A new study led by researchers at King’s College London in collaboration with the University of Manchester and the University of Dundee has found a strong link between exposure to peanut protein in household dust during infancy and the development of peanut allergy in children genetically predisposed to a skin barrier defect.

Around 2% of school children in the UK and the US are allergic to peanuts. Severe eczema in early infancy has been linked to food allergies, particularly peanut allergy. A major break-through in the understanding of eczema developed with the discovery of the FLG gene which codes for the skin barrier protein filaggrin. Mutations in the FLG gene result in an impaired skin barrier which is thought to allow allergens to penetrate the skin and predispose the body towards an allergic response.

Immunology, looked at the amount of peanut protein children were exposed to in household dust in their first year of life by vacuuming dust from the living room sofa and measuring peanut in the dust. A group of 577 children were assessed at 8 and 11 years of age for peanut allergy and their DNA was checked for FLG mutations. The study was conducted in children recruited to the Manchester Asthma and Allergy Study.

A strong link was found between early-life exposure to peanut protein in household dust and peanut allergy in children with FLG mutations. A three-fold increase in house dust peanut exposure during infancy was associated with a three-fold increase in risk of school-age peanut allergy. One in five children with peanut allergy had an FLG mutation. There was no significant effect of environmental peanut exposure in children without FLG mutations.

Dr Helen A Brough, first author from the Department of Paediatric Allergy, Division of Asthma, Allergy & Lung Biology, King’s College London, said: “Our findings provide evidence that peanut allergy may develop via the skin in children with mutations in the gene that codes for filaggrin which damage the function of this important skin protein. These findings are also an example of how an individual’s response to their environment can be modified by their genes. Our study raises the possibility of being able to identify a group of children with FLG mutations through genetic testing in the future, and altering their environmental exposure to peanut early in life to reduce the risk of developing peanut allergy.” King’s College London

A team led by Ludwig and Memorial Sloan Kettering (MSK) researchers has published a landmark study on the genetic basis of response to a powerful cancer therapy known as immune checkpoint blockade. Their paper describes the precise genetic signatures in melanoma tumours that determine whether a patient will respond to one such therapy. It also explains in exquisite detail how those genetic profiles translate into subtle molecular changes that enable the immune system attack of cancer cells in response to immune checkpoint blockade.

“The genetic signature we have found will be invaluable to understanding the biological mechanisms that drive therapeutic responses to immunotherapy for metastatic melanoma,” says Jedd Wolchok, MD, PhD, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center for Cancer Immunotherapy at MSK, who co-led the study with Timothy Chan, MD, PhD, of MSK’s Human Oncology and Pathogenesis Program. “Further, our strategy can now be applied to determine the genetic signatures associated with the efficacy of a number of other immunotherapies and cancers.”

Few approaches to treating cancer have generated as much excitement as immunotherapy, in which the immune system is engaged to destroy malignancies. One class of such treatments targets CTLA-4, a molecule expressed on the surface of killer T cells that ordinarily blocks their proliferation. Antibody drugs that block CTLA-4 thus stimulate killer T cell responses—which can target cancer cells—and significantly extend survival for many melanoma patients. Yet not all patients respond equally to this treatment: some, remarkably, survive many years; others fail to respond at all.

“There is a subset of melanoma patients who are living far longer than anyone would have expected in the past, largely because of this treatment and other recently developed targeted and immunologic treatments,” says Wolchok. “But we did not know how to identify them, and that’s what really drove this investigation.”

Cancer cells are swift but sloppy proliferators, generating countless mutations across their genome as they multiply. Those mutations are often expressed as changes in the chains of amino acids that make protein molecules. Like all cells, cancer cells chop up and hold out short fragments of such proteins—each about 9 amino acids in length—for the immune system to assess. These “peptides” are held up and presented to immune cells by a protein complex known as MHC Class I, which varies significantly between people.

“Previous studies by Jedd and others had shown that the particular MHC type of a patient doesn’t appear to influence the efficacy of CTLA-4 blockade,” says Chan. “So we decided to see if the tumour genome has anything to say about whether or not people respond to this therapy. The result was entirely unexpected, and the answer is exceedingly important.”

Chan, Wolchok and their colleagues initially hypothesized that tumours that harboured highly mutated cells would be most responsive to CTLA-4 blockade. To test that hypothesis, they sequenced and compared all of the genes expressed as proteins (collectively known as the “exome”) in tumours taken from 25 patients treated with anti-CTLA-4 antibodies and found that this was, to some degree, true. “But looking at the data a little more deeply,” says Wolchok, “we saw that there were outliers—patients who had over one thousand mutations who didn’t respond, and some with just a few dozen who did. This was a strong indication that the quality of the mutations matters.”

A sophisticated computational analysis of the cancer genomes revealed that a set of core peptide sequences—each four amino acids long (tetrapeptides)—within MHC Class I-presented peptides were unequivocally associated with response to treatment. To test the prognostic power of this genetic signature, the researchers sequenced the exomes of tumours from another 39 melanoma patients treated with CTLA-4 blockade. They found that all those in this set who had responded to the therapy had at least one and typically several more of the tetrapeptides they had identified. Those who failed to respond did not. Their results show that the mutant DNA sequences, can occur anywhere in the genome—not just within mutant “driver” genes that are already known to contribute to cancer.

“The more mutated the tumor’s genome is,” says Chan, “the more likely it is that immunotherapy will work. Since tumours induced by tobacco—such as those of non-small cell lung cancer—have more mutations than most other cancers except melanoma, this finding has enormous medical implications for these genetically diverse cancers.”

It also helps explain, says Wolchok, why the relatively more mutated cancers have been found in clinical trials to be the most responsive to checkpoint blockade. Ludwig Cancer Research

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Scientists from UCL and Queen Mary University of London have identified what they believe could be a cause of pre-term premature rupture of the foetal membrane (PPROM) which accounts for 40 per cent of pre-term births, the main reason for infant death world-wide.

The researchers used bioengineering techniques to test the effect of repetitive stretch on tissues of the amniotic membrane which surrounds and protects the baby prior to birth.

They found that stretching of the amniotic membrane leads to the overproduction of prostaglandin E2 (PGE2) which is damaging to both the cells and mechanical structure of the tissue. This overproduction activates the stretch-sensitive protein connexin 43 (Cx43) and reduces the mechanical properties of the membrane potentially, leading to rupture and pre-term birth.

The research is the first to look at the role of Cx43 in causing PPROM.

The team are now researching possible treatments that would allow the amniotic membrane to be repaired.

Co-author of the research, Dr Tina Chowdhury from the School of Engineering and Material Sciences at Queen Mary University of London, said, “To have potentially found a way to reduce pre-term births and prevent early deaths of young babies worldwide is incredibly exciting. The unique bioengineering tools at QMUL have allowed us to test the tissue in a way that has never been done before. This gives us an understanding of both the mechanical as well as biological mechanisms involved and will help us to develop therapies that will reduce the number of pre-term births.”

Dr Anna David, a consultant in obstetrics and pre-term birth from the UCL Institute for Women’s Health and a co-author of the paper, said,“Our findings have provided a new understanding of why pregnant women who have pre-term contractions go on to rupture their membranes early. The new project funded by the Rosetrees Trust could lead to a therapy that will heal the amniotic membrane and reduce preterm births. This has the potential to save many lives worldwide and improve the health and well-being of women during pregnancy and their families after birth.” University College London

Scientists from Uppsala University, the Science for Life Laboratory (SciLifeLab) in Stockholm and Uppsala University Hospital have developed a new method of rapidly identifying which bacteria are causing an infection and determining whether they are resistant or sensitive to antibiotics.

‘Clinical use of the method would mean that the right antibiotic treatment could be started straightaway, reducing unnecessary use of antibiotics,’ says Professor Dan I. Andersson of Uppsala University, who headed the study jointly with Professor Mats Nilsson of SciLifeLab in Stockholm and Stockholm University.

Antibiotic resistance is a growing medical problem that threatens human health all over the world. Today, many people are dying because of infections caused by resistant bacteria. When an infected person is treated with antibiotics, ‘empirical therapy’ is usually provided. This means that the choice of antibiotic is based on the resistance situation of the bacteria in a large population (such as the Swedish population), rather than on the resistance, if any, of the bacteria in the infected person’s body. The result is sometimes selection of an antibiotic drug that is ineffective against the bacteria concerned, because the latter is resistant to the drug chosen. This, in turn, boosts the use of antibiotics, especially what are known as ‘broad-spectrum’ antibiotics that work on many types of bacteria. One possible solution to these problems would be for us to have reliable methods of quickly and easily identifying the bacterial species causing the infection and its resistance pattern, and apply the correct treatment immediately.

Professor Andersson continues: ‘This is just what we’ve been working on in our study. We have developed a new method that permits identification of both the species and the resistance pattern of bacteria in urinary infections in less than four hours. By comparison, the resistance determination done at present takes one to two days.’

The method is based on highly sensitive, bacterium-specific measurement of bacterial growth in the absence and presence of various antibiotics. If the bacterium is resistant, it can multiply with antibiotic present; this is detected as a rise in the number of copies of a specific DNA sequence. If it is sensitive, on the other hand, no growth takes place. The researchers showed that the method could identify correctly both the bacteria and their resistance patterns in all the clinical samples analysed.

Anja Mezger, the principal author, says that the method is highly specific and sensitive, and can be automated for use in a clinical laboratory. What is more, it is entirely general in application and could, in principle, be used for all types of bacteria and antibiotics.

An instrument based on the method is currently being developed at Q-linea, a company in Uppsala of which Mats Nilsson was a co-founder. This instrument focuses on blood infections. Such infections are life-threatening and it is extremely important for effective treatment that the patient should start taking the correct antibiotic without delay. The company expects to launch a working instrument on the market in 2017.

‘We hope that the method can be used in the future at hospitals and health centres, so that the right treatment is given promptly, and also so that the use of antibiotics is reduced,’ says Dan Andersson. Uppsala University