The team of Professor Dirk Haller at the Technical University of Munich (TUM) made an unexpected discovery while investigating the triggering factors of colon cancer:  Cell stress in combination with an altered microbiota in the colon drives tumour growth.  Previously, it was assumed that this combination only contributes to inflammatory intestinal diseases.
"With our study we originally wanted to study the role of bacteria in the intestines in the development of intestinal inflammation," explains Professor Dirk Haller from the Department of Nutrition and Immunology at the Weihenstephan Science Centre of the TUM. "However, the surprising result for us was the discovery that bacteria together with stress in cells caused tumours (exclusively in the colon) and without the involvement of inflammation". 
The investigations were initially carried out using the mouse model.  In germ-free (i.e. sterile) animals, in which the activated transcription factor ATF6 regulated stress in the intestinal mucosa (intestinal epithelium), no change could be observed.  But as soon as the microbiota, i.e. all the microorganisms in the intestine, were transplanted back into germ-free animals, tumours developed in the colon of the mice. Using Koch’s postulates, Haller and his team were able to show that microorganisms are involved in the development of cancer in the colon.
The transcription factor ATF6 regulates stress in cells, and the intensity and duration of activation is increased with diseases. "However, it is not cell stress alone that leads to tumour growth, but the combination of stress and microbiota that favours cancer growth," says Haller, head of ZIEL – the Institute for Food & Health at TUM.
Subsequently, in cooperation with the clinic on the right side of the Isar (Prof. Janssen), the data of 541 patients with colon cancer were examined. In those cases where the level of transcription factor ATF6, which triggers cell stress, was significantly increased, the recurrence rate after surgery increased: About ten percent of patients were at risk of getting colon cancer a second time. 
"In certain patients, the protein ATF6 could serve as a diagnostic marker for an increased risk of colon cancer and could indicate the start of therapy at an early stage," said Prof.  Haller – "a microbial therapy is conceivable, when we know more about the composition of the bacterial flora.  What now became clear, however: Chronic inflammation has no effect on cancer development in the colon."

Technical University of Munich
www.tum.de/en/about-tum/news/press-releases/detail/article/34947/

Tel Aviv University researchers have developed a new blood test for genetic disorders that may allow parents to learn about the health of their baby as early as 11 weeks into pregnancy.
The simple blood test lets doctors diagnose genetic disorders in fetuses early in pregnancy by sequencing small amounts of DNA in the mother’s and the father’s blood. A computer algorithm harnessing the results of the sequencing would then produce a “map” of the fetal genome, predicting mutations with 99% or better accuracy depending on the mutation type.
Prof. Noam Shomron of TAU’s Sackler School of Medicine led the research.
“Non-invasive prenatal tests are already available for chromosome disorders such as Down syndrome,” Prof. Shomron says. “Our new procedure is based on fetal DNA fragments that circulate freely in maternal blood and bears only a minimal risk for the mother and fetus compared with such invasive techniques as the amniotic fluid test. We will now be able to identify numerous mutations and diseases in a safe and simple procedure available at the doctor’s office.
“The genetic mechanism behind Down syndrome affects a very large portion of the genome and therefore is easier to detect,” Prof. Shomron explains. “We performed upgraded non-invasive fetal genotyping, using a novel approach and an improved algorithm, to detect many other diseases that are caused by smaller parts of the genome. This is like looking at a map of the world and noticing not only that a continent is missing, but also that a single house is missing.
“The practical applications are endless: a single blood test that would detect a wide range of genetic diseases, such as Tay-Sachs disease, cystic fibrosis and many others.”
Prof. Shomron and colleagues tested blood samples from three families at Rabin Medical Center in the 11th week of gestation. They extracted maternal and paternal DNA from their white blood cells and fetal DNA from a placental cell sample. They also extracted circulating cell-free fetal DNA from the maternal blood.
“We sequenced all these DNA samples and created a computer algorithm that utilizes the parental DNA as well as the cell-free fetal DNA to reconstruct the fetal genome and predict mutations,” says Prof. Shomron. “We compared our predictions to the true fetal DNA originating from the placenta. Our model is the first to predict small inherited insertions and deletions. The method described can serve as a general framework for non-invasive prenatal diagnoses.”

American Friends of Tel Aviv Universityhttps://tinyurl.com/y43kk6sx

New research on the X chromosome from the School of Veterinary Medicine points to an abnormality in the immune system’s T cells as a possible contributing factor in lupus and other autoimmune diseases.
The autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, strikes females far more often than males. Eight-five percent of people with lupus are female, and their second X chromosome seems partly to blame. According to a new study by Penn researchers, females with lupus don’t fully “silence” their second X chromosome in the immune system’s T cells, leading to abnormal expression of genes linked to that chromosome.
The work, led by Montserrat Anguera of the School of Veterinary Medicine is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus—the first time that nuclear organization has been noted as a feature of this disease.
“In normal circumstances, the inactive X should be silenced, and what we show is, in lupus, it’s not,” says Anguera, a biologist at Penn Vet. “And it’s ultimately affecting gene expression.”
Anguera’s lab has paid close attention to the link between X chromosome inactivation, an epigenetic process that balances gene expression between males and females, and autoimmune disease. In earlier studies, the team found that, in females, both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule that is necessary for X inactivation.
In the new work, Anguera and colleagues wanted to more closely examine this process in T cells and specifically in the context of an autoimmune disease, in this case, lupus.
They first tracked the process of X inactivation in T cells from healthy mice. Their observations revealed that, as T cells develop, Xist temporarily diffuses away from the inactive X chromosome. But when a T cell is activated, as it would be upon encountering a potential pathogen, for example, then Xist RNA returns to this chromosome.
To see what happens in autoimmune disease, the researchers used a mouse model that spontaneously develops lupus in a female-biased manner, similar to the human disease. All female mice of this strain develop the disease, while only 40 percent of males do. Examining the animals’ T cells, the researchers discovered that those at early stages of disease resembled healthy controls in their patterns of Xist localization. But those in the later stages of disease had a dramatically different pattern.
The only differences we detected happened at late stages of disease,” Anguera says. “What this means is that abnormal X inactivation is a consequence of the disease; it’s not predisposing the animal to develop the disease.”
Interestingly, when the researchers looked at T cells from paediatric lupus patients, provided by study co-author Edward M. Behrens of the Perelman School of Medicine and Children’s Hospital of Philadelphia, they found the same mislocalization of Xist that they had seen in the mice with lupus, even though the children were in remission from their disease.  
Even stimulating those patients’ cells in vitro wasn’t enough to coax Xist into the normal pattern. “Even though they don’t have active disease, there’s something missing that’s preventing the RNA from staying targeted at that inactive X chromosome,” Anguera says.
University of Pennsylvania https://tinyurl.com/y3nsrssw

Roche announced in July that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Device Designation to Elecsys® ß-Amyloid (1-42) CSF and Elecsys® Phospho-Tau (181P) CSF. These in vitro diagnostic immunoassays are for the measurement of the ß-Amyloid (1-42) and Phospho-Tau concentrations in cerebrospinal fluid (CSF) in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) or other causes of dementia.
Currently, the diagnosis of AD is largely based on clinical symptoms, including cognitive testing, with a significant number of patients diagnosed when their disease has already advanced. A diagnosis of AD based on cognitive measures alone is only correct in 70 – 80 percent of cases. Measuring biomarkers with CSF immunoassays, associated with AD pathology, increases certainty of a diagnosis of AD and can help to evaluate the progression of the disease. The Breakthrough Device Designations are for indication of use with Elecsys β-Amyloid (1-42) CSF and Elecsys Phospho-Tau (181P) CSF in concordance with amyloid PET visual read result and risk of cognitive or functional decline. The Breakthrough Devices Program is a voluntary program for certain medical devices that provide for more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition. This program is designed to expedite the development and review of these medical devices.
“We are excited about FDA’s recognition of the potential clinical benefit the Elecsys CSF assays can bring to clinicians, laboratories and their patients in diagnosing AD at an early stage,” said Roland Diggelmann, CEO of Roche Diagnostics. “Roche was one of the first companies to use biomarkers in clinical trials and we will continue to explore high-performing diagnostic and disease-monitoring solutions.”

A genetic discovery will make treatment for Crohn’s disease and ulcerative colitis safer, by identifying patients who are at risk of potentially deadly drug side effects.
A ground-breaking and large-scale NHS research collaboration, led by the University of Exeter and the Royal Devon & Exeter NHS Foundation Trust, has discovered a gene mutation that allows the identification of patients at risk of a drug side effect, allowing clinicians to tailor alternative treatments to these individuals.
This finding will reduce the risk of drug side effects caused by treatment with thiopurines (consisting of azathioprine and mercaptopurine). This group of drugs is commonly used for the treatment of autoimmune and inflammatory diseases.
Crohn’s disease and ulcerative colitis (collectively known as inflammatory bowel disease –IBD) are incurable lifelong conditions that affect approximately 1 in 150 people in the UK. The main symptoms are urgent diarrhoea, often with rectal bleeding, abdominal pain, profound fatigue and weight loss. The condition disrupts people’s education, working, social and family life. Drugs to suppress the immune system are the mainstay of treatment, however more than half of patients with Crohn’s Disease and about 20 per cent of patients with ulcerative colitis will require surgery at some point. The lifetime medical costs associated with the care of a person with IBD are similar to the costs of treating diabetes or cancer.
About a third of patients with IBD are treated with a thiopurine drug, however, approximately 7 per cent of patients develop an adverse reaction called “bone marrow suppression”. This means that the body’s immune system is less able to fight infection and patients are at risk of sepsis.
Previous studies have identified mutations in a gene known as TPMT, which predisposes patients to thiopurine-induced bone marrow suppression. Clinicians either adjust the dose or avoid thiopurines altogether if routine tests show that patients are likely to carry faulty versions of the TPMT gene. However, only a quarter of patients who suffer from bone-marrow suppression have abnormalities in TPMT, suggesting that other genes may be involved.
Through the National Institute of Health Research Clinical Research Network, 82 NHS hospitals in the UK recruited patients to the study. In addition patients were recruited from international collaborators in the Netherlands, USA, Australia, France, New Zealand, South Africa, Malta, Denmark, Sweden, Italy and Canada. The Exeter IBD Research Group also recruited UK patients via the Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme, which collects reports of patients who have experienced complications of treatment.
DNA from approximately 500 patients with IBD that suffered thiopurine-induced bone marrow suppression and 680 controls (IBD patients who had received thiopurines and had no history of bone marrow suppression), were analysed to identify genes possibly associated with this adverse drug reaction.
The researchers found an association between mutations in a gene called NUDT15 and bone marrow suppression. This gene mutation had previously only been thought important in patients of East Asian descent.
Chief Investigator of the study, Dr Tariq Ahmad, of the University of Exeter Medical School, said: “In the largest genetic analysis into the side effects of thiopurine drugs we’ve discovered variation in a gene that can help us identify who is susceptible to thiopurine-induced bone marrow suppression. In line with the NHS 10 year plan to increase personalised medicine, testing for this genetic abnormality prior to prescribing thiopurine drugs will reduce the risks to patients, and costs to the NHS, associated with this potentially serious drug side effect.

Exeter Universitywww.exeter.ac.uk/news/research/title_706404_en.html