Culture

Effector and killer T cells are types of immune cells. Their job is to attack pathogens and cancers. These cells can also go after normal cells causing autoimmune diseases. But, if harnessed properly, they can destroy cancer cells that resist treatment.

Scientists at St. Jude wanted to understand how these T cells are controlled. They looked at enhancers, sequences of DNA that when bound to certain proteins determine how genes are turned on or off.

The scientists found that enhancers of a gene named Foxp3 work as a pair to keep effector and killer T cells in check. The enhancers working together is essential.

"These enhancers go together like your left and right hands," said Yong Feng, PhD, of St. Jude Immunology. "They work together in different ways to curb the effector and killer T cells, playing a critical role in how the immune system makes sure it only attacks the right target."

Physicists in Israel have created a quantum interferometer on an atom chip. This device can be used to explore the fundamentals of quantum theory by studying the interference pattern between two beams of atoms. University of Groningen physicist, Anupam Mazumdar, describes how the device could be adapted to use mesoscopic particles instead of atoms. This modification would allow for expanded applications. A description of the device, and theoretical considerations concerning its application by Mazumdar, were published on 28 May in the journal Science Advances.

The device which scientists from the Ben-Gurion University of the Negev created is a so-called Stern Gerlach Interferometer, which was first proposed one hundred years ago by German physicists Otto Stern and Walter Gerlach. Their original aim of creating an interferometer with freely propagating atoms exposed to gradients from macroscopic magnets has not been practically realized until now. 'Such experiments have been done using photons, but never with atoms', explains Anupam Mazumdar, Professor of Theoretical Physics at the University of Groningen and one of the co-authors of the article in Science Advances.

Diamonds
The Israeli scientists, led by Professor Ron Folman, created an interferometer on an atom chip, which can confine and/or manipulate atoms. A beam of rubidium atoms is levitated over the chip using magnets. Magnetic gradients are used to split the beam according to the spin values of the individual atoms. Spin is a magnetic moment that can have two values, either up or down. The spin-up and spin-down atoms are separated by a magnetic gradient. Subsequently, the two divergent beams are brought together again and recombined. The spin values are then measured, and an interference pattern is formed. Spin is a quantum phenomenon, and throughout this interferometer, the opposing spins are entangled. This makes the interferometer sensitive to other quantum phenomena.

Mazumdar was not involved in the construction of the chip, but he contributed theoretical insights to the paper. Together with a number of his colleagues, he previously proposed an experiment to determine whether gravity is in fact a quantum phenomenon using entangled mesoscopic objects, namely tiny diamonds that can be brought in a state of quantum superposition. 'It would be possible to use these diamonds instead of the rubidium atoms on this interferometer', he explains. However, this process would be highly complex as the device, which is currently operated at room temperature, would need to be cooled down to around 1 Kelvin for the mesoscopic experiment.

Free fall
If this is realized, two of these atom chips could free fall together (to neutralize external gravity), so that any interaction occurring between them would depend on the gravitational pull between the two chips. Mazumdar and his colleagues aim to determine whether quantum entanglement of the pair occurs during free fall, which would mean that the force of gravity between the diamonds is indeed a quantum phenomenon. Another application of this experiment is the detection of gravity waves; their deformation of space-time should be visible in the interference pattern.

The actual implementation of this experiment is still a long way off, but Mazumdar is very excited now that the interferometer has been created. 'It is already [a] quantum sensor, although we still have to work out exactly what it can detect. The experiment is like the first steps of a baby - now, we have to guide it to reach maturity.'

Researchers in Lund, Copenhagen and Norwich have shown that harmful mutations present in the DNA play an important - yet neglected - role in the conservation and translocation programs of threatened species.

"Many species are threatened by extinction, both locally and globally. For example, we have lost about ten vertebrate species in Sweden in the last century. However, all these species occur elsewhere in Europe, which means that they could be reintroduced into Sweden. Our computer simulations show how we could theoretically maximize the success of such reestablishments", says Bengt Hansson, biologist at Lund University.

In a new study published in Science, the researchers investigated which individuals might be most suited for translocation to new populations. To date, conservation geneticists have opted to select the most genetically variable individuals. However, the authors argue that is important to consider what type of genetic variation is being move around. Using computer simulations, they showed that harmful mutations present in the genome of translocated individuals can cause problems in future generations. This so called "mutation load" could jeopardize the viability of the new population in the long run and eventually led to extinction.

According to Hansson and van Oosterhout, geneticist at University of East Anglia, Norwich, who led the study, the best choice is to exclude individuals with many harmful mutations, whilst at the same time, selecting individuals from multiple different source populations.

"Active translocation of animals between localities is sometimes the last option available to conservation biologists. By carefully selecting individuals based on their low mutation load, we can minimize the loss of fitness that is normally associated with inbreeding in small populations", says Bengt Hansson.

Huge advances have been made in DNA sequencing technologies, and the whole genomes of individuals can now be sequenced for relatively little costs. This opens up new possibilities to improve the conservation management of threatened species.

"For many species of mammals and birds, we now know which mutations are harmful. Similar mutations are also found in humans, so we understand what they do, and hence, we know what to look out for when analyzing the sequence data of those species. The advantage of using DNA sequencing is that we can see these mutations in the genome, even if an individual carries just a single copy of the mutant gene. This means we can select against those bad mutations even before they cause a problem. Our computer model shows that at least theoretically, this ensures the best probability for population survival. This could help conservation managers in picking the optimal individuals of a threatened species for translocation into a new habitat", says van Oosterhout.

The COVID-19 pandemic forced instructors to adapt their courses for online learning. Laboratory courses were particularly difficult due to lack of access to specialized equipment for remote learners. To overcome this challenge, researchers from the University of Illinois Urbana-Champaign designed a laboratory exercise to teach students how to use micropipettes, through remote learning, using at-home kits.

Micropipettes are common--and essential--laboratory instruments and are used in several fields including molecular biology, microbiology, and biochemistry. They are used to accurately transfer very small volumes of liquid. To teach students how to use these instruments, the researchers developed kits, costing $135 per student, that were a fraction of the cost of the instructional equipment that is normally used for in-person classes.

"Although lab kits have been developed previously, they did not focus on micropipetting skills," said Karin Jensen, Teaching Assistant Professor of Bioengineering, who worked with Associate Professor of Bioengineering Pablo Perez-Pinera (ACPP) to develop the project. "In an effort to provide remote students with lab experience, we developed and shipped kits to students. These kits contained equipment and reagents for them to practice their technique and perform experiments remotely."

Each kit contained a mini-scale, a glucose meter, a pipet-aid, and a set of micropipettes. Each student was provided with the kit, an instructional video, and a laboratory manual. They were instructed to follow the protocol step by step with the goal of learning how to correctly dilute the glucose solutions and verifying their accuracy using the glucose meter. They also shared their data with the instructors for feedback and grading.

The students also filled out surveys and course feedback forms about the effectiveness of these online classes. "We found that most of the students were excited to use lab equipment despite being in an online section," Jensen said.

The researchers are now working to improve the exercise. "Beyond COVID-19, there is still a need to develop remote lab learning opportunities for students who cannot attend in-person labs," Jensen said. "Remote lab activities, similar to what we describe, will be important in increasing access to STEM education."

A research group of the Department of Pharmacy and Biotechnology of the University of Bologna analyzed more than one million SARS-CoV-2 genome sequences. This analysis led to the identification of a new variant that, over the past weeks, has been spreading mostly in Mexico but has also been found in Europe. Their paper published in the Journal of Medical Virology presented the so-called "Mexican variant", whose scientific name is T478K. Like other strains, this presents a mutation in the Spike protein, which allows coronaviruses to attach to and penetrate their targeted cells.

"This variant has been increasingly spreading among people in North America, particularly in Mexico. To date, this variant covers more than 50% of the existing viruses in this area. The rate and speed of the spread recall those of the 'British variant'", explains Federico Giorgi, who is the study coordinator and a professor at the Department of Pharmacy and Biotechnology of the University of Bologna. "The mutation of the Spike protein is structurally located in the region of interaction with human receptor ACE2. Coronaviruses attach to this receptor to infect cells, thus spreading the infection with more efficacy".

The researchers started from the analysis of almost 1.2 million sequenced samples of the SARS-CoV-2 genome found in international databases until April 27, 2021. The new T478K variant was detected in 11435 samples. This is double the number of samples that presented the same variant just a month earlier. Such an increase since the beginning of 2021 alarmed the researchers.

The "Mexican variant" spreads evenly across males and females and age ranges. This variant represents 52.8% of all sequenced coronaviruses in Mexico, whereas in the United States it shows up only in 2.7% of the sequenced samples. As concerns Europe, the "Mexican variant" has spread feebly in Germany, Sweden, and Switzerland. In Italy is virtually non-existent with only 4 reported cases.

The mutation characterizing this variant is located in a region of the Spike protein that is responsible for the interaction with the human receptor ACE2: this is the mechanism allowing coronaviruses to access the cells. Similar mutations are common to all variants that have been at the center of attention in the past months. Indeed, recent coronavirus variants stand out for their high infection rates, which made them pervasive in many areas of the world.

Researchers tested the action of T478K Spike protein with in silico simulations and found out that this mutated protein can alter the superficial electrostatic charge. Consequently, it can change not only the interaction with the ACE2 human protein but also with the antibodies of the immune system and thus hinder drug efficacy.

"Thanks to the great amount of data available in international databases, we can hold an almost real-time control over the situation by monitoring the spread of coronavirus variants across different geographical areas", concludes Giorgi. "Keeping up this effort in the next months will be crucial to act promptly and with efficient means".

Tiny algae in Earth's oceans and lakes take in sunlight and carbon dioxide and turn them into sugars that sustain the rest of the aquatic food web, gobbling up about as much carbon as all the world's trees and plants combined.

New research shows a crucial piece has been missing from the conventional explanation for what happens between this first "fixing" of CO2 into phytoplankton and its eventual release to the atmosphere or descent to depths where it no longer contributes to global warming. The missing piece? Fungus.

"Basically, carbon moves up the food chain in aquatic environments differently than we commonly think it does," said Anne Dekas, an assistant professor of Earth system science at Stanford University. Dekas is the senior author of a paper published June 1 in Proceedings of the National Academy of Sciences that quantifies how much carbon goes into parasitic fungi that attack microalgae.

Underwater merry-go-round

Researchers until now have predicted that most carbon fixed into colonies of hard-shelled, single-celled algae known as diatoms then funnels directly into bacteria - or dissolves like tea in the surrounding water, where it's largely taken up by other bacteria. Conventional thinking assumes carbon escapes from this microbial loop mainly through larger organisms that graze on the bacteria or diatoms, or through the CO2 that returns to the atmosphere as the microbes breathe.

This journey is important in the context of climate change. "For carbon sequestration to occur, carbon from CO2 needs to go up the food chain into big enough pieces of biomass that it can sink down into the bottom of the ocean," Dekas said. "That's how it's really removed from the atmosphere. If it just cycles for long periods in the surface of the ocean, it can be released back to the air as CO2."

It turns out fungus creates an underappreciated express lane for carbon, "shunting" as much as 20 percent of the carbon fixed by diatoms out of the microbial loop and into the fungal parasite. "Instead of going through this merry-go-round, where the carbon could eventually go back to the atmosphere, you have a more direct route to the higher levels in the food web," Dekas said.

The findings also have implications for industrial and recreational settings that deal with harmful algal blooms. "In aquaculture, in order to keep the primary crop, like fish, healthy, fungicides might be added to the water," Dekas said. That will prevent fungal infection of the fish, but it may also eliminate a natural check on algal blooms that cost the industry some $8 billion per year. "Until we understand the dynamics between these organisms, we need to be pretty careful about the management policies we're using."

Microbial interactions

The authors based their estimates on experiments with populations of chytrid fungi called Rhizophydiales and their host, a type of freshwater algae or diatom named Asterionella formosa. Coauthors in Germany worked to isolate these microbes, as well as bacteria found in and around their cells, from water collected from Lake Stechlin, about 60 miles north of Berlin.

"Isolating one microorganism from nature and growing it in the laboratory is difficult, but isolating and maintaining two microorganisms as a pathosystem, in which one kills the other, is a true challenge," said lead author Isabell Klawonn, who worked on the research as a postdoctoral scholar in Dekas' lab at Stanford. "Only a few model systems are therefore available to research such parasitic interactions."

Scientists surmised as early as the 1940s that parasites played an important role in controlling the abundance of phytoplankton, and they observed epidemics of chytrid fungus infecting Asterionella blooms in lake water. Technological advances have made it possible to pick apart these invisible worlds in fine and measurable detail - and begin to see their influence in a much bigger picture.

"We're realizing as a community that it's not just the capabilities of an individual microorganism that's important for understanding what happens in the environment. It's how these microorganisms interact," Dekas said.

The authors measured and analyzed interactions within the Lake Stechlin pathosystem using genomic sequencing; a fluorescence microscopy technique that involves attaching fluorescent dye to RNA within microbial cells; and a highly specialized instrument at Stanford - one of only a few dozen in the world - called NanoSIMS, which creates nanoscale maps of the isotopes of elements that are present in materials in vanishingly small amounts. Dekas said, "To get these single-cell measurements to show how photosynthetic carbon is flowing between specific cells, from the diatom to the fungus to the associated bacteria, it's the only way to do it."

The exact amount of carbon diverted to fungus from the microbial merry-go-round may differ in other environments. But the discovery that it can be as high as 20 percent in even one setting is significant, Dekas said. "If you're changing this system by more than a few percent in any direction, it can have dramatic implications for biogeochemical cycling. It makes a big difference for our climate."

Though it might seem inanimate, the soil under our feet is very much alive. It's filled with countless microorganisms actively breaking down organic matter, like fallen leaves and plants, and performing a host of other functions that maintain the natural balance of carbon and nutrients stored in the ground beneath us.

"Soil is mostly microorganisms, both alive and dead," says Jennifer Bhatnagar, soil microbiologist and Boston University College of Arts & Sciences assistant professor of biology. It's typical to see several hundred different types of fungi and bacteria in a single pinch of soil off the ground, she says, making it one of the most diverse ecosystems that exist.

Because there's still so much unknown about soil organisms, until now scientists have not attempted to predict where certain species or groups of soil microbes live around the world. But having that knowledge about these organisms— too small to see with the naked eye—is key to better understanding the soil microbiome, which is made up of the communities of different microbes that live together.

A team of BU biologists, including Bhatnagar, took on that challenge—and their research reveals, for the first time, that it is possible to accurately predict the abundance of different species of soil microbes in different parts of the world. The team recently published their findings in a new paper in Nature Ecology & Evolution.

"If we know where organisms are on earth, and we know how they change through space and time due to different environmental forces, and something about what different species are doing, then we can much better predict how the function of these communities will change in terms of carbon and nutrient cycling," Bhatnagar says. That kind of knowledge would have huge implications for agriculture, climate change, and public health.

"The health of the soils is so tied to the soil microbes," says Michael Dietze, senior author on the study and a BU College of Arts & Sciences professor of earth and environment. Dietze, Bhatnagar, and researchers from their labs joined forces to work on this project, which involved analyzing hundreds of soil samples collected by National Ecological Observatory Network (NEON) research sites. Bhatnagar and her lab members brought to the team their soil expertise, while Dietze and his lab offered their unique ability to develop precise ecological forecasts and near-term environmental predictions.

The team learned that microbe predictability increases as spatial area increases, so the bigger the piece of land their model makes forecasts about, the more likely the predictions about what types of microbes live there will be accurate.

Dietze says the ability to accurately predict which microbes would likely be found in a given soil sample also increased as the researchers looked at organism groupings higher up on the phylogenetic scale, a system that classifies organisms based on evolutionary relatedness. On the smallest end of the scale, a "species" represents the finest level of classification; on the other end, a "phylum" makes up the largest and most diverse groupings of organisms. They were surprised to find that they were better able to predict the presence of a whole phylum, as opposed to individual species.

After receiving the genomic data of the soil samples from NEON, the research team's forecasting models take into account environmental factors specific to the place where the soil came from—what plants live there, the soil acidity (pH), temperature, climate, and many others. They found their model was best able to predict the presence of microorganisms based on their symbiotic relationship with local plant species. Mycorrhizal fungi, for example, is a very common soil microbe that about 90 percent of plant families associate with, including pines and oak trees in New England.

In contrast, the team found it was more difficult to predict large groups of organisms based on their relationship with soil acidity. Despite knowing soil acidity levels, and what types of bacteria would typically like to live in that environment, their model couldn't accurately predict the amount of bacteria that were actually present in the soil sample, Bhatnagar says. "That means there is something else beyond the relationship with [acidity], beyond the relationship with any other environmental factor that we typically measure in our ecosystems," she says.

Now, Dietze and Bhatnagar's team are expanding their forecasts beyond predicting microbes based on only their location, to also include specific times of the year.

"Building a framework for forecasting the soil microbiome at sites across the US will improve our understanding of seasonal and interannual change," says Zoey Werbin, a PhD student working in Bhatnagar's lab and an author on the paper. "This could help us anticipate how climate change could affect microbial processes like decomposition or nitrogen cycling."

With her dissertation project, Werbin hopes to answer fundamental questions about how and why the soil microbiome varies over time and space.

"The more we learn, the more we realize how important soil microbes are for agriculture, public health, and climate change. It's really exciting to investigate how microscopic organisms can have such large-scale effects," Werbin says. "We know certain factors, like temperature and moisture, affect microbial communities. But we don't know how important those factors are compared to natural variability, or interactions between microbes. My PhD project will help identify the driving forces of the soil microbiome, as well as the biggest sources of uncertainty."

Like all metals, silver, copper, and gold are conductors. Electrons flow across them, carrying heat and electricity. While gold is a good conductor under any conditions, some materials have the property of behaving like metal conductors only if temperatures are high enough; at low temperatures, they act like insulators and do not do a good job of carrying electricity. In other words, these unusual materials go from acting like a chunk of gold to acting like a piece of wood as temperatures are lowered. Physicists have developed theories to explain this so-called metal-insulator transition, but the mechanisms behind the transitions are not always clear.

"In some cases, it is not easy to predict whether a material is a metal or an insulator," explains Caltech visiting associate Yejun Feng of the Okinawa Institute for Science and Technology Graduate University. "Metals are always good conductors no matter what, but some other so-called apparent metals are insulators for reasons that are not well understood." Feng has puzzled over this question for at least five years; others on his team, such as collaborator David Mandrus at the University of Tennessee, have thought about the problem for more than two decades.

Now, a new study from Feng and colleagues, published in Nature Communications, offers the cleanest experimental proof yet of a metal-insulator transition theory proposed 70 years ago by physicist John Slater. According to that theory, magnetism, which results when the so-called "spins" of electrons in a material are organized in an orderly fashion, can solely drive the metal-insulator transition; in other previous experiments, changes in the lattice structure of a material or electron interactions based on their charges have been deemed responsible.

"This is a problem that goes back to a theory introduced in 1951, but until now it has been very hard to find an experimental system that actually demonstrates the spin-spin interactions as the driving force because of confounding factors," explains co-author Thomas Rosenbaum, a professor of physics at Caltech who is also the Institute's president and the Sonja and William Davidow Presidential Chair.

"Slater proposed that, as the temperature is lowered, an ordered magnetic state would prevent electrons from flowing through the material," Rosenbaum explains. "Although his idea is theoretically sound, it turns out that for the vast majority of materials, the way that electrons interact with each other electronically has a much stronger effect than the magnetic interactions, which made the task of proving the Slater mechanism challenging."

The research will help answer fundamental questions about how different materials behave, and may also have applications in technology, for example in the field of spintronics, in which the spins of electrons would form the basis of electrical devices instead of the electron charges as is routine now. "Fundamental questions about metal and insulators will be relevant in the upcoming technological revolution," says Feng.

Interacting Neighbors

Typically, when something is a good conductor, such as a metal, the electrons can zip around largely unimpeded. Conversely, with insulators, the electrons get stuck and cannot travel freely. The situation is comparable to communities of people, explains Feng. If you think of materials as communities and electrons as members of the households, then "insulators are communities with people who don't want their neighbors to visit because it makes them feel uncomfortable." Conductive metals, however, represent "close-knit communities, like in a college dorm, where neighbors visit each other freely and frequently," he says.

Likewise, Feng uses this metaphor to explain what happens when some metals become insulators as temperatures drop. "It's like winter time, in that people--or the electrons--stay home and don't go out and interact."

In the 1940s, physicist Sir Nevill Francis Mott figured out how some metals can become insulators. His theory, which garnered the 1977 Nobel Prize in Physics, described how "certain metals can become insulators when the electronic density decreases by separating the atoms from each other in some convenient way," according to the Nobel Prize press release. In this case, the repulsion between the electrons is behind the transition.

In 1951, Slater proposed an alternate mechanism based on spin-spin interactions, but this idea has been hard to prove experimentally because the other processes of the metal-insulator transition, including those proposed by Mott, can swamp the Slater mechanism, making it hard to isolate.

Challenges of Real Materials

In the new study, the researchers were able at last to experimentally demonstrate the Slater mechanism using a compound that has been studied since 1974, called pyrochlore oxide or Cd2Os2O7. This compound is not affected by other metal-insulator transition mechanisms. However, within this material, the Slater mechanism is overshadowed by an unforeseen experimental challenge, namely the presence of "domain walls" that divide the material into sections.

"The domain walls are like the highways or bigger roads between communities," says Feng. In pyrochlore oxide, the domain walls are conductive, even though the bulk of the material is insulating. Although the domain walls started out as an experimental challenge, they turned out to be essential to the team's development of a new measurement procedure and technique to prove the Slater mechanism.

"Previous efforts to prove the Slater metal-insulator transition theory did not account for the fact that the domain walls were masking the magnetism-driven effects," says Yishu Wang (PhD '18), a co-author at the Johns Hopkins University who has continuously worked on this study since her graduate work at Caltech. "By isolating the domain walls from the bulk of the insulating materials, we were able to develop a more complete understanding of the Slater mechanism." Wang had previously worked with Patrick Lee, a visiting professor at Caltech from MIT, to lay the basic understanding of conductive domain walls using symmetry arguments, which describe how and if electrons in materials respond to changes in the direction of a magnetic field.

"By challenging the conventional assumptions about how electrical conductivity measurements are made in magnetic materials through fundamental symmetry arguments, we have developed new tools to probe spintronic devices, many of which depend on transport across domain walls," says Rosenbaum.

"We developed a methodology to set apart the domain-wall influence, and only then could the Slater mechanism be revealed," says Feng. "It's a bit like discovering a diamond in the rough."

A new drug reduced tumor size in patients who have lung cancer patients with a specific, disease-causing change in the gene KRAS, a study found.

The results of the CODEBREAK 100 phase 2 clinical trial were presented June 4, 2021, at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in the New England Journal of Medicine. The efficacy and safety of the drug sotorasib, developed by Amgen Inc., was tested in patients with non-small-cell lung cancer (NSCLC) harboring a specific change, or mutation, in the DNA code for KRAS.

The KRAS mutant protein targeted in the study was p.G12C, in which a glycine building block has been mistakenly replaced a cysteine at position 12 in the protein's structure. This change is present in about 13 percent of the more than 200,000 patients diagnosed with lung cancer each year in the United States. KRAS encodes a protein switch that regulates growth but becomes "stuck in the "on" mode" when mutated, signaling cells to continually multiply in tumors.

Sponsored by Amgen - and led by researchers from Perlmutter Cancer Center at NYU Langone Health, Washington University School of Medicine, MD Anderson Cancer Center, and Memorial Sloan Kettering - the global trial included 126 patients that received daily, oral sotorasib. This KRASG12C inhibitor was recently approved by the U.S. Food and Drug Administration for the treatment of adult patients with KRAS G12C-mutated NSCLC.

The researchers found that 37.1 percent of patients in the study saw their tumors shrink by at least 30 percent, termed an "objective response." About 82 percent of those treated experienced some slowing of tumor growth or "disease control."

All patients in the study had been treated previously with either immunotherapy (PD1-inhibitors) or platinum-based combination chemotherapy, but those treatments were no longer effective for them, and their cancers had begun to regrow. With no targeted options, such patients typically do poorly, with response rates to standard treatments between 6 and 20 percent, according to previous studies.

"The excitement surrounding this trial result is that sotorasib, just approved for clinical use, becomes the first targeted therapy for lung cancer patients with KRAS mutations," says co-corresponding study author Vamsidhar Velcheti, MD, associate professor of Medicine at NYU Grossman of Medicine, and director of thoracic medical oncology at Perlmutter Cancer Center. "KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited therapeutic options."

The average duration of responses to sotorasib in the current trial was 11.1 months, with a median period during which disease did not worsen (progression-free survival) of 6.8 months, say the study authors. With currently available treatments, median progression-free survival for these patients is between two and four months.

"Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer," says co-corresponding author Ramaswamy Govindan MD, the Anheuser Busch Chair in Medicine at Washington University School of Medicine. "Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patient's cancer cells."

First of Its Kind

The RAS gene family is among the most frequently mutated in human cancers, with one member of the group, KRAS, the most commonly occurring mutant in solid tumors. KRAS has considered "undruggable" for decades because its active form does not include a suitable pocket to which drugs can attach.

Sotorasib is a novel covalent inhibitor that, thanks to recent advances in medical chemistry, can target a specific building block (cysteine residue) only present in the inactive form of KRAS. When the mutated KRAS switch toggles into its inactive state, sotorasib can attach to a structural feature called the switch II pocket and react with the mutant cysteine at position 12, freezing KRAS in the inactive state.

The phase 2 trial CodeBreak 100 study also focused on safety, finding that, while nearly 70 percent of patients had treatment-related adverse events, only about 20 percent had more severe events that required reduction of the dose of sotorasib. About 7 percent of patients had to stop treatment because of severe side effects. The most frequent of these were diarrhea, nausea, fatigue, and an increase in liver enzyme levels. There were no life-threatening side effects, and no treatment-related deaths in the study.

All patients in the single-arm CodeBreak 100 trial were treated with sotorasib, and none with placebo, as is standard in early studies of this type. The ongoing phase 3 CodeBreak 200 trial (NCT04303780), which is comparing the effect of sotorasib against a chemotherapy, docetaxel, will seek to confirm the current results in 345 patients with NSCLC harboring the KRAS p.G12C mutation.

Oak Brook, IL - The June edition of SLAS Discovery features the cover article, "A Perspective on Synthetic Biology in Drug Discovery and Development--Current Impact and Future Opportunities" by Florian David, Ph.D. (Chalmers University of Technology, Gothenburg, Sweden), Andrew M. Davis, Ph.D. (AstraZeneca, Cambridge, England, UK). Michael Gossing, Ph.D., Martin A. Hayes, Ph.D., and Elvira Romero, Ph.D., and Louis H. Scott, Ph.D. (AstraZeneca, Gothenburg, Sweden), and Mark J. Wigglesworth, Ph.D. (AstraZeneca, London, England, UK).

In January 2021, a survey of immunologists, infectious-disease researchers and virologists found that 90% of respondents believe SARS-CoV-2 will become endemic, continuing to circulate in pockets of the global population for years to come. Even as vaccines are becoming more widely available, there are people who either do not respond to the treatment or are not suitable for vaccination. There is a critical need to develop small molecule inhibitors for this pathogen.
The cover article highlights the work of the Drug Discovery Unit at the University of Dundee (Dundee, Scotland, UK) reporting on the development of a high-throughput biochemical assay to assess the impact of small molecules on the methyltransferase activity of SARS-CoV-2 nonstructural protein 14 (nsp14). This enzyme is responsible for the N7-methylation of the cap at the 5' end of viral RNA and is critical in helping coronaviruses evade host defenses. The label-free MS-based assay developed was used to screen a library of 1771 FDA-approved drugs. The chemical hits that were identified may serve as starting points for drug discovery programs aimed at delivering therapeutics for the SARS-CoV-2 virus.

The June issue of SLAS Discovery includes nine articles of original research.

These include:

Development and Validation of High-Content Analysis for Screening HDAC6-Selective Inhibitors

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform

Identification and Kinetic Characterization of Serum- and Glucocorticoid-Regulated Kinase Inhibitors Using a Fluorescence Polarization-Based Assay

Reducing False Positives through the Application of Fluorescence Lifetime Technology: A Comparative Study Using TYK2 Kinase as a Model System

Biochemical and Cellular Profile of NIK Inhibitors with Long Residence Times

A Novel High-Throughput FLIPR Tetra-Based Method for Capturing Highly Confluent Kinetic Data for Structure-Kinetic Relationship Guided Early Drug Discovery

A Multipronged Screening Approach Targeting Inhibition of ETV6 PNT Domain Polymerization

Unbiased High-Throughput Drug Combination Pilot Screening Identifies Synergistic Drug Combinations Effective against Patient-Derived and Drug-Resistant Melanoma Cell Lines

Regenerable Biosensors for Small-Molecule Kinetic Characterization Using SPR

Other articles include:

A Perspective on Synthetic Biology in Drug Discovery and Development--Current Impact and Future Opportunities

Public-Private Partnerships: Compound and Data Sharing in Drug Discovery and Development

A High-Throughput RNA Displacement Assay for Screening SARS-CoV-2 nsp10-nsp16 Complex Toward Developing Therapeutics for COVID-19

Development of a High-Throughput Assay to Identify Inhibitors of ENPP1

Access to June's SLAS Discovery issue is available at https://journals.sagepub.com/toc/jbxb/current. For more information about SLAS and its journals, visit https://www.slas.org/publications/slas-discovery/ Access a "behind the scenes" look at the latest issue with SLAS Discovery Author Insights podcast. Tune in by visiting https://www.buzzsprout.com/1099559.

Oak Brook, IL - The June edition of SLAS Technology is a Special Issue entitled, "Emerging Trends in 3D Cell Culture: High-Throughput Screening, Disease Modeling and Translational Medicine." Free online access to the articles in this collection is courtesy of Corning Life Sciences, the issue's sponsor.

Precision medicine is becoming an increasingly popular and powerful way to target and treat human diseases. Patient-derived cellular models ushered in high-throughput screenings (HTS) in laboratory automation. While the upkeep and expansion of cells for HTS is predominantly manual, this special issue explores an automated avenue for HTS in research settings that considers the expansion of cells. This design is flexible for research and development of various cell types. The June issue analyzes protocols for controlled cell seeding, splitting and expansion of human fibroblasts, induced pluripotent stem cells (iPSCs), and neural progenitor cells (NPCs). These multiple platforms lend themselves well for research on patient-derived cellular models for precision medicine. "Significant improvements have been made in formation of complex 3D structures, but challenges remain in automating assay protocols with these models. The flowchips described in the issue contain protected sample chambers to allow media exchange, sample staining, wash steps, and supernatant sampling to occur without disruption to or loss of 3D sample," says SLAS Technology author Evan F. Cromwell, Ph.D. (Protein Fluidics, Inc.).

The June issue of SLAS Technology includes six articles of original research including:

Toxicity of Combinations of Kinase Pathway Inhibitors to Normal Human Cells in a Three-Dimensional Culture

Spheroid Trapping and Calcium Spike Estimation Techniques toward Automation of 3D Culture

Miniaturized Drug Sensitivity and Resistance Test on Patient-Derived Cells Using Droplet-Microarray

Automating Human Induced Pluripotent Stem Cell Culture and Differentiation of iPSC-Derived Retinal Pigment Epithelium for Personalized Drug Testing

Creating an Affordable, User-Friendly Electronic Inventory System for Lab Samples

Adapting a Low-Cost and Open-Source Commercial Pipetting 311 Robot for Nanoliter Liquid Handling

Other articles include:

Disease Modeling with 3D Cell-Based Assays Using a Novel Flowchip System and High-Content Imaging

Three-Dimensional Macroporous Sponge for the Culture of Hepatocellular Carcinoma Patient-Derived Xenograft Organoids

Automated Device for Uncapping Multiple-Size Bioanalytical Sample Tubes Designed to Reduce Technician Strain and Increase Productivity

Literature Highlights Column: Life Sciences Discovery and Technology Highlights

Access to June's SLAS Technology issue is available at https://journals.sagepub.com/toc/jlad/26/2. For more information about SLAS and its journals, visit https://www.slas.org/publications/slas-technology/.

Bottom Line: The majority of surveyed Americans had an inadequate understanding of palliative care, and frequency of health care utilization was one determinant of knowledge.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research

Author: Motolani Ogunsanya, PhD, an assistant professor at The University of Oklahoma Health Sciences Center

Background: Palliative care aims to improve the quality of life for patients and caretakers by addressing the physical, psychological, and logistical challenges associated with a disease or its treatment. In contrast to hospice, which provides comfort care for patients who have stopped treatment and are near the end of life, palliative care serves as an adjunct to life-sustaining treatments by addressing the side effects of treatment or symptoms of the disease.

"Despite the known benefits of palliative care and its endorsement by the American Society of Clinical Oncology and the National Comprehensive Cancer Network, we have not seen an increased uptake of palliative care by those who need it most," said Ogunsanya. "A common misconception is that palliative care is only for end-of-life care when, in fact, it can begin at any point in the disease course."

How the Study was Conducted: To study the extent of people's knowledge about palliative care and understand how various factors impact knowledge of palliative care across the American population, Ogunsanya and colleagues analyzed data from a National Cancer Institute's Health Information National Trends Survey (HINTS) from 2018. The dataset included self-reported demographic and clinical information, such as sex, age, education level, current health status, cancer history, and frequency of health care utilization, among others. Respondents self-reported their knowledge of palliative care by selecting between: "I've never heard of it," "I know a little bit about palliative care," and "I know what palliative care is, and I could explain it to someone else." The first two responses were grouped together as inadequate knowledge, and the final response was considered adequate knowledge.

Results: Among the 3,450 survey respondents, approximately 65 percent identified as non-Hispanic white, at least 90 percent had health insurance, about 60 percent had utilized the health care system more than twice in the past year, and about 10 percent had been previously diagnosed with cancer.

Overall, only 11 percent of the respondents reported adequate knowledge of palliative care. Women and married individuals were twice as likely to have adequate knowledge when compared with men and single respondents, respectively. Those who had a college degree were over 13-times more likely to have adequate knowledge of palliative care compared with respondents without a high school degree.

Health care utilization was also associated with knowledge of palliative care, as those with a regular source of medical care were 2.67 times more likely to have adequate knowledge of palliative care than those without regular medical care. In addition, respondents with a prior cancer diagnosis were 51 percent more likely to have adequate knowledge of palliative care than those who had never been diagnosed with cancer. Ogunsanya noted that this might be due to the increased engagement patients with cancer have with the health care system.

Author's Comments: "We found that in addition to personal factors, such as education level or marital status, the frequency of health care utilization had a significant impact on an individual's understanding of palliative care," said Ogunsanya. "This is a novel finding for the palliative care field and provides important insight into how we might be able to improve knowledge of this service.

"Since health care providers are often the first and most trusted source of health care information, educating physicians on palliative care and encouraging them to discuss it with their patients and caretakers is one potential strategy to increase understanding of palliative care," Ogunsanya noted. She added that addressing additional barriers to palliative care, such as misconceptions and lack of resources or time, are also important approaches to increasing awareness.

Study Limitations: A limitation of the study was that knowledge of palliative care was self-reported; however, Ogunsanya noted that this mode of data collection also provided an important perspective. "How someone perceives their own knowledge of palliative care may reveal more about their likelihood to pursue palliative care than a more objective measure," she explained. "If someone is not confident in their knowledge of palliative care, they may be less inclined to ask for it, regardless of how well they do understand it."

Additional limitations of the study included the exclusion of individuals who did not speak English or Spanish and those without a permanent address.

Dogs may have earned the title "man's best friend" because of how good they are at interacting with people. Those social skills may be present shortly after birth rather than learned, a new study by University of Arizona researchers suggests.

Published today in the journal Current Biology, the study also finds that genetics may help explain why some dogs perform better than others on social tasks such as following pointing gestures.

"There was evidence that these sorts of social skills were present in adulthood, but here we find evidence that puppies - sort of like humans - are biologically prepared to interact in these social ways," said lead study author Emily Bray, a postdoctoral research associate in the UArizona School of Anthropology in the College of Social and Behavioral Sciences.

Bray has spent the last decade conducting research with dogs in collaboration with California-based Canine Companions, a service dog organization serving clients with physical disabilities. She and her colleagues hope to better understand how dogs think and solve problems, which could have implications for identifying dogs that would make good service animals.

To better understand biology's role in dogs' abilities to communicate with humans, Bray and her collaborators looked at how 375 of the organization's 8-week-old budding service dogs, which had little previous one-on-one interaction with humans, performed on a series of tasks designed to measure their social communication skills.

Because the researchers knew each puppy's pedigree - and therefore how related they were to one another - they were also able to look at whether inherited genes explain differences in dogs' abilities. Genetics explained more than 40% of the variation in puppies' abilities to follow human pointing gestures, as well as variation in how long they engaged in eye contact with humans during a task designed to measure their interest in people.

"People have been interested in dogs' abilities to do these kinds of things for a long time, but there's always been debate about to what extent is this really in the biology of dogs, versus something they learn by palling around with humans," said study co-author Evan MacLean, assistant professor of anthropology and director of the Arizona Canine Cognition Center at the University of Arizona. "We found that there's definitely a strong genetic component, and they're definitely doing it from the get-go."

At the time of the study, the puppies were still living with their littermates and had not yet been sent to live with a volunteer puppy raiser. Therefore, their interactions with humans had been limited, making it unlikely that the behaviors were learned, Bray said.

The researchers engaged the puppies in four different tasks. In one task, an experimenter hid a treat beneath one of two overturned cups and pointed to it to see if the puppy could follow the gesture. To ensure that the pups weren't just following their noses, a treat was also taped to the inside of both cups. In another version of the task, puppies watched as the researchers placed a yellow block next to the correct cup, instead of pointing, to indicate where the puppy should look for the food.

The other two tasks were designed to observe puppies' propensity to look at human faces. In one task, the researchers spoke to the puppies in "dog-directed speech," reciting a script in the sort of high-pitched voice people sometimes use when talking to a baby. They then measured how long the puppy held a gaze with the human. In the final task - a so-called "unsolvable task" - researchers sealed a treat inside a closed container and presented it to the puppy, then measured how often the puppy looked to the human for help opening the container.

While many of the puppies were responsive to humans' physical and verbal cues, very few looked to humans for help with the unsolvable task. That suggests that while puppies may be born knowing how to respond to human-initiated communication, the ability to initiate communication on their own may come later.

"In studies of adult dogs, we find a tendency for them to look to humans for help, especially when you look at adult dogs versus wolves. Wolves are going to persist and try to independently problem solve, whereas dogs are more likely to look to the social partner for help," Bray said. "In puppies, this help-seeking behavior didn't really seem to be part of their repertoire yet."

In many ways, that mirrors what we see in human children's development, Bray said.

"If you think about language learning, children can understand what we're saying to them before they can physically produce the words," she said. "It's potentially a similar story with puppies; they are understanding what is being socially conveyed to them, but the production of it on their end is probably going to take a little bit longer, developmentally."

MacLean said the next step will be to see if researchers can identify the specific genes that may contribute to dogs' capacity to communicate with humans.

"We've done some previous studies that show that dogs who tend to be successful as service dogs respond to people in different ways than dogs who aren't successful," MacLean said. "If you could identify a potential genetic basis for these traits, you might be able to predict, even before the puppy is born, if they are part of a litter that would be good service dog candidates, because they have the right genetic background. It's a long way down the road, but there is potential to start applying this."

WASHINGTON (June 3, 2021) - Nearly three-quarters of breast cancer patients (73%) report using at least one type of complementary medicine after cancer diagnosis, while oncologists believe that less than half (43%) of patients are using these approaches during cancer care. These and other findings from a national survey of oncologists and breast cancer patients were released in conjunction with the 2021 ASCO Annual Meeting. The study found that doctors report discussing integrative health with only about half of patients, leading patients to seek information outside the clinic.

"Cancer is a complex disease that affects every component of a patient's life. While conventional medicine is effective for curing disease, it can fall short in helping patients heal," said Wayne Jonas, MD, report co-author and executive director for Integrative Health Programs at the Samueli Foundation. "Patients are turning to these therapies to looking for hope and to improve their quality of life and wellbeing after diagnosis, but they are looking for more guidance from their oncologists."

A national survey of 115 clinical oncologists who treat breast cancer was conducted in late 2020 alongside a similar survey of 164 breast cancer patients who had been diagnosed within two years of the survey. The poll was conducted by IQVIA, a global provider of advanced analytics, technology solutions, and clinical research services to the life sciences industry, to understand awareness, usage, and attitudes toward the use of complementary and lifestyle therapies in addition to medical treatment.

In the study, the researchers found that two-thirds of oncologists (66%) and patients (65%) believe using complementary and lifestyle therapies improve patients' quality of life. Many patients (60%) also believe these treatments lead to better health outcomes. Interestingly, patient use of tai chi/chi gong or acupuncture had the strongest correlation with positive impact on quality of life among the 12 modalities tested.

The survey also gauged patients' and physicians' awareness of complementary and lifestyle therapies and sources of information for patients. Most oncologists reported familiarity with at least one therapy. These physicians saw nutrition consultation, support groups, psycho-oncology support, and exercise consultation as the most important integrative services. However, they gave relatively low marks to spiritual services and meditation or mindfulness--two approaches that patients see as important. Patients also recall their care teams providing fewer recommendations about these two modalities than the others.

While oncologists and patients agree that an oncologist, oncology nurse, or patient navigator is a good source of information for complementary medicine and lifestyle therapies, patients have a slight preference to hear directly from the oncologists.

"Many oncologists are generally supportive of integrating complementary and lifestyle therapies with conventional medical treatment, but the education and guidance given to patients varies widely," said Terri Crudup, Senior Principal of Primary Intelligence at IQVIA. "Oncologists and the institutions at which they practice should look for methods to educate and expose patients to a variety of safe and effective complementary and lifestyle therapies to find the ones that will help their patients most."

Astronomers studying the fast-moving jet of material ejected by a still-forming, massive young star found a major difference between that jet and those ejected by less-massive young stars. The scientists made the discovery by using the U.S. National Science Foundation's Karl G. Jansky Very Large Array (VLA) to make the most detailed image yet of the inner region of such a jet coming from a massive young star.

Both low- and high-mass young stars, or protostars, propel jets outward perpendicular to a disk of material closely orbiting the star. In stars with masses similar to the Sun, these jets are narrowed, or focused, relatively tightly near to the star in a process called collimation. Because most high-mass protostars are more distant, studying the regions close to them has been more difficult, so astronomers were unclear if this was the case with them.

A team of scientists observed a massive protostar called Cep A HW2, located about 2,300 light-years from Earth in the constellation Cepheus. Cep A HW2 is expected to develop into a new star about 10 times more massive than the Sun. The new VLA images showed the finest detail yet seen in such an object, giving the astronomers their first view of the innermost portion of the jet, a portion roughly as long as the diameter of the Solar System.

"What we saw is very different from what usually is seen in the jets from low-mass stars," said Adriana Rodriguez-Kamenetzky, of the National Autonomous University of Mexico (UNAM).

In lower-mass protostars, observations have shown the jets to be collimated as close to the star as only a few times the Earth-Sun distance.

In Cep A HW2, however, "We see not a single jet, but two things -- a wide-angle wind originating close to the star, then a highly-collimated jet some distance away," said Alberto Sanna, of the Osservatorio Astronomico di Cagliari (INAF) in Italy. The collimated jet starts at a distance from the star comparable to the distance from the Sun to Uranus or Neptune.

The discovery raises two main possibilities, the astronomers said.

First, the same mechanism could be at work in both high-mass and low-mass protostars, but the collimation distance could be determined by the mass, occurring farther away in more-massive systems. The second possibility is that high-mass stars might produce only the wide-angle wind seen in Cep A HW2, with collimation only coming when physical conditions around the star restrict the flow.

"That case would point to a major difference in the mechanisms at work in protostars of different masses," said Carlos Carrasco-Gonzalez, also of UNAM, leader of the work. "Answering this question is important to understanding how stars of all masses form," he added.