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Cancer cases have been rising over the years and according to the statistics, the number of people living with cancer will continue to increase. Despite decades of research, cancer treatments are still inefficient and have unacceptable side effects that continue to prompt an urgent need for new approaches to prevention and treatment. Uncovering novel mechanisms associated with cancer would fill current knowledge gaps and help meet this need.

"We discovered a mechanism involving MBNL1 protein that predicts several characteristics of cancer such as progression and relapse," said Dr Debleena Ray, Senior Research Fellow at Duke-NUS' Cancer and Stem Cell Biology (CSCB) programme, the lead author of this study. "We found that MBNL1 protein is present in low amounts in many of the common cancers in the world, including breast, colorectal, stomach, lung and prostate cancers, which when combined account for about 49 per cent of all cancers diagnosed in 2018. This can cause poor overall survival in many of these commonly-occurring cancers."

The team also found that this mechanism can be reversed by blocking the JNK protein, a well-known target in cancer treatment, in cancer cells with low levels of MBNL1.

"While JNK inhibitors have been tested as a cancer drug previously, currently there are no clinical trials for the same. However, if in the future there is a JNK inhibitor against cancer, MBNL1 could be used as a biomarker to select patients for the treatment," said Adjunct Associate Professor David Epstein at the Duke-NUS' CSCB programme and the co-corresponding author of this study.

"Cancer is a global health challenge and Singapore is no exception. This study provides important information about novel targets and biomarkers that are implicated in several major cancers, which could lead to the development of new treatment strategies that can improve the lives of patients," said Prof Patrick Casey, Senior Vice Dean for Research at Duke-NUS.

Over the next year, the team will be investigating the role of MBNL1 in colorectal cancer and exploring the potential of anti-JNK therapeutic for cancer using antisense technology, a tool that is used for the inhibition of gene expression.

Many small regulatory elements, including miRNAs, miRNA binding sites, and cis-acting elements, comprise only 5~24 nucleotides and play important roles in regulating gene expression, transcription and translation, and protein structure, and thus are promising targets for gene function studies and crop improvement.

The CRISPR-Cas9 system has been widely applied in genome engineering. In this system, a sgRNA-guided Cas9 nuclease generates chromosomal double-strand breaks (DSBs), which are mainly repaired by nonhomologous end joining (NHEJ), resulting in frequent short insertions and deletions (indels) of 1~3 bp. However, the heterogeneity of these small indels makes it technically challenging to disrupt these regulatory DNAs. Thus, the development of a precise, predictable multi-nucleotide deletion system is of great significance to gene function analysis and application of these regulatory DNAs.

A research team led by Prof. GAO Caixia from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS) has been focusing on developing novel technologies to achieve efficient and specific genome engineering. Based on the cytidine deamination and base excision repair (BER) mechanism, the researchers developed a series of APOBEC-Cas9 fusion-induced deletion systems (AFIDs) that combine Cas9 with human APOBEC3A (A3A), uracil DNA-glucosidase (UDG) and AP lyase, and successfully induced novel precise, predictable multi-nucleotide deletions in rice and wheat genomes.

"AFID-3 produced a variety of predictable deletions extending from the 5?-deaminated Cs to the Cas9 cleavage sites, with the average predicted proportions over 30%," said Prof. GAO.

The researchers further screened the deamination activity of different cytosine deaminases in rice protoplasts, and found that the truncated APOBEC3B (A3Bctd) displayed not only a higher base-editing efficiency but also a narrower window than other deaminases.

They therefore replaced A3A in AFID-3 with A3Bctd, generating eAFID-3. The latter produces more uniform deletions from the preferred TC motifs to double-strand breaks, 1.52-fold higher than AFID-3.

Moreover, the researchers used the AFID system to target the effector-binding element of OsSWEET14 in rice, and found that the predictable deletion mutants conferred enhanced resistance to rice bacterial blight.

AFID systems are superior to other current tools for generating predictable multi-nucleotide targeted deletions within the protospacer, and thus promise to provide robust deletion tools for basic research and genetic improvement.

The team's scientific paper, entitled "Precise, predictable multi-nucleotide deletions in rice and wheat using APOBEC-Cas9," was published in Nature Biotechnology.

Analysis of symptom diaries kept by 256 pregnant women shows that is inaccurate to describe nausea and vomiting in pregnancy as 'morning sickness'

Team led by University of Warwick finds that symptoms can occur at any time of the day

Although likelihood of experiencing symptoms is highest in the morning, nausea was still likely to occur later in the day

First time that the symptom patterns of nausea and vomiting in pregnancy have been mapped

The term 'morning sickness' is misleading and should instead be described as nausea and sickness in pregnancy, argue researchers led by the University of Warwick who have demonstrated that these symptoms can occur at any time of the day - not just the morning.

The researchers call for the change in a study published today (30 June) in the British Journal of General Practice which shows that, while the most likely time for pregnancy sickness symptoms to occur is in the morning, a significant number of women can experience them at any time of the day.

'Morning sickness' has long been used to describe nausea and vomiting that women often experience in the early stages of pregnancy. Although pregnant women often report experiencing nausea and sickness throughout the waking day, until now no research has described the likelihood of these symptoms occurring at different times of the day.

For this study, the researchers used data from daily symptom diaries kept by 256 pregnant women. In these diaries, the women recorded their experience of nausea and vomiting for each hour in the day, from the day they discovered they were pregnant until the 60th day of their pregnancy. The researchers then used this data to map the likelihood of experiencing nausea and experiencing vomiting in each hour of the day, broken down into weeks following last ovulation.

They found that whilst vomiting was most common between the hours of 7.00 am and 1.00 pm, nausea is highly likely throughout the whole daytime, not just the morning. Furthermore, many women still reported vomiting as a symptom even into the evening. The most common hour for participants to experience nausea and vomiting was between 9.00 am and 10.00 am with 82% experiencing nausea in this hour, and 29% experiencing vomiting.

94.2% of participants experienced at least one of these symptoms during the study, with 58% experiencing both.

In addition, by comparing occurrence of symptoms across the first 7 weeks of pregnancy, measured from last ovulation, the researchers found that the later the week, the higher the probability of experiencing symptoms. The probability of experiencing nausea is at its highest in weeks 5, 6 and 7 while for vomiting it is in week 7. As the study only examined the first seven weeks of pregnancy, the probabilities after week 7 are not known.

Professor Roger Gadsby, of Warwick Medical School, said: "Morning sickness is widely used by the general public, media and even healthcare professionals but it doesn't give an accurate description of the condition.

"If a pregnant woman experiences sickness in the afternoon she may feel that this is unusual and wrong, or if she experiences no vomiting but feels nauseated all day she might think she is not covered by the term 'morning sickness'. And those women who experience severe symptoms feel it trivialises the condition.

"Nausea and vomiting in pregnancy (NVP) can have a significant negative impact on the lives of sufferers. It can cause, feelings of depression, of being unable to look after the family, and of loss of time from paid work. Very severe NVP called hyperemesis gravidarm (HG) is the commonest cause of admission to hospital in the first trimester of pregnancy."

It is estimated that the annual costs of managing nausea and vomiting in pregnancy to the NHS in England and Wales are around £62 million.

The study authors said: "The continued use of the term 'morning sickness' could imply that symptoms only rarely occur in the afternoon and evening so that sufferers will have significant parts of the day symptom-free.

"This study shows that this is an incorrect assumption and that symptoms, particularly nausea, can occur at any time of the day."

PHOENIX (June 30, 2020) - Summertime means Americans are spending more time around grills, firepits, and fireworks, increasing their risk for fire-related burn injuries. While 53% of Americans say they know some or a lot about burn injuries and treatment, many mistakenly underestimate their risks with these activities, according to a new Arizona Burn Center at Valleywise Health/Ipsos survey. In fact, only 11% know that fire-flame injuries such as those from a firepit or grill are the most common types of burn injuries.

"Burn injuries increase in the summer months as more people are grilling outside, sitting around firepits, and setting off fireworks," said Kevin Foster, MD, director of Burn Services for the Arizona Burn Center at Valleywise Health. "It's important for people to be aware of not only their risk for suffering from a burn injury, but what to do if they or a loved one experience a burn."

The online survey of 1,000 adults conducted in June by Ipsos, a multinational independent market research firm, shows that a majority of Americans are unaware that applying ice to a burn is not recommended. Nearly six in 10 either think you should immediately apply ice directly to a burn (39%) or do not know whether it is okay (18%), when doing so can actually increase tissue damage.

Additionally, 40% of Americans say they are planning to use their own fireworks or sparklers this summer, activities that put a significant number of people at risk for serious burns. Children are particularly at risk because parents are more likely than the general population to report they will be around fire hazards, including fireworks (65.8% vs. 40%), and firepits or campfires (65% vs. 50%). Additionally, of those parents planning to use or be around fireworks, half (50%) say they don't know much or anything at all about burn injuries and treatments.

Lack of knowledge can be especially dangerous around grills, as they account for thousands of visits to the emergency room every year. Seventy-one percent of respondents say they are planning to grill this summer, but one in four incorrectly thinks water is the best way to put out a grill fire. Additionally, while nearly two-thirds (59%) of parents who plan to grill this summer know it is not okay to put out a grill fire with water, 41% falsely think it is okay or don't know.
"Burns are one of the leading causes of injury-related death in children, so the lack of knowledge that Americans demonstrate around burn injuries is concerning," said Dr. Foster. "People need to be aware of the dangers, even with something as common as grilling, so that they are prepared to react appropriately and safely in an emergency. I encourage anyone planning to grill or use a firepit or fireworks this summer to review basic safety measures for these activities and understand what to do if someone experiences a burn."

If you plan to use or be around a grill, firepit, fireworks, or sparklers this summer, here are just a few tips to help keep you and your family safe:

When grilling, cook your food in batches to avoid overloading the grill, particularly with fatty meats that can cause a flare-up.

If you are faced with a grill fire, use a fire extinguisher to put out the flames, not water.

Keep children and pets at least three feet away from the grill area at all times.

If the flame goes out on your gas grill, turn the grill and gas off and wait at least 5 minutes before re-lighting.

Fire pits should be placed at a minimum of ten feet away from your house.

Store matches and lighters out of children's sight and reach.

Use a metal screen over wood-burning firepits to keep sparks and embers contained.

When using fireworks or sparklers, keep a supply of water or fire extinguisher at hand.

Never hold lighted fireworks in your hands and never use fireworks while impaired by alcohol.

Instead of sparklers, consider using safer alternatives, such as glow sticks, confetti poppers or colored streamers.

If you or someone with you experiences a burn, please seek immediate medical attention if the burn is larger than your palm; it covers your hands, joints, or face; if the pain progressively gets worse; or if the skin is peeling. For more information on burn safety, please visit The Arizona Burn Center's website: https://valleywisehealth.org/patient-education-resource/burn-care-patient-education/

Hospitalized patients who report an allergy to penicillin are often prescribed alternative antibiotics for infection that can be harmful, even though diagnostic testing or evaluations would show that the vast majority of these reported allergies could be disproven, according to researchers from Massachusetts General Hospital.

In a national study published in JAMA Internal Medicine, the team found that the 16% of hospitalized patients with a documented penicillin allergy were twice as likely to be prescribed alternative antibiotics. Given that more than 90 percent of documented penicillin allergies are unconfirmable, those antibiotic substitutions by physicians were likely unnecessary.

"Too often clinicians are making inferior antibiotic decisions based on unverified penicillin allergy histories that may date back to a patient's childhood and are no longer valid," says Kimberly Blumenthal , MD, MSc, with the Division of Rheumatology, Allergy, and Immunology, MGH, and lead author of the study.

"As a result, patients are often prescribed antibiotics other than penicillins and cephalosporins - some of our core infection fighters - that may increase the risk of adverse side effects and antibiotic resistance.

"This pattern could be changed with a little more testing or, in many cases, by simply taking the time to talk to patients in order to learn more about a reported penicillin allergy, instead of taking the penicillin allergy label at face value."

Approximately half of hospitalized patients today receive antibiotics to treat or prevent infections caused by bacteria, and more than 10 percent have a penicillin allergy documented in their medical records.

In the first study to investigate antibiotic use patterns in documented penicillin allergy on a national scale, Mass General researchers combed the records of nearly 11,000 patients at 106 hospitals.

They found that the 16 percent of inpatients with a penicillin allergy on their medical records were typically treated with β-lactam alternative antibiotics, including significantly increased use of clindamycin, linezolid, fluoroquinolones, aminoglycosides, tetracyclines, and vancomycin.

The highest risk exposure was to clindamycin, which is associated with C difficile infection. Patients with a documented penicillin allergy were five times more likely to be given clindamycin than those without such an allergy.

Another key finding involved inpatients with a documented penicillin allergy who received antibiotics as prophylaxis for an upcoming surgical procedure to prevent infections. Although a β-lactam is the recommended antibiotic for this indication in most cases, the study found that patients with a documented penicillin allergy were nine-fold less likely to receive a β-lactam, but seven-fold more likely to receive a β-lactam alternative antibiotic.

"Hospitals should especially be targeting penicillin allergy evaluations for patients with planned surgical procedures and those who are otherwise likely to be prescribed clindamycin," says Rochelle Walensky, MD, MPH, chief of Infectious Diseases at MGH, Steve and Deborah Gorlin MGH Research Scholar and senior author of the study.

"For patients who claim a penicillin allergy, those interventions could be as simple as asking the right questions and compiling a comprehensive history. Unfortunately, antibiotic decisions are often made based on limited information or without a thorough investigation. We learned from our study that antibiotic prescribing without full allergy information can ultimately do the patient more harm than good."

Blumenthal, an expert in allergy and immunology, underscores the need for hospitals across the country to more aggressively address penicillin allergy risk detection. While a diagnostic test exists to help clinicians accurately make that determination, less than half of hospitals have access to it, she points out.

"Hospitals should clearly be treating patients with the most targeted and effective antibiotic for their infection, rather than being influenced by a penicillin reaction years earlier that might have been nothing more than itching or a headache," Blumenthal declares. "That will require hospitals to become much more vigilant and proactive in penicillin allergy assessment as part of their inpatient antibiotic stewardship programs."

MINNEAPOLIS, MN- June 30, 2020 - Prostate MRI is an emerging technology used to identify and guide treatment for prostate cancer and has recently gained wide acceptance at many institutions. However, there has been concern that different institutions perform imaging of different quality. A recent multi-site study published in Radiology was designed to gauge the difference in imaging quality for prostate MRI by looking retrospectively at performance across 26 institutions.

Researchers reviewed the results of prostate biopsies on over 3,400 men who had targets identified on prostate MRI. They found that the positive predictive value of the test for prostate cancer was highly variable at different sites.

"The quality of prostate MRI was, indeed, heterogeneous across a number of institutions," said Ben Spilseth, MD, associate professor in the Department of Radiology at the University of Minnesota Medical School and U of M site coordinator for the study. "There are a lot of possible reasons why this is the case. It is not just the MRI itself, but it has to do with how the image is interpreted and then how it's biopsied and sampled."

The detection of prostate cancer with prostate MRI and biopsy is an important tool and improves patient outcomes, but the experience isn't the same across all centers. Spilseth believes there is more work to be done to better understand how all institutions can have a similar outcome. He hopes that this research will bring more training and standardization across the country for prostate MRI and biopsy guidelines.

"It is important that each center has a robust quality improvement process in order to get the outcomes that we all want to see," Spilseth said.

June 30, 2020 - Using an in-home portable air cleaner (PAC) can significantly reduce exposure to fine-particle air pollutants - a major risk factor for cardiovascular events in people with pre-existing heart disease, reports a pilot study in the July issue of Journal of Cardiopulmonary Rehabilitation and Prevention. The journal is published in the Lippincott portfolio by Wolters Kluwer.

"We show here for the first time that providing cardiac patients with PAC for use in their homes results in approximately a 40 percent reduction in personal-level exposure to PM2.5 air pollution," according to the new research by Robert L. Bard, MS, of Michigan Medicine, Ann Arbor, and colleagues. They plan further studies to see if the reducing particulate exposure with PACs leads to reductions in cardiovascular events.

In-Home PACs Reduce Particulate Exposure, Can They Reduce Cardiovascular Events?

The Cardiac Rehabilitation Air Filter Trial (CRAFT) pilot study included 20 patients, average 71 years, undergoing cardiac rehabilitation at the authors' medical center. Each patient received two PACs to use at home, running continuously: one in their bedroom and one in their main living space.

For the first five days, patients were randomly assigned to use their PAC in active mode, using a high-efficiency particulate air (HEPA) filter; or in sham mode, with no HEPA filter installed. For a subsequent five-day period, patients were crossed over to the other PAC mode. The study was "double-blind" - patients and researchers were both unaware of the order of the two modes.

After four days on each mode, patients were given a portable monitor to measure their personal exposure to fine-particle pollutants: particles or droplets measuring 2.5 microns in width. (A micron, or micrometer, is one-millionth of a meter.) Exposure to PM2.5 is a major risk factor for myocardial infarction, sudden death, and other events throughout the population, but especially in patients with cardiac disease.

In 18 patients who completed the study, exposure to fine-particle pollutants was significantly lower with the PAC in active mode. Compared to the sham period, active in-home PAC use reduced personal PM2.5 exposure by about 44 percent.

The improvement remained significant on analysis excluding a few patients with very high short-term PM2.5 values, possibly related to secondhand smoke or cooking. Use of active PAC with a HEPA filter reduced personal PM2.5 exposure for all but two of the 18 patients.

The results were similar to a previous study evaluating PAC use in a senior facility. The researchers also note that the reductions in PM2.5 exposure were achieved in a region (southeast Michigan) with good air quality; in more-polluted areas, even greater reductions might be achieved. The PAC devices are relatively inexpensive: retail cost of about $120 each.

"These pilot study findings are important because they validate the effectiveness of PAC in a real-world clinical setting and represent a critical next step required to rationalize and design large scale outcome trials," Mr. Bard and coauthors write. By conservative estimates, the reported PM2.5 reductions might lower the cardiovascular event rate by five percent in the general population, and by up to 20 percent in high-risk cardiac patients.

The results support moving forward with the full-scale CRAFT study, which aims to show that PAC use can improve risk markers such as blood pressure or blood vessel (endothelial) function. The researchers conclude: "Such data are required to design future outcome trials which are urgently needed to help inform on how to protect the global public health from the threats posed by air pollution."

SAN FRANCISCO, CA June 30, 2020--For the nascent brain of a human embryo to develop into the complex organ that controls human consciousness, a finely tuned sequence of genetic events has to take place; hundreds of genes are activated and deactivated in a precise symphony. Mutations in these genes disrupt the molecular instruments of the symphony and, if they occur in genes that are important for brain development, can result in neurological diseases such as autism and epilepsy. Researchers have long struggled to understand how mutations in regulatory regions of the genome--the conductors, rather than the instruments--can also make this process go awry.

Now, researchers at Gladstone Institutes and UC San Francisco (UCSF) Weill Institute for Neurosciences have created a comprehensive region-specific atlas of the regulatory regions of the genome linked to human embryonic brain development.

"This gives us a searchable, data-rich atlas of part of the developing human brain," said Katie Pollard, PhD, director of the Gladstone Institute of Data Science and Biotechnology. "This is a valuable tool for probing the underlying biology of neurodevelopmental disorders."

Pollard and UCSF professor of psychiatry John Rubenstein are the senior authors of the new study, published online in the journal Cell.

Only about two percent of the human genome encodes actual genes. Much of the rest of the genome contains regulatory elements, the conductors that control when and where those genes are activated. Genes important for specific aspects of liver function, for example, don't need to be turned on in brain cells, so different regulatory elements are needed to control gene expression in those tissues.

When researchers analyze the DNA of people with neurodevelopmental disorders, they often uncover dozens, if not hundreds, of natural variations in DNA sequences. However, only a minority of those variants may be related to the disorder itself, and pinning down which are important is difficult.

"Much of the genome is still this vast and mysterious place because we don't know which parts of the genome play roles in which tissues," said Eirene Markenscoff-Papadimitriou, PhD, a postdoctoral researcher at the UCSF Weill Institute for Neurosciences and co-first author of the paper.

In the new study, the researchers studied cells from a section of the developing human brain called the telencephalon. This region contains structures responsible for sensory processing, voluntary movement, language, and communication.

The team took advantage of the fact that inside cells, the genome is tightly wound into a dense structure known as chromatin. This three-dimensional structure reveals the important parts of the genome in any given cell by exposing the stretches of regulatory DNA needed for the cell to function. Using a technology called ATAC-seq, the team cut up exposed DNA in embryonic brain cells. By analyzing where these cuts are made, they were able to surmise what parts of the genome are exposed and might contain important regulatory regions.

Their initial experiments revealed more than 103,000 regions of open chromatin in the developing brain cells. To narrow down that list, the researchers turned to a machine-learning approach. They wrote a computer program that uses information already known about regulatory DNA to help pick out patterns specific to brain cells.

"We wanted to whittle this initial list down to a smaller set that was the most likely to be important to regulating brain development," said Gladstone Research Scientist Sean Whalen, PhD, co-first author of the new paper.

If a regulatory region was similar to one known to only be active in limbs or lungs, for instance, the machine-learning program concluded that it wasn't a brain-specific enhancer. In the end, the group came up with a set of about 19,000 regulatory regions of the genome expected to play a role in brain development.

To show the utility of the new dataset, the researchers looked more closely at two sections of the genome that appeared in the new atlas that had also been previously implicated in autism and epilepsy. The DNA sequences, they showed, did indeed act as enhancers in brain cells--they had the ability to turn on genes.

"We can now use this approach to ask how all sorts of other mutations affect the non-coding genome," said Markenscoff-Papadimitriou. "This atlas points us in the direction of specific brain regions that are affected by genetic mutations."

If a research team finds hundreds of genetic variants associated with a neurodevelopmental disease, for instance, they can now use the atlas to cross-check which variants are part of the 19,000 regions identified as critical to brain development. That can help them home in on which variants are worth follow-up studies, rather than spending months testing genetic variants that end up to be unrelated to disease.

"We think our data will help a lot of other research groups further their work," agreed Whalen. Beyond studying diseases, he says the resource will be useful for basic science on how the brain develops.

An international team of scientists from Switzerland Spain, has studied the genetic basis of aromatase deficiency, a rare metabolic disorder that prevents the production of estrogens in humans, according to new research in JCEM (Journal of Clinical Endocrinology and Metabolism). The latest studies on aromatase deficiency in humans come from the group of Amit V. Pandey and Christa E. Flück at the Department for BioMedical Research, University of Bern, and Pediatric Endocrinology, University Children's Hospital Bern, done in collaboration with Laura Audí at Hospital Vall d'Hebron, Autonomous University of Barcelona, Spain. Scientists found the answers by analysis of the DNA map of patients with aromatase deficiency and comparing those with DNA of the broader human population from different ethnic groups.

"Supplementation with steroids can target multiple different pathways, so we wanted to know which part of genetic code was changed in patients in order to target therapies to the appropriate place," writes Dr. Amit Pandey, University of Bern and Inselspital, University Hospital Bern, with coauthors. "We knew we had cases of genetic disorders leading to aromatase deficiency, but we needed to find the exact cause of disease, and modern DNA sequencing helped us find it."

Bern expertise helps solving a special case

Collaborating with genetics specialists at the Vall d'Hebron Hospital in Barcelona (Laura Audi, Núria Camats and Mónica Fernández-Cancio) and Hospital Universitario La Paz, Madrid (Sara Benito-Sanz), Pandey focused on a patient with aromatase deficiency identified by Dr. Juan-Pedro López-Siguero at Hospital Carlos Haya, Universidad de Málaga, Spain. What caused the attention of geneticists in Barcelona and Madrid was the observation that patient has symptoms of aromatase deficiency, but, when the gene for aromatase (CYP19A1) was sequenced, no defects were found.

Through the use of next-generation sequencing technology that simultaneously looks at billions of pieces of genetic code, Spanish scientists identified an error in the gene for cytochrome P450 oxidoreductase (POR). Laboratory of Pediatric Endocrinology in Bern, Switzerland, is a world leader in metabolic disorders caused by mutations in POR

The Swiss and Spanish teams joined forces and set out to find how the aromatase deficiency was being caused by a defect in the POR gene. Amit Pandey has been studying the POR gene for many years and knew that aromatase activity to produce estrogens requires energy supply from POR and had the systems in place to measure the impact of changes in POR on estrogen production. Dr. Shaheena Parween, in the laboratory of Amit Pandey, was able to genetically modify the POR gene to duplicate the defect found in the patient and used E.coli bacteria in the laboratory to produce a copy of POR enzyme matching the genetic sequence of the patient.

Scientists in Bern could show that POR made with the genetic code of the patient had lost most of its ability to provide energy to the aromatase enzyme. Therefore, even with a correct aromatase enzyme, the patient could not produce sufficient estrogens. Learning the exact metabolic step where the aromatase deficiency was originating from, allows the physicians to guide the therapy very precisely and prevent side effects associated with steroid supplementation. The study demonstrated the powerful diagnostic ability of next-generation sequencing technologies.

Supporting research in Africa and India

The Bern team extended their studies by looking at more patients with aromatase deficiency from Africa and India and identified the exact causes of genetic defects responsible for the loss of estrogen production. These findings have been reported in JES (Journal of the Endocrine Society), and recently been discussed in PNAS (Proceedings of the National Academy of Sciences of the United States of America). Collaboration with the scientists in Bern, Switzerland, allowed the use of advanced diagnostic and assay technologies not available in local hospitals, which highlights the role of international collaborations in the diagnosis and therapy of rare metabolic disorders.

Variations of POR common in specific populations

The research team of Pandey and Flück is also studying genetic mutations in POR that cause other diseases, such as congenital adrenal hyperplasia, a common inherited disorder that affects a large number of people each year. Pandey highlights the value of translational medicine in his research. From his previous work, Pandey knew that the POR gene in humans has lots of variations, and some populations carry specific mutations to a greater extent than others.

The Laboratory of Gianfranco Gilardi and Giovanna Di Nardo at the University of Torino, Italy, had studied a common variation of aromatase that was predominant in the south-east Asian population. The scientists in Bern and Turin teamed up to check what if the same individual has an alternative form of both the POR and aromatase genes. By preparing the variations of POR and aromatase proteins based on genetic changes observed in the South-east Asian population, scientists could show that a compounding effect can be found when there is a change in POR and aromatase genes at the same time. These findings have been reported in JSBMB (Journal of Steroid Biochemistry and Molecular Biology).

The power of genomics for Precision Medicine

Some of the variations in the POR gene are quite common in specific populations, so Pandey advises looking at changes in the POR gene whenever a defect in other genes that are dependent on POR is identified. With the power of whole-genome sequencing at our disposal, it is time to move on from the theories of monogenic disorders as individual patients in the world are not the same in their genetic composition, says Pandey. "All humans have very similar genes, but still may have up to a million or more differences in their genetic code, even between a daughter and her mother, so if we find out exactly what causes a disease, then precise therapies can be used that are tailored for individual patients," Pandey said. "We are now seeing the power of genomics tailored for use in Precision Medicine, allowing the design of specific treatments for a patient according to their genetic makeup."

Precision medicine will be a vital component of the NextGen Precision Health Initiative by helping to accelerate medical breakthroughs for both patients in Switzerland and beyond. A center of rare diseases has recently been established at Inselspital, University Hospital Bern, to focus on diagnosis and research on rare metabolic disorders.

Researchers from the Moscow Institute of Physics and Technology and their colleagues have developed the first technique for personalizing stomach cancer therapy based on RNA sequencing of tumor cells. The study, supported by the Russian Science Foundation, was published in Cold Spring Harbor Molecular Case Studies.

Stomach cancer is the fifth-deadliest oncological disease. It is seldom diagnosed in the early stages, which complicates treatment. There are several treatment options available that rely on chemotherapy and therapeutic antibodies. However, patient response is often unpredictable, so personalized therapies with drug prescriptions tailored to individual cases are required.

Problematic recurrent tumors of the stomach are treated with therapeutic antibodies. They block the receptors on the surface of cells that are responsible for receiving growth-promoting signals. Without them, cell division stops and the tumor does not increase in size. Preventing the growth of blood vessels is particularly important, because they supply nutrients and oxygen to the tumor. Ramucirumab is a therapeutic antibody used to disrupt the growth of blood vessels in tumor tissue. The efficacy of this drug varies widely from patient to patient.

MIPT bioinformaticians and their colleagues from medical research centers and the industry have proposed that a patient's data on the gene expression levels in cancer be used to evaluate ramucirumab efficacy in each individual case.

"This is virtually the first published case of successful [ramucirumab] prescription to patients with gastric cancer, which was not random but rather informed by the analysis of the molecular markers we track based on RNA sequencing," said Maxim Sorokin, a senior researcher at the MIPT Laboratory for Translational Genomic Bioinformatics and the head of the Bioinformatics Department at Oncobox.

Combined with information technology, modern molecular biology methods enable researchers to collect qualitative data on the expression of every gene in a cell. By analyzing these data, it is possible to find the key to diagnosing oncological diseases and predicting the efficacy of their treatment.

OAK BROOK, Ill. - Researchers using MRI have found that iron accumulation in the outer layer of the brain is associated with cognitive deterioration in people with Alzheimer's disease, according to a study published in the journal Radiology.

Alzheimer's disease is a progressive type of dementia that impairs and eventually destroys memory and other brain functions. There is no cure, although some treatments are thought to slow the progression.

Previous research has linked abnormally high levels of iron in the brain with Alzheimer's disease. Iron deposition correlates with amyloid beta, a protein that clumps together in the brains of people with Alzheimer's disease to form plaques that collect between neurons and disrupt cell function. Associations have also been found between iron and neurofibrillary tangles, abnormal accumulations of a protein called tau that collect inside neurons. These tangles block the neuron's transport system, which harms the communication between neurons.

It is known that deep gray matter structures of patients with Alzheimer's disease contain higher brain iron concentrations. Less is known about the neocortex, the deeply grooved outer layer of the brain that is involved with language, conscious thought and other important functions. The neocortex is challenging to assess by MRI, as the anatomy of the area makes MRI prone to distortions, signal decays and artifacts.

"The best solution to minimize these artifacts would be using ultra-high-resolution scans," said study coauthor Reinhold Schmidt, M.D., professor of neurology and chairman of the Department of Neurology at the Medical University of Graz in Graz, Austria. "However, in the clinical setting, scan time is a limiting factor, and a compromise has to be found."

For the new study, Dr. Schmidt and colleagues developed an approach using a 3T MRI scanner that allowed the best tradeoff between resolution and scan time, along with postprocessing to correct the influence of the distortions.

They used the MRI system to investigate baseline levels of brain iron in 100 individuals with Alzheimer's disease and 100 healthy controls. Of the 100 participants with Alzheimer's disease, 56 had subsequent neuropsychological testing and brain MRI at a mean follow-up of 17 months.

The technique enabled the researchers to create a map of brain iron, determining iron levels in parts of the brain like the temporal lobes, or the areas of the brain lying underneath the temples, and the occipital lobes in the back of the head.

"We found indications of higher iron deposition in the deep gray matter and total neocortex, and regionally in temporal and occipital lobes, in Alzheimer's disease patients compared with age-matched healthy individuals," Dr. Schmidt said.

The brain iron accumulation was associated with cognitive deterioration independently of brain volume loss. Changes in iron levels over time in the temporal lobes correlated with cognitive decline in individuals with Alzheimer's disease.

"These results are all in keeping with the view that high concentrations of iron significantly promote amyloid beta deposition and neurotoxicity in Alzheimer's disease," Dr. Schmidt said.

The results point to a potential role in Alzheimer's disease treatment for drugs that reduce the iron burden in the brain. These drugs, known as chelators, can remove excess iron from the body.

"Our study provides support for the hypothesis of impaired iron homeostasis in Alzheimer's disease and indicates that the use of iron chelators in clinical trials might be a promising treatment target," Dr. Schmidt said. "MRI-based iron mapping could be used as a biomarker for Alzheimer's disease prediction and as a tool to monitor treatment response in therapeutic studies."

OAK BROOK, Ill. - A 3D ultrasound system provides an effective, noninvasive way to estimate blood flow that retains its accuracy across different equipment, operators and facilities, according to a study published in the journal Radiology.

Measures of blood flow are important in helping clinicians determine how much oxygen and nutrient-carrying blood is reaching organs and tissues in a patient's body. In emergency situations, accurate blood flow measurements can show if there is adequate blood supply to organs like the heart and brain. Blood flow measurements are important in chronic conditions too, as in the cases of measuring blood flow to the feet and lower limbs of people with diabetes.

Despite its importance, there is no ideal way to measure blood flow noninvasively and inexpensively. Current methods like blood pressure and 2D ultrasound (i.e., spectral Doppler) provide only surrogate metrics rather than the desired volumetric flow or have substantial limitations and are prone to errors. True flow measurements with 2D ultrasound are rarely used clinically due to reliability issues and cumbersome implementation. In addition, results often vary considerably between facilities and operators. Measurements from an experienced ultrasound technologist might differ significantly from those of a less experienced one.

"Right now, we just don't have anything better to quantify blood flow," said study lead author Oliver D. Kripfgans, Ph.D., associate professor of radiology from the Department of Radiology at Michigan Medicine in Ann Arbor, Michigan.

Dr. Kripfgans and his Michigan Medicine colleagues J. Brian Fowlkes, Ph.D., Stephen Z. Pinter, Ph.D., and Jonathan M. Rubin, M.D., Ph.D., have spent years developing and studying a 3D approach for quantitatively measuring blood flow. For the new study, he and his colleagues, along with other volunteers involved in the Quantitative Imaging Biomarkers Alliance (QIBA), tested this 3D approach on three clinical scanners using a custom flow phantom, a device that mimics blood flow in humans. They used seven different laboratories and manipulated the testing conditions by changing flow rate, imaging depth and other parameters for a total of eight distinct testing conditions.

The results showed that blood volume flow estimated by 3D color-flow ultrasound was accurate and reproducible among the seven laboratories.

"We had less than 10% error or variation," Dr. Kripfgans said. "For some of the systems, we were down to only 3% to 5% difference between labs. These are fantastic results that show that, from a technology point of view, some systems could be ready to go to the clinic."

Dr. Kripfgans credited the simplicity of the 3D approach, ease of data collection and elimination of assumptions plaguing other methods for minimizing the variation in results between users and systems. That simplicity, coupled with the availability of 3D on many existing ultrasound systems, is likely to hasten its arrival to clinical medicine, Dr. Kripfgans said.

"Once the technique becomes available commercially on scanners, clinical adoption will be much faster because then it's not a research project anymore, it's something that's readily available, and after that it's just a matter of time before it reaches the clinic," he said.

QIBA, an alliance of researchers, health care professionals and industry representatives, was organized by the Radiological Society of North America in 2007 to improve current biomarkers and investigate new ones. Biomarkers are measurable indicators of the state of a person's health.

The QIBA initiative includes collaboration to identify needs, barriers and solutions to create consistent, reliable, valid and achievable quantitative imaging results across imaging platforms, clinical sites, and time. QIBA aims to accelerate development and adoption of hardware and software standards to achieve accurate and reproducible quantitative results from imaging methods.

"Because of QIBA and this study I'm confident that this 3D ultrasound technology is on a path to the clinic," Dr. Kripfgans said.

ANN ARBOR, Mich. - In a new paper, published in Annals of Emergency Medicine, three female emergency physicians share the need for emergency departments to adopt best practices and strategies to support lactating emergency physicians.

"In the often hectic and unpredictable emergency department environment, lactating physicians can find it challenging to have set breaks to pump," says Mary Haas, M.D., an instructor in emergency medicine at Michigan Medicine and the lead author of the paper.

Haas and her colleagues note that a lack of support in the workplace, including lack of appropriate lactation spaces and departmental policies, can impair an emergency physicians' ability to meet lactation goals and lead to early cessation of breastfeeding.

The authors call for three broad categories of strategies -- time, space and support -- including tactics within each, that lactating physicians, their colleagues and departmental leadership can implement. For example, in the time category, the authors note that lactating physicians should set telephone reminders to pump, colleagues can recognize the need for lactating physicians to pump every three hours and departmental leadership can allow flexibility in clinical scheduling.

"It truly 'takes a village' to support lactating mothers," Haas says. "We hope this paper showcases the need for all parties in emergency medicine to be involved and supportive of our lactating colleagues."

A study of COVID-19 in the quarantined Italian town of Vò, where most of the population was tested, reveals the importance of asymptomatic cases.

The authors of the new research, from the University of Padova and at Imperial College London, published today in Nature, suggest asymptomatic or pre-symptomatic people are an important factor in the transmission of COVID-19. They also argue that widespread testing, isolating infected people, and a community lockdown effectively stopped the outbreak in its tracks.

The town of Vò, with a population of nearly 3,200 people, experienced Italy's first COVID-19 death on 21 February 2020. The town was put into immediate quarantine for 14 days. During this time, researchers tested most of the population for infection of SARS-CoV-2, the virus that causes COVID-19, both at the start of the lockdown (86 percent tested) and after two weeks (72 percent tested).

The testing revealed that at the start of the lockdown, 2.6 percent of the population (73 people) were positive for SARS-CoV-2, while after a couple of weeks only 1.2 percent (29 people) were positive. At both times, around 40 percent of the positive cases showed no symptoms (asymptomatic). The results also show it took on average 9.3 days (range of 8-14 days) for the virus to be cleared from someone's body.

None of the children under ten years old in the study tested positive for COVID-19, despite several living with infected family members. This is in contrast to adults living with infected people, who were very likely to test positive.

As a result of the mass testing any positive cases, symptomatic or not, were quarantined, slowing the spread of the disease and effectively suppressing it in only a few short weeks.

Co-lead researcher Professor Andrea Crisanti, from the Department of Molecular Medicine of the University of Padua and the Department of Life Sciences at Imperial, said: "Our research shows that testing of all citizens, whether or not they have symptoms, provides a way to manage the spread of disease and prevent outbreaks getting out of hand. Despite 'silent' and widespread transmission, the disease can be controlled."

The results of the mass testing programme in Vò informed policy in the wider Veneto Region, where all contacts of positive cases were offered testing. "This testing and tracing approach has had a tremendous impact on the course of the epidemic in Veneto compared to other Italian regions, and serves as a model for suppressing transmission and limiting the virus' substantial public health, economic and societal burden," added Professor Crisanti.

As well as identifying the proportion of asymptomatic cases, the team also found that asymptomatic people had a similar 'viral load' - the total amount of virus a person has inside them - as symptomatic patients.

Viral load also appeared to decrease in people who had no symptoms to begin with but later developed symptoms, suggesting that asymptomatic and pre-symptomatic transmission could contribute significantly to the spread of disease, making testing and isolating even more important in controlling outbreaks.

Co-lead researcher Dr Ilaria Dorigatti, from the MRC Centre for Global Infectious Disease Analysis, Jameel Institute (J-IDEA), at Imperial College London, said: "The Vò study demonstrates that the early identification of infection clusters and the timely isolation of symptomatic as well as asymptomatic infections can suppress transmission and curb an epidemic in its early phase. This is particularly relevant today, given the current risk of new infection clusters and of a second wave of transmission.

"There are still many open questions about the transmission of the SARS-CoV-2 virus, such as the role of children and the contribution of asymptomatic carriers to transmission. Finding answers to these questions is crucial to identifying targeted and sustainable control strategies to combat the spread of SARS-CoV-2 in Italy and around the world."

Professor Enrico Lavezzo, from the Department of Molecular Medicine at the University of Padua said: "The result concerning asymptomatic carriers is key. We took a picture of the Vò population and found that about half of the population testing positive had no symptoms at the time of testing and some of them developed symptoms in the following days. This tells us that if we find a certain number of symptomatic people testing positive, we expect the same number of asymptomatic carriers that are much more difficult to identify and isolate.

"The fact that the viral load is comparable between symptomatic and asymptomatic carriers means even asymptomatic infections have the potential to contribute to transmission, as some of the reconstructed chain of transmission obtained from the detailed contact tracing conducted in Vò confirmed.

"On the one hand, it is likely that a symptomatic infection transmits large quantities of virus, for example via coughing, but it is also reasonable to think that symptoms may induce a person with a symptomatic infection to stay at home, limiting the number of contacts and hence the transmission potential. On the other hand, someone with an asymptomatic infection is entirely unconscious of carrying the virus and, according to their lifestyle and occupation, could meet a large number of people without modifying their behaviour."

Winter squash is an important crop grown in the Willamette Valley, and the most important processing cultivar, Golden Delicious, has been grown in Oregon since the 1970s. Over the last two decades, however, growers have noticed yield declines throughout the valley. Agriculture specialists have identified an association between yield decline and disease symptoms such as stunting, vascular discoloration, late-season vine collapse, and root and crown rot, all symptoms of soilborne disease.

As causal agents for this problem had not been characterized, pathologists conducted two surveys. One to identify fungi associated with symptomatic squash tissue to establish the population present in diseased squash. The second identified fungi associated with squash randomly selected from 49 fields to establish the general fungal population associated with squash. The fungi collected from each field was compared to identify factors associated with the presence or absence of disease symptoms.

"The results of our analyses show that certain fungi are able to colonize particular tissues better than others and a history of squash production was often indicative of greater disease severity," explained Hannah Rivedal, the paper's first author. "Ultimately we identified a shortlist of five potential causal agents that will be studied further, to determine if they can reproduce the symptoms associated with winter squash yield decline."

This research has instructed growers to stop overwatering early in the growing season, which is when primary infections can occur, and has also highlighted the need for rotation out of winter squash for at least 3 to 4 years.

Rivedal and her colleagues' work is unique due to its usage of statistical analyses from community ecology. This method could be helpful to other plant pathologists diagnosing similar disease problems without a clear causal agent.

"These analyses can identify likely causal agents out of a relatively large pool of potential pathogens, which is helpful as disease systems change with climate and are caused by less conspicuous disease agents."

As for Rivedal and her lab, in future studies they will report the pathogenic ability of these fungi, how that ability is enhanced or diminished in different combinations, and which winter squash and other cucurbits are most susceptible to the disease.