Culture

In an elegant choreography, plants take cues from their environment and channel them into flowers, roots, or branches. In a new paper in Nature Communications, biologist Doris Wagner of the School of Arts & Sciences and colleagues identified some of the behind-the-scenes machinations that go into arriving at these variations in plant architecture.

Long interested in the translation of these environmental inputs to physical traits, Wagner and her team have been studying two key groups of proteins that influence plant form and timing of developmental transitions. Terminal Flower 1 (TLF1) proteins promote branch formation. When it is repressed, flowers grow. Flowering Locus T (FT) proteins, on the other hand, promote flowering in response to seasonal cues like day length. Strangely enough, the two proteins are almost identical.

"These two elements have significance galore," Wagner says. "Besides flowering, they're involved in tuberization in potatoes, bulb formation in onions, tendril formation in grapes, growth cessation in trees, lots of things."

Manipulating these genes, some have argued, could lead to the next "green revolution" as one could theoretically "trick" a plant that normally only flowers in the long days of summer to flower quickly, and thus produce fruit or seed, in the short days of winter with a deft genetic edit of TFL1. Or, in an area with a longer growing season, a clever manipulation of growth architecture via FT could encourage increased branching and then a later, and more abundant, flowering and fruit development on the many branches.

Plants have already been bred to have reduced TFL1 activity. Tomato gardeners may know these as determinant plants, which set all their flowers at the same time, as opposed to the indeterminant variety, which continue to branch, flower, and fruit over a period of months. Determinant plants make commercial agriculture more efficient, as fruits can be harvested in one go as opposed to repeated passes.

It was known that TFL1 and FT1 acted in opposing directions, each "tuning" the activity of the other, but the mechanism of their antagonism has remained fuzzy. In part this was because studying them has presented a technical challenge: They are only present in low levels in a limited number of cells.

Wagner's groups, however, had overcome similar challenges in studying a regulator of plant chromatin in earlier work, so they were undeterred in taking on these two dueling proteins.

In the current study, to flesh out TFL1 and FT1's molecular mechanism, they first looked to see where TFL1 was found in the nuclei of plant cells, using the model species Arabidopsis thaliana. They found thousands of sites to which it bound, acting through the transcription factor FD, as neither TFL1 nor FT otherwise can bind directly to DNA. The sites to which TFL1 was recruited were consistent with its role in suppressing flowering and in suppressing gene expression.

The researchers next examined the relationship of both TFL1 and FT with LEAFY, a gene that is known to give rise to flowers. When they mutated the sites where TFL1 regulates the LEAFY gene, LEAFY protein was now found in parts of the plant where TFL1 is present.

"We also saw something that we didn't expect," Wagner says. "LEAFY was gone from all the regions that should make flowers."

That suggested to the team that an unknown factor may be activating the LEAFY gene specifically in the flowering portion of plants via the same site through which TFL1 acts. So, they looked to FT, because of its importance in promoting flowering. By experimentally augmenting FT expression, they found that FT, also binding to the FD transcription factor, was required to act upon LEAFY to promote flower formation.

Seeing that FT and TFL1 both required FD in order to act, they sought to confirm how this competition played in plants. "We wanted to really test its biological contribution: What does it mean to the plant to lose this?" Wagner says.

They saw that under conditions that would normally induce the plant to flower, plants that still had normal FT failed to. "It was a strong phenotype and made it very clear to us that FT and TFL1 compete for this FD factor binding site," she says.

TFL1 and FT are mobile and easily convert from one to another. Wagner is very interested in learning more about their mechanism of action to understand how plants can "tune" their growth to best adapt to their environment. In future work, she and her lab plan to continue working out the details, including how both proteins respond to cues from the environment like day length or shade under a tree. She also wants to know how they can control such different processes like flower, bulb, or tendril formation.

And Wagner believes the findings have ample potential for applications in plant breeding and agriculture. "You can imagine locally adapting crops, maybe for a high-altitude site in the Himalayas or maybe a location in the far north where days are short," she says. "These elements could even play a role in rational solutions for climate change, breeding plants that are specifically adapted for new conditions."

PITTSBURGH, Oct. 12, 2020 - Variations in a gene that regulates dopamine levels in the brain may influence the mobility of elderly and frail adults, according to new research from the University of Pittsburgh Graduate School of Public Health.

These results, published today in the Journal of The American Geriatrics Society, add to a growing body of evidence hinting that lower dopamine levels could contribute to the slower, often disabling walking patterns seen in some elderly populations.

"Most people think about dopamine's role in mobility in the context of Parkinson's disease, but not in normal aging," said senior author Caterina Rosano, M.D., M.P.H., professor of epidemiology at Pitt Public Health. "We were curious to see if a genetic predisposition to produce more or less dopamine was related to mobility in individuals who had some level of frailty, yet did not have dementia, parkinsonism or any other neurological condition."

While several genetic elements control dopamine signaling, Rosano and her team focused on a gene called COMT, which breaks down dopamine to control its levels within the brain. They also considered the frailty status of participants, which is a common consequence of aging marked by a decline in physiological function, poor adjustment to stressors and a susceptibility toward adverse health outcomes. The researchers suspected that frail participants could be particularly vulnerable to COMT-driven differences in dopamine levels.

Rosano and her collaborators examined this gene in more than 500 adults above the age of 65 in Pennsylvania, North Carolina, California and Maryland, excluding any participants taking dopamine-related medications or diagnosed with Parkinson's disease. The researchers then looked for potential links between genotype, frailty and speed.

"We found that in older, frail adults, those who have a high-dopamine genotype are more likely to maintain a faster gait and may be more resilient to mobility disablement as they age," said Rosano.

The team discovered that frail participants with a high-dopamine COMT genotype had a 10% faster walking speed compared with participants with the low-dopamine COMT genotype.

"This 10% difference may seem small, but it could make a big difference for a person walking across a busy street while negotiating traffic," said Rosano. "This difference is even more striking when you consider just how many complex genes influence walking."

Rosano and study co-author Nicolaas Bohnen, M.D., Ph.D., professor of neurology and radiology at the University of Michigan School of Medicine, are working with a team of scientists at Pitt to quantify what level of dopamine could give elders greater resilience to gait-slowing and mobility disablement. Their hope is that older adults with low dopamine levels could one day receive pharmacologic supplements of dopamine to help preserve their mobility.

"There are a lot of individuals living in the community who have dopamine levels toward the lower end of normal who don't have Parkinson's disease or psychiatric conditions," said Rosano. "If we give dopamine to these people, could we make them more resilient? That's what we don't know yet."

In the meantime, she suggests that there are actions that seniors can take today to keep moving. She recommends that elders focus on physical activities that are enjoyable and involve both the body and the brain, especially multi-sensory activities, such as dancing or walking with a loved one.

"I love to see grandparents walking around holding hands with their grandchildren because they have to look where they are going, where the child is going, keep an eye on the surroundings and pay attention to what the grandchild is saying, all at the same time," said Rosano. "They get an amazing multi-sensory rehab, and it's fantastic."

COLUMBUS, Ohio - As COVID-19 cases surged this spring, the pandemic led some people more than others to ponder their own mortality. A new study in China and the United States suggests that these people were the ones who showed the highest levels of stress and the least engagement at work.

But the research also uncovered a bright spot: The right kind of boss helped reduce stress and increase engagement and pro-social behavior in their workers who were anxious about COVID-19.

"A global pandemic can lead some people to think about their own mortality, which will understandably make them more stressed and less engaged at work," said Jia (Jasmine) Hu, lead author of the study and associate professor of management and human resources at The Ohio State University's Fisher College of Business.

"But business leaders who are attentive to employees' emotional needs and unite them behind a common purpose made a positive difference and helped workers stay engaged at work and contribute to their communities."

The study was published online recently in the Journal of Applied Psychology.

The researchers conducted three studies.

One study involved 163 workers at an information technology company in eastern China who filled out surveys twice a day over three weeks while cases of COVID-19 were surging in the country.

Results showed that the more that the employees thought about COVID-19 related deaths, the more anxious they felt and the less engaged they were in their jobs.

But the employees' anxiety and engagement were influenced by the type of boss they had. Employees did better if their boss exhibited what is called "servant leadership." As the name implies, servant leaders prioritize fulfillment of others' needs, attend to employees' emotional suffering, work to empower employees, and emphasize serving the community.

Employees in the study rated on a scale of 1 to 7 how much "My supervisor makes my career development a priority" and other statements that measured servant leadership.

Those who rated their supervisors higher on servant leadership showed less anxiety and were more engaged with their jobs than other employees, Hu said.

"Servant leaders care about their employees' well-being and prioritize their personal growth and happiness at their jobs," she said.

"These types of leaders made it easier for their employees to deal with the anxiety associated with the pandemic."

But servant leaders did more than that: They helped their employees channel their stress into positive behaviors.

The findings showed that employees who rated their bosses as higher on servant leadership were more likely to report that they engaged in pro-social behavior, such as volunteering for a charitable group in their community.

"Servant leaders encouraged their employees to find meaning in the pandemic by channeling their anxiety into helping less fortunate people in their communities," Hu said.

These results were confirmed in two U.S. studies in which participants were told to imagine they were consultants advising a retail company on how to increase sales. The researchers recruited Americans online who said they had full-time jobs.

In both studies, the researchers had participants first read about COVID-19. Half read information that was designed to make them think about how dangerous and deadly the disease is. The other half read less stressful information about COVID-19, such as how to prevent transmission.

Half of the participants read a scenario in which their boss exhibited servant leadership and half read a scenario in which their boss was less supportive.

In one of the two studies, the researchers asked specifically about how much participants were worried about their own deaths.

Results were similar to the study in the Chinese company.

Those who read the more alarming news about COVID-19 reported more anxiety - general anxiety in study two and anxiety related to their own death in study three - than those who read the neutral news.

But once again, in both American studies, those who had servant leaders in their scenarios showed less anxiety, even after reading about how deadly the disease was.

And just like in the Chinese employees, the type of leadership had an impact on pro-social behavior.

Participants were paid a small amount to take part in the studies. At the end, they were given the opportunity to donate some or all of their payment to a charity fighting hunger.

Participants who had servant leaders in their scenarios were more generous to the charity than those whose bosses in the scenarios were less supportive, the study showed.

Overall, the three studies showed that companies play an important role in helping their employees cope with the stress of the COVID-19 pandemic, Hu said, which benefits both the firms and their communities.

"We found that servant leaders who keep their employees' well-being as a top concern can help their anxious workers stay engaged at work and encourage them to contribute to the broader community," she said.

Volume 11, Issue 26 of Oncotarget reported that in this study the authors studied the differences in mi RNA expression between sporadic and FAP-associated Desmoid tumors using microarray confirmed by quantitative PCR.

Among them, mi R-133b levels were significantly lower in FAP-associated Desmoid tumors than in sporadic Desmoid tumors. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated Desmoid tumor than in sporadic Desmoid tumor, whereas no differences in ELAVL1 expression was observed between these two Desmoid tumor types.

In addition, a negative correlation was observed between mi R-133b and SIRT1 in FAP-associated Desmoid tumors, but not in sporadic Desmoid tumors The mi R-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated Desmoid tumor.

Dr. Maria Teresa Rotelli from The Department of Emergency and Organ Transplantation at The University of Bari “Aldo Moro” in Bari Italy said, "Desmoid tumor (DT) is a rare, mesenchymal benign tumor, characterized by monoclonal, fibroblastic proliferation with local invasiveness, high risk of recurrence and even mortality, despite metastatization never occurs."

The CNNTB1 mutations have been found in approximately 85% of DTs by routine Sanger sequencing, however, using a highly sensitive technique like next-generation sequencing, they may account for 90–95% of sporadic DT cases.

In these DTs, the germline mutations in the APC gene are responsible for the nuclear accumulation of β-catenin.

While the risk of death in sporadic DT is low, FAP-associated DTs are the most frequent cause of death in patients with FAP after the colon has prophylactically been removed.

It must be emphasized that the disruption of the Wnt signaling represents a common pathway in both DT forms, but sporadic and FAP-associated DTs are associated with mutually exclusive molecular alterations.

In a previous study, the authors have investigated a possible correlation between mi RNA expression and CTNNB1 mutations in sporadic DTs.

The Rotelli Research Team concluded in their Oncotarget Research Paper that the dialog between MSCs and tumor cells in FAP-associated DT tissue microenvironment could lead to β-catenin deacetylation driven by SIRT1, promoting Wnt/β-catenin signaling cascade in this tumor.

Although the number of specimens of FAP-associated DTs used in the present study was limited, it could be speculated that the β-catenin deacetylation process in FAP-associated DTs mimics the stabilization of that protein induced by CTNNB1 gene mutations occurring in sporadic DTs.

"It could be speculated that the β-catenin deacetylation process in FAP-associated DTs mimics the stabilization of that protein induced by CTNNB1 gene mutations occurring in sporadic DTs"

Therefore, in addition to APC gene mutations, the mi R-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying the progression of FAP-associated DT. However, further studies are needed to fully understand the influence of mi R-133b-SIRT1 in the genesis or progression of FAP-associated DT.

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DOI - https://doi.org/10.18632/oncotarget.27622

Full text - https://www.oncotarget.com/article/27622/text/

Correspondence to - Maria Teresa Rotelli - mariateresa.rotelli@uniba.it

Keywords -
desmoid tumor,
miRNA,
familial adenomatous polyposis,
B-catenin,
Wnt pathway

About Oncotarget

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Journal

Oncotarget

DOI

10.18632/oncotarget.27622

BEER-SHEVA, Israel -- Many mothers are experiencing an increase in insomnia severity and mild-to-high levels of acute COVID?19 anxiety, according to a new study by researchers at Ben-Gurion University of the Negev and The Max Stern Yezreel Valley College in Israel.

"In the study, we addressed, for the first time, consequences of the COVID?19 pandemic and home confinement on maternal anxiety, insomnia, as well as reports of sleep problems among children between six and 72 months-old," says Prof. Liat Tikotzky, head of the BGU Parenting, Child Development and Sleep Lab and a member of the BGU Department of Psychology. The study was published by the Journal of Sleep Research.

The results indicated that maternal clinical insomnia (Insomnia Severity Score > 15) during the COVID?19 pandemic more than doubled to 23% during the pandemic, compared with only 11% before the pandemic. Approximately 80% of mothers also reported mild?to?high levels of current COVID?19 anxiety.

In the study, mothers were asked to complete a self-reporting questionnaire with reference to two time points: (a) retrospectively one to two months before the COVID?19 outbreak in Israel, and (b) during home confinement. The researchers then computed a score representing the mother's perception of change in her sleep quality.

"We further observed that mothers who reported an increase in insomnia symptoms had significantly higher levels of acute COVID?19 anxiety than mothers who reported no change in insomnia symptoms, while no group differences were detected in their typical (trait) anxiety levels, suggesting that current anxiety may contribute to the increase in severity of insomnia symptoms," Prof. Tikotzky says.

Moreover, the researchers found that about 30% of mothers reported a negative change in their child's sleep quality and a decrease in sleep duration. However, it is important to note that the majority of mothers reported no change in their child's sleep quality, duration, arrangement, and their perception of child's sleep as problematic. Moreover, 12% of mothers even reported a positive change in their child's sleep quality, and 25% reported an increase in sleep duration.

Finally, the researchers observed that mothers who reported higher scores of insomnia were also more likely to report that their children had poorer sleep quality and shorter sleep duration. This is consistent with previous studies demonstrating significant links between maternal and child sleep quality during normal times.

The findings emphasize the importance of further exploring familial resiliency factors that may explain the different patterns of responses in children's and mothers' sleep during times of crises. This is particularly important given the role of sleep in child development and parental functioning.

Wearable sensors are evolving from watches and electrodes to bendable devices that provide far more precise biometric measurements and comfort for users. Now, an international team of researchers has taken the evolution one step further by printing sensors directly on human skin without the use of heat.

Led by Huanyu "Larry" Cheng, Dorothy Quiggle Career Development Professor in the Penn State Department of Engineering Science and Mechanics, the team published their results in ACS Applied Materials & Interfaces.

"In this article, we report a simple yet universally applicable fabrication technique with the use of a novel sintering aid layer to enable direct printing for on-body sensors," said first author Ling Zhang, a researcher in the Harbin Institute of Technology in China and in Cheng's laboratory.

Cheng and his colleagues previously developed flexible printed circuit boards for use in wearable sensors, but printing directly on skin has been hindered by the bonding process for the metallic components in the sensor. Called sintering, this process typically requires temperatures of around 572 degrees Fahrenheit (300 degrees Celsius) to bond the sensor's silver nanoparticles together.

"The skin surface cannot withstand such a high temperature, obviously," Cheng said. "To get around this limitation, we proposed a sintering aid layer -- something that would not hurt the skin and could help the material sinter together at a lower temperature."

By adding a nanoparticle to the mix, the silver particles sinter at a lower temperature of about 212 F (100 C).

"That can be used to print sensors on clothing and paper, which is useful, but it's still higher than we can stand at skin temperature," Cheng said, who noted that about 104 F (40 C) could still burn skin tissue. "We changed the formula of the aid layer, changed the printing material and found that we could sinter at room temperature."

The room temperature sintering aid layer consists of polyvinyl alcohol paste -- the main ingredient in peelable face masks -- and calcium carbonate -- which comprises eggshells. The layer reduces printing surface roughness and allows for an ultrathin layer of metal patterns that can bend and fold while maintaining electromechanical capabilities. When the sensor is printed, the researchers use an air blower, such as a hair dryer set on cool, to remove the water that is used as a solvent in the ink.

"The outcome is profound," Cheng said. "We don't need to rely on heat to sinter."

The sensors are capable of precisely and continuously capturing temperature, humidity, blood oxygen levels and heart performance signals, according to Cheng. The researchers also linked the on-body sensors into a network with wireless transmission capabilities to monitor the combination of signals as they progress.

The process is also environmentally friendly, Cheng said. The sensor remains robust in tepid water for a few days, but a hot shower will easily remove it.

"It could be recycled, since removal doesn't damage the device," Cheng said. "And, importantly, removal doesn't damage the skin, either. That's especially important for people with sensitive skin, like the elderly and babies. The device can be useful without being an extra burden to the person using it or to the environment."

Next, the researchers plan to alter the technology to target specific applications as needed, such as a precise on-body sensor network placed to monitor the particular symptoms associated with COVID-19.

People who have recovered from COVID-19, and their close contacts, could hold the key to understanding how immunity to the disease develops, how long it lasts and what happens when immunity is lost.

The COVID PROFILE study, led by the Walter and Eliza Hall Institute, will use blood samples from people in Victoria to look in detail at immune responses to COVID-19, to reveal how people are protected - and how long people are protected - from future COVID-19 infection. This information is vital for vaccine development - and could explain whether future vaccines can be given once, or whether they will need to be regularly repeated, like the annual influenza vaccine. This information will be critical for planning for the long-term 'COVID-normal' both locally and internationally.

At a glance

Melbourne researchers are investigating the immunity effects of COVID-19

The study is recruiting people who have had COVID-19 and their close contacts who haven't contracted the virus

The research will help inform decisions about vaccine development and other public health measures to control the virus, including operating in a 'COVID-normal' society

Understanding immunity against COVID-19

The study is looking for 300 adult volunteers, both those who have had COVID-19 and those who were close contacts (such as household members) but did not contract the disease. These participants will be followed for 12 months after their exposure to COVID-19, through regular blood samples and nose and throat swabs.

Lead researcher Professor Ivo Mueller said there were big questions in the scientific community about whether people could be re-infected with COVID-19 or how long immunity offered protection against the virus.

"While we know their immune response protects people after they recover from COVID-19, we suspect this protection wanes over time and reinfection of COVID-19 may be possible. We don't know how long this immunity lasts and whether it differs between people who have had severe, mild or asymptomatic infections," he said.

"Understanding immunity to COVID-19 is vital for developing vaccination strategies. It will also drive greater awareness and understanding to help us better manage this virus in the community.

"If we can predict the way immunity to the virus develops over time, whether and when people can be reinfected, and whether symptoms are less severe upon reinfection, we will be able to plan accordingly and stay ahead of the virus," he said.

Explaining different disease outcomes

As researchers across the world race to make sense of this global pandemic, many vital factors remain unknown.

"Concerningly, it may be possible that a second COVID-19 infection could be worse than the first, if immunity has waned. Our study will look closely at whether people could have more severe symptoms if they are re-infected," Professor Mueller said.

Study investigator Dr Vanessa Bryant said the research was crucial in helping to understand the wide range of symptoms experienced by people with COVID-19.

"Some people get severely ill and require hospitalisation, while others are almost completely asymptomatic. Understanding why this happens will help us identify 'biomarkers' that could be used to predict which people may be at higher risk of contracting the virus or developing the most severe symptoms," she said.

"This will enable us to find new treatments that can help strengthen patients' immune systems to help them recover faster."

(Vienna, October 12, 2020) New research presented today at UEG Week Virtual 2020 has shown that delays in colorectal cancer (CRC) screening caused by COVID-19 has resulted in significantly increased death rates for the cancer.

Researchers at the University of Bologna produced a model to forecast the impact of time delays in CRC screening on CRC mortality caused by COVID-19. The results found that moderate (7-12 months) and large (>12 months) delays in screening caused a 3% and 7% increase in advanced stage CRC respectively.

Based on survival rates at 5 years for stage III-IV CRC, the results showed a significant 11.9% increase in deaths when comparing a 0-3 month delay to a >12 month delay.

CRC (or bowel cancer) is Europe's second largest cancer killer and the most common digestive cancer. Annually, there are 375,000 newly diagnosed cases in the EU and it claims the lives of over 170,000 people.

Screening aids the early detection of CRC, and since the rollout of screening programmes across Europe there has been a steady decline in mortality rates. However, since the start of the pandemic, screening programmes have been suspended in many areas across Europe.

Led author of the study, Professor Luigi Ricciardiello, comments, "Across the globe, healthcare systems are facing serious difficulties while dealing with COVID-19 and it is imperative that support is given to the public and patients throughout the crisis, including for high-impact diseases such as colorectal cancer. Healthcare authorities need to act urgently on how they reorganise activities during COVID-19, without compromising the diagnosis of other high-impact diseases like this research shows."

Unhealthy lifestyles, such as diets high in processed foods, smoking and heavy alcohol consumption are linked to the development of CRC. Symptoms include persistent rectal bleeding, a change in bowel habits, abdominal pain and unexplained weight loss.

"Early-stage diagnosis of colorectal cancer is crucial - it's far easier to treat and enhances optimal patient outcomes", adds Professor Ricciardiello. "It is therefore essential that vital diagnosis tools, like screening programmes, continue and help to prevent mortality rates from rising even further."

(Vienna, October 12, 2020) Weight loss surgery significantly cuts the risk of developing pancreatic cancer in people who are obese with diabetes, a new 20-year analysis has found.

The study, presented today at UEG Week 2020 Virtual, analysed 1,435,350 patients with concurrent diabetes and obesity over a 20-year period. A total of 10,620 patients within the study had undergone bariatric (weight loss) surgery, an operation that helps patients lose weight by making changes to the digestive system.

The research found that obese patients with diabetes were significantly less likely to develop pancreatic cancer if they had undergone bariatric surgery (prevalence of 0.32% vs 0.19%, p

Lead author Dr Aslam Syed, from the Allegheny Health Network, Division of Gastroenterology in Pittsburgh, USA, commented, "Obesity and diabetes are well-known risk factors for pancreatic cancer via chronic inflammation, excess hormones and growth factors released by body fat. Previously, bariatric surgery has been shown to improve high blood sugar levels in diabetic patients and our research shows that this surgery is a viable way in reducing the risk of pancreatic cancer in this growing, at-risk group."

The findings are particularly timely, with rates of diabetes, obesity and pancreatic cancer all on the rise.

For pancreatic cancer, cases in the EU increased by 5% between 1990 and 2016 - the highest increase in the EU's top five cancers - with the disease expected to be the second leading cause of cancer death in the near future. A total of 46,200 people are estimated to die from the disease in Europe in 2020, compared to 42,200 deaths recorded in 2015. The increase in cases is believed to be fuelled by rising rates of obesity and type 2 diabetes.

Obesity rates continue to increase at a rapid and concerning pace across Europe, with little expectation that these figures will decrease or plateau. Over half (52%) of the adult EU population is either overweight or obese, with growing rates also prevalent in children.

Dr Syed explains how preventing pancreatic cancer is crucial, with a lack of improvements in the survival of the disease for four decades. "The average survival time at diagnosis is particularly bleak for this silent killer, at just 4.6 months, with patients losing 98% of their healthy life expectancy. Only 3% of patients survive more than five years."

Often referred to as the 'silent killer', symptoms of pancreatic cancer - which include pain in the back or stomach, jaundice and unexplained weight loss - can be hard to identify which adds difficulties in diagnosing patients early.

"Clinicians should consider bariatric surgery in patients with metabolic disorders, such as diabetes and obesity, to help reduce the risk and burden of pancreatic cancer," adds Dr Syed.

Researchers at CSIRO, Australia's national science agency, have found that SARS-CoV-2, the virus responsible for COVID-19, can survive for up to 28 days on common surfaces including banknotes, glass - such as that found on mobile phone screens - and stainless steel.

The research, undertaken at the Australian Centre for Disease Preparedness (ACDP) in Geelong, found that SARS-CoV-2:

survived longer at lower temperatures

tended to survive longer on non-porous or smooth surfaces such as glass, stainless steel and vinyl, compared to porous complex surfaces such as cotton

survived longer on paper banknotes than plastic banknotes.

Results from the study The effect of temperature on persistence of SARS-CoV-2 on common surfaces was published in Virology Journal.

CSIRO Chief Executive Dr Larry Marshall said surface survivability research builds on the national science agency's other COVID-19 work, including vaccine testing, wastewater testing, Personal Protective Equipment (PPE) manufacture and accreditation, and big data dashboards supporting each state.

"Establishing how long the virus really remains viable on surfaces enables us to more accurately predict and mitigate its spread, and do a better job of protecting our people," Dr Marshall said.

"Together, we hope this suite of solutions from science will break down the barriers between us, and shift focus to dealing with specific virus hotspots so we can get the economy back on track.

"We can only defeat this virus as Team Australia with the best Australian science, working alongside industry, government, research and the Australian community."

Dr Debbie Eagles is Deputy Director of ACDP, which has been working on both understanding the virus and testing a potential vaccine.

"Our results show that SARS-CoV-2 can remain infectious on surfaces for long periods of time, reinforcing the need for good practices such as regular handwashing and cleaning surfaces," Dr Eagles said.

"At 20 degrees Celsius, which is about room temperature, we found that the virus was extremely robust, surviving for 28 days on smooth surfaces such as glass found on mobile phone screens and plastic banknotes.

"For context, similar experiments for Influenza A have found that it survived on surfaces for 17 days, which highlights just how resilient SARS-CoV-2 is."

The research involved drying virus in an artificial mucus on different surfaces, at concentrations similar to those reported in samples from infected patients and then re-isolating the virus over a month.

Further experiments were carried out at 30 and 40 degrees Celsius, with survival times decreasing as the temperature increased.

The study was also carried out in the dark, to remove the effect of UV light as research has demonstrated direct sunlight can rapidly inactivate the virus.

"While the precise role of surface transmission, the degree of surface contact and the amount of virus required for infection is yet to be determined, establishing how long this virus remains viable on surfaces is critical for developing risk mitigation strategies in high contact areas," Dr Eagles said.

Director of ACDP Professor Trevor Drew said many viruses remained viable on surfaces outside their host.

"How long they can survive and remain infectious depends on the type of virus, quantity, the surface, environmental conditions and how it's deposited - for example touch vs droplets emitted by coughing," Professor Drew said.

"Proteins and fats in body fluids can also significantly increase virus survival times.

"The research may also help to explain the apparent persistence and spread of SARS-CoV-2 in cool environments with high lipid or protein contamination, such as meat processing facilities and how we might better address that risk."

Volume 11, Issue 28 of Oncotarget features "Genetic analysis of the cooperative tumorigenic effects of targeted deletions of tumor suppressors Rb1, Trp53, Men1, and Pten in neuroendocrine tumors in mice" by Xu et, al. which reported that the authors examined whether the TSGs Rb1, Trp53, Pten, and Men1 have cooperative effects in suppressing neuroendocrine tumors in mice.

By monitoring growth and examining the histopathology of the pituitary and pancreas in these mice, the authors demonstrated that pRB had the strongest cooperative function with PTEN in suppressing Pit NETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing Pit NETs and Pan NETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions.

Collectively, the data indicated that pRB and PTEN pathways play significant roles in suppressing Pit NETs, while the Menin-mediated pathway plays a significant role in suppressing Pan NETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans.

Dr. Eugenia Y. Xu from Rutgers and Princeton University as well as Dr. Daniel A. Notterman from Princeton University said, "Human pituitary neuroendocrine tumors (PitNETs) are the third most common intracranial neoplasms and represent approximately 10–25% of all primary intracranial tumors."

Additionally, in rare cases, RB1 has been found with epigenetic mutations in the promoter region in Pit NETs suggesting that inactivation of the RB pathway contributes to the development of Pit NETs. Compound mice with concomitant deletions of Men1 and Pten develop Pit NETs and Pan NETs and mice with p18–/– Pten+/– mutations develop Pit NETs, suggesting that PTEN plays a role in pituitary and pancreatic islet tumorigenesis.

However, Men1 deletion mice develop pars distalis prolactinomas and Rb1 deletion mice develop pars intermedia tumors of the pituitary, suggesting that the functions of Menin and pRB may not fully overlap.

Here they investigate the question of whether Men1 and Rb1 have cooperative tumorigenic effects on NETs using tissue-specific double homozygous deletions of Men1 and Rb1 in mice.

The Oncotarget authors report that the characterization of Pit NETs and Pan NETs with double homozygous deletions of TSGs and illustrate that pRB has the strongest cooperative function with PTEN in suppressing Pit NETs and has a strong cooperative function with Menin and TRP53, respectively, in suppressing Pit NETs and Pan NETs in mice.

"The Oncotarget authors report that the characterization of Pit NETs and Pan NETs with double homozygous deletions of TSGs and illustrate that pRB has the strongest cooperative function with PTEN in suppressing Pit NETs and has a strong cooperative function with Menin and TRP53, respectively, in suppressing Pit NETs and Pan NETs in mice."

The Xu/Notterman Research Team concluded in their Oncotarget Research Paper, "our data clearly demonstrate that TSGs Rb1, Pten, Men1, and Trp53 have distinct tissue specificity in neuroendocrine tumorigenesis in mouse and likely in man. The mouse models here and deletion of these TSGs in MIP-Cre mice will help further our understanding the molecular function of these TSGs and their pathways in PitNET and PanNET pathogenesis, which will help develop targeted novel therapeutic options in treating human patients."

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DOI - https://doi.org/10.18632/oncotarget.27660

Full text - https://www.oncotarget.com/article/27660/text/

Correspondence to - Eugenia Y. Xu - exu@princeton.edu and Daniel A. Notterman - dan1@princeton.edu

Keywords -
neuroendocrine tumors,
RB1,
Trp53,
PTEN,
Men1

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27660

Volume 11, Issue 28 of Oncotarget features "Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation" by Gaba et, al. which reported that reliable development of Oncopig HCC cell lines was demonstrated through hepatocyte isolation and Cre recombinase exposure across 15 Oncopigs.

Oncopig and human HCC cell lines displayed similar cell cycle lengths, alpha-fetoprotein production, arginase-1 staining, chemosusceptibility, and drug-metabolizing enzyme expression.

The ability of Oncopig HCC cells to consistently produce tumors in vivo was confirmed via subcutaneous injection into immunodeficient mice and Oncopigs.

Reproducible development of intrahepatic tumors in an alcohol-induced fibrotic microenvironment was achieved via engraftment of SQ tumors into fibrotic Oncopig livers.

Finally, Oncopig HCC cells are amenable to gene editing for the development of personalized HCC tumors.

Dr. Kyle M. Schachtschneider from The Department of Radiology and The Biological Resources Laboratory at The University of Illinois at Chicago as well as The National Center for Supercomputing Application at The University of Illinois at Urbana-Champaign said, "Hepatocellular carcinoma (HCC)–the most common type of primary liver cancer–is an aggressive cancer that spans more than 850,000 new yearly diagnoses and causes 800,000 annual deaths, representing the fifth most common cancer globally and the second most common cause of cancer-related death worldwide."

The rabbit VX2 model has been considered the most relevant and widely used model to test HCC LRTs to date.

As such, there is a crucial need for more clinically relevant large animal models that faithfully recapitulate human HCC to address unmet clinical needs and serve as a bridge between murine studies and clinical practice.

This study describes the utilization of the Oncopig Cancer Model for the development of a clinically relevant, translational porcine HCC model.

The Oncopig Cancer Model is a transgenic pig model that develops site and cell-specific tumors following Cre recombinase induced expression of heterozygous KRASG12D and TP53R167H transgenes.

The large size of the pig and its similarities with humans in terms of anatomy, physiology, metabolism, immunity, and genetics make it an ideal model species for the development of a large animal cancer model.

Development of Oncopig HCC cell lines has been previously described, however, prior work was limited to characterization of HCC cell lines derived from three Oncopigs, minimal in vitro and in vivo profiling, and no description of intrahepatic tumors.

As such, this study was undertaken to test the hypothesis that phenotypically consistent Oncopig HCC cells that faithfully recapitulate the in vitro features of human HCC can be developed across a large Oncopig cohort and that these cells can be utilized to develop clinically relevant intrahepatic HCC tumors in Oncopigs.

The Schachtschneider Research Team concluded in their Oncotarget Research Paper, "the Oncopig HCC model offers a novel, physiologically and anatomically relevant cancer model for which a multitude of innovative therapeutic modalities can be applied and tested while significantly reducing the costs, confounding variables seen in human subjects, and lengthy conduct of human clinical trials. Importantly, the Oncopig can be utilized to conduct correlative studies for more efficient and consistent investigation of new therapies. Its size allows for utilization of the same methods and instruments used in human clinical practice, including CT and magnetic resonance imaging technologies. This model is thus amenable to developing and establishing medical imaging standards related to diagnosing HCC tumors and tracking treatment response using accepted radiologic criteria, a critical facet of therapeutic discovery and validation. Importantly, the Oncopig is also immunocompetent, lending itself to investigation of immunotherapies [32]. Therefore, the Oncopig fulfills the currently unmet clinical modeling needs for HCC, particularly for pilot investigations of experimental therapies or experimental therapeutic combinations not feasible in human subjects."

"The Oncopig HCC model offers a novel, physiologically and anatomically relevant cancer model for which a multitude of innovative therapeutic modalities can be applied and tested while significantly reducing the costs, confounding variables seen in human subjects, and lengthy conduct of human clinical trials. Importantly, the Oncopig can be utilized to conduct correlative studies for more efficient and consistent investigation of new therapies. Its size allows for utilization of the same methods and instruments used in human clinical practice, including CT and magnetic resonance imaging technologies. This model is thus amenable to developing and establishing medical imaging standards related to diagnosing HCC tumors and tracking treatment response using accepted radiologic criteria, a critical facet of therapeutic discovery and validation. Importantly, the Oncopig is also immunocompetent, lending itself to investigation of immunotherapies [32]. Therefore, the Oncopig fulfills the currently unmet clinical modeling needs for HCC, particularly for pilot investigations of experimental therapies or experimental therapeutic combinations not feasible in human subjects."

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DOI - https://doi.org/10.18632/oncotarget.27647

Full text - https://www.oncotarget.com/article/27647/text/

Correspondence to - Kyle M. Schachtschneider - kschach2@uic.edu

Keywords -
liver cancer,
transgenic pigs,
large animal model,
interventional radiology,
personalized medicine

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27647

The same stem cells that heal broken bones can also generate arthritic bone spurs called osteophytes, according to a new study in the Annals of the Rheumatic Diseases.

"Although these stem and progenitor cells promote healthy bone repair in other contexts, they are inappropriately activated to cause a pathological bony protuberance in the context of arthritis," said Gage Crump, a professor of stem cell biology and regenerative medicine at USC. Crump is the paper's co-corresponding author, along with Cosimo de Bari from the University of Aberdeen in the UK.

Led by Crump and de Bari, an international team of scientists made this discovery by studying mice that had sustained a type of knee injury that causes arthritis. In these mice, a different colored fluorescent protein labeled each of eight distinct cell populations. This allowed the scientists to view the fluorescent labels under a microscope and trace how the various cell populations contribute to the formation of arthritic bone spurs.

The major culprit turned out to be a type of stem cell with activity in a gene called Sox9, which is also involved in bone repair. At the edge of the arthritic joint, these cells contributed to cartilage outgrowths that later turned into pathological bone spurs. These cartilage outgrowths had many of the distinctive hallmarks of the cartilage seen during bone regeneration, suggesting further parallels between pathological bone spur formation and normal bone repair.

"By resolving the cellular origins of osteophytes, our work provides clues for how to target these painful bone spurs that develop at the edge of joints in many arthritis patients," Crump said.

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team's results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an "extrafollicular" pathway outside germinal centers - looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory's Asthma/Allergy Immunology program.

"We came in pretty unbiased," Sanz says. "It wasn't until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE."

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of "autoantibodies" that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

"It's an important question that we need to address through careful long-term follow-up," he says. "Not all severe infections do this. Sepsis doesn't look like this."

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, PhD, an instructor in Sanz's lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team's findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

Some COVID-19 patients have been given drugs that push back against IL-6, but results have been mixed in clinical trials. Patients with markers of unregulated immune responses may be appropriate candidates for treatment with anti-inflammatory drugs that target the corresponding pathways, Sanz suggests.

The American Medical Association has joined the African American Tobacco Control Leadership Council in suing the Food and Drug Administration on their inaction to ban menthol-flavored tobacco products which have been heavily marketed by cigarette companies to Black communities for decades.

Cristine Delnevo, director of the Rutgers Center for Tobacco Studies and a professor at the Rutgers School of Public Health, recently published three studies showing that menthol cigarette smoking persists in the United States, particularly among vulnerable populations, despite population-level cigarette declines. Another co-authored paper with Ollie Ganz, an instructor at the Rutgers School of Public Health and a researcher at the tobacco center, called for a ban of menthol cigarettes, saying banning the product should be considered a social justice issue. They both discuss why actions at the state and federal level need to be taken to make the ban a reality.

Why should menthol cigarettes concern public health officials?

Delnevo: The FDA's Tobacco Product Scientific Advisory Committee (TPSAC) was tasked by Congress to review the scientific evidence of menthol cigarette use among specific groups given the high use rates among youth smokers and Black smokers. It concluded that menthol in cigarettes reduced the harshness of smoking and was associated with increased initiation, higher dependence and had lower quit success.

The continued availability of menthol cigarettes in the U.S. should be viewed as a social justice issue. The majority of Black smokers in the U.S. smoke menthol cigarettes and there is extensive research showing that the tobacco industry has targeted these African American communities with advertising for menthol cigarettes for decades.

Additionally, as TPSAC pointed out, menthol cigarettes are particularly appealing to the youth, especially minorities. In the past, the industry manipulated menthol levels in cigarettes to be more appealing to young smokers. Even data from the National Youth Tobacco Survey reported that while menthol use declined overall among youth from 2011-2018, there was no decline among Black and Hispanic students.

Our study, published in the journal Nicotine & Tobacco Research draws attention to other populations for which menthol use is high, including sexual minorities, pregnant women and those with mental health problems.

How has the consumption of cigarettes, especially menthol cigarettes, changed over the years following Congress' Passage of the Family Smoking Prevention and Tobacco Control Act which banned flavored cigarettes, but exempted menthol?

Delnevo: Our study, published in JAMA Network Open, which analyzed cigarette consumption data in the U.S. between 2000 to 2018, found there was a 46 percent decline in cigarette consumption during this period. However, 85 percent of that decline was attributed to non-menthol cigarettes. During this time, menthol consumption was fairly stable and the market share of menthol cigarettes increased by nearly 10 percent. This pattern is consistent with scientific evidence that menthol in cigarettes increases initiation and progression to regular smoking and decreases smoking cessation success.

Additionally, we found that although consumption for non-menthol cigarettes declined 33.1 percent since the passage of the Tobacco Control Act in 2009, but there was only an 8.2 percent decline for menthol cigarettes, with 91 percent of that decline attributed to non-menthol cigarettes between 2009 and 2018.

Why is it important to ban menthol cigarettes and why has it been difficult to enact a nationwide ban? Why have other products like flavored vapes been banned and not menthol cigarettes?

Ganz: Research shows that a ban on menthol cigarettes would significantly impact public health and positively impact the African American community. A 2011 study modeling the effects of a menthol ban in the U.S. estimated that 633,252 deaths could have been averted and that one of three of these lives lost would be a Black person. Our youth and other vulnerable communities like pregnant women and Hispanic and Black populations are also at risk if this issue continues.

Delnevo: Our paper, published in the journal Nicotine & Tobacco Research, questioned if menthol cigarettes would have been banned by now if the typical consumer was young, white and upper-middle class. It is fascinating to consider how quickly flavored e-cigarettes were banned in numerous locations spurred on by the efforts of Parents against Vaping E-cigs -- an advocacy group created in 2018 led by three white mothers. Contrast this with the battle to ban menthol cigarettes for over a decade by numerous advocacy groups and organizations, including the African American Tobacco Control Leadership Council and the National African American Tobacco Prevention Network, to protect their communities, but had no meaningful action taken.

What can be done to enact a ban on menthol cigarettes?

Ganz: We urge policymakers in other states across the country to take action and follow the lead of California and Massachusetts, who banned menthol cigarettes just this year.

Delnevo: Our research has also found that local bans at the city level are likely insufficient to reduce menthol cigarette availability. That isn't to say local bans are a bad idea. They aren't. A local movement can grow to a statewide campaign, just like it did in California. But ideally, we should be addressing this at a national level. The Senate should step up and pass HR 2339, also known as the "Reversing the Youth Tobacco Epidemic Act of 2019"--which would ban menthol cigarettes nationwide and be an important step in protecting public health and achieve health equity in the U.S.