Culture

Cold Spring Harbor, NY -- Maize is a staple crop that came from humble beginnings. If you look at its wild ancestor, teosinte, the plant looks nearly unrecognizable. Human selection has persuaded the maize plant to grow in a way that produces higher yields and can be more efficiently harvested. But scientists and farmers are looking for ways, in the face of climate change, population growth, and other factors, to even further optimize maize yields.

Now, researchers at Cold Spring Harbor Laboratory (CSHL) have identified a relationship between crop yield in the maize plant and specific genetic activity associated with one of the plant's metabolic pathways. The discovery has implications for plant breeding, potentially opening the door for increasingly resilient, higher-yield maize plants.

CSHL Professor David Jackson and his team have connected the RAMOSA3 gene to branching, which can affect its yield. When a maize plant has too many branches, it will expend more energy towards making those branches, and less towards making seeds. More branches often means lower or less efficient yields.

Ears, the part of maize that we eat, are normally not branched at all--they just form one straight cob. But maize mutants that don't have the RAMOSA3 gene can end up with gnarly-looking branched ears.

Jackson and his team initially hypothesized that the enzyme that RAMOSA3 encodes, called TPP, and a sugar phosphate called T6P which TPP acts on, are likely responsible for the ear-branching. Although the precise function of T6P remains "largely elusive," the scientists believe that it has signaling properties.

Then, in a surprising twist, they found that a related gene, TPP4, also helps to control branching, but that gene's effect was unrelated to its enzymatic activity. They wondered if the same might be true for RAMOSA3 and its own enzymatic activity. To follow up on this, they blocked only the enzyme activity associated with RAMOSA3, and not the gene itself, and got normal-looking ears of maize. This indicates that although RAMOSA3 controls the activity of the enzyme, it seems the enzyme activity is not responsible for controlling branching. Thus, the gene may be "moonlighting" with a hidden activity, explains Jackson. The question of what that moonlighting may entail is a launching-off point for future research.

The team's findings were published in Nature Plants. Their work could lead to better crop yields and more efficient harvesting for the maize plant, as well as for other crops, like rice and quinoa.

Hamilton, ON (April 1, 2019) - The legalization of medical assistance in dying (MAID) in Canada has resulted in some people choosing to donate their bodies to anatomy programs, but it has raised profound ethical issues, says McMaster University's head of anatomy.

Bruce Wainman, director of the Education Program in Anatomy at McMaster, said the anatomical scientist community needs to establish guidelines around these donations.

The use of MAID, also known as 'active voluntary euthanasia' or 'voluntary euthanasia', is legally obtainable in Belgium, Canada, Colombia, Germany, Luxembourg, the Netherlands, Switzerland, the United States, and some parts of Australia.

As a result, Wainman said, there are issues about the appropriateness of accepting or using MAID body donations; communication with donors including consenting processes, and the transparency surrounding MAID donation with staff, faculty and students.

"These are profound questions that scrape at morals and ethics," Wainman said. "I don't think any of us have the answers right now."

His article on the topic, co-authored with medical ethicist Jon Cornwall of the University of Otago in New Zealand, was published in the journal Anatomical Sciences Education.

"At this point, it is unclear how many anatomical programs have accepted or are accepting bodies of persons who end their life using MAID, as no reliable information exists on this topic," said Wainman, professor of pathology and molecular medicine at McMaster.

"I wrote this discussion paper to raise the potential difficulties and ethical questions facing body donation programs where MAID exists, and to open the conversation. The last thing we would want to do is compromise our association with our community."

The McMaster University body donation program has accepted six MAID bodies between the time the legislation was enacted in June 2016 and November 2018.

"Right after the law was passed in Canada, the bodies began to arrive," Wainman said. "MAID makes up five per cent of our body donations now, but I can see it easily going to 10 per cent before the end of the year. That makes it five to 10 bodies a year."

Wainman said the process of receiving and using bodies from donors who undertake MAID poses many challenges for institutions like McMaster.

"We have a tremendous relationship with many people in the palliative care field, so it comes up as a discussion point: 'Are you interested in donating your body to anatomic study?'" he said. "We find the potential MAID donors are far more likely to want to donate their bodies to science. As a result, we are typically in contact with the donor themselves who reach out to us to talk about donation.

"An ethical question I face is that for these people who are so vulnerable, who are at that moment trying to decide if theirs is a life worth living, are we somehow inducing them to want to donate? Are we providing them with additional impetus to donate? It's a serious issue as the last thing we want to do is to bring about any pressure at this difficult point in their lives."

Then, there's the complexity about how to communicate the circumstances of these body donations with students in anatomy education programs at academic institutions, he noted.

Wainman said he decided upon the arrival of the first MAID body donation that his policy of transparency and openness at McMaster's anatomy program would continue. He said everyone, from faculty members to students, who interact with the body donations know the circumstances. To date, no concerns have been expressed.

"We are having discussions - important discussions - in our anatomy lab on what it means to receive a body that has not died of natural causes," he said. "On the death certificate it lists the cause which compelled them to seek MAID, not from medical assistance in death, but we are aware of the circumstances beyond that. It's important in every possible way to be transparent. Everyone we train here at McMaster has an interest in human health, and this is an additional ethical issue for them to think about.

"Human health is not just about the function of your lungs and kidneys, it's also about the person who lives in that body."

There are guidelines around body donation to anatomy facilities, such as those from the International Federation of Associations of Anatomists (2012) and the American Association of Anatomists (2009).

However, Wainman pointed out these guidelines do not refer directly to the acceptance of MAID bodies, likely due to the newness of euthanasia laws. As such, the current guidelines are silent on the use of MAID bodies in the anatomical sciences.

"Further guidance from local and international recommendations are needed to raise awareness on this sensitive topic and ensure that MAID donors are treated with respect and that good practice around MAID donations can be consistently adopted," said Wainman.

Wainman and Cornwall will be presenting on the issue at a summer meeting of the International Federation of Associations of Anatomists in London, England.

He said he expects there to be significant discussion as a result of the paper and subsequent presentations.

"This is such a new discussion for our field," he said. "I'm sure we're going to ignite a huge discussion, which is exactly the point of this article."

Wainman added that the authors consulted with Sabine Hildebrandt, a medical ethicist and associate professor of pediatrics at Harvard University.

ORLANDO, Fla., March 31, 2019 -- The sugar maple tree yields autumn foliage, maple syrup and Tennessee whiskey. Wood from the tree is chopped into planks, stacked in piles and burned to form charcoal. Freshly distilled, un-aged whiskey is filtered over the charcoal in a mysterious, but necessary step known as the Lincoln County Process (LCP). By law, a product cannot be called Tennessee whiskey without it. Researchers now say they have some clues as to what the process imparts to the final product.

The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition. ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features nearly 13,000 presentations on a wide range of science topics.

"Although Tennessee whiskey and traditional bourbon both have to be made from 51 percent corn and aged in charred oak barrels, the distinction is really this filtration step," says graduate student Trenton Kerley, who performed the work.

Even in this modern age, whiskey making is still a bit of an art form. Distillers currently adjust their product empirically at the end of a long process of brewing, filtering and aging. They blend different batches to achieve a certain flavor. But until now, no one has systematically studied the effects of the LCP step, so named for the county where the original Jack Daniel's distillery was located. John Munafo, Ph.D., leader of the study at the University of Tennessee, says that by probing the fundamental chemistry of this process, his team could help distilleries achieve the flavor profile they desire and reduce product variability.

Munafo's group partnered with the Sugarlands Distilling Company in Gatlinburg, Tennessee, to figure out how LCP affected the flavor of their Roaming Man Tennessee whiskey. To do that, the researchers first established baseline values for its flavor. They began with unfiltered whiskey provided by the distillery. They identified all of the aroma-active molecules (odorants) of the beverage using a combination of gas chromatography-mass spectrometry and gas chromatography-olfactometry, a technique by which a scientist can smell the individual components of a sample as they are separated. They then determined which of these compounds was important to the whiskey's flavor with a technique called aroma extract dilution analysis, in which aroma-active compounds are diluted until they no longer be smelled. Finally, the key odorants were quantitated by stable isotope dilution assays.

After identifying the compounds that contributed to the unfiltered whiskey's flavor, they exposed it to sugar maple charcoal also obtained from Sugarlands. Based on a procedure established by the distiller, they left the whiskey soaking in the charcoal from one to five days. Afterward, they analyzed samples by spiking them with known quantities of the odorants previously identified so they could quantify how much of each compound was removed by the LCP step.

Kerley says that based on the whiskey's smell before and after filtration, he was not surprised by the change in chemical composition, but he was surprised by how much some of the levels changed. "I was expecting it to have an effect, but I wasn't expecting as large of an effect as we saw in some of the compounds. For example, levels of some compounds declined by up to 30 percent after LCP," he says.

Now that Munafo and his student better understand how LCP changes whiskey chemically, they want to adjust some of the parameters of the filtration process. Munafo says they will run a series of experiments varying the time the unfiltered whiskey is in contact with the charcoal, and another in which the whiskey-to-charcoal ratio is systematically altered. He also wants to investigate the sensory impact of combinations of compounds that are present. "There are some 'strong' flavor compounds present in low concentrations, but then there are 'weaker' aroma-active compounds such as branched alcohols that are present at high concentrations," Munafo says. "Even though they might not be potent aroma-active compounds, they could have an effect like a perception of burning that our senses pick up."

Down the road, the data Munafo and his students collect could be used to advise distillers on exactly what changes to make to their whiskey to produce the best flavor for their unique brand. "We want to give them levers to pull so they are not blindly trying to get the flavor target they want," Munafo says.

ATLANTA -- A combination of chemotherapy and chimeric antigen receptor (CAR) T cells designed to target the protein HER2 was found to be safe and showed clinical responses in pediatric and adult patients with advanced HER2-positive sarcoma, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29-April 3.

"Children and adults with recurrent or refractory sarcomas have limited treatment options," said Shoba Navai, MD, assistant professor of pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital in Houston. "Depending on the specific type of sarcoma, curative salvage chemotherapy regimens are available, but the chance of success is low and the therapies can be quite toxic."

While it is not known what percentage of sarcomas express HER2 on the tumor surface, osteosarcoma, one of the most common types of sarcoma, has been reported to be HER2-positive in up to 40 percent of patients, and HER2-positivity is associated with a higher likelihood of tumor metastasis, Navai explained. Prior clinical studies have shown that HER2-targeted antibodies such as trastuzumab are not effective for these patients. "Our group has previously shown in the laboratory that HER2-directed CAR T cells are better at targeting low levels of HER2 on tumor cells compared with trastuzumab, so these CAR T cells may have antitumor activity in patients with sarcoma even when HER2-antibody therapies do not," she added.

"Our study shows that HER2-targeted CAR T-cell therapy given in combination with lymphodepletion chemotherapy is safe, and though very early, it shows promising antitumor activity in some patients with advanced HER2-positive sarcomas," Navai said.

In this trial, Navai and colleagues treated 10 patients, ages 4 to 54, with refractory/metastatic HER2-positive sarcoma (five with osteosarcoma, three with rhabdomyosarcoma, and one each with Ewing sarcoma and synovial sarcoma). Patients had received up to five prior salvage therapies.

Patients received up to three infusions of HER2-targeted CAR T cells after lymphodepletion with either fludarabine or fludarabine and cyclophosphamide; those who had responses to this initial treatment received up to an additional five infusions of CAR T cells without lymphodepletion.

The investigators found that the CAR T cells expanded in all but two patients with a median peak expansion on day 7, and that they could detect the CAR T cells in all patients six weeks after infusion.

One pediatric patient whose rhabdomyosarcoma had metastasized to the bone marrow had a complete response (CR) for 12 months, but relapsed later; retreatment with CAR T cells resulted in a CR that has been ongoing for 17 months. Analysis of this patient's blood at multiple time points showed antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling, and in tumor processes such as invasion and metastasis, Navai said.

"Some antibodies in this patient's blood were newly detected and maintained after CAR T-cell infusions, suggesting that in addition to the expected direct effect of the CAR T cells targeting HER2 on the tumor, they may have engaged the patient's own immune system," she added. "Further studies are needed to identify the specificities and functional significance of these responses."

One pediatric patient with osteosarcoma that had metastasized to the lungs has an ongoing CR for 32 months. Three patients had stable disease, and five had progressive disease.

Navai noted that overall, the patients on this study had limited treatment-related toxicities. All patients had expected decreases in their blood counts following chemotherapy that subsequently improved, and none developed infections secondary to low blood counts, she added.

"Importantly, no patients experienced decreased heart function, which has been reported with other types of HER2-targeted therapies. We also did not observe any pulmonary toxicities in our patients despite expansion of the infused CAR T cells," Navai said.

A limitation to the study is that this is a small phase I trial, and further testing of the HER2-specific CAR T cells in larger cohorts of patients is warranted to define efficacy and optimal dosage, Navai said.

ATLANTA - A new combination of immunotherapy and chemotherapy for pancreatic cancer caused tumors to shrink in the majority of evaluable patients - 20 out of 24 as of an interim analysis of the phase 1b trial data. The early findings provide hope that this strategy involving a CD40 antibody, a checkpoint inhibitor, and standard-of-care chemotherapy could be effective for treating the nation's third deadliest type of cancer. Researchers from the Abramson Cancer Center at the University of Pennsylvania will present the findings today in a clinical trials plenary session at the American Association for Cancer Research 2019 Annual Meeting in Atlanta (Abstract #8060). The ongoing study is being conducted in collaboration with the Parker Institute for Cancer Immunotherapy and its other member institutions and partners. These are the first clinical trial data ever presented as a result of this collaboration.

"These findings give us clues that this new and innovative combination therapy can be effective against pancreatic cancer," said the study's co-lead author Mark H. O'Hara, MD, an assistant professor of Hematology-Oncology at Penn. "Although only time and further research will truly tell, our data are a reason for optimism." O'Hara will present the plenary at 12:45 p.m. in Marcus Auditorium, Bldg A-GWCC.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it kills more Americans each year than any cancer type other than lung and colorectal. Despite the fact that it only accounts for about three percent of new cancer cases, it is responsible for more than seven percent of all cancer deaths, and just 8.5 percent of patients survive five years with the disease. Previous research has shown PD-1 inhibitors are ineffective on their own against PDAC, but preclinical data showed combining PD-1 inhibitors with antibodies that target a different antigen known as CD40 can trigger an immune response.

For this study, patients with metastatic PDAC who were previously untreated received combinations of four different therapies. Each patient received gemcitabine and nab-paclitaxel, which are standard-of-care chemotherapies, as well as an experimental antibody targeting CD40 called APX005M. Half the patients also received the PD-1 inhibitor nivolumab. As of the data cutoff for the interim analysis, 20 of 24 patients (83 percent) saw their tumors shrink. Overall, although the majority of the patients experienced side effects from the treatment, they were expected and manageable, with several patients continuing on treatment for more than a year, which also suggests the combination treatment can produce a durable response.

"Seeing patients continue treatment for this length of time does give us hope that this combination approach holds promise, especially when you consider that for stage 4 pancreatic cancer, the median survival is just two to six months," said senior author Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center and a Parker Institute member researcher. Vonderheide previously led the first-in-human clinical trial of APX005M reported in 2017 that enabled the current study.

The Parker Institute holds the Investigational New Drug application from the U.S. Federal Drug Administration. Patients on this trial were treated at seven Parker member institutions, leveraging a unique ability to develop faster and more efficient clinical studies.

"This study represents the first illustration that our unique collaborative model, which we used to bring together partners from across academia, pharma, and biotech, can help speed the process of translating laboratory findings into efficient, impactful clinical trials in areas with high unmet medical need," said Ramy Ibrahim, MD, the chief medical officer at the Parker Institute for Cancer Immunotherapy. "Based on these early but promising findings, we are excited to see results from the next phase of the study."

In addition to Penn, Parker member institutions who treated patients on this study were Memorial Sloan Kettering Cancer Center; The University of Texas MD Anderson Cancer Center; University of California, Los Angeles; University of California, San Francisco; Stanford University; and Dana-Farber Cancer Institute.

The randomized phase two portion of the trial evaluating chemotherapy, APX005M, and/or nivolumab is currently underway.
Apexigen, which manufactures APX005M, and Bristol-Myers Squibb, which manufactures nivolumab, each supplied the drugs for this study. Additional support was provided by the Cancer Research Institute.

A combination of two common immunotherapy drugs shrinks rare, aggressive neuroendocrine tumors, according to new research results presented at the American Association for Cancer Research Annual Meeting 2019, held March 29-April 3 in Atlanta.

Results from the SWOG Cancer Research Network trial known as DART, short for Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors, show a significant clinical benefit for patients with high-grade neuroendocrine carcinoma, a cancer of the neuroendocrine cells that often forms tumors in the lungs and along the digestive tract. This cancer is rare - about 12,000 people in the U.S. are diagnosed each year - but the general prevalence of the disease grew six-fold between 1973 and 2012. Patients with the high-grade, or rapidly growing, form have few treatment options.

"We saw a benefit in patients with high-grade carcinoma, which is the population that really needs an effective treatment option," said Sandip Patel, MD, the DART clinical study chair, an associate professor of medicine at the University of California at San Diego School of Medicine, and a medical oncologist with Moores Cancer Center at UC San Diego Health.

"These early results are really encouraging - and intriguing," Patel said. "We found a clear difference in response to treatment between the high-grade and low-grade forms of this cancer type. So tumor biology makes a difference. We don't yet know why, but we've opened another treatment arm of the trial to patients with just high-grade neuroendocrine carcinoma to see if we see the same response to the immunotherapy combination."

The DART trial, also known as S1609, is managed by SWOG, the cancer clinical trials group that is part of the National Cancer Institute's National Clinical Trials Network (NCTN). DART features an innovative "basket" design which allows the testing of a single drug or drug combination in a variety of tumor types. DART currently tests the immunotherapy combination of ipilimumab and nivolumab in patients with 37 types of rare cancers, which together make up almost a quarter of all cancers diagnosed worldwide.

Results presented at the AACR Annual Meeting 2019 represent one of the 37 cohorts of DART, in which researchers enrolled 33 patients with neuroendocrine tumors. Of those 33 patients, 19 had high-grade disease. Most patients' tumors were located in the gastrointestinal tract or the lungs. All patients received doses of ipilimumab every six weeks and doses of nivolumab every two weeks, and continue on the treatment for as long as their bodies respond to the drugs.

Results showed that 42 percent of patients with the high-grade form of neuroendocrine carcinomas saw their tumors shrink partially or completely after treatment, while none of the low-grade patients did. For all patients, 70 percent saw their cancer spread within six months. Patients survived a median of at least 11 months after treatment. Some patients are alive more than a year after treatment, and doctors continue to track their progress on the study drugs.

DART has enrolled over 550 patients since it opened in 2017 - an uncommon success for a rare cancers trial. The trial is open at over 800 hospitals, cancer centers, and community clinics across the U.S., widespread availability that is a unique feature of trials run through the NCTN and the NCI's Community Oncology Research Program.

"There's a myth that you can't successfully complete clinical trials in rare cancers," Patel said. "Researchers think it's too hard to find patients. But DART shows us that we can run rare cancer trials, and enroll patients quickly and learn if therapies are effective in rare diseases. Through the NCTN, we can also offer investigational drugs to patients right in their communities. They don't necessarily need to travel to a cancer center to get enrolled in a clinical trial."

ATLANTA -- Adding the investigational MET inhibitor savolitinib to the EGFR inhibitor osimertinib (Tagrisso) yielded clinical responses in patients who had EGFR-mutant non-small cell lung cancer (NSCLC) that had developed resistance to prior EGFR-targeted therapies through MET-gene amplification, according to interim results from two expansion cohorts of the phase Ib clinical trial TATTON, presented at the AACR Annual Meeting 2019, March 29-April 3.

"To date, targeted therapy for lung cancer patients with EGFR mutations has consisted solely of monotherapy with various EGFR tyrosine kinase inhibitors (TKIs), though we have known for more than 10 years that a proportion of resistance to EGFR TKIs results from activation of the MET bypass pathway," said Lecia V. Sequist, MD, MPH, a thoracic medical oncologist and director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center.

Prior research has shown that MET amplification is a bypass pathway observed in about 5 to 10 percent of patients whose disease has progressed after treatment with first- or second-generation EGFR TKIs and in about 25 percent of those whose disease has progressed after treatment with third-generation EGFR TKIs, Sequist explained.

Prior clinical trials of combinations of EGFR- and MET-targeted therapeutics have not been successful, partly due to the drug combinations studied, and largely because patients were not chosen based on appropriate biomarkers, Sequist said. "In the TATTON trial, newer TKIs that have increased specificity for EGFR and MET are used, and patients with EGFR-mutant NSCLC are required to have documented MET-driven resistance," she added.

Interim results from two distinct expansion cohorts are presented here. In the first cohort, a combination of osimertinib and savolitinib was tested in patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with a first- or second-generation EGFR TKI; these patients' tumors were also negative for T790M mutation. In the second cohort, the same combination was tested in patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with osimertinib or another experimental third-generation EGFR TKI.

"Data from the TATTON trial demonstrate for the first time the benefit of adding a MET inhibitor to an EGFR inhibitor in patients with EGFR-mutant NSCLC and with MET-driven acquired resistance," Sequist said. "The study has shown efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option.

"This finding illustrates the value of careful patient selection in studies of targeted therapies," Sequist said, adding, "These clinically meaningful responses also demonstrate that as different heterogeneous resistance clones come up, they can in turn be brought under control by tailoring therapy."

In the cohort of 46 patients who had received prior first- or second-generation EGFR TKI, treatment with osimertinib plus savolitinib yielded an objective response rate (ORR) of 52 percent, with 24 partial responses. The median duration of response (DOR) was 7.1 months.

In the cohort of 48 patients who had received prior third-generation EGFR TKI, treatment with osimertinib plus savolitinib yielded an ORR of 28 percent, with 12 partial responses. The median DOR was 9.7 months.

"Overall the regimen was tolerable, though there was added toxicity with the combination of osimertinib and savolitinib compared to osimertinib given alone, and we saw that some patients discontinued treatment due to toxicity," Sequist said. The most frequent adverse events were nausea, diarrhea, and lowered numbers of leukocytes and platelets.

One patient, who had brain metastases, died from kidney failure a few days after starting the combination treatment. The treating investigator considered that this serious adverse event was difficult to evaluate with respect to relation to the study drugs, Sequist said. "Our understanding of the adverse event profile of the osimertinib-savolitinib combination, and how to manage the adverse events, is improving," she added.

Since the initiation of the TATTON trial, osimertinib was approved for treatment in first-line setting for patients with EGFR-mutant NSCLC. Because of this, only a subset of patients in the trial had received prior first-line osimertinib and had developed MET-driven resistance. "The newly opened phase II SAVANNAH study will further explore the combination of osimertinib plus savolitinib in patients whose disease has progressed on osimertinib and is MET-positive," Sequist said.

These are early-phase trials and the findings need confirmation in larger trials, Sequist noted.

ORLANDO, Fla., March 31, 2019 -- As current antibiotics dwindle in effectiveness against multidrug-resistant pathogens, researchers are seeking potential replacements in some unlikely places. Now a team has identified bacteria with promising antibiotic activity against known pathogens -- even dangerous organisms, such as the microbe that causes MRSA infections -- in the protective mucus that coats young fish.

The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition. ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features nearly 13,000 presentations on a wide range of science topics.

"For us, any microbe in the marine environment that could provide a new compound is worth exploring," says Sandra Loesgen, Ph.D., the group's principal investigator.

According to Loesgen, who is at Oregon State University, while novel chemical reagents have been found in the human microbiome, the marine equivalent remains relatively unstudied. One potential goldmine of microbes is the mucus that coats the surfaces of fish. This viscous substance protects fish from bacteria, fungi, and viruses in their environment, trapping the microbes before they can cause infections. The slime is also rich in polysaccharides and peptides known to have antibacterial activity.

"Fish mucus is really interesting because the environment the fish live in is complex," says Molly Austin, an undergraduate chemistry student in Loesgen's laboratory, who conducted some of the studies. "They are in contact with their environment all the time with many pathogenic viruses." According to Austin, it would be interesting to figure out if anything in the mucus, which protects the fish, could actually help protect humans.

Collaborator Erin (Misty) Paig-Tran, Ph.D., who is at California State University, Fullerton, supplied the mucus, swabbed from juvenile deep-sea and surface-dwelling fish caught off the Southern California coast. The team examined young fish because they have a less-developed immune system and more mucus on the outside of their scales that could contain a greater concentration of active bacteria than adult fish.

Loesgen, Austin and graduate student Paige Mandelare isolated and screened 47 different strains of bacteria from the slime. Five bacterial extracts strongly inhibited methicillin-resistant S. aureus (MRSA), and three inhibited Candida albicans, a fungus pathogenic to humans. A bacteria from mucus derived from a particular Pacific pink perch showed strong activity against MRSA and against a colon carcinoma cell line. Austin is now focusing her work on the Pseudomonas aeruginosa, a Gram-negative bacteria derived from that fish, to study the many potentially interesting phenazine natural products and antibiotics that this bacteria makes.

While the team members are interested in new sources for antibiotics to help humans, they are also looking at other ways to apply this knowledge. For example, the study of fish mucus could also help reduce the use of antibiotics in fish farming by leading to better antibiotics specifically targeted to the microbes clinging to certain types of fish.

But first, the researchers want to understand more fundamental questions. For example, "We don't even know what a healthy microbiome is," Loesgen says. She explains that it's unclear whether the bacteria they studied in the fish slime were typical of their microbiomes and are protecting their hosts, or if these bacteria just happened to hitch a ride on these individual fish. Learning more about healthy fish microbiomes and how environmental factors in the Pacific can affect them could help inform conservation efforts, the researchers say.

ORLANDO, Fla., March 31, 2019 -- The U.S. opioid epidemic is being driven by an unprecedented surge in deaths from fentanyl and other synthetic opiates. Fentanyl's powerful effects are long-lasting, and even tiny amounts of the drug can lead to an overdose. Antidotes, such as naloxone, do not last long enough in the body to fully counter the drug, requiring repeated injections. Now, scientists report that they are developing single-dose, longer-lasting opioid antidotes using polymer nanoparticles.

The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition. ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features nearly 13,000 presentations on a wide range of science topics.

"We became interested in this problem while trying to make non-addictive pain medications," Saadyah Averick, Ph.D., says. "In that course of research, we realized the limitations of current opioid antidotes."

According to the U.S. Centers for Disease Control, opioids, such as heroin, oxycodone and fentanyl, were implicated in more than 47,000 deaths from overdose in 2017. These drugs all bind to the mu opioid receptor (MOR) in the brain, which is the body's natural pleasure receptor, explains Averick, a scientist at Allegheny Health Network Research Institute. "The drugs bind, turn on the receptor and stimulate a euphoric feeling. The synthetic opioids, such as fentanyl, turn this on really, really well," he says.

And their effects are long-lasting. Fentanyl, which is much stronger than morphine, another opioid, can be absorbed into fat tissue, which protects it from being metabolized right away. It is then slowly released from this tissue, causing effects for several hours. Naloxone, an MOR antagonist and antidote, only stays in the system for about 30 minutes to an hour, however. Because of this mismatch, repeated doses are required to help the patient recover. But not all patients want to undergo the entire treatment course, and they can end up succumbing to an overdose after the naloxone is metabolized.

To overcome this challenge, Averick and his colleagues developed a drug delivery system intended to ensure that a steady, sufficient dose of antagonist is delivered over 24 hours. The researchers reacted naloxone, which has a multi-ringed chemical structure, with polylactic acid (PLA), thus creating a naloxone polymer. They then prepared covalent nanoparticles (CNPs) by adding this polymer to a solution of polyvinyl alcohol. They used a variety of analytical methods to purify and analyze the resulting particles, which are 300 nanometers in diameter.

"In collaboration with the Benedict Kolber laboratory at Duquesne University, proof-of-concept research has shown that these nanoparticles can deliver sufficient naloxone in a linear time-release fashion to block morphine's analgesic effect for 24 hours," Averick notes. "As a next step, the study will be extended to fentanyl." Although the most recent work was performed with mice, future studies will include an animal model that more closely simulates how humans metabolize opioids.

The researchers are also planning to investigate how particle size impacts naloxone release from the nanoparticle. "Ultimately, we hope to develop a therapeutic intervention for fentanyl overdose that can be used in the field, perhaps supplanting short-acting naloxone as an overdose antidote of choice," Averick says. "We anticipate that this drug delivery system will also be effective for other non-fentanyl opioids."

Given the fact that naloxone and the other compounds the team uses are already deemed safe, Averick predicts that the time-to-market could be less than five years for the nanoparticle system.

Yokohama, Japan 30 March 2019: Trips to the toilet at night are a sign of high blood pressure, according to results from the Watari study presented today at the 83rd Annual Scientific Meeting of the Japanese Circulation Society (JCS 2019).

"Our study indicates that if you need to urinate in the night - called nocturia - you may have elevated blood pressure and/or excess fluid in your body," said study author Dr Satoshi Konno, of the Division of Hypertension, Tohoku Rosai Hospital, Sendai, Japan. "If you continue to have nocturia, ask your doctor to check your blood pressure and salt intake."

JCS 2019 takes place from 29 to 31 March in Yokohama. Joint scientific sessions are being held by the European Society of Cardiology (ESC) and JCS as part of the ESC Global Activities programme.1

Previous research from Japan has reported that high salt intake is associated with nocturia.2 Compared to western countries, people in Japan eat more salt and are more likely to be "salt sensitive", meaning that their blood pressure rises more when salt is consumed. Taken together, these two factors mean that people in Japan are at greater risk of developing high blood pressure.

This study examined the link between nocturia and hypertension in the general Japanese population. The study enrolled 3,749 residents of Watari who had an annual health check in 2017. Blood pressure was measured and information on nocturia was obtained by questionnaire. Participants with blood pressure 140/90 mmHg or higher or prescribed antihypertensive drugs were considered hypertensive.

Nocturia (one or more nocturia events per night) was significantly associated with hypertension after controlling for possible confounders (odds ratio 1.4; p

"We found that getting up in the night to urinate was linked to a 40% greater chance of having hypertension," said Dr Konno. "And the more visits to the toilet, the greater the risk of hypertension."

Of the 1,882 participants who answered the questionnaire, 1,295 (69%) had nocturia. Dr Konno said the results do not prove a causal relationship between nocturia and hypertension and may not apply to populations outside Japan. He said: "The relationship may be influenced by various factors including lifestyle, salt intake, ethnicity, and genetic background."

Dr Mutsuo Harada, press coordinator for JCS 2019, said: "Hypertension is a national disease in Japan. The average salt intake in Japan is approximately 10 g/day, which is more than double the average salt intake worldwide (4 g/day). This excessive salt intake is related to our preference for seafood and soy sauce-based food, so salt restriction is difficult to carry out. Early detection and management of hypertension are very important to prevent cardiovascular diseases. We should keep in mind that nocturia is not only caused by urinary organ problems but also by systemic diseases such as hypertension."

ESC President Professor Barbara Casadei said: "More than one billion people have high blood pressure worldwide. High blood pressure is the leading global cause of premature death, accounting for almost ten million deaths in 2015. ESC guidelines recommend medication to reduce the risk of stroke and heart disease.3 A healthy lifestyle is also advised, including salt restriction, alcohol moderation, healthy eating, regular exercise, weight control, and smoking cessation."

A new study published in the April 2019 issue of the American Journal of Roentgenology (AJR) considers several potential factors that might have led to disparities in follow-up imaging rates among patients with indeterminate initial abdominal imaging findings.

The study, "Patient Factor Disparities in Imaging Follow-Up Rates After Incidental Abdominal Findings," reviewed the records of 1588 patients with inconclusive abdominal imaging results consecutively registered between July 1, 2013, and March 20, 2014. Factors studied included distance between the flagship hospital of the health system patients' home zip codes, age, race, and health insurance status.

Of the 1,513 patients included in the study, 554 (36.62%) did not undergo follow-up abdominal imaging within 1 year of the index abdominal imaging. Follow-up rates varied depending on the initial patient setting. More than 60 percent of the emergency department patients in the study did not undergo follow-up imaging, while less than 30 percent of outpatients failed to complete their follow-up imaging.

The study also found that those at the extremes of age had lower rates of follow-up completion. Of the 959 patients who received follow-up imaging, 9.28% were younger than 40 years, compared 13.72% of patients who did not receive follow-up imaging. Only 5.63% of patients who underwent follow-up imaging were older than 80 years, compared with 12.64% patients who did not undergo follow-up imaging.

While the study found emergency department patients and those at the extremes of age had lower rates of follow-up completion, the authors recommend further investigation of additional factors that may influence rates of follow-up imaging. For example, more white patients and fewer black patients were found in the follow-up imaging group, but the authors caution that "confounders may affect this conclusion."

A new study published in the April 2019 issue of the American Journal of Roentgenology (AJR) investigates the safety of uterine artery embolization (UAE) for symptomatic leiomyomas in patients with various autoimmune diseases.

Between January 2007 and June 2018, 1183 consecutive patients underwent UAE for symptomatic leiomyomas at Yonsei University College of Medicine. Nine of those patients with autoimmune disease ranging in age from 34-49 years (mean age of 42.6 years) were included in the study, "Uterine Artery Embolization in Patients With Autoimmune Disease: A Matched Case-Control Study." All UAE procedures were performed by one interventional radiologist with 16 years of UAE experience.

Using the patient registry, researchers randomly generated an age- and disease-matched control group (n = 8) to compare volume reduction rates of the uterus and dominant leiomyoma and the change in C-reactive protein (CRP) levels before and after UAE to evaluate the safety and effectiveness of UAE in patients with autoimmune disease. The authors defined clinical success as "improvement or resolution of symptoms" following UAE and technical success as "successful embolization of the bilateral uterine arteries."

UAE was technically and clinically successful in all patients in both groups. No significant difference was found between the autoimmune and control groups in the volume reduction rates of uterus and dominant leiomyoma. However, CRP level in the autoimmune patient group was found to be significantly higher 1 day after UAE (1.23 ± 0.6 mg/L vs 9.54 ± 6.63 mg/L; p = 0.001).

While the authors conclude UAE appears to be safe and effectual in the management of symptomatic leiomyoma in patients with autoimmune disease that is well controlled, they note that due to the inclusion of a variety of autoimmune diseases in the case series, a small sample size, and the retrospective nature of the study, the results should be interpreted with some caution.

Purely educating doctors about the importance of prescribing certain therapies may not be enough to make a meaningful impact, according to a new Penn Medicine study. Using acid suppression therapy--an effective method of reducing the risk of gastrointestinal bleeding in vulnerable cardiac patients--Penn researchers tested interventions that utilized both education and an electronic "dashboard" system linked to patients' electronic medical records (EMRs) which gave doctors up-to-date information on which patients would likely benefit from the therapy. Researchers found that the education on acid suppression therapy alone did not have a noticeable effect on prescribing rates, but adding use of the dashboard resulted in an 18 percent increase in needed medication orders. The study was published this month in the Joint Commission Journal on Quality and Patient Safety.

"This study shows that education alone is typically not a sufficient method for changing the behavior of providers and care teams," said the study's senior author, Shivan Mehta, MD, MBA, associate chief innovation officer and an assistant professor of Medicine. "We demonstrated that although clinical leaders should collaborate to identify best practices, care redesign, technology, and behavior change strategies are also needed."

Acid suppression therapy involves prescribing patients with medications to reduce the level of acid in their stomach, which helps reduce heartburn symptoms and treat ulcers. It can also decrease some patients' risk of even developing ulcers, such as cardiac patients who are on certain medications that may increase their chance of bleeding.

"The main reason the patients are at risk is because they're placed on medications--or combinations of medications--such as anti-platelet agents or anticoagulation," said the study's lead author, Carolyn Newberry, MD, a Penn Medicine Gastroenterology fellow at the time the research was conducted who is currently an assistant professor of Medicine in the division of Gastroenterology and Hepatology at Weill Cornell Medicine in New York. "These medications are important for treating or preventing cardiovascular disease but they also have side effects such as increased bleeding in the G.I. tract."

Before the study's EMR-linked dashboard was developed and implemented, through help from Penn Medicine's Center for Health Care Innovation, prescription rates for cardiac patients who could benefit from acid suppression therapy was just shy of 73 percent, according to the health system's data of inpatients in the Cardiac Intensive Care Unit (CICU) from September 2016 and January 2017. Afterward, from January until September 2017 when the "dashboard" was implemented, rates quickly jumped to 86 percent for patients in the CICU.

Great gains were made using this type of technology-assisted nudge, which the study team notes could improve desired outcomes in other clinical areas. Software developers at the Center for Health Care Innovation are working on similar dashboards or alerts in many other clinical areas where there is an opportunity to increase adoption of evidence-based practices. However, the researchers emphasized that this "nudge" approach is not one size fits all.

"No one dashboard or technology will work in every area, so it is important to partner with clinicians and identify workflows and processes where it can complement care," Newberry said. "Our experience highlights this individualized nature and the importance of continued collaboration, along with process redesigns, to achieve sustainable success."

"The fluorescent patterns are only visible to the human eye under a UV lamp. In nature, if they were visible to other animals, they could be used as intra-specific communication signals or as reinforcement of their aposematic coloration, warning potential predators of their toxicity," says Sandra Goutte

Pumpkin toadlets (also called Brachycephalus ephippium) are tiny, brightly-colored, and poisonous frogs that can be found in the Brazilian Atlantic forest. During the mating season, they can be seen by day walking around the forest and producing soft buzzing calls in search of a mate.

An international team of researchers led by NYU Abu Dhabi Postdoctoral Associate Sandra Goutte was studying the acoustic communications of these miniature frogs. When they discovered that Brachycephalus ephippium could not hear its own mating calls, they searched for alternative visual signals the frogs could use to communicate instead. Unexpectedly, when they shone an ultra-violet (UV) lamp on the frogs, their backs and heads glowed intensely.

In a new paper published in the journal Scientific Reports, the researchers report that fluorescent patterns are created by bony plates lying directly beneath a very thin skin. In fact, the toadlet's entire skeleton is highly fluorescent, but the fluorescence is only externally visible where the layer of skin tissue over the bones is very thin (about seven micrometers thick). The lack of dark skin pigment cells (which block the passage of light) and the thinness of the skin allow the ultraviolet light to pass through and excite the fluorescence of the bony plates of the skull. The fluorescent light is then reflected back from the frog's bone, and can be seen as bluish-white markings by the observer if they have a UV lamp.

"The fluorescent patterns are only visible to the human eye under a UV lamp. In nature, if they were visible to other animals, they could be used as intra-specific communication signals or as reinforcement of their aposematic coloration, warning potential predators of their toxicity," said Goutte. "However, more research on the behavior of these frogs and their predators is needed to pinpoint the potential function of this unique luminescence."

The researchers compared the skeletons of the two species of pumpkin toadlets to closely related, non-fluorescent species. The pumpkin toadlets' bones proved to be much more fluorescent. Pumpkin toadlets are diurnal, and in their natural habitat, the UV or near-UV components of daylight might be able to create fluorescence at a level detectable by certain species.

According to an independent study released today by the International Institute for Applied Systems Analysis (IIASA) and the Council on Energy, Environment, and Water (CEEW), more than 674 million Indian citizens are likely to breathe air with high concentrations of PM2.5 in 2030, even if India were to comply with its existing pollution control policies and regulations.

The study shows that only about 833 million citizens would be living in areas that meet India's National Ambient Air Quality Standards (NAAQS) in 2030 and that implementation failure could increase these numbers significantly. However, aligning sustainable development policies to the implementation of advanced emission control technologies could provide NAAQS-compliant air quality to about 85% of the Indian population. The study was released at a CEEW dialogue, On Air: Pathways to Achieving India's Ambient Air Quality Standards, held in New Delhi today (Friday, 29 March).

In 2015, more than half the Indian population - about 670 million citizens - were exposed to PM2.5 concentrations that did not comply with India's NAAQS for PM2.5 (40 μg/m³). Further, less than 1% enjoyed air quality that met the World Health Organisation (WHO) benchmark limit of 10 μg/m³.

"A significant share of emissions still originates from sources associated with poverty and underdevelopment such as solid fuel use in households and waste management practices," explains Markus Amann, Air Quality and Greenhouse Gases Program director at IIASA.

In January 2019, the Indian government launched the National Clean Air Program (NCAP), a five-year action plan to curb air pollution, build a pan-India air quality monitoring network, and improve citizen awareness. The program focuses on 102 polluted Indian cities and aims to reduce PM2.5 levels by 20-30% over the next five years. The analysis conducted by researchers from IIASA and CEEW however suggests that NCAP needs to be backed by a legal mandate to ensure successful ground-level implementation of emission control measures. In the long-term, NCAP also needs to be scaled-up significantly to ensure that rapid economic growth and meeting NAAQs are aligned.

Pallav Purohit, an IIASA researcher and lead author of the study said, "While current ambient PM2.5 monitoring in India reveals high levels in urban areas, remote sensing, comprehensive air quality modeling, and emission inventories, suggest large-scale exceedances of the NAAQS, also in rural areas. Pollution from rural areas is transported into the cities (and vice versa), where it constitutes a significant share of pollution making the coordination of urban-rural and inter-state responses critical."

Hem Dholakia, a senior research associate at CEEW, and one of the authors of the study added, "The health burden of air pollution is significant in India. Limited control of air pollution will aggravate this burden in the future. The IIASA-CEEW study clearly shows that the policy choices of today will impact future air quality and its aftermaths. The central and state governments must do more to align air quality, climate change, and sustainable development goals in a resource efficient manner."

The study also found that the Indo-Gangetic plain, covering parts of states such as Punjab, Haryana, Uttar Pradesh, Bihar, and West Bengal, has the highest population exposure to significant PM2.5 concentrations. This is mainly due to the high density of polluting sources and reduced ventilation by the obstructing presence of the Himalayas. Citizens living in parts of Bihar, West Bengal, Chhattisgarh, and Odisha are also exposed to high levels of PM2.5. The governments in these regions must design state-specific policies to comply with NAAQS and embrace a low-carbon growth model to ensure better air quality for its citizens.

Further, the study highlighted a stark variance in factors contributing to air pollution across the states. Solid fuel, including biomass combustion for residential cooking, is the largest contributor in the major states of the Indo-Gangetic Plain. However, in Delhi and Goa, it contributes only a small amount due to enhanced access to clean fuels in these states. Instead, NOx emissions from transportation are major contributors to air pollution in these two states. Similarly, SO2 emissions from power plants are dominant contributors to air pollution in Haryana and Maharashtra. In coming years, every state government must commission detailed scientific studies to better understand the sources contributing to air pollution in their cities.

Another challenge for many states is that emission sources that are outside their immediate jurisdiction contribute significantly to ambient pollution levels of PM2.5. For example, transboundary transport or crop burning are sources of secondary pollution in some states. Such states could achieve significant improvements in air quality only with a region-wide coordinated approach to reduce air pollution and strict on-ground enforcement to ensure compliance with emissions control measures.

The IIASA-CEEW study also recommends focusing on energy efficiency, enhanced public transport, increased use of cleaner fuels, improved agricultural production practices, and replacement of coal with natural gas and renewables in the power and industrial sector to achieve better air quality and meet multiple Sustainable Development Goals (SDGs).

This is a joint press release from the International Institute for Applied Systems Analysis (IIASA) in Laxenburg, Austria and the Council on Energy, Environment, and Water (CEEW) in Delhi, India.