A suspected case of sexual transmission of Ebola virus disease (EVD) in Liberia was confirmed using genomic analysis, thanks to in-country laboratory capabilities established by U.S. Army scientists in collaboration with the Liberian Institute for Biomedical Research (LIBR).
The work provides molecular evidence of Ebola virus (EBOV) transmission between an EVD survivor and his female partner. It also demonstrates the value of real-time genomic surveillance during an outbreak, according to senior author Gustavo Palacios, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

CPT Suzanne Mate, Ph.D., of USAMRIID, said scientists working at the LIBR earlier this year analysed blood samples from a female patient who tested positive for EBOV in March 2015 when there had been no new documented cases for 30 days. The patient was reported have had recent sexual intercourse with a male partner who had survived EVD and had been declared EBOV negative in early October 2014.

Following the patient’s death on March 27, Mate said, public health officials were able to secure the consent of the male survivor to obtain and test a semen sample from him. The semen sample tested EBOV positive by quantitative RT-PCR, but the assay indicated that the level of viral RNA was low and required a different sample preparation method than the one originally deployed to sequence EBOV RNA from acute samples.

“We implemented a new enrichment strategy in collaboration with scientists from Illumina, Inc. that was pivotal in obtaining the required coverage to complete downstream genomic analysis,” said Michael Wiley, Ph.D, of USAMRIID. Next-generation sequencing of the enriched EBOV RNA extracted from the male survivor’s semen was used to compare the genome for similarity to the virus RNA extracted from the female patient’s blood sample.

“Ebola virus genomes assembled from the patient’s blood and the survivor’s semen were consistent with direct transmission,” commented Jason Ladner, Ph.D., of USAMRIID. “The samples shared three genetic substitutions that have not been found in any other Ebola virus sequences in Western Africa.”

In addition, said Ladner, these three genetic changes were distinct from the last
documented transmission chain in Liberia prior to this case. Combined with epidemiologic data, the genomic analysis provides support for sexual transmission of Ebola virus and for the persistence of infective EBOV in semen for more than 179 days after disease onset. This caused both the Centers for Disease Control and Prevention and the World Health Organization to change their recommendations for convalescent patients regarding sexual contact until more definitive information is obtained about how long Ebola virus can persist in semen. Research Institute of Infectious Diseases

Not all cancers are the same, even if they originate from the same tissue type. A new study by University of Wisconsin Carbone Cancer Center (UWCCC) researchers has found a small subset of pancreatic cancers may be caused by a gene mutation that can be therapeutically targeted, leading to new treatment options for those patients with the mutation.

‘My lab is interested in what the mutation profiles are in cancers,’ said Dustin Deming, MD, assistant professor of medicine at UWCCC. ‘Nearly ninety percent of pancreas cancers have a mutation in the KRAS gene, but there is currently no successful drug therapy to target those mutations, making pancreas cancer one of the more difficult cancers to treat.’

‘The idea behind this study was to ask if there is potentially any other mutation in the remaining cases that can be targeted,’ Deming said.

He and his research team searched through publicly available datasets of pancreas cancer mutation profiles to see if they could identify a gene other than KRAS that appeared with some frequency.

‘We found that, though uncommon, there appears to be a small percentage of pancreas cancers that have a mutation in the PIK3CA gene, a gene we know from our work in colon cancer that we can target therapeutically, and target it pretty well,’ Deming said.

PIK3CA encodes a protein, called PI3K, that is responsible for activating many downstream targets that promote cell growth, and mutant forms of the gene can lead to persistent, uncontrollable signalling of these targets. PIK3CA mutations have been implicated in many human cancers including colorectal and breast, and an estimated three to five percent of pancreas cancers have mutations in this gene.

To directly assess the role of PIK3CA mutations in pancreas cancer development, Deming and his team generated mouse models where the mutant gene was expressed only in pancreatic cells but no other tissue types. They then performed histology and pathology tests on pancreas sections from these mice and found several hallmarks of pancreas cancer development were present.

‘We were able to show that this mutation can initiate pancreas cancer in mice, and therefore the idea that it initiates pancreas cancers in humans, though more uncommonly than KRAS mutations, might be valid,’ Deming said.

Next, they wanted to see if drugs that inhibit PI3K, like those used with some success to treat colorectal cancers, could reduce the pancreas cancer burden in these genetically altered mice. They administered a dual inhibitor drug that targets both PI3K and one of its downstream targets, and found that nearly all of the cancer hallmarks previously seen in the untreated mice were not present in the treated group.

‘Our next goal is to find patients who have this mutation, look at their clinical characteristics and try to figure out if there is some way, other than genotyping everyone’s cancer for this mutation, to predict who might benefit,’ Deming said. “We are excited that this work might have identified a more treatable subtype of pancreatic cancer that could respond to drugs that are already in clinical development.” University of Wisconsin-Madison School of Medicine

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.