Cancer Immunotherapy Blossoms Are Starting to Bear Fruit
Over the last decade, there has been unprecedented success and progress in immunotherapy for cancer treatment, so says Ira Mellman, PhD, the president of research at the Parker Institute for Cancer Immunotherapy during his opening keynote at the Frontiers in Cancer Immunotherapy Symposium hosted by The New York Academy of Sciences, held on June 23, 2026.
Through his talk, Mellman described the research and clinical seeds that were sown over the last two decades. He showed how these seeds have blossomed, and his expectations for which blossoms will bear fruit, with the right focus and pruning.

The last decade of cancer immunotherapy
Before considering therapeutic options, Mellman summarized the biological events required for stimulating an effective immune response in patients. He described the dual stages of T cell activation and T cell exhaustion. Most therapies have relied on interventions that activate T cells, but over time, these T cells become exhausted—they don’t die, but go into senescence.
The next logical step in therapeutic investigation was to explore methods to pull exhausted T cells from senescence back into an active state. While some new therapies are being tested, there is still significant work to be done and there have been many false starts.
Vaccine therapy has emerged to get ahead of the activation-exhaustion problem by developing primed and more efficient T cells.
“The sole purpose of vaccine therapy, as we think of it, is to generate more and better T cells by immunizing against presumptive tumor associated antigens or neo antigens and …having those cells feed into the cycle,” Mellman said. He explained that the idea behind using vaccines is akin to the goal of adaptive therapies, like CAR T, that increase the number of primed and functional T cells, but vaccines do it endogenously.
Broadening his scope further, Mellman spoke about cancers not just in terms of the direct interaction between cancer cells and T cells, but in the broader context of the body. “The tumor microenvironment (TME),” he said, “plays an immense role—both positive and negative—with respect to allowing T cells to do their jobs in the case of anti-tumor immunity.” Consideration of the interactions between cancer and the TME present both opportunities and challenges to developing therapies.
Current progress
“We’ve had unprecedented success both clinically and commercially” within the last 15 years for a variety of cancer therapies that have come from the research stage to FDA approval in a relatively short time. Mellman pointed out that these therapies not only have been created quickly, are effective across a variety of diseases, are well tolerated, and improve survival of patients.
“All of this activity together has really changed the standard of care in a wide variety of cancer types,” he stressed. “That this has happened over a 15-year period is truly extraordinary.”
Why is a renaissance needed?
With this progress, Mellman returned to his original thesis that the field of cancer immunotherapy is on the precipice of big change.
He asked, “With this success—including clinical and financial—why do we need a renaissance in this area?” He answered his own question stating, that “We are the victims of our own success.”
He described challenges and setbacks stemming from the early progress. He described that identifying new checkpoint targets have not been successful, TIL research is somewhat successful, but outcomes are inconsistent, solid tumors post problems for therapies like CAR T, and cancer vaccines efficacy is unconfirmed except in their use as a post-operative adjuvant.
Reflecting on the history and progress, Mellman presented his four top priorities in progressing cancer immunotherapy over the next ten years. First, focusing on the next generation of cell therapy, especially focusing on treating solid tumors. Second, he suggests moving past CARs to using neoantigen-driven targeting (including vaccines, synthetic neoAg, and TCR platforms). Third, prioritizing in vivo immune engineering to reduce costs and improve accessibility and scalability. Fourth, he stresses the need to focus on a holistic approach to cancer immunology, understanding and optimizing the TME cancer interactions, developing synthetic modulators and utilizing AI models guided by patient insights.
Current steps to the future
Mellman further explained that through his work over the last two decades, he’s learned many lessons. He pointed out that researchers and clinicians need to remember that there are many therapeutic opportunities derived from various approaches; he cautioned against forgetting that mice are not humans and vice versa, pointing out that what may work in one species may not in the other; he encouraged the use of new technologies, including integrating AI into analysis procedures; and finally he suggested that researchers build on clinical research not just laboratory work.
Focusing on his own work, Mellman described how his team integrated these lessons in studying the application of mRNA vaccines. He described a study comparing the outcomes of patients with pancreatic cancer given mRNA vaccines intravenously (IV) or with an intramuscular (IM) dose. They were surprised to find that patients receiving IV delivery responded to the vaccine, but the response was inconsistent at first glance. Through deeper investigation, they determined that non-responsive patients previously had a splenectomy in addition to the removal of their pancreatic tumor. They reasoned that the IV infusion in responsive patients impacted immune cells developing in the spleen. While this study helped explain part of the process, Mellman pointed out that the fundamental mechanisms by which vaccines can be functional as an adjuvant are still unclear and his team is currently working on addressing these questions.
“There is a wealth of new understanding that we can generate if we move to the clinic quickly but do so in a way that really still concentrates on the underlying basic science,” he concluded. He stressed the importance of following approaches with an established proof of concept and suggested that engineering will enable research and scaling up to positively impact many patients.
Tending to the blossoming research and application of cancer therapy will allow for patients to have the opportunity to have better therapies in the future. Though he said this early in his discussion, it seems appropriate to end with Mellman’s assertion that, “This is a remarkable field.”
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Merck KGaA to Acquire Bio-Techne for $11.3B, Expanding Life Science Tools Presence
Merck KGaA, Darmstadt, Germany, has agreed to acquire Bio-Techne for approximately $11.3 billion, the companies said today, in a deal designed to position the buyer as more of a leader across the life science value chain by expanding its presence in high-growth, next-generation life-sci markets with Bio-Techne’s tools, analytical technologies, and consumables.
The deal would add Bio-Techne’s multiomics offerings, analytical technologies, and integrated workflow solutions to German Merck’s platforms and services in research, bioprocessing and advanced therapeutics, with the aim of creating a combined company capable of helping customers from discovery and translational research through development, testing and commercial manufacturing.
Merck KGaA added that acquiring Bio-Techne would directly deliver on its mid- to long-term strategic agenda, which focuses on adding to its high-growth value drivers, integrated workflows, platformed capabilities—as well as scaling and sourcing innovation through merger-and-acquisition (M&A) deals like the Bio-Techne transaction.
That transaction is the latest in a series of acquisitions for Merck KGaA totaling more than $35 billion, including in the U.S. with acquisitions such as Millipore (for about $7 billion in 2010), as well as Sigma-Aldrich (for $17 billion in a deal announced in 2014 and completed the following year), Versum Materials (for €5.8 billion [about $6.6 billion] in 2019), and last year, SpringWorks Therapeutics (for $3.95 billion).
Merck KGaA said it would also benefit from Bio-Techne’s position as a leading provider of materials, analytics, and process technologies to cell therapy developers. Bio-Techne expects to acquire the ownership in Wilson Wolf it does not own immediately following the end of calendar year 2027 under the terms of a two-part forward contract between the company and Wilson Wolf, a manufacturer of cell culture devices, including the G-Rex product line. Bio-Techne holds 19.9% of Wilson Wolf that it acquired in the fiscal year that ended June 30, 2023.
Merck KGaA employs more than 14,000 people in the U.S. across over 70 company and customer sites.
The $11.3 billion Bio-Techne acquisition is the new third largest biopharma merger-and-acquisition (M&A) deal announced so far this year, behind the €10.7 billion ($12.268 billion) cash buyout offer for Italian-based Recordati being pursued by CVC Capital Partners and Groupe Bruxelles Lambert, which aim to take the company private; and Sun Pharmaceutical Industries’ planned $11.75 billion purchase of Organon, the women’s health drug developer spun out of Merck & Co., in a deal expected to close in early 2027.
The previous third-largest M&A deal this year, now fourth-largest, is the $10.9 billion AbbVie purchase of Apogee Therapeutics, announced on Monday. The fifth largest deal is GlaxoSmithKline (GSK)’s planned $10.6 billion buyout of Nuvalent, announced June 9 and expected to close in the third quarter.
“Outstanding fit”
“Bio-Techne is an outstanding fit that directly supports our strategic direction focused on delivering cutting-edge products and solutions across the entire industry value chain—from lab customers to those manufacturing in the biotech and pharmaceutical industries,” Kai Beckmann, chairman of the executive board and group CEO of Merck KGaA, Darmstadt, Germany, said in a statement.
“By combining Bio-Techne’s scientific depth, innovation engine and differentiated portfolio with the global scale, manufacturing excellence and customer reach of Merck KGaA, Darmstadt, Germany, we are in a strong position to address some of the most important opportunities in life sciences and support our customers in accelerating the next generation of scientific discovery and therapeutic innovation. This positions us to deliver compelling strategic and financial benefits for shareholders, customers and employees,” Beckmann added.
Those benefits, according to German Merck, include immediate accretion to the company’s earnings before interest, taxes, depreciation, and amortization (EBITDA) pre margin for both the Group as a while and its Life Science business segment upon closing of the acquisition deal.
The Life Sciences segment finished last year with €8.98 billion ($10.36 billion) in revenue. Merck KGaA does not break down its businesses further than its three segments, which also include healthcare (drug development, focused on oncology, neurology and immunology, and “global health” treatments such as for malaria) and electronics (high-tech materials).
The deal is expected to close by late 2026 or early 2027, subject to satisfying customary closing conditions that include obtaining regulatory approvals and approval by Bio-Techne shareholders.
Bio-Techne’s board of directors and the corporate bodies overseeing Merck KGaA, Darmstadt, Germany, have already approved the transaction, which will also add to earnings per share (EPS) by year three after closing, German Merck said.
€140M in “synergies”
Merck KGaA said it will carry out cost-cutting “synergies” of approximately €140 million (about $159.3 million) that are expected to be fully realized by the third year after closing.
The planned acquisition will be funded through a combination of existing cash on hand and proceeds from new debt, Merck KGaA said, adding that it will preserve its “strong” investment-grade credit rating.
For Minneapolis-based Bio-Techne, the acquisition is expected to increase its geographic and omnichannel access for its customers through integration of its offerings with those of Merck KGaA through a synergistic platform.
Bio-Techne has more than 3,000 employees, with approximately 2,300 employees based in the U.S. The company operates 34 global locations and 15 manufacturing facilities across the U.S., Canada, the U.K., Switzerland and China, and generated net sales of more than $1.2 billion in the fiscal year that ended June 30, 2025.
A leader in recombinant proteins with a half-century of heritage in next-generation R&D and new modalities, Bio-Techne said it would bring to German Merck a globally recognized portfolio of cytokines, growth factors, antibodies, and immunoassay kits. Bio-Techne is expected to strengthen the analytical and bioprocess solutions of Merck KGaA by adding to its offerings ProteinSimple, a leader in automated protein detection and analysis instruments. Bio-Techne added that its RNAscope and related in situ hybridization technologies would strengthen the capabilities of Merck KGaA, in spatial biology and diagnostics.
“For 50 years, Bio-Techne has enabled scientific breakthroughs across proteomics, spatial biology, and novel therapeutics,” stated Kim Kelderman, president and CEO of Bio-Techne. “This transaction is a testament to the remarkable company our team has built and to the enduring value we create for our customers and stakeholders.”
Muted enthusiasm
Bio-Techne investors appeared to share only muted enthusiasm for the deal, as the company’s shares traded on Nasdaq rose just 19.8% to $70.53 as of 12:48 pm ET, from Wednesday’s close of $58.88 per share. Merck KGaA shares traded on XETRA rose 4.93% to €147.00 ($167.25).
Puneet Souda, senior managing director, life science tools and diagnostics, and a senior research analyst with Leerink Partners, offered a possible explanation in a research note today: “The acquisition appears to be only a 24% premium to yesterday’s close and 26x the Street’s forecast for FY27 [enterprise value]/EBITDA compared to 16x for its LST [life science technologies] peer group.”
“We see the acquisition multiple undervaluing what is a highly accretive asset in our view,” Souda wrote. “Historically, TECH [Bio-Techne’s stock ticker] traded at much higher multiples given their highly accretive consumables profile (80%+ consumables) of consistent 70%+ gross margins and operating margin potential.”
One rival company in particular may benefit from the deal, Souda said: “The announcement is likely to be viewed positive for peer LST companies today, especially RVTY [Revvity] in our view.”
At $73 per share cash, the deal price represents a 36% premium to Bio-Techne’s one-month volume weighted average trading price.
“As part of Merck KGaA, Darmstadt, Germany, we will have greater scale and expanded capabilities to accelerate innovation and deepen our impact. Together, we will empower our customers to tackle the most important challenges in science and healthcare, helping to improve outcomes worldwide,” Kelderman added.
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BIO 2026: FDA Leadership Confront Workforce Losses, China Competition in Drug Development
SAN DIEGO — The U.S. Food and Drug Administration (FDA) is in the middle of a cultural and operational shift that goes beyond leadership changes. U.S.–China biotechnology competition is driving discussions around regulatory reform in the U.S. where traditional paradigms are being reviewed and reconsidered, particularly for rare diseases. And patient perspectives need to be a more integral part of the drug development continuum.
Those were some of the major themes that emerged from a town hall that took place at this year’s Biotechnology Innovation Organization (BIO) meeting in San Diego, which featured members of the current FDA leadership team.
John Crowley, BIO president and CEO, moderated the discussion with the acting directors of Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) and the acting chief of staff at the FDA. During the hour-long conversation in a room packed to the hilt with BIO attendees, they spoke about the agency’s current priorities and its plans to increase its headcount, among other initiatives.
Much of the discussion centered on ongoing plans to stabilize the agency’s workforce following the massive reduction in staffing implemented by the Department of Government Efficiency (DOGE) as well as departures of several leaders in rapid succession. The panelists acknowledged the disruptions to operations, the loss of institutional knowledge, and the past unpredictability at the agency, but did not dwell on it.
The consensus seems to be that stabilizing the agency’s workforce is an important prerequisite for successfully launching several planned initiatives. In fact, Michael Davis, MD, PhD, acting director of CDER, noted that this has been one of his top priorities. His initial efforts were aimed at “fortifying the center and specifically the workforce” as well as finding ways to retain staff retention and boost recruitment.
The conversation covered plans to improve overall morale, boost staff numbers, and to refocus on executing the agency’s mission. That includes implementing “some initiatives that were announced” or “have been in discussion for some time” and thinking through what is needed to support those programs, said Lowell Zeta, JD, acting chief of staff at the FDA.
Karim Mikhail, CBER acting director, stated that in addition to working through existing submissions, his team is also planning for future challenges and ways to address them quickly to avoid backlogs.
In terms of recruitment, the agency is looking to fill more than 2,200 authorized positions across the agency, Zeta said. About 600 people are currently being onboarded as part of the hiring push “so we feel like we’re making good progress.” CDER’s Davis said he is open to “bringing back good people” who would be interested in returning, as well as recruiting new candidates interested in public health who have the requisite skills.
The agency is also intentional about its efforts to minimize attrition, including offering opportunities for staff to meet with leadership to discuss challenges and support needs. And those efforts may be working. In CDER, for example, staff attrition has slowed to its historical rate.
Modernizing clinical development
Earlier this week, the FDA announced a slate of early actions aimed at “modernizing” and expediting early and late-stage clinical development. These were unveiled as part of Operation TrailBlazer, a U.S. Department of Health and Human Services initiative. The proposed changes are aimed at streamlining Phase I submission requirements so that drug developers have more clarity about what is necessary at this stage and what can be deferred. The agency is seeking public comments from the scientific community on some of these proposed actions.
The panelists positioned the proposed actions as a fundamental shift from the traditional comprehensive review approach to drug development towards a more adaptive design process. “Everybody understands the challenge we have,” Mikhail said. “We have incredible rigor” but “we need to make sure that we’re also as fast as we are rigorous.”
Importantly, the agency is also seeking to make patient perspectives more central to the drug development process. Asked by Crowley how this will work, Davis shared an anecdote about taking part in a listening session coordinated by the FDA for parents of patients with the rare disorder, Smith-Magenis syndrome. Asking questions like “What is it like to have children with this condition? What effect does that have on the children? What effect does that have on the family dynamic?” makes it “more real when connecting the data to what families and patients are experiencing.”
China crisis
Another major theme here and indeed throughout the conference was maintaining U.S. competitiveness and leadership in biotech. The panelists acknowledged China’s current competitive advantage in terms of the development of its biotech infrastructure and the reality of clinical trials moving overseas due to increasing costs and the regulatory burden in the U.S.
As Crowley put it, “China frankly is eating our lunch” and “we’re forcing so many of our innovators and companies to go to China” for early-stage clinical trials. In this climate, he noted that the FDA has a crucial role to play.
The FDA has traditionally been viewed as the “guardian of public health, which is an important, primary role,” Crowley said, but “this notion of being a beacon of innovation and U.S. competitiveness tied to our national security is a new and important role.” The panelists also highlighted the growing use of artificial intelligence tools, digital health technologies, and wearable sensors as an important source of innovation within the agency
The FDA has recently signaled a willingness to revisit decisions it made over the past several months if those companies whose applications were rejected choose to resubmit them. “I want to make sure that we’re getting the decisions right in a way they have the confidence of the American public,” Davis said. “I think the public really trusts the FDA to make the right decisions” and “doing this closely with the multidisciplinary expert staff that we have.”
To be clear, the agency is not going to approve everything, Mikhail said. But it will make sure that patient safety is prioritized, and that a multidisciplinary group of scientific experts at the FDA provide critical input.
“I think everybody wants what is best for the patients,” he said. So “making sure that safety is paramount” and that “everybody is on the same page with regards to that second chance.”
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Imaging Technique Scans Entire Donor Livers for Transplant Viability
A new imaging approach to assess donor livers before transplantation could provide a much more comprehensive view of the condition of the whole organ, complementing conventional pathology tests that are typically restricted to localized areas.
In a study published in Science Translational Medicine, researchers at the University of Oklahoma used polarization-sensitive optical coherence tomography (PS-OCT) to noninvasively measure multiple relevant parameters across the entire surface of donor livers. Using polarized light, this imaging technique was able to detect signs of steatosis, fibrosis, inflammation, and necrosis in donor livers—all of which are critical indicators of transplant viability.
“PS-OCT offers a noninvasive assessment of liver viability by quantifying hepatic parameters across the entire donor liver, effectively complementing current pathological analysis,” write the authors of the study, led by Qinggong Tang, PhD, associate professor of biomedical engineering at the University of Oklahoma. “These results suggest that PS-OCT provides a robust approach to assessing donor liver viability, which could potentially decrease the discard rate of high-risk livers, thereby expanding the donor pool.”
Liver transplants are limited by a shortage of viable donor livers, which is driven by a high demand for donor livers and high rates of organ discard. In the U.S. alone, there are over 9,000 people on the liver transplant waitlist, which has driven healthcare providers to progressively expand the criteria used to evaluate potential donors.
Assessing whether a donor liver is viable for transplantation currently relies on biopsies. However, these are invasive procedures that only provide information about the specific location within the liver the sample was taken from. As a result, this approach can sometimes miss critical signs of damage or disease elsewhere in the organ, potentially increasing the risk of transplanting a compromised liver.
Tang and colleagues first evaluated the performance of PS-OCT imaging in discarded human donor livers, comparing the results to biopsies and functional tests. Using a machine learning algorithm to analyze the imaging data enabled the identification of key signs of injury and disease with 80% accuracy compared to conventional pathology assessments. The team then scanned five viable donor livers slated for transplantation and stratified them into different risk categories, accurately predicting clinical outcomes a week after transplantation.
While biopsy tests can take several days to give back results, PS-OCT scans can produce a complete picture of the condition of the entire liver within about 15 minutes, offering a fast and noninvasive tool to assess multiple markers of transplant viability. Although the imaging technique is not intended to replace current evaluation methods, it could significantly reduce sampling error and add valuable information when screening potential donors. Ultimately, improving the assessment of donor livers could address the urgent need for increasing transplant numbers while simultaneously improving clinical outcomes for transplant recipients.
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Evaluating Source-Based Large Language Models for Preclinical Dermatology Education: Comparative Study
Background: Large language models (LLMs) have gained increasing popularity in medical education, with evidence supporting their educational value when framed through the lens of cognitive load theory. Source-based LLMs, which explicitly ground responses in user-uploaded material via retrieval-augmented generation algorithms, may offer additional educational value by using student-developed materials to conceptualize new areas of learning within a familiar framework. This has applications for areas like medical education in dermatology, which could benefit from inclusive sources and enhanced education to alleviate health care gaps. However, no prior studies have examined whether the inclusion of student-authored notes alters the response characteristics of a source-based LLM when responding to medical questions. Objective: This study aims to conduct an observational, comparative performance evaluation study assessing the accuracy, response reproducibility, and intermodel response similarity of freely available LLMs on text-only step 1 dermatology questions, and to explore whether providing extensive student-generated notes to a source-based LLM alters these performance characteristics. Methods: In December 2024, 4 LLMs were evaluated: NotebookLM (NLM) with uploaded preclerkship study guides (NLM w/ Notes), NLM with an uploaded blank sheet of paper (NLM w/o Notes), ChatGPT-4o Mini, and Google Gemini 1.5 Flash. Each model completed 3 trials of 121 text-based United States Medical Licensing Examination (USMLE) step 1 dermatology questions from the AMBOSS question bank. They were evaluated for overall majority-consensus accuracy, accuracy by question difficulty, intertrial reproducibility, and agreement in answer choice selection between models. Differences were analyzed through a Cochran omnibus test and subsequent pairwise McNemar tests with Benjamini-Hochberg correction. Response reproducibility and intermodel agreement were analyzed through Fleiss κ statistics with 95% CI. Results: ChatGPT-4o Mini achieved the highest overall majority-consensus accuracy (102/121, 84.3%). NLM w/ Notes demonstrated the highest intertrial reproducibility (Fleiss κ=0.927, 95% CI 0.875‐0.978) and strong performance on lower-difficulty questions but comparatively reduced accuracy on higher-difficulty items. NLM w/o Notes exhibited significantly higher omission rates (38/363, 10.5% vs ≤7/363, 1.92% for other models) than other tested LLMs. Sensitivity analysis excluding omissions increased NLM w/o Notes’ accuracy from 66.9% (81/121) to 77.8% (77/99), matching NLM w/ Notes’ accuracy of 74.4% (90/121). Intermodel agreement was significantly higher between NLM w/ Notes and ChatGPT-4o Mini compared to NLM w/o Notes and Gemini 1.5 Flash. Conclusions: Provision of student-generated notes substantially increased response reproducibility in a source-based LLM, likely reflecting consistent retrieval of similar source excerpts across trials. However, note-grounding appeared to constrain performance on higher-difficulty questions, suggesting a retrieval-augmented generation algorithm retrieval error when question stems excluded characteristic “keywords” present in lower-difficulty items. The results highlight potential challenges of a student-level, cognitive load theory–grounded educational LLM that must deal with notes not curated by experts, balance source use and internal reasoning, and meaningfully appraise uploaded sources to assess a student’s individual learning gaps.
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Mental Illness Shows Context-Specific Genetic Effects
Many DNA variants linked with neuropsychiatric disorders (NPD) that do not code for proteins depend on neuronal activation, a study suggests.
The findings, in Science, highlight the power of cell stimulation to reveal context-specific “hidden” genetic effects in conditions such as schizophrenia.
They suggest that genetic regulation is not fully revealed by measuring gene expression alone.
Instead, gene activity—at least in the brain—may depend on context and the physiological state of neurons.
“Liang et al. demonstrate that the genetic processes that underlie neuropsychiatric disease are heavily determined by a dynamic physiological environment rather than by fixed cellular conditions,” said Biao Zheng, PhD, and Panos Roussos, PhD, from Icahn School of Medicine at Mount Sinai in New York, in a Perspective article accompanying the study.
They added: “To understand disease genetics, we might need to study the genome in motion and not at rest.”
Genome-wide association studies have revealed hundreds of genetic loci associated with mental illness, with more than 280 identified for schizophrenia alone.
But many of these DNA regions do not encode proteins and their impact is often subtle and difficult to detect.
To investigate further, Lifan Liang, PhD, from the University of Chicago, and co-workers studied gene expression and chromatin accessibility in single neurons derived from induced pluripotent stem cells collected from a hundred human donors.
The single-cell multi-omics study involved assessing transcriptional and epigenomic profiles before and after neurons were activated through potassium-induced depolarization.
The team found that much of the activity in regulatory DNA regions only became apparent with neuronal stimulation.
Both the number of detectable expression quantitative trait loci (eQTLs)—genetic variants associated with differences in gene expression—and chromatin accessibility QTLs (caQTLs)—DNA variants associated with differences in chromatin accessibility—rose after neuronal stimulation.
Shared and cell type-specific transcription factors worked together, possibly through regulatory cascades, to drive cell type-specific neuronal responses to stimuli.
eQTLs after stimulation had substantially weaker overlap with brain eQTL catalogs derived from postmortem tissue compared with eQTLs before stimulation.
This suggested that many relationships between regulatory DNA activity and gene expression become detectable only during neuronal activation and could be missed by traditional tissue-based studies.
A higher number of caQTLs were associated with neuropsychiatric disease compared with eQTLs, suggesting that disease-associated genetic variants could have detectable effects on regulatory DNA even when downstream changes in gene expression were not obvious.
Supporting this, chromatin accessibility and transcriptional responses to neuronal activation often occurred at different times.
Regulatory regions associated with genes that respond rapidly to neuronal stimulation often remained accessible after transcription subsided. By contrast, some late response genes exhibited accessible chromatin before their expression was induced.
When taken together, these observations implied that chromatin accessibility can be an indication of both prior and future transcriptional potential.
“We identified thousands of cell type–specific and activity-dependent quantitative trait loci for gene expression (eQTLs) and chromatin accessibility (caQTLs), helping prioritize NPD risk variants and genes that manifested functional effects only upon neuronal stimulation,” the researchers asserted.
They added: “Our work provides mechanistic insights on neuron subtype–specific activity-dependent gene regulation, substantially expanding the repertoire of context-specific causal variants and genes for NPD and other brain traits.”
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Angry Kids: Dealing With Explosive Behavior
When a child — even a small child — melts down and becomes aggressive, they can pose a serious risk to themselves and others, including parents and siblings.
It’s not uncommon for kids who have trouble handling their emotions to lose control and direct their distress at a caregiver — screaming and cursing, throwing dangerous objects, or hitting and biting. It can be a scary, stressful experience for you and your child, too. Children often feel sorry after they’ve worn themselves out and calmed down.
So what are you to do?
It’s helpful to first understand that behavior is communication. A child who is so overwhelmed that they are lashing out is a distressed child. They don’t have the skill to manage their feelings and express them in a more mature way. They may lack language, impulse control, or problem-solving abilities.
Sometimes parents see this kind of explosive behavior as manipulative. But kids who lash out are usually unable to handle frustration or anger in a more effective way — say, by talking and figuring out how to achieve what they want.
Nonetheless, how you react when a child lashes out has an effect on whether they will continue to respond to distress in the same way or learn better ways to handle feelings so they don’t become overwhelming.
Behavioral techniques for anger management
Here are some pointers to help kids learn techniques to regulate their emotions:
- Stay calm. Faced with a raging child, it’s easy to feel out of control and find yourself yelling at them. But when you shout, you have less chance of reaching them. Instead, you will only be making them more aggressive and defiant. As hard as it may be, if you can stay calm and in control of your own emotions, you can be a model for your child and teach them to do the same thing.
- Don’t give in. Don’t encourage them to continue this behavior by agreeing to what they want in order to make it stop.
- Praise appropriate behavior. When they have calmed down, praise them for pulling themselves together. And when they do try to express their feelings verbally, calmly, or try to find a compromise on an area of disagreement, praise them for those efforts.
- Help them practice problem-solving skills. When your child is not upset is the time to help them try out communicating their feelings and coming up with solutions to conflicts before they escalate into aggressive outbursts. You can ask them how they feel and how they think you might solve a problem.
- Time-outs and reward systems. Time-outs for nonviolent misbehavior can work well with children younger than 7 or 8 years old. When using time-outs, be sure to be consistent with them and balance them with other, more positive forms of attention. If a child is too old for time-outs, you want to move to a system of positive reinforcement for appropriate behavior — points or tokens toward something they want.
- Avoid triggers. Vasco Lopes, PsyD, a clinical psychologist, says most kids who have frequent meltdowns do it at very predictable times, like homework time, bedtime, or when it’s time to stop playing, whether it’s Legos or video games. The trigger is usually being asked to do something they don’t like, or to stop doing something they do like. Time warnings (“we’re going in 10 minutes”), breaking tasks down into one-step directions (“first, put on your shoes”), and preparing your child for situations (“please ask to be excused before you leave Grandma’s table”) can all help avoid meltdowns.
What kind of tantrum is it?
How you respond to a tantrum also depends on its severity. The first rule in handling nonviolent tantrums is to ignore them as often as possible, since even negative attention, like telling the child to stop, can be encouraging.
But when a child is getting physical, ignoring is not recommended since it can result in harm to others as well as your child. In this situation, Dr. Lopes advises putting the child in a safe environment that does not give them access to you or any other potential rewards.
Critics of time-outs argue that they can be emotionally isolating for kids, but research shows that they are effective and do not cause children harm. (For more on the debate around time-outs, read our full article on the topic.) However, it’s very important to use them as just one technique in a nurturing, supportive parenting strategy. Be sure to balance use of time outs with lots of praise for kids’ positive behaviors. It’s also important to manage your own stress so that kids can learn how to regulate their emotions from your positive example.
If the child is young (usually 7 or younger), try placing them in a time out chair. If they won’t stay in the chair, take them to a backup area where they can calm down on their own without anyone else in the room. Again, for this approach to work there shouldn’t be any toys or games in the area that might make it rewarding.
Your child should stay in that room for one minute and must be calm before they are allowed out. Then they should come back to the chair for time out. “What this does is gives your child an immediate and consistent consequence for their aggression and it removes all access to reinforcing things in their environment,” explains Dr. Lopes.
If you have an older child who is being aggressive and you aren’t able to carry them into an isolated area to calm down, Dr. Lopes advises removing yourself from their vicinity. This ensures that they are not getting any attention or reinforcement from you and keeps you safe. In extreme instances, it may be necessary to call 911 to ensure your and your child’s safety.
Help with behavioral techniques
If your child is doing a lot of lashing out — enough that it is frequently frightening you and disrupting your family — it’s important to get some professional help. There are good behavioral therapies that can help you and your child get past the aggression, relieve your stress, and improve your relationship. You can learn techniques for managing their behavior more effectively, and they can learn to rein in disruptive behavior and enjoy a much more positive relationship with you.
- Parent-child interaction therapy (PCIT). PCIT has been shown to be very helpful for children between the ages of 2 and 7. The parent and child work together through a set of exercises while a therapist coaches parents through an ear piece. You learn how to pay more attention to your child’s positive behavior, ignore minor misbehaviors, and provide consistent consequences for negative and aggressive behavior, all while remaining calm.
- Parent management training (PMT). PMT teaches similar techniques as PCIT, though the therapist usually works with parents, not the child.
- Collaborative and Proactive Solutions (CPS). CPS is a program based on the idea that explosive or disruptive behavior is the result of lagging skills rather than, say, an attempt to get attention or test limits. The idea is to teach children the skills they lack to respond to a situation in a more effective way than throwing a tantrum.
Figuring out explosive behavior
Tantrums and meltdowns are especially concerning when they occur more often, more intensely, or past the age in which they’re developmentally expected — those terrible twos up through preschool. As a child gets older, aggression becomes more and more dangerous to you, and the child. And it can become a big problem for them at school and with friends, too.
If your child has a pattern of lashing out it may be because of an underlying problem that needs treatment. Some possible reasons for aggressive behavior include:
- ADHD: Kids with ADHD are frustrated easily, especially in certain situations, such as when they’re supposed to do homework or go to bed.
- Anxiety: An anxious child may keep their worries secret, then lash out when the demands at school or at home put pressure on them that they can’t handle. Often, a child who “keeps it together” at school loses it with one or both parents.
- Undiagnosed learning disability: When your child acts out repeatedly in school or during homework time, it could be because the work is very hard for them.
- Sensory processing issues: Some children have trouble processing the information they are taking in through their senses. Things like too much noise, crowds and even “scratchy” clothes can make them anxious, uncomfortable, or overwhelmed. That can lead to actions that leave you mystified, including aggression.
- Autism: Children with autism spectrum disorder are often prone to meltdowns when they are frustrated or faced with unexpected change. They also often have sensory issues that make them anxious and agitated.
Given that there are so many possible causes for emotional outbursts and aggression, an accurate diagnosis is key to getting the help you need. You may want to start with your pediatrician. They can rule out medical causes and then refer you to a specialist. A trained, experienced child psychologist or psychiatrist can help determine what, if any, underlying issues are present.
When behavioral plans aren’t enough
Professionals agree, the younger you can treat a child, the better. But what about older children and even younger kids who are so dangerous to themselves and others that behavioral techniques aren’t enough to keep them and others around them safe?
- Medication. Medication for underlying conditions such as ADHD and anxiety may make your child more reachable and teachable. Kids with extreme behavior problems are often treated with antipsychotic medications like Risperdal or Abilify. But these medications should be partnered with behavioral techniques.
- Holds. Parent training may, in fact, include learning how to use safe holds on your child so that you can keep both them and yourself out of harm’s way.
- Residential settings. Children with extreme behaviors may need to spend time in a residential treatment facility — sometimes, but not always, in a hospital setting. There, they receive behavioral and, most likely, pharmaceutical treatment. Therapeutic boarding schools provide consistency and structure around the clock, seven days a week. The goal is for the child to internalize self-control so they can come back home with more appropriate behavior with you and the world at large.
- Day treatment. With day treatment, a child with extreme behavioral problems lives at home but attends a school with a strict behavioral plan. Such schools should have trained staff prepared to safely handle crisis situations.
Explosive children need calm, confident parents
It can be challenging work for parents to learn how to handle an aggressive child with behavioral approaches, but for many kids it can make a big difference. Parents who are confident, calm, and consistent can be very successful in helping children develop the anger management skills they need to regulate their own behavior.
This may require more patience and willingness to try different techniques than you might with a typically developing child, but when the result is a better relationship and happier home, it’s well worth the effort.
Frequently Asked Questions
One way to handle a child’s anger is to stay calm when they lose their temper. Controlling your emotions sets an example for the child. You can praise them when they express their feelings calmly and when they calm themselves down after an explosion. Adults who are confident, calm, and consistent help children develop the skills to regulate their behavior.
In parent-child interaction therapy, a therapist coaches parents on how to pay more attention to positive behavior, ignore minor misbehaviors, and provide consistent consequences for negative and aggressive behavior, all while remaining calm. Other forms of therapy also center on teaching the parent how to model emotional stability.
Stay calm and ensure they are in a safe space. Yelling can escalate aggression. Speak in a steady voice, avoid giving in, and use time-outs to prevent meltdowns. When they calm down, praise them for it and for expressing their emotions appropriately. If they are frequently aggressive, behavioral therapy may help.
Children who lash out often lack the skills to manage emotions. Identifying triggers, teaching problem-solving, and using praise or rewards can encourage better behavior. Time-outs work for younger kids, while older ones may need structured reinforcement. If outbursts are severe, you might need professional help. Programs like parent-child interaction therapy (PCIT), parent management training (PMT), or collaborative and practical solutions (CPS) can help.
The post Angry Kids: Dealing With Explosive Behavior appeared first on Child Mind Institute.
Virtual Reality Simulation in Postgraduate Pediatric Critical Care Training Based on Trainee Perceptions in London: Exploratory Mixed Methods Study
Background: Simulation-based training has established itself as integral to clinical education, particularly for high-stakes, low-frequency pediatric emergencies. Innovations incorporating virtual reality (VR) are rapidly gaining traction for offering scalable, repeatable, and immersive opportunities for scenario-based learning. Understanding its role and applicability in postgraduate pediatric training, however, remains limited, with further exploration required into how pediatric trainees perceive, conceptualize, and anticipate VR-based simulation within real-world training contexts. Objective: This study explored London-based pediatric trainees’ perceptions of VR simulation as an adjunct for developing skills in recognizing and managing critically ill children. Methods: An exploratory mixed methods study was conducted among pediatric trainees across all training levels within the London School of Paediatrics between April 2024 and July 2024. Data were collected using a 35-item online questionnaire containing Likert-scale, categorical, and open-ended questions, alongside virtual semistructured interviews. The questionnaire explored current training practices; confidence and preparedness in managing critically ill children; familiarity and experience with VR; and perceived benefits, limitations, barriers, and facilitators to adoption. Quantitative data were analyzed descriptively, with exploratory Mann-Whitney tests and Spearman correlations where appropriate. Internal consistency of key domains was assessed using Cronbach α. Qualitative data from open-ended responses and interviews were analyzed thematically using the Braun and Clarke reflexive approach. Quantitative and qualitative strands were integrated at the interpretation stage to contextualize survey patterns with illustrative qualitative insights. Results: Thirty trainees participated in the survey (30/450, 6.7%; female: 16/30, 53%), with participants spanning all 8 training years. Two senior trainees participated in interviews. Clinical exposure or experience and simulation training were identified as central to developing skills in managing pediatric emergencies. Trainees also described limited exposure to high-acuity scenarios; variable access to high-fidelity simulation; and constraints related to workload, supervision, and feedback. Most participants (21/30) had no prior VR exposure in a medical setting, while 17% (5/30) had used VR training, and all reported positive experiences. Despite limited exposure, 93% (28/30) of participants were willing to try VR simulation for exposure to rare scenarios, structured decision-making, and confidence-building. Key perceived barriers included high cost (24/30, 80%), technological literacy (17/30, 57%), infrastructure (15/30, 50%), and limited stakeholder familiarity or support (25/30, 83%). Participants suggested taster sessions, faculty advocacy, leadership engagement, and phased implementation as potential facilitators. Internal consistency of attitudinal survey items was good (Cronbach α=0.80). Conclusions: Despite limited exposure, pediatric trainees viewed VR simulation as a valuable adjunct to existing critical care training, particularly for those in earlier stages of training. However, these findings represent anticipatory perceptions rather than evidence of educational effectiveness. The implementation of VR will depend on addressing key infrastructural, organizational, educational, and equity-related barriers. Further multicenter studies are needed to evaluate the educational impact and feasibility, learning outcomes, and cost-effectiveness in postgraduate pediatric critical care training programs.
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