A combination of three proteins found at high levels in urine can accurately detect early-stage pancreatic cancer, researchers at the BCI have shown. The discovery could lead to a non-invasive, inexpensive test to screen people at high risk of developing the disease.

Dr Tatjana Crnogorac-Jurcevic’s group has shown that the three-protein ‘signature’ can both identify the most common form of pancreatic cancer when still in its early stages  – and distinguish between this cancer and the inflammatory condition chronic pancreatitis, which can be hard to tell apart.

The study looked at 488 urine samples: 192 from patients known to have pancreatic cancer, 92 from patients with chronic pancreatitis and 87 from healthy volunteers.  A further 117 samples from patients with other benign and malignant liver and gall bladder conditions were used for further validation.

Around 1500 proteins were found in the urine samples, with approximately half  being common to both male and female volunteers. Of these, three proteins –  LYVE1, REG1A and TFF1 –  were selected for closer examination, based on biological information and performance in statistical analysis.

Patients with pancreatic cancer were found to have increased levels of each of the three proteins when compared to urine samples from healthy patients, while patients suffering from chronic pancreatitis had significantly lower levels than cancer patients. When combined, the three proteins formed a robust panel that can detect patients with stages I-II pancreatic cancer with over 90 per cent accuracy.

With few specific symptoms even at a later stage of the disease, more than 80 per cent of people with pancreatic cancer are diagnosed when the cancer has already spread. This means they are not eligible for surgery to remove the tumour – currently the only potentially curative treatment.

The five-year survival rate for pancreatic cancer is the lowest of any common cancer, standing at 3 per cent. This figure has barely improved in 40 years. There is no early diagnostic test available.

Lead researcher, Dr Tatjana Crnogorac-Jurcevic, said: “We’ve always been  keen to develop a diagnostic test in urine as it has several advantages over using blood. It’s an inert and far less complex fluid than blood and can be repeatedly and non-invasively tested. It took a while to secure proof of principle funding in 2008 to look at biomarkers in urine, but it’s been worth the wait for these results. This is a biomarker panel with good specificity and sensitivity  and we’re hopeful that a simple, inexpensive test can be developed and be in clinical use within the next few years.” Barts Cancer Institute

Research led by Maria Clara Franco of the Burnett School of Biomedical Sciences has implications for the treatment of cancer and neurodegenerative diseases.

New research from the University of Central Florida has shed light on the workings of a particular protein found in the human body that could have future implications for the treatment of cancer and neurodegenerative conditions.

Previous research by Maria C. Franco and Alvaro Estevez of the Burnett School of Biomedical Sciences at UCF’s College of Medicine showed that a modified version of a protein known as “heat shock protein 90” or Hsp90 is a trigger for killing cells in the nervous system in neurodegenerative disorders.

Now, Franco’s latest findings show that Hsp90 doesn’t treat all cells the same. In fact, the same protein that kills some cells may help cancer cells.

“We have found a protein that is modified only in pathological conditions,” said Franco, an assistant scientist at the Burnett School who led the research team. “In the nervous system, it is toxic to the cells that are affected by neurodegenerative diseases, while in tumour cells it may actually be acting as a pro-survival agent. In both cases, targeting this oxidized protein may be a potential therapeutic alternative.”

Hsp90 is one of the most studied proteins in terms of potential cancer-fighting drugs, but progress has been slow. Franco’s work provides more clarity on the complex nature of the protein’s impact on cells.

Her research team discovered that a nitration of Hsp90 limits oxygen to the cell’s mitochondria, decreasing its energy production. It sounds like a death knell for the cell, but the reduction of oxygen consumption may actually help the cancerous cells by increasing their resistance to hypoxia since these cells rely on other energy sources.

Franco has been studying the role of Hsp90 and other oxidized proteins in the regulation of cellular metabolism for the past eight years, with the goal of identifying new targets for drugs to combat tumour cells. She is eager to find ways to combat tumour cells while keeping healthy cells intact. University of Central Florida

A new test developed by UBC researchers allows physicians to measure the effects of gene silencing therapy in Huntington’s disease and will support the first human clinical trial of a drug that targets the genetic cause of the disease.

The gene silencing therapy being tested by UBC researchers aims to reduce the levels of a toxic protein in the brain that causes Huntington’s disease.

The test was developed by Amber Southwell, Michael Hayden, and Blair Leavitt of UBC’s Centre for Molecular Medicine and Therapeutics and the Centre for Huntington Disease in collaboration with colleagues from Mayo Clinic.

“This is an important breakthrough for several promising gene silencing therapies in Huntington’s disease that are now moving from the bench to the bedside,” said Leavitt. “We can move forward with these clinical trials and accurately measure whether our treatments are working.”

Huntington’s disease is a genetic disorder but symptoms generally don’t appear until later in life. It affects the brain and gradually worsens, causing problems with coordination and movement, mental decline and psychiatric issues.

The genetic mutation responsible for Huntington’s produces a toxic form of a protein called huntingtin, which progressively injures brain cells. Reducing brain levels of this toxic protein should prevent or delay the onset of symptoms. Several huntingtin-lowering therapies have already shown great promise in animal models of Huntington’s disease and are rapidly approaching trials in humans.

The UBC research team found that they could accurately measure the levels of mutant huntingtin protein in the brain by collecting cerebrospinal fluid from a spinal tap. The ultrasensitive test detects small amounts of the toxic protein and can be used to follow changes in brain levels of the protein over time in response to new therapies.

This study enables Leavitt to initiate a new clinical trial of a huntingtin gene-silencing therapy for patients at the Centre for Huntington Disease at the Djavad Mowafaghian Centre for Brain Health, a partnership between UBC and Vancouver Coastal Health. This trial will test the safety of a novel gene-silencing treatment in patients and is already in the process of screening patient candidates. The trial will be the first human study of a drug targeting mutant huntingtin. University of British Columbia

Scientists who analysed the genes involved in 10 autoimmune diseases that begin in childhood have discovered 22 genome-wide signals shared by two or more diseases. These shared gene sites may reveal potential new targets for treating many of these diseases, in some cases with existing drugs already available for non-autoimmune disorders.

Autoimmune diseases, such as type 1 diabetes, Crohn’s disease and juvenile idiopathic arthritis, collectively affect 7 to 10 percent of the population in the Western Hemisphere.

Dr. Hakonarson“Our approach did more than finding genetic associations among a group of diseases,” said study leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP). “We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy.”

The international study team performed a meta-analysis, including a case-control study of 6,035 subjects with automimmune disease and 10,700 controls, all of European ancestry. The study’s lead analyst, Yun (Rose) Li, an MD/PhD graduate student at the University of Pennsylvania and the Center for Applied Genomics, mentored by Hakonarson and his research team, applied highly innovative and integrative approaches in supporting the study of pathogenic roles of the genes uncovered across multiple diseases.

The research encompassed 10 clinically distinct autoimmune diseases with onset during childhood: type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency disease, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, psoriasis, autoimmune thyroiditis and ankylosing spondylitis.

Because many of these diseases run in families and because individual patients often have more than one autoimmune condition, clinicians have long suspected these conditions have shared genetic predispositions. Previous genome-wide association studies have identified hundreds of susceptibility genes among autoimmune diseases, largely affecting adults.

The current research was a systematic analysis of multiple paediatric-onset diseases simultaneously. The study team found 27 genome-wide loci, including five novel loci, among the diseases examined. Of those 27 signals, 22 were shared by at least two of the autoimmune diseases, and 19 of them were shared by at least three of them.

Many gene signals found on biological pathways linked to cell activation, proliferation and signalling

Many of the gene signals the investigators discovered were on biological pathways functionally linked to cell activation, cell proliferation and signalling systems important in immune processes. One of the five novel signals, near the CD40LG gene, was especially compelling, said Hakonarson, who added, “That gene encodes the ligand for the CD40 receptor, which is associated with Crohn’s disease, ulcerative colitis and celiac disease. This ligand may represent another promising drug target in treating these diseases.”

Gene signals have biological relevance to autoimmune disease processes, opportunities to better target gene networks and pathways

Many of the 27 gene signals the investigators uncovered have a biological relevance to autoimmune disease processes, Hakonarson said. “Rather than looking at overall gene expression in all cells, we focused on how these genes upregulated gene expression in specific cell types and tissues, and found patterns that were directly relevant to specific diseases. For instance, among several of the diseases, we saw genes with stronger expression in B cells. Looking at diseases such as lupus or juvenile idiopathic arthritis, which feature dysfunctions in B cells, we can start to design therapies to dial down over-expression in those cells.”

He added that “the level of granularity the study team uncovered offers opportunities for researchers to better target gene networks and pathways in specific autoimmune diseases, and perhaps to fine tune and expedite drug development by repurposing existing drugs, based on our findings.” The Children’s Hospital of Philadelphia

Research has led to a greater understanding of how certain genetic variants can ‘switch’ on or off the regulatory elements which control the expression of genes and ultimately the manifestation of an individual’s characteristics and disease predispositions.

These variants are found in regions of the genome which are not directly responsible for coding genes, but which instead have a regulatory function. Not much is yet known about these regions, however, research into how the variants work could eventually lead to new clues about how human diseases might be understood at a genetic level and, ultimately, controlled.

“We know many genetic variants are associated with different diseases, but since most of them lie in the non-coding part of the genome, we often don’t know what the precise mechanisms underlying these associations are,” explains Judith Zaugg, who led the study at EMBL. “Our results, and the computational approaches we have developed mean it will now be possible to take these variants and link them back to the regulatory network within the DNA to identify the specific gene that is associated with them. This might enable us to unravel the causal mechanisms behind certain inherited diseases.”

‘Switches’ controlling gene expression might be far apart on DNA strand, but close in 3D space.

Key to the process are regions in the non-coding part of the DNA that harbour specific sequences, called enhancers and promoters. These are responsible for activating the expression of a particular gene. Promoters are located close to the gene they regulate. Enhancers, in contrast, can be far away from their target gene in terms of genomic location and might require physical interaction with the promoter of a gene to propagate the activity signal. One of the big challenges in understanding how genes are controlled is to link these enhancers to their target genes.

In this study, the team has generated molecular profiles from 75 human individuals that were sequenced as part of the 1000 Genomes Project – an international collaboration to produce an extensive catalogue of human genetic variation.

They used epigenetic marks to identify enhancers and promoters within the subjects’ genome and, using a second technology (Hi-C) were able to map how enhancers and promoters were interacting in three-dimensional space. As well as charting the specific interactions between promoters and enhancers using genotype information, the team were able to find genetic associations between physically interacting regions of the genome, thus providing evidence for functional interactions between enhancers and promoters.

Map of genetic ‘switches’ will pave the way for understanding the molecular basis of complex genetic diseases.

An unexpected finding was that often it was not only genetic variants in enhancers that were associated with gene expression, but also regulatory elements in promoters of a distal genes that were physically and genetically connected to the gene of interest.

Genes are known to physically interact with multiple enhancers. In addition, the team also discovered that some promoters are genetically controlled by two or more enhancers, meaning that the enhancers either work in combination to affect gene expression or compensate each other. For example, if one individual lacks a particular enhancer there might be a backup enhancer that could compensate for the loss. Such a compensation mechanism could explain why it is so difficult to identify the causal variants of complex genetic diseases.

“The approach we used enables us to map links between genes and their regulatory elements,” says Fabian Grubert, who led the work at Stanford University, in Michael Snyder’s lab. “Further studies in different tissues will add even more detail to the map, and hopefully will allow us to identify all the enhancers and promoters that influence a single gene under different conditions.” EMBL