Researchers have identified a new set of genes that may be responsible for the two most common and disabling neurological conditions, stroke and dementia.

The study may help researchers better understand, treat and prevent ischemic and haemorrhagic stroke, and perhaps Alzheimer’s disease and other dementias.

Stroke is the leading neurological cause of death and disability worldwide. Previous studies have looked mainly at genes causing atherosclerosis and genes affecting the function of platelets and clotting processes as risk factors for ischemic stroke (clot obstructing blood flow to the brain). A different set of genes has been associated with haemorrhagic stroke (bleeding into the brain).

Researchers from Boston University School of Medicine looked for new stroke genes using genome wide association as well as meta-analysis. They identified a new gene called FOXF2 which increased the risk of having a stroke due to small vessel disease in the brain. No previous study has identified a gene for the common type of small vessel disease stroke although some genes associated with familial small vessel diseases such as CADASIL are known.

Sudha-Seshadri“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and haemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries. Unravelling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke,” explained corresponding author Sudha Seshadri, MD, professor of neurology at BUSM.

According to the researchers small vessel disease not only causes stroke but is also a major contributor to dementia risk, and is associated with gait problems and depression. “Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke,” she added. Boston School of Medicine

Three manuscripts published recently explored the versatility of liquid biopsies by identifying EGFR mutations using circulatingu tumour DNA (ctDNA) in urine and plasma and examining circulating tumour cells (CTCs) in plasma to predict the risk of lung cancer recurrence after surgical resection. Collectively, these findings illustrate the potential and reach of liquid biopsies in both identifying patients suitable for targeted treatment as well as predicting cancer recurrence.

Lung cancer is the most common type of cancer with the highest cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for roughly 85% of lung cancer and most patients present with advanced disease at diagnosis. Surgical resection is the preferred treatment option for patients with medically operable tumours. However, disease recurrence occurs in approximately 50% of cases. Patients with advanced disease are often not candidates for surgical resection and commonly harbour driver mutations that can be targeted by drugs. A major challenge for assessing driver mutations, such as epidermal growth factor receptor (EGFR) mutations, in advanced disease is the scarcity of suitable biopsy tissue for molecular testing. A minimally invasive alternative to invasive tissue biopsy is the use of liquid biopsy, which analyses ctDNA or CTCs in a liquid biological sample (i.e. urine, blood, or serum).

The first manuscript entitled, Circulating Free Tumor-derived DNA (ctDNA) Determination of EGFR Mutation Status in Real-World European and Japanese Patients with Advanced NSCLC: the ASSESS Study, used samples from the large ASSESS study to evaluate EGFR mutation status by analysing ctDNA from blood plasma. The results of the study demonstrated that analysing ctDNA from plasma is feasible for the identification of EGFR mutations with mutation status concordance in 1,162 matched samples of 89% (sensitivity 46%; specificity 97%; positive predictive value [PPV] 78%; negative PV 90%). The authors comment that, “Accurate and accessible ctDNA mutation testing to address the unmet need in patients without an available/evaluable tumour sample will be important to enable more patients to receive therapies personalized to the mutation status of their tumor.”

The second manuscript entitled, A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma, analysed samples from patients enrolled in TIGER-X, a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC, to interrogate EGFR activating mutations and the T790M resistance mutation by analysing ctDNA from urine or blood plasma. The results from the study show that ctDNA derived from NSCLC tumours can be detected with high sensitivity in urine and plasma, sensitivity 93% for T790M, 80% L858R, and 83% exon 19 deletions and sensitivity 93% for T790M, 100% L858R, and 87% exon 19 deletions, respectively. The authors comment that, “In conclusion, our data demonstrates that urine testing using mutation enrichment NGS method successfully identifies EGFR mutations in patients with metastatic NSCLC and has a high concordance with tumour and plasma, suggesting that EGFR mutation detection from urine or plasma should be considered as a viable approach for assessing EGFR mutation status.”

Finally, a third manuscript on liquid biopsies entitled, Circulating tumour cells detected in the tumour-draining pulmonary vein are associated with disease recurrence after surgical resection of non-small cell lung cancer, used blood and tumour-draining pulmonary vein samples from patients pre-surgical resection and intra-operatively to analyse CTCs and circulating tumour microemboli (CTM, clusters). The investigators reported that combining CTC/CTM enumeration in tumour-draining pulmonary veins and peripheral blood at the time of curative-intent surgical resection of NSCLC better identifies those patients at higher risk of lung cancer recurrence than peripheral CTC/CTM numbers alone. “In addition to the potential role of CTCs as a prognostic/predictive biomarker, isolation and genetic analysis of individual CTCs from liquid biopsies may shed light on tumour biology and the metastatic process,” said Phil AJ Crosbie, MD, PhD, first author of the article.

The International Association for the Study of Lung Cancer www.iaslc.org/news/liquid-biopsies-identification-egfr-mutations-and-prediction-lung-cancer-recurrence

Bacteria in your intestines may play an important role in determining if you will develop blinding wet Age-related Macular Degeneration (AMD).

Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.

AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.

While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.

“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.

University of Montreal nouvelles.umontreal.ca/en/article/2016/11/15/microbes-in-your-gut-influence-major-eye-disease/

Researchers at the Perelman School of Medicine at the University of Pennsylvania and other institutions have uncovered a site of genetic variation that identified which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The Penn team also found that patients with this genetic variation had a slower rate of Parkinson’s disease progression, and lower amounts of alpha-synuclein in the brain. Alpha-synuclein is a protein that experts know plays a role in the development of Parkinson’s disease.

Clinicians have long noted that the presence of tremors, rather than balance and walking problems, as the initial or dominant symptom of Parkinson’s may suggest slower progression of the disease. The Penn-led study is one of the first to link this difference to a specific genetic variation. Tremor-dominant patients are also less likely to develop dementia, although this symptom was not assessed in the study.

“We have never understood the reason why some people present with more tremor vs. walking/balance difficulties in Parkinson’s disease,” said the study’s lead author, Christine A. Cooper, MD, a fellow in movement disorders at Penn Medicine. “This finding gives us information, for the first time, that has implications for diagnosis, prognosis, treatment, and prevention efforts.”

In the study, the investigators ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed.

The researchers found that 39 of the 251 patients who had a genetic variation known as the GG genotype at the rs356182 SNP 3’ to the SNCA gene were more likely to have: 1) tremors rather than walking/balance problems; 2) slower physical progression of the disease; and 3) lower levels of alpha-synuclein in the brain. Patients were followed up to seven years in some cases. The investigators carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of PD symptoms.

“This is how we can start thinking about precision medicine in action,” said the study’s senior author, Alice S. Chen-Plotkin, MD, an assistant professor of neurology at Penn. “We found that a relatively common genetic variation can both serve as a biomarker for and influence the disease course of Parkinson’s patients. This opens up the possibility of achieving a hallmark of precision medicine: targeted therapies for different ‘versions’ of what was once thought to be a single disease.” University of Pennsylvania Health System

Ribonucleic acid (RNA) binding fluorescent probes have been powerful and important analytical tools for the study of RNA structures and functions.

A research group led by Professor Seiichi Nishizawa at Tohoku University’s Graduate School of Science has reported a new RNA probe that binds to double-stranded RNA (dsRNA) in a sequence-specific manner.

The probe has a weak response to mismatch-containing dsRNA sequences, thus enabling sequence-selective fluorescence sensing of dsRNA at the single-base pair resolution. It also shows a preference for binding with dsRNA over dsDNA, which is an important selective process for future applications in a cellular environment where RNA and DNA co-exist.

In contrast to the conventional analytical method which is limited to single-stranded regions of RNA, the new analytical method allows for fluorescent sensing of target dsRNA structure and sequence for the first time.

It is expected that the probe will open up new possibilities for analysing the functions of dsRNA-containing structures, which are closely related to various biological phenomena and diseases.

Tohoku University www.tohoku.ac.jp/en/press/fluorescence_detection_of_rna.html