Scientists have identified a gene that could potentially open the door for the development of new treatments of the lethal disease sepsis.

Researchers from The Australian National University (ANU) and the Garvan Institute of Medical Research worked with Genentech, a leading United States biotechnology company, to identify a gene that triggers the inflammatory condition that can lead to the full-body infection sepsis.

‘Isolating the gene so quickly was a triumph for the team,’ said Professor Simon Foote, Director of The John Curtin School of Medical Research (JCSMR) at ANU.

Sepsis is a severe whole-body infection that kills an estimated one million people in the US alone each year. It occurs as a complication to an existing infection, and if not treated quickly can lead to septic shock and multiple organ failure, with death rates as high as 50 per cent.

Researchers were aware that sepsis occurs when molecules known as lipopolysaccharides (LPS) on the surface of some bacteria infiltrate cells, triggering an immune response that causes the cells to self-destruct. But exactly how the self-destruct button was pressed remained a mystery.

Scientists at Genentech showed that Gasdermin-D usually exists in cells in an inactive form. When the LPS molecules enter the cells they trigger an enzyme called caspase-11, a kind of chemical hatchet, to lop the protective chemical cap off Gasdermin-D, which in turn leads the cells to self-destruct.

The team employed a large-scale forward genetics discovery platform to screen thousands of genes for those involved in the LPS driven self-destruct pathway of cells.

The team found that the new gene created a protein, Gasdermin-D, that triggers cell death as part of the pathway to sepsis.

Nobuhiko Kayagaki, PhD, Senior Scientist from Genentech, said the work will help researchers understand and treat other diseases as well as sepsis.

‘The identification of Gasdermin-D can give us a better understanding not only of lethal sepsis, but also of multiple other inflammatory diseases,’ he said. Australian National University

The researchers from University College London studied a group of genes that have previously been linked to an increased risk of disease in the arteries. They studied data from nearly 4,000 men and women from across Europe, comparing their genes, their artery thickness and their artery health.

The scientists, led by BHF Professor Steve Humphries, believe they have pinpointed the gene in the group that is associated with an increased risk of a heart attack or stroke in women, but not in men.

Called BCAR1, the gene they identified is involved in many processes in the body that are affected by the female sex hormone oestrogen. The researchers believe that a high risk version of the BCAR1 gene – the GG version – when combined with a woman’s naturally occurring high oestrogen levels, could lead to the increased risk of cardiovascular disease compared with the low risk version – the AA version. Men with the GG version of the BCAR1 gene do not seem to be affected.

Over the five-year study, women with the high risk BCAR1 gene – around a third of those studied – had an increased risk (6.1%) of having a heart attack, stroke or diseased blood vessels compared with those with the low risk version of the gene (2.5%).

Heart disease is the major cause of heart attack and someone has a heart attack in the UK every three minutes. Understanding what puts people at risk of heart attacks is an important part of finding ways to prevent them and potentially treat people with medication to lower their risk of having a heart attack. British Heart Foundation

The Beatson Institute of Cancer Research, Bearsden, Glasgow, hosted ‘Circulating Biomarkers 2015’, a Biotexcel conference and workshop. The role of circulating biomarkers in early diagnosis and treatment monitoring is gaining momentum with kits for analysing DNA and RNA from circulating tissue already on the market, and liquid biopsy products in development. The analysis of circulating biomarkers allows less expensive and less invasive screening of patients, and so would enable the early diagnosis of disease and hence timely treatment, for example in pancreatic cancer where presentation typically occurs too late for a cure to be achieved. Also, monitoring of treatment in, for example, breast cancer patients by screening of circulating tumour cells will allow clinicians to make better and quicker decisions about the best therapy for the patient.
In the now familiar format, the meeting included a mix of lectures, a networking workshop, a panel debate, and technology presentations.  The lectures included, among others, presentations on the analysis of circulating tumour DNA (Prof. Charles Coombes, Imperial College London, UK; Dr Gerhardt Attard, Institute of Cancer Research and the Royal Marsden, Surrey, UK), RNA (Prof. Sue Burchill, Leeds Institute of Cancer and Pathology, UK), circulating tumour cells (CTCs) (Dr Vera Cappelletti, National Cancer Institute, Milan, Italy; Dr François-Clément Bidard, Institut Curie, Paris, France) and micro RNA (Dr Alberto Rocci, Manchester Royal Infirmary, Manchester, UK). Other talks discussed the potential of metabolomic biomarkers in cancer (Dr Oliver Maddocks, Beatson Institute for Cancer Research, Glasgow, UK) and how to use a variety of biomarkers and other parameters for the evaluation of the complex  situation of ageing and lifespan (Prof. Paul Shiels, University of Glasgow, Glasgow, UK).
The technology presentations included talks on technology for the enrichment of circulating cell-free DNA (Dr Vipulkumar Patel, Analytik Jena), coupling the CellSearch system (CellSearch) and DEPArray platform (Silicon Biosystems) to isolate single CTCs (by Dr Francesca Fontana (Silicon Biosystems) and targeted biomarker detection by MassARRAY (Dr Malcolm Plant, Agena Bioscience).
The panel debate was centred around the question, ‘CTCs vs. cfDNA vs. miRNA vs. mRNA: which is better and why?’ but perhaps the more interesting discussion that evolved was on the ethics of biomarker analysis (Is it ethical to screen for a condition where there is no treatment ?) and the practicalities of screening (How do we screen for conditions that need to be caught before the presentation of symptoms?). Additionally, the meeting provided many networking opportunities and the benefit of such discussion will, no doubt, be borne out by the development and continuation of new and existing collaborations. A very profitable meeting for all involved.

The largest genetic study of atopic dermatitis ever performed permitted a team of international researchers to identify ten previously unknown genetic variations that contribute to the development of the condition. The researchers also found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

Atopic dermatitis, a type of eczema, afflicts approximately one out of every five children and one out of every twelve adults. Though knowledge of the genome is crucial to assessing the likelihood that an individual will develop atopic dermatitis, most genes responsible for the condition have not yet been discovered.

The team of international researchers that conducted the largest genetic study of atopic dermatitis to this point pooled data obtained from 377,000 subjects in 40 different projects around the world.

 “We identified ten new genetic variations, making a total of 31 that are currently known to be associated with atopic dermatitis,” says Bo Jacobsson, a professor at Sahlgrenska Academy who was a member of the team. “Of particular interest is that each of the new ones has a role to play in regulation of the immune system.”
The researchers found evidence of genetic overlap between atopic dermatitis and other illnesses, including inflammatory bowel disease.

 “While the new variations contribute in only a small way to the risk of developing atopic dermatitis, knowing about them will raise our awareness about the mechanisms of the various diseases,” Professor Jacobsson says. “Our ultimate hope is that additional treatment methods will emerge as a result.”
Although the importance of genetic factors in the pathogenesis of atopic dermatitis had already been established, the sheer size of this study allowed researchers to fine tune their understanding and obtain more information about the ways that autoimmune mechanisms run amok as the disease develops.

A total of 21,399 cases of European, African, Japanese and Latino ancestry were first compared in 22 different studies with 95,464 controls. The findings were then replicated in 18 studies of 32,059 cases and 228,628 controls.

“Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis” was published in Nature Genetics online on October 19. University of Gothenburg

Scientists at the Salk Institute have uncovered a molecule whose mutation leads to the aggressive growth of a common and deadly type of lung cancer in humans.

This enzyme, called EphA2, normally polices a gene responsible for tissue growth. But when EphA2 is mutated, the Salk team discovered, cellular systems can run amok and quickly develop tumours. The new work suggests that EphA2 could be a new target for a subset of lung cancer, which affects non-smokers as well as smokers, and is the leading cause of cancer-related deaths worldwide.

 “Sometimes there are hundreds of mutations in the genes of a patient’s tumors, but you don’t know whether they are drivers of the disease or by-products,” says senior author Inder Verma, professor of genetics and holder of Salk’s Irwin and Joan Jacobs Chair in Exemplary Life Science. “We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies.”

Two gene mutations in particular are known to spur the growth of human tumours: KRAS and p53. Though both genes have been heavily studied, they are difficult to therapeutically target, so the Salk team decided to look at genes that might police KRAS and p53 instead.

The researchers narrowed in on the 4,700 genes in the human genome related to cellular signalling–specifically, genes that have the ability to tamp down cell growth and proliferation. Then the team adapted a genetic screening technique to quickly and efficiently test the effect of these thousands of genes on tumour development. In animal models, the Salk team found that 16 of these cell-signalling genes produced molecules that had a significant effect on KRAS- and p53-related tumours.

Of these 16 molecules, one especially stood out: the EphA2 enzyme, originally discovered in the lab of another Salk scientist, Tony Hunter. Previously, EphA2’s significance in lung cancer was unclear, but the team discovered that its absence let KRAS-associated tumours grow much more aggressively.

“With a mutation in KRAS, a tumour forms in 300 days. But without EphA2, the KRAS mutation leads to tumours in half the time, 120 to 150 days,” says Verma, who is also an American Cancer Society Professor of Molecular Biology. “This molecule EphA2 is having a huge effect on restraining cancer growth when KRAS is mutated.” Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and human lung cancer.

 “Since activating EphA2 led to the suppression of both cell signalling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,” says Narayana Yeddula, a Salk research associate and first author of the paper. Salk Institute for Biological Studies