Lower levels of defective viral RNA molecules can make influenza viruses that affect humans more dangerous. This finding could help to guide patient treatment and provide important information for the design of influenza prevention strategies.
Flu viruses have defective genetic material that can activate the infected patient’s immune system, and lower levels of these molecules can increase the severity of the virus infection. This is the main conclusion reached by researchers from the Centre for Biomedical Research in Respiratory Diseases Network (CIBERES) and in the laboratory of Dr. Amelia Nieto at the Centro Nacional de Biotecnología of the CSIC (CNB-CSIC), in a study led by Dr. Ana Falcón that has just been published in the journal PLOS Pathogens.
Influenza is particularly dangerous for babies, the elderly, and people with underlying medical conditions, although healthy people can also suffer a serious infection. Of the many flu virus strains that circulate every year, some are more virulent than others. "So far we have found severity markers for specific strains, but not a more general marker like this, which applies to many strains and would be more useful in clinical decision-making and in the design of prevention strategies," explains Falcón.
To identify this marker, scientists from CIBERES and the CNB-CSIC, in collaboration with other health and research institutions, centred on defective viral genomes (DVG). These molecules, which consist of viral RNA fragments with defective genetic information, are found in many influenza virus strains.
Previous studies suggested that DVG activate the immune system in infected animals, and could restrict the severity of influenza infection; in this study, the scientists tested whether these molecules could serve as a general marker of influenza severity.
The validity of the marker was tested in infected mice and in cell cultures of human respiratory tissue with different strains of influenza A H1N1 virus, the subtype responsible for the 2009 influenza pandemic. The results showed that strains with lower DVG accumulation in cell cultures produced a more serious infection in mice.
The team also analysed the genomes of viruses isolated from samples from people who had a severe infection or died from the flu during the 2009 "swine flu" pandemic, or in later flu outbreaks with similar characteristics. They found that H1N1 strains that caused severe symptoms had significantly less DVG accumulation than influenza A strains from people who had only mild symptoms.
Overall, these results suggest that low DVG levels indicate an increased risk of serious illness in patients infected with the influenza A virus. With more research, these findings could help predict flu severity, guide patient treatment, and prompt new flu prevention strategies.

Centro Nacional de Biotecnología of the CSIC (CNB-CSIC)
www.cnb.csic.es/index.php/en/science-society/news/item/1450-identifican-un-marcador-viral-que-permitiria-predecir-la-gravedad-de-la-gripe-en-pacientes-infectados

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 have developed a more precise way of diagnosing suicide risk, by developing blood tests that work in everybody, as well as more personalized blood tests for different subtypes of suicidality that they have newly identified, and for different psychiatric high-risk groups.
The research team, led by scientists at Indiana University School of Medicine, also showed how two apps, one based on a suicide risk checklist and the other on a scale for measuring feelings of anxiety and depression, work along with the blood tests to enhance the precision of tests and to suggest lifestyle, psychotherapeutic and other interventions. Lastly, they identified a series of medications and natural substances that could be developed for preventing suicide.
"Our work provides a basis for precision medicine and scientific wellness preventive approaches," said Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience at IU School of Medicine and attending psychiatrist and research and development investigator at the Richard L. Roudebush Veterans Affairs Medical Center.
The research builds on earlier studies from the Niculescu group.
"Suicide strikes people in all walks of life. We believe such tragedies can be averted. This landmark larger study breaks new ground, as well as reproduces in larger numbers of individuals some of our earlier findings,” said Dr. Niculescu.
There were multiple steps to the research, starting with serial blood tests taken from 66 people who had been diagnosed with psychiatric disorders, followed over time, and who had at least one instance in which they reported a significant change in their level of suicidal thinking from one testing visit to the next. The candidate gene expression biomarkers that best tracked suicidality in each individual and across individuals were then prioritized using the Niculescu group’s Convergent Functional Genomics approach, based on all the prior evidence in the field.
Next, working with the Marion County (Indianapolis, Ind.) Coroner’s Office, the researchers tested the validity of the biomarkers using blood samples drawn from 45 people who had committed suicide.
The biomarkers were then tested in another larger, completely independent group of individuals to determine how well they could predict which of them would report intense suicidal thoughts or would be hospitalized for suicide attempts.
The biomarkers identified by the research are RNA molecules whose levels in the blood changed in concert with changes in the levels of suicidal thoughts experienced by the patients. Among the findings reported in the current paper were:

• An algorithm that combines biomarkers with the apps that was 90 percent accurate in predicting high levels of suicidal thinking and 77 percent accurate in predicting future suicide-related hospitalizations in everybody, irrespective of gender and diagnosis.
• A refined set of biomarkers that apply universally in predicting risk of suicide among both male and female patients with a variety of psychiatric illnesses, including new biomarkers never before linked to suicidal thoughts and behavior.
• Four new subtypes of suicidality were identified (depressed, anxious, combined, and non-affective/psychotic), with different biomarkers being more effective in each subtype.
• Biomarkers that were associated with specific diagnoses and genders, such as one, known as LHFP, that appears to be a very strong predictor for depressed men.
• Two of the biomarkers, APOE and IL6, have broad evidence for involvement in suicidality and potential clinical utility as targets for drug therapies, as well as suggest a neurodegenerative and inflammatory component to the predisposition to suicide. APOE is responsible for proteins involved with managing cholesterol and fats, and some forms of the gene have been strongly implicated as risks for Alzheimer’s disease. IL6 expresses proteins involved in the body’s inflammation response.

Indiana University School of Medicine
news.medicine.iu.edu/releases/2017/08/precision-medicine-opens-door-scientific-wellness-preventive-approaches-suicide.shtml

Vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.
Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.
“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of Perlmutter Cancer Center.
Changes in the genetic code, or mutations, that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of preleukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.
Along with these diseases, new tests suggest that about 2.5 percent of all United States cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumours, say the authors.
The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context. These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.
The back-and-forth attachment and removal of methyl groups also fine tunes gene expression in stem cells, which can mature, specialize, and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection.
The enzyme studied in this report TET2, enables a change in the molecular structure, or oxidation, of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a countdown toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Dr. Neel.
To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.
Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.
Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.
NYU Langone Healthhttp://tinyurl.com/y8pvrxso

A new diagnostic developed by Alberta scientists will allow men to bypass painful biopsies to test for aggressive prostate cancer. The test incorporates a unique nanotechnology platform to make the diagnostic using only a single drop of blood, and is significantly more accurate than current screening methods.
The Extracellular Vesicle Fingerprint Predictive Score (EV-FPS) test uses machine learning to combine information from millions of cancer cell nanoparticles in the blood to recognize the unique fingerprint of aggressive prostate cancer. The diagnostic, developed by members of the Alberta Prostate Cancer Research Initiative (APCaRI), was evaluated in a group of 377 Albertan men who were referred to their urologist with suspected prostate cancer. It was found that EV-FPS correctly identified men with aggressive prostate cancer 40 percent more accurately than the most common test—Prostate-Specific Antigen (PSA) blood test—in wide use today.
"Higher sensitivity means that our test will miss fewer aggressive cancers," said John Lewis, the Alberta Cancer Foundation’s Frank and Carla Sojonky Chair of Prostate Cancer Research at the University of Alberta. "For this kind of test you want the sensitivity to be as high as possible because you don’t want to miss a single cancer that should be treated."
According to the team, current tests such as the PSA and digital rectal exam (DRE) often lead to unneeded biopsies. Lewis says more than 50 per cent of men who undergo biopsy do not have prostate cancer, yet suffer the pain and side effects of the procedure such as infection or sepsis. Less than 20 per cent of men who receive a prostate biopsy are diagnosed with the aggressive form of prostate cancer that could most benefit from treatment.
It’s estimated that successful implementation of the EV-FPS test could eventually eliminate up to 600-thousand unnecessary biopsies, 24-thousand hospitalizations and up to 50 per cent of unnecessary treatments for prostate cancer each year in North America alone. Beyond cost savings to the health care system, the researchers say the diagnostic test will have a dramatic impact on the health care experience and quality of life for men and their families.

Medicalexpress
medicalxpress.com/news/2017-06-blood-nanotechnology-aggressive-prostate-cancer.html