A comprehensive review by University of North Carolina researchers and colleagues of hundreds of publications, incorporating more than two dozen articles on prevention screening for lung cancer with low-dose spiral computed tomography (LDCT), shows there are both benefits and harms from screening. The review is published in JAMA on March 9, 2021.
The results of the decade-long National Lung Screening Trial (NLST) showed that LDCT could detect lung cancer better than conventional X-rays in current or previous heavy smokers. Based on those results, the United States Preventive Services Task Force (USPSTF) initially recommended low-dose CT screening for people ages 55 to 80 with a 30 pack-year smoking history. Subsequently, other screening trial results have been published, including a European trial called NELSON, the next-largest study to the NLST. NELSON also found a reduction in deaths due to lung cancer because of screening.
It has been nearly a decade since the initial recommendations were formulated, so the USPSTF initiated an updated review of the evidence. UNC scientists and their collaborators evaluated and synthesized data from the seven trials to arrive at a comprehensive, current assessment of harms and benefits of screening.
New recommendations, based on this evidence review, broaden the criteria for screening eligibility by lowering the screening age from 55 to 50 and reducing the pack-year requirement from 30 to 20 pack-years. There were several reasons for this change in eligibility according to the reviewers; one was to promote health equity, in part because African Americans have higher lung cancer risk even with lower levels of smoking exposure.
“Two large studies have now confirmed that screening can lower the chance of dying of lung cancer in high-risk people. However, people considering screening should know that a relatively small number of people who are screened benefit, and that screening can also lead to real harms,” said Daniel Reuland, MD, MPH, one of the review authors, a member of the UNC Lineberger Comprehensive Cancer Center, and a professor in the division of General Medicine and Clinical Epidemiology at UNC School of Medicine.
In screening with CT scans, doctors are looking for lung spots or nodules that might represent early lung cancer. Harms from screening can come from the fact that the large majority of the nodules found on screening are not cancer. These findings are known as false positives, and patients with these results usually require additional scans to see if the spots are growing over time. In some cases, these false positives lead to unnecessary surgery and procedures. Throughout the process, patients may experience the mental distress of a possible cancer diagnosis.
“Applying screening tests to a population without symptoms of disease can certainly benefit some people but also has the potential for some harms,” said lead author Daniel Jonas, MD, MPH, who conducted most of this research while he was a professor at the UNC School of Medicine and now is director of the division of general internal medicine at Ohio State University. “In the case of lung cancer screening, we now have more certainty that some individuals will benefit, with some lung cancer deaths prevented, and we also know others will be harmed. The USPSTF has weighed the overall benefits and harms, and on balance, based on our review and from modeling studies, has determined that screening with LDCT has an overall net benefit for high-risk people ages 50 to 80.”
Reuland and Jonas note that, encouragingly, lung cancer rates are declining, reflecting changing smoking patterns in recent decades. Therefore, the population eligible for screening is also projected to decline. At this point, however, they don’t foresee these trends changing screening recommendations during the next decade or so.
“Different trials have used different screening approaches, and we still do not know how often screening should be done or which approach to categorizing lesions is best for reducing the harms, costs and burdens of screening while retaining the benefits,” said Reuland, who is also a research fellow at UNC’s Cecil G. Sheps Center for Health Services Research. “I would prioritize this as an important area of future research, as it could likely be addressed by implementing less expensive studies or using approaches other than those used in the large trials we just reviewed.”

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report.
The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.
The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia and the study’s corresponding author.
There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia investigators write in the Journal of Alzheimer’s Disease.
“Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. “But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.
The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

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They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.
That up and down expression in health and disease could make IL-33 both a good biomarker and treatment target for disease, the investigators say.
CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.
Low levels of TREM2 and rare variations in TREM2 are associated with Alzheimer’s, and in their mouse model TREM2 and IL-33 were both low.
Both are essential to a natural, ongoing housekeeping process in the brain called phagocytosis, in which microglial cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of amyloid-beta precursor protein, which is important to the synapses, or connection points, between neurons, and which the plaque interrupts.

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They found CBD treatment increased levels of IL-33 and TREM2 — sevenfold and tenfold respectively.
CBD’s impact on brain function in the mouse model of early onset Alzheimer’s was assessed by methods like the ability to differentiate between a familiar item and a new one, as well as observing the rodents’ movement.
People with Alzheimer’s may experience movement problems like stiffness and an impaired gait, says Dr. Hesam Khodadadi, a graduate student working in Baban’s lab. Mice with the disease run in an endless tight circle, behavior which stopped with CBD treatment, says Khodadadi, the study’s first author.
Next steps include determining optimal doses and giving CBD earlier in the disease process. The compound was given in the late stages for the published study, and now the investigators are using it at the first signs of cognitive decline, Khodadadi says. They also are exploring delivery systems including the use of an inhaler that should help deliver the CBD more directly to the brain. For the published studies, CBD was put into the belly of the mice every other day for two weeks.
A company has developed both animal and human inhalers for the investigators who also have been exploring CBD’s effect on adult respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that is a major and deadly complication of COVID-19, as well as other serious illnesses like sepsis and major trauma. The CBD doses used for the Alzheimer’s study were the same the investigators successfully used to reduce the “cytokine storm” of ARDS, which can irrevocably damage the lungs.
Familial disease is an inherited version of Alzheimer’s in which symptoms typically surface in the 30s and 40s and occurs in about 10-15% of patients.
CBD should be at least equally effective in the more common, nonfamilial type Alzheimer’s, which likely have more targets for CBD, Baban notes. They already are looking at its potential in a model of this more common type and moving forward to establish a clinical trial.
Plaques as well as neurofibrillary tangles, a collection of the protein tau inside neurons, are the main components of Alzheimer’s, Morgan says. Beta-amyloid generally appears in the brain 15-20 years or more before dementia, he says, and the appearance of tau tangles, which can occur up to 10 years afterward, correlates with the onset of dementia. There is some interplay between beta amyloid and tau that decrease the dysfunction of each, Morgan notes.
The Food and Drug Administration is scheduled to make a ruling by early June on a new drug aducanumab, which would be the first to attack and help clear beta amyloid, Morgan says.
Other coauthors include Drs. David Hess, neurologist and MCG dean, and MCG neuroscientists Kumar Vaibhav and Krishnan Dhandapani. The research was supported by the National Institutes of Health.

Researchers at Utah State University are using silkworm silk to grow skeletal muscle cells, improving on traditional methods of cell culture and hopefully leading to better treatments for muscle atrophy.
When scientists are trying to understand disease and test treatments, they generally grow model cells on a flat plastic surface (think petri dish). But growing cells on a two-dimensional surface has its limitations, primarily because muscle tissue is three-dimensional. Thus, USU researchers developed a three-dimensional cell culture surface by growing cells on silk fibers that are wrapped around an acrylic chassis. The team used both native and transgenic silkworm silk, the latter produced by silkworms modified with spider silk genes.
Native silkworm silks have been used previously as three-dimensional cell culture models, but this is the first time that transgenic silkworm silk has been used for skeletal muscle modeling. Elizabeth Vargis, Matthew Clegg, and Jacob Barney of the Biological Engineering Department, and Justin Jones, Thomas Harris, and Xiaoli Zhang of the Biology Department published their findings in ACS Biomaterials Science & Engineering.
Cells grown on silkworm silk proved to more closely mimic human skeletal muscle than those grown on the usual plastic surface. These cells showed increased mechanical flexibility and increased expression of genes required for muscle contraction. Silkworm silk also encouraged proper muscle fiber alignment, a necessary element for robust muscle modeling.
Skeletal muscle is responsible for moving the skeleton, stabilizing joints, and protecting internal organs. The deterioration of these muscles can happen for myriad reasons, and it can happen swiftly. For example, after only two weeks of immobilization, a person can lose almost a quarter of their quadricep muscle strength. Understanding how muscles can atrophy so quickly must begin at a cellular level, with cells grown to better represent reality.
“The overarching goal of my research is to build better in vitro models,” said Elizabeth Vargis, associate professor of biological engineering at USU. “Researchers grow cells on these 2D platforms, which aren’t super realistic, but give us a lot of information. Based on those results, they usually transition into an animal model, then they move onto clinical trials, where a vast majority of them fail. I’m trying to add to that first step by developing more realistic in vitro models of normal and diseased tissue.”

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Materials provided by Utah State University. Original written by Anessa Pennington. Note: Content may be edited for style and length.

Some of Princeton’s leading cancer researchers were startled to discover that what they thought was a straightforward investigation into how cancer spreads through the body — metastasis — turned up evidence of liquid-liquid phase separations: the new field of biology research that investigates how liquid blobs of living materials merge into each other, similar to the movements seen in a lava lamp or in liquid mercury.
“We believe this is the first time that phase separation has been implicated in cancer metastasis,” said Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology. He is the senior author on a new paper featured on the cover of the current issue of Nature Cell Biology.
Not only does their work tie phase separations to cancer research, but the merging blobs turned out to create more than the sum of their parts, self-assembling into a previously unknown organelle (essentially an organ of the cell).
Discovering a new organelle is revolutionary, Kang said. He compared it to finding a new planet within our solar system. “Some organelles we have known for 100 years or more, and then all of a sudden, we found a new one!”
This will shift some fundamental perceptions of what a cell is and does, said Mark Esposito, a 2017 Ph.D. alumnus and current postdoc in Kang’s lab who is the first author on the new paper. “Everybody goes to school, and they learn ‘The mitochondria is the powerhouse of the cell,’ and a few other things about a few organelles, but now, our classic definition of what’s inside a cell, of how a cell organizes itself and controls its behavior, is starting to shift,” he said. “Our research marks a very concrete step forward in that.”
The work grew out of collaborations between researchers in the labs of three Princeton professors: Kang; Ileana Cristea, a professor of molecular biology and leading expert in the mass spectroscopy of living tissue; and Cliff Brangwynne, the June K. Wu ’92 Professor of Chemical and Biological Engineering and director of the Princeton Bioengineering Initiative, who pioneered the study of phase separation in biological processes.

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“Ileana is a biochemist, Cliff is a biophysicist and engineer, and I am a cancer biologist — a cell biologist,” Kang said. “Princeton is just a wonderful place for people to connect and collaborate. We have a very small campus. All the science departments are right next to each other. Ileana’s lab is actually on the same floor of Lewis Thomas as mine! These very close relationships, among very diverse research areas, allow us to bring in technologies from many different angles, and allow breakthroughs to understanding the mechanisms of metabolism in cancer — its progression, metastasis and the immune response — and also come up with new ways to target it.”
The latest breakthrough, featuring the as-yet unnamed organelle, adds new understanding to the role of the Wnt signaling pathway, a system whose discovery led to the 1995 Nobel Prize for Eric Wieschaus, Princeton’s Squibb Professor in Molecular Biology and a professor in the Lewis-Sigler Institute for Integrative Genomics. The Wnt pathway is vital to embryonic development in countless organisms, from tiny invertebrate insects to humans. Wieschaus discovered that cancer can co-opt this pathway, essentially corrupting its ability to grow as rapidly as embryos must, to grow tumors.
Subsequent research has revealed that the Wnt signaling pathway plays multiple roles in healthy bone growth as well as in cancer metastasizing to bones. Kang and his colleagues were investigating the complex interplay between Wnt, a signaling molecule called TGF-b, and a relatively unknown gene named DACT1 when they discovered this new organelle.
Think of it as panic-shopping before a storm, said Esposito. Buying up bread and milk before a blizzard — or hoarding hand sanitizer and toilet paper when a pandemic is looming on the horizon — aren’t just human traits, it turns out. They happen on the cellular level, too.
Here’s how it works: The panicked shopper is DACT1, and the blizzard (or pandemic) is TGF-ß. The bread and hand sanitizer are Casein Kinase 2 (CK2), and in the presence of a storm, DACT1 grabs up as much of them as possible, and the newly discovered organelle sequesters them away. By hoarding CK2, the shopper prevents other folks from making sandwiches and sanitizing their hands, i.e. preventing the healthy operation of the Wnt pathway.

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Through a series of detailed and complex experiments, the researchers pieced together the story: bone tumors initially induce Wnt signaling, to disseminate (spread) through the bone. Then, TGF-b, which is abundant in bones, inspires the panicked shopping, suppressing Wnt signaling. The tumors then stimulate the growth of osteoclasts, which scrub away old bone tissue. (Healthy bones are constantly being replenished in a two-part process: osteoclasts scrub away a layer of bone, then osteoblasts rebuild the bone with new material.) This further increases the TGF-b concentration, prompting even more DACT1 hoarding and subsequent Wnt suppression that has been shown to be important in further metastasis.
By discovering the roles of DACT1 and this organelle, Kang and his team have found new possible targets for cancer drugs. “For example, if we have a way to disrupt the DACT1 complex, perhaps the tumor will disseminate, but it will never be able to ‘grow up’ to be life-threatening metastasis. That’s the hope,” Kang said.
Kang and Esposito recently co-founded KayoThera to pursue the development of medications for patients with late-stage or metastatic cancers, based on their work together in the Kang lab. “The kind of fundamental study that Mark is doing both presents groundbreaking science findings and can also lead to medical breakthroughs,” said Kang.
The researchers have found that DACT1 plays many other roles as well, which their team is only beginning to explore. The mass spectrometry collaboration with Cristea’s team revealed more than 600 different proteins in the mysterious organelle. Mass spectrometry allows scientists to find out the exact components of almost any substance imaged on a microscope slide.
“This is a more dynamic signaling node than just controlling Wnt and TGF-b.” said Esposito. “This is just the tip of the iceberg on a new field of biology.”
This bridge between phase separations and cancer research is still in its infancy, but it already shows great potential, said Brangwynne, who was a co-author on the paper.
“The role that biomolecular condensates play in cancer — both its genesis but particularly its spread through metastasis — is still poorly understood,” he said. “This study provides new insights into the interplay of cancer signaling pathways and condensate biophysics, and it will open up new therapeutic avenues.”

Smoke from local wildfires can affect the health of Colorado residents, in addition to smoke from fires in forests as far away as California and the Pacific Northwest.
Researchers at Colorado State University, curious about the health effects from smoke from large wildfires across the Western United States, analyzed six years of hospitalization data and death records for the cities along the Front Range, which reaches deep into central Colorado from southern Wyoming.
They found that wildfire smoke was associated with increased hospitalizations for asthma, chronic obstructive pulmonary disease and some cardiovascular health outcomes. They also discovered that wildfire smoke was associated with deaths from asthma and cardiovascular disease, but that there was a difference in the effects of smoke from local fires and that from distant ones.
Long-range smoke was associated with expected increases in hospitalizations and increased risk of death from cardiovascular outcomes.
But when the research team separated out health effects of smoke from local wildfires in early summer 2012 from long-range smoke from late summer 2012 and summer 2015, they found that local wildfires were associated with meaningful decreases in hospitalizations, especially for asthma.
The study, “Differential Cardiopulmonary Health Impacts of Local and Long-Range Transport of Wildfire Smoke,” was recently published in GeoHealth, a journal from the American Geophysical Union.

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Residents protect themselves from local fires
Sheryl Magzamen, lead author of the study and an associate professor in the Department of Environmental and Radiological Health Sciences at CSU, said the team believes that evacuation efforts and related media coverage of local wildfires may have helped protect residents from adverse health effects of smoke exposure as well as direct impacts of the fires.
“There’s a lack of communication about smoke from distant wildfires,” said Magzamen. “Generally when there are local fires, there are advisories in the news that are associated with evacuations and local fire conditions. Due to the presence of the fire, people take measures to protect themselves. This could be why we see this lower risk of health effects from smoke associated with local fires.”
Researchers described the long-range wildfire smoke as resembling fog, which is what Magzamen said she noticed in Fort Collins in August 2015. At the time, she was collaborating on a project with Jeff Pierce, associate professor in the Department of Atmospheric Science.
“I thought it was weird to see fog on that day,” she explained. “Jeff said, ‘That’s actually smoke.’ We all took a step back.”
Smoke changes with age

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Pierce, a co-author on this study, said researchers don’t really know how harmful smoke is as it gets older, or becomes long-range smoke.
“In Fort Collins, about half the time we had smoke in late August or September 2020, this was smoke from the Cameron Peak Fire,” he explained. “This smoke was only a couple hours old when it got here. At other times, we were getting smoke from California, and the smoke from the Cameron Peak Fire was either going over our heads or further south.”
The Cameron Peak Fire was reported on Aug. 13, 2020, and burned into October, consuming 208,913 acres on the Arapaho and Roosevelt National Forests in Larimer and Jackson Counties and Rocky Mountain National Park. It was the first wildfire in Colorado history to burn more than 200,000 acres.
The average person would not notice a difference in wildfire smoke, Pierce said.
“If the smoke is even two days old, things happen chemically, which changes the smoke a lot,” he explained. “If it didn’t smell like wood burning, it was long-range smoke from California.”
Magzamen said that the team is working to better understand these chemical changes.
“As the small particles found in wildfire smoke age, they can cause more oxidative stress and more respiratory health effects,” she said. “But wildfire smoke itself is a mixture of particles and gases. Teasing apart the effects of all the components of smoke and what happens to the mixture across space and time — and how those changes impact health — is an enormous scientific challenge.”
Better air quality monitoring
Magzamen said the gap in understanding the source of wildfire smoke is because it historically has been measured by land-based sensors, which are primarily located in large urban areas and sparsely located in other regions, even along the Front Range.
“Even over the last five years, our air quality monitoring networks have been enhanced with new technologies and better measurements of real-time smoke effects,” she said.
CSU researchers are now collaborating with local government officials on messaging related to the different types of wildfire smoke, with a specific aim to reach the most vulnerable populations. This includes caretakers of young children, people experiencing homelessness and others who can’t shelter safely in place during wildfire season.
“We want people to be smoke-aware,” she said. “On the Front Range, we have wildfire smoke every summer. We may not get Cameron Peak-size type of fires every year, but we are downwind for pretty much the entire Western United States,” she said. “It’s critical that we keep people healthy and safe.”

Scientists at Washington University School of Medicine in St. Louis have implicated a type of immune cell in the development of chronic lung disease that sometimes is triggered following a respiratory viral infection. The evidence suggests that activation of this immune cell — a type of guardian cell called a dendritic cell — serves as an early switch that, when activated, sets in motion a chain of events that drives progressive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD).
The new study, published in The Journal of Immunology, opens the door to potential preventive or therapeutic strategies for chronic lung disease. More immediately, measuring the levels of these dendritic cells in clinical samples from patients hospitalized with a viral infection, such as influenza or COVID-19, could help doctors identify which patients are at high risk of respiratory failure and death.
Studying mice with a respiratory viral infection that makes the animals prone to developing chronic lung disease, the researchers showed that these dendritic cells communicate with the lining of the airway in ways that cause the airway-lining cells to ramp up their growth and inflammatory signals. The inflammation causes airway-lining cells to grow beyond their normal boundaries and turn into cells that overproduce mucus and cause inflammation, which in turn causes cough and difficulty breathing.
“We’re trying to understand how a viral infection that seems to be cleared by the body can nevertheless trigger chronic, progressive lung disease,” said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine. “Not everyone experiences this progression. We believe there’s some switch that gets flipped, triggering the bad response. We’re identifying that switch and ways to control it. This work tells us that this type of dendritic cell is sitting right at that switch point.”
Holtzman’s past work had implicated the lining of the airway — where the viral infection takes hold — as the likely trigger for this process.
“But this study suggests that the cascade starts even further upstream,” said Holtzman, also director of the Division of Pulmonary and Critical Care Medicine. “Dendritic cells are telling the cells lining the airway what to do. There’s more work to be done, but this data tells us that the dendritic cells play an important role in getting the airway-lining cells onto the wrong path.”
Holtzman calls this dendritic cell a type of sentinel because its job is to detect an invading virus and trigger the body’s initial immune response against the infection. The problem comes when the cell doesn’t shut down properly after the threat has passed.
“Many people never develop chronic lung disease after a viral infection,” Holtzman said. “But others have a genetic susceptibility to this type of disease. People who are susceptible to virus-triggered disease include patients with asthma, COPD, and viral infections such as COVID-19. It’s really critical to look for ways to fix this disease response and prevent the problems that might occur after the virus has gone.”
In the meantime, Holtzman said, high levels of these dendritic cells and their products in the lungs of hospitalized patients could serve as a warning to doctors that such patients are likely to develop severe disease and should be provided with respiratory interventions and other supportive therapies that are precisely tailored to their disease process.
“Similarly, if this process is not underway, the patient might be more likely to avoid these types of long-term problems,” Holtzman said. “We’re pursuing this line of research to help improve prediction of severe lung disease after infection and to provide companion therapies that could prevent this switch from being flipped or flip it back to reverse the disease.”
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), grant number R01 AI130591 and the National Heart, Lung, and Blood Institute (NHLBI), grant number R35 HL145242, both of the National Institutes of Health (NIH); the Cystic Fibrosis Foundation; and the Hardy Trust and Schaeffer Funds.

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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.