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In this population-based study with more than 26 million live births the findings indicated that women belonging to the most vulnerable social group were exposed to a greater burden of factors that increased the likelihood of having a live birth with CA. However, the patterns of risk factors varied according to the group of anomalies. Maternal education was a risk factor only for neural tube defects, while lack of prenatal care and multifetal gestation were associated with greater odds of having a live birth with CA in all groups, except for those with Down syndrome. Advanced maternal age and previous fetal loss were the factors that increased the odds of CA in all groups.

Distal risk factors, known as socioeconomic factors, have been shown to increase the odds of children born with CA. Black maternal race/skin color and low education (0 to 3 years), increased the odds of CA by 16% and 8%, respectively. Similarly, Anele et al. (2022) reported that a low education level was associated with a 2.08 times higher risk of births affected by CA, mainly in mothers with higher incomes, indicating the impact of low education on the outcome [27]. Regarding black maternal race/skin color, studies carried out in the United States showed that the risk of birth with CA among African Americans varied according to the CA group, with a greater risk for musculoskeletal malformations and a lower risk for cardiac anomalies [28, 29]. Furthermore, in a study carried out in the southern region of Brazil, Trevilato et al. (2022) reported that black women had 20% higher odds of having children with CA than white women [6]. Both factors are related to greater social vulnerability and are consequently associated with low income [30, 31].

The contribution of socioeconomic vulnerability to CA has different origins, acts indirectly, and encompasses environmental conditions, such as poor nutrition, as well as social and structural conditions, e.g., lack of access to prenatal care [10, 11, 20, 32]. Thus, we observed that not having had any prenatal consultations during pregnancy or having started late has been shown to increase the odds of birth with CA. Trevilato et al. (2022) reported that women with no prenatal visits had 97% greater odds than women with seven or more prenatal visits of having children with congenital anomalies [6]. Prenatal care assistance allows important guidance on modifiable risks in the mother’s lifestyle, such as smoking, alcohol consumption, diabetes control, and exposure to certain teratogens, to be provided at an early stage of pregnancy, reducing the risk of births with CA [11].

Women in more vulnerable socioeconomic groups can find difficulties accessing prenatal care since women with lower incomes face barriers such as difficulty covering the cost of services, long waiting times, and difficulties obtaining transportation to reach appointment locations, which can lead to negative attitudes toward health care [33, 34]. Furthermore, Dingemann et al. (2019) reported that women with low education attend fewer prenatal consultations, in addition to having a greater chance of future complications in their children with CA [35]. The absence of prenatal consultations may be related to extreme socioeconomic vulnerability [36, 37]. Furthermore, it was observed that in Brazil, among women who underwent prenatal care, the largest proportion underwent (at least once) an ultrasound (99.7%). However, many congenital anomalies require other complementary exams for accurate diagnosis, which are often not available free of charge for the poorest population [38,39,40].

Neural tube defects were strongly associated with not having any prenatal consultations during pregnancy and low maternal education. Mothers exposed to these factors may not correctly supplement folic acid in the diet during the critical period of pregnancy in which neural tube development occurs (up to the fourth week of gestation) [27, 41]. It is recommended that supplementation begin as early as possible; ideally, supplementation should be started before pregnancy during conception planning, to reduce the likelihood of birth with neural tube defects [42]. Cui et al. (2021) reported that women with less education and who had unplanned pregnancies had less knowledge about folic acid and had higher odds of not starting to use it before becoming pregnant [43].

Additionally, there were significant variations in the odds of children being born with CA between regions of the country and CA groups. The leading cause of this variation is underreporting, and the Southeast is the region that best reports births with CA compared to others [7]. The greater chance of mothers living in the Northeast Region having children with neural tube defects has not yet been fully explained. According to a previous study, the Northeast and Southeast regions had the highest prevalence of neural tube defects [44]. The Northeast region of Brazil concentrates almost half of the Brazilian population living in poverty [45], which may help explain the greater odds of residence mothers of having births with neural tube defects, since this condition is highly associated with low income, low education attainment and poor diet (insufficient supplementation) [46, 47]. In addition, the Zika virus epidemic in Brazil in 2014 resulted in an increase in the reporting of live births with microcephaly and other congenital anomalies of the nervous system, especially in the Northeast region [5, 7], which may have contributed to the observed results.

The odds of having children with cardiac CA also varied widely between regions. Women who lived in the North and Northeast regions were less odds to have children affected by cardiac CA. This result reflects considerable underreporting of this group of CA across regions, which is more pronounced in the country’s poorest regions [7]. A similar result was observed by Salim et al. (2020), who reported fewer cardiac CA notifications in these regions [48]. Early diagnosis of cardiac CA may require a more complex structure than some centers can offer, in addition to trained professionals [49], which leads to underreporting of this group, which is more accentuated in the population and economically vulnerable regions.

Multifetal pregnancy and fetal loss were also associated with birth with CA. Previous fetal loss can be an indication of previous gestational problems, such as a fetus with severe anomalies. A history of prior anomalies has been shown in other studies to be a risk factor for birth with CA [6, 50], which, therefore, may be related to fetal loss in previous pregnancies. Furthermore, as noted by Al-Dewik et al. (2023), multifetal gestation increased the chances of birth with different types of CA, including cardiac CA and nervous system CA [51], as seen in the present work.

Maternal biological factors also demonstrated an association with the outcome. Thus, consistent with the literature, advanced maternal age was found to be the factor most strongly associated with the occurrence of births with Down syndrome, as already well known [52]. Additionally, advanced maternal age also elevated the odds of having children born with other CA, such as central nervous system defects and heart defects [52, 53]. The association between advanced maternal age and the risk of chromosomal defects and other CA has been widely recognized, it is seen that the CA risk varies by anomaly type and maternal age. It is worth noting that pregnancies in women under the age of 20 years have also been shown to increase the odds of births with CA, which is primarily attributed to social factors, as early pregnancy may be linked to low income and other lifestyle-related risk factors, such as the use of drugs and alcohol, as previously discussed [54,55,56].

A relevant aspect of this study was the extensive sample size, as it included all births evaluated nationwide over a long period. Additionally, through the linkage process, it was possible to include live births that were not reported in the SINASC database but were registered in the SIM database. Correcting an information error and substantially enhancing the case group’s size. However, it is important to emphasize that the CA recorded in the SIM were those that were severe enough to result in the individual’s death, which may introduce a bias in this regard. In addition, CA that were not recorded in the SINASC at birth and were not registered in the SIM, were not captured in the notifications and consequently were not included in the analyses. Several factors contribute to this underreporting, including the fact that some CA are not detected at birth because they are not noticeable. In addition, the health team is often not trained to recognize certain more important CA, a capability that varies among Brazilian regions, reinforcing the need for active surveillance of the most important defects [17, 57]. Furthermore, there was no information available on the use of folic acid during pregnancy, which made a more detailed analysis in this regard impossible.

In summary, this study showed that socioeconomically vulnerable women have an increased odds of having a pregnancy affected by CA, mainly for neural tube defects, due to the sum of the risk factors to which they are exposed. Maternal characteristics such as low education, region of residence, race/black skin color, and late start of prenatal care were associated with the outcome. Biological characteristics, such as advanced maternal age and multifetal gestation, were also shown to be strongly associated with birth with CA. Advanced maternal age had a strong association with birth with Down syndrome, whereas multifetal gestation was mainly associated with neural tube defects. Thus, although many CA are not preventable, primary care measures to reduce associated factors greatly impact preventing births with CA [58, 59]. As noted in this study, there is a great need to identify the factors associated with CA and outcomes at the population level, thereby supporting the establishment of effective public policies that can effectively reduce the incidence of preventable CA, as a broad-coverage support for families wishing to become pregnant, including genetic counseling for families with a history of congenital anomalies in the family, control of maternal infections before conception, nutritional support and folic acid supplementation before conception also, among others, in addition to health actions to monitor and care of those born and living with CA.

For the first time, scientists have systematically studied the genetic effects of chemotherapy on healthy tissues.

Researchers from the Wellcome Sanger Institute, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust (CUH) and their collaborators analysed blood cell genomes from 23 patients of all ages who had been treated with a range of chemotherapies.

Published today (1 July 2025) in Nature Genetics, the researchers show that many but not all chemotherapy agents cause mutations and premature aging in healthy blood.

As part of Cancer Grand Challenges team Mutographs, the researchers uncovered new patterns of DNA damage, or mutational signatures, associated with specific chemotherapy drugs.

The researchers suggest that the damaging genetic effects of chemotherapy identified by whole genome sequencing could guide the future treatment of patients with effective chemotherapies that have less harmful effects on healthy tissues.

Chemotherapy is a type of anti-cancer treatment that works by killing cancer cells. It is a systemic treatment, meaning it works throughout the body, and can be administered as a single chemotherapy drug or a combination of drugs. In developed countries, it is estimated that around 10 per cent of the population has received chemotherapy treatments for cancer and other diseases at some point in their lifetime.

Chemotherapy can have long-term side effects on healthy, non-cancerous tissues, and is associated with an increased risk of secondary cancers. However, there is limited understanding of the biological mechanisms underlying these side effects.

With new genomic technologies, researchers can explore mutations in normal cells and begin to investigate the extent and long-term consequences of DNA damage from chemotherapy on healthy tissues.

In a new study, scientists set out to research the effects of chemotherapy on healthy blood. The Mutographs team at the Sanger Institute, University of Cambridge, CUH and their collaborators chose to study blood due to its ease in sampling and ability to culture blood in the laboratory. Plus, the numbers of mutations in normal blood are very consistent between people, giving a good baseline to see whether they are higher in individuals who have received chemotherapy.

The researchers sequenced blood cell genomes from 23 individuals aged three to 80 years, who had been treated with a range of chemotherapies for various blood and solid cancers. Most of the patients were treated at Addenbrooke’s Hospital in Cambridge and had received a combination of chemotherapy drugs. Collectively, they had been exposed to 21 drugs from all of the main chemotherapy classes, including alkylating agents, platinum agents and anti-metabolites. The results were compared with genomic data from nine healthy people who had never received chemotherapy.

From analyzing the whole genome sequence data, the team found that many classes of chemotherapeutics, but not all, do produce higher numbers of mutations in normal blood cells. For example, a three-year-old patient who was treated for neuroblastoma, a cancer of nerve tissue, had more than the number of mutations found in 80-year-olds who had never received chemotherapy.

By looking at patterns of damage in the DNA, known as mutational signatures, the researchers showed that different chemotherapeutics have different mutational signatures, and identified four new signatures found in chemotherapy-treated patients.

For instance, the researchers found that some platinum agents, such as carboplatin and cisplatin, caused very high numbers of mutations. Whereas other drugs in the same class, such as oxaliplatin, did not.

The researchers suggest that if these drugs are used interchangeably in cancer treatment, and assuming they have the same effectiveness, then this sort of genetic information could be incorporated in order to administer chemotherapies with fewer harmful effects.

The team also made discoveries around the effects of chemotherapy on the population of cells that generate blood, known as hematopoietic stem cells.

In normal aging, the hematopoietic stem cells producing blood decrease in diversity, due to the expansion of clones of cells that have “driver” mutations in cancer genes. Chemotherapy caused a similar pattern of change, but prematurely in some middle-aged adults. Particularly in children who have had chemotherapy, their blood appeared to prematurely age, which may increase the risk of secondary cancer later in life.

Scientists suggest that genomic data could help in choosing the chemotherapies for children that minimise this premature aging, and genomic technologies could monitor for further changes later in life.

“For the first time, we have taken a systematic view of the genetic effects of chemotherapy on healthy tissues – in this case, blood. We find that some, but not all chemotherapies cause genetic mutations and premature ageing in normal blood. This study lays the groundwork for future research into the effects of chemotherapy on many other normal tissues, including multiple tissue sampling pre and post treatment, across a range of chemotherapies in a larger group of patients. This comprehensive view would reveal the full range of effects of different chemotherapies, and help us to optimise patient health in the long term.”

Dr Emily Mitchell, first author at the Wellcome Sanger Institute and clinician at CUH

“The effects of chemotherapy we see here – increasing numbers of mutations and premature ageing of healthy blood – reasonably contribute to the heightened risk of additional cancers and the patient’s ability to tolerate further treatments in the future. Given that for many cancers, chemotherapy drugs can be switched with other agents to achieve similar results, we hope such genomic data will guide the optimisation of future treatment plans to deliver effective chemotherapies with much fewer damaging side effects for patients.”

Dr Jyoti Nangalia, co-lead author at the Wellcome Sanger Institute and Consultant Haematologist at CUH

“This important research helps us better understand how some chemotherapy drugs can affect healthy cells as well as cancer cells. While many cancers can now be targeted using precision therapies, chemotherapy remains a key way to treat some cancers and saves many lives every year, so it’s vital that patients continue with the treatment recommended by their doctor. At the same time, studies like this are crucial for helping scientists improve cancer treatments in the future – making them not only more effective but also safer for people living with cancer.”

David Scott, Director of Cancer Grand Challenges

“I believe that the results of this study hold implications for the way that chemotherapies are used to treat cancer patients. We are constantly on the lookout for better ways of giving therapy and minimising the side effects of toxic, systemic treatments. I’m hopeful that the genomic information from this and future studies will guide choices of chemotherapies, and their adoption in clinical practice.”

Professor Sir Mike Stratton, Mutographs team lead and co-lead author at the Wellcome Sanger Institute

Reference: Mitchell E, Pham MH, Clay A, et al. The long-term effects of chemotherapy on normal blood cells. Nat Genet. 2025:1-11. doi: 10.1038/s41588-025-02234-x

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A potential treatment for glioblastoma crafted by scientists at The Wertheim UF Scripps Institute renders the deadly brain cancer newly sensitive to both radiation and chemotherapy drugs, and blocks the cancer’s ability to invade other tissue, a new study shows.

The experimental medication, called MT-125, has received approval from the FDA to move to clinical trials as a possible first-line treatment for the most aggressive form of the brain cancer.

Each year, 14,000 people in the United States receive the devastating news that they have glioblastoma. It is a cancer with an average survival of just 14 to 16 months. Standard treatments include surgery, radiation and chemotherapy. But half of glioblastoma patients have a subtype that doesn’t respond to any approved cancer drugs, said Courtney Miller, PhD, a professor and academic affairs director at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.

New options are urgently needed for those patients, said Miller, a member of the University of Florida Health Cancer Center.

“We know glioblastoma patients are awaiting a breakthrough, and we are moving as fast as humanly possible,” she said.

Miller and her colleagues have long focused on molecular “motors” in the cell, nanoscale proteins called myosin. They look and act like machines, converting the cell’s energy into activity. Myosin motors enable cells to move, connect to other cells or contract and expand, Miller said. They are found throughout the body, including in heart, muscle and brain tissue.

As a result, they have potential as therapeutic targets for a wide range of conditions, from cancer to substance use disorders, she said. However, there are no current medications that target them, or even selective drug-like tools that scientists can use to study them.

Miller teamed up with her Wertheim UF Scripps colleagues to design a spectrum of potential drug candidates to block myosin motors in different contexts. Their work was published Tuesday, July 1, in the scientific journal Cell.

Medicinal chemist Theodore Kamenecka, PhD, engineered the array of compounds, in consultation with structural biologist Patrick Griffin, PhD, The Wertheim UF Scripps Institute’s scientific director.

To test the oncology potential of the myosin motor drugs, the team joined forces with Steven Rosenfeld, MD, PhD, a scientist and neuro-oncologist at the Mayo Clinic in Jacksonville.

Their out-of-the-box strategy appears to have opened a new route to attacking the hardest-to-treat glioblastoma. It works in four ways, the scientists reported in a companion paper published in Cell on June 10.

“In animal studies, MT-125 makes malignant cells that were previously resistant to radiation responsive to it,” Miller said. “You also end up with multinucleated cells that cannot separate, and so they get marked for cell death.”

MT-125 also blocks the cells’ ability to squeeze and change shape, which means they cannot proliferate and invade other parts of the brain, she said. And if MT-125 is combined with existing chemotherapy drugs, including sunitinib, the drug appears to deliver a very powerful response, Rosenfeld said. Sunitinib belongs to a class of chemotherapy drugs called kinase inhibitors.

“We found in mice that combining MT-125 with a number of kinase inhibitors created long periods of a disease-free state that we haven’t seen in these mouse models before,” Rosenfeld said. 

The scientists cautioned that many potential drugs that perform well in mice fail in human studies, due to differences in biology, so it will take time and study to learn if MT-125 is the hoped-for breakthrough, Rosenfeld said.

Toxicity is another worry. But because the cancer cells are much more sensitive to MT-125 than healthy cells, and because the drug doesn’t stay in the body long, pulsed administration of the medication over a brief period seems to address the issue, Rosenfeld said.

“I have been in the field for 35 years, and I always thought the solution to this problem would have to come from out-of-the-box thinking,” Rosenfeld said. “The tried-and-true methods don’t seem to work for this disease.”

The compound, MT-125, has been licensed to a Jupiter, Florida-based biotechnology company started by the scientists, Myosin Therapeutics. They are working hard to begin first-in-human clinical trials within the year in glioblastoma patients, Miller said. The US Food and Drug Administration has given them the green light to proceed. They are awaiting release of a federal grant that has internal approval, she said. The National Institutes of Health has provided study funding, as well as the William Potter Glioblastoma Research Fund at The Wertheim UF Scripps Institute, which was established by William Potter’s wife, Ronnie Potter, in his memory.

Looking ahead, Miller says there is evidence that MT-125 could prove beneficial not only against the aggressive variant of glioblastoma, but for malignant gliomas and other cancers.

In parallel, Miller and her collaborators are working to prepare a clinical trial for a related compound, MT-110, which appears to block drug cravings for people with methamphetamine use disorder. This compound is described in more detail in the July 1 Cell study.

Reference: Radnai L, Young EJ, Kikuti C, et al. Development of clinically viable non-muscle myosin II small molecule inhibitors. Cell. 2025. doi: 10.1016/j.cell.2025.06.006

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Alzheimer’s disease (AD) is a debilitating neurodegenerative condition that affects a significant proportion of older people worldwide. Synapses are points of communication between neural cells that are malleable to change based on our experiences. By adding, removing, strengthening, or weakening synaptic contacts, our brain encodes new events or forgets previous ones. In AD, synaptic plasticity, the brain’s ability to regulate the strength of synaptic connections between neurons, is significantly disrupted. This worsens over time, reducing cognitive and memory functions leading to reduced quality of life. To date, there is no effective cure for AD, and only limited treatments for managing the symptoms.

Studies have shown that repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique that uses electromagnetic pulses to target specific brain regions, has therapeutic potential to manage dementia and related diseases. From previous studies, we know that rTMS can promote synaptic plasticity in healthy nervous systems. Moreover, it is already used to treat certain neurodegenerative and neuropsychiatric conditions. However, individual responses to rTMS for AD management are variable, and the underlying mechanisms are not clearly understood.

Recently, researchers from the University of Queensland (Australia) and the Wicking Dementia Research and Education Centre at the University of Tasmania investigated the effects of rTMS on synapses in the brain cortex of mice with Alzheimer’s type dementia. Their report is published in Neurophotonics.

“Since synaptic dysfunction is a key mechanism in AD, in this study, we quantified the changes in synaptic axonal boutons in AD mouse model in response to rTMS, comparing them to those in healthy mice,” explains corresponding author Dr. Barbora Fulopova, a professor at University of Queensland.

Axonal boutons are specialized endings of an axon, which is the long slender part of a neuron that connects neurons by transmitting neural signals. These are sites where synapses form, allowing neurons to communicate. Therefore, any change in the number or function of these boutons can have profound effects on brain connectivity. In this study, the researchers observed structural changes of two types of excitatory boutons, namely “terminaux boutons” (TBs) (short protrusions from the axon shaft typically connecting neurons in a local area) and “en passant boutons” (EPBs) (small bead-like structures along axons typically connecting distal regions). They used two-photon imaging to visualize individual axons and synapses in the brain of a live animal.

The study was conducted on the APP/PS1 xThy-1GFP-M strain of mice, which is a cross between the APP/PS1 strain (genetically modified to show AD-like symptoms seen in humans) and the Thy1-GFP-M strain, which expresses a fluorescent protein in certain neurons. This combination causes axons to glow during imaging, enabling precise tracking of synaptic bouton changes over time. The team monitored the dynamics of the axonal boutons in these mice at 48-hour intervals for eight days, both before and after a single rTMS session. They then compared these findings to healthy wild-type (WT) mice.

They found that both TBs and EPBs in the AD mouse model had comparable density to those in healthy WT mice. However, the turnover of both bouton types was significantly lower in the AD mouse model before rTMS, likely due to the amyloid plaque buildup, a key marker of dementia, and potentially causing diseases like AD. After a single session of low-intensity rTMS, the turnover of TBs in both strains increased significantly, while there was no change in the EPB turnover. Notably, the largest changes were observed two days after stimulation with an 88 percent increase in TB turnover for the WT strain and a 213 percent increase in the APP-GFP strain. However, this increase returned to pre-stimulation levels by the eighth day.

Furthermore, in the AD mouse model, this increased turnover was comparable to the turnover levels in the WT mice seen before stimulation. This indicates that low-intensity rTMS can potentially restore the synaptic plasticity of TBs to those seen in healthy mice. Moreover, the fact that only TBs, and not EPBs, responded to rTMS points to the possibility that the mechanisms of rTMS might be cell-type specific.

“This is the first study to provide evidence of pre-synaptic boutons responding to rTMS in a healthy nervous system as well as a nervous system marked by the presence of dementia,” remarks Fulopova. “Given the established link between synaptic dysfunction and cognitive decline in dementia and the use of rTMS for the treatment of other neurodegenerative conditions, our findings highlight its potential as a powerful addition to currently used AD management strategies.”

This study marks a significant step forward in understanding AD. While further research is required, the findings of this study pave the way for targeted rTMS treatments that could improve the quality of life of patients with Alzheimer’s disease.

Reference: Fulopova B, Bennett W, Canty AJ. Repetitive transcranial magnetic stimulation increases synaptic plasticity of cortical axons in the APP/PS1 amyloidosis mouse model. Neurophoton. 2025;12(S1). doi: 10.1117/1.NPh.12.S1.S14613

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