The study, published today in Nature Nanotechnology, details the use of this platform to artificially attach an activation molecule to the surface of tumor cells, triggering an immune response in both in vivo and in vitro models. Wen Jiang, M.D., Ph.D., assistant professor of Radiation Oncology, and Betty Kim, M.D., Ph.D., professor of Neurosurgery, co-led the study.

“With this new platform, we now have a strategy to convert a solid tumor, at least immunologically, to resemble a hematological tumor, which often has a much higher response rate to immunotherapy treatments,” Jiang said. “If we are able to translate and validate this approach in the clinic, it may enable us to get closer to the maximum level of activity from immunotherapy drugs with cancers that have not traditionally responded well.”

Immunotherapy has high response rates in blood cancers like leukemia and lymphoma, but success has been variable across solid tumors. Scientists have been working to further understand the mechanisms prohibiting a better response. One explanation is that varied expression of immune regulatory molecules on blood cancer versus solid tumor cells impact how they interact with immune cells.

The signaling lymphocytic activation molecule family member 7 (SLAMF7) receptor is critical in activating the body’s immune cells against cancer cells, acting as an “eat me” signal. However, it is found almost exclusively on the surface of blood cancer cells and not in solid tumor cells, making it an attractive target for the researchers’ immune conversion approach.

To promote the expression of SLAMF7 on solid tumor cells, the researchers developed their bispecific tumor-transforming nanoconjugate (BiTN) platform. These nanosystems are designed with one molecule to bind to the surface of targeted tumor cells and a second molecule to activate an immune response.

In this study, the researchers used BiTN with SLAMF7 and a HER2-recognizing antibody to target HER2-positive breast cancer cells. In laboratory models, the nanoconjugate successfully attached SLAMF7 to the breast cancer cells, resulting in phagocytosis, or ingestion, by immune cells. The approach also sensitized the breast cancer cells to treatment with an anti-CD47 antibody, which blocks the “don’t eat me” signal from tumor cells to further increase responses in solid tumors.

According to the authors, one of the most exciting things about this platform is its broad potential applications. The approach would not be specific to one cancer type or one regulatory molecule, rather it has the potential to be a universal strategy for several different solid tumor types. As a proof of concept, the authors also developed BiTN with folate instead of the anti-HER2-antibody to target triple-negative breast cancer with similar results.

“Because these are engineered constructs, this can be used as a plug-and-play approach to incorporate different tumor-targeting agents or immune molecules onto the surface of the nanoparticle,” Kim said. “For patients with solid tumors that have not responded to immunotherapy, we see this as an added advantage to target the part of the tumor that didn’t respond.”

The study was supported in part by the Susan G. Komen Foundation Career Catalyst Research Grant, the National Cancer Institute/National Institutes of Health (1K08 CA241070, P30 CA016672) and the United States Department of Defense.

Materials theorists Boris Yakobson and Ksenia Bets at Rice University’s George R. Brown School of Engineering show how putting constraints on growing nanotubes could facilitate a “holy grail” of growing batches with a single desired chirality.

Their paper in Science Advances describes a strategy by which constraining the carbon feedstock in a furnace would help control the “kite” growth of nanotubes. In this method, the nanotube begins to form at the metal catalyst on a substrate, but lifts the catalyst as it grows, resembling a kite on a string.

Carbon nanotube walls are basically graphene, its hexagonal lattice of atoms rolled into a tube. Chirality refers to how the hexagons are angled within the lattice, between 0 and 30 degrees. That determines whether the nanotubes are metallic or semiconductors. The ability to grow long nanotubes in a single chirality could, for instance, enable the manufacture of highly conductive nanotube fibers or semiconductor channels of transistors.

Normally, nanotubes grow in random fashion with single and multiple walls and various chiralities. That’s fine for some applications, but many need “purified” batches that require centrifugation or other costly strategies to separate the nanotubes.

The researchers suggested hot carbon feedstock gas fed through moving nozzles could effectively lead nanotubes to grow for as long as the catalyst remains active. Because tubes with different chiralities grow at different speeds, they could then be separated by length, and slower-growing types could be completely eliminated.

One additional step that involves etching away some of the nanotubes could then allow specific chiralities to be harvested, they determined.

The lab’s work to define the mechanisms of nanotube growth led them to think about whether the speed of growth as a function of individual tubes’ chirality could be useful. The angle of “kinks” in the growing nanotubes’ edges determines how energetically amenable they are to adding new carbon atoms.

“The catalyst particles are moving as the nanotubes grow, and that’s principally important,” said lead author Bets, a researcher in Yakobson’s group. “If your feedstock keeps moving away, you get a moving window where you’re feeding some tubes and not the others.”

The paper’s reference to Lamarck giraffes — a 19^th-century theory of how they evolved such long necks — isn’t entirely out of left field, Bets said.

“It works as a metaphor because you move your ‘leaves’ away and the tubes that can reach it continue growing fast, and those that cannot just die out,” she said. “Eventually, all the nanotubes that are just a tiny bit slow will ‘die.'”

Speed is only part of the strategy. In fact, they suggest nanotubes that are a little slower should be the target to assure a harvest of single chiralities.

Because nanotubes of different chiralities grow at their own rates, a batch would likely exhibit tiers. Chemically etching the longest nanotubes would degrade them, preserving the next level of tubes. Restoring the feedstock could then allow the second-tier nanotubes to continue growing until they are ready to be culled, Bets said.

“There are three or four laboratory studies that show nanotube growth can be reversed, and we also know it can be restarted after etching,” she said. “So all the parts of our idea already exist, even if some of them are tricky. Close to equilibrium, you will have the same proportionality between growth and etching speeds for the same tubes. If it’s all nice and clean, then you can absolutely, precisely pick the tubes you target.”

The Yakobson lab won’t make them, as it focuses on theory, not experimentation. But other labs have turned past Rice theories into products like boron buckyballs.

“I’m pretty sure every single one of our reviewers were experimentalists, and they didn’t see any contradictions to it working,” Bets said. “Their only complaint, of course, was that they would like experimental results right now, but that’s not what we do.”

She hopes more than a few labs will pick up the challenge. “In terms of science, it’s usually more beneficial to give ideas to the crowd,” Bets said. “That way, those who have interest can do it in 100 different variations and see which one works. One guy trying it might take 100 years.”

Yakobson added, “We don’t want to be that ‘guy.’ We don’t have that much time.”

Yakobson is the Karl F. Hasselmann Professor of Engineering and a professor of materials science and nanoengineering and of chemistry.

The National Science Foundation (1605848) and the Robert Welch Foundation (C-1490) supported the research.

So it was a weird puzzle when Duke physician Jason Stout M.D. encountered a Wake County TB outbreak in the mid-2000s in which the infection had spread beyond the lungs in six people. “Four out of six were in the bone,” Stout said. “That’s way more than 2 percent.”

The index case, the first person in Raleigh to have this strain of the disease, apparently contracted the bacterium in Vietnam, but he wasn’t feeling very sick and had been working around 400 people in his workplace.

“So it was prolonged exposure in a workplace,” said Stout, a Duke professor of medicine who tracked down and identified seven subsequent infections through contact tracing and health department records.

All eight people were treated with antibiotics and other co-workers received preventative care and then the strange outbreak went away. But the mystery was never really solved. “I’m an epidemiologist and clinical trial specialist and I was left scratching my head,” Stout said.

Until several years later when Stout had a chance conversation with his colleague and TB researcher David Tobin, Ph.D., an associate professor in molecular genetics and microbiology and immunology at Duke.

“We met up and we’re having coffee one day, and we’re talking about this,” Stout recalls. Academic medical centers like Duke routinely keep biological specimens, and Stout still had samples of the puzzling bug. “David said, ‘Well, give it to me and we’ll take a look.’ And then this amazing science came from that,” Stout said.

The amazing science is that Tobin’s lab, with several colleagues at Duke, Notre Dame, and the University of Texas, figured out precisely how and why these particular TB bacteria were so mobile. Their findings appear online Nov. 9 in the journal Cell.

“Certain infections tend to go certain places,” Stout said. “And the question is always, why does it do that?” In TB strains found in the Americas and Europe, the bacteria seem more likely to stay put in the lungs. But this strain was highly mobile.

Tobin’s team, led by Joseph Saelens, Mollie Sweeney and Gopinath Viswanathan, ran genetic sequencing on the Raleigh bug and found it most resembled an ancestral strain from a group of strains called lineage 1. In the U.S. we tend to see the modern strains, lineages 2, 3, and 4, but lineage 1 is still out there, mostly in South and Southeast Asia.

Mycobacterium tuberculosis generally infects a type of white blood cell called a macrophage, a highly mobile street sweeper cell that moves around looking for invaders and then engulfs them and chews them up. (Macrophage is Latin for big eater.) One part of the pathogenic bacteria’s toolkit is a set of unique chemical signals — secreted factors — to protect itself from the immune system and tell its macrophage host what to do.

Tobin’s team wanted to find the difference that allowed the Wake County bug’s macrophages to be more mobile and leave the lungs.

They compared genetic variants from 225 different strains of TB with particular attention to the genes for their secreted factors. What they found is a secretion factor called EsxM that was active in the Raleigh bacteria, but had been inactivated by a mutation in the modern strains.

Then, working with Craig Lowe, an evolutionary biologist and assistant professor of molecular genetics and microbiology at Duke, they looked at genetic sequencing from 3236 different strains of TB and found the pattern persisted: the modern strains have a silenced version of the EsxM secretion factor. “Over a few thousand strains, that really holds up,” Tobin said. “They’ve maintained that and presumably it’s something that’s evolutionarily advantageous to them.”

To further prove their point, the researchers put active versions of EsxM into safely attenuated versions of modern strains and watched as their macrophage hosts in a lab dish became more active and mobile. “We can see these changes in macrophage shape and structure and they become more migratory,” Tobin said. They also knocked out EsxM in a strain with the ancestral version and made the infected macrophages less mobile.

While being careful not to overstate their findings, Tobin said it would appear that the broadly distributed modern strains of TB benefit from staying within the lungs because of the way they spread through the air by breathing. Staying in the lungs would presumably give them a better launching pad to a new host.

Fortunately, the migratory TB strain hasn’t been seen again locally, Stout said, “hopefully because we did good work and got a lot of people preventative therapy.” But the mystery of its strange mobility has been solved.

“This may well have ended with me saying, ‘Wow, that was weird. There’s got to be something about the strain because all these patients had healthy immune systems,'” Stout said. “But the kind of science that I do is not the kind of science that David does. This is a wonderful example of people from different disciplines coming together to answer a really interesting clinical problem.”

This research was supported by the National Institutes of Health (AI-125517, AI-130236, AI-127115, AI-142127, AI-149147, AI-106872, 1DP2-GM146458-01, UC6-AI-058607).

The research conducted by Warren Vaz, an associate engineering professor on UWO’s Fox Cities campus, is the first to quantify the effects of pandemic disruptions on energy consumption trends across all 50 states and the District of Columbia.

“By capturing these trends, it is hoped that policymakers and utilities managers can be better prepared for future challenges,” Vaz said.

The study appeared recently in a special issue of the journal Energies focused on the economic and social consequences of the pandemic in the energy sector based on federal data available publicly.

“Lockdowns had a significant impact on energy consumption, about 30% in some cases,” Vaz said. “There were wide discrepancies in state’s consumption trends. Hawaii saw the largest decrease of about 26%, while Alaska at plus 4% was the only state to record an increase.”

Vaz attributed Hawaii’s large decrease in consumption to its isolation from other states and its dependence on the tourism industry, which was virtually shut down by the pandemic. Alaska’s small increase was likely due to a harsher winter in 2020 compared with 2019 as well as less strict lowdown practices across the state, he said.

Other results showed:

• Fossil fuel consumption decreased, particularly petroleum.
• Renewable energy increased but biofuels decreased, up to 88% in Nebraska.
• All major greenhouse gas emissions decreased.
• Carbon dioxide emissions fell by 10.4%.

In addition, Vaz compared the U.S. energy consumption in 2020 to that of other populous countries around the globe, which all showed decreases except for China and Iran, which each experienced slight increases.

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Materials provided by University of Wisconsin Oshkosh. Original written by Natalie Johnson. Note: Content may be edited for style and length.