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The most common type of brain tumor in children, pilocytic astrocytoma (PA), accounts for about 15% of all pediatric brain tumors. Although this type of tumor is usually not life-threatening, the unchecked growth of tumor cells can disrupt normal brain development and function. Current treatments focus mainly on removing the tumor cells, but recent studies have shown that non-cancerous cells, such as nerve cells, also play a role in brain tumor formation and growth, suggesting novel approaches to treating these cancers.

Scientists have long known that a nerve cell signaling chemical called glutamate can increase growth of cancers throughout the body, but despite years of investigation, they haven’t figured out exactly how this happens, or how to stop it. Now, an interdisciplinary team of researchers at Washington University School of Medicine in St. Louis has uncovered how glutamate regulates pediatric brain tumor growth. Using tumor cells isolated from patient PA samples, they found that PA cells hijack the function of proteins on cells’ surface that normally respond to glutamate, called glutamate receptors. Instead of transmitting glutamate’s typical electrical signal, these receptors are reprogrammed to send signals to increase cell growth.

They also observed that drugs that block these glutamate receptors – including memantine, which is approved to treat dementia and Alzheimer’s disease – reduced human pediatric brain tumor growth in mice, a finding that points to a potential new treatment opportunity.

The results appear September 1 in Neuron.

With these kinds of pediatric brain tumors, we just don’t have that many tools in our toolbox for treating patients. The potential to repurpose drugs that are already in use for other neurological disorders means we may have another trick up our sleeves for treating patients.”

David Gutmann, MD, PhD, senior author, the Donald O. Schnuck Family Professor of Neurology at WashU Medicine

The research team, which included first author Corina Anastasaki, PhD, a research assistant professor of neurology at WashU Medicine, also showed for the first time that glutamate receptors abnormally couple with growth receptors in PAs to fuel the tumors. The findings offer a roadmap for future studies to explore if the same process is happening in different types of cancers.

New uses for familiar tools

Glutamate is what is known as a neurotransmitter, a molecule that nerve cells, including neurons in the brain, use to communicate with each other. On their path to understand how glutamate helps brain tumors grow, Gutmann, who is also the director of the Neurofibromatosis Center at WashU Medicine, and Anastasaki worked closely with collaborators across WashU Medicine – including in neurosurgery, pediatrics, genetics, neuropathology, biostatistics and more – to acquire and analyze samples of PAs that had been surgically removed. They found that these PA cells had unusually high levels of glutamate receptors.

By testing how glutamate affected these tumors, the researchers discovered that glutamate increased PA cell numbers by kicking off a chain reaction inside the tumor cells that urged cells to divide. These findings suggest that tumor cells exploit normal brain-cell interactions to spur their own growth.

“This novel mechanism for tumor growth combines two normal but unconnected brain processes – growth and electrical signaling – in an aberrant way,” Anastasaki said. “Now that we’ve figured out how these cells work and grow, the sky’s the limit for looking at other neurotransmitters and the different avenues of communication between neurons and cancer cells. Understanding that will tell us why tumors grow and behave the way they do. That may lead to us treating them very differently.”

Such new treatments might come from familiar sources. The researchers showed that inhibiting glutamate receptors of tumor cells in mice with PAs – either with medications or by genetically altering the cells – reduced tumor growth. This points to a potential opportunity to repurpose glutamate receptor-targeting drugs such as memantine for the treatment of PAs.

The next steps are to determine whether such medications are safe to use in children with brain tumors and in what amounts they would be effective, Gutmann noted, which will require clinical trials.

“This study provides compelling preclinical data to look at medications that are otherwise safe and approved to treat other neurological conditions,” Gutmann said. “That would enable new therapeutic approaches and could help minimize the damage to a child’s developing brain by reducing engagement between brain cells and tumor cells.”

Anastasaki C, Mu R, Kernan CM, Li X, Barakat R, Koleske JP, Gao Y, Cobb OM, Lu X, Eberhart CG, Phillips JJ, Strahle JM, Dahiya S, Mennerick SJ, Rodriguez FJ, Gutmann D. Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain tumor growth. Neuron. September 1, 2025.

The researchers come to the conclusion that these olfactory dysfunctions arise because immune cells of the brain called “microglia” remove connections between two brain regions, namely the olfactory bulb and the locus coeruleus. The olfactory bulb, located in the forebrain, analyzes sensory information from the nose’s scent receptors. The locus coeruleus, a region of the brainstem, influences this processing by means of long nerve fibers originating from neurons in the locus coeruleus and extending all the way to the olfactory bulb. “The locus coeruleus regulates a variety physiological mechanisms. These include, for example, cerebral blood flow, sleep-wake cycles, and sensory processing. The latter applies, in particular, also to the sense of smell,” says Dr. Lars Paeger, a scientist at DZNE and LMU. “Our study suggests that in early Alzheimer’s disease, changes occur in the nerve fibers linking the locus coeruleus to the olfactory bulb. These alterations signal to the microglia that affected fibers are defective or superfluous. Consequently, the microglia break them down.”

Alterations in the membrane

Specifically, the team of Dr. Lars Paeger and Prof. Dr. Jochen Herms, who is a co-author of the current publication, found evidence of changes in the composition of the membranes of the affected nerve fibers: Phosphatidylserine, a fatty acid that usually occurs inside a neuron’s membrane, had been moved to the outside. “Presence of phosphatidylserine at the outer site of the cell membrane is known to be an “eat-me” signal for microglia. In the olfactory bulb, this is usually associated with a process called synaptic pruning, which serves to remove unnecessary or dysfunctional neuronal connections,” explains Paeger. “In our situation, we assume that the shift in membrane composition is triggered by hyperactivity of the affected neurons due to Alzheimer’s disease. That is, these neurons exhibit abnormal firing.”

A wide range of data

The findings of Paeger and colleagues are based on a plethora of observations. These include studies on mice with features of Alzheimer’s disease, analysis of brain samples from deceased Alzheimer’s patients, and positron emission tomography (PET) scans of the brains of individuals with Alzheimer’s or mild cognitive impairment. “Smell issues in Alzheimer’s disease and damage to the associated nerves have been discussed for some time. However, the causes were unclear until yet. Now, our findings point to an immunological mechanism as cause for such dysfunctions – and, in particular, that such events already arise in the early stages of Alzheimer’s disease,” says Joachim Herms, a research group leader at DZNE and LMU as well as a member of the Munich-based “SyNergy” Cluster of Excellence.

Perspectives for early diagnosis

So-called amyloid-beta antibodies have recently become available for the treatment of Alzheimer’s. For this novel therapy to be effective, it needs to be applied at an early stage of the disease, and this is precisely where the current research could be significant. “Our findings could pave the way for the early identification of patients at risk of developing Alzheimer’s, enabling them to undergo comprehensive testing to confirm the diagnosis before cognitive problems arise. This would allow earlier intervention with amyloid-beta antibodies, increasing the probability of a positive response,” says Herms.

Ethic statements

The Institutional Animal Care and Use Committee of Tokyo Medical and Dental University (TMDU) (A2021-131A) approved all animal experiments, which were conducted under the Department of Parasitology and Tropical Medicine, TMDU.

Materials

Deferoxamine mesylate salt (Sigma-Aldrich); 1,10-Phenanthroline monohydrate (Tokyo Chemical Industry); 5-Methyl-1,10-phenanthroline (Tokyo Chemical Industry); 4,7-Dimethyl-1,10-phenanthroline (Tokyo Chemical Industry); 3,4,7,8-Tetramethyl-1,10-phenanthroline (Tokyo Chemical Industry); 2,9-Dimethyl-1,10-phenanthroline hydrochloride monohydrate (Tokyo Chemical Industry); 4,7-Diphenyl-1,10-phenanthroline (Sigma-Aldrich); 4,7-Dimethoxy-1,10-phenanthroline (Sigma-Aldrich); 1,10-Phenanthroline-4,7-diamine (Enamine); N4,N4,N7,N7-Tetramethyl-1,10-phenanthroline-4,7-diamine (Enamine); Iron(II) sulfate heptahydrate (FUJIFILM Wako Pure Chemicals). All other reagents obtained from commercial sources were used as received unless otherwise stated.

Maintenance of S. mansoni using animals

According to previously described methods [18, 19], to maintain the life cycle of S. mansoni, Biomphalaria glabrata as an intermediate host (Puerto Rico strain), was individually infected with eight miracidia. The infected snails were kept in a thermostatic chamber at 28 °C for over 2 months and subsequently exposed to light to release the cercariae. Moreover, 6-week-old ICR mice (SLC, Hamamatsu, Japan) were infected by placing their tails in a tube containing 180 cercariae in tap water.

Following the Institutional Animal Care and Use Committee of TMDU (2010002C2), the infected mice were kept in a controlled temperature and humid environment with a 12:12 h light/dark cycle and had free access to food and water. Humane endpoints were considered when severe pain, suffering, excessive distress, or impending death was observed in any animal. All mice were euthanized using CO₂ gas inhalation after the experiments. The status of the mice was monitored daily using a composite score, including vitality, fur quality, secretions, mobility, dyspnea, neurological signs, ascites, and their ability to ingest food or water. All mice were handled according to the ARRIVE guidelines and relevant regulations.

Preparation of schistosomula and adult worms

Schistosomula were appropriately prepared as follows: over 1000 cercariae obtained from the infected snails after exposure to light, were collected in tubes through centrifugation. The cercariae were passed through a syringe attached to a 20G needle approximately 10 times to produce mechanically transformed schistosomula. The larvae were subsequently placed in 0.2 mL of RPMI1640 medium in a 96-well plate and incubated for 24 h at 37 °C in an atmosphere containing 5% CO₂. Adult worms were collected from euthanized mice at 7-week post-infection and placed in 2 mL of RPMI1640 containing 10% FBS (Thermo Fisher Science, USA), streptomycin, penicillin, and l-glutamine (Thermo Fisher Science) in 12-well plates. After incubation for 24 h at 37 °C in an atmosphere containing 5% CO₂, all worms were washed thrice with the conditioned medium and were then used for the experiments.

Assessment of in vitro larvicidal activities of the compounds

The prepared schistosomula were placed in a 96-well plate (20–180 larvae/well) and the number of viable larvae was counted. Next, the compounds were added to individual wells and adjusted to final concentrations of 50, 10, 5, 1, 0.5, 0.1, and 0.05 μM. After incubation for 72 h at 37 °C in an atmosphere containing 5% CO₂, the number of larvae was counted using previous methods [20, 21]. Dead larvae were identified based on their characteristic lack of movement and a disintegrated or completely crushed outer tegument. The IC₅₀ and IC₉₀ values were calculated based on the curves obtained from viability plots.

Assessment of in vitro anti-fecundity effects of the compounds

Surviving adult worm pairs were placed in a 24-well plate (three pairs/well), and 1 mL of culture medium was added to each well [18]. Subsequently, the compounds were added at the concentration of 5 µM. To promote egg production, 1 × 10⁸ erythrocytes obtained from mice were added, and the solutions were adjusted to 2 mL by adding more culture medium. After incubation for 72 h at 37 °C in an atmosphere containing 5% CO₂, the adult worms were removed, and 1 mL of the supernatant was discarded. Then, 2 mL of distilled water was added to each well, and the samples were incubated at room temperature for 1 h to lyse erythrocytes. After adding 1 mL of 50 mM NaOH and incubation at 4 °C overnight, the number of eggs was counted using inverted microscope to calculate the egg production rates.

Assessment of in vivo bio-activities of the compounds

Female 6-week-old BALB/c mice were infected with 180 cercariae (five mice/group). At 2-, 4-, and 6-week post-infections, 0.1 mL of the solution containing compounds dissolved in olive oil was orally administered to each mouse for three consecutive days. After euthanizing the mice at 8-week post-infection, adult worms were collected through perfusion, and the liver and intestinal tracts were removed. The obtained male and female adult worms were separately counted to determine their survival rates. Simultaneously, the liver and intestinal tracts were completely lysed using 4% KOH solution at 37 °C overnight with shaking. After treating the solution with distilled water, 10 µL of the resulting solution was placed on a glass slide, and the eggs were counted under a microscope to calculate the egg production and fecundity rates.

Observation of the ovaries of female adult worms

Ten female adult worms were collected from the groups of mice treated with or without PHN-(OMe)₂ at 6-week post-infection. The adult worms were fixed for 1 week using a solution of 10% formalin, 48% alcohol, and 2% glacial acetic acid. Afterwards, the worms were stained overnight with acetocarmine solution (FUJIFILM Wako, Osaka, Japan). They were then destained in 70% acidic ethanol and were dehydrated in a graded ethanol series (70, 90, and 100%). Subsequently, the worms were cleared in a 50% xylene solution diluted in 100% ethanol for 1 min, and were mounted on slides using Bioleit (Okenshoji Co., Ltd., Japan). Finally, images were acquired using a Leica STELLARIS 5 confocal laser scanning microscopy, equipped with a 40x (NA = 1.25) oil-immersion objective and an argon laser at 488 nm as the excitation source. Images were collected as single stacks from at least ten individuals in each group. The size of the ovaries was determined by measuring the area of the images using Fiji software and calculating the means.

Electrospray ionization mass (ESI–MS) spectroscopic analysis

The reaction of PHN-(OMe)₂ and Fe(II) ions was initiated by mixing PHN-(OMe)₂ (5.0 mM) and FeSO₄ (1.67 mM) in a DMSO solution that has been degassed to remove dissolved dioxygen. The solution containing the generated iron complex was exposed to molecular dioxygen and diluted with MeOH to prepare the sample. The chemical composition of the iron complex was then determined using an ESI–MS spectrophotometer (Q Exactive, Thermo Fisher Scientific).

Statistical analysis

Statistical comparisons were carried out using Student’s t test to evaluate the differences between treated and untreated groups. Differences were considered significant at p < 0.05 at a 95% confidence interval.

Bottom Line: Mount Sinai researchers developed an AI model to make individualized treatment recommendations for atrial fibrillation (AF) patients-helping clinicians accurately decide whether or not to treat them with anticoagulants (blood thinner medications) to prevent stroke, which is currently the standard treatment course in this patient population. This model presents a completely new approach for how clinical decisions are made for AF patients and could represent a potential paradigm shift in this area.

In this study, the AI model recommended against anticoagulant treatment for up to half of the AF patients who otherwise would have received it based on standard-of-care tools. This could have profound ramifications for global health.

Why the study is important: AF is the most common abnormal heart rhythm, impacting roughly 59 million people globally. During AF, the top chambers of the heart quiver, which allows blood to become stagnant and form clots. These clots can then dislodge and go to the brain, causing a stroke. Blood thinners are the standard treatment for this patient population to prevent clotting and stroke; however, in some cases this medication can lead to major bleeding events.

This AI model uses the patient’s whole electronic health record to recommend an individualized treatment recommendation. It weighs the risk of having a stroke against the risk of major bleeding (whether this would occur organically or as a result of treatment with the blood thinner). This approach to clinical decision-making is truly individualized compared to current practice, where clinicians use risk scores/tools that provide estimates of risk on average over the studied patient population, not for individual patients. Thus, this model provides a patient-level estimate of risk, which it then uses to make an individualized recommendation taking into account the benefits and risks of treatment for that person.

The study could revolutionize the approach clinicians take to treat a very common disease to minimize stroke and bleeding events. It also reflects a potential paradigm change for how clinical decisions are made.

Why this study is unique: This is the first-known individualized AI model designed to make clinical decisions for AF patients using underlying risk estimates for the specific patient based on all of their actual clinical features. It computes an inclusive net-benefit recommendation to mitigate stroke and bleeding. 

How the research was conducted: Researchers trained the AI model on electronic health records of 1.8 million patients over 21 million doctor visits, 82 million notes, and 1.2 billion data points. They generated a net-benefit recommendation on whether or not to treat the patient with blood thinners.

To validate the model, researchers tested the model’s performance among 38,642 patients with atrial fibrillation within the Mount Sinai Health System. They also externally validated the model on 12,817 patients from publicly available datasets from Stanford.

Results: The model generated treatment recommendations that aligned with mitigating stroke and bleeding. It reclassified around half of the AF patients to not receive anticoagulation. These patients would have received anticoagulants under current treatment guidelines.

What this study means for patients and clinicians: This study represents a new era in caring for patients. When it comes to treating AF patients, this study will allow for more personalized, tailored treatment plans.

Quotes:  

“This study represents a profound modernization of how we manage anticoagulation for patients with atrial fibrillation and may change the paradigm of how clinical decisions are made,” says corresponding author Joshua Lampert, MD, Director of Machine Learning at Mount Sinai Fuster Heart Hospital. “This approach overcomes the need for clinicians to extrapolate population-level statistics to individuals while assessing the net benefit to the individual patient-which is at the core of what we hope to accomplish as clinicians. The model can not only compute initial recommendations, but also dynamically update recommendations based on the patient’s entire electronic health record prior to an appointment. Notably, these recommendations can be decomposed into probabilities for stroke and major bleeding, which relieves the clinician of the cognitive burden of weighing between stroke and bleeding risks not tailored to an individual patient, avoids human labor needed for additional data gathering, and provides discrete relatable risk profiles to help counsel patients.”

“This work illustrates how advanced AI models can synthesize billions of data points across the electronic health record to generate personalized treatment recommendations. By moving beyond the ‘one size fits none’ population-based risk scores, we can now provide clinicians with individual patient-specific probabilities of stroke and bleeding, enabling shared decision making and precision anticoagulation strategies that represent a true paradigm shift,”adds co-corresponding author Girish Nadkarni, MD, MPH, Chair of the Windreich Department of Artificial Intelligence and Human Health at the Icahn School of Medicine at Mount Sinai. 

“Avoiding stroke is the single most important goal in the management of patients with atrial fibrillation, a heart rhythm disorder that is estimated to affect 1 in 3 adults sometime in their life”, says co-senior author, Vivek Reddy MD, Director ofCardiac Electrophysiology at the Mount Sinai Fuster Heart Hospital. “If future randomized clinical trials demonstrate that this Ai Model is even only a fraction as effective in discriminating the high vs low risk patients as observed in our study, the Model would have a profound effect on patient care and outcomes.”

“When patients get test results or a treatment recommendation, they might ask, ‘What does this mean for me specifically?’ We created a new way to answer that question. Our system looks at your complete medical history and calculates your risk for serious problems like stroke and major bleeding prior to your medical appointment. Instead of just telling you what might happen, we show you both what and how likely it is to happen to you personally. This gives both you and your doctor a clearer picture of your individual situation, not just general statistics that may miss important individual factors,” says co-first author Justin Kauffman, Data Scientiest with the Windreich Department of Artificial Intelligence and Human Health.

Dual antiplatelet therapy after heart bypass surgery is not more effective than aspirin alone – and it increases the risk of excessive bleeding. This has now been shown in a study of 2,201 patients at 22 Nordic heart surgery units.

The study was published on Monday in The New England Journal of Medicine at the same time that the results are being presented in Madrid at this year’s ESC Congress, the leading international cardiology congress.

The lead investigator is Anders Jeppsson, professor in cardiothoracic surgery at the University of Gothenburg and senior consultant at Sahlgrenska University Hospital, as well as initiator and chair of the steering committee of the TACSI trial.

Risk reduction unclear until now

The TACSI study compares two different antiplatelet (blood thinning) therapies after heart bypass surgery for acute coronary heart disease. On the one hand single antiplatelet therapy with acetylsalicylic acid (Aspirin) alone, and on the other hand dual antiplatelet therapy with aspirin and ticagrelor (Brilique). Dual antiplatelet therapy is currently recommended for these patients in international guidelines.

It is unequivocal that this patient group needs antiplatelet therapy. However, until now it has been unclear whether dual therapy after surgery further reduces the risks of death and cardiovascular complications after the operation.

The 2,201 patients included in the study were randomly assigned to receive either ticagrelor and aspirin (1,104 patients) or aspirin alone (1,097 patients). The average age of the participants was 66 years and the proportion of women was 14.4 percent. The follow-up period was 12 months after surgery.

The results show no difference between the groups within the study’s primary focus: a composite measure of the risks of dying, having a heart attack or stroke, or needing another coronary intervention. The proportion affected within one year was just under 5 percent for both groups.

No support for dual therapy

However, the researchers found that the groups did differ if excessive bleeding was also included. When including excessive bleeding, the proportion affected was 9.1 percent in the group receiving both ticagrelor and aspirin and 6.4 percent in the group receiving aspirin alone. Excessive bleeding was seen in 4.9 percent of patients on dual therapy, as compared to 2.0 percent in the other patient group.

Anders Jeppsson notes that while the patients need to be followed up for more than one year, we can still draw some conclusions:

“Our 12-month data do not support the use of dual therapy over aspirin alone in patients with acute coronary syndrome who have undergone heart bypass surgery. We did not observe any improvement in serious cardiovascular events, but a higher risk of excessive bleeding in the dual antiplatelet therapy group,” he says.