Researchers at The Johns Hopkins Kimmel Cancer Center have developed a test for urine, gathered during a routine procedure, to detect DNA mutations identified with urothelial cancers.
UroSEEK uses urine samples to seek out mutations in 11 genes or the presence of abnormal numbers of chromosomes that would indicate the presence of DNA associated with bladder cancer or upper tract urothelial cancer (UTUC).
The researchers said the test, when combined with cytology, the gold standard non-invasive test currently used for detection, significantly enhanced early detection for patients who are considered at risk for bladder cancer and surveillance of patients who had already been treated for bladder cancer.
“There were nearly 80,000 new cases of bladder cancer and more than 18,000 deaths in 2017,” said George Netto, M.D., a senior author on the UroSEEK paper, formerly at The Johns Hopkins University and currently chair of pathology at the University of Alabama-Birmingham. “This is about using the urine to detect the cancer. UroSEEK is a method of detection that many people have tried to find that is non-invasive.”
Most cancers are curable if they are detected early, and the researchers are exploring ways to use cancer gene discoveries to develop cancer screening tests to improve cancer survival. They announced the development of CancerSEEK, a single blood test that screens for eight cancer types, and PapSEEK, a test that uses cervical fluid samples to screen for endometrial and ovarian cancers.
UroSEEK is aimed toward early detection of bladder cancer in at-risk patients, those who may have blood in their urine or people who smoke, as well as patients who have already gone through a procedure to treat bladder cancer and need to be monitored for any recurrence of the disease.
“In almost one-third of patients, bladder cancer detection is late. The cancer has already gotten into the surrounding muscle,” Netto said. “Even in those detected at an earlier stage, the tumours frequently recur. Patients are committed to a lifelong surveillance that requires invasive cystoscopy procedures and biopsies and is costly.”
Saying current non-invasive approaches for detection of urothelial cancer are suboptimal, researchers wanted to develop a test for bladder and UTUC cancer that would allow it to be found sooner and cheaper than current methods using cytology, which is not particularly sensitive and does not do well in detecting low-grade bladder cancer or UTUC.
Researchers studied 570 patients who were considered at risk for bladder cancer and found UroSEEK was 83 percent positive in those who developed cancer. When combined with cytology, the sensitivity increased to 95 percent of patients who developed the disease.
“When you combine them, you get better results,” said Nickolas Papadopoulos, Ph.D., a senior author and an investigator at the Ludwig Center at Johns Hopkins. “Side by side, UroSEEK has better sensitivity. There are some cases when cytology detects when UroSEEK doesn’t. Combining them produces the best results.”
John Hopkins Kimmel Cancer Centerwww.hopkinsmedicine.org/news/media/releases/gene_based_test_for_urine_detects_monitors_bladder_cancer

Until very recently, Parkinson’s had been thought a disease that starts in the brain, destroying motion centres and resulting in the tremors and loss of movement. New research shows the most common Parkinson’s gene mutation may change how immune cells react to generic infections like colds, which in turn trigger the inflammatory reaction in the brain that causes Parkinson’s. The research offers a new understanding of Parkinson’s disease.                                                     
“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” said Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Vickie and Jack Farber Institute for Neuroscience. “But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”
Together with Dr. Smeyne, first author Elena Kozina, PhD, looked at the mutant version of the LRRK2 gene (pronounced ‘lark’). Mutations in the LRRK2 gene are the most common cause of inherited Parkinson’s disease and are found in 40 percent of people of North African Arab descent and 18 percent of people of Ashkenazi Jewish descent with Parkinson’s. However there’s been controversy around the exact function of the LRRK2 gene in the brain.
“We know that gene mutation is not enough to cause the disease,” said Dr. Kozina, Post-Doctoral student at Jefferson.“We know that twins who both carry the mutation, won’t both necessarily develop Parkinson’s. A second ‘hit’ or initiating event is needed.”
Based on his earlier work showing that the flu might increase risk of Parkinson’s disease, Dr. Smeyne decided to investigate whether that second hit came from an infection. Suspecting that the LRRK2 mutations might be acting outside of the brain, the researchers used an agent — the outer shell of bacteria, called lippopolysaccharide (LPS) – that causes an immune reaction. LPS itself does not pass into the brain, nor do the immune cells it activates, which made it ideal for testing whether this second hit was acting directly in the brain.
When the researchers gave the bacterial fragments to the mice carrying the two most common LRRK2 gene mutations, the immune reaction became a “cytokine storm,” with inflammatory mediators rising to levels that 3-5 times higher than a normal reaction to LPS. These inflammatory mediators were produced by T and B immune cells expressing the LRRK2 mutation.
Despite the fact that LPS did not cross the blood-brain barrier, the researchers showed that the elevated cytokines were able to enter the brain, creating an environment that caused the microglia to activate pathologically and destroy the brain region involved in movement.
“Although more tests are needed to prove the link, as well as testing whether the same is true in humans, these findings give us a new way to think about how these mutations could cause Parkinson’s,” said Dr. Smeyne. “Although we can’t treat people with immunosuppressants their whole lives to prevent the disease, if this mechanism is confirmed, it’s possible that other interventions could be effective at reducing the chance of developing the disease.”
Thomas Jefferson Universitywww.jefferson.edu/university/news/2018/03/21/Parkinsons_gene_triggers_the_disease_from_outside_brain.html

Newly discovered gene mutations may help explain the cause of a disease that drastically impairs walking and thinking.
Mutations have been found in the bassoon (BSN) gene, which is involved with the central nervous system, in patients with symptoms similar to, but different from, a rare brain disorder called progressive supranuclear palsy (PSP).
PSP, a form of Parkinson’s disease, is often difficult to diagnose because it can affect people in different ways. Serious problems often include difficulty with walking and balance in addition to a decline in cognitive abilities such as frontal lobe dysfunction.
A team of Japanese researchers investigated patients whose symptoms resembled not only PSP but also Alzheimer’s disease. Despite similarities in the symptoms, detailed pathological analyses showed no resemblance to either disease, which prompted the team to further research the new disease’s underlying mechanism.
They first analysed the genomes of a Japanese family with several members displaying PSP-like symptoms. They identified a mutation in the BSN gene only in family members with symptoms. These individuals did not have mutations in the 52 other genes associated with PSP and other neurological disorders such as Alzheimer’s and Parkinson’s. This was the first time BSN gene is associated with a neurological disorder.
The researchers also detected three other mutations in the BSN gene in four out of 41 other patients displaying sporadic, or non-familial, PSP-like symptoms. None of the BSN mutations were detected in a random sample of 100 healthy individuals, underscoring the strong involvement of BSN mutations in the disease.
An autopsy done on one of the family members with the BSN mutation showed an accumulation of a protein called tau in the brain, which is not seen in a normal brain. The researchers believe that the BSN mutation is involved in the tau accumulation, which could cause the development of PSP-like symptoms. An experiment introducing a mutated rat BSN gene to cultured cells also suggested that the mutation causes the accumulation of tau. Communication between nerve fibres could also be affected, as BSN protein play a role in it.
ScienceDailywww.sciencedaily.com/releases/2018/03/180323093731.htm

There is as yet no cure for Alzheimer’s disease. It is often argued that progress in drug research has been hampered by the fact that the disease can only be diagnosed when it is too late for an effective intervention. Alzheimer’s disease is thought to begin long before patients show typical symptoms like memory loss. Scientists have now developed a blood test for Alzheimer’s disease and found that it can detect early indicators of the disease long before the first symptoms appear in patients. The blood test would thus offer an opportunity to identify those at risk and may thereby open the door to new avenues in drug discovery.
One of the hallmarks of Alzheimer’s disease is the accumulation of amyloid-β plaques in the patient’s brain. The blood test, developed by Klaus Gerwert and his team at Ruhr University Bochum, Germany, works by measuring the relative amounts of a pathological and a healthy form of amyloid-β in the blood. The pathological form is a misfolded version of this molecule and known to initiate the formation of toxic plaques in the brain. Toxic amyloid-β molecules start accumulating in the patients’ body 15-20 years before disease onset. In the present study, Gerwert and colleagues from Germany and Sweden addressed whether the blood test would be able to pick up indications of pathological amyloid-β in very early phases of the disease.
The researchers first focused on patients in the early, so called prodromal stages of the disease from the Swedish BioFINDER cohort conducted by Oskar Hanson. They found that the test reliably detected amyloid-β alterations in the blood of participants with mild cognitive impairment that also showed abnormal amyloid deposits in brain scans.
In a next step, Gerwert and colleagues investigated if their assay was able to detect blood changes well ahead of disease onset. They used data from the ESTHER cohort study, which Hermann Brenner started in 2000 at DKFZ, comparing blood samples of 65 participants that were later in the follow-up studies diagnosed with Alzheimer’s disease with 809 controls. The assay was able to detect signs of the disease on average eight years before diagnosis in individuals without clinical symptoms. It correctly identified those with the disease in almost 70% of the cases, while about 9% of true negative subjects would wrongly be detected as positive. The overall diagnostic accuracy was 86%.
Currently available diagnostic tools for Alzheimer’s disease either involve expensive positron emission tomography (PET) brain scans, or analyse samples of cerebrospinal fluid that are extracted via lumbar puncture. The researchers suggest that their blood test serves as a cheap and simple option to pre-select individuals from the general population for further testing by these more invasive and costly methods to exclude the falsely positive subjects.
EMBOwww.embo.org/news/press-releases/2018/a-new-blood-test-useful-to-detect-people-at-risk-of-developing-alzheimer-s-disease