Culture

In 2013, the Nobel Prize in Physiology or Medicine was awarded to three scientists for their contributions to uncovering the mechanisms governing vesicle transport in cells. Their explanations provided both a conceptual and a mechanistic understanding of basic processes at the most fundamental level.

At the heart of this Nobel Prize-winning intracellular process lies SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors), a superfamily of 60 proteins in mammalian cells that transport lipids and membrane proteins across the cells by facilitating the fusion of vesicles to their target membranes.

Biologists at UC Santa Barbara have now discovered a surprising, additional function for syntaxin 3S, a soluble form of a SNARE protein. The researchers found a new signaling pathway widely used by human and other mammalian cells. The team's results appear in the Journal of Biological Chemistry.

"What we found was very unorthodox and hadn't been known before," explained corresponding author Thomas Weimbs, a professor in UCSB's Department of Molecular, Cellular, and Developmental Biology. "Syntaxin 3S binds to transcription factors -- proteins involved in converting DNA into RNA -- and regulates the expression of the genes controlled by those factors. In fact, our initial results suggest that these genes play a role in cancer progression, but that remains to be definitively proved."

In a scientific first, the UCSB researchers showed that besides the well-established role of syntaxin 3 in membrane fusion, its novel soluble version is transported to the cell's nucleus and carries out a completely different function. In nature, many proteins have more than one function -- a phenomenon known as protein moonlighting.

That syntaxins -- and SNARE proteins in general -- are capable of moonlighting was unknown until now. Given that syntaxins are present in all cells and responsible for a large number of essential cell functions, the discovery that these proteins can carry out additional functions suggests that much more is yet to be discovered.

"Finding that syntaxin 3S functions as a nuclear regulator is the beginning of a story that opens up a new field of research," Weimbs said. "It's like a field of snow with no footsteps on it because nobody has done research on this, so we can pick and choose the most exciting directions to follow."

Weimbs and his colleagues identified similar nuclear-targeted soluble forms of other syntaxins, which indicates that this signaling pathway is a conserved, novel function common among these membrane-trafficking proteins.

In the future, the UCSB biologists would like to delineate how far-reaching the functions of these new soluble syntaxin versions are. Are there other unidentified forms of syntaxin that bind to similar nuclear import factors? Do they bind to different or similar transcription factors? Do they regulate different genes?

Researchers at the University of Washington have designed a convenient and natural product that uses proteins to rebuild tooth enamel and treat dental cavities.

The research finding was first published in ACS Biomaterials Science and Engineering.

"Remineralization guided by peptides is a healthy alternative to current dental health care," said lead author Mehmet Sarikaya, professor of materials science and engineering and adjunct professor in the Department of Chemical Engineering and Department of Oral Health Sciences.

The new biogenic dental products can -- in theory -- rebuild teeth and cure cavities without today's costly and uncomfortable treatments.

"Peptide-enabled formulations will be simple and would be implemented in over-the-counter or clinical products," Sarikaya said.

Cavities are more than just a nuisance. According to the World Health Organization, dental cavities affect nearly every age group and they are accompanied by serious health concerns. Additionally, direct and indirect costs of treating dental cavities and related diseases have been a huge economic burden for individuals and health care systems.

"Bacteria metabolize sugar and other fermentable carbohydrates in oral environments and acid, as a by-product, will demineralize the dental enamel," said co-author Sami Dogan, associate professor in the Department of Restorative Dentistry at the UW School of Dentistry.

Although tooth decay is relatively harmless in its earliest stages, once the cavity progresses through the tooth's enamel, serious health concerns arise. If left untreated, tooth decay can lead to tooth loss. This can present adverse consequences on the remaining teeth and supporting tissues and on the patient's general health, including life-threating conditions.

Good oral hygiene is the best prevention, and over the past half-century, brushing and flossing have reduced significantly the impact of cavities for many Americans. Still, some socio-economic groups suffer disproportionately from this disease, the researchers said. And, according to recent reports from the Centers for Disease Control and Prevention, the prevalence of dental cavities in Americans is again on the rise, suggesting a regression in the progress of combating this disease.

Taking inspiration from the body's own natural tooth-forming proteins, the UW team has come up with a way to repair the tooth enamel. The researchers accomplished this by capturing the essence of amelogenin -- a protein crucial to forming the hard crown enamel -- to design amelogenin-derived peptides that biomineralize and are the key active ingredient in the new technology. The bioinspired repair process restores the mineral structure found in native tooth enamel.

"These peptides are proven to bind onto tooth surfaces and recruit calcium and phosphate ions," said Deniz Yucesoy, a co-author and a doctoral student at the UW.

The peptide-enabled technology allows the deposition of 10 to 50 micrometers of new enamel on the teeth after each use. Once fully developed, the technology can be used in both private and public health settings, in biomimetic toothpaste, gels, solutions and composites as a safe alternative to existing dental procedures and treatments. The technology enables people to rebuild and strengthen tooth enamel on a daily basis as part of a preventive dental care routine. It is expected to be safe for use by adults and children.

UCLA biochemists have achieved a first in biology: viewing at near-atomic detail the smallest protein ever seen by the technique whose development won its creators the 2017 Nobel Prize in chemistry. That technique, called cryo-electron microscopy, enables scientists to see large biomolecules, such as viruses, in extraordinary detail.

Until now, this method has not worked with the thousands of much smaller proteins, which can cause diseases if defective, that are inside cells. A team led by Todd Yeates, a UCLA professor of chemistry and biochemistry, reports results that hold the promise of using cryo-electron microscopy to better understand many important proteins. The research is published in the journal Proceedings of the National Academy of Sciences.

"This new method should be useful broadly," said Yeates, who is a member of the Institute for Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Yeates' research team published the first research, in 2001, in the scientific field of designing molecular cages built from protein molecules. In the new research, his team used "protein engineering" to attach 12 copies of a small protein to a cube-shaped molecular cage, which was designed by a former graduate student of Yeates'. The small protein, called a DARPin, is too small to analyze using cryo-electron microscopy alone. But when the researchers attached the copies to the protein cage, they succeeded in seeing the DARPin with cryo-electron microscopy.

A challenge the researchers overcame was getting the copies of the protein to attach in a rigid manner. Their new method, which Yeates calls "scaffolding," can be modified easily to bind to many different proteins as a "universal protein scaffold."

"The small protein we attached can itself be made to bind to other proteins, which can then be studied by cryo-electron microscopy," said Yeates, whose research team is currently working on doing this.

The development of cryo-electron microscopy earned Jacques Dubochet, Joachim Frank and Richard Henderson the 2017 Nobel Prize in Chemistry.

Why is it so important to see a protein in such detail?

"The last 50 years of structural biology has been about trying to get detailed pictures of all the parts of the cell to understand them thoroughly," Yeates said. "A picture is worth 1,000 words, and very often, getting a first three-dimensional view of a component of the cell gives you valuable insight -- often surprising and unexpected -- that you could not anticipate. When you see it, you frequently think, now I see how it does what it does."

Many diseases are due to a mutation or defect in a protein. Seeing the defect can provide an understanding of what causes diseases, which can lead to new pharmaceuticals and treatments for diseases.

About a year and a half ago, a 6-year-old boy arrived at Children's Emergency Department after accidently removing his own gastrointestinal feeding tube. He wasn't a stranger to Children's National Health System: This young patient had spent plenty of time at the hospital since birth. Diagnosed in infancy with an intestinal pseudo-obstruction, a rare condition in which his bowels acted as if there were a blockage even though one was not present, parts of his intestine died and had been removed through multiple surgeries.

Because of this issue and associated health problems, at 4 years old he had a central line placed in a large vein that leads to his heart. That replaced other central lines placed in his neck earlier after those repeatedly broke. This latest central line in his chest als0 had frequent breaks. It also had become infected with multidrug-resistant Klebsiella bacteria two years before he was treated at Children's National for inadvertently removing his feeding tube.

On that day, he seemed otherwise well. His exam was relatively unremarkable, except for a small leak in his central line and a slight fever. Those findings triggered cultures taken both from blood flowing through his central line and the surrounding skin.

"No one expected him to grow anything from these cultures, especially from a child who looked so healthy," explains Madan Kumar, a fellow in Children's division of Pediatric Infectious Disease and a member of the child's care team. But a mold grew prolifically. Further investigation from a sample sent to the National Institutes of Health showed that it was a relatively new species known as Mucor velutinosus.

Because such an infection had never been reported in a child whose immune system wasn't extremely compromised from cancer, Kumar and team decided to publish a case report. The study appeared online Jan. 24, 2018, in the Journal of the Pediatric Infectious Diseases Society.

Kumar notes that this patient faced myriad challenges. Not only did he have a central line, but the line also had numerous problems, necessitating fixes that could increase the chance of infection. Additionally, because of his intestinal issues, he had a chronic problem with malabsorption of nutrients. Patients with this issue often are treated liberally with antibiotics. Although this intervention can kill "bad" bacteria that can cause an infection, they also knock out "good" bacteria that keep other microorganisms--like fungi--in check. On top of all of this, the patient was receiving a nutrient-rich formula in his central line to boost his caloric intake, yet another factor associated with infections.

Patients who develop this specific fungal infection are overwhelmingly adults who are immunocompromised, Kumar explains, including those with diabetes, transplant recipients, patients with cancer and those who have abnormally low concentrations of immune cells called neutrophils in their blood. The only children who tend to get this infection are preterm infants of very low birth weight who haven't yet developed a robust immune response.

Because there was only one other published case report about a child with M. velutinosus--a 1-year-old with brain cancer who had undergone a bone marrow transplant--Kumar notes that he and colleagues were at a loss as to how best to treat their patient. "There's a paucity of literature on what to do in a case like this," he says.

Fortunately, the treatment they selected was successful. As soon as the cultures came back positive for this mold, the patient went on a three-week course of an antifungal drug known as amphotericin B. Surgeons also removed his infected central line and placed a new one. These efforts cured the patient's infection and preventing it from spreading and potentially causing the multi-organ failure associated with these types of infections.

This case taught Kumar and colleagues quite a bit--knowledge that they wanted to share by publishing the case report. For example, it reinforces the importance of central line care. It also highlights the value of thoroughly investigating potential problems in a patient with risk factors, even one who appears otherwise healthy.

Finally, Kumar adds, the case emphasizes the importance of good antibiotic stewardship, which can help prevent patients from developing sometimes deadly secondary infections like this one. "This is not an organism that you see growing in a 6-year-old very often," he says. "The fact that we saw it here speaks to the need to be judicious with broad-spectrum antibiotics so that we have a number of therapeutic options should we see unusual cases like this one."

Deep space is not as silent as we have been led to believe. Every few minutes a pair of black holes smash into each other. These cataclysms release ripples in the fabric of spacetime known as gravitational waves. Now Monash University scientists have developed a way to listen in on these events. The gravitational waves from black hole mergers imprint a distinctive whooping sound in the data collected by gravitational-wave detectors. The new technique is expected to reveal the presence of thousands of previously hidden black holes by teasing out their faint whoops from a sea of static.

Last year, in one of the biggest astronomical discoveries of the 21st century, LIGO Scientific Collaboration (LSC) and Virgo Collaboration researchers measured gravitational waves from a pair of merging neutron stars.

Drs Eric Thrane and Rory Smith, from the ARC Centre of Excellence for Gravitational Wave Discovery (OzGrav) and Monash University, were part of the team involved in last year's discovery and were also part of the team involved in the detection of first gravitational-wave discovery in 2015, when ripples in the fabric of space time generated by the collision of two black holes in the distant Universe were first witnessed, confirming Albert Einstein's 1915 general theory of relativity.

To date, there have been six confirmed, or gold plated, gravitational-wave events announced by the LIGO and Virgo Collaborations. However there are, according to Dr Thrane, more than 100,000 gravitational wave events every year too faint for LIGO and Virgo to unambiguously detect. The gravitational waves from these mergers combine to create a gravitational-wave background. While the individual events that contribute to it cannot be resolved individually, researchers have sought for years to detect this quiet gravitational-wave hum.

In a landmark paper in the US journal, Physical Review X, the two researchers have developed a new, more sensitive way of searching for the gravitational-wave background.

"Measuring the gravitational-wave background will allow us to study populations of black holes at vast distances. Someday, the technique may enable us to see gravitational waves from the Big Bang, hidden behind gravitational waves from black holes and neutron stars," Dr Thrane said.

The researchers developed computer simulations of faint black hole signals, collecting masses of data until they were convinced that - within the simulated data - was faint, but unambiguous evidence of black hole mergers. Dr Smith is optimistic that the method will yield a detection when applied to real data. According to Dr Smith, recent improvements in data analysis will enable the detection of "what people had spent decades looking for." The new method is estimated to be one thousand times more sensitive, which should bring the long-sought goal within reach.

Importantly the researchers will have access to a new $4 million supercomputer, launched last month (March) at the Swinburne University of Technology. The computer, called OzSTAR, will be used by scientists to look for gravitational waves in LIGO data.

According to OzGRav Director, Professor Matthew Bailes, the supercomputer will allow OzGrav's researchers to attempt these kind of landmark discoveries.

"It is 125,000 times more powerful than the first supercomputer I built at the institution in 1998."

The OzStar computer differs from most of the more than 13,000 computers used by the LIGO community, according to Dr Smith, including those at CalTech and MIT. OzStar employs graphical processor units (GPUs), rather than more traditional central processing units (CPUs). For some applications, GPUs are hundreds of times faster. "By harnessing the power of GPUs, OzStar has the potential to make big discoveries in gravitational-wave astronomy," Dr Smith said.

First study to show 'owls' have higher risk of mortality

Switch to daylight savings time is much harder for them

They suffer from more diseases and disorders than morning larks

Employers should allow greater flexibility in working hours

Consider abolishing daylight savings time, scientists say

CHICAGO --- "Night owls" -- people who like to stay up late and have trouble dragging themselves out of bed in the morning -- have a higher risk of dying sooner than "larks," people who have a natural preference for going to bed early and rise with the sun, according to a new study from Northwestern Medicine and the University of Surrey in the United Kingdom (UK).

The study, on nearly half a million participants in the UK Biobank Study, found owls have a 10 percent higher risk of dying than larks. In the study sample, 50,000 people were more likely to die in the 6½ -year period sampled.

"Night owls trying to live in a morning lark world may have health consequences for their bodies," said co-lead author Kristen Knutson, associate professor of neurology at Northwestern University Feinberg School of Medicine.

Previous studies in this field have focused on the higher rates of metabolic dysfunction and cardiovascular disease, but this is the first to look at mortality risk.

The study will be published April 12 in the journal Chronobiology International.

The scientists adjusted for the expected health problems in owls and still found the 10 percent higher risk of death.

"This is a public health issue that can no longer be ignored," said Malcolm von Schantz, a professor of chronobiology at the University of Surrey. "We should discuss allowing evening types to start and finish work later, where practical. And we need more research about how we can help evening types cope with the higher effort of keeping their body clock in synchrony with sun time."

"It could be that people who are up late have an internal biological clock that doesn't match their external environment," Knutson said. "It could be psychological stress, eating at the wrong time for their body, not exercising enough, not sleeping enough, being awake at night by yourself, maybe drug or alcohol use. There are a whole variety of unhealthy behaviors related to being up late in the dark by yourself."

In the new study, scientists found owls had higher rates of diabetes, psychological disorders and neurological disorders?

Can owls become larks?

Genetics and environment play approximately equal roles in whether we are a morning or a night type, or somewhere in between, the authors have previously reported.

"You're not doomed," Knutson said. "Part of it you don't have any control over and part of it you might."

One way to shift your behavior is to make sure you are exposed to light early in the morning but not at night, Knutson said. Try to keep a regular bedtime and not let yourself drift to later bedtimes. Be regimented about adopting healthy lifestyle behaviors and recognize the timing of when you sleep matters. Do things earlier and be less of an evening person as much as you can.

Society can help, too

"If we can recognize these chronotypes are, in part, genetically determined and not just a character flaw, jobs and work hours could have more flexibility for owls," Knutson said. "They shouldn't be forced to get up for an 8 a.m. shift. Make work shifts match peoples' chronotypes. Some people may be better suited to night shifts."

In future research, Knutson and colleagues want to test an intervention with owls to get them to shift their body clocks to adapt to an earlier schedule. "Then we'll see if we get improvements in blood pressure and overall health," she said.

The switch to daylight savings or summer time is already known to be much more difficult for evening types than for morning types.

"There are already reports of higher incidence of heart attacks following the switch to summer time," says von Schantz. "And we have to remember that even a small additional risk is multiplied by more than 1.3 billion people who experience this shift every year. I think we need to seriously consider whether the suggested benefits outweigh these risks."

How the study worked

For the study, researchers from the University of Surrey and Northwestern University examined the link between an individual's natural inclination toward mornings or evenings and their risk of mortality. They asked 433,268 participants, age 38 to 73 years, if they are a "definite morning type" a "moderate morning type" a "moderate evening type" or a "definite evening type." Deaths in the sample were tracked up to six and half years later.

Analyzing the famous academic aphorism "publish or perish" through a modern digital lens, a group of emerging ecologists and conservation scientists wanted to see whether communicating their new research discoveries through social media--primarily Twitter--eventually leads to higher citations years down the road.

Turns out, the tweets are worth the time investment.

"There's a compelling signal that citation rates are positively associated with science communication through social media. Certainly, Twitter provides an accessible and efficient platform for scientists to do a majority of that communication," said Clayton Lamb, a University of Alberta PhD student and lead researcher on a new study out today.

"The good papers that get pushed on social media are what end up on people's minds and eventually as PDFs in their reference manager," he said.

As is common among scientists, what started as a personal curiosity turned into a full-scale study. Along with Sophie Gilbert, a former U of A post-doc now working in the Department of Fish and Wildlife Sciences at the University of Idaho, and Adam Ford, an assistant professor at UBC (Okanagan), Lamb explored the phenomenon of science communication in the social media age, measuring the association of altmetrics--alternative impact factors, which consider, amongst other avenues, social media attention surrounding science discoveries--with eventual citation of 8,300 ecology and conservation papers published between 2005 and 2015.

The three scientists, who use Twitter to communicate daily about their science (see @ClaytonTLamb, @SophieLGilbert, and @adamthomasford), found a positive correlation between social media engagement and traditional measures of scholarly activity.

"There's a big hype when a paper comes out, but then there is this underwhelming lull for a year or two as you wait for citations to accumulate, so you don't really know whether your science is reaching people. We quantified whether science communication may correlate with more citations. In the case of ecology and conservation science, it looks like it does," said Lamb, who is completing his PhD tracking grizzly bear population patterns with supervisors Stan Boutin in the Faculty of Science and Scott Nielsen in the Faculty of Agricultural, Life, & Environmental Sciences.

Science communication is viewed as critical to ecology and conservation, where research findings are often used to shape public policy and mainstream media attention. Lamb said though much of scientists' communication on social media is directed at other scientists, by virtue of the medium, information is making its way to the broader community, noting statistics showing that nearly half of ecologists' followers on Twitter are non-scientists, environmental groups and the media.

"Ecologists and conservation scientists are dealing with applied problems that the public cares a lot about. So when science gets stuck in the circles of academia and doesn't make it out to the public, it's doing that publicly funded research and its potential applications, a disservice," said Lamb.

"In this era of alternative facts and some mixed messaging surrounding science, data-driven scientific information offers a light of truth. Twitter is one of the ways we can help share science with policy-makers, other scientists and the public."

NEW YORK, April 11, 2018 - Salaries for U.S. physicians edged higher this past year, with compensation increasing modestly for most specialties, while jumping 16% for psychiatrists. Still, the gender gaps in compensation remain unchanged and failed to budge for African-American physicians, according to the results of the 2018 Medscape Physician Compensation Report. Yet, despite concerns regarding pay equity and skyrocketing bureaucratic demands, the majority of physicians remain committed to the profession and are happy they chose to be doctors.

The Report is the most comprehensive and widely used physical salary survey in the U.S. Now in its 8th year, it has been used by more than 470,000 physicians in the U.S. to assess information on compensation, hours worked, time spent with patients, and what they find most rewarding -- and challenging -- about their jobs. More than 20,000 U.S. physicians across 29 specialties responded to the survey.

"We're seeing the impact of supply and demand on physicians' salaries in this year's report," said Leslie Kane, MA, Senior Director, Medscape Business of Medicine. "The growing need for more doctors as the population ages is pushing salaries higher. At the same time, the amount of paperwork and bureaucratic demands escalate, leaving doctors with less time to see patients. We also see the influence of the opioid epidemic and the demand for psychiatrists to treat aging patients leading to increased salaries."

Regarding the continued gender pay disparity, one leading family practice physician is calling for greater salary transparency in the medical profession, so that women would know how much their male colleagues are earning.

"You would think that as we narrow the gap of representation of women in medicine, that would narrow the wage gap, but it's not happening," says Ranit Mishori, MD, professor of family medicine at Georgetown University School of Medicine. "The lack of salary transparency adds to the challenges of addressing gender-based pay disparities. Women don't even know what targets to shoot for."

Physician salaries average $299,999 in this year's report, up from $294,000 in 2017; specialists earn about $100,000 more than primary care physicians ($329,000 versus $223,000), and plastic surgeons ranked highest in salary at $501,000 -- outpacing orthopedists ($497,000) for the first time since the report has been conducted, which may be a reflection of greater demand fueled by increased popularity of cosmetic procedures. Pediatricians and family practice physicians report the lowest compensation, at $212,000 and $219,000 respectively.

The amount of time physicians spend on paperwork and administrative tasks continues to increase, with nearly three quarters (71%) spending more than 10 hours per week on paperwork -an increase of 13 percentage points in one year.

"Although physicians put paperwork and long hours at the top of their list of professional challenges, we continue to see an abiding sentiment across all specialties that being a physician is rewarding, despite the issues," said Medscape Chief Medical Director Michael Smith, M.D. "The majority of physicians feel fairly compensated, and even though about 40% might have chosen another specialty in hindsight, 77% are satisfied with their decision to become a doctor. It's important to note the rewards come from making a difference and gratitude from patients. Money ranks lower on the list of genuine rewards."

Additional Report Highlights

Gender Disparities Remain in Primary Care and Specialties

Male primary care doctors earned almost 18% more than female primary care doctors, and men in specialties earned 36% more than women this year versus 31% last year. Male primary care physicians' compensation averaged $239,000 versus $203,000 for women, and males in specialties earned an average $358,000 versus $263,000 for women.

Race/Ethnicity and Physician Income

Racial disparities in compensation remained unchanged, with African-American/black physicians earning an average $50,000 less per year than white physicians ($308,000 for white physicians versus $258,000 for black physicians). African-American/black women made nearly $100,000 less than male African-American physicians ($322,000 for men versus $225,000 for African American/black women). Asian-American physicians earned an average $293,000 per year and Hispanic/Latino physicians earned an average $278,000.

Location Makes a Difference

Less populated states continue to be more lucrative than more densely populated regions, with physicians in the North Central region earning the highest, at $319,000, and the Northeast the lowest, at $275,000. The states with the highest average physician salaries are Indiana, Oklahoma and Connecticut; New Mexico, Maryland and Washington DC rank lowest. The number of physicians in a region, percent of insured patients and the overall concentration of specialists play a role in regional compensation differences.

To view the full Medscape 2018 Physician Compensation Report, visit:
https://www.medscape.com/slideshow/2018-compensation-overview-6009667?faf=1

To view the 2018 report before the embargo, please use this link:
https://www.staging.medscape.com/slideshow/2018-compensation-overview-6009667?faf=1

Medscape Survey Methods:

The 2018 Medscape Physician Compensation Survey was completed by more than 20,000 physicians representing 29 specialty areas, including Medscape members and nonmembers. Respondents were invited to respond to the online survey. The margin of error for the survey was +/- 0.69% at a 95% confidence level.

About Medscape

Medscape is the leading source of clinical news, health information, and point-of-care tools for health care professionals. Medscape offers primary care physicians, subspecialists, and other health professionals the most robust and integrated medical information and educational tools. Medscape Education (medscape.org) is the leading destination for continuous professional development, consisting of more than 30 specialty-focused destinations offering thousands of free C.M.E. and C.E. courses and other educational programs for physicians, nurses, and other health care professionals.

PHILADELPHIA - A new type of cancer vaccine has yielded promising results in an initial clinical trial conducted at the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center of the University of Pennsylvania. The personalized vaccine is made from patients' own immune cells, which are exposed in the laboratory to the contents of the patients' tumor cells, and then injected into the patients to initiate a wider immune response. The trial, conducted in advanced ovarian cancer patients, was a pilot trial aimed primarily at determining safety and feasibility, but there were clear signs that it could be effective: About half of the vaccinated patients showed signs of anti-tumor T-cell responses, and those "responders" tended to live much longer without tumor progression than those who didn't respond. One patient, after two years of vaccinations, was disease-free for another five years without further treatment. The study is published today in Science Translational Medicine.

"This vaccine appears to be safe for patients, and elicits a broad anti-tumor immunity--we think it warrants further testing in larger clinical trials," said study lead author Janos L. Tanyi, MD, an assistant professor of obstetrics and gynecology at Penn Medicine.

The study was led by Lana Kandalaft, PharmD, PhD, MTR, George Coukos, MD, PhD, and Alexandre Harari, PhD, of the Lausanne Branch of the Ludwig Institute for Cancer Research. Kandalaft and Coukos devised a novel method for making a vaccine of this sort while at the Perelman School of Medicine at the University of Pennsylvania.

Most cancer vaccines developed to date have been designed to recognize and attack a specific known molecule--such as a cell-surface receptor--that is likely to be found on cancerous cells in any patient with that type of tumor. The approach taken by the Lausanne-Penn team is more ambitious. Each vaccine is essentially personalized for the individual patient, using the patient's own tumor which has a unique set of mutations and thus a unique presentation to the immune system. It is also a whole-tumor vaccine, meant to stimulate an immune response against not just one tumor-associated target but hundreds or thousands.

"The idea is to mobilize an immune response that will target the tumor very broadly, hitting a variety of markers including some that would be found only on that particular tumor," Tanyi said.

The vaccine harnesses the natural process of T-cell immunity to tumors, but enhances it to help overcome tumors' formidable defenses. Tanyi and colleagues made each patient's vaccine by sifting through the patient's own peripheral blood mononuclear cells for suitable precursor cells, and then growing these, in the lab, into a large population of dendritic cells. Dendritic cells are essential for an effective T-cell immune response. They normally ingest infectious pathogens, tumor cells, or anything else considered "foreign," and re-display pieces of the invader to T-cells and other elements of the immune system, to trigger a specific response. The researchers exposed the dendritic cells to specially prepared extracts of the patient's tumor, activated the cells with interferon gamma, and injected them into the patient's lymph nodes, in order to prime a T-cell response.

The team tested this strategy on a total of 25 patients, each of whom received a dose of tumor-exposed dendritic cells every three weeks, in some cases for more than six months. Half of the patients that could be evaluated showed big increases in the numbers of T-cells specifically reactive to tumor material, indicating a good response to vaccination.

"The 2-year overall survival rate of these responder patients was 100 percent, whereas the rate for non-responders was just 25 percent," Tanyi said.

One patient, a 46-year old woman, started the trial with stage 4 ovarian cancer--which generally has a very poor prognosis--following five prior courses of chemotherapy. She received 28 doses of her personalized vaccine over a two-year period, and thereafter remained disease-free for five years.

Also promising was the finding, in tests on several of the responders, of vaccine-induced T-cells that showed high affinity for unique structures ("neoepitopes") on their tumors. In principle, an attack by such T-cells on tumors should be particularly powerful as well as highly tumor-specific and thus sparing of healthy cells.

Tumors typically have a repertoire of molecular defenses they can use to suppress or evade immune attacks, which is why cancer vaccines and immunotherapies have had mixed results in clinical trials to date. Tanyi and colleagues therefore hope in future to enhance the effectiveness of their vaccine by combining it with other drugs that deactivate tumor anti-immune defenses.

(Millbrook, NY) Road salt applied during the winter lingers in the environment, where it can pollute drinking water supplies. In a recent study in the Journal of Environmental Quality, researchers identify landscape and geological characteristics linked to elevated well water salinity in a suburban township in Southeastern New York.

Victoria Kelly, lead author and Environmental Monitoring Program Manager at the Cary Institute of Ecosystem Studies, explains, "Each year, millions of metric tons of road salt are applied to roads in the US. Some of this salt seeps into the soil, where it accumulates and contaminates groundwater. We wanted to understand why some wells were more at risk than others, to inform management that protects water quality."

Kelly and colleagues analyzed publicly available data on water samples taken from 956 private drinking water wells in East Fishkill, New York between 2007 and 2013. More than half of the wells sampled exceeded US Environmental Protection Agency health standards for sodium. Distance to the nearest road and amount of nearby pavement strongly influenced well water salinity. Surprisingly, well depth and road type -- ranging from interstate highways to back roads -- did not have a significant impact.

GIS analysis of sodium and chloride concentrations was used to describe the pattern of road salt distribution in the aquifers tapped for drinking water, and to compare surface features in the surrounding area of each well location. The team assessed neighborhood-scale variables, including well depth, proximity to roads, well elevation relative to nearby roads, impervious surface, surface geology, and soil type to discern relationships between development and well salinity.

Findings linking pavement and other impervious surface cover to well salinity support a growing body of evidence that development and urbanization cause groundwater salinization. Proximity to a road increased a well's chloride concentration, yet road type - major or minor - did not have an impact. Well depth did not significantly impact saltiness and elevation in relation to nearby roads only affected wells when the roads were more than 30 meters from the nearest well.

Several hotspots, where salinization was especially high, were identified. Suggested contributing factors included sharp turns and steep grades that required heavier road salt application, and narrow streets that only accommodate older, less efficient salt trucks. There was only one cold spot, in an area of low housing density, reinforcing the relationship between urbanization, salt application, and freshwater salinization.

"Understanding the landscape features that lead to increased groundwater salinization can inform targeted salt application," explains Stuart Findlay, a freshwater ecologist at the Cary Institute of Ecosystem Studies. "The time to act is now, as we know it can take decades or more for the salt currently in groundwater to flush out."

Kelly adds, "In planning efforts to minimize road salt impacts, our findings tell us that smaller roads should not be overlooked and areas with a lot of pavement and porous, well-drained soils are most at risk of experiencing salinization. Road salting is not one-size-fits-all undertaking. More targeted approaches will keep roads safe while reducing unintended consequences to drinking water supplies."

Our emotional state in a given moment may influence what we see, according to findings published in Psychological Science, a journal of the Association for Psychological Science. In two experiments, researchers found that participants saw a neutral face as smiling more when it was paired with an unseen positive image.

The research shows that humans are active perceivers, say psychological scientist Erika Siegel of the University of California, San Francisco and her coauthors.

"We do not passively detect information in the world and then react to it - we construct perceptions of the world as the architects of our own experience. Our affective feelings are a critical determinant of the experience we create," the researchers explain. "That is, we do not come to know the world through only our external senses - we see the world differently when we feel pleasant or unpleasant."

In previous studies, Siegel and colleagues found that influencing people's emotional states outside of conscious awareness shifted their first impressions of neutral faces, making faces seem more or less likeable, trustworthy, and reliable. In this research, they wanted to see if changing people's emotional states outside awareness might actually change how they see the neutral faces.

Using a technique called continuous flash suppression, the researchers were able to present stimuli to participants without them knowing it. In one experiment, 43 participants had a series of flashing images, which alternated between a pixelated image and a neutral face, presented to their dominant eye. At the same time, a low-contrast image of a smiling, scowling, or neutral face was presented to their nondominant eye - typically, this image will be suppressed by the stimulus presented to the dominant eye and participants will not consciously experience it.

At the end of each trial, a set of five faces appeared and participants picked the one that best matched the face they saw during the trial.

The face that was presented to participants' dominant eye was always neutral. But they tended to select faces that were smiling more as the best match if the image that was presented outside of their awareness showed a person who was smiling as opposed to neutral or scowling

In a second experiment, the researchers included an objective measure of awareness, asking participants to guess the orientation of the suppressed face. Those who correctly guessed the orientation at better than chance levels were not included in subsequent analyses. Again, the results indicated that unseen positive faces changed participants' perception of the visible neutral face.

Given that studies often show negative stimuli as having greater influence on behavior and decision making, the robust effect of positive faces in this research is intriguing and an interesting area for future exploration, the researchers note.

Siegel and colleagues add that their findings could have broad, real-world implications that extend from everyday social interactions to situations with more severe consequences, such as when judges or jury members have to evaluate whether a defendant is remorseful.

Ultimately, these experiments provide further evidence that what we see is not a direct reflection of the world but a mental representation of the world that is infused by our emotional experiences.

(New York, NY- April 11, 2018) --Researchers from Mount Sinai and Sema4, a health information company and Mount Sinai venture, have discovered that giving metastatic bladder cancer patients simultaneous chemotherapy and immunotherapy is safe and that patients whose tumors have certain genetic mutations may respond particularly well to this combination approach, according to the results of a clinical trial published in European Urology.

Though chemotherapy and immunotherapy have become standard options for the treatment of metastatic bladder cancer, it was previously unknown whether these therapies could be given together and whether chemotherapy's side effect of weakening the immune system would inhibit immunotherapy. The phase 2 trial was conducted at six cancer centers, and patients in the trial did not show any additional or more severe side effects than patients given chemotherapy or immunotherapy alone, a finding that showed the combination therapy is a safe alternative.

Researchers also generated evidence showing that immunotherapy could boost immune cells in the blood of patients receiving concurrent chemotherapy, allaying previous concerns that chemotherapy might counteract the effects of immunotherapy.

"Because chemotherapy and immunotherapy are the two pillars of treatment for metastatic bladder cancer, we sought to better understand how these treatments might be best given together," said Matthew Galsky, MD, Director of Genitourinary Medical Oncology and Professor of Urology, Medicine, Hematology and Medical Oncology at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and Principal Investigator of the study. "Already the results of this trial have inspired the creation of two more trials that seek to better the treatment of bladder cancer patients by combining chemotherapy with immunotherapy."

One of the new trials, which Dr. Galsky is heading at Mount Sinai and other centers, gives chemotherapy and immunotherapy to a subset of patients with earlier-stage bladder cancer to determine if this combination can head off the need for surgery to remove the bladder, a standard treatment but one with quality-of-life-altering implications that include wearing a urostomy bag outside the body to collect urine. The other trial combines two different chemotherapy regimens with immunotherapy to determine the best types of chemotherapy drugs to combine with immunotherapy.

Dr. Galsky said that the current trial epitomizes the importance of team science. Dr. Galsky, as well as Andrew Uzilov, PhD, Director of Cancer Genomics for Sema4, and Huan Wang, PhD, Sema4 bioinformatics scientist, and other researchers hypothesized that patients with tumors with particular genetic mutations might respond best to the combination of chemotherapy and immunotherapy. And indeed, they found that certain types of mutations in DNA damage response (DDR) genes were associated with better response to the combined chemotherapy and immunotherapy. If validated in subsequent studies, these findings could add a novel biomarker to the "precision oncology toolbox" and refine the selection of patients who might benefit from concurrent administration of chemotherapy and immunotherapy.

"Our work is an example of using genomics to enable precision medicine. By looking for loss-of-function mutations in DDR genes, we may be able to predict who will do well on a combined chemotherapy plus immunotherapy regimen," explained Dr. Uzilov. "In our study, we looked at a pool of 55 DDR genes as predictive biomarkers. We are now exploring further which of these genes, and what types of mutations within them, best predict treatment response, as well as the interplay of DDR status with other predictors of immunotherapy response."

BLOOMINGTON, Ind. -- At a time when more Americans are living longer, the companies where many people spend their working lives have increasingly shorter lifespans, according to research from Indiana University's Kelley School of Business.

A paper by two Kelley professors, forthcoming in the Academy of Management Annals, found that the odds of a company surviving more than five years has declined dramatically since the 1960s and that this trend also holds for firms lasting 10, 15 and 20 years.

Companies emerging as publicly listed firms in the 1960s had a 50-50 shot of making it to their 20-year anniversary. By the 1990s, that percentage fell to 20 percent. Similarly, such companies used to have an 80 percent chance of being around after 10 years, but those odds were down to 50 percent for firms established after 2000.

These findings are based on an empirical analysis of nearly 32,000 U.S. publicly listed companies between 1960 and 2015 by Rene Bakker, assistant professor of management and entrepreneurship, and Matthew Josefy, assistant professor of strategy and entrepreneurship.

The researchers believe that long-held views about the age of companies have changed as organizations have become increasingly temporary in nature. Research on firm age dates back to the mid-1960s, but little has been done since the early 1990s. Bakker and Josefy question whether firm age today is anything more than a number and suggest that it may no longer predict organizational success.

"We believe this trend reflects an important shift in our understanding of the very DNA of what constitutes an organization," the researchers wrote. "Short-lived, temporary organizations that rapidly accomplish a complex task and disband on its accomplishment are increasingly common across a broad range of industries."

In the previous century, many businesses were run with the expectation that they'd be taken over by the next generation of a family.

"The history of American businesses was centered around these family enterprises," Josefy said. "The whole reason of incorporating was so the organization would live longer than the founder, giving them a sense of immortality. Here's the irony: These large corporations aren't even going to live as long as the founder, much less get passed down to the next generation of owners."

Classic management theory suggests that firm age is positively associated with learning, reliability and legitimacy. But today it may have more negative connotations in certain contexts, such as the tech sector, which rewards novelty and youthfulness.

In their paper, Bakker and Josefy raise the question of whether the American corporation is becoming more disposable, reflecting the temporary nature of other aspects of our society. They suspect that the diminishing lifespan of U.S. companies is partly due to more active merger and acquisition activity in recent years. But they also attribute it to a culture that encourages start-ups.

"We live in an environment where starting and liquidating a business is quite easy," Bakker said. "Many young firms today seem destined to become 'organizational supernovas,' which burn brighter but die quicker."

Once a start-up reaches its desired objectives, it may be acquired or morph into another entity with new goals.

"While society is often concerned to see businesses fail, sometimes it may be better for a company to die to free up resources and allow people to go on and do something else, rather than persist with uncertainty and stagnation," Josefy said. "Apparent failure of one entity may actually be the precursor to success of another."

URBANA, Ill. - When a natural disaster strikes, major disaster databases tend to compile information about losses such as damages to property or cost of repairs, but other economic impacts after the disaster are often overlooked--such as how a company's lost ability to produce products may affect the entire supply-chain within the affected region and in other regions.

Without using the right model to study these losses, the data may give an incomplete picture of the full financial impact of the disaster as it doesn't fully portray business interruptions incurred locally, or by trade partners, after the event. As a result, a locality may receive less than it should in state or federal government recovery support.

In a recent study, published in Earth System Dynamics, an interdisciplinary journal devoted to the study of Earth and global change, economists at the University of Illinois partnered with atmospheric scientists and hydrologists from U of I and UCLA, and with the Army Corps of Engineers to capture the characteristics of an atmospheric river--a transporter of water vapor in the sky--that hit the western part of Washington State in 2007. This event resulted in record flooding (a 500-year stream peak event in some parts of the river) and record damages.

The team hopes to show that carefully selecting the characteristics of the extreme weather event under study and the correct model to estimate losses--based on characteristics of the disaster and the affected region, and on the interdependence between one area and another--can help in determining vulnerability and preparing for future disasters, from an economic standpoint.

"This is quite different from what insurance companies do," explains Sandy Dall'Erba, an associate professor in the Department of Agricultural and Consumer Economics at U of I, and a co-author of the study. "After a disaster, when an insurance company comes, they basically say that your building has been destroyed by this particular amount. And because you were out of the building for, say, a week, you couldn't produce anything for a week. What insurance companies forget, and what our paper is trying to demonstrate is that the total amount of economic losses is much greater."

The ripple effects from a disaster can be significant if major industrial chains are disrupted when infrastructure is comprised. For instance, while the study finds that intersectoral and interregional linkages add up to around 10 percent in standard economic damage estimates in the small rural area chosen in this study, that share could go up to 50-70 percent for a major metropolitan area like Houston, Texas, because of its enormous transportation system and interregional trade.

"Let's say for instance that a company producing tires is flooded. Obviously, no tires are coming from that company," Dall'Erba explains. "The car company, which could be located in a place that wasn't flooded, suddenly is expecting a delay in the tires that are not coming on time anymore. There are all of these connections from one city to the next that are traditionally not accounted for after a disaster."

In his U of I lab, the Regional Economic Applications Laboratory (REAL), Dall'Erba studies very specific disaster events using a technique called input-output--a technique that shows the interdependencies between the sectors within a region and across different regions. He also teaches this technique in his home department (ACE) on a regular basis.

"We look at each industry. What kind of products and services do they buy? To whom do they sell their goods and services? In the case of Chehalis, Washington, that was flooded in 2007, it was mainly companies selling to other companies, not to individual households. Those are the kinds of links that we try to include in the work we do in REAL, how to understand that level of dependence between one location and other places. We also provide measurements that are very specific to each locality," Dall'Erba says.

Using the input-output technique helped the researchers calculate the actual losses after the event in Chehalis. "We rely on a huge amount of data to do it. We have information from each locality about how each industry is connected to every industry within that locality and outside of that locality so we can understand how dollars flow," he adds.

In addition, they must account for the timing of the event. "While the affected area is very agricultural, the luck it had is that the flood took place in December, way ahead of the growing season of the crop the locality depends the most on, corn. If it had taken place a few months later, the local economy would have experienced much larger losses," Dall'Erba says.

Finally, Dall'Erba's team is particularly careful to account for the location of the companies in charge of reconstruction. "Most of the literature assumes without evidence that reconstruction will dampen the local losses and boost employment. It turns out that for small rural communities--like the one in our study--no local construction company is present or is large enough to be in charge of reconstruction. As such, reconstruction efforts are delivered by companies outside of the affected economy and it is these other localities that see an increase in output and construction jobs," Dall'Erba adds.

The latter part of their study focuses on the future. Assuming that climate change will result in 15 percent more streamflow (water from rivers or streams) for all return periods, the authors find that the total losses would increase from $6.2 million, the figure seen during the actual event, to $8.6 million (a 39 percent increase).

"Adaptation strategies could include, among others, larger floodplains in upstream locations, levees close to critical buildings, and/or developing a more resilient supply-chain," Dall'Erba says. "However it is particularly hard for small rural communities as they do not always have the budget necessary to implement large adaptation projects; yet they have already been more frequently affected by floods than urban areas over the last few decades."

British researchers have discovered a hormone imbalance that explains why it is very difficult to control blood pressure in around 10 per cent of hypertension patients.

The team, led by Queen Mary University of London, found that the steroid hormone 'aldosterone' causes salt to accumulate in the bloodstream. The salt accumulation occurs even in patients on reasonable diets, and pushes up blood pressure despite use of diuretics and other standard treatments.

Two patients in the study with previously resistant hypertension were able to come off all drugs after a benign aldosterone-producing nodule was discovered in one adrenal and removed at surgery.

High blood pressure is one of the most common and important preventable causes of heart attack, heart failure, stroke and premature death. It affects over 1 billion people across the world and accounts for approximately 10 million potentially avoidable deaths per year.

Most patients can be treated effectively with adjustments to their lifestyle and the use of regular medication. However, in as many as 1 in 10 patients, blood pressure can be difficult to control and is termed 'resistant hypertension'. These patients are at the highest risk of stroke and heart disease because their blood pressure remains uncontrolled.

The new results come from a six-year trial in 314 patients with resistant hypertension, undertaken by investigators in the British Hypertension Society, funded by the British Heart Foundation and the National Institute for Health Research, and published in the journal The Lancet Diabetes & Endocrinology.

Chief Investigator Professor Morris Brown from Queen Mary University of London said: "This has been a wonderful story of using sophisticated modern methods to solve an old problem - why some patients have apparently intractable hypertension. The discovery of salt overload as the underlying cause has enabled us to identify the hormone which drives this, and to treat or cure most of the patients."

Professor Bryan Williams from University College London said: "These results are important because they will change clinical practice across the world and will help improve the blood pressure and outcomes of our patients with resistant hypertension.

"It is remarkable when so many advances in medicine depend on expensive innovation, that we have been able to revisit the use of drugs developed over half a century ago and show that for this difficult-to-treat population of patients, they work really well."

In previous work, the team showed that resistant hypertension is controlled much better by the drug spironolactone (a steroid blocker of aldosterone) than by drugs licensed for use in hypertension. Now they have shown that the superiority of spironolactone is due to its ability to overcome the salt excess in resistant hypertension.

They also found that spironolactone can be substituted, to good effect, by a drug, amiloride, which could be an option for patients unable to tolerate spironolactone.

The research comes from the PATHWAY-2 study, part of a series of studies designed to develop more effective ways of treating high blood pressure. It investigated the hypothesis that resistant hypertension was mainly caused by a defect in eliminating salt and water and that the high blood pressure in these patients would be best treated by additional diuretic therapy to promote salt and water excretion by the kidneys.