Body

Polluted air is a public health hazard that cannot be evaded. It is widely known that long-term exposure to air pollution enhances the risks of cardiovascular and respiratory diseases. Scientists from the Max Planck Institute for Chemistry and the University Medical Center Mainz now calculated in a new study that the global, public loss of life expectancy caused by air pollution is higher than many other risk factors such as smoking, infectious diseases or violence.

Air pollution caused 8.8 million premature deaths worldwide in 2015. This corresponds to an average reduction in life expectancy per capita of 2.9 years. In comparison, tobacco smoking reduces the life expectancy by an average of 2.2 years (7.2 million deaths), HIV / AIDS by 0.7 years (1 million deaths), parasitic and vector-borne diseases such as malaria - by 0.6 years (600,000 deaths). "Air pollution exceeds malaria as a cause of premature death by a factor of 19; it exceeds violence by a factor of 17 and HIV / AIDS by a factor of 9. Given the huge impact on public health and the global population, one could say that our results indicate an air pollution pandemic", said Jos Lelieveld, director at Max Planck Institute for Chemistry and first author of the study.

This study is the first to examine the global impact of air pollution on human health compared to other risk factors worldwide. "Our comparison of different global risk factors shows that ambient air pollution is a leading cause of premature mortality and loss of life expectancy, in particular through cardiovascular diseases", says Thomas Münzel, director of the Cardiology Center at the University Medical Center in Mainz and co-author of the paper.

Relationship between pollution and disease

The scientists examined the connection between exposure to pollutants and the occurrence of diseases. In order to calculate the worldwide exposure to pollutants, which primarily include fine particles and ozone, the researchers used an atmospheric chemical mode. They then combined the exposure data with the Global Exposure - Mortality Model that derives from many epidemiological cohort studies. Using these tools and data, scientists investigated the effects of different pollution sources, distinguishing between natural (wildfires, aeolian dust) and anthropogenic emissions, including fossil fuel use. Based on their results they could estimate the disease-specific excess mortality and loss of life expectancy in all countries world-wide.

The study results show that the mortality caused by ambient air pollution is highest in East Asia (35 percent) and South Asia (32 percent), followed by Africa (11 percent), Europe (9 percent) and North- and South America (6 percent). Lowest mortality rates are found in Australia (1,5 percent) associated with the strictest air quality standards of all countries. "We understand more and more that fine particles primarily favor vascular damage and thus diseases such as heart attack, stroke, cardiac arrhythmia and heart failure. It is of outmost importance that air pollution is adopted as a cardiovascular risk factor and that it is distinctly mentioned in the ESC/AHA guidelines of prevention, acute and coronary syndromes and heart failure", continued Münzel.

Avoidable deaths

According to the findings of the study, almost two thirds of the deaths caused by air pollution, namely around 5.5 million a year are avoidable, and the majority of polluted air comes from the use of fossil fuels. The researchers estimate that the average life expectancy world-wide would increase by more than a year if the emissions from the use of fossil fuels were eliminated.

The team from the University Medical Center Mainz and Max Planck Institute for Chemistry published a similar paper last year focusing on the consequences of air pollution in Europe. According to the earlier study, nearly 800,000 Europeans die prematurely every year due to illnesses caused by air pollution. Polluted air shortens the lifespan of Europeans by more than two years.

DALLAS - March 5, 2020 - The bacteria that cause the deadly lung disease tuberculosis appear to facilitate their own spread by producing a molecule that triggers cough, a new study led by UTSW researchers shows. The findings, published online March 5, 2020, in Cell, could lead to new ways to prevent the spread of tuberculosis, which is responsible for the death of more than 1.5 million people per year worldwide.

People have known since ancient times that coughing is a primary symptom of tuberculosis and that cough allows for the spread of disease from person to person. However, the cause of tuberculosis-related coughs has been unclear says study leader Michael Shiloh, M.D., Ph.D., an associate professor in UTSW's Department of Internal Medicine's Division of Infectious Disease and Department of Microbiology. The prevailing hypothesis has been that coughing is triggered by infection-induced lung irritation and inflammation, but this has never been definitively proved.

Shiloh and his colleagues had a different idea: They speculated that the bacterial agent that causes tuberculosis, mycobacterium tuberculosis, itself might produce a substance that triggers nerves in the airway responsible for causing someone with the disease to cough, thereby allowing for propagation of disease.

To test this idea, the team relied on guinea pigs, a lab animal often used to study both tuberculosis and cough. Although guinea pigs have been used as an experimental model for tuberculosis infection for more than a century, it was not clear whether the disease causes these animals to cough. To answer this question, Shiloh and his colleagues placed guinea pigs infected with tuberculosis into special chambers that registered pressure and volume changes caused by coughing. Sure enough, tuberculosis-infected animals coughed significantly more than those that were tuberculosis-free.

To determine whether the bacteria produce a substance that can trigger coughing, the researchers isolated and tested various components from mycobacterium tuberculosis, trying to determine if these components could do two things. First, could the components on their own make guinea pigs cough? And second, could the components make pain-sensing nerve cells grown in the lab - the type of cell responsible for stimulating coughing in the lungs - behave as if they were being triggered to induce a cough reflex?

After a series of experiments with components from mycobacterium tuberculosis as well as from a large assortment of other mycobacterial species, Shiloh's team ultimately identified the mycobacterial cell-surface fatty molecule known as sulfolipid-1 (SL-1) as the principal molecule that activates neurons grown in the lab. This response also occurred in human pain-sensing nerve cells, suggesting that SL-1 and its function has been conserved through evolution among different mammalian species. Importantly, when guinea pigs were exposed to purified SL-1, the animals indeed coughed.

To show that SL-1 is the culprit behind cough, the researchers infected guinea pigs with a genetically altered strain of mycobacterium tuberculosis that cannot produce SL-1. These guinea pigs developed all the typical symptoms of tuberculosis, but did not cough, which led the research team to conclude that SL-1 is critical for triggering cough during tuberculosis infection.

Together, Shiloh says, the findings suggest that tuberculosis-causing bacteria produce SL-1 primarily to stimulate a cough reflex in order to propagate the spread of mycobacteria from infected to uninfected people. Eventually, he says, if research shows that suppressing cough is not harmful to infected individuals, scientists may be able to develop a way to prevent transmission by either counteracting SL-1 or preventing its production.

"In many places where tuberculosis is endemic, people with active tuberculosis are frequently not admitted to the hospital, but simply sent home with antibiotics. People can cough for months and spread disease even when they are receiving appropriate treatment," he says. "Someday, doctors may give antibiotics in conjunction with a medication that prevents coughing, which in turn could prevent spread."

Conversely, he adds, this molecule could be harnessed to help patients cough in conditions where it's beneficial, such as cystic fibrosis or for patients who require breathing tubes. Administering an aid that encourages coughing could help relieve the buildup of thick mucus in patients' lungs.

BOSTON - (March 5, 2020) -Diabetic retinopathy can be diagnosed and graded with the use of a newer scanning technology called ultra-wide field (UWF) imaging, a system that generates high-quality pictures showing most of the retina. Research from the Joslin Diabetes Center's Beetham Eye Institute has now shown that one technique, UFW fluorescein angiography, detects over three times more microaneurysms than UWF color imaging, suggesting that the two modalities should not be used interchangeably when evaluating and treating this vision-threatening condition. The research is published this month in the British Journal of Ophthalmology.

"Existing research often uses fluorescein angiography and color imaging as two interchangeable sides of the same coin when assessing microaneurysms. However, our research shows that these modalities aren't the same and we have to be cautious before using them in that way," says lead study author Mohamed Elmasry, M.D., Chief Retina Fellow at Joslin Diabetes Center.

With UWF imaging, clinicians are able to see over 80 percent of the retina in a single picture. UWF color imaging is used more frequently in the U.S. than UWF fluorescein angiography because the technology is non-invasive.

"We know that the amount and location of microaneurysms is key in determining the risk of diabetic retinopathy progression", says Lloyd Paul Aiello, M.D., Ph.D., Director of the Beetham Eye Institute, Professor of Ophthalmology at Harvard Medical School and senior author on the paper.

"With the growth of artificial intelligence, we need to know if we can automate the way we count these tiny blood vessel changes in order to grade retinopathy better, faster and more precisely predict its progression."

The study involved 193 patients with diabetic retinopathy--from mild disease to the most advanced stages of the disease. All patients had UWF color imaging and UWF fluorescein angiography done on the same day.

In total, 288 eyes were included in the analysis. Researchers manually counted microaneurysms on both color images and fluorescein angiography and then directly compared the results. Additionally, they compared the number of microaneurysms they identified at each level of disease severity and compared those results.

The study showed that, overall, fluorescein angiography detected 3.5-fold more microaneurysms than color imaging. This held true even after researchers adjusted for the patient's diabetes duration, average blood sugar levels and gender.

In addition, fluorescein angiography identified up to 3.5-fold more retinal areas with more than 20 microaneurysms (severe retinopathy) than color imaging.

However, when applying a correction factor of four to the fluorescein angiography results for each grade of disease severity, the interpretation of the two techniques became more comparable.

"This study should help inform artificial intelligence and other imaging studies looking to automate the grading process using ultra-wide field color imaging or fluorescein angiogram, and make them more precise and more comparable," says Dr. Aiello.

Diabetic retinopathy is a leading cause of blindness worldwide.

"The core message for the public is that if you have diabetes, it is essential that you be receiving regular ongoing eye examinations. In certain situations, a fluorescein angiogram is a very important test, and in others, color imaging is essential for grading or diagnosing diabetic retinopathy," says Dr. Elmasry. "It's also important for physicians to understand how, when and what test to order, and how each modality can affect patient care."

By performing a few simple physical exercises daily, and receiving information about their disease regularly, 500 osteoarthritis patients were able to on average halve their pain in 6 months - and improve their physical function. The participants in the study from Lund University in Sweden used a newly developed mobile app to help them keep track.

"We expected patients to see an improvement, but these results exceeded our expectations. This demonstrates that using digital tools when treating chronic illnesses such as osteoarthritis can work very well", says researcher and physiotherapist Håkan Nero at Lund University.

The study is published in the scientific journal PLOS ONE, and is somewhat unique in that the researchers followed the patients over a longer time period, in some cases for up to a year.

"As far as we are aware, no study has previously followed osteoarthritis patients who engaged consistently in self-treatment, and reported their results for up to a year. There are similar studies from the US, but they involved patients with type 2 diabetes", explains Håkan Nero.

The study included 500 patients from all over Sweden with osteoarthritis of the hip or the knee, with a majority of slightly overweight women around the age of 60 (an average BMI of 28 for those with knee osteoarthritis and 27 for those with hip osteoarthritis). At the beginning of the study, they filled out a health form, something they then had to repeat every three months. They received new exercises and lessons on osteoarthritis daily for the entire period.

"The exercises were designed to strengthen the muscles in the affected area. It was no more than two to three exercises daily, and took only five to ten minutes", says Håkan Nero.

Each week, the patients reported their pain levels in the app, and tested their physical ability every two weeks.

"After 6 months, the group averaged almost half the amount of pain, and their physical mobility had improved by an average of 43 percent. The results were equally good for those who continued the program for up to a year. Normally, hip osteoarthritis is more difficult to treat, but in our study we saw no difference between knee and hip, and the same applied to gender and age", says Håkan Nero.

Osteoarthritis is a common disease that causes joint pain. It can affect anyone, but the prevalence increases with age. In Sweden, one in four people over 45 is estimated to have osteoarthritis. Physical therapy, information and daily physical activity is recommended to relieve the symptoms.

"Some patients with osteoarthritis may prefer conventional therapy at a clinic, but the results of the study show that it is possible to use digital technology as well. A mobile app is easily accessible regardless of where you are in the world", concludes Håkan Nero.

Monitoring of both, lactate and bio-ADM®, in sepsis patients allows early identification of patients that require immediate intervention at admission to the ICU.

Sphingotec is set to launch a point-of-care bio-ADM® assay running on its proprietary automated Nexus IB10 instrument in mid-2020.

Hennigsdorf/Berlin, Germany, March 5, 2020 - Diagnostics company SphingoTec GmbH ("sphingotec", Hennigsdorf Germany) today reported on new data on the utility of endothelial function biomarker bioactive Adrenomedullin (bio-ADM®). The data show that bio-ADM® allows identification of sepsis patients who are at high risk of fatal outcomes despite low or decreasing levels of the routinely monitored parameter lactate. Lactate, a parameter that identifies reduced blood oxygenation of tissue, is routinely used as a reference in the diagnosis of septic shock. However, lactate is rather unspecific to sepsis and insensitive. This limitation can be overcome by monitoring, in addition to lactate, the blood levels of bio-ADM®, a biomarker that can reliably detect blood vessel leakage, one of the main causes of septic shock.

According to recent findings published in Critical Care1, data from over 500 sepsis patients enrolled in the AdrenOSS-1 study demonstrate the added value of bio-ADM® to lactate monitoring. The AdrenOSS-1 study investigators could show that even though normalizing lactate levels indicate a significantly decreased risk of mortality, an additional measurement of bio-ADM® blood levels can help identify those patients that are still at risk of fatal outcomes despite their lower lactate levels. Among septic patients with decreasing lactate, high bio-ADM® levels identified patients who had a 4-time higher mortality risk than patients with low bio-ADM levels. According to the authors of the study, measurement of bio-ADM® on top of lactate may help refine risk stratification and thus guide resuscitation during sepsis.

Lactate has been used for more than 30 years to monitor organ hypoperfusion in sepsis patients. However, lactate blood levels are influenced by many other physiological and pathological processes. Clinical data from more than 22,000 patients demonstrate that high bio-ADM® levels independently from inflammation and co-morbidities indicate distortions in the barrier function of the inner cell sheet of blood vessels, the endothelium. Loss of this barrier function is considered a key driver in the development of hypotension and eventually septic shock with loss of organ perfusion in sepsis patients2. According to sphingotec's research, bio-ADM® can explain about 60% of the fatal outcomes in sepsis.

"Our biomarker bio-ADM® can reliably support acute care physicians in identifying high-risk sepsis patients" said Dr. Andreas Bergmann, founder and CEO of sphingotec. "We are set to launch the fully automated CE-IVD-marked point-of-care bio-ADM® assay on our widely established Nexus IB10 immunoassay instrument by mid-2020. We are convinced that this rapid test for bio-ADM® will support earlier treatment decisions and thereby will assist clinical decisions that may improve the outcomes of patients at ICUs and emergency departments."

Social isolation could be associated with increased inflammation in the body new research from the University of Surrey and Brunel University London has found.

In the largest study of its kind researchers investigated the link between social isolation and loneliness with inflammation in the body. Analysing 30 previous studies in this area researchers found that social isolation could be linked to increased inflammation in the body.

Inflammation is the body's way of signalling the immune system to heal and repair damaged tissue, as well as defending itself against viruses and bacteria. Inflammation can eventually start damaging healthy cells, tissues and organs and lead to an increased risk of developing non-communicable diseases such as cardiovascular disease.

Researchers found that social isolation, the objective state of being isolated from other people, was associated with the presence of C-reactive protein, a protein substance released into the bloodstream within hours of a tissue injury, and increased levels of the glycoprotein fibrinogen, which is converted into fibrin-based blood clots.

Interestingly, researchers also identified that the link between social isolation and physical inflammation was more likely to be observed in males than females. Further work is needed to clarify why this might be, but previous work suggests that males and females might respond differently to social stressors.

The link between loneliness and inflammation was less clear-cut with results indicating a possible link between loneliness and the pro inflammatory cytokine IL-6. However, this finding was not consistent across the studies examined. Taken in combination with previous knowledge the researchers propose that it is likely that loneliness changes how the inflammatory system responds to stress rather than directly impacting inflammatory response.

Dr Kimberley Smith, Lecturer in Health Psychology at the University of Surrey, said: "Loneliness and social isolation have been shown to increase our risk of poorer health. Many researchers propose that part of the reason for this is because they influence the body's inflammatory response.

"The evidence we examined suggests that social isolation may be linked with inflammation, but the results for a direct link between loneliness and inflammation were less convincing. We believe these results are an important first step in helping us to better understand how loneliness and social isolation may be linked with health outcomes."

Christina Victor, Professor of Gerontology and Public Health at Brunel, added: "Our results suggest loneliness and social isolation are linked with different inflammatory markers. This shows how important it is to distinguish between loneliness and isolation, and that these terms should neither be used interchangeably nor grouped together."

Philadelphia, March 5, 2020--Researchers at Children's Hospital of Philadelphia (CHOP) have found that children with a rare food allergy known as food protein-induced enterocolitis syndrome, or FPIES, have a significantly higher chance of being diagnosed with other allergic conditions, including eczema, traditional food allergy and asthma. But the researchers also found that FPIES did not directly cause those other allergies.

The study was published in the March issue of The Journal of Allergy and Clinical Immunology: In Practice.

"This work refines our view of the natural history of FPIES and expands our understanding of the relationship between this condition and other allergic diseases," said first author Melanie Ruffner, M.D., Ph.D., attending physician in the Division of Allergy and Immunology and the Center for Pediatric Eosinophilic Disorders at CHOP. "It's important for clinicians to keep in mind that patients with FPIES have a higher frequency of allergic manifestations and therefore provide appropriate screening and care as needed."

FPIES causes repetitive vomiting, diarrhea, and lethargy several hours after eating a trigger food, frequently cow's milk, soy, and grains. The condition typically develops during infancy, though it can occasionally occur in older children and adults.

Although previous research has collectively shown patients with FPIES have increased rates of eczema, other food allergies and asthma - so-called atopic allergies - researchers have not investigated the association between FPIES and other allergies to look for a potential causal link.

To do so, Ruffner and her collaborators looked at a cohort of more than 150,000 pediatric patients, of which 214 had FPIES. The investigators compared the rate of atopic allergies in FPIES patients to those without FPIES. They also followed the patients over time to see if there were differences in the timing of when FPIES patients developed atopic allergies compared to other patients.

The authors found that those with FPIES had substantially higher allergy rates than patients without the condition. FPIES patients were diagnosed with traditional food allergy at about six times the rate of those without FPIES and with atopic dermatitis at about twice the rate. There was a slightly smaller increase in the rate of asthma diagnoses, but those with FPIES were still diagnosed at a higher rate than those without the disease.

However, when the research team looked at the timing of the development of allergies, and whether a diagnosis of FPIES would lead to atopic allergies later in life, they did not find a causal link between the two. Thus, unlike the so-called atopic march - the progression of atopic disorders from eczema in infants to hay fever, food allergy and asthma in older children - FPIES does not cause other allergic disorders but instead is associated with them.

"Although there is an increased rate of atopic allergies in patients with FPIES, our analyses demonstrate that a prior diagnosis of FPIES does not increase the rate of atopic allergies later in life," said corresponding author David Hill, M.D., Ph.D., attending physician in CHOP's Division of Allergy and Immunology. "This pattern of association supports a yet-unknown cause, such as a shared predisposition to both types of allergy."

Philadelphia, March 5, 2020--Researchers at Children's Hospital of Philadelphia (CHOP) have developed a novel treatment for sepsis - one of the leading causes of hospital death - that enhances the body's bacteria-capturing neutrophil extracellular traps (NETs) so that they more effectively capture infectious bacteria, resist degradation, and improve sepsis outcomes and survival.

The approach is described in the March 2020 issue of Blood and was also presented as an abstract at the 61st American Society of Hematology annual meeting, where it was one of the highest scoring abstracts considered from a group of more than 4,500 submissions.

"These results indicate that our NET-stabilizing interventions enhance that ability of NETs to capture bacteria while preventing them from releasing antibacterial compounds that can cause organ damage, dramatically improving bacterial clearance as well as survival in a mouse model of sepsis," said Kandace Gollomp, MD, a physician researcher in CHOP's Division of Hematology and first author of the paper. "Given that the treatment was most effective when combined with antibiotics, it's possible that these two treatments may act synergistically to lead to better outcomes."

Sepsis is a deadly complication of infection that occurs when the immune system response to an infectious agent becomes dysregulated, leading to life-threatening damage to the lungs, kidneys and other vital organs. It is a leading cause of hospital death and contributes significantly to high health care costs. Treatment currently consists of antibiotics and supportive care, but neither targets the host response that makes sepsis so deadly, and the poor survival rate has not changed significantly in several decades.

In an effort to seek new treatments that would improve survival, CHOP researchers developed a treatment that targets NETs, extracellular webs of DNA that are released during infection as part of the body's inflammatory response. These NETs ensnare infectious pathogens, but they also cause collateral damage by injuring nearby organ tissue. By the time patients are diagnosed with sepsis, they often already have high NET levels, so treatments that inhibit NET release would be too little, too late. Similarly, treatments that destroy NETs may be ineffective because they liberate captured bacteria and release toxic NET degradation products, exacerbating the septic response.

Instead, CHOP researchers developed an intervention that compacts and stabilizes NETs and sequesters NET degradation products. To do so, they developed a modified version of KKO, an antibody that typically induces blood clots, and changed the portion of the antibody that interacts with cell receptors so that it wouldn't activate an immune response and lead to blood clots. This antibody binds to complexes of NETs and platelet factor 4 (PF4), a protein released by activated platelets, which causes the NETs to resist degradation and improves their ability to capture bacteria.

Testing the treatment on mice with sepsis, the research team found that the modified antibody reduced the severity of illness, decreased the levels of bacteria circulating in the blood and improved survival.

"This approach represents a novel way of approaching NETs in sepsis," Gollomp said. "Not only could this transform the way we treat sepsis in the future, but the findings could have implications for the treatment of other immune conditions in which NETs are involved."

An international team of researchers led by scientists at Baylor College of Medicine has new insights into the function of neurofibromin, a tumor suppressor produced by the NF1 gene. It is well known that neurofibromin keeps cancer growth in check by repressing the activity of a cancer driver called Ras. The new research reveals a previously unknown function of neurofibromin -- directly repressing gene expression controlled by the estrogen receptor-α (ER). Thus, when neurofibromin is lost, Ras and ER functions are both activated, causing treatment resistance and metastasis for ER+ breast cancer.

These findings, appearing in Cancer Cell, suggest that a therapeutic approach must combine two different drugs, a SERD (e.g., fulvestrant) to degrade ER and a MEK inhibitor (e.g., selumetinib or binimetinib) to inhibit Ras downstream signaling, in order to effectively treat neurofibromin-depleted ER+ breast cancer. When this combination therapy was tested in animal models, the result was tumor regression. The next step is to begin clinical trials of the effectiveness of this therapeutic approach in patients.

Neurofibromin loss drives tamoxifen and aromatase inhibitor resistance

This team first studied the importance of neurofibromin loss in a study they published in 2018 (Nature Communications PMC6123466) in which tumor DNA was sequenced to seek mutations that can promote resistance to tamoxifen, which is commonly used to prevent relapses from ER+ breast cancer.

"When we examined the mutational patterns in NF1, we observed that poor patient outcome only occurred when neurofibromin was lost, not through mutations that selectively affect Ras regulation. This suggested to us that neurofibromin may have more than one function," said Dr. Eric C. Chang, one of two senior authors on the paper, an associate professor in the Department of Molecular and Cellular Biology and a member in the Dan L Duncan Comprehensive Cancer Center's Lester and Sue Smith Breast Center.

This thought triggered studies, spearheaded by Dr. Zeyi Zheng in Chang's lab, into the function of neurofibromin in ER+ breast cancer cells. One of his early experiments showed that when expression of NF1 is inhibited (to mimic neurofibromin loss in tumors), the resulting ER+ breast cancer cells were instead stimulated by tamoxifen and, not as usual, inhibited. Furthermore, these neurofibromin-depleted cells became sensitive to a very low concentration of estradiol, a form of estrogen.

"The clinical relevance of these findings was immediately apparent because it suggested that tamoxifen or aromatase inhibitors, which lower estrogen levels available to the cancer cells, would be the wrong choice for treatment when neurofibromin is lost by the tumor," said co-senior author Dr. Matthew Ellis, professor and director of the Lester and Sue Smith Breast Center and a McNair Scholar at Baylor.

A key breakthrough: physically linking neurofibromin to ER

Follow-up gene expression studies all strongly suggest that neurofibromin behaves like a classic ER co-repressor.

"A co-repressor must bind ER directly, but the group hesitated to conduct such an experiment without more evidence because it is not trivial to do so," Chang said.

A breakthrough came when Dr. Charles Foulds, a co-author on the paper and assistant professor at the Center for Precision Environmental Health at Baylor, searched the "Epicome," a massive proteomic database created by Dr. Anna Malovannaya and Dr. Jun Qin at Baylor, as part of an effort by Dr. Bert O'Malley, chancellor and professor of molecular and cellular biology at Baylor, to comprehensively document all the proteins associated with ER. Foulds found neurofibromin in the database, which encouraged the team to ultimately demonstrate that ER and neurofibromin interact directly. However, to seriously consider NF1 as an ER co-repressor, there was still another missing piece of the puzzle.

"One day Charles casually asked me whether neurofibromin has a region rich in the amino acids leucine and isoleucine, because co-repressors use these motifs to bind ER, and it dawned on me that neurofibromin indeed does," said Chang. "In fact, neurofibromin has two such motifs that mediate ER binding in a cooperative manner. These motifs are frequently mutated in cancers but are not required for Ras regulation."

Approaches to treat neurofibromin-deficient ER+ breast cancer

Since tamoxifen or aromatase inhibitors were found to be ineffective for neurofibromin-deficent ER+ breast cancer tumors, preclinical models were used to show that the ER-degrading drug fulvestrant was still effective. However, fulvestrant only temporarily inhibited tumor growth because secondary Ras-dependent fulvestrant resistance was induced by neurofibromin-loss. This Ras-dependent growth phase could be inhibited with the addition of a MEK inhibitor, which shuts off a key signaling pathway downstream of Ras.

The team validated this combination treatment strategy using a patient-derived xenograft (PDX) mouse model which can maintain the genomics and drug response of the original human tumor from which is was derived (Cell Reports 2013 PMC3881975). In this case, this PDX was derived from a patient who failed several lines of endocrine therapy and already developed fulvestrant resistance.

"The results of the combination therapy were encouraging -- the tumor shrunk to almost undetectable levels," Chang said. "Our next goal is to test this combination therapy in clinical trials in order to determine its therapeutic potential in the clinic."

"Neurofibromin loss is present in at least 10% of metastatic ER+ tumors. As a result of these new data, we are now working on a clinical trial that combines a MEK inhibitor, with fulvestrant," said Ellis, Susan G. Komen scholar and associate director of Precision Medicine at the Dan L Duncan Comprehensive Cancer Center at Baylor. "Interestingly, MEK inhibitors are also being used to control peripheral nerve tumors in patients with neurofibromatosis, where a damaged NF1 gene is inherited. Our findings contribute to an understanding of why female neurofibromatosis patients also have a much higher incidence of breast cancer."

Researchers have identified a promising new drug combination that could significantly help the immune system target cancer cells and kill them.

The study published in Cell, describes a treatment that works by combining an intravenous dosage of a well known anti-nausea drug, prochlorperazine (called Stemetil in Australia), with existing cancer treatments.

University of Queensland (UQ) scientist Associate Professor Fiona Simpson, who led the exhaustive research project, said it could lead to new treatments for some cancers.

Dr Simpson has spent the past decade working on the research project, a tribute to her mother who she lost to cancer in 1999.

"The anti-nausea drug works by changing the surface of the tumour cells so that existing cancer drugs which target tumours are better able to interact with the immune system," Dr Simpson said.

"The result is that cancer cells become sitting targets that can no longer escape the immune system.

"We observed a process we haven't seen before and which increased the 'natural killer' immune cells' ability to attach to, and kill the cancer. It is almost as if the killer cells become zipped to the tumour cells."

The treatment can be combined with and improve the effectiveness of existing cancer drugs like cetuximab, trastuzumab and avelumab and was studied on tumours from head and neck, breast and metastatic colorectal cancers in mice, as well as five patients with head and neck cancer.

"These heroic patients volunteered for a 'no benefit trial', consenting to have a tumour biopsy followed by a 20-minute intravenous transfusion of Stemetil, and then another biopsy," Dr Simpson said.

"We were able to show that the Stemetil altered the tumour cell surface in these patients."

Following the initial findings, the researchers combined Stemetil with an anti-cancer antibody drug resulting in the disappearance of all the tumours from ten mice with head and neck cancer.

Dr Simpson was curious to see what would happen if they re-introduced the same cancer back into the mice four weeks later.

"Amazingly, their cancer was rapidly eliminated - as if the new combination, in addition to being more effective, was also able to teach the immune system how to better recognise cancer cells," Dr Simpson said.

"The mice developed a long-term immunity to the cancer they initially had."

The Fiona Simpson Cancer Research group has been working with expert immunologists including UQ's Dr James Wells to translate the research findings to patient treatments.

"Our long-term vision is to use this approach to not only clear a patient's cancer in the immediate term, but to prevent their cancer coming back in the future by establishing protective 'immune memory'," Dr Wells said.

Dr Simpson's team is now completing a safety trial of the combination of Stemetil and cetuximab in head and neck cancer, triple-negative breast cancer and adenoid cystic carcinoma patients at the Princess Alexandra Hospital.

The collaboration involved researchers and doctors from UQ's Diamantina Institute and Institute for Molecular Bioscience, The Princess Alexandra Hospital, Children's Medical Research Institute, The University of Newcastle and The University of Sydney.

The University of Queensland's technology transfer company UniQuest will seek to identify commercialisation opportunities.

What The Study Did: The secretion of melatonin is an important indicator of the body's circadian rhythm. An internal circadian rhythm misaligned with the outside world and a low concentration of melatonin secretion have been associated with risk for a variety of diseases. This randomized clinical trial investigated whether cataract surgery, which increases a person's perception of light, affected melatonin secretion in patients 60 and older having their first cataract surgery compared with those whose cataract surgery was delayed.

Authors: Keigo Saeki, M.D., Ph.D., of the Nara Medical University School of Medicine in Nara, Japan, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamaophthalmol.2020.0206)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

March 5, 2020, CLEVELAND: Cleveland Clinic researchers have identified a gut microbe generated byproduct - phenylacetylglutamine (PAG) - that is linked to development of cardiovascular disease, including heart attack, stroke and death. The study was published in Cell today.

Phenylalanine is an amino acid found in many foods, including plant- and animal-based protein sources like meat, beans and soy. The researchers - led by Stanley Hazen, M.D., Ph.D., chair of the Department of Cardiovascular & Metabolic Sciences in Lerner Research Institute and co-section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart, Vascular & Thoracic Institute - found that when phenylalanine is broken down by microbes in the gut, it produces a byproduct (metabolite) that ultimately shows up in blood called phenylacetylglutamine (PAG) that contributes to heart disease.

"Over the past decade there has been an increasing amount of data to suggest that gut microbes play a role in health, especially as it relates to heart disease," said Dr. Hazen, who also directs the Cleveland Clinic Center for Microbiome and Human Health. "We found that blood levels of PAG contribute to cardiovascular disease risk in a couple of different ways."

Analyzing samples from more than 5,000 patients over three years revealed that elevated PAGln levels predicted subjects who went on to experienced adverse cardiac events like heart attack and stroke in the future, and also in those with type 2 diabetes (an independent risk factor for cardiovascular disease). Animal model and microbe transplantation studies suggest the gut microbe-produced PAG can play an important role in driving cardiovascular disease.

The researchers also analyzed whole blood, platelet-rich plasma and isolated platelets from patient samples to understand how PAG affects cell processes. They then analyzed animal models of arterial injury to see how PAG induced cellular changes manifest into disease. Dr. Hazen and his team found that PAG enhanced platelet reactivity and clotting potential, which increases the likelihood of blood clots, a major cause of adverse cardiac events like heart attack and stroke.

"Part of the reason we were so interested to have made this discovery is because we found that PAG binds to the same receptors as beta blockers, which are drugs commonly prescribed to help treat cardiac diseases." said Hazen.

Administering beta blockers to animal models with elevated PAG was shown to reverse cardiovascular endpoints driven by PAG. Additionally, researchers found that using gene editing technology or drugs to block PAG - receptor signaling significantly reduced clotting activity.

"We believe our findings suggest that some of the benefits of beta blockers may be attributed to preventing PAG - related activity," said Hazen. "Beta blockers have been widely studied and are prescribed to many cardiac patients, but, to our knowledge, this is the first time that this mechanism has been suggested as an explanation for some of their benefits."

Psychologists at the University of Bath, King's College London, and Cardiff have found that a common test used by doctors and researchers to measure autistic personality traits lacks reliability and might not be capturing the right signs of autism.

This means that research including scores from this test may lack validity and raises new questions about its use for screening for autism in the general population.

The 10-item Autism-Spectrum Quotient (AQ10) questionnaire asks people to report if they have personality characteristics associated with autism. There are many forms of these types of questionnaires, with the AQ10 being the shortest and most commonly used by GPs.

The National Institute for Health and Care Excellence (NICE), the government body responsible for making recommendations for clinical practice and to the NHS, recommends the AQ10 as a screening tool for autism in adults. For research purposes, results from the questionnaire are used in large-scale studies to measure autistic traits in the general population.

These autistic traits/tendencies are then linked to their performance on other tasks, in order to inform how autism may be related to other social behaviours and difficulties.

In a new study, published today (Thursday 5 March) in Cambridge University Press' new journal Experimental Results, researchers used data from over 6,500 participants from the general population to examine the effectiveness of AQ10 in measuring autism.

Their results found that the measure had poor reliability across several statistical techniques and the team now suggest the reliance on AQ10 as a measure of autistic traits needs to be questioned. They suggest we need new systems in place designed to better capture the range of autistic personality traits across the population.

Dr Punit Shah, senior author of the study and expert on cognitive processing at the University of Bath's Department of Psychology, explained: "Our findings add further evidence to a growing body of literature indicating that the measures of autism and autistic traits currently used in research are inadequate.

"A lot of what we know about autism - and how to help people with autism - has come from studies where these tools are used. However, if the measure of autism is unreliable, as we suggest, so too are the findings and conclusions. Without reliable measures, it is unclear if the findings from these studies are valid, and may be hampering the support we provide for people with autistic personalities or diagnosed autism in society."

Emily Taylor, a PhD researcher on the team, added: "This is an important finding, which will hopefully initiate a more concerted effort at examining and refining tools used in autism research and clinical practice. Our analyses used a large sample without medical diagnoses, so the next step would be to conduct follow-up studies in equally large clinical samples.

"More generally, we have focussed on a measure of autistic traits, but we know that there are similar reliability problems with measures of mental health tools. We need far more 'basic' science to examine and address these issues in future research, towards improving their application in the management of mental health difficulties in society."

Researchers from Tokyo Medical and Dental University (TMDU) develop an artificial intelligence system that effectively evaluates endoscopic mucosal findings from patients with ulcerative colitis without the need for biopsy collection

Tokyo, Japan - Assessments of patients with ulcerative colitis (UC), which is a type of inflammatory bowel disease, are usually conducted via endoscopy and histology. But now, researchers from Japan have developed a system that may be more accurate than existing methods and may reduce the need for these patients to undergo invasive medical procedures.

In a study published this February in Gastroenterology, researchers from Tokyo Medical and Dental University (TMDU) have revealed a newly developed artificial intelligence (AI) system that can evaluate endoscopic findings of UC with an accuracy equivalent to that of expert endoscopists.

Accurate evaluations are critical in providing optimal care for patients with UC. Previous studies have indicated that both endoscopic remission, evaluated via assessment of endoscopic procedure, and histological remission, as indicated by the degree of microscopic inflammation, can predict patient outcomes, and are thus frequently used as treatment goals. However, intra- and inter-observer variations occur in both endoscopic and histological analyses, and histological analysis frequently requires the collection of tissue via biopsies, which are invasive and costly.

"The interpretation of endoscopic images is subjective and based on the experience of individual endoscopists, thereby making the standardization of evaluation and real-time characterization challenging," says lead author of the study Kento Takenaka. "To address this, we sought to develop a deep neural network (DNN) system for consistent, objective, and real-time analysis of endoscopic images from patients with UC (DNUC)."

To do this, the researchers developed a system with DNNs to evaluate endoscopic images from patients with UC. DNNs are a type of AI machine-learning method that is based on the construction of artificial neural networks.

"We constructed the DNUC algorithm, using 40,758 images of colonoscopies and 6885 biopsy results from 2012 patients with UC," says senior author Mamoru Watanabe. "This comprised the training set for machine-learning, which enabled the algorithm to learn to accurately evaluate and classify the data".

The researchers then validated the accuracy of the DNUC algorithm using 4187 endoscopic images and 4104 biopsy specimens from 875 patients with UC.

"We found that the DNUC achieved a level of accuracy that was equivalent to that of expert endoscopists," says Takenaka. "Thus, our system was able to predict histologic remission from UC using endoscopic images only, as opposed to both histological and endoscopic data. This represents an important development given the costs and risks associated with biopsies."

The DNUC may be able to identify UC patients who are in remission without requiring them to undergo biopsy collection and analysis. This could save time and money for medical institutions, and limit exposure to invasive medical procedures for individuals with UC.

An artificial intelligence (AI) device that has been fast-tracked for approval by the Food and Drug Administration may help identify newborns at risk for aggressive posterior retinopathy of prematurity (AP-ROP). AP-ROP is the most severe form of ROP and can be difficult to diagnose in time to save vision. The findings of the National Eye Institute-funded study published online February 7 in Ophthalmology.

"Artificial intelligence has the potential to help us recognize babies with AP-ROP earlier. But it also provides the foundation for quantitative metrics to help us better understand AP-ROP pathophysiology, which is key for improving how we manage it," said the study's lead investigator, J. Peter Campbell, M.D., M.P.H., Casey Eye Institute, Oregon Health and Science University in Portland.

Babies born prematurely are at risk for retinopathy. That is, they have fragile vessels in their eyes, which can leak blood and grow abnormally. If left untreated, vessel growth can worsen and cause scarring, which can pull on and cause detachment of the retina, the light-sensing tissue at the back of the eye. Retinal detachment is the main cause of vision loss from ROP. Each year, the incidence of ROP in the United States is approximately 0.17%. Most cases are mild and resolve without treatment.

Upon birth, the eyes of preemies are screened and closely watched for signs of retinopathy. But ROP-related changes occur along a spectrum of severity. AP-ROP can elude diagnosis because its features can be more subtle and harder to appreciate than typical ROP. AP-ROP was formally recognized as a diagnostic entity in 2005. Yet in everyday practice there's significant variation in how clinicians interpret whether fundus images taken of the inside of the eye show signs of AP-ROP. "Even the most highly experienced evaluators have been known to disagree about whether fundus images indicate AP-ROP," said Campbell.

In a previous study, deep learning, a type of AI used for image recognition, was more accurate than experts at detecting subtle patterns in fundus images and at classifying ROP. Using the automated deep learning ROP classifier, researchers devised a quantitative vascular severity score (1-9 scale) for evaluating newborns, monitoring disease progression and response to treatment. The study, however, did not specifically address AP-ROP detection.

For the current study, nine neonatal care centers used deep learning to determine how well it detected AP-ROP. The 947 newborns in the study were followed over time and fundus images from a total of 5945 eye examinations were analyzed both by the deep learning system and a team of expert fundus image graders.

Among all eyes followed, 3% developed AP-ROP.

There was a significant level of inter-reader disagreement among the expert graders, suggesting the need for objective metrics of disease severity.

Importantly, a clearer, quantifiable AP-ROP patient profile emerged, which could help identify at-risk infants earlier. Infants who developed AP-ROP tended to be more premature. Compared with infants who needed treatment but never developed AP-ROP-, AP-ROP infants were born lighter (617 g vs. 679 g) and younger (24.3 weeks vs. 25.0 weeks). No infants born after 26 weeks developed AP-ROP in this population.

AP-ROP also tended to onset rapidly and quickly grow worse. Although rapid progression of disease has always been implied in the diagnosis of AP-ROP, to date there has been no way to measure this clinical feature. Monitoring the rate of vascular severity score changes could therefore improve detection of AP-ROP risk, according to the study findings.

Infants with AP-ROP also were more likely to have comorbidities such as chronic lung disease, compared to infants without AP-ROP. The requirement for higher oxygen concentrations among infants with lung disease may have played a role in their eye disease, said Campbell. Decades ago, researchers made a connection between the routine use of high concentrations of oxygen at birth and an increase in the development of retinopathy. Oxygen is nearly always required for survival, but is titrated very carefully to maximize survival while minimizing the risk to vision. "It's still a balancing act," said Campbell.

"It's important to acknowledge that there is currently no gold standard for diagnosing AP-ROP. But having objective, AI-based metrics for detecting AP-ROP is a step in the right direction for this highly vulnerable population of infants," said Grace L. Shen, Ph.D., who manages the retinal diseases program for the Division of Extramural Science Programs at the NEI.

The deep learning system in the clinical trial, the i-ROP DL system, was recently granted breakthrough status by the FDA, which accelerates its development and FDA review. Development of the device was supported by the NEI, part of the National Institutes of Health.