Body

Announcing a new publication for BIO Integration journal. In this opinion article the authors Daiyun Xu, Yonghui Lü, Yongxiao Li, Shengbin Li, Zhe Wang and Junqing Wang from Sun Yat-Sen University, Guangzhou, China discuss ferroptosis resistance in cancer.

Ferroptosis is a lethal consequence of accumulated lipid peroxidation catalyzed by ferrous iron and oxygen. This unique cell death process appears to involve many diseases, such as neurodegeneration, ischemia/ reperfusion injury, kidney disease, and a druggable target in therapy-resistant cancers. Ferroptosis may provide hope for the treatment of as yet incurable diseases. However, ferroptosis susceptibility is linked to various regulation pathways.

In this article the authors integrate the current understanding of signaling mechanisms for ferroptotic defences with a view to development of novel cancer therapeutic strategies.

In a letter published in the December issue of the American Heart Association's medical journal Circulation a group of researchers at Vanderbilt University Medical Center (VUMC) dispute the most recent findings of the incidence of myocarditis in athletes with a history of COVID-19.

The Vanderbilt study, COVID-19 Myocardial Pathology Evaluation in AthleTEs with Cardiac Magnetic Resonance (COMPETE CMR), found a much lower degree of myocarditis in athletes than what was previously reported in other studies.

"The differences in the findings are extremely important. The whole world paused after seeing the alarmingly high rates of myocardial inflammation and edema initially published," said Dan Clark, MD, MPH, first author of the report, instructor of Cardiovascular Medicine, and a adult congenital heart disease fellow. "Our study evaluated 59 Vanderbilt University athletes and compared them to a healthy control group as well as a group of 60 athletic controls.

"The degree of myocarditis found by cardiac MRI in Vanderbilt athletes was only 3%, which is really good news," said Clark. "Since our first evaluation, we have screened almost double that number and the same findings are holding true.

"But there was also a piece of disappointing news," he said. "None of the other screening tests helped us to identify the athletes with myocarditis, and none of those athletes had experienced symptoms of COVID.

"Initially, we hoped that the standard screening tests for athletes would be definitive because we wanted something that was widely available and quick," said Clark. "We hoped that a cardiac MRI would only be used if absolutely necessary.

"However, their blood work, clinical exams, EKG, echocardiograms and other cardiovascular screening were normal. All of those traditional screening results would have led us to agree to allow some athletes to participate in a sporting event or practice, while the MRI told a different story."

Myocarditis is a disorder of abnormal inflammation of the heart muscle and is a leading cause of sudden cardiac death among athletes. The findings highlight the importance of considering cardiac MRI in addition to traditional screening measures to detect myocarditis.

It is well documented that COVID-19 may affect the heart.

"Our data also demonstrated more scarring in healthy heart muscle than we would have thought," Clark said.

Those findings led the group to dig deeper and compare a healthy, athletic population with normal cardiac MRI values against those who had recovered from COVID.

The athletic control group without COVID showed 24% (1 in 4) scarring in the heart muscle while the COVID athlete group had a 27% (1 in 4) scarring ratio. According to Clark, athletes commonly have a small area of benign scar due to athletic remodeling. This scarring related to athletic changes was evident in both athletic groups studied.

"This particular piece of information is very important to share - myocarditis after COVID-19 tends to be in a similar spot," he said. "Without the knowledge that this area of scarring is common in healthy athletes, clinicians could attribute the scarring to consequences from COVID-19. Those assumptions might unnecessarily restrict some athletes from competition."

Clark says his team's findings suggest that the addition of cardiac MRI as an assessment tool for athletes may be very helpful in determining safe return-to-play guidelines.

COMPETE CMR is the first study that the group is aware of to use an appropriate athletic control group to assess athletes after COVID-19.

"Myocarditis among recovering COVID-19 athletes is less common than previously reported," said Clark. "We also want to highlight that the comparison to a healthy athletic control group without COVID is critically important to show that many changes on a cardiac MRI are related to athleticism and not COVID-19. However, despite the lower incidence of myocarditis than expected, cardiac MRI remains a very useful tool for evaluating competitive athletes prior to a return to sports."

Across the world, health care workers and high-risk groups are beginning to receive COVID-19 vaccines, offering hope for a return to normalcy amidst the pandemic. However, the vaccines authorized for emergency use in the U.S. require two doses to be effective, which can create problems with logistics and compliance. Now, researchers reporting in ACS Central Science have developed a nanoparticle vaccine that elicits a virus-neutralizing antibody response in mice after only a single dose.

The primary target for COVID-19 vaccines is the spike protein, which is necessary for SARS-CoV-2's entry into cells. Both of the vaccines currently authorized in the U.S. are mRNA vaccines that cause human cells to temporarily produce the spike protein, triggering an immune response and antibody production. Peter Kim and colleagues wanted to try a different approach: a vaccine consisting of multiple copies of the spike protein displayed on ferritin nanoparticles. Ferritin is an iron storage protein found in many organisms that self-assembles into a larger nanoparticle. Other proteins, such as viral antigens, can be fused to ferritin so that each nanoparticle displays several copies of the protein, which might cause a stronger immune response than a single copy.

The researchers spliced spike protein and ferritin DNA together and then expressed the hybrid protein in cultured mammalian cells. The ferritin self-assembled into nanoparticles, each bearing eight copies of the spike protein trimer. The team purified the spike/ferritin particles and injected them into mice. After a single immunization, mice produced neutralizing antibody titers that were at least two times higher than those in convalescent plasma from COVID-19 patients, and significantly higher than those in mice immunized with the spike protein alone. A second immunization 21 days later produced even higher antibody levels. Although these results must be confirmed in human clinical trials, they suggest that the spike/ferritin nanoparticles may be a viable strategy for single-dose vaccination against COVID-19, the researchers say.

More than half of people who use medical marijuana products to ease pain also experience clusters of multiple withdrawal symptoms when they're between uses, a new study finds.

And about 10% of the patients taking part in the study experienced worsening changes to their sleep, mood, mental state, energy and appetite over the next two years as they continued to use cannabis.

Many of them may not recognize that these symptoms come not from their underlying condition, but from their brain and body's reaction to the absence of substances in the cannabis products they're smoking, vaping, eating or applying to their skin, says the University of Michigan Addiction Center psychologist who led the study.

When someone experiences more than a few such symptoms, it's called cannabis withdrawal syndrome - and it can mean a higher risk of developing even more serious issues such as a cannabis use disorder.

In the new research published in the journal Addiction, a team from the U-M Medical School and the VA Ann Arbor Healthcare System reports findings from detailed surveys across two years of 527 Michigan residents. All were participating in the state's system to certify people with certain conditions for use of medical cannabis, and had non-cancer-related pain.

"Some people report experiencing significant benefits from medical cannabis, but our findings suggest a real need to increase awareness about the signs of withdrawal symptoms developing to decrease the potential downsides of cannabis use, especially among those who experience severe or worsening symptoms over time," says Lara Coughlin, Ph.D., the addiction psychologist who led the analysis.

Long-term study in medical cannabis use

The researchers asked the patients whether they had experienced any of 15 different symptoms - ranging from trouble sleeping and nausea to irritability and aggression - when they had gone a significant time without using cannabis.

The researchers used an analytic method to empirically group the patients into those who had no symptoms or mild symptoms at the start of the study, those who had moderate symptoms (meaning they experienced multiple withdrawal symptoms) and those who had severe withdrawal issues that included most or all of the symptoms.

They then looked at how things changed over time, surveying the patients one year and two years after their first survey.

At baseline, 41% of the study participants fell into the mild symptoms group, 34% were in the moderate group and 25% were classed as severe.

Misconceptions about medical cannabis

Many people who turn to medical cannabis for pain do so because other pain relievers haven't worked, says Coughlin, an assistant professor in the Department of Psychiatry who sees patients as part of U-M Addiction Treatment Services. They may also want to avoid long-term use of opioid pain medications because they pose a risk of misuse and other adverse health consequences.

She notes that people who experience issues related to their cannabis use for pain should talk with their health care providers about receiving other pain treatments including psychosocial treatments such as cognitive behavioral therapy.

The perception of cannabis as "harmless" is not correct, she says. It contains substances called cannabinoids that act on the brain - and that over time can lead the brain to react when those substances are absent.

In addition to a general craving to use cannabis, withdrawal symptoms can include anxiety, sleep difficulties, decreased appetite, restlessness, depressed mood, aggression, irritability, nausea, sweating, headache, stomach pain, strange dreams, increased anger and shakiness.

Previous research has shown that the more symptoms and greater severity of symptoms a person has, the less likely they are to be able to reduce their use of cannabis, quit using it or stay away from it once they quit.

They may mistakenly think that the symptoms happen because of their underlying medical conditions, and may even increase the amount or frequency of their cannabis use to try to counteract the effect - leading to a cycle of increasing use and increasing withdrawal.

Coughlin says people who decide to use a cannabis product for a medical purpose should discuss the amount, route of administration, frequency and type of cannabis product with their regular health provider. They should also familiarize themselves with the symptoms of cannabis withdrawal and tell their provider if they're experiencing them.

Feeling the urge to use cannabis after a period without use, such as soon after waking up, can be a sign of a withdrawal syndrome, she notes. So can the inability to cut back on use without experiencing craving or other symptoms of withdrawal.

Because there is no medically accepted standard for medical cannabis dosing for different conditions, patients are often faced with a wide array of cannabis products that vary in strength and route of administration. Some products could pose more risk for development of withdrawal symptoms than others, Coughlin says.

For example, people who smoked cannabis tended to have more severe withdrawal symptoms than others, while people who vaped cannabis reported symptoms that tended to stay the same or get worse, but generally did not improve, over time.

As more states legalize cannabis for medical or general use, including several states that will legalize its use based on the results of last November's election, use is expected to grow.

More about the study

The researchers asked the patients about how they used cannabis products, how often, and how long they'd been using them, as well as about their mental and physical health, their education and employment status.

Over time, those who had started off in the mild withdrawal symptom group were likely to stay there, but some did progress to moderate withdrawal symptoms.

People in the moderate withdrawal group were more likely to go down in symptoms than up, and by the end of the study the number of the people in the severe category had dropped to 17%. In all, 13% of the patients had gone up to the next level of symptoms by the end of the first year, and 8% had transitioned upward by the end of two years.

Sleep problems were the most common symptom across all three groups, and many in the mild group also reported cravings for cannabis. In the moderate group, the most common withdrawal symptoms were sleep problems, depressed mood, decreased appetite, craving, restlessness, anxiety and irritability.

The severe withdrawal symptom group was much more likely to report all the symptoms except sweatiness. Nearly all the participants in this group reported irritability, anxiety, and sleep problems. They were also more likely to be longtime and frequent users of cannabis.

Those in the severe group were more likely to be younger and to have worse mental health. Older adults were less likely to go up in withdrawal symptom severity, while those who vaped cannabis were less likely to transition to a lower withdrawal-severity group.

The study didn't assess nicotine use, or try to distinguish between symptoms that could also be related to breakthrough pain or diagnosed/undiagnosed mental health conditions during abstinence.

Future directions

Coughlin and her colleagues hope future research can explore cannabis withdrawal symptoms among medical cannabis patients further, including the impact of different attempts to abstain, different types of use and administration routes, and interaction with other physical and mental health factors. Most research on cannabis withdrawal has been in recreational users, or "snapshot" looks at medical cannabis patients at a single point in time.

Further research could help identify those most at risk of developing problems, and reduce the risk of progression to cannabis use disorder, which is when someone uses cannabis repeatedly despite major impacts on their lives and ability to function.

PHILADELPHIA--Medications to treat high blood pressure did not affect outcomes among patients hospitalized with COVID-19, found an international team led by researchers in the Perelman School of Medicine at the University of Pennsylvania. The study, published today in The Lancet Respiratory Medicine, is the first randomized controlled trial to show there is no risk for patients continuing these medications while hospitalized for COVID-19.

As part of the REPLACE COVID trial, investigators examined whether ACE inhibitors (ACEIs) or Angiotensin Receptor Blockers (ARBs) -- two classes of medications to treat high blood pressure -- could help mitigate complications or lead to more severe symptoms. More than 49 million U.S. adults take medication to treat hypertension, and among those, about 83 percent (41 million) take an ACEI or ARB, according to the Centers for Disease Control and Prevention.

Early during the pandemic, a concern arose regarding the use of ACEIs or ARBs in the setting of COVID-19, since some studies had suggested that these medications could upregulate cellular receptors for the SARS-CoV-2 virus potentially aiding viral replication. However, it was also considered that some effects of these medications could be protective against the virus.

"Observational studies were rapidly done, but randomized trials are important to establish a definitive answer regarding the potential impact of these commonly used blood pressure medications in the setting of COVID-19," said study corresponding and senior author Julio A. Chirinos, MD, PhD, an associate professor of Cardiovascular Medicine in the Perelman School of Medicine. "Our trial results importantly show that these medications can be safely continued for patients hospitalized with COVID-19."

ACEIs and ARBs are among the most commonly prescribed medications in the world, and a potential link between those medications and COVID-19 outcomes has large global health implications, the authors say. Several observational studies suggested no association between outpatient ACEI or ARB use and risk of COVID-19 hospitalization, but high-quality randomized trial evidence was lacking, until now.

For the trial, investigators enrolled 152 participants across several countries between March 31 and August 20, 2020, who were hospitalized with COVID-19 and already using one of the medications. The participants were randomly assigned to either stop or continue taking their prescribed medication and closely monitored to evaluate the effect of temporarily stopping the therapy.

Investigators developed an innovative global rank score to classify patient outcomes based on four factors: time to death, length of time supported by mechanical ventilation or extracorporeal membrane oxygenation (ECMO), length of time on renal replacement therapy, and a modified sequential organ failure assessment score. Through analyzing the patient outcome data, the team found discontinuation of ACEIs and ARBs compared with continuation of these medications had no effect on the global rank score.

This evidence supports international society recommendations for continuing ACEI and ARB therapy in patients admitted to the hospital with COVID-19, unless there is a clear, alternate medical issue with ongoing therapy.

"At the start of the pandemic, patients were worried about perceived harm based on limited and incomplete information, and unfortunately, some insisted on stopping their medications. However, stopping these medications unnecessarily can increase the risk for severe complications, including heart attack and stroke," said first author Jordana B. Cohen, MD, MSCE, an assistant professor in the division of Renal-Electrolyte and Hypertension, and a co-principal investigator with Chirinos. "Now we have high quality evidence to support our recommendation that patients continue to take these medications as prescribed."

Currently, trials are underway to determine if use of these medications is effective for the treatment of COVID-19.

The trial was sponsored by the investigators from the various enrolment centers; the REPLACE COVID Trial Social Fundraising Campaign supported a portion of enrolment at Penn Medicine; FastGrants supported enrolment at the University of Michigan.

Wuhan City in China was the first place to report COVID-19 in the world and--between December 2019 and May 2020--caused nearly two-thirds of all COVID-19 cases in China. Now, researchers reporting in PLOS Neglected Tropical Diseases have tested more than 60,000 healthy individuals in China for SARS-CoV-2 antibodies and concluded that thousands of Wuhan residents were infected with asymptomatic cases of COVID-19 after the infection was believed to be under control in China.

Rapid antibody tests are used to diagnosis present and past infections with the SARS-CoV-2 virus that causes COVID-19; positive IgG antibodies suggests a previous infection while IgM antibodies mean a current or recent infection. Detection of both types of antibodies can give a better understanding of the number of asymptomatic infections in a population over time. In Wuhan, the number of COVID-19 cases peaked in February 2020 and the city was initially declared to be free of disease in late April, although small clusters of cases appeared in later months.

In the new work, Xue-jie Yu of Wuhan University, China, and colleagues studied the prevalence of IgG and IgM antibodies in blood samples collected between March 6 and May 3, 2020, from 63,107 individuals in China. All people tested were healthy and were undergoing screening before returning to work.

Consistent with a large number of cases having occurred in Wuhan, the percentage of people with positive SARS-CoV-2 antibodies, about 1.68%, was significantly higher than in other regions of China, where antibody positivity averaged 0.38%. Moreover, according to the IgM positive rate of 0.46% in Wuhan, the researchers estimated that thousands of people in Wuhan were infected asymptomatically between March and May 2020, when there were not clinically reported cases of COVID-19.

"We conclude that... a large amount of asymptomatic carriers of SARS-CoV-2 existed after elimination of clinical cases of COVID-19 in Wuhan City," the researchers say. "Avirulent SARS-CoV-2 strains may still cause symptoms in extremely susceptible individuals and it may also revert to a highly virulent strain to reignite the epidemic of COVID-19 in China."

New treatments to cut the global death rate from dengue, Zika and West Nile viruses could result from research led by The University of Queensland.

Associate Professor Daniel Watterson from UQ's School of Chemistry and Molecular Biosciences said the team identified an antibody that improved survival rates in laboratory trials and reduced the presence of virus in the blood.

"We made a discovery in 2015 in the wake of the Zika outbreak that identified a new target for flavivirus treatments, a viral protein called NS1," Dr Watterson said.

"Now we've shown for the first time that a single NS1 antibody can be protective against multiple flaviviruses including dengue, Zika and West Nile.

"No other antibody reported has shown such a broad range of protection.

"The improved protection we saw compared to existing treatments was really unexpected."

An estimated 390 million people are infected with dengue globally each year, particularly in tropical and sub-tropical areas.

Of those cases, about half a million people develop a more severe form of the disease, which can be fatal.

Dr Watterson said the discovery was important, as the development of a vaccine for viruses like dengue is an unmet global challenge.

"Creating vaccines and therapies has been greatly hindered because antibodies that target the main viral envelope protein can also enhance disease.

"This phenomenon is called antibody dependent enhancement (ADE), and contributed to the complications arising from large-scale roll-out of the first licensed dengue vaccine.

"But because NS1 antibodies don't drive ADE, our findings provide the blueprint for new and safe broad-spectrum vaccines against multiple flaviviruses, including dengue."

Lead author UQ's Dr Naphak Modhiran said the antibody could also provide the first line of defence in future viral outbreaks across the world.

"The antibody binds to a wide range of flaviviruses including Usuto virus in Europe, and Rocio and Ilheus viruses in South America," Dr Modhiran said.

"These viruses have already caused local outbreaks in the past and have the potential to be the next Zika."

Co-author Professor Paul Young said the antibodies were first developed in his group more than 30 years ago.

"Since then, they have provided numerous insights into the biology of dengue and have been employed in the development of diagnostics," Professor Young said.

"It's great to see them now progressing as potential templates for therapeutics.

"This highlights the critical nature of discovery research in providing the foundation for translation into clinical practice."

PHILADELPHIA -- (Jan. 7, 2021) -- Scientists at The Wistar Institute characterized an inhibitor that targets acetate metabolism in cancer cells. Cancer cells use acetate metabolism to support tumor growth in conditions of low nutrient and oxygen availability. This molecule caused tumor growth inhibition and regression in preclinical studies, demonstrating the promise of this approach as a novel therapeutic strategy for solid tumors. Study results were published today in Cancer Research, a journal of the American Association for Cancer Research.

Highly proliferating cancer cells within a tumor often experience severe oxygen and nutrient deprivation. Over time, to satisfy their large metabolic demands for energy generation and synthesis of macromolecules, cancer cells adapt and evolve to survive and continue growing using different nutrient sources. The changes that accompany this metabolic rewiring represent a critical barrier to cancer treatment.

The laboratory of Zachary T. Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program at The Wistar Institute Cancer Center, studies the metabolic changes that arise during tumor progression to identify targets that can be exploited for new effective cancer treatments.

In particular, they focus on the role of acetate metabolism. They and others have identified acetate as an important alternative nutrient source for cancer cells and discovered that the ACSS2 enzyme, which converts acetate into acetyl-CoA, is crucial for tumor growth under nutrient stress conditions. Acetyl-CoA is an essential metabolite used by cancer cells for many fundamental cellular processes and to generate energy.

"We wanted to verify whether pharmacological inhibition of ACSS2 could prevent tumor growth and offer a significant therapeutic opportunity for cancers that rely on acetate for fuel," said Schug, who is the lead author of the study.

In a collaboration with Joseph Salvino, Ph.D., professor in The Wistar Institute Cancer Center and a medicinal chemistry expert, Schug and colleagues synthesized and tested an inhibitor of the ACSS2 enzyme and showed that this molecule, called VY-3-135, is potent and highly specific in blocking the function of ACSS2 in breast cancer cell lines. Importantly, VY-3-135 treatment was able to inhibit acetate metabolism in tumors in vivo and caused marked inhibition of tumor growth in preclinical breast cancer models with high ACSS2 levels.

"Multiple studies have now shown that ACSS2 is essential in a wide variety of cancers, suggesting that acetate metabolism plays a near universal role in cancer and supports the promise of ACSS2 inhibitors for cancer treatment," said Katelyn D. Miller, Ph.D., postdoctoral fellow in the Schug lab and first author of the study.

"We look forward to furthering our studies and creating safe, potent ACSS2 inhibitors for translation into the clinic," added Schug.

As the first doses of COVID-19 vaccines are being rolled out, it is still unclear whether enough Americans are willing to be vaccinated to allow the nation to return to normalcy. Many believe a key part of the equation lies in how effective vaccine communication teams are at convincing the public to get vaccinated. And the key to effective communication tactics in promoting the vaccines may lie in demonstrated behavioral economics and consumer behavior theory, experts say.

"The country has made an incredible investment in fast-tracking SARS-CoV-2 vaccines from conception to market, which would make it even more tragic if we fail to curtail the virus simply because Americans are hesitant to be vaccinated," says Stacy Wood, an expert on how consumers respond to change and innovation, and first author of a paper published in the New England Journal of Medicine titled "Beyond Politics - Promoting COVID-19 Vaccination in the U.S." Wood is a professor of marketing and executive director of the Consumer Innovation Collaborative at the NC State Poole College of Management

Recent surveys indicate that the proportion of the U.S. population willing to be vaccinated has fluctuated in recent months - from a high of 72 percent in May, to 51 percent in September and increasing slightly to 60 percent in November. Of those respondents who indicated that they probably or definitely would not get the vaccine, less than half said they might be open to vaccination once others start getting it and more information becomes available.

Since Anthony Fauci has said that at least 80% of the population will need to be vaccinated to get the country back to normalcy, Wood notes that this means it will be necessary to get 100% follow-through from those who are more likely to get the vaccine and 100% conversion of those who are unlikely now but willing to keep an open mind. That's a daunting prospect.

To address this challenge, Wood and her colleague Kevin Schulman of Stanford drew on their expertise in behavioral economics and consumer research to develop 12 strategies that could, collectively, create an effective vaccine-promotion effort.

Proposed strategies include:

Use Analogy: Many attitudes toward the current pandemic are responses to complex medical information. Analogies are short-cuts to conceptual understanding. Saying "the war against COVID" is a term rich in meaning-coming together, making sacrifices, doing tough things, and emerging on the other side with new improvements and inventions in hand. Or one can explain that mRNA vaccines are not weak doses of the virus, but instead are "instruction manuals" that teach the immune system how to defend itself.

Increase Observability: Studies have shown consumers' ability to observe others' choices can increase an innovation's rate of adoption. Distributing tokens, such as Livestrong-style bracelets or stickers, or digital badges, such as social media profile frames, may prove to be effective in increasing consumer buy-in. They can even be specific to different populations (e.g. stickers that say "COVID-19 Frontline Hero -- I'm Vaccinated!" or "America Honors Her Veterans -- I'm Vaccinated!")

Leverage Natural Scarcity: In consumer markets, scarcity often signals exclusivity and prompts greater interest or desirability. Communicators should frame early access to vaccines as a mark of honor or respect for people we want to protect, such as the elderly, teachers or essential workers. Leveraging scarcity, especially as the vaccine is slowly rolled out, may help to counteract many individuals' natural hesitancy to "go first."

Promote Compromise Options: Consider coffee shops that offer three serving sizes and typically sell more of the middle option. This decision rule-of-thumb is based on choice preferences for "compromise" or middle options. When it comes to the vaccine, communicators should not make vaccination seem like an either-or decision, but rather should frame it as three options where vaccination is in the middle. For instance, options could include allowing people to get the shot now, signing up for a later date, or not getting it at all. Or all three options could include the vaccine - such as get the shot now and donate plasma, simply get the shot now, or get the shot later. The key is to avoid depicting vaccination as the most extreme action in a range of choices.

Engineering researchers have developed a new technique for eliminating particularly tough blood clots, using engineered nanodroplets and an ultrasound "drill" to break up the clots from the inside out. The technique has not yet gone through clinical testing. In vitro testing has shown promising results.

Specifically, the new approach is designed to treat retracted blood clots, which form over extended periods of time and are especially dense. These clots are particularly difficult to treat because they are less porous than other clots, making it hard for drugs that dissolve blood clots to penetrate into the clot.

The new technique has two key components: the nanodroplets and the ultrasound drill.

The nanodroplets consist of tiny lipid spheres that are filled with liquid perfluorocarbons (PFCs). Specifically, the nanodroplets are filled with low-boiling-point PFCs, which means that a small amount of ultrasound energy will cause the liquid to convert into gas. As they convert into a gas, the PFCs expand rapidly, vaporizing the nanodroplets and forming microscopic bubbles.

"We introduce nanodroplets to the site of the clot, and because the nanodroplets are so small, they are able to penetrate and convert to microbubbles within the clots when they are exposed to ultrasound," says Leela Goel, first author of a paper on the work. Goel is a Ph.D. student in the joint biomedical engineering department at North Carolina State University and the University of North Carolina at Chapel Hill.

After the microbubbles form within the clots, the continued exposure of the clots to ultrasound oscillates the microbubbles. The rapid vibration of the microbubbles causes them to behave like tiny jackhammers, disrupting the clot's physical structure, and helping to dissolve the clots. This vibration also creates larger holes in the clot mass that allow blood borne anti-clotting drugs to penetrate deep into the clot and further break it down.

The technique is made possible by the ultrasound drill - which is an ultrasound transducer that is small enough to be introduced to the blood vessel via a catheter. The drill can aim ultrasound directly ahead, which makes it extremely precise. It is also able to direct enough ultrasound energy to the targeted location to activate the nanodroplets, without causing damage to surrounding healthy tissue. The drill incorporates a tube that allows users to inject nanodroplets at the site of the clot.

In in vitro testing, the researchers compared various combinations of drug treatment, the use of microbubbles and ultrasound to eliminate clots, and the new technique, using nanodroplets and ultrasound.

"We found that the use of nanodroplets, ultrasound and drug treatment was the most effective, decreasing the size of the clot by 40%, plus or minus 9%," says Xiaoning Jiang, Dean F. Duncan Distinguished Professor of Mechanical and Aerospace Engineering at NC State and corresponding author of the paper. "Using the nanodroplets and ultrasound alone reduced the mass by 30%, plus or minus 8%. The next best treatment involved drug treatment, microbubbles, and ultrasound - and that reduced clot mass by only 17%, plus or minus 9%. All these tests were conducted with the same 30-minute treatment period.

"These early test results are very promising."

"The use of ultrasound to disrupt blood clots has been studied for years, including several substantial studies in patients in Europe, with limited success," says co-author Paul Dayton, William R. Kenan Jr. Distinguished Professor of Biomedical Engineering at UNC and NC State. "However, the addition of the low-boiling point nanodroplets, combined with the ultrasound drill has demonstrated a substantial advance in this technology."

"Next steps will involve pre-clinical testing in animal models that will help us assess how safe and effective this technique may be for treating deep vein thrombosis," says Zhen Xu, a professor of biomedical engineering at the University of Michigan and co-author of the paper.

FOR IMMEDIATE RELEASE

In what is believed to be the most comprehensive molecular characterization to date of the most common type of head and neck cancer, researchers from the Johns Hopkins departments of pathology and oncology, the Johns Hopkins Kimmel Cancer Center, the Johns Hopkins University School of Medicine, and 18 other centers around the U.S. and Poland have clarified the contribution of key cancer-associated genes, proteins and signaling pathways in these cancers, while proposing possible new treatment avenues.

Their deep-dive investigation of HPV-negative head and neck squamous cell carcinomas (HNSCCs), described in the Jan. 7 issue of the journal Cancer Cell, involved tumors from 108 patients who had not yet received cancer treatment, and 66 samples of healthy tissue surrounding the tumors. The study systematically catalogued HPV-negative HNSCC-associated proteins, phosphosites (areas where they are modified by phosphate groups) and signaling pathways, finding three distinct subtypes of HNSCCs.

HNSCCs arise in the cells that line the upper aerodigestive tract, including the lips, mouth, tongue, nose, throat, vocal cords, and part of the esophagus and windpipe. The first subtype of HNSCC identified by researchers, dubbed CIN, showed the worst prognosis. It was associated with the larynx, a strong history of smoking and high instability of chromosomes. Because this subtype was associated with frequent aberrations of the CCND1 and CDKN2A genes, and high activity of the enzymes CDK4 and CDK6, this type of cancer may respond best to anti-cancer drugs called CDK4/6 inhibitors.

The second subtype, dubbed Basal, showed protein elevations of several basal factors, the most basic set of proteins needed to activate gene transcription. It was characterized by high activity in a signaling pathway called EGFR (epidermal growth factor receptor) and high expression of molecules called AREG and TNFA, which attach to the EGFR tumor protein. Therefore, researchers say, these cancers may respond best to anti-cancer drugs called monoclonal antibodies that are aimed at EGFR.

The third subtype, called Immune, was found among tumors in people who did not smoke and showed high expression of multiple immune checkpoint proteins. Researchers say these tumors may best respond to anti-cancer drugs called immune checkpoint inhibitors. Overall, 32% of CIN tumors, 62% of Basal tumors and 83% of Immune tumors had high potential for the suggested treatments.

Researchers also found two modes of activation of EGFR, suggesting a new strategy to stratify HNSCCs based on the number of molecules bound to EGFR, for effective treatment with monoclonal antibody drugs that enlist the natural immune system to fight cancer. Additionally, they noted that widespread deletion of immune modulatory genes among these cancers accounts for a loss of ability to produce an immune response.

"This study extends our biological understanding of HPV-negative HNSCCs and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly guided precision medicine treatment of this aggressive cancer type," says Daniel Chan, Ph.D., principal investigator, a professor of pathology and oncology, and director of the Center for Biomarker Discovery and Translation at the Johns Hopkins University School of Medicine.

The three subtypes and suggested treatments "are quite major findings," says Hui Zhang, Ph.D., co-principal investigator of the study, professor of pathology and oncology, and director of the Mass Spectrometry Core facility at the Johns Hopkins University School of Medicine. "Previously, patients would be treated using different options, but there was no systematic way to know which treatment would be the best option for certain patients." The team has begun similar work to tease out the properties of HPV-positive HNSCCs, she says.

Researchers used the most advanced genomic and proteomic technologies available to tease out HNSCC proteogenomic characteristics, defined as genetic makeup (genomics), chemical modifications to DNA (epigenomics), messenger RNA located in cells that serves as a template to make proteins (transcriptomics), and proteins (proteomics) and their modification by phosphate groups (phosphoproteomics), a modification known to regulate protein functions by switching on or off. The work was completed as part of the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), a national effort to better understand cancers through proteogenomics.

INDIANAPOLIS-- Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center published promising findings today in the New England Journal of Medicine on preventing a common complication to lifesaving blood stem cell transplantation in leukemia.

Sherif Farag, MD, PhD, found that using a drug approved for Type 2 diabetes reduces the risk of acute graft-versus-host disease (GVHD), one of the most serious complications of blood stem cell transplantation. GVHD occurs in more than 30 percent of patients and can lead to severe side effects and potentially fatal results. Farag is the Lawrence H. Einhorn Professor of Oncology and professor of medicine at IU School of Medicine, a member of the IU Simon Comprehensive Cancer Center and program and medical director of the hematological malignancies and bone marrow and blood stem cell transplantation at IU Health.

In the IU clinical study, blood stem cell transplant patients received the oral drug called sitagliptin. Acute GVHD occurred in only two of 36 patients within 100 days of their transplant. The 5 percent occurrence represents a drastic reduction of GVHD, which studies have found can affect 34 percent to 51 percent of patients in the first three months after transplant.

Graft-versus-host disease occurs when the donated blood stem cells (the graft) attack the transplant recipient's (the host) tissue.

"The rate looks very encouraging and it's achieved with a very simple and relatively inexpensive intervention of sitagliptin," Farag said. "This result is significant and offers a new approach and a new target for inhibition of graft-versus-host disease. We achieved a much lower rate than we could have hoped."

Sitagliptin targets an enzyme called dipeptidyl peptidase-4 (DPP-4), which is involved in a variety of processes in the body. It is used for Type 2 diabetes to improve insulin secretion and glucose control.

Hal Broxmeyer, PhD, a pioneer in the field of umbilical cord blood stem cell transplantation and distinguished professor at IU School of Medicine and a co-author with Farag, previously found that DPP-4 regulates blood cell production and explored if taking sitagliptin would improve engraftment for cord blood transplants. While there seemed to be some improvement in engraftment of cord blood transplants, one striking finding was the patients had a much lower rate of acute graft-versus-host disease than expected. Farag's lab took on that data and found targeting DPP-4 with sitagliptin inhibits the immune T cell activation that leads to GVHD.

Farag noted that repurposing sitagliptin offers a relatively inexpensive and accessible approach to preventing GVHD.

"These findings are very significant because there are a lot of other different drugs that are being tested, including ones that are very expensive or require administration intravenously for a prolonged time well beyond the time of recovery and transplant," Farag said.

Patients in the study were ages 18 to 60 and had one of the following blood cancer or diseases: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia or myelodysplastic syndrome. The patients in the study received sitagliptin orally one day before their transplant and the day of their transplant, plus 14 days after their transplant.

Patients in the study did not face any unexpected or unusual toxicities or higher relapse rates than what's expected post-transplant.

"This is a drug that is used to treat diabetes, and we're using it at a much higher dose. We asked if we are going to cause people to have low blood sugar or hypoglycemia--and we didn't find that," Farag said. "As long as it's not combined with other drugs that lower the blood glucose in non-diabetic patients, it doesn't do that; we certainly confirm that in our findings."

Farag's findings now need to be confirmed with a larger, multi-center randomized study. He also hopes to explore combination therapies with sitagliptin and if it could prevent chronic graft-versus-host disease.

Alexandria, Va., USA -- The COVID-19 pandemic has significantly impacted dental education and training. The study "COVID-19 and Dental and Dental Hygiene Students' Career Plans," published in the JDR Clinical & Translational Research (JDR CTR), examined the short-term impact of the COVID-19 pandemic on dental hygiene and dental students' career intentions.

An anonymous online survey was emailed to dental and dental hygiene students enrolled at Virginia Commonwealth University School of Dentistry, Richmond, USA. The survey consisted of 81 questions that covered a wide range of topics including demographics, anticipated educational debt, career plans post-graduation, readiness to enter clinical practice or residency and student wellness. The authors found that students at all levels of training have become concerned about the limited employment opportunities, long-term stability of the dental profession and on the interruptions to clinical education and licensure examinations consequent to the pandemic.

More than 10% of all student study respondents felt anxious about the future of dentistry, with approximately 40% of those in their final year choosing to change their career post-graduation plans. Students who reported an intent to change their career plans had significantly higher perceived stress and anxiety scores and lower resilience scores than students who reported no change to their career plans. Compared to white students, more black, indigenous and people of color reported that they had changed their career plans.

Lead author Dina Garcia of Virginia Commonwealth University concluded, "A comprehensive effort inclusive of adeptly designed clinical and curriculum experiences paired with wellness interventions and support tailored to students is needed."

"The impact of the COVID-19 pandemic on the career plans of dental and dental hygiene students may negatively affect the future dental workforce," said JDR CTR Editor-in-Chief Jocelyne S. Feine, McGill University, Montréal, Quebec, Canada. "We lack understanding of both the short-term and long-term effects of prolonged and unanticipated public health crises on the dental workforce. More studies are needed to provide this information so that these issues can be appropriately addressed."

In a large-scale study of electronic health records, Vanderbilt University Medical Center investigators have determined the prevalence of functional seizures and characterized comorbidities associated with them.

Functional seizures are sudden attacks or spasms that look like epileptic seizures but do not have the aberrant brain electrical patterns of epilepsy.

The research team, headed by Lea Davis, PhD, associate professor of Medicine and an investigator in the Vanderbilt Genetics Institute, confirmed associations between functional seizures and psychiatric disorders including posttraumatic stress disorder, anxiety and depression as well as sexual assault trauma. They also discovered a novel association between functional seizures and cerebrovascular disease, including stroke.

The findings were reported in the journal JAMA Network Open.

Also known as psychogenic nonepileptic seizures, functional seizures have been historically understudied. Patients often experience a long delay -- on average seven years -- before they receive an accurate diagnosis.

About 80% of patients experiencing functional seizures are initially misdiagnosed with epilepsy and treated with anti-epileptic drugs, said Slavina Goleva, a graduate student in Molecular Physiology and Biophysics and first author of the study. An accurate diagnosis requires assessment with video electroencephalogram (EEG).

Davis got interested in functional seizures after hearing an NPR story several years ago.

"The story gave the patient perspective on these seizures -- the stigma that patients felt and the difficulties they experienced in the medical system," Davis recalled. "I felt like studies within electronic health records could potentially be really impactful for this community."

Working with Kevin Haas, MD, PhD, associate professor of Neurology, the researchers developed an algorithm to identify people with functional seizures in the VUMC-EHR system.

"We initially recognized that finding these patients within the EHR would be a challenge because the ICD (International Classification of Diseases) codes are not as specific as they are for a lot of diseases," Goleva said. In addition to ICD codes, the researchers included Current Procedural Terminology (CPT) codes and used natural language processing to search within the records for a list of keywords.

Goleva and Haas manually reviewed charts to confirm that the algorithm correctly identified patients with functional seizures.

The study included more than 2.3 million patients 18 or older in the VUMC-EHR system from 1989 to 2018. The researchers identified 3,341 patients with functional seizures, 74% of whom were women. They calculated a prevalence of 0.14% (140 cases per 100,000 people); previous estimates ranged from 2 to 33 cases per 100,000 people.

"Our report is the first direct calculation of the prevalence of functional seizures," Goleva said. She noted that the epilepsy monitoring unit at VUMC may result in a higher prevalence of functional seizures in patients in the VUMC-EHR compared to the general population.

Among the patients with functional seizures, the researchers validated comorbidities including psychiatric disorders and sexual assault trauma and discovered a novel association with cerebrovascular disease. They also found that sexual assault trauma explained about a quarter of the increased rate of functional seizures among women, Goleva said.

"Functional seizures are not occurring in isolation; patients who are experiencing these seizures are also experiencing a higher burden of additional health care issues," Davis said.

"If there is a suspicion that someone presenting with seizures could have functional seizures rather than epileptic seizures, it's critical to refer those patients to an epilepsy monitoring unit for accurate diagnosis and appropriate treatment," Haas said. "Historically, even once diagnosed, care of these patients has often fallen through the cracks between neurology and psychiatry, but we are now actively developing a more integrated approach to care for this patient population."

The researchers recommended that patients experiencing seizures who have psychiatric comorbidities or a history of sexual assault trauma be referred for video-EEG assessment. Patients who develop seizures after a stroke and do not initially respond to treatment with medications should also be considered for early video-EEG assessment.

Up to 30% of patients referred for video-EEG are eventually diagnosed with functional seizures, they noted.

"It's frustrating that there is no ICD code for functional seizures, given how common the diagnosis is and the fact that codes exist for strange things like alligator bite, second occurrence," Davis said. "It really emphasizes how little attention this population of patients has gotten."

The investigators are currently exploring the genetics of functional seizures using genome-wide association studies of biobanks including Vanderbilt's BioVU.

Patients and healthcare providers at the Princess Margaret Cancer Centre rated virtual care during COVID-19 as highly satisfactory overall for quality of care and convenience, while at the same time saving patients millions in costs.

Research led by Princess Margaret Radiation Oncologist Dr. Alejandro Berlin showed that virtual care can be implemented rapidly and safely across a highly-specialized and high-volume cancer centre. Eighty (80) per cent of patients reported they were either very satisfied or satisfied with it, citing convenience as a main factor, with 72 per cent of physicians reporting similar satisfaction with it.

Moreover, 64 per cent of healthcare providers and 85 per cent of patients indicated that the quality of care was comparable or better than the in-person model of care. Sixty-six per cent (66%) of respondents in both groups - patients and physicians - were either very likely or likely to recommend virtual care for future appointments.

The overall cost savings for 22,085 patients studied during the research study period between March 23, 2020 and May 22, 2020 was more than $3M ($3,085,274.00CAD) - potentially $18M for one year.

Study findings are published in JAMA Oncology, January 7, 2021.

"The surprising result of implementing virtual care almost overnight were the impressive benefits for our patients and clinicians," says Dr. Keith Stewart, Director, Princess Margaret Cancer Centre, Vice President, Cancer, University Health Network and one of the study authors

"With these findings, a new normal emerges which includes virtual care as a feasible and important part of care for many patients. They will help guide the transformation of telemedicine in the post COVID-19 era, firmly establishing virtual care as a standard option that we can offer appropriate patients."

Virtual care was developed and launched at Princess Margaret 12 days after the COVID-19 pandemic was declared on March 11, 2020.

This was done to protect patients from preventable exposure and to minimize the impact of infection control measures and concerns about availability of personal protective equipment for patients and staff.

Four days after the digital solution supporting virtual care was launched on March 23, 2020, more than 50 percent of outpatient clinic visits had shifted to virtual care, consisting of either video or telephone calls.

By one month after the March 23 start date, outpatient clinic volumes (in person and virtual) were restored to pre-COVID-19 levels - about 3,900 clinic visits weekly.

In total, from March 23, 2020 to May 22, 2020, 22,085 virtual visits by phone or video took place, accounting for an average of 68 per cent of the daily clinic visits.

Importantly, both chemotherapy and radiotherapy on-site visits, along with metrics for safety and timeliness of cancer care remained stable throughout the study, comparable to the pre-COVID-19 period.

"The shift to virtual care, helped ensure that patients needing in-person visits, such as those receiving chemotherapy and radiation treatments could continue, while decreasing traffic and facilitating physical distancing on premises," explains Dr. Berlin.

"It enabled our high-volume centre to take care of all our patients during an unsettling and uncertain time - without compromising on either the safety or quality of care."

Institutional and province-defined quality standards of cancer care - such as safety incidents and referrals seen within 14 days - were tracked throughout the study, and beyond, and no changes were observed.

"Virtual care became a safety net for patients," says Dr. Berlin, who is also an Assistant Professor, Department of Radiation Oncology, University of Toronto. "It was reassuring for patients during the uncertainty of COVID-19. Their care team was still there for them, but in a different way.

"For the future, we aim to examine what criteria - in addition to clinical - make this a good or even preferred option for select patients."

Dr. Berlin describes several factors that contributed to the success of the project, including:

A sense of urgency to complete a well-defined and clearly communicated goal (a shift of more than 50% of visits to virtual care) that is high impact for patients and clinicians,

An agile design and implementation approach, relying on existing software, and continuous feedback which was folded back into new iterations,

Involvement of many stakeholders, including front-line staff, to map out "pain points" and work flows,

A tightly-knit, multi-disciplinary team - from engineering design to patient and family input - which pulled together seamlessly to respond to the unprecedented challenge.

"We went broad and bold because of the needs of the moment," says Dr. Berlin.

"This was a huge effort on the part of everyone at Princess Margaret," he emphasizes. "Behind every patient call or video was a clinician committed to continuity of care for our patients. Working behind the scenes of every appointment there was a whole team with varied expertise.

"It was heart-warming for our patients. What came through our surveys is that patients felt supported, cared for, and comforted as uncertainty continues to be the norm.

"Patients could focus on what was most important to them - their health."