The survival benefit demonstrates that an immune checkpoint inhibitor together with a targeted kinase inhibitor drug “is important in the first-line treatment of patients with advanced renal cell carcinoma,” said the authors of a study published in The New England Journal of Medicine today and simultaneously presented during American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium. The senior author is Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The phase 3 CLEAR study results showed significant benefits from the combination comprised of lenvatinib, an oral kinase inhibitor that targets proteins involved in the formation of blood vessels supplying a tumor, and pembrolizumab, a checkpoint inhibitor given by infusion that helps the immune system attack the cancer. Another group of patients received a combination of lenvatinib and everolimus, a drug that targets a protein, mTOR.

The comparison drug was sunitinib, an inhibitor that targets multiple kinases and has been the standard treatment in these patients with advanced kidney cancer, which carries a poor prognosis. However, standard-of-care options now include treatment with immune checkpoint inhibitors, either as a combination of two checkpoint inhibitors or a checkpoint inhibitor plus a kinase inhibitor. These combinations have achieved improved outcomes for advanced kidney cancer patients compared with sunitinib.

The results of the CLEAR study showed that those receiving the combination of lenvatinib and pembrolizumab not only had longer overall survival but also longer progression-free survival — the period before their disease worsened — and a higher response rate. In addition to lenvatinib plus pembrolizumab, the clinical trial also tested the combination of lenvatinib and everolimus, which is approved for patients with advanced kidney cancer whose disease progresses following sunitinib treatment.

The primary endpoint of the trial was progression-free survival (PFS). Both combinations proved superior to sunitinib alone: lenvatinib/pembrolizumab achieved a median PFS of 23.9 months vs 9.2 for sunitinib; PFS for lenvatinib/everolimus was 14.7 months.

The 24-month overall survival rate was 79.2% with lenvatinib/pembrolizumab, 66.1% with lenvatinib/everolimus, and 70.4% with sunitinib.

The confirmed objective response rate (percentage of patients whose disease shrank) was 71% with lenvatinib/pembrolizumab, 53.5% with lenvatinib/everolimus, and 35.1% with sunitinib. The rate of complete responses — total tumor shrinkage — was 16.1% in patients receiving lenvatinib/pembrolizumab, 9.8% in the lenvatinib plus everolimus group, and 4.2% in the sunitinib group.

“The rate of responses and complete responses, and the progression-free survival were the longest we have seen to date in a phase 3 combination of a targeted VEGF inhibitor and an immune checkpoint inhibitor,” said Choueiri. The CLEAR trial is the last of the clinical trials that were launched to compare immunotherapy and targeted drug combinations to sunitinib, and sunitinib will not be the comparison drug in future trials because the combinations have proven superior in these advanced kidney cancer patients, said Choueiri.

Almost all patients in the CLEAR trial experienced some adverse events from treatment. The most frequent adverse events were diarrhea and hypertension. These side effects led to stopping the treatment in 37.2% of patients in the lenvatinib/pembrolizumab group, and dose reduction of lenvatinib in 68.5% of patients. “Although the combination of lenvatinib and pembrolizumab was associated with some notable side effects, these adverse events are often adequately managed” the researchers said.

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The current experiments involve newborn mice, which have ear canals that open 11 days after birth. In human fetuses, the ear canal opens prenatally, at about 20 weeks gestation.

The findings, published online Feb. 12 in Science Advances, may eventually help scientists identify ways to detect and intervene in abnormal wiring in the brain that may cause hearing or other sensory problems.

“As scientists, we are looking for answers to basic questions about how we become who we are,” says Patrick Kanold, Ph.D., professor of biomedical engineering at The Johns Hopkins University and School of Medicine. “Specifically, I am looking at how our sensory environment shapes us and how early in fetal development this starts happening.”

Kanold started his career in electrical engineering, working with microprocessors, a natural conduit for his shift to science and studying the circuitry of the brain.

His research focus is the outermost part of the brain, the cortex, which is responsible for many functions, including sensory perception. Below the cortex is the white brain matter that in adults contains connections between neurons.

In development, the white matter also contains so-called subplate neurons, some of the first to develop in the brain — at about 12 weeks gestation for humans and the second embryonic week in mice. Anatomist Mark Molliver of Johns Hopkins is credited with describing some of the first connections between neurons formed in white matter, and he coined the term subplate neurons in 1973.

These primordial subplate neurons eventually die off during development in mammals, including mice. In humans, this happens shortly before birth through the first few months of life. But before they die off, they make connections between a key gateway in the brain for all sensory information, the thalamus, and the middle layers of the cortex.

“The thalamus is the intermediary of information from the eyes, ears and skin into the cortex,” says Kanold. “When things go wrong in the thalamus or its connections with the cortex, neurodevelopmental problems occur.” In adults, the neurons in the thalamus stretch out and project long, armlike structures called axons to the middle layers of the cortex, but in fetal development, subplate neurons sit between the thalamus and cortex, acting as a bridge. At the end of the axons is a nexus for communication between neurons called synapses. Working in ferrets and mice, Kanold previously mapped the circuitry of subplate neurons. Kanold also previously found that subplate neurons can receive electrical signals related to sound before any other cortical neurons did.

The current research, which Kanold began at his previous position at the University of Maryland, addresses two questions, he says: When sound signals get to the subplate neurons, does anything happen, and can a change in sound signals change the brain circuits at these young ages?

First, the scientists used genetically engineered mice that lack a protein on hair cells in the inner ear. The protein is integral for transforming sound into an electric pulse that goes to the brain; from there it is translated into our perception of sound. Without the protein, the brain does not get the signal.

In the deaf, 1-week-old mice, the researchers saw about 25% — 30% more connections among subplate neurons and other cortex neurons, compared with 1-week-old mice with normal hearing and raised in a normal environment. This suggests that sounds can change brain circuits at a very young age, says Kanold.

In addition, say the researchers, these changes in neural connections were happening about a week earlier than typically seen. Scientists had previously assumed that sensory experience can only alter cortical circuits after neurons in the thalamus reach out to and activate the middle layers of the cortex, which in mice is around the time when their ear canals open (at around 11 days).

“When neurons are deprived of input, such as sound, the neurons reach out to find other neurons, possibly to compensate for the lack of sound,” says Kanold. “This is happening a week earlier than we thought it would, and tells us that the lack of sound likely reorganizes connections in the immature cortex.”

In the same way that lack of sound influences brain connections, the scientists thought it was possible that extra sounds could influence early neuron connections in normal hearing mice, as well.

To test this, the scientists put normal hearing, 2-day-old mouse pups in a quiet enclosure with a speaker that sounds a beep or in a quiet enclosure without a speaker. The scientists found that the mouse pups in the quiet enclosure without the beeping sound had stronger connections between subplate and cortical neurons than in the enclosure with the beeping sound. However, the difference between the mice housed in the beeping and quiet enclosures was not as large as between the deaf mice and ones raised in a normal sound environment.

These mice also had more diversity among the types of neural circuits that developed between the subplate and cortical neurons, compared with normal hearing mouse pups raised in a quiet enclosure with no sound. The normal hearing mice raised in the quiet enclosure also had neuron connectivity in the subplate and cortex regions similar to that of the genetically-engineered deaf mice.

“In these mice we see that the difference in early sound experience leaves a trace in the brain, and this exposure to sound may be important for neurodevelopment,” says Kanold.

The research team is planning additional studies to determine how early exposure to sound impacts the brain later in development. Ultimately, they hope to understand how sound exposure in the womb may be important in human development and how to account for these circuit changes when fitting cochlear implants in children born deaf. They also plan to study brain signatures of premature infants and develop biomarkers for problems involving miswiring of subplate neurons.

Funding for the research was provided by the National Institutes of Health’s National Institute on Deafness and other Hearing Disorders (R01DC009607) and the National Institute of General Medical Sciences (R01GM056481).

The planets were discovered in TESS images taken between October and December 2018. Follow-up studies of TOI 451 and its planets included observations made in 2019 and 2020 using NASA’s Spitzer Space Telescope, which has since been retired, as well as many ground-based facilities. Archival infrared data from NASA’s Near-Earth Object Wide-Field Infrared Survey Explorer (NEOWISE) satellite — collected between 2009 and 2011 under its previous moniker, WISE — suggests the system retains a cool disk of dust and rocky debris. Other observations show that TOI 451 likely has two distant stellar companions circling each other far beyond the planets.

“This system checks a lot of boxes for astronomers,” said Elisabeth Newton, an assistant professor of physics and astronomy at Dartmouth College in Hanover, New Hampshire, who led the research. “It’s only 120 million years old and just 400 light-years away, allowing detailed observations of this young planetary system. And because there are three planets between two and four times Earth’s size, they make especially promising targets for testing theories about how planetary atmospheres evolve.”

A paper reporting the findings was published on Jan. 14 in The Astronomical Journal and is available online.

Stellar streams form when the gravity of our Milky Way galaxy tears apart star clusters or dwarf galaxies. The individual stars move out along the cluster’s original orbit, forming an elongated group that gradually disperses.

In 2019, a team led by Stefan Meingast at the University of Vienna used data from the European Space Agency’s Gaia mission to discover the Pisces-Eridanus stream, named for the constellations containing the greatest concentrations of stars. Stretching across 14 constellations, the stream is about 1,300 light-years long. However, the age initially determined for the stream was much older than we now think.

Later in 2019, researchers led by Jason Curtis at Columbia University in New York City analyzed TESS data for dozens of stream members. Younger stars spin faster than their older counterparts do, and they also tend to have prominent starspots — darker, cooler regions like sunspots. As these spots rotate in and out of our view, they can produce slight variations in a star’s brightness that TESS can measure.

The TESS measurements revealed overwhelming evidence of starspots and rapid rotation among the stream’s stars. Based on this result, Curtis and his colleagues found that the stream was only 120 million years old — similar to the famous Pleiades cluster and eight times younger than previous estimates. The mass, youth, and proximity of the Pisces-Eridanus stream make it an exciting fundamental laboratory for studying star and planet formation and evolution.

“Thanks to TESS’s nearly all-sky coverage, measurements that could support a search for planets orbiting members of this stream were already available to us when the stream was identified,” said Jessie Christiansen, a co-author of the paper and the deputy science lead at the NASA Exoplanet Archive, a facility for researching worlds beyond our solar system managed by Caltech in Pasadena, California. “TESS data will continue to allow us to push the limits of what we know about exoplanets and their systems for years to come.”

The young star TOI 451, better known to astronomers as CD-38 1467, lies about 400 light-years away in the constellation Eridanus. It has 95% of our Sun’s mass, but it is 12% smaller, slightly cooler, and emits 35% less energy. TOI 451 rotates every 5.1 days, which is more than five times faster than the Sun.

TESS spots new worlds by looking for transits, the slight, regular dimmings that occur when a planet passes in front of its star from our perspective. Transits from all three planets are evident in the TESS data. Newton’s team obtained measurements from Spitzer that supported the TESS findings and helped to rule out possible alternative explanations. Additional follow-up observations came from Las Cumbres Observatory — a global telescope network headquartered in Goleta, California — and the Perth Exoplanet Survey Telescope in Australia.

Even TOI 451’s most distant planet orbits three times closer than Mercury ever approaches to the Sun, so all of these worlds are quite hot and inhospitable to life as we know it. Temperature estimates range from about 2,200 degrees Fahrenheit (1,200 degrees Celsius) for the innermost planet to about 840 F (450 C) for the outermost one.

TOI 451 b orbits every 1.9 days, is about 1.9 times Earth’s size, and its estimated mass ranges from two to 12 times Earth’s. The next planet out, TOI 451 c, completes an orbit every 9.2 days, is about three times larger than Earth, and holds between three and 16 times Earth’s mass. The farthest and largest world, TOI 451 d, circles the star every 16 days, is four times the size of our planet, and weighs between four and 19 Earth masses.

Astronomers expect planets as big as these to retain much of their atmospheres despite the intense heat from their nearby star. Different theories of how atmospheres evolve by the time a planetary system reaches TOI 451’s age predict a wide range of properties. Observing starlight passing through the atmospheres of these planets provides an opportunity to study this phase of development and could aid in constraining current models.

“By measuring starlight penetrating a planet’s atmosphere at different wavelengths, we can infer its chemical composition and the presence of clouds or high-altitude hazes,” said Elisa Quintana, an astrophysicist at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. “TOI 451’s planets offer excellent targets for such studies with Hubble and the upcoming James Webb Space Telescope.”

Observations from WISE show that the system is unusually bright in infrared light, which is invisible to human eyes, at wavelengths of 12 and 24 micrometers. This suggests the presence of a debris disk, where rocky asteroid-like bodies collide and grind themselves to dust. While Newton and her team cannot determine the extent of the disk, they envision it as a diffuse ring of rock and dust centered about as far from the star as Jupiter is from our Sun.

The researchers also investigated a faint neighboring star that appears about two pixels away from TOI 451 in TESS images. Based on Gaia data, Newton’s team determined this star to be a gravitationally bound companion located so far from TOI 451 that its light takes 27 days to get there. In fact, the researchers think the companion is likely a binary system of two M-type dwarf stars, each with about 45% of the Sun’s mass and emitting only 2% of its energy.

TESS is a NASA Astrophysics Explorer mission led and operated by MIT in Cambridge, Massachusetts, and managed by NASA’s Goddard Space Flight Center. Additional partners include Northrop Grumman, based in Falls Church, Virginia; NASA’s Ames Research Center in California’s Silicon Valley; the Center for Astrophysics | Harvard & Smithsonian in Cambridge, Massachusetts; MIT’s Lincoln Laboratory; and the Space Telescope Science Institute in Baltimore. More than a dozen universities, research institutes, and observatories worldwide are participants in the mission.

NASA’s Jet Propulsion Laboratory in Southern California manages NEOWISE for NASA’s Science Mission Directorate in Washington. Ball Aerospace & Technologies Corp. of Boulder, Colorado, built the spacecraft. Science data processing takes place at IPAC at Caltech in Pasadena. Caltech manages JPL for NASA.

The study, led by researchers in the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), found that face masks substantially increase the humidity in the air that the mask-wearer breathes in. This higher level of humidity in inhaled air, the researchers suggest, could help explain why wearing masks has been linked to lower disease severity in people infected with SARS-CoV-2, because hydration of the respiratory tract is known to benefit the immune system. The study published in the Biophysical Journal.

“We found that face masks strongly increase the humidity in inhaled air and propose that the resulting hydration of the respiratory tract could be responsible for the documented finding that links lower COVID-19 disease severity to wearing a mask,” said the study’s lead author, Adriaan Bax, Ph.D., NIH Distinguished Investigator. “High levels of humidity have been shown to mitigate severity of the flu, and it may be applicable to severity of COVID-19 through a similar mechanism.”

High levels of humidity can limit the spread of a virus to the lungs by promoting mucociliary clearance (MCC), a defense mechanism that removes mucus ? and potentially harmful particles within the mucus ? from the lungs. High levels of humidity can also bolster the immune system by producing special proteins, called interferons, that fight against viruses ? a process known as the interferon response. Low levels of humidity have been shown to impair both MCC and the interferon response, which may be one reason why people are likelier to get respiratory infections in cold weather.

The study tested four common types of masks: an N95 mask, a three-ply disposable surgical mask, a two-ply cotton-polyester mask, and a heavy cotton mask. The researchers measured the level of humidity by having a volunteer breathe into a sealed steel box. When the person wore no mask, the water vapor of the exhaled breath filled the box, leading to a rapid increase in humidity inside the box.

When the person wore a mask, the buildup of humidity inside the box greatly decreased, due to most of the water vapor remaining in the mask, becoming condensed, and being re-inhaled. To ensure no leakage, the masks were tightly fitted against the volunteer’s face using high-density foam rubber. Measurements were taken at three different air temperatures, ranging from about 46 to 98 degrees Fahrenheit.

The results showed that all four masks increased the level of humidity of inhaled air, but to varying degrees. At lower temperatures, the humidifying effects of all masks greatly increased. At all temperatures, the thick cotton mask led to the most increased level of humidity.

“The increased level of humidity is something most mask-wearers probably felt without being able to recognize, and without realizing that this humidity might actually be good for them,” Bax said.

The researchers did not look at which masks are most effective against inhalation or transmission of the virus and defer to the CDC for guidance on choosing a mask. Earlier studies from Bax and his colleagues showed that any cloth mask can help block the thousands of saliva droplets that people release through simple speech ? droplets that, if released, can remain in the air for many minutes. While the current study did not examine respiratory droplets, it does offer more evidence as to why masks are essential to battling COVID-19.

“Even as more people nationwide begin to get vaccinated, we must remain vigilant about doing our part to prevent the spread of the coronavirus that causes COVID-19,” said NIDDK Director Dr. Griffin P. Rodgers. “This research supports the importance of mask-wearing as a simple, yet effective, way to protect the people around us and to protect ourselves from respiratory infection, especially during these winter months when susceptibility to these viruses increases.”

The research was supported by the NIDDK Intramural Research Program and the NIH Intramural Antiviral Target Program.