Mutations in the potent oncogene known as KRAS occur in about one in four patients with NSCLC, and approximately 13% of NSCLC patients’ tumors are driven by a specific KRAS mutation called G12C. KRAS mutations have long been considered nearly impossible to attack with targeted drugs after many years of research attempts. However, in 2021 a targeted drug, sotorasib, became the first drug approved by the Food and Drug Administration for NSCLC patients whose tumors harbored the G12C mutation, based on a clinical trial showing a 36% response rate in those patients after having initially received treatment with chemotherapy and a PD-1 immune checkpoint inhibitor.

Reporting the results of a new phase 2 trial presented at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO) and simultaneously published in the New England Journal of Medicine, investigators led by Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber, showed that treatment with a different KRAS^G12C mutant inhibitor, adagrasib, yielded a 42.9% objective response rate and a median overall survival rate of 12.6 months in a cohort of 112 patients who had previously received both chemotherapy and immunotherapy with a PD-1 immune checkpoint blocker. Notably, adagrasib treatment also achieved a 33.3% response rate in 33 patients who had stable metastatic lesions in the brain and central nervous system that had spread from the lung tumors.

“These data highlight that inhibiting KRAS^G12C can lead to clinically meaningful benefits to NSCLC patients with this form of lung cancer,” said Jänne. “Brain metastases are challenging to treat and having a pharmacologic agent that shows activity in this setting is an advancement and movement in the right direction.”

Patients with KRAS^G12C have had few options after initial chemotherapy and immunotherapy stopped working. In the new clinical trial of adagrasib, median progression-free survival (the time patients lived before the cancer began to worsen again) was 6.5 months and the median response duration was 8.5 months. The oral drug was taken twice a day.

Because the KRAS^G12C tumor cells typically continue to proliferate, researchers believe sustained inhibition with drugs may be necessary. Consequently, adagrasib was optimized for favorable properties including a long half-life (23 hours) and ability to penetrate the central nervous system. Clinical activity with adagrasib has been shown in patients with other KRAS^G12C tumors, including colorectal, pancreatic, biliary tract, and other cancers.

This clinical trial was sponsored by Mirati Therapeutics, Inc.

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS^G12C mutation (Abstract 9002) will be presented by Alexander I. Spira, MD, PhD, Virginia Cancer Specialists Research Institute, during the Lung Cancer — Non-Small Cell Metastatic Oral Abstract Session on Friday, June 3, 2022.

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Researchers at The University of Texas at Austin and Penn State University have created a new type of fiber that can perform like a muscle actuator, in many ways better than other options that exist today. And, most importantly, these muscle-like fibers are simple to make and recycle.

In a new paper published in Nature Nano, the researchers showed that these fibers, which they initially discovered while working on another project, are more efficient, flexible and able to handle increased strain compared to what’s out there today. These fibers could be used in a variety of ways, including medicine and robotics.

“You can basically build a limb from these fibers in a robot that responds to stimuli and returns power, instead of using a mechanical motor to do this, and that’s good because then it will have a softer touch,” said Manish Kumar, an associate professor in the Cockrell School of Engineering’s Department of Civil, Architectural and Environmental Engineering and one of the lead authors of the paper.

This kind of robotic arm could be used in an assistive exoskeleton to help people with weak arms regain movement and strength. Another potential application, the researchers say, could be a sort of “self-closing bandage” that could be used in surgical procedures and naturally degrade inside the body once the wound heals.

“Actuators are any material that will change or deform under any external stimuli, like parts of a machine that will contract, bend, or expand,” said Robert Hickey, assistant professor of materials science and engineering at Penn State and corresponding author on the paper. “And for technologies like robotics, we need to develop soft, lightweight versions of these materials that can basically act as artificial muscles. Our work is really about finding a new way to do this.”

The fiber material is known as a block co-polymer. Creating it only requires putting the polymer in a solvent and then adding water. One part of the polymer is hydrophilic (attracted to water), while the other part is hydrophobic (resistant to water). The hydrophobic parts of the polymer group together to shield themselves from the water, creating the structure of the fiber.

Similar existing fibers require an electric current to stimulate the reactions that bond parts together. This chemical cross-linking is harder to make happen, compared to the researchers’ new fiber, which is a mechanical reaction, meaning the parts take care of most of the work themselves. Another added bonus is it is simple to reverse the process and return the pieces of the fiber to their original states.

“The ease of making these fibers from the polymer and their recyclability are very important, and it’s an aspect that much of the other complicated artificial muscle research doesn’t cover,” Kumar said.

The researchers found their fibers were 75% more efficient in terms of converting energy to movement, able to handle 80% more strain and could rotate with more speed and force than current actuators. And it can stretch to more than 900% of its length before it breaks.

The discovery came while the researchers were working on something else. They were trying to use these polymers to make membranes for water filtration. However, the structures they made were too long for membranes. They stretched out to five times their original length and held that length. The researchers noticed that these characteristics were similar to muscle tissue, so they decided to shift the focus.

The researchers are early on in the project, and they next plan to learn more about the structural changes of the polymer and improve some of the actuation properties, including energy density and speed. They also may use this same design technique to create actuators that respond to different stimuli, such as light.

Venkat Ganesan, a professor in the McKetta Department of Chemical Engineering and Rui Huang, professor in the Department of Aerospace Engineering and Engineering Mechanics, are the other Texas Engineers on the team. Also on the team from Penn State are Chao Lang, Elisabeth Lloyd, Kelly Matuszewski and Yifan Xu. The Air Force Office of Scientific Research, National Science Foundation and Penn State funded the research.

Initially developed on an iMac computer, the new modeling approach had already garnered attention for successfully recreating the unexpected eruption of Alaska’s Okmok volcano in 2008. Gregg’s team, based out of the University of Illinois Urbana-Champaign and the National Center for Supercomputing Applications, wanted to test the model’s new high-performance computing upgrade, and Geist’s Sierra Negra observations showed signs of an imminent eruption.

“Sierra Negra is a well-behaved volcano,” said Gregg, the lead author of a new report of the successful effort. “Meaning that, before eruptions in the past, the volcano has shown all the telltale signs of an eruption that we would expect to see like groundswell, gas release and increased seismic activity. This characteristic made Sierra Negra a great test case for our upgraded model.”

However, many volcanoes don’t follow these neatly established patterns, the researchers said. Forecasting eruptions is one of the grand challenges in volcanology, and the development of quantitative models to help with these trickier scenarios is the focus of Gregg and her team’s work.

Over the winter break of 2017-18, Gregg and her colleagues ran the Sierra Negra data through the new supercomputing-powered model. They completed the run in January 2018 and, even though it was intended as a test, it ended up providing a framework for understanding Sierra Negra’s eruption cycles and evaluating the potential and timing of future eruptions — but nobody realized it yet.

“Our model forecasted that the strength of the rocks that contain Sierra Negra’s magma chamber would become very unstable sometime between June 25 and July 5, and possibly result in a mechanical failure and subsequent eruption,” said Gregg, who also is an NCSA faculty fellow. “We presented this conclusion at a scientific conference in March 2018. After that, we became busy with other work and did not look at our models again until Dennis texted me on June 26, asking me to confirm the date we had forecasted. Sierra Negra erupted one day after our earliest forecasted mechanical failure date. We were floored.”

Though it represents an ideal scenario, the researchers said, the study shows the power of incorporating high-performance supercomputing into practical research. “The advantage of this upgraded model is its ability to constantly assimilate multidisciplinary, real-time data and process it rapidly to provide a daily forecast, similar to weather forecasting,” said Yan Zhan, a former Illinois graduate student and co-author of the study. “This takes an incredible amount of computing power previously unavailable to the volcanic forecasting community.”

Bringing the moving parts into place to produce a modeling program of this strength requires a highly multidisciplinary approach that Gregg’s team did not have access to until working with NCSA.

“We all speak the same language when it comes to the numerical multiphysics analysis and high-performance computing needed to forecast mechanical failure — in this case of a volcanic magma chamber,” said Seid Koric, the technical assistant director at NCSA, a research professor of mechanical sciences and engineering and a co-author of the study.

With Koric’s expertise, the team said they hope to incorporate artificial intelligence and machine learning into the forecasting model to help make this computing power available to researchers working from standard laptop and desktop computers.

The results of the study are published in the journal Science Advances.

Geist is a program director at the National Science Foundation and a professor of geology at Colgate University. Falk Amelung of the University of Miami; Patricia Mothes of Instituto Geofísico Escuela Politecnica Nacional, Ecuador; and Zhang Yunjun of the California Institute of Technology also contributed to this research.

The National Science Foundation, NASA and NCSA supported this study.

In addition to showing stable personality, zebra finches innovated solutions to novel foraging tasks, where sometimes success was related to personality type.

The article was written by Lisa Barrett and Jessica Marsh, of the University of Wyoming; Neeltje Boogert, of the University of Exeter; Christopher Templeton, of Pacific University Oregon; and Sarah Benson-Amram, of the University of British Columbia, formerly of UW and the leader of UW’s Animal Behavior and Cognition Lab.

The authors of the paper tested 41 zebra finches at UW from 2016-18 to measure individual differences in the birds’ behavior through time.

The authors measured a host of traits — dominance, boldness, activity, risk-taking, aggressiveness and obstinacy — in the short term (two weeks) and the long term (two years), using standardized personality tests that had been established in the literature.

To assess boldness, for example, the authors placed a novel object in an enclosure with a bird that had been feeding and measured how long it took the bird to resume feeding in the presence of the novel object. To assess dominance, the authors recorded interactions of groups of birds at a single feeder. The authors measured obstinacy — or docility — while handling the birds by counting the number of escape attempts the birds made beneath a net.

“We were interested to see if personality would remain stable or if individuals would be flexible in their behavior over time,” says Barrett, the lead author. “Repeating our tests over two years with the exact same birds allowed us to answer that question.”

Barrett and colleagues found that not all traits were equally consistent. Of the traits they measured, many traits were consistent over two weeks, but only boldness and obstinacy were consistent over two years.

Next, the researchers tested whether personality related to problem-solving success on three novel tasks previously used with zebra finches.

“Since individuals vary in their personality type and in their cognitive ability, we wanted to see if these two sources of variation were linked,” says Marsh, who was an undergraduate at the time she worked on the study.

The authors found that problem-solving success related to boldness, dominance and obstinacy. For example, less dominant birds were more likely to solve two of the tasks compared to their more dominant counterparts. This result provides support for the “necessity drives innovation” hypothesis, which states that less dominant individuals — who receive fewer resources due to competition with their flock mates — may need to innovate new ways to access food.

“In this work, we leveraged a comprehensive suite of personality tests and multiple cognitive tasks, and we carried out our work over a longer period of time than traditional tests,” Benson-Amram says. “This allowed us to uncover the importance of measuring multiple traits for understanding the link between personality and problem-solving.”

Because not all traits were consistent over time or related to problem-solving performance, the authors emphasize that future research should focus on uncovering which measures of personality are most important for innovation — and why some traits are more plastic than others.

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The researchers studied condensin, a protein complex critical to the process of chromosome formation. Although this complex was discovered more than three decades ago, its mode of action remained largely unexplored. In 2018, researchers from the Häring group at EMBL Heidelberg and their collaborators showed that condensin molecules create loops of DNA, which may explain how chromosomes are formed. However, the inner workings by which the protein complex achieves this feat remained unknown.

“We have been working on this problem for a long time. But only now, by combining different experimental approaches, we have found an answer to this long-standing question,” said Christian Häring, former Group Leader at EMBL Heidelberg and now Professor at the Julius-Maximilians-Universität Würzburg.

Through meticulously designed experiments, some of which involved observing and manipulating single condensin molecules while they were in the process of forming DNA loops, the researchers found how different parts of the complex collectively act as a molecular machine: one part holds the DNA steady, like an anchor, whereas the other acts as a motor which moves the DNA forward, thus creating a wide loop.

Like other motor proteins, condensin takes ‘steps’ along the DNA, burning cellular energy in the form of ATP while doing so. However, these steps are more than 500 times longer than the steps taken by other DNA motor proteins, even though the amount of energy used is roughly the same. “It’s like a formula one racing car with the energy efficiency of an e-bike,” said Indra Shaltiel, the study’s first author.

“Advancements in cryo-electron microscopy techniques allowed us to visualise this complex mechanism in unprecedented detail,” said Sebastian Eustermann, Group Leader at EMBL Heidelberg and a senior author of the study published in Science. “We could capture condensin in action and derived a molecular choreography of how ATP fuels its motor activity — a key step towards understanding DNA loop formation. Similar loops and related molecular machines are involved in diverse genomic processes, including the control of how genes are switched on and off in between cell divisions. Consequently, our findings may have even wider implications.”

Condensins belong to one of the most evolutionarily ancient families of chromosomal proteins. The discovery of this new mechanism thus opens up a whole new field of study.

“Members of the class of motor proteins condensin belongs to are presumably essential for all life on earth,” Häring said. “It is obvious we are only just starting to understand their roles and how they might be affected in human conditions.”

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For years, experts have known that a thin layer of cells in the neocortex — the part of the brain that controls higher order functions such as cognition, perception and language — is directly correlated with intelligence in mammals. The larger the surface area of the neocortex, the more highly developed the mental capacity of that organism. For example, the thickness of the human neocortex is only about three-fold greater than that of mice. Yet, the surface area of the human neocortex is 1,000-fold greater than that of mice. Malformations in this part of the brain progress to developmental deficits that include autism spectrum disorders and intellectual disabilities.

What’s not understood is how evolutionary expansion of this part of the brain occurs preferentially in favor of expanding surface area of the neocortex at the expense of increasing its thickness. How the earliest populations of neural stem cells — the building blocks of the brain — distribute themselves is a key factor in this process.

“There are many, what we’ll call, individual processing units that are horizontally arranged in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” said Vytas A. Bankaitis, Distinguished Professor at the College of Medicine, E.L. Wehner-Welch Foundation Chair in Chemistry, and co-author of this study, which was published in Cell Reports. “The question is, why is the neocortical surface area so much greater relative to its thickness as one climbs up the mammalian evolutionary tree? Why do neural stem cells spread themselves in a lateral direction as they proliferate and not pile on top of each other?”

This question is key because when the cells do not spread out, but instead pile up, it creates a thicker neocortex with a smaller surface area — a characteristic that has been observed in cases of intellectual disability and even autism.

“One of the most studied genetic causes of intellectual disability is a mutation in a gene that was originally called LIS1,” said Zhigang Xie, assistant professor at the College of Medicine and co-author of the study. “This genetic mutation will cause a smooth brain, which is associated with intellectual disability. And one typical observation is that the neocortex of the patient is thicker than normal. There are also very recent studies that identify common differences in the brain of autism that include abnormally thickened regions of the neocortex in those individuals.”

Scientists have known for some time that as neural stem cells divide, their nuclei move up and down within their anatomical space as a function of the cell cycle, a process called interkinetic nuclear migration. They do so by employing a cytoskeletal network that acts like train tracks with engines that move the nuclei up or down in a closely regulated manner. Although several ideas have been proposed, it remains an enigma why the nuclei move in this way, how this network of train tracks is controlled, and what role interkinetic nuclear migration plays in development of the neocortex.

In their study, Xie and Bankaitis provide answers to these questions.

As for why, Bankaitis explains that when there are so many cells so close together in the embryonic stage of neocortical development, the movement of their nuclei up and down causes opposing upward and downward forces that spreads the dividing neural stem cells out.

“Think about a tube of toothpaste,” Bankaitis said. “If you were to take that toothpaste tube, put it between your hands, push up from the bottom and push down from the top, what would happen? It would flatten and spread out. That’s essentially how this works. You have an upward force and a downward force caused by the movement of the nuclei that spreads these cells out.”

Xie and Bankaitis also demonstrate how the cells do this by linking together several distinct pathways that cooperate to “tell” the newborn neural stem cells where to go.

“I think for the first time, this really puts together molecules and signaling pathways that indicate how this process is controlled and why it would be linked or associated with neurodevelopmental deficiencies,” Bankaitis said. “We have taken a biochemical pathway, linked it to a cell biological pathway, and linked it to a signaling pathway that talks to the nucleus to promote the nuclear behavior that generates a force that develops a complicated brain. It’s now a complete circuit.”

The results of this study uncover an important factor in the underlying causes of autism risk, intellectual disabilities and neural tube birth defects. The new knowledge on the basic principles regulating the shape of the neocortex will also help the design of in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.

“While there might prove to be many reasons why a neocortex thickens instead of spreads, our work provides a new perspective on why patients with autism and intellectual disabilities often display a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a core regulator of nuclear migration, including the interkinetic nuclear migration that we study in this work, supports the conclusions we reach in this paper.”

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Materials provided by Texas A&M University. Original written by Lindsey Hendrix. Note: Content may be edited for style and length.

Key Step Towards a Treatment

For the past 12 years, Meredith Hawkins, M.D., M.S., founding director of Einstein’s Global Diabetes Institute, has spearheaded an international collaborative effort aimed at finding the underlying metabolic defects that lead to malnutrition-related diabetes — a crucial step towards finding effective treatments. In the first comprehensive study of individuals with this poorly understood disease, Dr. Hawkins and colleagues have shown that malnutrition-related diabetes is significantly different metabolically from T1D and T2D and should be considered a distinct type of diabetes. Their findings were published today in Diabetes Care.

“Current scientific literature offers no guidance on managing malnutrition-related diabetes, which is rare in high-income nations but exists in more than 60 low- and middle-income countries,” said Dr. Hawkins, professor of medicine and the Harold and Muriel Block Chair in Medicine at Einstein. “The doctors in those countries read Western medical journals, so they don’t learn about malnutrition-related diabetes and don’t suspect it in their patients. We hope our findings will increase awareness of this disease, which is so devastating to so many people, and will pave the way for effective treatment strategies.”

Investigating Insulin’s Role

The research was conducted at the Christian Medical College in Vellore, India, in collaboration with Dr. Hawkins and other members of the Global Diabetes Institute. Using state-of-the-art techniques for assessing insulin secretion and insulin action, the researchers performed in-depth metabolic evaluations on 20 males aged 19 to 45 identified as likely to have malnutrition-related diabetes. For comparison, groups of individuals with T1D, T2D, as well as healthy controls underwent the same metabolic tests. The study was limited to male participants to minimize sex-specific variability and because males account for about 85% of people who develop malnutrition-related diabetes.

“We used highly sophisticated techniques to rigorously and carefully study these individuals — and our conclusions differ from earlier clinical observations,” said Dr. Hawkins.

More specifically, earlier findings had suggested that malnutrition-related diabetes stemmed from insulin resistance. (The hormone insulin enables glucose in the blood to enter the body’s cells to be used for energy; in insulin resistance, glucose in the blood rises to toxic levels because cells no longer respond to a person’s own insulin.) “But it turns out,” said Dr. Hawkins, “that people with malnutrition-related diabetes have a very profound defect in insulin secretion, which wasn’t recognized before. This new finding totally revolutionizes how we think about this condition and how it should be treated.”

The good news, according to Dr. Hawkins, is that many new drugs have recently become available for treating T2D, some of which boost insulin secretion from the pancreas — raising the possibility of finding safe and effective ways of treating the condition.

“Diabetes has become a true global pandemic,” Dr. Hawkins noted. “One in 10 adults worldwide has the disease, and three-quarters of them — some 400 million people — live in low- and middle-income countries,” she said. “In those countries where it’s been studied, the prevalence of malnutrition-related diabetes among people with diabetes is about 20%, meaning that about 80 million people may be affected worldwide. For comparison, an estimated 38 million people are now living with HIV/AIDS. So we clearly need to learn a lot more about malnutrition-related diabetes and how best to treat it.”

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