. However, once you’ve generated all that data, that’s the point where many groups hit a wall. After a genome is sequenced, scientists are left with billions of data points to analyse before any truly useful information can be gleaned for use in research and clinical settings.”

To overcome the challenges of analysing that large amount of data, Dr. White and his team developed a computational pipeline called “Churchill.” By using novel computational techniques, Churchill allows efficient analysis of a whole genome sample in as little as 90 minutes.

“Churchill fully automates the analytical process required to take raw sequence data through a series of complex and computationally intensive processes, ultimately producing a list of genetic variants ready for clinical interpretation and tertiary analysis,” Dr. White explains. “Each step in the process was optimized to significantly reduce analysis time, without sacrificing data integrity, resulting in an analysis method that is 100 percent reproducible.”

The output of Churchill was validated using National Institute of Standards and Technology (NIST) benchmarks. In comparison with other computational pipelines, Churchill was shown to have the highest sensitivity at 99.7 percent; highest accuracy at 99.99 percent and the highest overall diagnostic effectiveness at 99.66 percent.

“At Nationwide Children’s we have a strategic goal to introduce genomic medicine into multiple domains of paediatric research and healthcare. Rapid diagnosis of monogenic disease can be critical in new-borns, so our initial focus was to create an analysis pipeline that was extremely fast, but didn’t sacrifice clinical diagnostic standards of reproducibility and accuracy” says Dr. White. “Having achieved that, we discovered that a secondary benefit of Churchill was that it could be adapted for population scale genomic analysis.”

By examining the computational resource use during the data analysis process, Dr. White’s team was able to demonstrate that Churchill was both highly efficient (>90 percent resource utilization) and scaled very effectively across many servers. Alternative approaches limit analysis to a single server and have resource utilization as low as 30 percent. This efficiency and capability to scale enables population-scale genomic analysis to be performed. Nationwide Children’s Hospital

Eating disorders (ED) such as anorexia nervosa, bulimia, and binge eating disorder affect approximately 5-10% of the general population, but the biological mechanisms involved are unknown. Researchers at Inserm Unit 1073, ‘Nutrition, inflammation and dysfunction of the gut-brain axis’ (Inserm/University of Rouen) have demonstrated the involvement of a protein produced by some intestinal bacteria that may be the source of these disorders. Antibodies produced by the body against this protein also react with the main satiety hormone, which is similar in structure. According to the researchers, it may ultimately be possible to correct this mechanism that causes variations in food intake.

Anorexia nervosa, bulimia and binge eating disorder are all eating disorders (ED). If the less well defined and atypical forms are included, ED affect 15-20% of the population, particularly adolescents and young adults. Despite various psychiatric, genetic and neurobiological studies, the molecular mechanism responsible for these disorders remains mysterious. The common characteristic of the different forms of ED is dysregulation of food intake, which is decreased or increased, depending on the situation.

Sergueï Fetissov’s team in Inserm Joint Research Unit 1073, ‘Nutrition, inflammation and dysfunction of the gut-brain axis’ (Inserm/University of Rouen), led by Pierre Déchelotte, studies the relationships between the gut and the brain that might explain this dysregulation.

In this new study, the researchers have identified a protein that happens to be a mimic of the satiety hormone (melanotropin). This protein (ClpB) is produced by certain bacteria, such as Escherichia coli, which are naturally present in the intestinal flora. Where this protein is present, antibodies are produced against it by the body. These will also bind to the satiety hormone because of its structural homology to ClpB, and thereby modify the satietogenic effect of the hormone. The sensation of satiety is reached (anorexia) or not reached (bulimia or overeating). Moreover, the bacterial protein itself seems to have anorexigenic properties.

To obtain these results, the researchers modified the composition of the intestinal flora of mice to study their immunological and behavioural response. Food intake and level of antibodies against melanotropin in the 1st group of mice, which were given mutant E. coli bacteria (not producing ClpB) did not change. In contrast, antibody level and food intake did vary in the 2nd group of animals, which received E. coli producing ClpB protein.

The likely involvement of this bacterial protein in disordered eating behaviour in humans was established by analysing data from 60 patients.

The standardised scale ‘Eating Disorders Inventory-2’ was used to diagnose these patients and evaluate of the severity of their disorders, based on a questionnaire regarding their behaviour and emotions (wish to lose weight, bulimia, maturity fears, etc.). Plasma levels of antibodies to ClpB and melanotropin were higher in these patients. Furthermore, their immunological response determined the development of eating disorders in the direction of anorexia or bulimia.

These data thus confirm the involvement of the bacterial protein in the regulation of appetite, and open up new perspectives for the diagnosis and specific treatment of eating disorders.

Correcting the action of the protein mimicking the satiety hormone

‘We are presently working to develop a blood test based on detection of the bacterial protein ClpB. If we are successful in this, we will be able to establish specific and individualised treatments for eating disorders,’ say Pierre Déchelotte and Sergueï Fetissov, authors of this study.

At the same time, the researchers are using mice to study how to correct the action of the bacterial protein in order to prevent the dysregulation of food intake that it generates. ‘According to our initial observations, it would indeed be possible to neutralise this bacterial protein using specific antibodies, without affecting the satiety hormone,’ they conclude. EurekAlert

Genetic mutations may link smoking and alcohol consumption to destruction of the pancreas observed in chronic pancreatitis, according to a 12-year study led by researchers at the University of Pittsburgh School of Medicine. The findings provides insight into why some people develop this painful and debilitating inflammatory condition while most heavy smokers or drinkers do not appear to suffer any problems with it.

The process appears to begin with acute pancreatitis, which is the sudden onset of inflammation causing nausea, vomiting and severe pain in the upper abdomen that may radiate to the back, and is typically triggered by excessive drinking or gallbladder problems, explained senior investigator David Whitcomb, M.D., Ph.D., chief of gastroenterology, hepatology and nutrition, Pitt School of Medicine. Up to a third of those patients will have recurrent episodes of acute pancreatitis, and up to a third of that group develops chronic disease, in which the organ becomes scarred from inflammation.

“Smoking and drinking are known to be strong risk factors for chronic pancreatitis, but not everyone who smokes or drinks damages their pancreas,” Dr. Whitcomb said. “Our new study identifies gene variants that when combined with these lifestyle factors make people susceptible to chronic pancreatitis and may be useful to prevent patients from developing it.”

In the North American Pancreatitis Study II consortium, researchers evaluated gene profiles and alcohol and smoking habits of more than 1,000 people with either chronic pancreatitis or recurrent acute pancreatitis and an equivalent number of healthy volunteers. The researchers took a closer look at a gene called CTRC, which can protect pancreatic cells from injury caused by premature activation of trypsin, a digestive enzyme inside the pancreas instead of the intestine, a problem that has already been associated with pancreatitis.

They found that a certain variant of the CTRC gene, which is thought to be carried by about 10 percent of Caucasians, was a strong risk factor for alcohol- or smoking-associated chronic pancreatitis. It’s possible that the variant fails to protect the pancreas from trypsin, leaving the carrier vulnerable to ongoing pancreatic inflammation and scarring.

“This finding presents us with a window of opportunity to intervene in the diseases process,” Dr. Whitcomb said. “When people come to the hospital with acute pancreatitis, we could screen for this gene variant and do everything possible to help those who have it quit smoking and drinking alcohol, as well as test new treatments, because they have the greatest risk of progressing to end-stage chronic pancreatitis.” University of Pittsburgh Health Sciences