Researchers at the University of Helsinki, in cooperation with two research groups in the United States, have discovered that some Finnish mothers carry rare gene variants that protect them from pre-eclampsia, also known as toxaemia of pregnancy. This is the first time that mothers’ genotypes have been proven to contain factors that protect against pre-eclampsia.
Around 5 per cent of pregnant women get pre-eclampsia, which is one of the most common causes of maternal deaths and premature births. The underlying cause of pre-eclampsia is not yet known in detail, but the disease is known to increase the risk of cardiovascular diseases among mothers and their children later in life. Susceptibility to pre-eclampsia is hereditary: family history of this disease on the mother’s or father’s side increases its risk.
Researchers at the University of Helsinki have studied the effects of mothers’ genetic variations on developing pre-eclampsia. The study was based on the Finnish FINNPEC (Finnish Genetics of Pre-eclampsia Consortium) and FINRISK cohorts and compared samples from more than 600 pre-eclampsia patients and 2,000 non-pre-eclamptic controls.
“We chose candidate genes that were interesting in terms of pre-eclampsia, and studied the variation found in them among patients and controls,” says Inkeri Lokki, who is completing her doctoral dissertation on the subject. “The sFlt-1 protein is known to be linked to pre-eclampsia, and we found two single nucleotide polymorphisms in the gene that codes this protein. Pre-eclampsia is less common among mothers who carry these mutations than it is among other mothers.”
Too high an amount of sFlt-1 protein in the body causes vascular disorders. It is known that the amount of the sFlt-1 protein in the blood of the women who developed pre-eclampsia had increased before they fell ill.
The study also examined Finnish mothers’ health over the longer term, based on the FINRISK material.
“It seems that the women who carry gene variants that protect them from pre-eclampsia were also less likely to develop cardiac failure later in life than other women,” says Lokki.

University of Helsinki
www.helsinki.fi/en/news/rare-gene-variant-discovered-to-contribute-to-lower-risk-of-pre-eclampsia-in-finnish-mothers

A new portable device can quickly find markers of deadly, unpredictable sepsis infection from a single drop of blood.
A team of researchers from the University of Illinois and Carle Foundation Hospital in Urbana, Illinois, completed a clinical study of the device, which is the first to provide rapid, point-of-care measurement of the immune system’s response, without any need to process the blood.
This can help doctors identify sepsis at its onset, monitor infected patients and could even point to a prognosis, said research team leader Rashid Bashir, a professor of bioengineering at the U. of I. and the interim vice dean of the Carle Illinois College of Medicine.
Sepsis is triggered by an infection in the body. The body’s immune system releases chemicals that fight the infection, but also cause widespread inflammation that can rapidly lead to organ failure and death.
Sepsis strikes roughly 20 percent of patients admitted to hospital intensive care units, yet it is difficult to predict the inflammatory response in time to prevent organ failure, said Dr. Karen White, an intensive care physician at Carle Foundation Hospital. White led the clinical side of the study.
“Sepsis is one of the most serious, life-threatening problems in the ICU. It can become deadly quickly, so a bedside test that can monitor patient’s inflammatory status in real time would help us treat it sooner with better accuracy,” White said.
Sepsis is routinely detected by monitoring patients’ vital signs – blood pressure, oxygen levels, temperature and others. If a patient shows signs of being septic, the doctors try to identify the source of the infection with blood cultures and other tests that can take days – time the patient may not have.
The new device takes a different approach.
“We are looking at the immune response, rather than focusing on identifying the source of the infection,” Bashir said. “One person’s immune system might respond differently from somebody else’s to the same infection. In some cases, the immune system will respond before the infection is detectable. This test can complement bacterial detection and identification. We think we need both approaches: detect the pathogen, but also monitor the immune response.”
The small, lab-on-a-chip device counts white blood cells in total as well as specific white blood cells called neutrophils, and measures a protein marker called CD64 on the surface of neutrophils. The levels of CD64 surge as the patient’s immune response increases.
The researchers tested the device with blood samples from Carle patients in the ICU and emergency room. When a physician suspected infection and ordered a blood test, a small drop of the blood drawn was given to the researchers, stripped of identifying information to preserve patient confidentiality. The team was able to monitor CD64 levels over time, correlating them with the patient’s vital signs. Researchers found that the results from the rapid test correlated well with the results from the traditional tests and with the patients’ vital signs.
“By measuring the CD64 and the white cell counts, we were able to correlate the diagnosis and progress of the patient – whether they were improving or not,” said Umer Hassan, a postdoctoral researcher at Illinois and the first author of the study. “We hope that this technology will be able to not only diagnose the patient but also provide a prognosis. We have more work to do on that.”
Bashir’s team is working to incorporate measurements for other inflammation markers into the rapid-testing device to give a more complete picture of the body’s response, and to enable earlier detection.

University of Illinois
news.illinois.edu/blog/view/6367/526347

A new study conducted by an international team of lung cancer researchers, including Professor John Field from the University of Liverpool, have identified new genetic variants for lung cancer risk.
Lung cancer continues to be the leading cause of cancer mortality worldwide. Although tobacco smoking is the main risk factor, variations in a persons genetic makeup has been estimated to be responsible for approximately 12% of cases. However, the exact details of these variations have been previously unknown.
By gathering genotype data from different studies around the world, through the use of a special research platform called OncoArray, researchers were able to increase the sample size for this study making it the largest one of its type in the world. The Liverpool Lung Project, funded by the Roy Castle Foundation, has made a major contribution to this international project.
Researchers examined the data to identify the genetic variants associated with lung cancer risk.
During the study more than 29,200 lung cancer cases and more than 56,000 samples taken from people without lung cancer (controls) were examined. Researchers identified 18 genetic variations that could make people more susceptible to lung cancer and also 10 new gene variations.
Professor John Field, Clinical Professor of Molecular Oncology and the Chief Investigator of the UK Lung Cancer Screening Trial, said: "This study has identified several new variants for lung cancer risk that will translate into improved understanding of the mechanisms involved in lung cancer risk.
"Samples taken from the major Liverpool Lung Project, funded by the Roy Castle Foundation, was conducted by experts at the University of Liverpool, were used in this study.
"These results will help us to further improve the way we can screen for lung cancer in high risk individuals in the UK. Further studies will help in the targeting of specific genes to influencing lung cancer risk, smoking behaviour and smoking effects on brain biology."
"This study definitely leads to new ideas about mechanisms influencing lung cancer risk."

EurekAlert
www.eurekalert.org/pub_releases/2017-07/uol-lgs071017.php
 

Researchers at the University of Birmingham have identified inflammatory biomarkers which indicate whether the brain has suffered injury.
The team, led by Professor Antonio Belli, at the University’s College of Medical and Dental Sciences, now hopes to use these new biomarkers to develop a test which can be used on the side of a sports pitch or by paramedics to detect brain injury at the scene of an incident.
Dr Lisa Hill, of the Institute of Inflammation and Ageing at the University of Birmingham, said: “Traumatic brain injury (TBI) is the leading cause of death and disability among young adults and, according to the World Health Organization, by 2020 TBI will become the world’s leading cause of neurological disability across all age groups.
“Early and correct diagnosis of traumatic brain injury is one of the most challenging aspects facing clinicians.
“Being able to detect compounds in the blood which help to determine how severe a brain injury is would be of great benefit to patients and aid in their treatment.
“Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries that impair function, damage other brain structures and promote further cell death.
“Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions.”
Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins.
In this novel study blood samples were taken from 30 injured patients within the first hour of injury prior to the patient arriving at hospital.
Subsequent blood samples were taken at intervals of four hours, 12 hours and 72 hours after injury. These blood samples were then screened for inflammatory biomarkers which correlated with the severity of the injury using protein detection methods.
In the laboratory, the team used a panel of 92 inflammation-associated human proteins when analysing the blood samples, which were screened simultaneously.
The serum biomarkers were analysed from patients with mild TBI with extracranial injury, severe TBI with extracranial injury and extracranial injury only and all groups were compared to a control group of healthy volunteer patients.
The results identified three inflammatory biomarkers, known as CST5, AXIN1 and TRAIL, as novel early biomarkers of TBI.
CST5 identified patients with severe TBI from all other cohorts and, importantly, was able to do so within the first hour of injury.
AXIN1 and TRAIL were able to discriminate between TBI and uninjured patient controls in under an hour.
Dr Valentina Di Pietro, also of the Institute of Inflammation and Ageing at the University of Birmingham, said: “Early and objective pre-hospital detection of TBI would support clinical decision making and the correct triage of major trauma.
“Moreover, the correct diagnosis of TBI, which is one of hardest diagnosis to make in medicine, would allow clinicians to implement strategies to reduce secondary brain injury at early stage, for example, by optimising blood and oxygen delivery to the brain and avoiding manoeuvres that could potentially increase intracranial pressure.
“In addition, this has potential implications for drug development, as novel compounds could be given immediately after injury and potentially commenced at the roadside, if there was sufficient confidence in the diagnosis of TBI.
“We conclude that CST5, AXIN1 and TRAIL are worthy of further study in the context of a pre-hospital or pitch-side test to detect brain injury.”

University of Birmingham
www.birmingham.ac.uk/news/latest/2017/07/researchers-identify-inflammatory-biomarkers-indicating-brain-injury.aspx

An international team of researchers has identified genomic mutations for Carey-Fineman-Ziter (CFZS) syndrome, a very rare congenital myopathy (inherited muscle disorder) characterized by facial weakness, a small or retracted chin, a cleft palate and curvature of the spine (scoliosis), among other symptoms. The researchers determined that CFZS is caused by mutations in the gene MYMK that encodes for the protein myomaker. This protein is necessary for the fusion of muscle cells (myoblasts) into muscle fibres (myotubes) during the development of an embryo and the regeneration of muscle cells after injury.
"Advances in genomics technology and the power of team science have enabled us to identify the cause of this very rare disease 35 years after it was first described by Dr. John Carey and colleagues from the University of Utah," said National Institutes of Health Director Francis S. Collins, M.D., Ph.D., a co-author of the study.
"This discovery will improve physicians’ ability to diagnose this disease and offer families accurate genetic counselling and treatment," said Irini Manoli, M.D., Ph.D., co-lead author and a physician scientist and staff clinician in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI), part of NIH. People affected with CFZS have sometimes been misdiagnosed with Moebius syndrome, another very rare disorder characterized by facial paralysis.
Dr. Manoli said that uncovering that cell-cell fusion deficits can lead to congenital myopathies (inherited muscle disease) opens a new path of exploration for therapies for CFZS and other muscular diseases and tools for regenerating muscle. "In addition," she said, "this rare genetic syndrome provides novel insights into the effects of muscle development on craniofacial and skeletal bone formation."
The goal of the study was to learn more about the genetics and clinical characteristics of Moebius syndrome and other congenital facial weakness disorders. Toward this end, the consortium brought 63 people to the NIH Clinical Center affected with Moebius syndrome and other inherited facial weakness disorders, and their families for detailed multi-system evaluations, including brain and muscle imaging studies and muscle biopsies. The researchers collaborated through the Opportunities for Collaborative Research at the NIH Clinical Center, a new funding mechanism that encourages intramural and extramural researchers to work together at the NIH Clinical Center.
Researchers performed detailed phenotyping (identifying physical traits that are the result of a DNA sequence). They also employed the most up-to-date genomic tools, including exome sequencing of blood DNA in affected siblings from three unrelated families, as well as a muscle biopsy in one of the affected individuals. To identify the genomic mutations associated with CFZS, three laboratories – led separately by Elizabeth Engle, M.D., at the Boston Children’s Hospital, Stephen Robertson, M.D., from the University of Otago and John Carey, M.D., at the University of Utah – analysed exome sequence data from each of the three families. Among the genes harbouring mutations identified in each family, only the gene MYMK was common to all three. A knockout mouse model (genomically altered mice that are bred to lack a specific gene) displayed a complete lack of muscle development, leading to early death of the newborn mice, making this gene a promising candidate for further studies.
Using CRISPR-Cas9 technology, a tool for editing DNA at precise locations, a team led by Silvio Alessandro Di Gioia, Ph.D., and Dr. Engle, generated zebrafish with a mutated mymk gene. Affected mutant zebrafish were smaller and had abnormal muscle development and jaw deformities, resembling the patient phenotype. The researchers then performed further functional studies to validate the severity of each of the genomic mutations.
The researchers were able to correct affected zebrafish’s muscles by injecting the normal human MYMK gene product into the mutant fish. This success lends hope for restoring MYMK function in muscles as a treatment for CFZS and for reducing any potentially progressive features of this disorder.
Only eight people in the world have been diagnosed with CFZS with MYMK mutations, in part, because it hasn’t been readily recognized. Now that researchers have identified the genomic cause underlying the syndrome, it can be added to the diagnostic gene panels for congenital myopathies. This will improve the speed and accuracy of diagnosis and add to the understanding of the spectrum of disease severity and outcome, Dr. Manoli said.

The National Human Genome Research Institute (NHGRI)
www.genome.gov/27568961/2017-news-release-nih-and-collaborators-identify-the-genomic-cause-for-careyfinemanziter-syndrome/