Newcastle researchers have developed a genetic test providing a rapid diagnosis of mitochondrial disorders to identify the first patients with inherited mutations in a new disease gene.

The team of medics and scientists at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, together with international collaborators, have identified mutations in a gene, known as TMEM126B, involved in energy production in patient’s muscles.

Using next generation sequencing they have now developed a rapid test which provides a result within 2-3 days – previous techniques took months.

Mitochondrial diseases affect the batteries of the cell and can lead to muscular weakness, blindness, fatal heart failure, learning disability, liver failure, diabetes and can lead to death in early infancy.

Charlotte describes the technique which has already identified six patients from four families affected by this form of mitochondrial disease.

She said: “Identifying a fault in Complex I, one of the building blocks of mitochondria which is responsible for causing disease combined with our custom gene capture and the latest sequencing technology means we can screen many more genes to diagnose this debilitating disease.

“It means families can get a rapid diagnosis within days rather than the weeks and months that testing can currently take. For families who are waiting on a genetic diagnosis before trying for another baby, or they may already be expecting their next child, time really is of the essence.”

The research has confirmed the identity of a mutation causing mitochondrial disease affecting Complex I, one of five complexes involved in energy production. The gene, TMEM126B, makes a protein necessary for assembly of the complex, with defects causing problems with energy generation in patient’s muscles.

Finding a genetic cause is important to families as it means that they can find out what is wrong with their child enabling doctors and scientists to help them understand the risks to their future children and help prevent them losing another child.

Newcastle Universities www.ncl.ac.uk/press/news/2016/07/newrapidgenetestformitochondrialdisease/

Alzheimer’s disease is characterized by two types of cerebral lesion: amyloid plaques and neurofibrillary tangles. Amyloid beta peptide (Aβ), naturally present in the brain, builds up over the years as a result of genetic and environmental factors until it forms amyloid plaques. This build-up is toxic for nerve cells: it leads to a loss of neuronal structure and to what is known as ‘neurofibrillary’ tangles (abnormal aggregation of the tau protein), which in turn results in cell death.

In this study, the team led by Pierre Lafaye, Head of the Antibody Engineering Platform in the Citech at the Institut Pasteur, in collaboration with the Chemistry of Biomolecules and Integrative Neurobiology of Cholinergic Systems Units from the Institut Pasteur and the CNRS, developed two new types of antibody capable of detecting the extracellular and intracellular targets (respectively amyloid plaques and neurofibrillary tangles) that are characteristic of Alzheimer’s disease. To achieve this, they turned their attention to camelids, specifically llamas, since their small antibodies are easy to use. They used the variable region of the antibody, known as VHH or nanobodiesTM, to specifically recognize the markers of Alzheimer’s.

These antibodies have the rare ability to cross the blood-brain barrier, which generally protects the brain from microbial attacks but also prevents potential therapeutic molecules from reaching it.

This collaborative research project, jointly conducted by scientists from the Institut Pasteur, Inserm, the CNRS, the CEA, Pierre & Marie Curie and Paris Descartes Universities and the Roche Group, led to the development of anti-Aβ and anti-tau protein antibodies that specifically detect amyloid plaques and neurofibrillary tangles. These antibodies were subsequently tested in vitro on the brain tissue of Alzheimer’s patients.

The antibodies were then tested in vivo in two mouse models, each with one of the two characteristic lesions associated with Alzheimer’s disease. These antibodies, labelled with a green fluorochrome, were injected intravenously and crossed the blood-brain barrier, binding to the two targets the scientists were aiming to identify: amyloid plaques and neurofibrillary tangles. This made the signs of the disease visible in the brain using two-photon microscopy. The scientists involved in this collaborative project are currently working on the development of an MRI imaging technique to observe the lesions. In the long term this could be applied to humans.

‘Being able to diagnose Alzheimer’s at an early stage could enable us to test treatments before the emergence of symptoms, something we were previously unable to do,’ explained Pierre Lafaye. These VHH antibodies could be used in combination with therapeutic molecules so that the molecules can be delivered in a targeted way to the brain.

Institut Pasteurwww.pasteur.fr/en/institut-pasteur/press/press-documents/diagnosis-alzheimer-s-disease-llama-antibodies-detect-cerebral-lesions

Under the banner “GeT Perfect”, Greiner Bio-One has kicked off the European promotion of the Greiner eHealth Technologies Solution – GeT.  For this purpose, a modern microsite in German and English has been created.  The one page site provides all essential information at a glance. GeT utilizes a flexible modular based software solution whilst applying the advantages of pre-barcoded VACUETTE tubes. The aim is to increase the efficiency of routine procedures in and around the laboratory. This page provides information on events, reference customers as well as study material. Testimonials from reference customers report on their experiences. Advantages of the system and working procedures can be seen in the form of videos and animation. All in all, the user has here a compact version of all initial information required for initiating any further steps.

www.gbo.com/get

Prostate cancer patients have been offered hope after scientists at Newcastle University have identified a new group of molecules that could be targeted to slow tumour growth.

Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically. 

Experts used an advanced screening technique which found hundreds of genes were affected by the male hormone testosterone. It is believed this could lead to new diagnostic tests and treatments.

Among the 700 genes identified was an important set that add sugar groups – known as glycans – to the surface of prostate cancer cells. This group has never been investigated before.

Treatments targeting glycan sugar groups have been developed for other types of the illness, such as breast cancer. It is hoped these treatments could also be used for prostate cancer.

Results of the research suggest that testosterone changes glycans to make cancer cells more likely to survive, grow and spread to other parts of the body. 

Scientists say there is the potential to target these glycans which could stop the growth and spread of tumours and save lives.

Dr Jennifer Munkley, Research Associate at the Institute of Genetic Medicine, Newcastle University, co-led the three-year research project with Professor David Elliott.

She said: “Our findings are very significant for future treatments as they identify a new group of molecules in prostate cancer which could be targeted therapeutically.

“Now we have identified these glycans we will be able to develop strategies to inhibit them and help patients with this condition.

Glycans have the potential to be used as part of a diagnostic test to help doctors decide which prostate cancers need treatment.

One in eight men will be diagnosed with the condition. It is the most common cancer in UK males, and there is a need to identify how the disease progresses and for treatment options to be established.

Researchers at Newcastle University used a technique, called RNA-sequencing, to identify the new set of genes that are important.

The genes identified may provide novel ways the disease can be monitored in patients to predict the most aggressive prostate cancers that need to be treated.

Simon Grieveson, Head of Research Funding at Prostate Cancer UK, said: “There’s a desperate need for more treatments for men with advanced prostate cancer, who currently have too few options available to them.

“However, in order to develop new, effective treatments, we need to understand more about the genetic makeup of aggressive prostate cancers and identify what makes them tick.

“This promising research has unearthed a new group of genes which could play a part in cancer cell survival and development, and could pave the way for new treatments in the future.

Newcastle University www.ncl.ac.uk/press/news/2016/07/prostatecancerstudy/

Most melanomas are driven by mutations that spur out-of-control cell replication, while nevi (moles composed of non-cancerous cells at the skin surface) harbouring the same mutations do not grow wildly. However, changes in the level of gene expression can cause nevi to become melanomas.

Dermatologists surmise that 30 to 40 percent of melanomas (approximately 30,000 cases per year) may arise in association with a nevus. However, clinicians would like to be able to better distinguish between the two, especially in borderline cases when they examine skin tissue after a patient biopsy.

Senior author John T. Seykora, MD, PhD, a professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, led a study that found that decreased levels of the gene p15 represents a way to determine if a nevus is transitioning to a melanoma. The protein p15 functions to inhibit nevus cell proliferation.

“We showed that p15 expression is a robust biomarker for distinguishing nevus from melanoma,” said Seykora. “Making this distinction has been a long-standing issue for dermatologists. We hope that this new finding will help doctors determine if a nevus has transformed to melanoma. This could help doctors and patients in difficult cases. Current research will hopefully move this into the realm of standard practice in about one to two years.”

Decreased expression in the related protein p16 has also been associated with melanoma, but p15 appears to be a primary driver of oncogene-induced cell senescence in nevus cells. When p15 levels drop, then nevus cells begin to grow.

The team stained human nevus and melanoma tissue samples with p15 and p16 antibodies.  Staining was evaluated and graded for percentage and intensity to determine an “H score,” which correlates with the level of protein in the cells. This approach could also form the basis of a clinical determination, taking the form of an antibody test for p15 from a patient’s biopsy specimen. “If the staining level is high then that would be most consistent with a benign nevus,” Seykora said. “If the staining level is low then that would be consistent with a melanoma.”

RNA was also extracted from 14 nevus and melanoma tissue samples to determine levels of p15 mRNA.  The expression of p15 mRNA was significantly increased in melanocytic nevi compared with melanomas as determined by real-time quantitative RT-PCR analysis.

Penn Medicine www.uphs.upenn.edu/news/News_Releases/2016/11/seykora/