Publisher Health

Medical research has shown promising results regarding the potential of gene therapy to cure genetic conditions such as sickle cell disease and the findings of this study, published in Nature Medicine, offer important new insights into processes happening in the body after treatment.
The present study looked at samples from six patients with sickle cell disease who were undergoing gene therapy as part of a major clinical trial at Boston Children’s Hospital. The research brought together an international team of experts, to take a closer look at the genetic changes in the stem cells of patients before and after gene therapy and compare the cells that were modified with the therapy to those that weren’t.
The study highlights the importance of long-term and in-depth monitoring of stem cell samples from patients with genetic conditions to track mutations that could lead to blood cancer, the researchers say.
Co-senior author of the study Professor David Kent from the Department of Biology and York Biomedical Research Institute said: “Think of the gene therapy process like clearing a forest and planting new seedlings. If you imagine that some seedlings are red and some are green, then the ‘selection’ we are observing is akin to having the forest regrow red trees preferentially.
“Our research indicates that gene therapy imposes a selection on different blood stem cells, the ‘seed’ cells of our blood and immune system. After gene therapy, the treatment might favour growth of stem cells with certain mutations, and this in turn could potentially lead to expansion of blood cells containing these mutations. In other settings, such expansions have been associated with development of blood cancers, particularly in older individuals, but the relationship of this study’s findings to the risk of blood cancers is not yet fully understood.”
The researchers used new technologies in genome science that allow blood cells to be tracked and compared in patients, a new approach which could substantially influence gene therapy trials in the future.
Co-senior author of the study Dr David Williams from Boston Children’s Hospital and Harvard Medical School noted: “Gene therapy holds immense potential to cure genetic conditions such as sickle cell disease, and understanding how the process influences blood stem cell growth in the long run is crucial for safety. Notably, our study revealed that younger patients, with fewer genetic mutations in their stem cells, didn’t exhibit strong signs of mutations post-therapy. This suggests that treating patients with gene therapy at a younger age could be both safer and more effective, but substantial work needs to be done to test this formally.”
Sickle cell disease, an inherited genetic disorder, alters the natural round and flexible shape of red blood cells into a sickle or crescent shape, leading to severe health issues and putting patients at higher risk of developing blood cancer. Though approximately 100 million people carry the sickle cell trait worldwide, the disease only occurs if a child inherits the trait from both parents. In regions where the trait is prevalent, such as parts of sub-Saharan Africa, up to 20 percent of the population can be affected.

However, recent advances in gene therapy offer hope. This innovative approach involves modifying a patient’s own stem cells outside the body, correcting the faulty gene responsible for the abnormal cell shape. These corrected cells are reintroduced into the patient, aiming to replace the problematic cells with healthy, normal-shaped ones.
The study, funded by the Bill and Melinda Gates Foundation, reveals that the gene therapy treatment itself is not the likely cause of new DNA mutations in blood stem cells. Instead, the process of genetically modifying these stem cells outside the body and re-transplanting them back into the patient makes blood stem cells that already have these mutations more prominent, thereby increasing their influence on the blood and immune systems.
The research team say the findings also suggest that younger patients may have acquired fewer stem cell mutations in their lifetime, which may inform the optimal age for gene therapies in this and other diseases in the future.
Co-lead author of the paper, Dr Alyssa Cull from the Department of Biology and York Biomedical Research Institute, emphasised the need for further research: “We now require more in-depth studies to uncover the precise connections behind specific mutations and the gene therapy procedure. There are pressing questions regarding how we can refine gene therapy to avoid stem cells that might contain mutations that affect blood cell growth. Determining whether mutations within a sample of cells are dangerous in the long run remains challenging though and substantial further research is needed.”
Co-lead author Michael Spencer-Chapman from the Wellcome Sanger Institute echoes the need for longer term follow-up of patients saying: “Our research revealed that both gene-therapy modified and unaltered stem cells from sickle cell patients sometimes contained cancer-associated mutations leading to accelerated growth through the gene therapy procedure. Continuously tracking these mutations and gaining a deeper understanding of these processes will profoundly impact the future well-being of sickle cell patients around the world.”

Depression is one of the most common mental illnesses in the world, but current anti-depressants have yet to meet the needs of many patients. Neuroscientists from City University of Hong Kong (CityU) recently discovered a small molecule that can effectively alleviate stress-induced depressive symptoms in mice by preventing aversive memory formation with a lower dosage, offering a new direction for developing anti-depressants in the future.
“Depression affects millions of individuals worldwide, necessitating more effective treatments. Conventional methods, such as drug therapy with delayed onset of action and psychotherapy, have limitations in yielding satisfactory results for many patients. A pioneering advancement in treatment is urgently needed,” said Professor He Jufang, Wong Chun Hong Chair Professor in Translational Neuroscience at CityU.
Previous research found that stress leads to neural plasticity changes in brain’s valence-coding systems (“valence” refers to the degree to which something is pleasurable or aversive), which are strongly associated with depression, post-traumatic stress disorders and anxiety disorders. Also, some studies revealed that depression is correlated with the hyperactivated amygdala. “However, the neural mechanism that mediates depression in amygdala is still poorly understood,” said Professor He.
Over the years, Professor He’s research group has focused on memory formation and encoding studies. Previously, they discovered that cholecystokinin (CCK), a key neuromodulator, is crucial for inducing long-term potentiation (LTP) — a lasting increase in communication strength between neurons — to enable memory formation. They also found that the CCK and CCK-B receptors (CCKBR is one of three known types of CCK receptors in the central nervous system) mediate neuroplasticity, as well as visual and sound associative memory formation, in the auditory cortex, and trace fear memory formation in the amygdala. Other studies have found that CCKBR antagonist (which blocks the binding of the CCK and CCK-B receptors, thus inhibiting the effect of the binding) exhibited an anti-depressant effect in mice.
So Professor He’s group hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the basolateral amygdala (BLA) — a brain region involved in processing emotional memories and thought to be dysregulated in depression, thus enhancing the development of depression.
In their latest study, they tested this hypothesis using various experimental methods, including in vitro electrophysiological recording, optogenetic manipulation, drug manipulation and behavioural analysis of mice, to examine the critical role of CCK and CCKBR in depression. They found that a CCKBR antagonist called YM022 had an anti-depressant-like effect by blocking neuroplasticity-caused aversive memory formation in mice.
The results of the in-vitro recording in the BLA showed that the YM022 significantly suppressed neuroplasticity. The neuroplasticity induction rate reached 72.3% in the control group; but it was only 10.2% in the drug-treated group.
Moreover, the team underwent a series of behavioural tests to determine the antagonist’s efficacy. The results showed that depressive behaviours in mice treated with a CCKBR antagonist was reduced.
“Remarkably, the YM022 shows anxiolytic effects with a dose of 3.0 ug/kg, which is 3,000 times lower than the required dosage of current antidepressants,” said Professor He. “These results indicate that CCKBR is a potential target for depression treatment, and that the selected antagonist, YM022, may be a good anti-depressant candidate due to its extremely small effective dose. This paves the way for targeted drug development that specifically addresses the abnormalities observed in the basolateral amygdala.” Next, the research team will focus on the precise mechanisms and potential side effects of CCKBR antagonists to set the stage for future clinical trials involving human subjects.
The research was supported by Hong Kong Research Grants Council, the Innovation and Technology Fund, the Health and Medical Research Fund, and the following charitable foundations: the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation.

Cambridge scientists have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that supports these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke.
The study, published today in Stem Cell Reports, also identifies a drug target to ‘plug’ these leaks and prevent so-called small vessel disease in the brain.
Cerebral small vessel disease (SVD) is a leading cause of age-related cognitive decline and contributes to almost half (45%) of dementia cases worldwide. It is also responsible for one in five (20%) ischemic strokes, the most common type of stroke, where a blood clot prevents the flow of blood and oxygen to the brain.
The majority of cases of SVD are associated with conditions such as hypertension and type 2 diabetes, and tend to affect people in their middle age. However, there are some rare, inherited forms of the disease that can strike people at a younger age, often in their mid-thirties. Both the inherited and ‘spontaneous’ forms of the disease share similar characteristics.
Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, used cells taken from skin biopsies of patients with one of these rare forms of SVD, which is caused by a mutation in a gene called COL4.
By reprogramming the skin cells, they were able to create induced pluripotent stem cells — cells that have the capacity to develop into almost any type of cell within the body. The team then used these stem cells to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.
Dr Alessandra Granata from the Department of Clinical Neurosciences at Cambridge, who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease. Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”
Our blood vessels are built around a type of scaffolding known as an extracellular matrix, a net-like structure that lines and supports the small blood vessels in the brain. The COL4 gene is important for the health of this matrix.
In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called ‘tight junctions’, which ‘zip’ cells together. This leads to the small blood vessels becoming leaky — a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.
The researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure — similar to how in The Sorcerer’s Apprentice, a single broom can help mop the floor, but too many wreak havoc.
When the team treated the blood vessels with drugs that inhibit MMPs — an antibiotic and anti-cancer drug — they found that these reversed the damage and stopped the leakage.
Dr Granata added: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”
The study was funded by the Stroke Association, British Heart Foundation and Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.

During even the most routine visits, physicians listen to sounds inside their patients’ bodies — air moving in and out of the lungs, heart beats and even digested food progressing through the long gastrointestinal tract. These sounds provide valuable information about a person’s health. And when these sounds subtly change or downright stop, it can signal a serious problem that warrants time-sensitive intervention.
Now, Northwestern University researchers are introducing new soft, miniaturized wearable devices that go well beyond episodic measurements obtained during occasional doctor exams. Softly adhered to the skin, the devices continuously track these subtle sounds simultaneously and wirelessly at multiple locations across nearly any region of the body.
The new study will be published on Thursday (Nov. 16) in the journal Nature Medicine.
In pilot studies, researchers tested the devices on 15 premature babies with respiratory and intestinal motility disorders and 55 adults, including 20 with chronic lung diseases. Not only did the devices perform with clinical-grade accuracy, they also offered new functionalities that have not been developed nor introduced into research or clinical care.
“Currently, there are no existing methods for continuously monitoring and spatially mapping body sounds at home or in hospital settings,” said Northwestern’s John A. Rogers, a bioelectronics pioneer who led the device development. “Physicians have to put a conventional, or a digital, stethoscope on different parts of the chest and back to listen to the lungs in a point-by-point fashion. In close collaborations with our clinical teams, we set out to develop a new strategy for monitoring patients in real-time on a continuous basis and without encumbrances associated with rigid, wired, bulky technology.”
“The idea behind these devices is to provide highly accurate, continuous evaluation of patient health and then make clinical decisions in the clinics or when patients are admitted to the hospital or attached to ventilators,”said Dr. Ankit Bharat, a thoracic surgeon at Northwestern Medicine, who led the clinical research in the adult subjects. “A key advantage of this device is to be able to simultaneously listen and compare different regions of the lungs. Simply put, it’s like up to 13 highly trained doctors listening to different regions of the lungs simultaneously with their stethoscopes, and their minds are synced to create a continuous and a dynamic assessment of the lung health that is translated into a movie on a real-life computer screen.”
Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery at Northwestern’s McCormick School of Engineering and Northwestern University Feinberg School of Medicine. He also directs the Querrey Simpson Institute for Bioelectronics. Bharat is the chief of thoracic surgery and the Harold L. and Margaret N. Method Professor of Surgery at Feinberg. As the director of the Northwestern Medicine Canning Thoracic Institute, Bharat performed the first double-lung transplants on COVID-19 patients in the U.S. and started a first-of-its-kind lung transplant program for certain patients with stage 4 lung cancers.

Comprehensive, non-invasive sensing network
Containing pairs of high-performance, digital microphones and accelerometers, the small, lightweight devices gently adhere to the skin to create a comprehensive non-invasive sensing network. By simultaneously capturing sounds and correlating those sounds to body processes, the devices spatially map how air flows into, through and out of the lungs as well as how cardiac rhythm changes in varied resting and active states, and how food, gas and fluids move through the intestines.
Encapsulated in soft silicone, each device measures 40 millimeters long, 20 millimeters wide and 8 millimeters thick. Within that small footprint, the device contains a flash memory drive, tiny battery, electronic components, Bluetooth capabilities and two tiny microphones — one facing inward toward the body and another facing outward toward the exterior. By capturing sounds in both directions, an algorithm can separate external (ambient or neighboring organ) sounds and internal body sounds.
“Lungs don’t produce enough sound for a normal person to hear,” Bharat said. “They just aren’t loud enough, and hospitals can be noisy places. When there are people talking nearby or machines beeping, it can be incredibly difficult. An important aspect of our technology is that it can correct for those ambient sounds.”
Not only does capturing ambient noise enable noise canceling, it also provides contextual information about the patients’ surrounding environments, which is particularly important when treating premature babies.
“Irrespective of device location, the continuous recording of the sound environment provides objective data on the noise levels to which babies are exposed,” said Dr. Wissam Shalish, a neonatologist at the Montreal Children’s Hospital and co-first author of the paper. “It also offers immediate opportunities to address any sources of stressful or potentially compromising auditory stimuli.”
Non-obtrusively monitoring babies’ breathing

When developing the new devices, the researchers had two vulnerable communities in mind: premature babies in the neonatal intensive care unit (NICU) and post-surgery adults. In the third trimester during pregnancy, babies’ respiratory systems mature so babies can breathe outside the womb. Babies born either before or in the earliest stages of the third trimester, therefore, are more likely to develop lung issues and disordered breathing complications.
Particularly common in premature babies, apneas are a leading cause of prolonged hospitalization and potentially death. When apneas occur, infants either do not take a breath (due to immature breathing centers in the brain) or have an obstruction in their airway that restricts airflow. Some babies might even have a combination of the two. Yet, there are no current methods to continuously monitor airflow at the bedside and to accurately distinguish apnea subtypes, especially in these most vulnerable infants in the clinical NICU.
“Many of these babies are smaller than a stethoscope, so they are already technically challenging to monitor,” said Dr. Debra E. Weese-Mayer, a study co-author, chief of autonomic medicine at Ann & Robert H. Lurie Children’s Hospital of Chicago and the Beatrice Cummings Mayer Professor of Autonomic Medicine at Feinberg. “The beauty of these new acoustic devices is they can non-invasively monitor a baby continuously — during wakefulness and sleep — without disturbing them. These acoustic wearables provide the opportunity to safely and non-obtrusively determine each infant’s ‘signature’ pertinent to their air movement (in and out of airway and lungs), heart sounds and intestinal motility day and night, with attention to circadian rhythmicity. And these wearables simultaneously monitor ambient noise that might affect the internal acoustic ‘signature’ and/or introduce other stimuli that might affect healthy growth and development.”
In collaborative studies conducted at the Montreal Children’s Hospital in Canada, health care workers placed the acoustic devices on babies just below the suprasternal notch at the base of the throat. Devices successfully detected the presence of airflow and chest movements and could estimate the degree of airflow obstruction with high reliability, therefore allowing identification and classification of all apnea subtypes.
“When placed on the suprasternal notch, the enhanced ability to detect and classify apneas could lead to more targeted and personalized care, improved outcomes and reduced length of hospitalization and costs,” Shalish said. “When placed on the right and left chest of critically ill babies, the real-time feedback transmitted whenever the air entry is diminished on one side relative to the other could promptly alert clinicians of a possible pathology necessitating immediate intervention.”
Tracking infant digestion
In children and infants, cardiorespiratory and gastrointestinal problems are major causes of death during the first five years of life. Gastrointestinal issues, in particular, are accompanied by reduced bowels sounds, which could be used as an early warning sign of digestion issues, intestinal dysmotility and potential obstructions. So, as part of the pilot study in the NICU, the researchers used the devices to monitor these sounds.
In the study, premature babies wore sensors at four locations across their abdomen. Early results aligned with measurements of adult intestinal motility using wire-based systems, which is the current standard of care.
“When placed on the abdomen, the automatic detection of reduced bowel sounds could alert the clinician of an impending (sometimes life-threatening) gastrointestinal complication,” Shalish said. “While improved bowel sounds could indicate signs of bowel recovery, especially after a gastrointestinal surgery.”
“Intestinal motility has its own acoustic patterns and tonal qualities,” Weese-Mayer said. “Once an individual patient’s acoustic ‘signature’ is characterized, deviations from that personalized signature have potential to alert the individual and health care team to impending ill health, while there is still time for intervention to restore health.”
In addition to offering continuous monitoring, the devices also untethered NICU babies from the variety of sensors, wires and cables connected to bedside monitors.
Mapping a single breath
Accompanying the NICU study, researchers tested the devices on adult patients, which included 35 adults with chronic lung diseases and 20 healthy controls. In all subjects, the devices captured the distribution of lung sounds and body motions at various locations simultaneously, enabling researchers to analyze a single breath across a range of regions throughout the lungs.
“As physicians, we often don’t understand how a specific region of the lungs is functioning,” Bharat said. “With these wireless sensors, we can capture different regions of the lungs and assess their specific performance and each region’s performance relative to one another.”
In 2020, cardiovascular and respiratory diseases claimed nearly 800,000 lives in the U.S., making them the first and third leading causes of death in adults, according to the Centers for Disease Control and Prevention. With the goal of helping guide clinical decisions and improve outcomes, the researchers hope their new devices can slash these numbers to save lives.
“Lungs can make all sorts of sounds, including crackling, wheezing, rippling and howling,” Bharat said. “It’s a fascinating microenvironment. By continuously monitoring these sounds in real time, we can determine if lung health is getting better or worse and evaluate how well a patient is responding to a particular medication or treatment. Then we can personalize treatments to individual patients.”
The study, “Wireless broadband acousto-mechanical sensors as body area networks for continuous physiological monitoring,” was supported by the Querrey-Simpson Institute for Bioelectronics at Northwestern University. The paper’s co-first authors are Jae-Young Yoo of Northwestern, Seyong Oh of Hanyang University in Korea and Wissam Shalish of the McGill University Health Centre.

A rare but potent genetic mutation that alters a protein in the brain’s immune cells, known as microglia, can give people as much as a three-fold greater risk of developing Alzheimer’s disease. A new study by researchers in The Picower Institute for Learning and Memory at MIT details how the mutation undermines microglia function, explaining how it seems to generate that higher risk.
“This TREM2 R47H/+ mutation is a pretty important risk factor for Alzheimer’s disease,” said study lead author Jay Penney, a former postdoc in the MIT lab of Picower Professor Li-Huei Tsai. Penney is now an incoming assistant professor at the University of Prince Edward Island. “This study adds clear evidence that microglia dysfunction contributes to Alzheimer’s disease risk.”
In the study in the journal GLIA, Tsai and Penney’s team shows that human microglia with the R47H/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimer’s pathology. Mutant microglia are prone to inflammation yet are worse at responding to neuron injury and less able to clear harmful debris including the Alzheimer’s hallmark protein amyloid beta. And when the scientists transferred TREM2 mutant human microglia into the brains of mice, the mice suffered a significant decline in the number of synapses, or connections between their neurons, which can impair the circuits that enable brain functions such as memory.
The study is not the first to ask how the TREM2 R47H/+ mutation contributes to Alzheimer’s, but it may advance scientists’ emerging understanding, Penney said. Early studies suggested that the mutation simply robbed the protein of its function, but the new evidence paints a deeper and more nuanced picture. While the microglia do exhibit reduced debris clearance and injury response, they become overactive in other ways, such as their overzealous inflammation and synapse pruning.
“There is a partial loss of function but also a gain of function for certain things,” Penney said.
Misbehaving microglia
Rather than rely on mouse models of TREM2 R47H/+ mutation, Penney, Tsai and their co-authors focused their work on human microglia cell cultures. To do this they used a stem cell line derived from skin cells donated by a healthy 75-year-old woman. In some of the stem cells they then used CRISPR gene editing to insert the R47H/+ mutation and then cultured both edited and unedited stem cells to become microglia. This strategy gave them a supply of mutated microglia and healthy microglia, to act as experimental controls, that were otherwise genetically identical.

The team then looked to see how harboring the mutation affected each cell line’s expression of its genes. The scientists measured more than 1,000 differences but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses. Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.
In further experiments with the cells, the team exposed them to three kinds of the debris microglia typically clear away in the brain: myelin, synaptic proteins and amyloid beta. The mutant microglia cleared less than the healthy ones.
Another job of microglia is to respond when cells, such as neurons, are injured. Penney and Tsai’s team co-cultured microglia and neurons and then zapped the neurons with a laser. For the next 90 minutes after the injury the team tracked the movement of surrounding microglia. Compared to normal microglia, those with the mutation proved less likely to head toward the injured cell.
Finally, to test how the mutant microglia act in a living brain, the scientists transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. The scientists then stained that region to highlight various proteins of interest. Having mutant or normal human microglia didn’t matter for some measures, but proteins associated with synapses were greatly reduced in mice where the mutated microglia were implanted.
By combining evidence from the gene expression measurements and the evidence from microglia function experiments, the researchers were able to formulate new ideas about what drives at least some of the microglial misbehavior. For instance, Penney and Tsai’s team noticed a decline in the expression of a “purinergic” receptor protein involving sensing neuronal injury perhaps explaining why mutant microglia struggled with that task. They also noted that mice with the mutation overexpressed “complement” proteins used to tag synapses for removal. That might explain why mutant microglia were overzealous about clearing away synapses in the mice, Penney said, though increased inflammation might also cause that by harming neurons overall.
As the molecular mechanisms underlying microglial dysfunction become clearer, Penney said, drug developers will gain critical insights into ways to target the higher disease risk associated with the TREM2 R47H/+ mutation.
“Our findings highlight multiple effects of the TREM2 R47H/+ mutation likely to underlie its association with Alzheimer’s disease risk and suggest new nodes that could be exploited for therapeutic intervention,” the authors conclude.
In addition to Penney and Tsai, the paper’s other authors are William Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, and Hannah Woolf.
The Robert A. and Renee Belfer Family Foundation, The Cure Alzheimer’s Fund, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory and the Human Frontier Science Program provided funding for the study.

Children whose mothers are highly stressed, anxious or depressed during pregnancy may be at higher risk for mental health and behavior issues during their childhood and teen years, according to research published by the American Psychological Association.
“Our research suggests that psychological distress during the pregnancy period has a small but persistent effect on children’s risk for aggressive, disinhibited and impulsive behaviors,” said study author Irene Tung, PhD, of California State University Dominguez Hills. “These findings add to the evidence that providing widely accessible mental health care and support during pregnancy may be a critical step to help prevent childhood behavior problems.”
Tung and her colleagues analyzed data from 55 studies with more than 45,000 total participants. All the studies measured women’s psychological distress during pregnancy (including stress, depression or anxiety) and then later measured their children’s “externalizing behaviors” — mental health symptoms directed outward, such as attention deficit hyperactivity disorder or aggression.
Overall, the researchers found that women who reported more anxiety, depression or stress while pregnant were more likely to have children with more ADHD symptoms or who exhibited more difficulties with aggressive or hostile behavior, as reported by parents or teachers.
The research was published in the journal Psychological Bulletin.
Research has long suggested a link between mothers’ mental health during pregnancy and children’s externalizing behaviors. However, many previous studies have not disentangled the effects of stress, anxiety or depression during pregnancy from the effects of parents’ psychological distress after a child is born.
In the current study, the researchers only included research in which mothers’ psychological distress was measured both during and after pregnancy. They found that even after controlling for later (postnatal) psychological distress, distress during pregnancy in particular increased children’s risk of developing externalizing problems.

The effect held true regardless of whether the children were boys or girls. And it held true for children in early childhood (ages 2-5), middle childhood (6-12) and adolescence (13-18), though the effect was strongest in early childhood.
The findings are consistent with theories that suggest that exposure to stress hormones in utero can affect children’s brain development, according to the researchers.
Future research should focus on increasing diversity to understand the cultural and socioeconomic variables that affect prenatal stress and to develop effective interventions, according to Tung.
“Most existing research has focused on white, middle-class and higher educated samples. But experiences of racism, economic disparities and lack of health care access are known contributors to stress during pregnancy. Understanding how psychological distress during pregnancy impacts underrepresented families is key to developing equitable public health policies and interventions,” she said.
She and her colleagues are now conducting two studies focused on understanding the types of support and resources that promote resilience and recovery from stress during pregnancy, particularly for families facing health inequities. The goal is to help inform culturally inclusive preventive interventions during pregnancy to help support early mental health resilience and well-being for parents and their children.

Immunotherapies that target the CD20 antigen have revolutionized how patients with a variety of blood cancers and hematologic disorders have been treated. However, many patients develop resistance to these treatments due to a loss of the antigen that’s being targeted. Now, a new study from researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) has found that gene splicing occurring within these cells can cause significant changes in CD20 protein levels that render the therapies ineffective.
The findings, published today by the journal Blood, also demonstrate that patients with very low levels of CD20 may still be responsive to CAR-T therapy, something that was previously thought not possible. These findings may lead to more appropriate choices for therapy that maximize benefits to patients affected by a variety of blood cancers.
CD20 is a cell-surface protein involved in the fine-tuning of B cell responses to foreign agents like viruses. It is expressed exclusively on the surface of normal and malignant B cells and is not expressed by other cell types in the body. This makes CD20 an attractive target for monoclonal antibody therapies which have been used to treat a variety of B-cell lymphomas, including follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphomas and high-grade B-cell lymphomas.
Despite anti-CD20 therapies revolutionizing the way these conditions are treated, some patients with these conditions do not respond to antibodies targeting CD20, while others initially respond before eventually developing resistance. Prior research had shown that a loss of CD20 reduced the effectiveness of these immunotherapies, since it would remove their intended target. However, the mechanism by which CD20 levels can be reduced were poorly understood. Researchers at CHOP suspected that CD20 messenger RNA was not being properly translated into the CD20 protein expressed on the surfaces of cells.
“It does not matter how much mRNA is being made, it’s how effectively it is translated that matters,” said senior study author Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology and a professor with the Department of Pathology and Laboratory Medicine at CHOP and Penn. “In this study, we found that certain isoforms of the mRNA responsible for producing CD20 were impacted by splicing in a way that the proteins were not being made at the levels necessary for these immunotherapies to do their job.”
In the study, researchers focused on the MS4A1 gene, which encodes for CD20. The gene undergoes splicing, or stitching together of its building blocks called exons, to produce several mRNA isoforms, which may encode the identical amino acid sequence, but differ in the efficiency with which the protein is made. The researchers identified four variants in total among normal and malignant cells. Of the four variants, V1 and V3 were by far the most abundant, yet only V3 is efficiently translated into CD20. In contrast, variant V1 had trouble recruiting ribosomes responsible for making proteins, making it difficult for monoclonal antibodies to target affected cells.
Surprisingly, CHOP researchers and their Penn collaborators, including Drs. Steven Schuster and Marco Ruella, also found that CAR T-cells were still able to effectively kill both V3- and V1-expressing cells. CAR T-cell therapy modifies patient’s own immune cells to kill cancer cells. Historically, CAR T-cell therapy presented challenges and was thought not to be effective in these malignancies, but the study showed that it was more effective in targeting both variants compared with the monoclonal antibody mosunetuzumab, which was only effective against V3-expressing cells.
“If a patient has relapsed because CD20 levels are downregulated, CAR T-cell therapy may still be an option, as it requires a lower threshold of the protein in order to be effective,” said first study author Zhiwei Ang, PhD, Research Associate Scientist in the Thomas-Tikhonenko lab. “These findings may help clinical staff offer more precise options when treating these hematologic malignancies.”
This study was supported by grants from the National Institutes of Health grants U01 CA232563, U01 CA232563-S3, U01 CA232486, U01 CA243072, and T32 CA009615, United States Department of Defense grant CA180683P1, The V Foundation for Cancer Research grant T2018-014, The Emerson Collective grant 886246066, the Leukemia & Lymphoma Society, the Joshua Kahan Endowed Chair in Pediatric Leukemia Research and the Mildred L. Roeckle Endowed Chair in Pathology at CHOP.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects neurons in the brain and spinal cord causing loss of muscle control. A study by the University of Barcelona has designed a potential therapeutic strategy to tackle this pathology that has no treatment to date. It is a molecular trap that prevents one of the most common genetic ALS-causing peptide compounds, the Poly-GR dipeptide, from causing its toxic effects in the body. The results show that this strategy reduces the death of neurons in patients and in an animal model (vinegar flies) of the disease.
The first authors of this international research study published in the journal Science Advances are the experts Juan Alberto Ortega Cano, from the Faculty of Medicine and Health Sciences and the UB Institute of Neurosciences (UBneuro), and Ivan Sasselli, from the Materials Physics Centre (CSIC-UPV/EHU). Researchers from the University of Zaragoza and Northwestern University (United States) have also participated in the study.
One of the most frequent causes of ALS is the mutation in the C9orf72 gene, found in approximately 33% of patients affected by familial ALS (FALS) and 5% of those affected by sporadic ALS in Spain. In these patients, dipeptides with a large number of positive charges are generated and they provoke highly toxic effects on motor neurons. In the first part of the study, the researchers combined computational and experimental techniques to improve the molecular understanding of these dipeptides and how they produce this pathological process.
A toxic union for neurons
The results showed that the toxicity of these compounds is partly due to those that bind to ribosomal RNA (rRNA), a molecule involved in the process of translation of genetic information and protein synthesis in the cell. “We have observed that these dipeptides, specially those rich in the amino acid arginine (poly-glycine-arginine or Poly-GR), bind to a specific region of rRNA, affecting the biosynthesis of ribosomes (small structures responsible for synthesising proteins in our body) and protein translation in human motor neurons, leading to their death,” says Professor Juan Alberto Ortega Cano. “Moreover — the researcher adds — this interaction between Poly-GR and the rRNA is stronger than the interaction between the Poly-GR with other ribosomal proteins that had been previously described in other studies, and it tells us why these dipeptides have a high affinity for binding to ribosomes in cells.”
Given these results, the researchers designed an innovative strategy to trick the Poly-GR dipeptides and reduce their toxicity. They created a trap, a molecule that mimicked the specific rRNA sequence to which Poly-GR dipeptides bin during the pathological process, in order to avoid the neurotoxic effects of this binding.
The application of this strategy in neurons derived from in vitro patient tissue and in in vivo models of the disease (vinegar flies) shows that “it reduces the defects in ribosome biosynthesis in protein translation and toxicity in cells expressing Poly-GR, as well as death in motor neurons of ALS patients with mutations in the C9orf72 gene,” notes the researcher.
Although much research remains to be done to validate and fully understand how this strategy works, the researchers note that these promising results reinforce the idea that the use of RNA traps is useful “not only to study RNA-protein interactions, but also to protect neurons from the detrimental effects of abnormal proteins generated in other neurodegenerative diseases.”

After 40 years of treating metastatic bladder cancer with chemotherapy as a primary treatment, scientists now present a new approach using immunotherapy combinations. The results of not just one, but two studies have been presented at the European Society for Medical Oncology (ESMO) conference in Madrid. The outcomes of these studies are going to revolutionize the landscape of bladder cancer treatment.
Traditionally, cisplatin-based chemotherapy has been the standard treatment for bladder cancer patients who are able to tolerate this drug. However, responses have been limited, and durable outcomes rare. Over the past years, two phase-3 clinical trials studied the effects of combining immunotherapy with either chemotherapy or a new drug, enfortumab vedotin, to treat bladder cancer (more exact: urothelial carcinoma). With success, both studies show a significant increase in both overall survival as well as progression-free survival.
Medical oncologist Michiel van der Heijden from the Netherlands Cancer Institute (NKI) explains: “these results mark a milestone in bladder cancer research, providing the first evidence of a survival benefit of combination therapy involving immune checkpoint inhibitors over chemotherapy. This is an exciting development in our field, as these findings will thoroughly change the treatment landscape for advanced bladder cancer. It is a testament to the collaborative efforts of researchers, and most importantly, the resilience of all patients who participated in this study.”
Combining therapies
The CheckMate 901 trial investigated a new combination of the drugs nivolumab and gemcitabine-cisplatin and compared this to treatment with only chemotherapy. The results demonstrated that patients treated with both drugs showed a 22% reduction in the risk of death compared to patients only treated with chemotherapy. The findings also showed that the combination of nivolumab and chemotherapy led to a significant improvement in progression-free survival vs chemotherapy alone.
The results will be published in the New England Journal of Medicine at the same time as the presentation at ESMO.
During this ESMO presidential session, the results of another phase-3 in the same treatment line will be presented, featuring a novel combination of an antibody-drug conjugate with immune checkpoint inhibition, using Enfortumab Vedotin + pembrolizumab. This study found a statistically significant and clinically meaningful improvement in overall survival and progression-free survival as well. These results will be published in a scientific journal at a later time.
Both treatments are yet to be registered and approved in the Netherlands for health insurance coverage, meaning that they will not yet be readily available. In the US, the Enfortumab Vedotin + pembrolizumab is already available for a subgroup of bladder cancer patients, based on a phase 2 study.
Unique
Michiel van der Heijden is involved in both these trials, making it a special occasion for the NKI to have such a leading role in two large studies that can change clinical practice. “It is very special to give a presidential lecture during ESMO. I have not had this honor before and it may very well not happen again anytime soon. Last year was a very special occasion as well, as two NKI researchers, Myriam Chalabi and John Haanen, both presented their findings in the presidential session. Not many researchers have received this honor, making this a really unique moment for the NKI once again.”

Scientists at The University of Texas at Dallas Center for Vital Longevity (CVL) have published new evidence that shows changes in brain network patterns that occur in early-stage Alzheimer’s disease differ from those associated with normal aging.
The findings, published Nov. 15 in The Journal of Neuroscience, also show that the impact of Alzheimer’s on brain function is broader than previously believed. In addition to detecting characteristic changes in the brain circuits supporting memory and attention as expected, the researchers found distinct changes in circuits involved in sensory and motor processing.
“Some Alzheimer’s disease-accompanied brain dysfunction that goes beyond memory and attention might be detectable at very early stages, even during mild cognitive impairment before a diagnosis of Alzheimer’s,” said Dr. Gagan Wig, associate professor of psychology in the School of Behavioral and Brain Sciences and corresponding author of the study.
The research team found that the Alzheimer’s-related changes in brain networks — interconnected regions of the brain sharing similar functions — were independent of other factors typically associated with the disease, such as elevated levels of amyloid plaques, which form when protein pieces called beta-amyloid clump together.
This brain-network dysfunction could be a new way of characterizing Alzheimer’s-related cognitive impairment and provide a target for potential treatment, Wig said.
“We’ve come to realize that the targets we’ve been focusing on might not be sufficient, including the idea of amyloid being the primary culprit of Alzheimer’s disease,” he said. “We’ve been seeking other ways of quantifying Alzheimer’s dysfunction, and in this paper, we show that even when you account for amyloid burden, circuit dysfunction is still there.”
Neuroscientists have distinguished brain regions and systems by function for more than a century. Some of these networks govern sensory or motor operations, while other so-called association systems integrate and retain that information and oversee attention, memory and language.

This distinction could play a key role in separating healthy aging from Alzheimer’s degradation, Wig said.
“In healthy aging, changes seem largely focused on association systems. Sensory and motor systems are generally stable,” Wig said. “For example, the brain of an 80-year-old is very likely to have noticeable atrophy in an association cortex but may have relatively more preserved visual and auditory cortex.”
In the study, researchers examined the effects of age and Alzheimer’s severity on resting-state brain system segregation, a measure of the brain network’s organization and integrity, in 326 cognitively healthy and 275 cognitively impaired individuals who were scanned as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a private-public partnership funded in part by the National Institutes of Health (NIH).
“With the brain-scan data we now have available, we can account for age-related brain differences and observe alterations unique to dementia severity. Exploring this, we found worsening dementia is associated not only with alterations to association systems, but also to the sensory and motor systems,” Wig said. “This work would be impossible without the massive, multisite ADNI database that has been made available to Alzheimer’s disease researchers such as our group.”
Cognition and neuroscience doctoral student Ziwei Zhang, the first author of the paper and a member of Wig’s neuroimaging lab, said the network interactions affected in Alzheimer’s are a broader group than those affected by healthy aging.
“In older adults who don’t show any cognitive impairment, the interactions altered are primarily among brain regions performing similar functions, or within brain systems,” she said. “However, in patients diagnosed with Alzheimer’s disease, the interactions between regions that perform distinct functions — such as visual processing and memory — are also altered.”
Neuroscientists have struggled to explain why some people may have typical Alzheimer’s pathologies — amyloid plaques and neurofibrillary, or tau, tangles — yet seem cognitively unaffected.

Wig said the new findings show that the cognitive dysfunction that comes with the disease is likely tied to functional network changes that can be dissociated from amyloid levels.
“These observations offer important clues toward identifying the types of behavioral deficits that are most impacted at early stages of Alzheimer’s disease and other forms of dementia,” he said. “As we continue to refine the brain network-based biomarkers of Alzheimer’s, we are honing in on a new, unique source of information to aid both Alzheimer’s diagnosis and for measuring disease risk in otherwise healthy individuals.”
Other authors of the paper are CVL research scientist Micaela Chan MS’12, PhD’16; cognition and neuroscience doctoral student Ezra Winter-Nelson; and former Wig lab members Claudia Carreno MS’17 and Liang Han PhD’22.
The research was supported by grants from the NIH’s National Institute on Aging (R01AG063930) and the James S. McDonnell Foundation.