JUNE 8, 2021, NEW YORK – A study conducted by researchers at the Ludwig Center at Harvard has demonstrated how a drug screening method known as dynamic BH3 profiling can be used to quickly identify potentially effective combinations of existing drugs for personalized cancer therapy.
“We know that cancer cells and healthy cells have different metabolisms,” said Ludwig Harvard investigator Anthony Letai who, with former postdoctoral researcher Veerle Daniels, led the study reported in the current issue of Science Signaling. “Using BH3 profiling, we found a specific metabolic dependency in triple negative breast cancer cells obtained from a patient that we could target with an existing drug, making the cells more susceptible to death and priming them for a second targeted drug that could then trigger their death.”
Daniels, Letai and colleagues also showed that the strategy suppresses growth of triple negative breast cancer (TNBC) in mice bearing patient-derived tumors.
Though tumors often have unique metabolic adaptations on which they depend, specifically targeting those vulnerabilities with drugs has proved challenging. Such drugs have often failed in clinical trials because they were poorly targeted or too toxic at the doses required to kill cancer cells when used as single agents.
“We wanted to see which of the drugs known to perturb metabolism would bring the TNBC cells closer to dying, but leave normal cells unaffected,” said Daniels. The researchers reasoned that such cells could then be selectively targeted by existing therapies known as BH3 mimetics to push them over the edge. Because the initial priming treatment requires low doses of the drug, this strategy could lower the risk of toxicities that have troubled the development of drugs targeting cancer metabolism.
Therapy often induces in cancer cells a type of programmed death known as apoptosis, which is orchestrated by an elaborate protein machinery. Cells, however, also produce anti-death proteins that inhibit key elements of that machinery. Whether a stressed cell dies or survives depends on the balance of pro-death and anti-death proteins, and cancer cells tend to produce large quantities of the latter to escape apoptosis and resist therapy.
BH3 mimetics inhibit anti-death proteins, tipping the balance in favor of cell suicide. Notably, one BH3 mimetic has already been approved for the treatment of certain blood cancers, and other such drugs are in various stages of development.
Dynamic BH3 profiling (DBP), developed in Letai’s laboratory, measures that same balance of pro-death and anti-death proteins to gauge how primed a patient’s tumor cells are for apoptosis following exposure to a drug. It thus represents a potentially rapid and unbiased method for screening hundreds of drugs at a time to find those most likely to treat a given patient’s tumors.
Daniels, Letai and colleagues used DBP to examine a “library” of 192 compounds that perturb metabolism–developed in the laboratory of Ludwig Harvard Co-Director Joan Brugge–for their effects on normal and TNBC cells. Eight disrupted cancer cell metabolism but left normal cells unperturbed.
Two of these drugs target an enzyme known as NAMPT, which participates in one of three biochemical pathways that produce NAD+, a molecule of critical importance to metabolism. Some sensitive TNBC cell lines, the researchers showed, were dependent on the pathway involving NAMPT. They also ran a DBP screen to find out which specific anti-death proteins the TNBC cells depended on for survival following NAMPT inhibition. They used this information to identify the most effective BH3 mimetic drug to use in combination with NAMPT inhibitors.
Using two mouse models of patient-derived TNBC tumors developed in Brugge’s lab, the researchers showed that only the mice bearing NAMPT-dependent tumors responded to a combination of the NAMPT inhibitor and the BH3 mimetic. They propose that the NAMPT inhibitor, which proved too toxic as a single agent, might be repurposed as a combination therapy given at lower doses with BH3 mimetics.
“What we’ve shown overall is that we can use DBP to find metabolic regulators of apoptotic priming and specific anti-apoptotic dependencies in tumors–and so identify powerful combinations of metabolic compounds and BH3 mimetics for therapy,” said Daniels.
Letai’s laboratory is using DBP to methodically identify other drug combinations for the treatment of a variety of cancers. Because it is a functional drug screen–examining only whether a given drug primes cancer cells for death–DBP does not require prior knowledge of a cancer’s inner workings or genetic aberrations.
“We don’t have to be limited to drug targets that are identifiable only by genetic mutations, which are only a tiny fraction of the true targets out there in the cancer world,” said Letai.
He and his colleagues are also planning a clinical trial using DBP to identify tailored therapies for individual patients diagnosed with myelogenous leukemia.
Letai and Daniels note that the regular inter-lab meetings and collaborative model of the Ludwig Harvard Center were critical to the conception, design and conduct of the study.
“It was a way of combining a unique set of expertise,” said Letai. “I’m good at cell death, not good at metabolism. Veerle is good at metabolism and cell death, but was lacking some key tools to do her initial screening, so we turned to other members of the Ludwig Harvard Center who actually had those tools. We wouldn’t have been aware of that expertise if we weren’t at the Center because Harvard is a very big place.”
Anthony Letai is a Professor in Medicine at Harvard Medical School and the Dana Farber Cancer Institute.
Veerle Daniels is now a research scientist at Flamingo Therapeutics in Leuven, Belgium.
This study was supported by Ludwig Cancer Research, the U.S. National Institutes of Health, the Terri Brodeur Breast Cancer Foundation, Alex’s Lemonade Stand Foundation, Tap Cancer Out, Brazil’s National Council for Scientific and Technological Development, The Breast Cancer Research Foundation, Breast Cancer Coalition of Rochester and the American Association for Cancer Research.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.
For further information please contact Rachel Reinhardt, [email protected] or +1-212-450-1582.
Frangopol awarded ISHMII Mufti Medal for civil structural health monitoring achievements
Lehigh University professor will be recognized for lifetime achievements during 10th International Conference on Structural Health Monitoring of Intelligent Infrastructure (SHMII10)
The International Association of Structural Health Monitoring of Intelligent Infrastructure (ISHMII) has honored Dan M. Frangopol, the inaugural Fazlur R. Khan Endowed Chair of Structural Engineering and Architecture at Lehigh University, with the 2021 Aftab Mufti Medal for lifetime achievement in civil structural health monitoring. The medal will be presented at the ISHMII award ceremony during the 10th International Conference on Structural Health Monitoring of Intelligent Infrastructure (SHMII10), June 30-July 2, 2021, in Porto, Portugal.
Frangopol has made seminal scholarly contributions to structural health monitoring (SHM) by bringing reliability and optimization methods into this field. He is internationally recognized for pioneering the integration of health monitoring in life-cycle performance assessment, prediction, and optimization of structural systems under uncertainty. His innovative methodologies have been instrumental to tremendous advances in health monitoring of structural systems.
His contributions to the field of SHM include: (a) formulating an approach for the inclusion of monitoring data in the structural reliability assessment process; (b) demonstrating the use of monitoring data for the development of structural reliability prediction models; (c) optimizing the planning of structural performance monitoring based on reliability importance assessment; (d) optimizing maintenance strategies based on multiple limit states and monitoring; (d) integrating SHM in life-cycle performance assessment of civil infrastructure systems under uncertainty; (e) proposing cost-effective lifetime SHM based on availability; and (f) optimizing scheduling of inspection and monitoring for fatigue-sensitive structures.
These contributions are fully documented in (a) a recent book: Life-Cycle of Structures under Uncertainty: Emphasis on fatigue-sensitive civil and marine structures, which Frangopol published in 2019 (CRC Press, Science Publishers) with his former student S. Kim as co-author, (b) several book chapters, and (c) about 40 papers in archival journals.
Frangopol is the Founding President of both the International Association for Bridge Maintenance and Safety (IABMAS) and the International Association for Life-Cycle Civil Engineering (IALCCE) as well as founding vice-president of ISHMII. He is also the past vice-president of the International Association for Structural Safety and Reliability (IASSAR) and past vice-president of the Engineering Mechanics Institute (EMI) of ASCE, as well as past member of its Board of Governors.
He has authored/co-authored three books, more than 50 book chapters, and over 420 articles in archival journals (117 in ASCE journals), including 11 prize-winning papers.
Frangopol is the founder and editor-in-chief of Structure and Infrastructure Engineering, an international peer-reviewed journal launched in 2005, and of the book series Structures and Infrastructures.
He is the recipient of several medals, awards, and prizes from ASCE, IABSE, IASSAR, ISHMII, and other professional organizations, including the Newmark, Freudenthal, Housner, Lin, Khan, and Croes (twice) medals; the Ang, Howard, Moisseiff, and State-of-the Art of Civil Engineering (three times) awards; the Munro, Noble, Reese, and Wellington prizes; the Lifetime Achievement Award in Education (OPAL); and the Civil Engineer of the Year Award.
Frangopol holds four honorary doctorates, 14 honorary professorships, and six guest professorships from major universities.
He is an Elected Member of the US National Academy of Construction, a Foreign Member of the Academy of Europe (London), a Foreign Associate of the Engineering Academy of Japan, a Foreign Member of the Royal Academy of Belgium, an Honorary Member of the Romanian Academy, an Honorary Member of the Romanian Academy of Technical Sciences, and a Distinguished Member of ASCE.
Read more about Frangopol’s research and achievements here.
Website: Dan M. Frangopol
International Association of Structural Health Monitoring of Intelligent Infrastructure
Metal catalysts used for environmental sustainability found to degrade and become less effective
New research is showing that some tiny catalysts being considered for industrial-scaled environmental remediation efforts may be unstable during operation.
Chemists from the University of Waterloo studied the structures of complex catalysts known as “nanoscale electrocatalysts” and found that they are not as stable as scientists once thought. When electricity flows through them during use, the atoms may rearrange. In some cases, the researchers found, electrocatalysts degrade completely.
Understanding why and how this rearrangement and degradation happens is the first step to using these nanoscale electrocatalysts in environmental remediation efforts such as removing atmospheric carbon dioxide and groundwater contaminants and transforming them into higher-value products such as fuels.
“Current electrocatalysts rely on complex nanoscale structures in order to optimize their efficiency,” said Anna Klinkova, a professor in Waterloo’s Department of Chemistry. “What we found, however, is that the superior performance of these complex nanomaterials often come at a cost of their gradual structural degradation, as there is a trade-off between their effectiveness and stability.”
Klinkova and her team discovered that the rearrangement of atoms in the catalyst depended on the type of metal, structural shape, and the reaction conditions of the catalyst.
They identified two reasons for the rearrangements. Some small molecules can temporarily attach to the surface of the catalyst and reduce the energy needed for an atom to move across the surface. In other cases, narrow areas within the catalyst concentrate the electron’s current, causing the metal atoms to displace via a process called electromigration.
Electromigration has been previously identified in microelectronics, but this is the first time it has been connected to nanoscale catalysts.
These findings establish a framework for assessing structural stability and mapping the changing geometry of nanoscale catalysts, which is an important step to designing better catalysts in the future.
“These structural effects could be used as one of the design rules in future catalyst development to maximize their stability,” Klinkova said. “You could also purposefully induce reconstruction to a different structure that becomes active as the reaction starts.”
The study, Interplay of electrochemical and electrical effects induces structural transformations in electrocatalysts, was recently published in the journal Nature Catalysis.
The MedWalk diet: A step closer to walking away from dementia
It’s been named the world’s best diet for weight loss, but now researchers at the University of South Australia are confident that the Mediterranean Diet – combined with a daily bout of exercise – can also stave off dementia, slowing the decline in brain function that is commonly associated with older age.
In the world-first study starting this week, researchers at the University of South Australia and Swinburne University, along with a consortium of partners* will explore the health benefits of older people adhering to a Mediterranean diet, while also undertaking daily walking.
Termed the MedWalk Trial, the two-year, $1.8 million NHMRC-funded study will recruit 364 older Australians – aged 60-90 years, living independently in a residential village, and without cognitive impairment – across 28 residential sites in South Australia and Victoria.
It’s a timely study, particularly given Australia’s ageing population, where around a quarter of all Australians will be aged 65+ by 2050.
Lead UniSA researcher, Associate Professor Karen Murphy, says combining the dietary benefits of the Mediterranean Diet with the health benefits of an exercise intervention could deliver significant benefits.
“Dementia is a condition that affects a person’s thinking, behaviour and ability to perform everyday tasks. While it is more common in older Australians, it’s not a normal part of ageing,” Assoc Prof Murphy says.
“In Australia, around 472,000 people are living with dementia. Each year it costs the economy more than $14 billion which is expected to balloon to more than $1 trillion over the next 40 years.
“While there is currently no prevention or cure for dementia, there is growing consensus that a focus on risk reduction can have positive outcomes. That’s where our study comes in.
“Early pilots of our MedWalk intervention show improved memory and thinking in a sub-group of older participants adhering to a combination of Mediterranean diet and daily walking for six months.
“We’re now extending this study across a broader group of older Australians, using carefully-designed behavioural change and maintenance strategies in the hope of substantially reducing the incidence of dementia across Australia.”
A Mediterranean diet is high in fruit, vegetables, legumes, whole grains, and fish, while being low in saturated fats, red meat, and alcohol.
The 24-month study will randomly assign residential community sites the MedWalk intervention, or their usual lifestyle (the control group), so that all participants who live at one facility will be in the same group. Changes to diet and walking will be supported through organised and regular motivational, dietary and exercise sessions.
Head of Neurocognitive Ageing Research at Swinburne’s Centre for Human Psychopharmacology and Chief Investigator, Professor Andrew Pipingas, says this trial is about trying to prevent the onset of dementia.
“As it’s extremely difficult to find a cure and treat those in the later stages of the disease, focusing our efforts on helping those at risk of developing dementia to stay healthy is one-way to ensure Australians stay well in future.”
Notes for editors:
- May is National Mediterranean Diet Month
- The full list of partners involved in this study are: Swinburne University; University of South Australia; Deakin University; La Trobe University; RMIT University; Murdoch University; Sheffield Hallam University, UK; University of East Anglia, UK; University College Cork, Ireland.
Media contact: Annabel Mansfield T: +61 8 8302 0351 M: +61 417 717 504
E: [email protected]
Researchers: UniSA: Associate Professor Karen Murphy T: +61 8 8302 1033
E: [email protected]
Swinburne: Professor Andrew Pipingas T: +61 3 9214 5215 E: [email protected]
Researchers trace dust grain’s journey through newborn solar system
Combining atomic-scale sample analysis and models simulating likely conditions in the nascent solar system, the study revealed clues about the origin of crystals that formed more than 4.5 billion years ago
A research team led by the University of Arizona has reconstructed in unprecedented detail the history of a dust grain that formed during the birth of the solar system more than 4.5 billion years ago. The findings provide insights into the fundamental processes underlying the formation of planetary systems, many of which are still shrouded in mystery.
For the study, the team developed a new type of framework, which combines quantum mechanics and thermodynamics, to simulate the conditions to which the grain was exposed during its formation, when the solar system was a swirling disk of gas and dust known as a protoplanetary disk or solar nebula. Comparing the predictions from the model to an extremely detailed analysis of the sample’s chemical makeup and crystal structure, along with a model of how matter was transported in the solar nebula, revealed clues about the grain’s journey and the environmental conditions that shaped it along the way.
The grain analyzed in the study is one of several inclusions, known as calcium-aluminum rich inclusions, or CAIs, discovered in a sample from the Allende meteorite, which fell over the Mexican state of Chihuahua in 1969. CAIs are of special interest because they are thought to be among the first solids that formed in the solar system more than 4.5 billion years ago.
Similar to how stamps in a passport tell a story about a traveler’s journey and stops along the way, the samples’ micro- and atomic-scale structures unlock a record of their formation histories, which were controlled by the collective environments to which they were exposed.
“As far as we know, our paper is the first to tell an origin story that offers clues about the likely processes that happened at the scale of astronomical distances with what we see in our sample at the scale of atomic distances,” said Tom Zega, a professor in the University of Arizona’s Lunar and Planetary Laboratory and the first author of the paper, published in The Planetary Science Journal.
Zega and his team analyzed the composition of the inclusions embedded in the meteorite using cutting-edge atomic-resolution scanning transmission electron microscopes – one at UArizona’s Kuiper Materials Imaging and Characterization Facility, and its sister microscope located at the Hitachi factory in Hitachinaka, Japan.
The inclusions were found to consist mainly of types of minerals known as spinel and perovskite, which also occur in rocks on Earth and are being studied as candidate materials for applications such as microelectronics and photovoltaics.
Similar kinds of solids occur in other types of meteorites known as carbonaceous chondrites, which are particularly interesting to planetary scientists as they are known to be leftovers from the formation of the solar system and contain organic molecules, including those that may have provided the raw materials for life.
Precisely analyzing the spatial arrangement of atoms allowed the team to study the makeup of the underlying crystal structures in great detail. To the team’s surprise, some of the results were at odds with current theories on the physical processes thought to be active inside protoplanetary disks, prompting them to dig deeper.
“Our challenge is that we don’t know what chemical pathways led to the origins of these inclusions,” Zega said. “Nature is our lab beaker, and that experiment took place billions of years before we existed, in a completely alien environment.”
Zega said the team set out to “reverse-engineer” the makeup of the extraterrestrial samples by designing new models that simulated complex chemical processes, which the samples would be subjected to inside a protoplanetary disk.
“Such models require an intimate convergence of expertise spanning the fields of planetary science, materials science, mineral science and microscopy, which was what we set out to do,” added Krishna Muralidharan, a study co-author and an associate professor in the UArizona’s Department of Materials Science and Engineering.
Based on the data the authors were able to tease from their samples, they concluded that the particle formed in a region of the protoplanetary disk not far from where Earth is now, then made a journey closer to the sun, where it was progressively hotter, only to later reverse course and wash up in cooler parts farther from the young sun. Eventually, it was incorporated into an asteroid, which later broke apart into pieces. Some of those pieces were captured by Earth’s gravity and fell as meteorites.
The samples for this study were taken from the inside of a meteorite and are considered primitive – in other words, unaffected by environmental influences. Such primitive material is believed to not have undergone any significant changes since it first formed more than 4.5 billion years ago, which is rare. Whether similar objects occur in asteroid Bennu, samples of which will be returned to Earth by the UArizona-led OSIRIS-REx mission in 2023, remains to be seen. Until then, scientists rely on samples that fall to Earth via meteorites.
“This material is our only record of what happened 4.567 billion years ago in the solar nebula,” said Venkat Manga, a co-author of the paper and an assistant research professor in the UArizona Department of Materials Science and Engineering. “Being able to look at the microstructure of our sample at different scales, down to the length of individual atoms, is like opening a book.”
The authors said that studies like this one could bring planetary scientists a step closer to “a grand model of planet formation” – a detailed understanding of the material moving around the disk, what it is composed of, and how it gives rise to the sun and the planets.
Powerful radio telescopes like the Atacama Large Millimeter/submillimeter Array, or ALMA, in Chile now allow astronomers to see stellar systems as they evolve, Zega said.
“Perhaps at some point we can peer into evolving disks, and then we can really compare our data between disciplines and begin answering some of those really big questions,” Zega said. “Are these dust particles forming where we think they did in our own solar system? Are they common to all stellar systems? Should we expect the pattern we see in our solar system – rocky planets close to the central star and gas giants farther out – in all systems?
“It’s a really interesting time to be a scientist when these fields are evolving so rapidly,” he added. “And it’s awesome to be at an institution where researchers can form transdisciplinary collaborations among leading astronomy, planetary and materials science departments at the same university.”
The study was co-authored by Fred Ciesla at the University of Chicago and Keitaro Watanabe and Hiromi Inada, both with the Nano-Technology Solution Business Group at Hitachi High-Technologies Corp. in Japan.
Funding was provided through NASA’s Emerging Worlds Program; NASA’s Origins Program; and NASA’s Nexus for Exoplanet System Science (NExSS) research coordination network, which is sponsored by NASA’s Science Mission Directorate. NASA and the National Science Foundation provided the funding for the instrumentation in LPL’s Kuiper Materials Imaging and Characterization Facility.
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