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The highly selective RET inhibitor pralsetinib was well-tolerated and demonstrated robust, durable responses in patients with RET fusion-positive cancers regardless of tumor type, according to results from the international Phase I/II ARROW trial led by researchers at The University of Texas MD Anderson Cancer Center.
The study results, published today in Nature Medicine, showed an overall response rate of 57% and a disease control rate of 83% in 23 patients with a range of cancer types. These findings build upon positive results previously reported in RET-altered non-small cell lung cancer (NSCLC) and thyroid cancer, suggesting the targeted therapy may offer tissue-agnostic benefits to patients with RET fusions.
“We’ve had an explosion in clinical next-generation sequencing that allows us to understand shared biomarkers across multiple tumor types, and this study was important to determine if RET fusions are actionable across cancer types,” said corresponding author Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics. “We observed responses regardless of tumor type, prior therapy or gene fusion partner. These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition.”
RET fusions occur when a piece of the chromosome containing the RET gene is broken and rejoined with another chromosome, creating a fusion protein that fuels the cancer. RET alterations are most common in medullary thyroid cancers, papillary thyroid cancers and NSCLC, but they occur infrequently in many other tissue types.
Based on earlier results from this trial, the Food and Drug Administration approved pralsetinib as a treatment for RET fusion-positive NCLSCs in September 2020 and for advanced RET-altered thyroid cancers in December 2020.
To determine if the therapy provided benefit beyond NSCLC and thyroid cancers, the open-label, single-arm study also enrolled patients with diverse RET fusion-positive solid tumors. Common cancers in this cohort included pancreatic cancer, cholangiocarcinoma, neuroendocrine tumors and sarcoma.
The study enrolled 29 patients with 12 different cancer types. Of these, 23 patients were able to be evaluated for efficacy based on data cut-off dates and pre-specified evaluation criteria. The median age of these patients was 53 years; 14 (61%) were female. Racial demographics were 65% white, 30% Asian and 4% Black. Most patients had metastatic disease (87%) and received prior therapies for their cancer (87%).
Of these, three patients (13%) had a confirmed complete response and 10 (43%) had a confirmed partial response. The median duration of response was 11.7 months, the median progression-free survival was 7.4 months, and the median overall survival was 13.6 months.
Treatment-related side effects were observed in 25 patients (86%), and 20 patients (69%) experienced grade 3 or higher adverse events. The most common side effects were increased levels of the liver enzymes aspartate transaminase and alanine transaminase, and decreased levels of white blood cells (neutropenia). A total of 17 patients (59%) had short-term dose interruptions and 13 patients (45%) had permanent dose reductions due to side effects.
“Although RET fusions are extremely rare beyond lung and thyroid cancers, these patients need effective therapies,” Subbiah said. “These findings demonstrate the potential for RETinhibitors to benefit patients across tumor types and show the power of precision medicine to match patients to the right targeted therapy based on the unique features of their cancer.”
Going forward, Subbiah and his colleagues will focus on RET inhibitor resistance mechanisms in order to potentially further improve outcomes for patients with RET alterations. His team already has begun to identify resistance pathways and is working to develop novel therapeutic approaches.

From the perspective of chemists, pleurotin is an intriguing molecule.
There is strong evidence of untapped therapeutic properties as a tumor inhibitor and antibiotic. It has a fascinating complex structure (six rings! eight stereocenters!). And it has been difficult to synthesize over the decades. The last time chemists pulled that off, the year was 1988 and they needed 26 steps in which to do it.
For Princeton Chemistry’s Sorensen Lab, those qualities were part of the attraction for a long-term investment of time and energy that has come to fruition.
The lab reports a concise synthesis of pleurotin by way of the Diels-Alder reaction and a radical epimerization that flips a cis-hydrindane to the desired trans-hydrindane. Their late-stage intermediate intersects the milestone 1988 synthesis towards the end of the process, thereby reducing the total number of steps needed for the synthesis by thirteen.
The lab’s process could yield an expanded family of pleurotin-like anticancer screening candidates which, down the line, may be useful to pharmaceutical companies looking to exploit the promise of pleurotin as a next-generation drug.
“Pleurotin is a very sensitive molecule, it’s very reactive. But it hasn’t worked out as a drug yet, partly because it’s not very water-soluble,” said third-year graduate student John Hoskin, lead author on the paper. “Ideally you want to alter its structure: tweak here, change here, put a hydroxy here or a phosphate there, do some very careful modifications.

Chemist Jixin Chen looked at the rapid spread of COVID-19 early in the pandemic and saw a novel opportunity for his kinetics lab, where they study the rates of reactions.
The first time he ran the lab in spring 2021, undergraduate students concluded that social regulations such as lockdowns, face masks and social distancing were effective ways to slow the speed of the spread of COVID. But they also discovered the limitations of modeling, noting that a large number of confirmed cases didn’t necessarily associate with an increasing rate of spread.
Students in the next lab wrote in a journal article on their experience that researchers should continue this work when infection and vaccination rate became significant.
And that’s just what happened. The spring 2022 lab students extended the mathematical model to make predictions on the rate of spread of COVID-19 in the United States with massive vaccination.
They also ran the model for the state of Ohio through fall 2022 — correctly predicting the upsurge in cases the state is experiencing at the end of summer.
The second group of lab students also wrote up their lab experience, this time seeing it published in the Journal of Chemical Education. All the students walked away from the lab with the requisites filled. But they also could add several lines to their resumes — for modeling software experience, data analysis skills, and a journal publication.

Testosterone can foster friendly, prosocial behavior in males, a new animal study finds. The Proceedings of the Royal Society B published the research on Mongolian gerbils conducted by neuroscientists at Emory University.
“For what we believe is the first time, we’ve demonstrated that testosterone can directly promote nonsexual, prosocial behavior, in addition to aggression, in the same individual,” says Aubrey Kelly, Emory assistant professor of psychology and first author of the study. “It’s surprising because normally we think of testosterone as increasing sexual behaviors and aggression. But we’ve shown that it can have more nuanced effects, depending on the social context.”
The work also revealed how testosterone influences the neural activity of oxytocin cells — the so-called “love hormone” associated with social bonding.
Richmond Thompson, a neuroscientist at Oxford College of Emory University, is co-author of the study.
Kelly’s lab has recently focused on the neural effects of oxytocin using rodent experimental models. Thompson’s lab investigates the neural effects of steroids in fish. Both scientists are trying to get at the question of how hormones work in the brain to allow an animal to rapidly change its behavior, depending on the social context.
In addition to sharing this research interest, Kelly and Thompson share a home as a married couple.

After 20 years searching for a cure for tinnitus, researchers at the University of Auckland are excited by ‘encouraging results’ from a clinical trial of a mobile-phone-based therapy. The study randomised 61 patients to one of two treatments, the prototype of the new ‘digital polytherapeutic’ or a popular self-help app producing white noise.
On average, the group with the polytherapeutic (31 people) showed clinically significant improvements at 12 weeks, while the other group (30 people) did not. The results have just been published in Frontiers in Neurology. “This is more significant than some of our earlier work and is likely to have a direct impact on future treatment of tinnitus,” Associate Professor in Audiology Grant Searchfield says.
Key to the new treatment is an initial assessment by an audiologist who develops the personalised treatment plan, combining a range of digital tools, based on the individual’s experience of tinnitus. “Earlier trials have found white noise, goal-based counselling, goal-oriented games and other technology-based therapies are effective for some people some of the time,” says Dr Searchfield. “This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control.”
There is no pill that can cure tinnitus. “What this therapy does is essentially rewire the brain in a way that de-emphasises the sound of the tinnitus to a background noise that has no meaning or relevance to the listener,” Dr Searchfield says.
Audiology research fellow Dr Phil Sanders says the results are exciting and he found running the trial personally rewarding.
“Sixty-five percent of participants reported an improvement. For some people, it was life-changing — where tinnitus was taking over their lives and attention.”
Some people didn’t notice an improvement and their feedback will inform further personalisation, Dr Sanders says.
Tinnitus is a phantom noise and its causes are complex. It has so far defied successful treatment.
While most people experience tinnitus, or ringing in the ears at least on occasions, around five percent experience it to a distressing degree. Impacts can include trouble sleeping, difficulty carrying out daily tasks and depression.
Dr Searchfield says seeing his patients’ distress and having no effective treatment to offer inspired his research. “I wanted to make a difference.”
The next step will be to refine the prototype and proceed to larger local and international trials with a view to FDA approval.
The researchers hope the app will be clinically available in around six months.
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Materials provided by University of Auckland. Note: Content may be edited for style and length.

Tears, tantrums, and distress — when it comes to needles, many children struggle with anxiety. But with vaccinations becoming more regular, finding ways to help reduce needle-related fear and pain is high on the agenda.
Now, new research from the University of South Australia shows that children’s vaccination and needle fear can be lessened when nurses spend additional time supporting children in the vaccination process.
Working with children aged 8-12 years, the preliminary study found that two new nurse-led techniques show promise in reducing needle fear in primary-aged children: Divided Attention — where a child’s attention and expectations are drawn away from the needle. Positive Memory Reframing — where a child’s exaggerations about the distress and discomfort of needles are redressed through discussion about the positive elements of the experience so that the form more realistic memories of the event.Lead researcher, UniSA’s Dr Felicity Braithwaite, says helping children reduce fear and distress around vaccinations is a critical research priority given the current COVID-19 pandemic.
“For many children, undergoing a needle procedure can be painful and distressing,” Dr Braithwaite says.
“Negative experiences of vaccinations in childhood can often lead to medical avoidance and vaccine hesitancy into adulthood, which can have devastating consequences when it comes to outbreaks of preventable diseases.
“By investing more time into techniques to help children manage their fears about needles, we hope to change these outcomes and deliver better health outcomes for the next generation.”
The study involved 41 children and their parents, with participants randomly allocated to one of four groups — usual care, divided attention, positive memory reframing, or a combination of the latter two interventions. Clinical outcomes were assessed at baseline, immediately post-vaccination and at two-weeks post-vaccination.
The Divided Attention technique involved a one-two minute distraction game where a nurse tapped the child’s arm above and below the vaccination spot in a random order, with the child focussing their attention on guessing which spot was touched each time. This game takes advantage of the potential analgesic effects of distraction.
The Positive Memory Reframing technique involved talking to children about a past injection and emphasising positive aspects, such as how brave the child was and praising specific strategies they used to reduce their own distress, for example, deep breathing and looking away. The aim is to foster a sense of self-efficacy to help children better cope.
Both strategies were tested in non-clinical settings (such as schools) to maximise the potential of broad vaccination programs that deliver minimal distress for children.
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Materials provided by University of South Australia. Note: Content may be edited for style and length.

An artificial intelligence (AI) algorithm that can detect subtle brain abnormalities which cause epileptic seizures has been developed by a UCL-led team of international researchers.
The Multicentre Epilepsy Lesion Detection project (MELD) used over 1,000 patient MRI scans from 22 global epilepsy centres to develop the algorithm, which provides reports of where abnormalities are in cases of drug-resistant focal cortical dysplasia (FCD) — a leading cause of epilepsy.
FCDs are areas of the brain that have developed abnormally and often cause drug-resistant epilepsy. It is typically treated with surgery, however identifying the lesions from an MRI is an ongoing challenge for clinicians, as MRI scans in FCDs can look normal.
To develop the algorithm, the team quantified cortical features from the MRI scans, such as how thick or folded the cortex/brain surface was, and used around 300,000 locations across the brain.
Researchers then trained the algorithm on examples labelled by expert radiologists as either being a healthy brain or having FCD — dependant on their patterns and features.
The findings, published in Brain, found that overall the algorithm was able to detect the FCD in 67% of cases in the cohort (538 participants).

Over the last 25 years, astronomers have found thousands of exoplanets around stars in our galaxy, but more than 99% of them orbit smaller stars — from red dwarfs to stars slightly more massive than our sun, which is considered an average-sized star.
Few have been discovered around even more massive stars, such as A-type stars — bright blue stars twice as large as the sun — and most of the exoplanets that have been observed are the size of Jupiter or larger. Some of the brightest stars in the night sky, such as Sirius and Vega, are A-type stars.
University of California, Berkeley, astronomers now report a new, Neptune-sized planet — called HD 56414 b — around one of these hot-burning, but short-lived, A-type stars and provide a hint about why so few gas giants smaller than Jupiter have been seen around the brightest 1% of stars in our galaxy.
Current exoplanet detection methods most easily find planets with short, rapid orbital periods around their stars, but this newly found planet has a longer orbital period than most discovered to date. The researchers suggest that an easier-to-find Neptune-sized planet sitting closer to a bright A-type star would be rapidly stripped of its gas by the harsh stellar radiation and reduced to an undetectable core.
While this theory has been proposed to explain so-called hot Neptune deserts around redder stars, whether this extended to hotter stars — A-type stars are about 1.5 to 2 times hotter than the sun — was unknown because of the dearth of planets known around some of the galaxy’s brightest stars.
“It’s one of the smallest planets that we know of around these really massive stars,” said UC Berkeley graduate student Steven Giacalone. “In fact, this is the hottest star we know of with a planet smaller than Jupiter. This planet’s interesting first and foremost because these types of planets are really hard to find, and we’re probably not going to find many like them in the foreseeable future.”
Hot Neptune desert

An extensive meta-analysis suggests that vitamin D supplementation may alleviate depressive symptoms in adults with depression. Conducted by an international team of researchers, the meta-analysis includes dozens of studies from around the world.
Depressive symptoms cause a significant disease burden worldwide. The therapeutic efficacy of current antidepressants is often insufficient, which is why further ways to alleviate the symptoms of depression have been sought, for example, from nutritional research.
Vitamin D is believed to regulate central nervous system functions the disturbances of which have been associated with depression. In addition, cross-sectional studies have observed an association between depressive symptoms and vitamin D deficiency. However, previous meta-analyses on the effects of vitamin D supplementation on depression have been inconclusive. In a meta-analysis, results from several different studies are combined and analysed statistically.
The new meta-analysis on the association of vitamin D supplementation with depression is the largest one published so far, including results from 41 studies from around the world. These studies have investigated the efficacy of vitamin D in alleviating depressive symptoms in adults by randomised placebo-controlled trials in different populations. The studies included those carried out in patients with depression, in the general population, and in people with various physical conditions. The results of the meta-analysis show that vitamin D supplementation is more effective than a placebo in alleviating depressive symptoms in people with depression. There were major differences in the vitamin D doses used, but typically the vitamin D supplement was 50-100 micrograms per day.
“Despite the broad scope of this meta-analysis, the certainty of evidence remains low due to the heterogeneity of the populations studied and the due to the risk of bias associated with a large number of studies,” Doctoral Researcher and lead author Tuomas Mikola of the Institute of Clinical Medicine at the University of Eastern Finland says. The meta-analysis is part of Mikola’s PhD thesis.
“These findings will encourage new, high-level clinical trials in patients with depression in order to shed more light on the possible role of vitamin D supplementation in the treatment of depression,” Mikola concludes.
The meta-analysis was carried out in international collaboration between Finnish, Australian and US researchers.
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Materials provided by University of Eastern Finland. Note: Content may be edited for style and length.

The new guidelines eliminate quarantines and put less emphasis on social distancing, routine surveillance testing and contact tracing.The Centers for Disease Control and Prevention loosened Covid-19 guidelines on Thursday, freeing schools and businesses from the onus of requiring unvaccinated people exposed to the virus to quarantine at home.The changes are a sharp move away from measures such as social distancing requirements and quarantining, which had polarized much of the country, and effectively acknowledge the way many Americans have been navigating the pandemic for some time. The agency’s action comes as children across the country return to school and many offices have reopened.“We know that Covid-19 is here to stay,” Greta Massetti, a C.D.C. epidemiologist, said at a news briefing on Thursday. “High levels of population immunity due to vaccination and previous infection, and the many tools that we have available to protect people from severe illness and death, have put us in a different place.”The C.D.C.’s new guidelines come after more than two years of a pandemic in which more than one million Americans have died. With the highly contagious BA.5 subvariant of Omicron spreading, the United States is recording more than 100,000 cases and nearly 500 deaths a day on average.But many Americans dispensed with practices such as social distancing, quarantine and mask-wearing long ago.“I think they are attempting to meet up with the reality that everyone in the public is pretty much done with this pandemic,” said Michael T. Osterholm, an infectious disease expert at the University of Minnesota, referring to the C.D.C.The agency has been working for months on the new guidance, which builds on previous recommendations issued in February, when the agency shortened isolation times for many Americans. The C.D.C. said it is making changes now because vaccination and prior infections have granted many Americans some degree of protection against the virus, and treatments, vaccines and boosters are available to reduce the risk of severe illness.The changes shift much of the responsibility for risk reduction from institutions to individuals. The C.D.C. no longer recommends that people stay six feet away from others. Instead, it notes that avoiding crowded areas and maintaining a distance from others are strategies that people may want to consider in order to reduce their risk.And the recommended prevention strategies no longer draw a distinction between people who are up-to-date on their vaccinations and those who are not, streamlining a complicated set of rules that could be difficult for schools and businesses to navigate.People who are exposed to the virus no longer must quarantine at home regardless of their vaccination status, although they should wear a mask for 10 days and get tested for the virus on Day 5, according to the new guidelines. Contact tracing and routine surveillance testing of people without symptoms are no longer recommended in most settings.Read More on the Coronavirus PandemicBoosters: Britain became the first country to authorize a coronavirus vaccine that targets two variants. Half of each dose of the Moderna-made shot will target the original variant, and the other half will target Omicron.New Guidelines: The Centers for Disease Control and Prevention loosened its Covid-19 guidance, saying those exposed to the virus no longer need to quarantine. A day later, the U.S. Food and Drug Administration recommended that people exposed to Covid who are asymptomatic take at least three at-home antigen tests, each spaced 48 hours apart, to reduce the risk of missing an infection.Parents and Pandemic Politics: They were once Democrats and Republicans. But fears for their children fueled by vaccine skepticism have turned them into single-issue voters, on the side of no vaccine mandates for their children.Coronavirus Origins: Two new studies exploring how the Covid outbreak began, concluded that the wet market in Wuhan, China, was the likely epicenter of its emergence.Instead of focusing on slowing transmission of the virus, the recommendations prioritize preventing severe illness. They emphasize the importance of vaccination and other prevention measures, including antiviral treatments and ventilation.The guidelines around masking — which recommend that people wear them indoors in places where community Covid-19 levels are high — have not changed.And people who test positive for the virus should still isolate at home for at least five days. Those who had moderate or severe illness, or are immunocompromised, should isolate through Day 10.The agency also addressed the rebound infections that some people reported after taking the antiviral treatment Paxlovid; if symptoms return, people should restart the clock on isolation, the C.D.C. said.Many health experts praised the new guidelines as representing a pragmatic approach to living with the virus in the longer term.“I think this a welcome change,” said Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security. “It actually shows how far we’ve come.”The new guidelines will also be easier for the public to follow, he added.But the pandemic has not ended, experts noted, and more stringent measures may be needed in the event of new variants or future surges.While nearly all Americans are now eligible to be vaccinated, many are not up to date on their shots. Just 30 percent of 5- to 11-year-olds and 60 percent of 12- to 17-year-olds have received their primary vaccine series nationwide. Among adults 65 and older, who are at highest risk of severe illness, 65 percent have received a booster. Critical therapeutics, such as antiviral treatments, remain difficult for many to access.“Obviously, we have to do more work to make sure that more people avail themselves of the protection that those tools have to offer and that more people can access those tools,” said Jennifer Nuzzo, director of the Pandemic Center at the Brown University School of Public Health. “I do think there’s been an overall dial-back in the ground game that’s needed to get people vaccinated.”The guidance moves away from sweeping, population-level precautions to more targeted advice for vulnerable populations and specific high-risk settings and circumstances.For instance, the guidelines note that schools may want to consider surveillance testing in certain scenarios, such as for when students are returning from school breaks or for those who are participating in contact sports.Unvaccinated students who are exposed to the virus will no longer need to test frequently in order to remain in the classroom, an approach known as “test to stay.” The C.D.C. no longer recommends a practice known as cohorting, in which schools divide students into smaller groups and limit contact between them to reduce the risk of viral transmission.Health experts said the change in guidance was particularly welcome as students head back to school, a setting in which quarantines had been especially disruptive.“This really will help to minimize the impact of Covid-19 on education,” said Christina Ramirez, a biostatistician at the University of California, Los Angeles.Mercedes Carnethon, an epidemiologist at the Northwestern University Feinberg School of Medicine, said that she did not view the changes, even the elimination of quarantines in favor of 10 days of masking, as a loosening of the agency’s guidance.“We certainly know that wearing a high-quality mask is going to provide some of the strongest protection against spreading it to somebody else, and quarantine is logistically burdensome,” she said. “That could be seen as a relaxing of guidelines, but I think it’s a much more appropriate and targeted solution.”Joseph Allen, a Harvard University researcher who studies indoor environmental quality, praised the new guidelines for putting more emphasis on improving ventilation.“Good ventilation is something that helps reduce the risk of transmission that isn’t political and doesn’t require any behavior change,” he said.Sheryl Gay Stolberg