Body

Washington, DC - June 24, 2019 - A team of investigators has developed a cancer vaccine technology using live, attenuated pathogens as vectors. A feature of the vaccine causes these bacteria to self-destruct once they've done their job, making it safe for use in humans. The research is published in Infection and Immunity, a journal of the American Society for Microbiology.

Unlike "prophylactic" vaccines that protect people from the becoming infected with diseases such as measles, influenza, tetanus, or hepatitis, the new vaccine is "therapeutic," that is, designed to treat existing infections or, in this case, prostate and colorectal cancer. It might also be used against hard-to-treat infectious diseases such as malaria or tuberculosis.

Using a bacterium in a platform for a vaccination has several benefits, said principal investigator Pete Lauer, PhD, formerly Executive Director, Molecular Biology at Aduro Biotech, Berkeley, CA. "Listeria is a little biological factory... it replicates itself in both the lab and after vaccination. This makes manufacturing as easy as inoculating a culture, and growing it for about a day."

Using a pathogen is useful because it "induces the type of immune response that is required to treat cancer--a CD8 T cell response," said Dr. Lauer. Using a non-pathogen, "we would have had to try to modify the bacterium to be more pathogenic in the right way, which can be really tricky."

The platform, known as "L. monocytogenes recombinase-induced intracellular death," or Lm-RIID for short, is a live recombinant, but highly attenuated (weakened) derivative of the common food-borne pathogen, Listeria monocytogenes. The strain on which Lm-RIID was based showed promise as a therapeutic vaccine in clinical trials in advanced cancer patients as early as 2009. But more safety precautions were needed, because Listeria can be life-threatening in people with weakened immune systems.

Early feedback on safety from regulatory experts at the Food and Drug Administration, as well as physicians treating cancer patients, was daunting, said Dr. Lauer. Experts from both groups were skeptical about injecting live bacteria into the veins of cancer patients."

That feedback was highly motivating. "Whereas Listeria-based vaccines have shown promise as therapeutic vaccines in clinical trials for various cancers, we have gone even further and developed a modified version of Listeria that upon entering host cells, deletes essential genes, rendering the bacterium incapable of replication," which in bacteria is tantamount to death, said Dr. Lauer. Besides enabling cancer vaccines, "This additional layer of safety may allow further development of this platform for use in vaccines for a variety of viral and parasitic (e.g. malaria) diseases that currently lack effective vaccines." Cancers of the cervix, lung, and liver, as well as melanoma are also possible targets, said Dr. Lauer.

The other major element of the recombinant L. monocytogenes is an antigen that is specific to the cancer type the vaccine is designed to combat. After vaccination, Lm-RIID is engulfed by immune cells, said Dr. Lauer. Therein, this platform expresses the target antigen. Then, these immune cells, called "antigen presenting cells," deliver the target antigen to their surface. There, CD8 T cells--also immune cells--recognize the antigen. That recognition activates the CD8 T cells to find and destroy the cancer, which Dr. Lauer explains is an immunotherapeutic effect, rather than an oncolytic effect.

(BOSTON) - The human microbiome, the vast collection of microbes that colonize the surfaces lining many of our organs and our skin - is a critical pillar sustaining our general health. At any one time, 500 to 1,000 different species of bacteria inhabit us, which together contain far more genes than our human genome. Researchers have also come to realize that no two individuals share the same microbiome, and that an individual's microbiome composition can change with diet, lifestyle, treatment with antibiotics and other drugs, and other factors. Whereas various links have been found between individual microbiomes and diseases as diverse as obesity, inflammatory bowel disease, arthritis, cancer, and autism, it remained unknown whether the opposite also could be true with the microbiome actively enhancing health and physical performance.

"At the start of this project, we hypothesized that the microbiomes of elite athletes must have highly adjusted bacterial species in common that could help with their performance and recovery, and that, once identified, these could become the basis of highly validated performance-enhancing probiotics," said co-first author Jonathan Scheiman, Ph.D., a former Postdoctoral Fellow who initiated the project with George Church, Ph.D. Core Faculty member at Harvard's Wyss Institute for Biologically Inspired Engineering and Professor at Harvard Medical School (HMS). Scheiman also is the CEO of FitBiomics Inc., and himself a former professional basketball player.

Now, a highly collaborative team of researchers led by Scheiman and Church at the Wyss Institute and HMS, and Aleksandar Kostic at Joslin Diabetes Center in Boston pinpointed one specific group of bacteria, called Veillonella, that they found was enriched in the gut microbiome of Boston Marathon runners after after completing the 26.2 race and in an independent group of 87 elite and Olympic athletes after competitions. Veillonella bacteria isolated from marathon athletes and given to mice increased the animals' performances in laboratory treadmill tests by 13% compared to control bacteria.

"We were able to demonstrate that the Veillonella-driven performance boost was due to the bacteria's ability to break down lactate, a metabolite known to accumulate with prolonged strenuous exercise, and to produce propionate, a short-chain fatty acid (SCFA), that in turn enhances the body's resilience to exercise stress," said co-corresponding author Kostic, Ph.D., who is Assistant Professor of Microbiology at Joslin Diabetes Center, and pursuing computational and experimental approaches geared at better understanding the relationship between the human microbiome and metabolic diseases such as diabetes.

In their initial analysis of 2015 Boston Marathon runners, the researchers analyzed the runners' microbiome composition by determining the DNA sequences of an omnipresent but highly species-specific cluster of genes from bacteria obtained from athletes' stool samples. "Collecting samples daily throughout the week before the run and the week following the run and analyzing them with the help of Aleksandar's bioinformatics pipeline, enabled us to identify meaningful fluctuations within the entire microbiome with the increase in the Veillonella genus as the most prominent one," said Scheiman.

Veillonella's ability to consume lactate as an energy source was known but the team went a crucial step further. They demonstrated that one single species of Veillonella, known as Veillonella atypica, which they isolated from athletes' microbiomes and added to the intestinal microbiomes of mice, by itself could boost the animals' performance in the treadmill running tests.

Key bioinformatics analysis and animal experiments were carried out by co-first authors Jacob Luber, and Theodore Chavkin who both are graduate students in Kostic's group.

But how? With lactate being produced in working muscles, circulating through the vascular system, and being cleared by the liver, and the bacteria on the other hand residing in the intestinal lumen, there was no obvious connection. Indeed, the team provided the first evidence that lactate can actually cross from the circulation through the intestinal epithelial wall into the gut lumen, where it becomes available to Veillonella and possibly other bacteria. Interestingly, the bacteria did not act as a "lactate sink" causing a sizable drop in systemic circulating lactate levels. Rather, it was a product of the bacteria's lactate fermentation, the short-chain fatty acid propionate, that crossed back from the gut lumen into the circulation to enhance performance.

The collaborators indeed showed that propionate, when instilled into the intestinal lumen of mice, can reproduce many of Veillonella's effects, like the increase in treadmill run time to exhaustion, and a decrease in the levels of common inflammatory markers in the intestinal tract that rise during and after extreme athletic performances and treadmill running in the mouse model. "We think that propionate could exhibit its performance benefits by counter-acting inflammation, serving as an energy source for the body, and other as yet unknown effects," speculated Kostic. "Of note, higher exercise capacity strongly correlates with milder progression and greater longevity in diabetes patients, which could potentially make a probiotic Veillonella approach therapeutic."

"The study nicely validated our original hypothesis and provides one of the most compelling examples of 'metabolic symbiosis' between the human host and microbiome that could be broadly harnessed as a probiotic strategy not only for athletes but also to improve health in patients," said co-corresponding author Church, who also is Professor of Genetics at HMS and of Health Sciences and Technology at Harvard University and the Massachusetts Institute of Technology (MIT) and the lead of the Wyss Institute's Synthetic Biology Platform. "Now that we have built out a platform for identifying microbes associated with extreme performances, we can explore the microbiomes of other types of extreme athletes or individuals that are highly adapted to environmental challenges, uncover additional beneficial functional links and work towards translating them into probiotic treatments."

Scheiman and Church are co-founders of FitBiomics, Inc., a microbiome biotechnology company targeted at athletes. Scheiman, Church and Kostic hold equity in Fitbiomics, Inc.

"This is a wonderful example of how our Institute provides creative young scientists with the freedom to follow their unconventional ideas wherever they might go. Scheiman's passion for sports and science merged in a such a wonderful way, and by collaborating with other outstanding scientists, each bringing his own expertise, a major discovery resulted that has the potential to change the quality of life of many people around the world using a low-cost probiotic approach," said Wyss Institute Founding Director Donald Ingber who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

Scientists investigating heart failure have been limited to studying diseased heart tissue in the lab -- understandably, as people don't tend to pluck out a healthy heart for the sake of research. But now, scientists with access to unusable, yet still healthy, donor hearts have been able to investigate the genomic pillars behind the transition from healthy hearts to heart failure.

In doing so, researchers at the Stanford University School of Medicine and their collaborators have created one of the first maps to reveal gene activity and connectivity as the heart shuts down.

Euan Ashley, MB ChB, DPhil, professor of medicine, of genetics and of biomedical data science at Stanford, calls it a gene network. These networks, he said, are akin to social networks. "Let's say we traced the whereabouts of the human resources department at Stanford. We could see that they tend to park in the same area, go to the same office, and get lunch in the same place," he said. "They move together, and so it can be reasonably inferred that they are somehow related to each other."

Tracing a gene network for heart failure is like that, only instead of watching physical movements, Ashley and his collaborators watched for changes in gene expression, paying attention to how it changes as healthy hearts degenerates.

By delineating these gene networks, the group has discovered one gene in particular that seems to be at the center of the action. It appears to be highly connected in heart failure, meaning its activity is similar to that of many neighbors. What's even more exciting, Ashley said, is that when the researchers disabled the function of this gene in mouse models of heart failure, the mice were protected and did not succumb to the cardiac condition.

"This study has a truly unique angle, which is that we had precious, healthy human tissue and we used it to tell us something new about how a disease manifests," said Victoria Parikh, MD, clinical instructor of cardiovascular medicine. "And now someday we might even be able to translate that into a treatment."

A paper providing details of the study will be published June 24 in Nature Communications. Ashley is the senior author. Parikh shares lead authorship with Pablo Cordero, PhD, a former Stanford graduate student.

Tracking the transition

Heart failure is not one simple condition, said Ashley. It's more like an umbrella term that describes the heart's inability to pump blood regardless of the cause. "It could be a heart attack, a genetic cause, high blood pressure, a valve problem or something else entirely," he said. "Regardless of how the heart deteriorates, we believe there's one final, common pathway that ultimately leads to heart failure."

Now, the web of genes that they've mapped is providing new insight into how that pathway unfolds, and which genes are crucial to its activation.

"Maybe someday we'll be able to peer into a cell and watch as the networks are actively changing in real time," he said. "But right now what we have is human tissue that's sort of frozen at a moment in time, and so we can use that to look at which genes are involved in this process."

The group took tissue samples from more than 300 hearts (half from hearts removed from patients with heart failure who were getting heart transplants and half from healthy donor hearts) and ran genomic tests to determine gene expression activity. It was essential, Ashley said, to have the healthy donor hearts available. "Sometimes, for logistical reasons, a donor's heart isn't usable for transplantation, so instead of wasting these organs, we repurposed them for our study." Thanks to a dedicated, multi-institutional surgical team that worked around-the-clock -- sometimes venturing out in the wee hours of night -- the group secured more than 100 healthy hearts.

A new target

To date, studies that compare the genomics of healthy hearts and heart failure have taken place mainly in mice. But with the healthy donor heart tissue, the team was able to compare and contrast genomic information in human hearts. They found that fewer biological pathways were involved in heart failure compared with healthy hearts, but there were more genes involved in those pathways. It's almost as if the cells were "focusing" their efforts, presumably as part of a last-ditch effort to restabilize the declining heart, said Ashley.

Perhaps most telling, PPP1R3A had one of the biggest leaps in gene connectivity during the transition to heart failure, meaning it became associated with the activity of many other genes. And although it hasn't been implicated in heart failure in the past, its role does seem to fit with some of the symptoms, Ashley said. The heart's energy source typically comes from fatty acids, but it switches to glucose when it goes into failure. PPP1R3A as a central regulator makes sense because the gene plays a critical role in the metabolism of glucose within cells, Ashley said.

What's more, the same networks that pointed researchers to PPP1R3A also turned up dozens of other new gene interactions during heartfailure.

Ashley and colleagues confirmed PPP1R3A's causal role in heart failure by testing the effect of the gene -- or lack thereof -- in mouse models of high blood pressure. It turned out that mice lacking the PPP1R3A gene maintained normal heart function, whereas those with the gene succumbed to heart failure.

"Across the population, there are plenty of people with high blood pressure who never go into heart failure, and there are some that do," Ashley said. "We're sort of mimicking that in these mouse studies. If we were able to inhibit this gene somehow in humans, we could potentially have a therapeutic drug that could protect patients from heart failure."

New Haven, Conn. -- Use of 3-D mammography, an advanced form of breast cancer screening, has risen rapidly in recent years, according to Yale researchers in a new study. But adoption of the technology varies widely, reflecting emerging disparities in care, they said.

The study was published in the journal JAMA Internal Medicine.

Three-D mammography is also commonly called digital breast tomosynthesis, or DBT. The technology combines low-dose X-rays with software that creates a 3-D image of the breast. Compared to 2-D mammography, DBT may make it easier for radiologists to detect an abnormality. Yet DBT has not been widely endorsed for routine breast cancer screening. Organizations like the U.S. Preventive Services Task Force and the American Cancer Society, which provide guidance to clinicians about cancer screening, have not made recommendations for or against the routine use of DBT.

To assess the extent of DBT use nationwide, the Yale team examined claims data from private health insurance plans. Their investigation included more than 9 million screening exams performed over three years. They also compared DBT use with privately insured versus Medicare-insured patients.

The researchers found that DBT use rose substantially, from 12.9% to 43.2% of screening exams between 2015 and 2017. The increase was consistent among women who were privately insured and women with Medicare.

"DBT has become very popular overall, although uptake has been uneven. In some areas of the country, it is rarely used while in others, it is the predominant mode of screening," said corresponding author Ilana Richman, M.D., assistant professor in the Section of General Internal Medicine at the Yale School of Medicine.

Richman and her co-authors also observed that adoption of DBT varied greatly by region and demographics. Use of the technology grew more quickly in the Northeast and Northwest but more slowly in the Southeast. DBT was more rapidly adopted in areas with higher incomes, greater education, and larger white populations, they said.

While there is evidence that DBT may boost cancer detection rates and reduce false-positive results, more research is needed to determine the true impact of the technology on breast cancer mortality, said the researchers.

"Although there is a lot of interest in this new technology, we don't know much about how it will affect the long-term health of women," Richman noted. "There are ongoing studies designed to answer these questions, and we hope to have clearer answers in the next few years."

The authors predict that, given these findings, DBT will replace 2-D mammography as the standard of care. "These findings highlight how quickly changes in medical practice -- the rate that doctors adopt these new tests -- can eclipse our ability to evaluate whether they are helping patients to live longer and healthier lives," said senior author and professor of medicine Cary Gross, M.D.

NEW YORK, Monday, June 24, 2019 – According to a first-of-its-kind study, cities with a higher incidence of a certain kind of racist tweets reported more actual hate crimes related to race, ethnicity, and national origin.

A New York University research team analyzed the location and linguistic features of 532 million tweets published between 2011 and 2016. They trained a machine learning model — one form of artificial intelligence — to identify and analyze two types of tweets: those that are targeted — directly espousing discriminatory views — and those that are self-narrative — describing or commenting upon discriminatory remarks or acts. The team compared the prevalence of each type of discriminatory tweet to the number of actual hate crimes reported during that same time period in those same cities.

The research was led by Rumi Chunara, an assistant professor of computer science and engineering at the NYU Tandon School of Engineering and biostatistics at the NYU College of Global Public Health, and Stephanie Cook, an assistant professor of biostatistics and social and behavioral sciences at the NYU College of Global Public Health.

“We found that more targeted, discriminatory tweets posted in a city related to a higher number of hate crimes,” said Chunara. “This trend across different types of cities (for example, urban, rural, large, and small) confirms the need to more specifically study how different types of discriminatory speech online may contribute to consequences in the physical world.”

The analysis included cities with a wide range of urbanization, varying degrees of population diversity, and different levels of social media usage. The team limited the dataset to tweets and bias crimes describing or motivated by race, ethnic or national origin-based discrimination. Hate crimes are categorized and tracked by the Federal Bureau of Investigation, and crimes motivated by race, ethnicity, or national origin represent the largest proportion of hate crimes in the nation. Statistics for sexual orientation crimes were not available in all cities, although the researchers previously studied this form of bias.

The group also identified a set of discriminatory terms and phrases that are commonly used on social media across the country, as well as terms specific to a particular city or region. These insights could prove useful in identifying groups that may be likelier targets of racially motivated crimes and types of discrimination in different places. While most tweets included in this analysis were generated by actual Twitter users, the team found that an average of 8% of tweets containing targeted discriminatory language was generated by bots.

There was a negative relationship between the proportion of race/ethnicity/national-origin-based discrimination tweets that were self-narrations of experiences and the number of crimes based on the same biases in cities. Chunara noted that while experiences of discrimination in the real world are known psychological stressors with health and social consequences, the implications of online exposure to different types of online discrimination — self-narrations versus targeted, for example — need further study.

These results represent one of the largest, most comprehensive analyses of discriminatory social media posts and real-life bias crimes in this country, although the researchers emphasize that the specific causal mechanisms between social media hate speech and real-life acts of violence need to be explored.

Immunotherapies have revolutionized the care of many cancers, teaching the body's own immune cells to recognize and attack tumor cells. Leading the way are drugs known as checkpoint inhibitors, which block a kind of "white flag" that tumors wave as a peace signal to T cells that would very much like to kill them. Really, this white flag is a protein called PD-L1 -- many tumors coat themselves in it. When PD-L1 on the surface of a cancer cell sees its partner, PD1, on T cells, these T cells are tricked into letting the cancer cell live. To counteract this dirty trick, checkpoint inhibitor drugs block the functions of PD-L1 on tumor cells (e.g. atezolizumab) or PD1 on T cells (e.g. pembrolizumab), allowing T cells to go about their cancer-killing business.

Unfortunately, checkpoint inhibitors don't work all the time. For reasons that have been largely unknown, some patients respond to checkpoint inhibitor therapies, while others do not. A University of Colorado Cancer Center study published in the journal Cancer Immunology Research offers insight and possibly an inroad into this problem: In mouse models of B-cell lymphoma, adding another drug, called a histone deacetylase (HDAC) inhibitor, sensitized cancers to anti-PD1 therapy.

"I think this combination is definitely worth trying," says Jing Wang, MD, PhD, investigator at CU Cancer Center and associate professor in the CU School of Medicine Department of Immunology and Microbiology.

The reason this combination works is a bit complex. However, it may help to explain not only why some patients fail to respond to anti-PD1 immunotherapy, but also why HDAC inhibitors, which have seemed so promising in the lab, have been largely unsuccessful with patients.

The reason has to do with another set of proteins, called major histocompatibility complex (MHC). In fact, MHC describes a few classes of proteins - think of them like silver platters, only in this case, instead of serving food, MHC proteins serve antigens. Basically, MHC proteins grab and little bits of proteins from inside a cell and present them on the cell surface for inspection by our T cells. And when our T cells recognize a dangerous antigen sitting on an MHC platter, they attack that cell (you know, unless the T cell is deactivated by the PD1/PD-L1 interaction).

If a cancer cell has no MHC proteins, it doesn't matter if immunotherapy blocks the PD1/PD-L1 interaction -- without MHC, the cancer cell presents no antigens and so the immune system sees no danger.

"T cells recognize antigens in the context of MHC. Without MHC, you can't present an antigen. And about 60 percent of diffuse large B cell lymphomas downregulate MHC," Wang says.

This is one side of the story: Anti-PD1 immunotherapies may not work in cancers that downregulate MHC. Here is the other side: It appears that the class of drugs known as HDAC inhibitors upregulate MHC. Specifically, the study showed that the experimental HDAC inhibitor OKI-179 (provided by OnKure Therapeutics, Inc. and currently in a phase 1 clinical trial at CU Cancer Center) was like a switch: Without OKI-179, the group's models of B-cell lymphoma resisted anti-PD1 therapy; with OKI-179 added to anti-PD1 therapy, cancer cells were killed.

"We treated our mouse model of B-cell lymphoma with this HDAC inhibitor. The inhibitor alone had some effect, but when we combined it with anti-PD1 it worked a lot better. Dual inhibition -- both HDAC and PD1 -- achieved a better effect," Wang says.

Finally, the study may help to explain why previous HDAC inhibitors have struggled. Remember, there are two systems at work -- the PD1/PD-L1 interaction (which is bad) and also MHC proteins that present antigens (which is good). HDAC inhibitors may upregulate MHC proteins (again, this is good), but the current study shows that HDAC inhibitors may also upregulate PD-L1, helping cancer cells to pepper themselves with these white flags that deactivate the immune system (which is bad).

Now imagine this solution: An HDAC inhibitor upregulates MHC and as an unfortunate byproduct upregulates PD-L1... but an anti-PD1 checkpoint inhibitor nixes the immune system's ability to recognize all this extra PD-L1. The HDAC inhibitor restores MHC, serving more antigens to T cells, making the anti-PD1 therapy work better; and the anti-PD1 therapy keeps our T cells from recognizing any extra PD-L1 on cancer cells, making the HDAC inhibitor work better. In this scenario, the combination of HDAC inhibitor with anti-PD1 is greater than the sum of each drug used alone.

"We think this immunologic effect is very important. This paper emphasizes the immunologic action of HDAC. If your HDAC inhibitor is upregulating PD-L1, you're not going to make it work alone. But if you also block PD1, HDAC inhibition looks much more successful," Wang says.

At least that's the theory. Ongoing work continues to explore the promise of this combination in systems closer to human cancer.

BOSTON -- (June 24, 2019) -- New research has identified a type of bacteria found in the microbiomes of elite athletes that contributes to improved capacity for exercise. These bacteria, members of the genus Veillonella, are not found in the guts of sedentary people.

By taking a closer look at the bacteria, the researchers from Joslin Diabetes Center determined Veillonella metabolizes lactic acid produced by exercise and converts it into propionate, a short chain fatty acid. The human body then utilizes that propionate to improve exercise capacity. The results were reported today in Nature Medicine.

"Having increased exercise capacity is a strong predictor of overall health and protection against cardiovascular disease, diabetes, and overall longevity," says Aleksandar D. Kostic PhD, TITLE., a co-author on the paper. "What we envision is a probiotic supplement that people can take that will increase their ability to do meaningful exercise and therefore protect them against chronic diseases including diabetes."

The work began in 2015 with fecal samples from Boston Marathon runners. Jonathan Scheiman, PhD, then a researcher in the lab of George Church, PhD, at Harvard Medical School, collected samples during a time span of one week before the Marathon to one week after the Marathon. He also collected samples from sedentary individuals. Dr. Scheiman then brought the samples to Dr. Kostic, who analyzed them to determine the species of bacteria in both cohorts.

"One of the things that immediately caught our attention was this single organism, Veillonella, that was clearly enriched in abundance immediately after the marathon in the runners. Veillonella is also at higher abundance in the marathon runners [in general] than it is in sedentary individuals." says Dr. Kostic.

They confirmed the link to improved exercise capacity in mouse models, where they saw a marked increase in running ability after supplementation with Veillonella. Next, they wanted to figure out how it worked.

"As we dug into the details of Veillonella, what we found was that it is relatively unique in the human microbiome in that it uses lactate or lactic acid as its sole carbon source," he says.

Lactic acid is produced by the muscles during strenuous exercise. The Veillonella bacteria are able to use this exercise by-product as their main food source.

"Our immediate hypothesis was that it worked as a metabolic sink to remove lactate from the system, the idea being that lactate build-up in the muscles creates fatigue," he says. "But talking to people like Sarah Lessard, [a clinical researcher at Joslin] and other people in the exercise physiology field, apparently this idea that lactate build-up causes fatigue is not accepted to be true. So, it caused us to rethink the mechanism of how this is happening."

Dr. Kostic and his team returned to the lab to figure out what could be causing the increase in exercise capacity. They ran a metagenomic analysis, meaning they tracked the genetics of all the organisms in the microbiome community, to determine what events were triggered by Veillonella's metabolism of lactic acid. They noted that the enzymes associated with conversion of lactic acid into the short chain fatty acid propionate were at much higher abundance after exercise.

"Then the question was maybe it's not removal of lactic acid, but the generation of propionate," says Dr. Kostic. "We did some experiments to introduce propionate into mice [via enema] and test whether that was sufficient for this increased running ability phenotype. And it was."

Dr. Kostic and his team plan to investigate the mechanisms of how propionate affects exercise capacity in a collaboration with Dr. Lessard.

Colonies of bacteria residing in our guts have a powerful impact on our health. Exercise is an important component of a healthy lifestyle meant to ward off diseases such as type 2 diabetes. Many people with metabolic disorders are not able to exercise at the level needed to see such benefits. Supplementing their microbiome using a probiotic capsule containing Veillonella could give them the boost they need for effective exercise. (Direct dosing with propionate pill would not work, as the short chain fatty acid would be broken down by digestive juices before it could take effect.) Dr. Scheiman has since spun this idea off into a company targeted at athletes.

"The microbiome is such a powerful metabolic engine," says Dr. Kostic. This is one of the first studies to directly show a strong example of symbiosis between microbes and their human host.

"It's very clear. It creates this positive feedback loop. The host is producing something that this particular microbe favors. Then in return, the microbe is creating something that benefits the host," he says. "This is a really important example of how the microbiome has evolved ways to become this symbiotic presence in the human host."

For patients with chest pain and presumably stable coronary heart disease (CHD), therapy depends primarily on how constricted the arteries that support the heart are (coronary arteries). This is often determined using an invasive procedure called cardiac catheterization. If necessary, the pressure in the coronary arteries is also measured. The combination of these methods is the currently the recognized standard for making therapy decisions. Cardiovascular magnetic resonance imaging (MRI) is an alternative for directly measuring the blood flow in the myocardium.

In contrast to cardiac catheterization, MRI is non-invasive, works without ionising radiation, can be done in 40 minutes and delivers direct measurements of the blood flow to the heart. The team headed by Professor Eike Nagel, Director of the Institute for Experimental and Translational Cardio Vascular Imaging at Goethe University was able to demonstrate that MRI measurements are as safe to guide decision-making as the currently used invasive procedure. Within the international MR-INFORM study, they examined 918 patients with an indication for cardiac catheterization to see if decision-making by an MRI scan led to the same results as the current invasive method.

Patients were randomly assigned to two groups. One group received the standard diagnostic investigation with cardiac catheterization and pressure measurement of the coronary arteries. The other had the 40 minute MRI scan of the heart to decide whether to send the patient on for invasive angiography.

In each study arm, constricted coronary vessels were dilated when indicated by the examination. In the following year, the physicians documented how many patients died, suffered a heart attack or required a repeated vascular dilation. In addition, they recorded whether the heart symptoms continued.

The result: in the group of patients examined by MRI, less than half required a diagnostic cardiac catheterization and fewer patients received a vascular dilation (36% vs 45 %). This means that with a fast and non-invasive MRI examination as the first test, both diagnostic and therapeutic cardiac catheterizations can be reduced. Importantly, the two groups did not differ in terms of continuing symptoms, the development of new symptoms, complications, or deaths.

"This means that patients with stable chest pains who previously would have received cardiac catheterization can alternatively be examined with MRI," concludes Professor Eike Nagel. "The results for the patients are just as good, but an examination by MRI has many advantages: the procedure takes about 40 minutes, patients merely receive a small cannula in their arm and are not subject to radiation." The physician hopes that the less invasive method will now be used as a method of first choice, reducing the need for cardiac catheterizations.

In contrast to Great Britain, where an MRI scan of the heart is paid for by the National Health Service (NHS), reimbursement is often difficult in Germany and usually has to be negotiated individually. In this regard, Nagel also hopes that the study will contribute to the acceptance of the non-invasive procedure and improve its availability.

A recent study conducted jointly by the Tissue Engineering Research Group of the Department of Histology and the Family Medicine Unit of the University of Granada (UGR) has highlighted the conceptual, attitudinal, and procedural profile of resident hospital doctors specialising in Family Medicine, in relation to the so-called advanced therapies.

According to the European Medicines Agency, such therapies--cell therapy, gene therapy, and tissue engineering--constitute a range of innovative therapies whose application presents extremely rigorous biofabrication requirements.

The progressive increase in demand for such therapies and consultations about their possible use by patients with different pathologies calls for relevant health education about them--a task in which Family Doctors have an important role to play.

Little training in this area

The study highlights a perception among resident doctors that they are receiving insufficient training, both at a conceptual level and also in terms of the regulatory framework in this area. It also notes a highly positive attitude towards the use and application of such therapies in hospitals and toward greater research into the topic. Furthermore, the findings point to a clear preference among these doctors for the necessary drugs to be developed within research centres, whereas the current regulation requires biofabrication to be carried out on GMP (Good Manufacturing Practice) approved premises, wherever these may be located.

The resident doctors consulted in the study expressed serious reservations about the monitoring of the patients undergoing such treatments being conducted in health centres, and about the fact that the biofabrication process is linked to the pharmaceutical industry.

The results of the research are potentially valuable for the design of future training programmes for resident doctors dealing with the conceptual, attitudinal, and procedural dimensions of this type of therapy. The findings are also relevant to the role of Family Doctors in the health education of the population with regard to advanced therapies.

Prior to the study, the UGR's Tissue Engineering Research Group successfully designed artificial corneas and human skin as advanced therapy treatments. These were developed at the university, and later transferred to clinical practice.

San Francisco, CA - June 23, 2019 - Researchers have used whole genome sequencing (WGS) to demonstrate transmission of a single bacterial strain that possessed a carbapenem-resistance gene in a northern California hospital. The gene armed the bacteria with resistance to carbapenems, a type of antimicrobial drug reserved as a last-line treatment for serious infections. The research is presented on Sunday, June 23rd at ASM Microbe, the annual meeting of the American Society for Microbiology.

Epidemiologists from the local public health department and the California Department of Public Health (CDPH) collaborated with laboratory scientists from the CDPH Microbial Diseases Laboratory (MDL) to characterize the strain and identify potential transmission pathways in combination with epidemiologic information.

The bacterial strain persisted in the hospital for over 3 years, potentially due to transmission from patient to patient combined with lengthy stays in the hospital intensive care unit (ICU). "Our investigation highlights the importance of regular epidemiological and microbiological monitoring of resistant strains in hospitals and the use of the advanced molecular technologies to track their spread," said Varvara Kozyreva, Ph.D. Genotyping Unit Chief, Microbial Diseases Laboratory Program, California Department of Public Health.

Between 2013 and 2015, the hospital identified eight patients who were positive for a strain of Klebsiella pneumoniae bacteria that produced an enzyme conferring resistance to carbapenems. The initial four patients identified with the resistant strain had overlapping stays in the ICU over a one-month period. One of these initial patients remained in the ICU for two years, during which time an additional four patients with the resistant bacterial strain were found in the facility. WGS analyses of the bacteria from the eight different patients demonstrated they were all highly related genetically.

"WGS allowed us to understand and demonstrate connections among the patients over a multiple year time period, which would not have been possible using epidemiologic information alone," said Dr. Kozyreva. WGS also showed that this particular bacterial strain's carbapenem-resistance gene appeared to be located on the chromosome. Normally, such resistance genes are located on additional "mobile" DNA pieces called plasmids, that can be transferred between different strains (and even different species) of bacteria.

"Since this particular strain had less means to efficiently share its carbapenem-resistance genes with other bacteria in the hospital environment, it is all the more likely that this one antibiotic-resistant clone of bacteria persisted in the hospital over multiple years," said Dr. Kozyreva. Using WGS to track resistant bacterial strains can help hospitals and public health officials target infection control interventions to halt transmission sooner.

Alexandria, Va., USA - At the 97th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 48th Annual Meeting of the American Association for Dental Research (AADR) and the 43rd Annual Meeting of the Canadian Association for Dental Research (CADR), Jaakko Leskela, University of Helsinki, Finland, gave an oral presentation on "Metabolomic Profiling of Antibody Response to Periodontal Pathogens." The IADR/AADR/CADR General Session & Exhibition is held at the Vancouver Convention Centre West Building in Vancouver, BC, Canada from June 19-22, 2019.

Detection of periodontopathogen antibodies in circulation indicate exposure to periodontal pathogens. Inflammation, such as present in periodontal disease, has shown to modify lipoprotein metabolism and composition. In this study, Leskela and coauthors investigated the association between serum periodontopathogen antibody levels and various metabolite levels.

The study population consisted of 2,398 individuals whose serum antibody levels against P. gingivalis and A. actinomycetemcomitans were determined by multiserotype-ELISA. Nuclear Magnetic Resonance (NMR)-metabolomics platform determined a total of 68 metabolic variables, including lipoprotein particles, fatty acids, amino acids, metabolic substrates, glycoproteins and ketone bodies. P. gingivalis IgG antibody levels were associated negatively with Apolipoprotein A-I, HDL-bound cholesterol and especially cholesterol bound to larger HDL particles. There was negative association in P. gingivalis IgA antibody levels with Serum total cholesterol and A. actinomycetemcomitans IgG.

The authors concluded that exposure to the major periodontal pathogens, P. gingivalis and A. actinomycetemcomitans, is associated with a proatherogenic lipoprotein profile, especially low high-density lipoprotein cholesterol levels. These results are in line with previous findings where periodontal disease is shown to associate with atherogenic diseases.

This oral presentation, #2936, was held on Saturday, June 22, 2019 at 8:30 a.m. in Room 224 of the Vancouver Convention Centre West Building, Vancouver, BC, Canada.

Alexandria, Va., USA - The International Association for Dental Research (IADR) and American Association for Dental Research (AADR) honored the legacy of Ricardo Teles in a symposium at the 97th General Session & Exhibition of the IADR, held in conjunction with the 48th Annual Meeting of the American AADR and the 43rd Annual Meeting of the Canadian Association for Dental Research (CADR). The IADR/AADR/CADR General Session & Exhibition is held at the Vancouver Convention Centre West Building in Vancouver, BC, Canada from June 19-22, 2019.

A native of Brazil, Teles earned his D.D.S. at Federal University of Rio de Janeiro, Brazil and received his D.M.Sc. in Oral Biology and certificate in periodontology from Harvard School of Dental Medicine, Boston, Massachusetts, USA. Teles last served as the Chair of the University of Pennsylvania Dental Medicine's Department of Periodontics in Philadelphia, USA.

The symposium gathered some of the many colleagues he connected with during his prolific career to acknowledge his legacy, recognize his achievements and pay tribute to his dedication and commitment to advancing the periodontal field. The symposium also reviewed the current knowledge in clinical periodontology and how it impacts clinical practice and patient care to help identify the current gaps in knowledge in the field and help shape the next wave of clinical periodontal studies. Speakers in this symposium included Flavia Teles, University of Pennsylvania, Philadelphia, USA, William Giannobile, University of Michigan, Ann Arbor, USA, Iain Chapple, University of Birmingham, UK, Marcelo Faveri, Guarulhos University, Brazil and Hatice Hasturk, The Forsyth Institute, Cambridge, Massachusetts.

The symposium, #281, "Pathogenesis and Treatment of Periodontitis: Honoring the Legacy of Ricardo Teles" was held on Friday, June 21 at 2 p.m. in Room 120. Teles was also honored in the Journal of Dental Research article "Ricardo Teles: His Life and Contributions to Periodontology."

Before and after comparisons don't tell the full story of chemical reactions in flowing fluids, such as those in chemical reactor, according to a new study from a collaboration based in Japan.

The researchers published their paper on May 6 in the Journal of Physical Chemistry B, a journal of the American Chemical Society. The results were featured on the journal's cover.

The team examined how a solution of dissolved polymers changed after the addition of Fe3+ solution. These types of solutions are used to better control variables in several fields, including manufacturing. In automobile manufacturing, for instance, the solutions help achieve a thorough evenness of paint coverage and control over how much a material expands or contracts under various temperatures.

Traditionally, researchers examine a solution before a reactant, such as Fe3+ solution, is added, and again after the reaction takes place.

"In other words, if a fluid property such as the viscosity of the solution is higher after the reaction than before, we would expect that an increase in viscosity occurs from the reaction during flow," said Yuichiro Nagatsu, corresponding author on the paper and an associate professor in the Department of Chemical Engineering at Tokyo University of Agriculture and Technology.

Nagatsu and the team discovered that the before and after comparison isn't as reliable as previously thought. They observed an increase in viscosity in the solution during a chemical reaction to Fe3+, but the solution had thinned back out by the end of reaction. They confirmed their chemical observations with infrared spectroscopy, which allows researchers to examine microscopic interactions without extensive preparation that could further disturb the sample.

Flow dynamics account for microscopic changes within these chemical reactions - molecules stripping other molecules of electrons and the like - that fundamentally change the composition of the solution. However, viscosity is known as a macroscopic change - it describes the solution as a whole rather than the individual interactions on the microscopic level.

It's incredibly unusual for such a solution to shift through such macroscopic phases only to lose the characteristics by the end of a chemical reaction, according to Nagatsu. This understanding could have major implications across industrial, environmental, and biological fields.

"Our ultimate goal is to establish a new research area to understand chemically reacting flow involving the diagnosis of molecule structure," Nagatsu said. He also noted that the plans to develop a novel method to control fluid dynamics through their new understanding of interactions.

BOSTON - As health officials in New Jersey, Illinois and New York State scramble to contain the spread of a highly infectious and deadly fungus, microbiologists at Beth Israel Deaconess Medical Center (BIDMC) have shown that a combination of anti-fungal and anti-bacterial medications may be an effective weapon against the recently discovered multidrug resistant, Candida auris (C. auris).

BIDMC's Thea Brennan-Krohn, MD, presented the findings Friday, June 21, 2019, at ASM Microbe 2019, the annual meeting of the American Society for Microbiology.

"Few treatment options are available for patients infected with Candida auris, which causes invasive, life-threatening infections, usually in patients who are already critically ill or have compromised immune systems," said Brennan-Krohn, MD, a post-doctoral research fellow in the lab of James E. Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC. "It has an alarming propensity to spread from patient to patient and survive on surfaces in rooms, resulting in hospital outbreaks."

First discovered in Japan in 2009, C. auris has been detected in patients in more than 20 countries and, as of April 2019, has sickened 643 Americans in 11 U.S. states, according to the U.S. Centers for Disease Control and Prevention (CDC). At present, most cases of C. auris are resistant to at least one antifungal drug, with about a third impervious to two or more.

In order to identify new treatment approaches for C. auris, Brennan-Krohn and colleagues used a modified inkjet printer - a method pioneered for rapid and uniform antimicrobial screening in the Kirby lab - to test three antifungal drugs, one from each of the main classes of antifungals, combined with two antibacterial antibiotics, which by themselves have no activity against fungal infections.

Using the inkjet technology to dispense uniform samples of C. auris into each of the 96 wells in a standard lab testing plate, Brennan-Krohn tested 10 combinations against 10 strains of C. auris, a painstaking process that would have taken at least 50 hours if done by hand. It took less than two hours in total using the inkjet dispenser for Brennan-Krohn to find three novel combinations of antifungal and antibacterial drugs that demonstrated activity against this insidious new pathogen.

Using a different method known as a time-kill test, Brennan-Krohn showed that two of the antibacterial-antifungal treatments not only prevented C. auris from growing but also succeeded in killing some of the strains tested.

While the drugs have not yet been tested in combination in humans infected with C. auris, all of the drugs Brennan-Krohn evaluated - the antifungals amphotericin and caspofungin and the antibacterials minocycline and rifampin - are FDA-approved antibiotics, currently in use patients with a variety of infections. If the drugs' combined power to inhibit or kill C. auris that they demonstrated in the lab is confirmed in studies in humans, it could mean physicians caring for patients with C. auris infections already have access to effective treatment options.

Scientists from the University of Sheffield have discovered a novel behaviour of the blood vessels of the brain in zebrafish that may explain some forms of stroke in humans.

The previously undescribed large structures are spherical and so have been termed kugeln (German for sphere) by the Sheffield team, who discovered them in collaboration with scientists from the USA and Germany.

No cell has ever been shown to develop kugeln in the past, possibly because they are easily mistaken for normal blood vessels. Kugeln contain a molecule called nitric oxide which is essential for the health of blood vessels.

Stroke is a life-threatening condition affecting more than 100,000 people in the UK each year. Some forms of stroke are caused by mutations in genes which the Sheffield researchers have shown are required to form kugeln. Although the function of kugeln is not yet fully understood, this link to genetic forms of stroke could provide new insights into neurological and cardiovascular research.

Elisabeth Kugler, a PhD student from the University of Sheffield's Department of Infection, Infection and Cardiovascular Disease and the main author of the study, said: "The finding of kugeln highlights the need for basic research to understand the mechanisms of development and disease.

"This study would not have been possible without an extremely strong international scientific team, underlining the significance of working across different countries."

The pioneering research was made possible thanks to state-of-the-art imaging with a revolutionary light sheet microscope (funded by the British Heart Foundation), and the ability to study vascular development using zebrafish as a model organism.

Elisabeth added: "We share 70 per cent of our genes with zebrafish. Therefore, zebrafish are hugely important for understanding processes that can lead to human disease."

The ground breaking research has been published in the journal EMBO reports.

Tim Chico, lead author of the study and Professor of Cardiovascular Medicine at the University of Sheffield, said: "Stroke is a devastating disease that affects millions of people and their families each year across the world.

"It is extremely exciting to discover an entirely new process that only happens in brain blood vessels, because this might explain why some mutations cause stroke but not diseases of other arteries.

"If we can discover the function of kugeln we may be able to manipulate them to reduce the effects of stroke."

The next step for researchers is to establish whether kugeln are present in human brains as well as gaining a deeper understanding of the mechanisms and functions of kugeln.