Columbia researchers have now completed one of the most comprehensive studies of the cells inside melanoma brain metastases, uncovering details that could spur the development of a new generation of therapies.

“Brain metastases are extremely common in patients with melanoma, but we have only had a rudimentary understanding of the underlying biology,” says study leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. “Our study gives us new insights into the genomics, immunology, and spatial organization of these tumors and serves as a foundation for further discovery and therapeutic exploration.”

The findings were published online in Cell.

Innovative methods allow for deeper analysis

To begin understanding why melanoma brain metastases evade current treatments, Izar and his team needed to invent new techniques for performing single-cell genetic analyses of frozen brain samples.

“Such studies are typically performed on fresh brain samples, which are in short supply, drastically limiting the number of tumors that can be analyzed. In contrast, we have many frozen melanoma samples in our tissue bank,” Izar says.

“This innovation also allowed us to analyze tissues from patients who had not been treated, letting us see the biology of the tumor and its microenvironment before they’re altered by therapy.”

Therapeutic targets revealed

With metastatic tumors from several dozen melanoma patients, Izar and his colleagues analyzed the genes expressed in more than 100,000 individual cells.

The analysis revealed that melanoma brain metastases are more chromosomally unstable than melanoma metastases in other parts of the body.

“Chromosomal instability is the perpetual gain and loss of large chromosomal fragments; this process triggers signaling pathways that make cells more likely to spread and better able to suppress the body’s immune response,” says Johannes C. Melms, MD, a molecular postdoctoral fellow in the Izar lab and one of the study’s first authors.

These pathways could be important therapeutic targets. “Several experimental drugs that reduce chromosomal instability are going to be tested in humans soon,” Melms says. “We now have a rationale to evaluate these drugs in patients with melanoma metastases in the brain.”

Hiding from immune system

The researchers also uncovered two other characteristics of melanoma brain metastases that may help to hide the cells from the patient’s immune system. The researchers found that the metastases alter immune cells, specifically macrophages and T cells, in the tumor microenvironment in a way that promotes cancer growth. And they found that the cells adopt a neuronal-like state inside the brain.

“It’s possible that these changes help tumor cells adapt and survive in their new environment while avoiding ensuing immune responses,” says Jana Biermann, PhD, a computational postdoctoral fellow in the Izar lab and one of the study’s first authors.

First spatial analysis

Finally, the researchers were able to perform the first spatial analysis of melanoma brain metastases, by analyzing and piecing together analyses of multiple slices of the tumors much the way a CT scanner creates three-dimensional images.

“It turns out there’s quite a bit of geographic variability from one tumor to the next and even within a given tumor, in terms of metabolic and immune pathways,” says Izar.

“We are just beginning to understand how to think of spatial variability, but it’s clear that this will be key to increasing chances for complete tumor responses to novel therapies.”

Biological organisms and tissues exhibit a constant turnover of cellular material; for instance, to maintain tissue integrity, in case of tumor growth, or for survival of bacterial communities. Intuitively, cell types which are able to proliferate the fastest or die less frequently in a given environment will dominate the confined space within an organism or compartment. “However, these traditional factors do not remain the only ones determining competitive fitness, when taking into account also the debris left behind by dying cells,” Ramin Golestanian, managing director at the MPI-DS says. In their study, the researchers from the department of Living Matter Physics showed that cell types being cleared out faster after death have an advantage that can make them the dominant species.

The scientists created a model to simulate growing cells filling a limited amount of space until mechanical pressure builds up and they reach a state in which division and cell death balance each other. “We wanted to find out what effect dead matter has on the growth of a living system. For this, we designed a simple model that is one of the first to explicitly consider the mechanical effects of dead cells,” Yoav Pollack, first author of the study, describes the approach. “We then analyzed two cell types differing exclusively in the dead-matter removal rate and tracked the proportion of both populations over time. To our excitement, we observed a clear impact on the overall fitness, leading to an advantage for the cell type whose dead cells are removed more quickly,” he explains.

Making room for new cells

At first sight, the removal of dead material might seem disconnected from the formation of new cells — or even counterproductive as it opens up space for other species to invade. But the model shows that by clearing out debris faster, the amount of alive compared to dead cells increases. Overall, this results in a more responsive growth when a species is presented with opportunities for expansion. While this is of little consequence in a homogeneous cell population of the same type, it makes a difference at the interface where different cell types are competing for space. The population with the higher clear-out rate is more likely to have a living cell in the vicinity available to fill vacated space through proliferation. In this way, the higher proportion of living cells gives a competitive advantage.

“In simplified terms, one could say that clearing out and occupying new space is more advantageous than holding on to already occupied space,” comments group leader Philip Bittihn. “In certain cases, this new contribution to competition might also explain why biological tissues and organisms evolved to use specific cell removal mechanisms; ones that are more efficient compared to the alternatives,” he concludes.

As this effect has now been described for the first time, it opens up several new lines of investigation, such as analyzing the extent to which it contributes to the overall fitness in relation to other fitness factors. Yet, the model demonstrates that cleaning up after yourself does indeed pay off for cells.

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Materials provided by Max Planck Institute for Dynamics and Self-Organization. Note: Content may be edited for style and length.

When you want advice to achieve something, whom would you rather ask: the top performer in that area or someone barely scraping by? Most people would choose the top performer. That person’s advice, however, may not be any more helpful.

“Skillful performance and skillful teaching are not always the same thing, so we shouldn’t expect the best performers to necessarily be the best teachers as well,” said David Levari (Harvard Business School), lead author of a recent Psychological Science article.

Across four studies, he and coauthors APS Fellows Daniel T. Gilbert (Harvard University) and Timothy D. Wilson (University of Virginia) found that top performers don’t give better advice than other performers, at least in some domains. Rather, they just give more of it.

“People seem to mistake quantity for quality,” the researchers wrote. “Our studies suggest that in at least in some instances, people may overvalue advice from top performers.”

In the first study, Levari and colleagues set out to determine whether people believe an advisor’s performance is a robust indicator of the quality of their advice.

More than 1,100 participants, sourced through Amazon Mechanical Turk, were told they would be playing a game called Word Scramble and then answering questions about it. Shown a board of letters, participants were given 60 seconds to form as many words as possible. Participants played three rounds, each time with a different board of letters.

The researchers then asked participants to choose which advisors they would prefer to receive advice from to get better at the task. Participants showed a strong preference for the best performers, regardless of how the question was asked (i.e., in a free-choice or forced-choice format).

In the second study, the researchers explored whether the best performers did indeed give the best advice. They asked 100 “advisors” to play six rounds of Word Scramble, write advice for future players, and rate the quality of their own advice. The best performers believed they had given the best advice.

In the same study, another 2,085 participants were randomly assigned to either an advice or a no-advice condition. After playing one round of Word Scramble, participants in the advice condition received direction from a random advisor, then played five more rounds. The no-advice participants played six rounds without feedback. Advisees performed better after receiving advice, and they tended to perform better with each subsequent round. But the advice from the best performers was no more helpful, on average, than the advice from the other performers. The researchers conducted a similar study with darts, showing a similar pattern of results.

“In our experiments, people given advice by top performers thought that it helped them more, even though it usually didn’t. Surprisingly, they thought this even though they didn’t know anything about the people who wrote their advice,” said Levari.

The researchers conducted two more studies to understand why the advice from better performers seemed better. Two undergraduate research assistants who were blind to the study’s purposes and hypotheses coded the advice for seven properties: authoritativeness, actionability, articulateness, obviousness, number of suggestions, “should” suggestions, and “should not” suggestions. Each property was analyzed for its perceived helpfulness and perceived improvement.

Only one property — number of suggestions — consistently predicted both the perceived helpfulness and the perceived improvement of the advice. However, there was no correlation between the number of suggestions and the efficacy of the advice.

“Top performers didn’t write more helpful advice, but they did write more of it, and people in our experiments mistook quantity for quality,” Levari told APS.

So, why wasn’t the advice more helpful? Levari and colleagues have a few ideas.

First, skilled performers may overlook fundamental advice because “natural talent and extensive practice have made conscious thought unnecessary. … A natural-born slugger who has played baseball every day since childhood may not think to tell a rookie about something they find utterly intuitive, such as balance and grip,” they wrote.

Second, top performers may not be skilled communicators. “Even when an excellent performer does have explicit information to share, they may not be especially adept at sharing it,” the researchers wrote. Finally, a large quantity of advice may be more than what can realistically be implemented.

“We spend a lot of time and money looking for good advice, whether from coworkers and coaches, teachers and tutors, or friends and family,” said Levari. “The next time you get advice, you may want to think less about how much of it there was, and more about how much of it you could actually use.”

Now, a collaboration between Cornell researchers and the U.S. Army Research Laboratory has leveraged hydrodynamic and magnetic forces to drive a rubbery, deformable pump that can provide soft robots with a circulatory system, in effect mimicking the biology of animals.

“These distributed soft pumps operate much more like human hearts and the arteries from which the blood is delivered,” said Rob Shepherd, associate professor of mechanical and aerospace engineering in the College of Engineering, who led the Cornell team. “We’ve had robot blood that we published from our group, and now we have robot hearts. The combination of the two will make more lifelike machines.”

The group’s paper, “Magnetohydrodynamic Levitation for High-Performance Flexible Pumps,” published July 11 in Proceedings of the National Academy of Sciences. The paper’s lead author was postdoctoral researcher Yoav Matia.

Shepherd’s Organic Robotics Lab has previously used soft material composites to design everything from stretchable sensor “skin” to combustion-driven braille displays and clothing that monitors athletic performance — plus a menagerie of soft robots that can walk and crawl and swim and sweat. Many of the lab’s creations could have practical applications in the fields of patient care and rehabilitation.

Like animals, soft robots need a circulatory system to store energy and power their appendages and movements to complete complex tasks.

The new elastomeric pump consists of a soft silicone tube fitted with coils of wire — known as solenoids — that are spaced around its exterior. Gaps between the coils allow the tube to bend and stretch. Inside the tube is a solid core magnet surrounded by magnetorheological fluid — a fluid that stiffens when exposed to a magnetic field, which keeps the core centered and creates a crucial seal. Depending on how the magnetic field is applied, the core magnet can be moved back and forth, much like a floating piston, to push fluids — such as water and low-viscosity oils — forward with continuous force and without jamming.

“We’re operating at pressures and flow rates that are 100 times what has been done in other soft pumps,” said Shepherd, who served as the paper’s co-senior author with Nathan Lazarus of the U.S. Army Research Laboratory. “Compared to hard pumps, we’re still about 10 times lower in performance. So that means we can’t push really viscous oils at very high flow rates.”

The researchers conducted an experiment to demonstrate that the pump system can maintain a continuous performance under large deformations, and they tracked the performance parameters so future iterations can be custom-tailored for different types of robots.

“We thought it was important to have scaling relationships for all the different parameters of the pump, so that when we design something new, with different tube diameters and different lengths, we would know how we should tune the pump for the performance we want,” Shepherd said.

Postdoctoral researcher Hyeon Seok An contributed to the paper.

The research was supported by the U.S. Army Research Laboratory.

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Materials provided by Cornell University. Original written by David Nutt, courtesy of the Cornell Chronicle. Note: Content may be edited for style and length.

New research led by researchers at Massachusetts General Hospital (MGH) with Ugandan and Kenyan colleagues published in The Lancet Global Health indicates that the best available chemotherapy for Kaposi sarcoma, which is infrequently used in Africa, would improve clinical outcomes and be cost-effective at its current price compared with therapies that are most frequently provided in the region.

For treating Kaposi sarcoma, different chemotherapy regimens vary in effectiveness, toxicity, and cost. Paclitaxel and pegylated liposomal doxorubicin (PLD) are the most effective and least toxic therapies, but they are more expensive than other options.

“Despite clinical guidelines that endorse the more effective and better tolerated chemotherapy regimens for Kaposi sarcoma, too many people with HIV are still treated with less effective chemotherapy because of logistics and cost,” says senior author Emily P. Hyle, MD, a physician-investigator at the Medical Practice Evaluation Center at Mass General and Assistant Professor of Medicine at Harvard Medical School.

Hyle and first author Esther Freeman, MD, PhD, Director of Clinical Innovation & Education for the Center for Global Health at Mass General and Associate Professor of Dermatology at Harvard Medical School, led an international collaboration to perform a cost-effectiveness analysis of different chemotherapy regimens for treating advanced Kaposi sarcoma in people with HIV on antiretroviral therapy in Kenya.

They found that paclitaxel would improve clinical outcomes and be very cost-effective at its current price compared with bleiomycin-vincristine, which is the most frequently used treatment for advanced Kaposi sarcoma in East Africa.

Over five years, using paclitaxel instead of bleomycin-vincristine to treat 19,150 people with HIV and advanced Kaposi sarcoma in Kenya would save 6,400 years-of-life and would increase cumulative healthcare expenditures by approximately $3.7 million, mostly from HIV-related costs due to a prolonged life expectancy among patients.

At current estimates, PLD would further extend life expectancy but would not be cost-effective compared with paclitaxel; however, this could be addressed if its price was reduced. “PLD is even better tolerated than paclitaxel, and our analysis showed that it would be cost-effective compared with paclitaxel if a 44% price reduction was achieved,” says Hyle.

At an individual level, paclitaxel would improve life expectancy by 4.2 years compared with bleomycin-vincristine, and PLD would improve life expectancy by an additional 0.6 years compared with paclitaxel.

“By encouraging hospitals, health systems, and others to reach for paclitaxel as first line treatment for HIV-associated Kaposi’s sarcoma, we can save lives. The majority of deaths from cancer in the world are in low and middle income countries, and it is our duty to advocate for the highest quality of care, which in this case, is also the most cost-effective,” says Freeman. “We also need to advocate for drug companies to reduce the price of effective chemotherapies in sub-Saharan Africa, similarly to what has been done for antiretroviral therapy pricing in the past, so that more people can have access to life-saving treatment.”

Additional study co-authors include, Nicole C. McCann, BA, Aggrey Semeere, MBChB, MMed, Krishna P. Reddy, MD, Miriam Laker-Oketta, MBChB, Helen Byakwaga, MBChB, PhD, Pamela P. Pei, PhD, Maya E. Hajny Fernandez, BA, Samson Kiprono, MBChB, MMed, Naftali Busakhala, MBChB, Jeffery N. Martin, MD, Toby Maurer, MD, Ingrid V. Bassett, MD, and Kenneth A. Freedberg, MD.

This work was supported by the National Institutes of Health, the Jerome and Celia Reich Endowed Scholar Award, and the Weissman Family MGH Research Scholar Award.

Stars are born when a large cloud of gas and dust collapses in on itself. The leftover material that doesn’t make it into the star ends up circling around it, not unlike how water swirls around the drain before falling in. This swirling mass of gas and dust is called a protoplanetary disc, and it’s where planets like the Earth are born.

Protoplanetary discs are often thought to be shaped like dinner plates — thin, round and flat. However, recent telescope images from the Atacama Large Millimeter/Submillimeter Array (ALMA) show that this is not always the case. Some of the discs seen by ALMA have shadows on them, where the part of the disc closest to the star blocks some of the stellar light and casts a shadow onto the outer part of the disc. From this shadow pattern, it can be inferred that the inner part of the disc is oriented completely differently to the outer part, in what is called a broken disc.

In this research, the team used high performance computers to run three-dimensional simulations of a broken disc. The team then produced a mock observation, modelling what such a disc would look like if it were to be observed through a telescope, and how it would change over time.

As the inner disc moved through the gravitational pull of the central star, the shadow it cast moved across the outer disc. But instead of the shadow pattern moving around the disc like a clock-hand as expected, it rocked back and forth with a see-saw-like motion. So although the inside disc kept turning in the same direction, its shadow looked like it was rocking forwards and backwards. The team suggest this is caused by a geometric projection effect, which is likely to occur in all broken discs.

Our research is important because it bridges the gap between theory and observations. In the light of new observations from telescopes like JWST, our cutting-edge numerical techniques mean we have a variety of tools to interpret these data and to learn more about how planets are born.

Rebecca says: “JWST promises to give us a look at embryonic planetary systems in unprecedented detail, and with our new models we’ll be able to find out a lot more about the birth of planets.”

Video: https://youtu.be/jGYLuEx-I78

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Materials provided by Royal Astronomical Society. Note: Content may be edited for style and length.