All life starts at a small scale, also in the ocean. Microscopic organisms, phytoplankton, form an important basis for the entire marine ecosystem, which ultimately determines how fish stocks develop and how much atmospheric carbon dioxide is taken up by the ocean. In this respect, understanding the basis of the marine ecosystem is important for two elementary questions for the future of our human population: nutrition and climate.

Scientists from Dalhousie University, University of Liverpool, GEOMAR Helmholtz Centre for Ocean Research Kiel and Scripps Institution of Oceanography have developed a new model for studying phytoplankton growth in the ocean. The model was coupled to metaproteomic and environmental data to allow accurate predictions of e.g. phytoplankton growth rates in the Southern Ocean. “You can think of phytoplankton growth like industrial manufacturing in a factory: Materials come into the factory and are processed on assembly lines, creating the final product,” explains Scott McCain, lead author of the study and a PhD student in the Department of Biology at Canada’s Dalhousie University. “We asked ourselves how to increase output, which is the amount of products leaving the factory,” McCain adds. Applied to phytoplankton, that means how can they grow faster?

“As part of the study, we found that phytoplankton rearrange their ‘cellular assembly lines’ to do this,” explained Prof. Dr. Eric Achterberg, co-author of the study from GEOMAR. “We were not concerned with the amount of available nutrients, including iron and manganese, that are important for the growth of phytoplankton, but rather with the question of how the ‘cellular assembly lines’ in the phytoplankton that process the source substances for their growth adapt to changes,” Achterberg continued. To do this, the researchers created a mathematical model of a phytoplankton that enabled them to simulate these processes. The model was linked to laboratory and cruise data from the Southern Ocean on metaproteomics, dissolved iron and manganese. This allowed them to obtain new explanations for various phytoplankton processes. “Our results show that cumulative cellular costs determine how environmental conditions change the growth of phytoplankton,” says Professor Achterberg.

“This fundamentally changes the way we look at phytoplankton growth and will lead to better predictions of how phytoplankton will grow in the ocean,” adds Scott McCain. According to the Canadian scientists these findings are also important for predictions on the development of fish stocks and global climate change.

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The UM Rosenstiel School of Marine and Atmospheric Science researchers designed an experiment to understand how effective commonly available air conditioner filters and face masks are at filtrating out the toxins emitted during harmful algal bloom events.

“We found that face masks and air conditioner filters with high filter performance ratings can reduce the risk of exposure by filtering out small, toxin-containing particles,” said the study’s lead author Cassandra Gaston, an assistant professor of atmospheric sciences at the UM Rosenstiel School.

“These filter materials can also be effective at filtering out other kinds of small particles as well,” said Haley Royer, a co-first author of the study and Ph.D. student at the UM Rosenstiel School’s Department of Atmospheric Sciences. “As we all know by now, face masks are essential in preventing the transmission of COVID-19 from person to person.”

Harmful algal blooms, often referred to as red tides and blue-green algae, are exacerbated by nutrient-rich runoff from agriculture and industrial waste that end up in waterways. Noxious particles enter the air mostly from the breaking of waves, resulting in airborne toxins that cause serious health problems to humans and marine life. Airborne toxins can also affect indoor air quality particularly for businesses and homes near contaminated waterways.

To conduct the experiment, the researchers created a bubbling device to produce airborne toxin-containing particles in the lab by bubbling air into the liquid containing cultures of a toxic-producing blue-green algae, Microcystis aeruginosa. Cutouts of three types of face masks and six types of AC filters purchased from home improvement stores were placed in-line with generated particles to determine how well the masks and filters blocked particles of different sizes. The researchers used N95, disposable surgical mask and medical-grade, odor-filtering carbon fiber masks. For AC filters, the researchers used filters for window units and central air conditioning units with different filter performance ratings.

They found that AC filters filtered out 20-90% of the airborne particles with particle filtration increasing with increasing filter performance rating. Face masks filtered out over 90% of toxin-containing particles. The findings suggest that low-cost, commercially available face masks and AC filters with high filtration efficiency ratings can help avoid both indoor and outdoor exposure to harmful algal bloom toxins in the air.

Harmful algal blooms are expected to become more prevalent worldwide due to climate change and increased nutrient runoff from a growing human population.

According to the researchers, the study also has relevance for the transmission of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. The virus has an average size of 60-140 nanometers, which is within the size of particles investigated in this study.

The study, titled “Filtration Efficiency of Air Conditioner Filters and Face Masks to Limit Exposure to Aerosolized Algal Toxins,” was accepted for publication on April 20, 2021 in the journal Aerosol and Air Quality Research.

The study’s authors include: Cassandra Gaston, Haley Royer, Raymond Leibensperger III, Daniela Maizel, Kaycie Lanpher, Helena Solo-Gabriele, Larry Brand, R. Grace Zhai, Alberto Caban-Martinez and Kimberly Popendorf from the University of Miami.

Funding for the study was provided by the UM Laboratory of Integrated Knowledge (U-LINK) and Florida Department of Health (DOH) project “Diversity and Innovation in Screening and Prevention of Exposure over the Long-term (DISPEL) to HABs.” DOH funding supported preparation of visual and video materials for communicating strategies to the public for reducing HAB exposures.

The device can also be used to detect specific viral mutations linked to some of the SARS-CoV-2 variants that are now circulating. This result can also be obtained within an hour, potentially making it much easier to track different variants of the virus, especially in regions that don’t have access to genetic sequencing facilities.

“We demonstrated that our platform can be programmed to detect new variants that emerge, and that we could repurpose it quite quickly,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering. “In this study, we targeted the U.K., South African, and Brazilian variants, but you could readily adapt the diagnostic platform to address the Delta variant and other ones that are emerging.”

The new diagnostic, which relies on CRISPR technology, can be assembled for about $15, but those costs could come down significantly if the devices were produced at large scale, the researchers say.

Collins is the senior author of the new study, which appears today in Science Advances. The paper’s lead authors are Helena de Puig, a postdoc at Harvard University’s Wyss Institute for Biologically Inspired Engineering; Rose Lee, an instructor in pediatrics at Boston Children’s Hospital and Beth Israel Deaconess Medical Center and a visiting fellow at the Wyss Institute; Devora Najjar, a graduate student in MIT’s Media Lab; and Xiao Tan, a clinical fellow at the Wyss Institute and an instructor in gastroenterology at Massachusetts General Hospital.

A self-contained diagnostic

The new diagnostic is based on SHERLOCK, a CRISPR-based tool that Collins and others first reported in 2017. Components of the system include an RNA guide strand that allows detection of specific target RNA sequences, and Cas enzymes that cleave those sequences and produce a fluorescent signal. All of these molecular components can be freeze-dried for long-term storage and reactivated upon exposure to water.

Last year, Collins’ lab began working on adapting this technology to detect the SARS-CoV-2 virus, hoping that they could design a diagnostic device that could yield rapid results and be operated with little or no expertise. They also wanted it to work with saliva samples, making it even easier for users.

To achieve that, the researchers had to incorporate a critical pre-processing step that disables enzymes called salivary nucleases, which destroy nucleic acids such as RNA. Once the sample goes into the device, the nucleases are inactivated by heat and two chemical reagents. Then, viral RNA is extracted and concentrated by passing the saliva through a membrane.

“That membrane was key to collecting the nucleic acids and concentrating them so that we can get the sensitivity that we are showing with this diagnostic,” Lee says.

This RNA sample is then exposed to freeze-dried CRISPR/Cas components, which are activated by automated puncturing of sealed water packets within the device. The one-pot reaction amplifies the RNA sample and then detects the target RNA sequence, if present.

“Our goal was to create an entirely self-contained diagnostic that requires no other equipment,” Tan says. “Essentially the patient spits into this device, and then you push down a plunger and you get an answer an hour later.”

The researchers designed the device, which they call minimally instrumented SHERLOCK (miSHERLOCK), so that it can have up to four modules that each look for a different target RNA sequence. The original module contains RNA guide strands that detect any strain of SARS-CoV-2. Other modules are specific to mutations associated with some of the variants that have arisen in the past year, including B.1.1.7, P.1, and B.1.351.

The Delta variant was not yet widespread when the researchers performed this study, but because the system is already built, they say it should be straightforward to design a new module to detect that variant. The system could also be easily programmed to monitor for new mutations that could make the virus more infectious.

“If you want to do more of a broad epidemiological survey, you can design assays before a mutation of concern appears in a population, to monitor for potentially dangerous mutations in the spike protein,” Najjar says.

Tracking variants

The researchers first tested their device with human saliva spiked with synthetic SARS-CoV-2 RNA sequences, and then with about 50 samples from patients who had tested positive for the virus. They found that the device was just as accurate as the gold standard PCR tests now used, which require nasal swabs and take more time and significantly more hardware and sample handling to yield results.

The device produces a fluorescent readout that can be seen with the naked eye, and the researchers also designed a smartphone app that can read the results and send them to public health departments for easier tracking.

The researchers believe their device could be produced at a cost as low as $2 to $3 per device. If approved by the FDA and manufactured at large scale, they envision that this kind of diagnostic could be useful either for people who want to be able to test at home, or in health care centers in areas without widespread access to PCR testing or genetic sequencing of SARS-CoV-2 variants.

“The ability to detect and track these variants is essential to effective public health, but unfortunately, variants are currently diagnosed only by nucleic acid sequencing at specialized epidemiological centers that are scarce even in resource-rich nations,” de Puig says.

The research was funded by the Wyss Institute; the Paul G. Allen Frontiers Group; the Harvard University Center for AIDS Research, which is supported by the National Institutes of Health; a Burroughs-Wellcome American Society of Tropical Medicine and Hygiene postdoctoral fellowship; an American Gastroenterological Association Takeda Pharmaceutical Research Scholar Award; and an MIT-TATA Center fellowship.

The research is published in the Proceedings of the National Academy of Sciences (PNAS.

The researchers worked with the University of Minnesota’s Technology Commercialization Office to patent the technology and have already garnered interest from industry.

Many metals and their compounds must be made into thin films before they can be used in technological products like electronics, displays, fuel cells, or catalytic applications. “Stubborn” metals, however — which include elements like platinum, iridium, ruthenium, and tungsten, among others — are very difficult to convert into thin films because they require extremely high temperatures (usually more than 2,000 degrees Celsius) to evaporate.

Typically, scientists synthesize these metal films using techniques like sputtering and electron beam evaporation. The latter consists of melting and evaporating metals at high temperatures and allowing a film to form on top of wafers. But, this conventional method is very expensive, uses a lot of energy, and may also be unsafe due to the high voltage used.

Now, University of Minnesota researchers have developed a way to evaporate these metals at significantly lower temperatures, fewer than 200 degrees Celsius instead of several thousands. By designing and adding organic ligands — combinations of carbon, hydrogen, and oxygen atoms — to the metals, the researchers were able to substantially increase the materials’ vapor pressures, making them easier to evaporate at lower temperatures. Not only is their new technique simpler, but it also makes higher quality materials that are easily scalable.

“The ability to make new materials with ease and control is essential to transition into a new era of energy economy,” said Bharat Jalan, the senior author of the study, an expert in material synthesis, and an associate professor and Shell Chair in the University of Minnesota Department of Chemical Engineering and Materials Science (CEMS). “There is already a historical link between the innovation in synthesis science and the development of new technology. Millions of dollars go into making materials for various applications. Now, we’ve come up with a simpler and cheaper technology that enables better materials with atomic precision.”

These metals are used to make myriad products, from semiconductors for computer applications to display technology. Platinum, for example, also makes a great catalyst for energy conversion and storage and is being looked at for use in spintronic devices.

“Bringing down the cost and complexity of metal deposition while also allowing for deposition of more complex materials like oxides will play a large role in both industrial and research efforts,” said William Nunn, a University of Minnesota chemical engineering and materials science graduate student, the paper’s first author, and a recipient of the department’s Robert V. Mattern Fellowship. “Now that depositing these metals like platinum will become easier, we hope to see renewed interest in the more complex materials which contain these stubborn metals.”

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While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer Cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

Psyche orbits the sun in the asteroid belt, a donut-shaped region of space between Earth and Jupiter that contains more than a million rocky bodies that range in size from 10 meters to 946 kilometers in diameter.

With a diameter of more than 200 km, Psyche is the largest of the M-Type asteroids, an enigmatic class of asteroids that are thought to be metal rich and therefore potentially may be fragments of the cores of proto-planets that broke up as the solar system formed.

“The early solar system was a violent place, as planetary bodies coalesced and then collided with one another while settling into orbits around the sun,” says Caltech’s Katherine de Kleer, assistant professor of planetary science and astronomy and lead author of the PSJarticle. “We think that fragments of the cores, mantles, and crusts of these objects remain today in the form of asteroids. If that’s true, it gives us our only real opportunity to directly study the cores of planet-like objects.”

Studying such relatively tiny objects that are so far away from Earth (Psyche drifts at a distance that ranges between 179.5 and 329 million km from Earth) poses a significant challenge to planetary scientists, which is why NASA plans to send a probe to Psyche to examine it up close. Typically, thermal observations from Earth — which measure the light emitted by an object itself rather than light from the sun reflected off of that object — are in infrared wavelengths and can produce only 1-pixel images of asteroids. That one pixel does, however, reveal a lot of information; for example, it can be used to study the asteroid’s thermal inertia, or how fast it heats up in sunlight and cools down in darkness.

“Low thermal inertia is typically associated with layers of dust, while high thermal inertia may indicate rocks on the surface,” says Caltech’s Saverio Cambioni, postdoctoral scholar in planetary science and co-author of the PSJ article. “However, discerning one type of landscape from the other is difficult.” Data from viewing each surface location at many times of day provide much more detail, leading to an interpretation that is subject to less ambiguity, and which provide a more reliable prediction of landscape type prior to a spacecraft’s arrival.

De Kleer and Cambioni, together with co-author Michael Shepard of Bloomsburg University in Pennsylvania, took advantage of the Atacama Large Millimeter/submillimeter Array (ALMA) in Chile, which became fully operational in 2013, to obtain such data. The array of 66 radio telescopes enabled the team to map the thermal emissions from Psyche’s entire surface at a resolution of 30 km (where each pixel is 30 km by 30 km) and generate an image of the asteroid composed of about 50 pixels.

This was possible because ALMA observed Psyche at millimeter wavelengths, which are longer (ranging from 1 to 10 millimeters) than the infrared wavelengths (typically between 5 and 30 microns). The use of longer wavelengths allowed the researchers to combine the data collected from the 66 telescopes to create a much larger effective telescope; the larger a telescope, the higher the resolution of the images it produces.

The study confirmed that Psyche’s thermal inertia is high compared to that of a typical asteroid, indicating that Psyche has an unusually dense or conductive surface. When de Kleer, Cambioni, and Shepard analyzed the data, they also found that Psyche’s thermal emission — the amount of heat it radiates — is just 60 percent of what would be expected from a typical surface with that thermal inertia. Because surface emission is affected by the presence of metal on the surface, their finding indicates that Psyche’s surface is no less than 30 percent metal. An analysis of the polarization of the emission helped the researchers to roughly determine what form that metal takes. A smooth solid surface emits well-organized polarized light; the light emitted by Psyche, however, was scattered, suggesting that rocks on the surface are peppered with metallic grains.

“We’ve known for many years that objects in this class are not, in fact, solid metal, but what they are and how they formed is still an enigma,” de Kleer says. The findings reinforce alternative proposals for Psyche’s surface composition, including that Psyche could be a primitive asteroid that formed closer to the sun than it is today instead of a core of a fragmented protoplanet.

The techniques described in this study provide a new perspective on asteroid surface compositions. The team is now expanding its scope to apply these techniques to other large objects in the asteroid belt.

The study was enabled by a related project by the team led by Michael Shepard at Bloomsburg University that utilized de Kleer’s data in combination with data from other telescopes, including Arecibo Observatory in Puerto Rico, to pin down the size, shape, and orientation of Psyche. That in turn allowed the researchers to determine which pixels that had been captured actually represented the asteroid’s surface. Shepard’s team was scheduled to observe Psyche again at the end of 2020, but damage from cable failures shut the telescope down before the observations could be made.

To learn more about the biological basis of LSCC, a team led by researchers from the Broad Institute of MIT and Harvard and the National Cancer Institute’s Clinical Proteomics Tumor Analysis Consortium (CPTAC), including collaborators from the Baylor College of Medicine, have developed the largest and most comprehensive molecular map to date of LSCC. Their effort, described in Cell, brings proteomic, transcriptomic, and genomic data together into a detailed “proteogenomic” view of LSCC. Analysis of that data has revealed potential new drug targets, immune regulation pathways that might help the cancer evade immunotherapies, and even a new molecular subtype of LSCC. Data from the study is available on the CPTAC portal (https://proteomics.cancer.gov/data-portal).

“Patients with lung squamous cell cancer have very limited therapeutic options, and even modest success in understanding this disease could make a difference in people’s lives,” said Shankha Satpathy, a group leader in the Broad Institute’s Proteomics team, and co-first and co-corresponding author on the Cell study with co-first authors Karsten Krug and Pierre Jean Beltran of Broad and Sara Savage of Baylor. “We hope the research community, from basic scientists to practicing oncologists, will make use of this new resource for testing hypotheses, stimulating further research, and opening new data-driven avenues for clinical trial design that, in the long run, could benefit patients.”

Targetable opportunities

In their study, the team analyzed DNA, RNA, proteins, and post-translational protein modifications (PTMs, i.e., phosphorylation, acetylation, and ubiquitylation) of 108 tumors before treatment, and compared them with normal tissue. Among the opportunities they saw for the development of new LSCC treatments, the researchers identified the gene NSD3 as a possible target for tumors harboring extra copies of FGFR1, another gene that is often duplicated or amplified in LSCC. Prior efforts have attempted, unsuccessfully, to target FGFR1 directly. The team’s proteogenomic findings suggest that NSD3 could be a critical driver of tumor growth and survival in these tumors, making it a potential therapeutic target.

They also noted a subset of patients whose tumors exhibited low expression of p63 but high expression of survivin, a protein that regulates cell proliferation and cell death and which is the target of clinical trials in other tumor types.

Additionally, the team’s data suggested that tumors driven by overexpression of the transcription factor SOX2 may be vulnerable to treatments directed against chromatin modifiers such as LSD1 and EZH2. SOX2 itself is generally considered an “undruggable” target; the team’s observations point to an opportunity to develop a therapeutic workaround.

“Proteomic and PTM data help us to see the functional effects of the genome,” explained Michael Gillette, a senior group leader in Proteomics at Broad, an attending physician in pulmonary and critical care medicine at Massachusetts General Hospital, and a co-senior author on the study with Steven Carr and DR Mani of Broad and Bing Zhang of Baylor. “Understanding which protein levels are impacted by copy-number alterations, and how mutations impact protein expression and pathway activity, provides deeper insights into cancer biology.

“Often those insights hint at unexplored therapeutic options, or at specific subpopulations that might benefit from specific treatments,” he added. “This is especially important with a disease like LSCC, where so many clinical trials have failed.”

Immune explorations

Even though immunotherapy represents the greatest advance in LSCC therapy in decades, patient outcomes lag behind those seen with LUAD; only a minority of patients with LSCC exhibit long-term responses. Based on their proteogenomic data, the team presented a detailed picture of the immune landscape of LSCC, highlighting several immune regulation pathways that could serve as targetable points. In particular, their analysis highlighted a subset of tumors that exhibit markers associated with response to immune checkpoint inhibitors (such as PD-1/PD-L1 blockers), and with immune evasion, providing some clues as to why immunotherapy outcomes are so uneven across patients with LSCC.

“A deeper understanding of the immune landscape of LSCC tumors could eventually lead to more effective immunotherapies and markers for patient stratification,” said Zhang, a professor in the Lester and Sue Smith Breast Center and the Department of Molecular and Human Genetics at Baylor.

Metabolic dysregulation and crosstalk revealed

Ubiquitylation is a process by which the cell flags proteins with another small protein called ubiquitin (or its biochemical relatives) to target them for destruction. While this process is important in normal function, when dysregulated it can contribute or lead to disease. The Broad team previously developed UbiFast, a technology that enables deep-scale, high-throughput analysis of ubiquitylation in patient tissue samples. Applied to LSCC, UbiFast revealed complex regulation of metabolic pathways such as glycolysis and oxidative stress driven by molecular crosstalk based on ubiquitylation (or ubiquitin-like modifications) and two other forms of protein modification, phosphorylation (which changes a protein’s enzymatic or catalytic activity) and acetylation (which can affect a protein’s structure, activity, localization, and stability).

A new subtype emerges

Prior efforts have identified four molecular subtypes of LSCC using genomics, corresponding to distinct cell types and processes. With their proteomic perspective, the research team not only gained a deeper understanding of immune, metabolic and proliferative signals associated with these subtypes, but also uncovered a new epithelial-to-mesenchymal transition subtype. The cells of this new type, they noted, may have greater potential for metastasis, but also feature active, kinase-driven molecular pathways that could be targeted therapeutically.

“This is remarkable because LSCC tumors generally lack the types of kinase alterations present in LUAD that have been the basis for development of a broad spectrum of therapeutic inhibitors,” said Ana Robles, program director in NCI’s Office of Cancer Clinical Proteomics Research.

The study collaborators performed their work under the auspices of CPTAC, an NCI-sponsored, multidisciplinary/multi-institutional effort to accelerate the understanding of the molecular basis of cancer through the application of large-scale proteogenomic analysis. This work builds on prior studies by CPTAC and the International Cancer Proteogenomics Consortium on LUAD. All datasets generated by CPTAC are available to the research community as a unique public resource that provides an exceptional foundation to guide further research and support development of therapeutic modalities in LSCC and other cancers.

“Studies like ours and others from the CPTAC network and beyond are increasingly demonstrating the importance of undertaking multi-omic, integrative analyses of tumors in order to provide a more detailed and nuanced understanding of cancer,” said Carr, senior director of Proteomics at Broad. “These studies have already revealed new, previously unrecognized targets for therapeutic intervention.”

Support for this study was provided by the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium.

The team has designed a new touch-sensing glove that can “feel” pressure and other tactile stimuli. The inside of the glove is threaded with a system of sensors that detects, measures, and maps small changes in pressure across the glove. The individual sensors are highly attuned and can pick up very weak vibrations across the skin, such as from a person’s pulse.

When subjects wore the glove while picking up a balloon versus a beaker, the sensors generated pressure maps specific to each task. Holding a balloon produced a relatively even pressure signal across the entire palm, while grasping a beaker created stronger pressure at the fingertips.

The researchers say the tactile glove could help to retrain motor function and coordination in people who have suffered a stroke or other fine motor condition. The glove might also be adapted to augment virtual reality and gaming experiences. The team envisions integrating the pressure sensors not only into tactile gloves but also into flexible adhesives to track pulse, blood pressure, and other vital signs more accurately than smart watches and other wearable monitors.

“The simplicity and reliability of our sensing structure holds great promise for a diversity of health care applications, such as pulse detection and recovering the sensory capability in patients with tactile dysfunction,” says Nicholas Fang, professor of mechanical engineering at MIT.

Fang and his collaborators detail their results in a study appearing today in Nature Communications. The study’s co-authors include Huifeng Du and Liu Wang at MIT, along with professor Chuanfei Guo’s group at the Southern University of Science and Technology (SUSTech) in China.

Sensing with sweat

The glove’s pressure sensors are similar in principle to sensors that measure humidity. These sensors, found in HVAC systems, refrigerators, and weather stations, are designed as small capacitors, with two electrodes, or metal plates, sandwiching a rubbery “dielectric” material that shuttles electric charges between the two electrodes.

In humid conditions, the dielectric layer acts as a sponge to soak up charged ions from surrounding moisture. This addition of ions changes the capacitance, or amount of charge between the electrodes, in a way that can be quantified and converted to a measurement of humidity.

In recent years, researchers have adapted this capacitive sandwich structure for the design of thin, flexible pressure sensors. The idea is similar: When a sensor is squeezed, the balance of charges in its dielectric layer shifts, in a way that can be measured and converted to pressure. But the dielectric layer in most pressure sensors is relatively bulky, limiting their sensitivity.

For their new tactile sensors, the MIT and SUSTech team did away with the conventional dielectric layer in favor of a surprising ingredient: human sweat. As sweat naturally contains ions such as sodium and chloride, they reasoned that these ions could serve as dielectric stand-ins. Rather than a sandwich structure, they envisioned two thin, flat electrodes, placed on the skin to form a circuit with a certain capacitance. If pressure was applied to one “sensing” electrode, ions from the skin’s natural moisture would accumulate on the underside, and change the capacitance between both electrodes, by an amount that they could measure.

They found they could boost the sensing electrode’s sensitivity by covering its underside with a forest of tiny, bendy, conductive hairs. Each hair would serve as a microscopic extension of the main electrode, such that, if pressure were applied to, say, a corner of the electrode, the hairs in that specific region would bend in response, and accumulate ions from the skin, the degree and location of which could be precisely measured and mapped.

Pressure pillars

In their new study, the team fabricated thin, kernel-sized sensing electrodes lined with thousands of gold microscopic filaments, or “micropillars.” They demonstrated that they could accurately measure the degree to which groups of micropillars bent in response to various forces and pressures. When they placed a sensing electrode and a control electrode onto a volunteer’s fingertip, they found the structure was highly sensitive. The sensors were able to pick up subtle phases in the person’s pulse, such as different peaks in the same cycle. They could also keep up accurate pulse readings, even as the person wearing the sensors waved their hands as they walked across a room.

“Pulse is a mechanical vibration that can also cause deformation of the skin, which we can’t feel, but the pillars can pick up,” Fang says.

The researchers then applied the concepts of their new, micropillared pressure sensor to the design of a highly sensitive tactile glove. They started with a silk glove, which the team purchased off the shelf. To make pressure sensors, they cut out small squares from carbon cloth, a textile that is composed of many thin filaments similar to micropillars.

They turned each cloth square into a sensing electrode by spraying it with gold, a naturally conductive metal. They then glued the cloth electrodes to various parts of the glove’s inner lining, including the fingertips and palms, and threaded conductive fibers throughout the glove to connect each electrode to the glove’s wrist, where the researchers glued a control electrode.

Several volunteers took turns wearing the tactile glove and performing various tasks, including holding a balloon and gripping a glass beaker. The team collected readings from each sensor to create a pressure map across the glove during each task. The maps revealed distinct and detailed patterns of pressure generated during each task.

The team plans to use the glove to identify pressure patterns for other tasks, such as writing with a pen and handling other household objects. Ultimately, they envision such tactile aids could help patients with motor dysfunction to calibrate and strengthen their hand dexterity and grip.

“Some fine motor skills require not only knowing how to handle objects, but also how much force should be exerted,” Fang says. “This glove could provide us more accurate measurements of gripping force for control groups versus patients recovering from stroke or other neurological conditions. This could increase our understanding, and enable control.”

This research was supported, in part, by the Joint Center for Mechanical Engineering Research and Education at MIT and SUSTech.