Non-invasive prenatal testing (NIPT) for chromosomal foetal disorders is used increasingly to test for conditions such as Down’s syndrome. NIPT examines DNA from the foetus in the mother’s blood, and therefore does not carry the risk of miscarriage involved in invasive testing methods. Now, for the first time, researchers have found another advantage of NIPT; it can detect maternal cancers at an early stage, before symptoms appear.

Nathalie Brison, PhD, a senior scientist in the Clinical Cytogenetics laboratory at the Centre for Human Genetics, UZ Leuven, Leuven, Belgium, reports that the team had set out to increase the accuracy of the NIPT test in order to overcome some of the technical problems that can cause it to come up with false negative or false positive results when screening for chromosomal disorders in the foetus. Down’s, or trisomy 21, is the most frequent chromosomal abnormality, and occurs in about one in 700 live-born babies. The risk of giving birth to a baby with Down’s increases with the age of the mother, and rises sharply from the age of 36 years.

“We therefore felt it important that we improved the accuracy of the test,” Dr Brison says.  ”Even though it is very reliable, we believed that we could make it even better, and in doing so we could also find other chromosomal abnormalities apart from the traditional trisomy syndromes – Down’s, Edward’s (trisomy 18), and Patau (trisomy 13). Using the new, adapted test in over 6000 pregnancies, and looking at other chromosomes, we identified  three different genomic abnormalities in three women that could not be linked to either the maternal or foetal genomic profile. We realised that the abnormalities bore a resemblance to those found in cancer, and referred the women to the oncology unit.”

Further examination, including whole body MRI scanning and pathological and genetic investigations, revealed the presence of three different early stage cancers in the women:  an ovarian carcinoma, a follicular lymphoma, and Hodgkin’s lymphoma. Although this incidence is within the range to be expected in the normal population (one per 1000-2000 person years in women aged 20 – 40), without NIPT these cancers would have been unlikely to have been detected until they became symptomatic, and therefore at a much later stage.

“Considering the bad prognosis of some cancers when detected later, and given that we know that it is both possible and safe to treat the disease during pregnancy, this is an important added advantage of NIPT,” comments principal investigator Professor Joris Vermeesch, Head of the Laboratory for Cytogenetics and Genome Research at Leuven. “During pregnancy, cancer-related symptoms may well be masked; fatigue, nausea, abdominal pain, and vaginal blood loss are easily interpretable as a normal part of being pregnant. NIPT offers an opportunity for the accurate screening of high risk women for cancer, allowing us to overcome the challenge of early diagnosis in pregnant women.”

The results suggest that NIPT might enable the detection of pre-symptomatic cancers not just in pregnant women, but more widely. “We now know that it is possible to offer the accurate detection of chromosomally imbalanced cancers to the general population via minimally invasive screening methods,” says Dr Brison. “The normalisation of the NIPT profile in these patients following treatment indicates that we can also measure response to treatment as early as after the first administration of chemotherapy.  Of course, larger scale studies will be required to validate these results further, but we are confident that we have made an important step towards the possibility of wide-scale, effective, non-invasive cancer screening capable of detecting disease at an early stage.” European Society of Human Genetics

Lupus, multiple sclerosis, and type-1 diabetes are among more than a score of diseases in which the immune system attacks the body it was designed to defend. But just why the immune system begins its misdirected assault has remained a mystery.

Now, researchers at Temple University School of Medicine (TUSM) have shown that bacterial communities known as biofilm play a role in the development of the autoimmune disease systemic lupus erythematosus — a discovery that may provide important clues about several autoimmune ailments.

A team led by TUSM researchers Çagla Tükel, PhD, and Stefania Gallucci, MD, show how bacterial biofilms found in the gut can provoke the onset of lupus in lupus-prone mice. Dr. Tükel is an Assistant Professor of Microbiology and Immunology at TUSM, and Dr. Gallucci is Associate Chair, Microbiology and Immunology, as well as an Associate Professor in Microbiology and Immunology at TUSM. Both are members of the Temple Autoimmunity Center.

‘This work stresses the importance of considering infections as a possible trigger for lupus,’ Dr. Gallucci said. ‘Very little was known about how biofilms interact with the immune system because most of the research has been looking at how biofilms protect bacteria, how they make bacteria resistant to antimicrobials such as antibiotics, but almost nothing was known about what biofilms do to the immune response,’ she said.

Biofilm is a densely packed bacterial community that excretes proteins and other substances. Those substances form a matrix that protects the bacteria from antimicrobials, the immune system, and other stressors. Biofilms can occur in our guts, among the bacteria that help us digest. They exist as dental plaque, or arise in urinary tract infections. They also can find a home on man-made surfaces such as intravenous catheters. Central to the lupus story is a biofilm protein deposit called an amyloid. In the common gut bacteria E. coli, as well as the bacteria often responsible for severe gastrointestinal distress that accompanies food poisoning, Salmonella Typhimurium, amyloids are called curli because of their curly fibre-like appearance.

Also part of the biofilm is DNA excreted by bacteria. The Temple team discovered that when curli amyloids and DNA meet, they form remarkably durable bonds in the biofilm. When the researchers attempted to separate the DNA from these bonds using a variety of enzymes as well as chemicals, the curli wouldn’t let go. Curli-DNA complexes speed up the creation of the biofilm, the researchers learned. And the Temple researchers found it is also in this composite of curli-plus-DNA that autoimmune trouble appears to arise.

It’s long been known that infection is associated with lupus flares — a flare in lupus is when symptoms worsen. Indeed, infections play a role in between 20 percent and 55 percent of lupus patient mortality. Up to 23 percent of hospitalizations in lupus patients are due to infectious disease complications. Further, the bacteria Salmonella are more aggressive in lupus patients, with the ability to create potentially lethal complications.

The new research shows that the complexes formed from curli amyloid and DNA in the biofilms of both Salmonella and E. coli give rise to not only inflammation, but the self-attacking antibodies of lupus.

To demonstrate the role of biofilms in immune response, the researchers wanted to see how the sentinels of the immune system, called dendritic cells, reacted to a biofilm. The dendritic cells sent ‘tendrils’ into the biofilm and ate up part of it to signal other molecules. Further, they produced large amounts of chemicals called proinflammatory cytokines. These cytokines are important in inciting the immune system to act. Among the cytokines was Type-1 interferon, known to be associated with lupus.

‘I was super excited when I saw how activated the dendritic cells were on the biofilm ‘ Dr. Gallucci said. The levels of cytokines released when dendritic cells were exposed to curli-DNA complexes actually exceeded the most robust response known previously — the response to lipopolysaccharide (LPS).

To test if the immune response seen in the laboratory would be enough to induce autoimmunity and the attack on self that occurs in lupus, the researchers used mice that are prone to develop autoimmune disease. As is the case with many diseases, lupus is the result of a genetic propensity that lies dormant in the absence of an environmental trigger. The researchers wanted to see if the curli-DNA complexes could provide that trigger. They injected susceptible mice with the amyloid-DNA composites or a placebo. Within two weeks, the researchers found the kind of antibodies that attack ‘self,’ known as autoantibodies. The autoantibodies, which target double-stranded DNA, are a diagnostic hallmark of lupus. The response was remarkably fast. It normally takes mice four to five months to develop autoantibodies.

Another strain of mice that do not develop lupus spontaneously but are genetically predisposed to autoimmunity also reacted to the curli-DNA composites with rapid production of autoantibodies. A third strain of mice with no propensity for any autoimmune disease, developed autoantibodies within two weeks of injection, but at lower levels than in the mice with a propensity toward lupus.

All mice developed the autoantibodies whether the curli-DNA composites came from Salmonella or from the kind of E. coli that’s found in a healthy digestive system. In fact, three of the four bacterial families that contain curli genes are found in the gut: Bacteroidetes, Proteobacteria, and Firmicutes, suggesting a possible source of vulnerability in susceptible patients. ‘How that happens, I think that will be the next level of our project,’ Dr. Gallucci said. The research team is already looking at mouse models to see what may lead to the escape of curli-DNA complexes from the gut. Further, the team is collaborating with rheumatologist Dr. Roberto Caricchio, Director of the Temple Lupus Clinic, to see if the patients show signs of exposure to the curli-DNA complexes.

‘The next step is to explore the mechanism of how these composites are stimulating autoimmunity,’ Dr. Tükel said. ‘The beneficial bacteria found in our guts can cause problems when they cross the intestinal barrier and reach to places they shouldn’t be. Thus, besides infectious bacteria, a leaky gut could cause many problems. We are now starting to understand how the bacteria in our gut may trigger complex human diseases including lupus. So it’s critical for us to understand the biology of the bacterial communities and their interactions with the immune system.’ EurekAlert

Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.

The child was one of six cases in which TGen sequenced – or decoded – the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms.

‘In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing – often over many years – without a successful diagnosis, until they enrolled in our study,’ said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.

This is a prime example of the type of ‘personalized medicine’ TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.  

‘Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,’ said Dr. Baumbach-Reardon. ‘This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.’

In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.

‘To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,’ said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.

Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease. Translational Genomics Research Institute (TGen)

Kidney disease is a major health concern worldwide. It’s estimated that 1 in 3 American adults are at risk of developing kidney disease, and 26 million adults already have kidney disease. Many are undiagnosed. Because kidney disease can go undetected until it’s too late, effective and consistent diagnosis is essential. Physicians on Mayo Clinic’s Rochester, Minn., campus – one of the world’s leading kidney disease centers – are at the forefront of an effort to standardize the diagnosis of kidney disease.

In a paper, Mayo Clinic researchers provide a detailed recommendation for standardizing the diagnosis of glomerulonephritis. This is a term used to describe various conditions involving inflammation of the glomeruli, which is the basic filtering unit in the kidneys. Inflammation prevents the kidneys from properly filtering toxins out of the blood and regulating fluid levels in the body, and, ultimately, can lead to permanent damage to the kidneys and potential kidney failure.

 “Earlier this year, we convened renal pathologists and nephrologists from around the world at Mayo Clinic to begin work on an effort that could transform the way kidney disease is diagnosed for patients everywhere,” says Sanjeev Sethi, M.D., Ph.D, professor, Department of Laboratory Medicine and Pathology, Mayo Clinic. “It was time to move the field toward diagnosing glomerulonephritis based on the underlying cause of the disease, which leads to a more personalized diagnosis and more targeted treatment for the patient.”

According to convention, glomerulonephritis historically has been classified by the pattern of inflammation in the glomerulus; however, this does not speak to the underlying cause of the disease. The recommendations published by Mayo Clinic provide a detailed approach to classifying and reporting glomerulonephritis that is based on pathology and etiology.

“The approach outlined in the consensus paper provides a detailed approach to diagnosing kidney disease that has many advantages for clinicians and patients,” says Fernando Fervenza, M.D., Ph.D., professor, Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic. “In addition to being focused on the individual patient’s pathology and potential cause of disease, this approach makes the data more adaptable should new diseases be identified by future research. It aligns with database reporting, and it focuses on information that is relevant to the patient and [his or her] potential treatment options.”

Drs. Sethi and Fervenza led the development of the consensus paper, which has been endorsed by the Renal Pathology Society with funding from the Fulk Foundation. The recommendations provided by the consensus report likely will form the basis of how glomerulonephritis is diagnosed and reported worldwide. Based on the recommendations, the kidney biopsy report will be disease and etiology based. This will provide the treating physician a clear pathway toward appropriate testing and evaluation of the underlying kidney disease, followed by correct and specific management of the underlying cause of the glomerulonephritis. The standardized reporting will make it easier for physicians to interpret the kidney biopsy report from various institutions. This is particularly true for Mayo physicians who see patients from different institutions. Thus, based on the etiology-driven kidney biopsy report, a patient visiting Mayo Clinic can be directed to the physician with expertise in the specific area, resulting in targeted, cost effective evaluation, and appropriate treatment of the underlying cause of kidney disease. Mayo Clinic

Chemicals used as flame retardants that are potentially harmful to humans are found in hair, toenails and fingernails, according to new research from Indiana University.

The discovery of an easily available biomarker should ease the way for further research to determine the human impact of chemicals commonly found in the environment, including in indoor dust, water and air.

Exposure to flame retardants in various forms has been linked to obesity, learning disabilities, neuro and reproductive toxicity, and endocrine disruption. Flame retardants are frequently added to plastic, foam, wood and textiles. They are used in both commercial and consumer products worldwide to delay ignition and to slow the spread of fire. Flame retardants persist in the environment and bio-accumulate in ecosystems and in human tissues.

“Little is known about the human exposure to flame retardants, especially new classes of the retardants,” said researcher Amina Salamova at the School of Public and Environmental Affairs at IU Bloomington. “The first step is to establish a relatively easy and reliable way of measuring chemical levels in people, especially children, and we’ve determined that hair and nails can provide exactly that.”

Until now, researchers depended on samples of human milk, blood and urine, and those samples are more difficult to obtain than hair and nails.

The researchers collected hair, fingernails and toenails from 50 students in Bloomington and compared the levels of chemicals found in those samples with what was found in blood from the same people.

Salamova and colleagues found that there was a strong relationship between the levels of a large group of flame retardants, the polybrominated diphenyl ethers or PBDEs, in hair and nails, on the one hand, and those in serum, on the other. In some cases, women had higher concentrations of common flame retardants, and the researchers speculate that was a result of nail polishes that contain these chemicals. Indiana University