Santosh Kumar, associate professor of development and global health economics at Notre Dame’s Keough School of Global Affairs, is co-author of the study, published in Communications Medicine. Kumar’s research explores the intersection of global health and poverty reduction. His latest work evaluates the relationship between anemia and school attendance in India.

The study investigated whether there was a link between anemia and school attendance in more than 250,000 adolescents ages 15 to 18. Earlier observational studies have shown a link between anemia and attendance, even after accounting for variables such as gender and household wealth, according to Kumar. But the new study, which applied more rigorous econometric statistical analysis, did not find such a link, he said.

“Most previous research on this topic has used conventional study designs or focused on small geographical areas, which limits its policy relevance,” Kumar said. “Earlier estimates may have been distorted by unobserved household factors related to both anemia and school attendance. So in this study, we focused on the relationship between anemia and attendance among adolescents who were living in the same household.

“Ultimately,” Kumar said, “we found that the link between anemia and schooling is more muted than previously suggested by studies that did not consider household-level factors.”

The findings have important implications for policymakers seeking to improve education in low- and middle-income countries like India, Kumar said. India has widespread school attendance issues and struggles with health conditions such as anemia caused by iron deficiency, particularly in children and adolescents. The country has pushed to improve educational outcomes, in keeping with the United Nations’ Sustainable Development Goals, Kumar said. But to achieve that, he said, more research is needed to pinpoint an evidence-based intervention.

This study is part of an ongoing project to do that work and was co-authored with Jan-Walter De Neve of the University of Heidelberg, Omar Karlsson of Lund University in Sweden, Rajesh Kumar Rai of Harvard University and Sebastian Vollmer of the University of Göttingen. The project received funding from the Alexander von Humboldt Foundation, the Swedish Research Council and the West Bengal State Department of Health and Family Welfare in India.

The latest study builds on an earlier one in which Kumar and fellow researchers helped evaluate the results of an iron fortification school lunch program for students ages 7 and 8 in India. That study showed that fortification reduced anemia but did not affect students’ performance in school. A forthcoming study, set to launch in summer 2024, will look at iron fortification for children ages 3 to 5. The research hypothesis is that an early-age nutritional intervention among preschoolers would make a significant impact on physical and cognitive development.

“Our findings have implications for policymakers who want to improve educational outcomes and reduce poverty,” Kumar said. “Effective policies are based on evidence. We need more rigorous statistical analysis to examine the causal relationship between anemia and education.

“This work ties into my larger research agenda, which explores the intersection of global health and poverty reduction. I want to use my academic research to support human dignity by helping to identify evidence-based health policies that will make a tangible difference in people’s lives.”

“I was shocked at how many households were above the new 200 ppm guideline,” said Gabriel Filippelli, a biochemist at Indiana University who led the new study. “I assumed it was going to be a more modest number. And results for the 100 ppm guideline are even worse.”

Remediating the roughly 29 million affected households using traditional “dig and dump” soil removal methods could cost upward of $1 trillion, the study calculated. The study was published in GeoHealth, an open-access AGU journal that publishes research investigating the intersection of human and planetary health for a sustainable future. Filippelli is the former editor-in-chief of GeoHealth.

National lead problem “nowhere near over”

Lead is a heavy metal that can accumulate in the human body, with toxic effects. In children, exposure to lead is associated with lower educational outcomes. In the United States, the burden of lead exposure has historically fallen on lower-income communities and communities of color because of redlining and other discriminatory practices. Lead pollution can come from aging water pipes, old paint, and remnant gasoline and industrial pollution, but today, most lead exposure are from contaminated soils and dust, even after lead-containing infrastructure was removed.

The Centers for Disease Control and Prevention first set a limit on the concentration of lead in blood in 1991 at 10 micrograms per deciliter, and it lowered that limit several times until reaching the current limit of 3.5 micrograms per deciliter. But the EPA’s soil lead screening level remained unchanged for more than 30 years until the January announcement. Some states had established their own lower guidelines; California has the lowest screening level, at 80 ppm.

The lag is likely due to “the immensity and ubiquity of the problem,” the study authors wrote. “The scale is astounding, and the nation’s lead and remediation efforts just became substantially more complicated.” That’s because once the EPA lowers a screening limit, they need to tell people what to do if their soils exceed it.

When the EPA lowered the screening level, Filippelli and his co-authors decided to make use of the database of 15,595 residential soil samples from the contiguous United States that they’d collected over the years to find out how many exceeded the new guideline.

Household health hazard

About 25% of the residential soil samples, collected from yards, gardens, alleys, and other residential spots, exceeded the new 200 ppm level, the study found. (Only 12% of samples had exceeded the older, 400 ppm level.) Extrapolating across the country, that equates to roughly 29 million households.

The EPA issued separate guidance for households with multiple sources of exposure, such as both lead-contaminated soil and lead pipes, setting the level in those situations at 100 ppm. In practice, that’s most urban households, Filippelli said. Forty percent of households exceed that limit, increasing the number of affected households to nearly 50 million, the study found.

Typically, contaminated soils are remediated with removal — colloquially, “dig and dump.” But the practice is costly and typically only used after an area is placed on the National Priority List for remediation, a process that can take years. To remediate all contaminated households with “dig and dump” would cost between $290 billion and $1.2 trillion, the authors calculated.

A cheaper option is “capping”: burying the contaminated soil with about a foot of soil or mulch. A geotechnical fabric barrier can also be installed. Most lead contamination is in the top 10 to 12 inches of soil, Filippelli said, so this simple method either covers up the problem or dilutes it to an acceptable level.

“Urban gardeners have been doing this forever anyway, with raised beds, because they’re intuitively concerned about the history of land use at their house,” Filippelli said.

And capping is quicker.

“A huge advantage of capping is speed. It immediately reduces exposure,” Filippelli said. “You’re not waiting two years on a list to have your yard remediated while your child is getting poisoned. It’s done in a weekend.“

Capping still requires time and effort; residents must find clean soil, transport it to their home and spread it out. But the health benefits likely outweigh those costs, Filippelli said.

Because capping has been done more informally, there’s still a lot to be learned about its lifespan and sustainability, Filippelli said. That’s where the research will go next.

Despite the “staggering” scale of the problem, “I’m really optimistic,” Filippelli said. “Lead is the most easily solvable problem that we have. We know where it is, and we know how to avoid it. It’s just a matter of taking action.”

Maps: https://www.mapmyenvironment.com/

Since 1958, Sweden has registered all cancer patients in the National Cancer Register. Swedish researchers have now used this register to study all cancer survivors who had cancer as a child, adolescent or adult to examine outcomes in later life. The results have been published in the scientific journal The Lancet Regional Health — Europe.

“If you’ve had cancer as a child or adolescent, you have an increased risk of almost all diagnoses in the future. This study lays the foundation for understanding why this is so and what decision-makers need to take into account when it comes to cancer care,” says Laila Hübbert, researcher at Linköping University and consultant at the Cardiology Clinic at Vrinnevi Hospital in Norrköping.

The study’s data spans 63 years. From this data, approximately 65,000 cancer patients under the age of 25 were compared with a control group of 313,000 individuals (a ratio of 1:5), where age, sex and housing situation were matched with the patient group. From other registers, the researchers retrieved information on morbidity, mortality and demography.

The researchers found that the cancer survivors were about three times more likely to develop cancer later in life, 1.23 times more likely to have cardiovascular disease and had a 1.41 times higher risk of accidents, poisoning and suicide.

At present, the healthcare system usually follows up cancer survivors five years after the end of treatment. In other words, you are usually considered healthy if the cancer has not returned after five years, and no further follow-up is planned. But the current study, and also previous ones, show that this is probably not enough.

“Cancer survivors carry with them a fragility for the rest of their lives that puts them at higher risk of new diseases. It’s mainly the chemotherapy and radiation treatment that increases the risk of cardiovascular disease. This means that patients shouldn’t be released prematurely without planned and ongoing follow-up. It’s important to identify these risk factors and diseases early,” says Laila Hübbert.

The researchers have also seen that socioeconomic factors play a major role in the risk of disease and death after cancer in young years. Thanks to a cross-check of registers, the researchers were able to see that the risk increases for those with a lower level of education, a foreign background, or who remain unmarried. At the same time, this study shows that the risk of disease and death after cancer in children and adolescents is the same regardless of where you live in Sweden.

Martin Singull is a professor of mathematical statistics and has worked closely with the clinics in order to analyse and combine the large amounts of data that come from many different sources.

“We have used proven statistical models. But it’s the complexity of the data that makes it challenging. It comes from different sources, and we also want to be able to pick out the information we want. That’s why we’ve also collaborated with computer scientist Robin Keskisärkkä, who has built the database,” says Martin Singull.

The next step for the researchers is to break down the results and probe into specific questions and understand why things look the way they do. This will include looking more at socioeconomic factors, cardiovascular disease linked to cancer, so-called cardio-oncology, and other forms of cancer.

“There aren’t really many countries that can carry out such a comprehensive survey. In Sweden, we have such fine comprehensive and high-quality national registers so it’s unique to be able to do this,” says Laila Hübbert.

And while most families have bedtime rituals to help their little ones ease into nighttime, many rely on strategies that may increase sleep challenges long term, according to the University of Michigan Health C.S. Mott Children’s Hospital National Poll on Children’s Health.

Overall, one in four parents describe getting their young child to bed as difficult — and these parents are less likely to have a bedtime routine, more likely to leave on a video or TV show, and more likely to stay with their child until they’re asleep.

“Our report reinforces the common struggle of getting young children to sleep. When this transition to bedtime becomes a nightly conflict, some parents may fall into habits that work in the moment but could set them up for more sleep issues down the road,” said Mott Poll co-director Sarah Clark, M.P.H.

“Establishing a consistent bedtime routine is crucial. When children don’t get enough rest, it can impact their physical development, emotional regulation and behavior.”

Nearly one in five parents say they have given their kids melatonin to help with sleep while a third stay in the room until their child completely dozes off, according to the nationally representative poll that includes responses from 781 parents of children ages one to six surveyed in February.

Nighttime worries interfere with sleep

Parents share common reasons behind bedtime struggles, with nearly a quarter saying their child’s sleep is often or occasionally delayed due to being worried or anxious.

A particular challenge, parents say, is when children don’t stay asleep. More than a third of parents say their child wakes up upset or crying, with more than 40% saying their child moves to their parents’ bed and about 30% saying children insist that the parent sleep in their room.

“Many young children go through stages when they become scared of the dark or worry that something bad might happen, causing them to delay bedtime or become distressed by parents leaving the room. Bad dreams or being awakened in the middle of the night can also disrupt sleep,” Clark said.

“Although this is a normal part of a child’s development, it can be frustrating when parents already feel tired themselves at the end of the day. Parents should find a balance between offering reassurance and comfort while maintaining some boundaries that help ensure everyone — both kids and adults — get adequate sleep.”

More findings from the report, plus Clark’s recommendations for helping young children fall and stay asleep:

Stick to a regular bedtime routine

Most parents polled report having a bedtime routine for their child, often including brushing teeth, reading bedtime stories and/or bathing. Less than half also say their child has a drink of water or snack, turns off devices, prays and talks about their day.

Other bedtime habits include holding a blanket or stuff animal or sucking a pacifier or fingers.

Not only does having a consistent bedtime routine help make the nighttime transition smoother, Clark says, it also provides one-on-one time, allowing the child to get their parent’s full attention.

“A predictable bedtime routine provides a sense of security and comfort and signals to the child that it’s time to slow down,” she said.

“Knowing what to expect next can reduce anxiety and help children feel safe and relaxed. Having this dedicated time with parents also promotes bonding and emotional connection, creating positive associations with bedtime.”

Nearly two-thirds of parents also said children staying up to play was a major factor in delaying sleep. Clark says, highlighting the need to wind down at least an hour before bed.

Promote an environment conducive to sleep

A little less than half of parents polled say their child sleeps in their own bedroom while less than a quarter share a bedroom with siblings or in the parents’ bedroom. One in 10 kids spend part the night in their own bedroom and part of the night with parents.

More than two-fifths of parents polled said noise from other rooms interfered with their child’s sleep.

“The sleep environment can have a major effect on a child’s sleep quality, including getting to sleep and staying asleep through the night,” Clark said.

“When possible, children should have their own bed in a room that is quiet, without a lot of noise from other family members.”

Many parents polled also use a nightlight or crack the bedroom door so the child isn’t in complete darkness, Clark says, but parents should make sure the light does not shine directly at the child’s face.

Some parents also play calming music or stories to help their child go to sleep, while others use a white noise machine or app. However, Clark cautions to keep white noise machines at no more than 50 decibels and placed at least seven feet from the child’s bed to prevent unintended damage to the child’s hearing.

Talk to a doctor before using aids like melatonin

Many types of melatonin products are advertised as being appropriate for children but these products have not undergone rigorous testing for safety and effectiveness, and their side effects and long term impact on a child’s growth and development are unknown, Clark says.

“Although melatonin is a natural hormone that regulates sleep-wake cycles and may be fine to use occasionally, parents shouldn’t rely on it as a primary sleep aid,” Clark said.

“Parents who are considering giving melatonin to their young child should consult with their pediatrician to discuss options and rule out other causes of sleep problems first.”

If using melatonin, parents should also start with the lowest dose possible.

In addition, it’s important to keep electronics such as tablets or televisions out of children’s bedroom, as the blue light emitted by many of these screens interferes with the natural production of melatonin.

Offer comfort but enforce boundaries

Parents can help ease little ones’ anxiety by allowing extra time to let them talk about their day, which might draw out specific worries and give parents a chance to provide compassion and reassurance, Clark said.

Rather than remaining in the room, parents can also offer to check on the child every few minutes, which acknowledges the child’s fears and offers a reassuring presence, but still maintains a calm sleep environment and promotes sleep independence.

“Families can incorporate comforting rituals to help transform nighttime fears into a calming experience,” Clark said.

Have a consistent approach when children wake up in the night

Some children are prone to vivid dreams or nightmares and may have difficulty getting back to sleep. Parents should decide on their approach to this situation and stick with it, Clark says, whether it’s taking the child back to bed or allowing them to stay in the parents’ room.

“Being consistent in carrying out that approach will help the child adjust and be more likely to return to sleep,” Clark said.

Ease into changes in sleep patterns, such as dropping naps

For young children, a major sleep-related transition is discontinuing daytime naps. In general, children ages one to two should get 11-14 hours of sleep with naps while the amount of recommended sleep decreases slightly from ages three to six.

If children are taking longer to fall asleep at nap time, resisting naps or suddenly having difficulty falling asleep at night or waking up earlier than usual in the morning, it may be time to drop the nap, Clark says.

“Parents may need to adjust sleep routines gradually to transition to changes to a child’s sleep patterns,” Clark said.

Other changes that can affect a child’s sleep include transitioning from a crib to a toddler bed, starting school, having a change in their daytime routine, or being outdoors for longer than usual.

Although some of these observations were made decades ago, the exact role of vitamin B6 in mental illness is still largely unclear. What is clear, however, is that an increased intake of vitamin B6 alone, for example in the form of dietary supplements, is insufficient to prevent or treat disorders of brain function.

Publication in eLife

A research team from Würzburg University Medicine has now discovered another way to increase vitamin B6 levels in cells more effectively: namely by specifically inhibiting its intracellular degradation. Antje Gohla, Professor of Biochemical Pharmacology at the Department of Pharmacology and Toxicology at Julius-Maximilians-Universität Würzburg (JMU), is responsible for this.

Other participants come from the Rudolf Virchow Center for Integrative and Translational Bioimaging at JMU, the Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP Berlin and the Institute for Clinical Neurobiology at Würzburg University Hospital. The team has now published the results of their investigations in the scientific journal eLife.

Enzyme Blockade Improves Learning Ability

“We were already able to show in earlier studies that genetically switching off the vitamin B6-degrading enzyme pyridoxal phosphatase in mice improves the animals’ spatial learning and memory capacity,” explains Antje Gohla. In order to investigate whether such effects can also be achieved by pharmacological agents, the scientists have now looked for substances that bind and inhibit pyridoxal phosphatase.

With success: “In our experiments, we identified a natural substance that can inhibit pyridoxal phosphatase and thus slow down the degradation of vitamin B6,” explains the pharmacologist. The working group was actually able to increase vitamin B6 levels in nerve cells that are involved in learning and memory processes. The name of this natural substance: 7,8-Dihydroxyflavone.

New Approach for Drug Therapy

7,8-Dihydroxyflavone has already been described in numerous other scientific papers as a molecule that can improve learning and memory processes in disease models for mental disorders. The new knowledge of its effect as an inhibitor of pyridoxal phosphatase now opens up new explanations for the effectiveness of this substance. This could improve the mechanistic understanding of mental disorders and represent a new drug approach for the treatment of brain disorders, the scientists write in their study.

The team also considers it a great success that 7,8-Dihydroxyflavone has been identified as an inhibitor of pyridoxal phosphatase for the first time — after all, this class of enzymes is considered to be particularly challenging for drug development.

A Long Way to a Drug

When will people benefit from this discovery? “It’s too early to say,” explains Marian Brenner, a first author of the study. However, there is much to suggest that it could be beneficial to use vitamin B6 in combination with inhibitors of pyridoxal phosphatase for various mental disorders and neurodegenerative diseases.

In a next step, Gohla and her team now want to develop improved substances that inhibit this enzyme precisely and highly effectively. Such inhibitors could then be used to specifically test whether increasing cellular vitamin B6 levels is helpful in mental or neurodegenerative diseases.

Antimicrobial resistance of pathogens is a worldwide problem, and recognized by the WHO as one of the top global public health and development threats. There are two ways to fight this: by developing new drugs, or by preventing the development of resistance. ‘We know that temperature affects the mutation rate in bacteria’, explains Timo van Eldijk, co-first author of the paper. ‘What we wanted to find out was how the increase in temperature associated with fever influences the mutation rate towards antibiotic resistance.’

Three antibiotics

‘Most studies on resistance mutations were done by lowering the ambient temperature, and none, as far as we know, used a moderate increase above normal body temperature,’ Van Eldijk reports. Together with Master’s student Eleanor Sheridan, Van Eldijk cultured E. coli bacteria at 37 or 40 degrees Celsius, and subsequently exposed them to three different antibiotics to assess the effect. ‘Again, some previous human trials have looked at temperature and antibiotics, but in these studies the type of drug was not controlled.’ In their laboratory study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin, and ampicillin.

The results showed that for two of the drugs, ciprofloxacin and rifampicin, increased temperature led to an increase in the mutation rate towards resistance. However, the third drug, ampicillin, caused a decrease in the mutation rate towards resistance at fever temperatures. ‘To be certain of this result, we actually replicated the study with ampicillin in two different labs, at the University of Groningen and the University of Montpellier, and got the same result,’ says Van Eldijk.

Fever-suppressing drugs

The researchers hypothesized that a temperature dependence of the efficacy of ampicillin could explain this result, and confirmed this in an experiment. This explains why ampicillin resistance is less likely to arise at 40 degrees Celsius. ‘Our study shows that a very mild change in temperature can drastically change the mutation rate towards resistance to antimicrobials,’ concludes Van Eldijk. ‘This is interesting, as other parameters such as the growth rate do not seem to change.’

If the results are replicated in humans, this could open the way to tackling antimicrobial resistance by lowering the temperature with fever-suppressing drugs, or by giving patients with a fever antimicrobial drugs with higher efficacy at higher temperatures. The team concludes in the paper: ‘An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.’

A paper just published in Scientific Reports- Nature by Sergio Dempsey as first author with colleagues Dr Soroush Safaei, Dr Gonzalo Maso Talou at Auckland Bioengineering Institute, along with co-author Dr Holdsworth (Mātai and FMHS & CBR at the University of Auckland), describes the new metric based on 4D flow MRI technology.

This innovative metric is particularly crucial because increased vascular pulsatility is linked to several brain conditions, including Alzheimer’s disease and other forms of dementia. By accurately measuring how pulsatility is transmitted in the brain, researchers can better understand the underlying mechanism of these diseases and potentiall guide development f new treatments.

Current MRI methods face limitations due to anatomical variations and measurement constraints. The new technique removes this issue by integrating thousands of measurements across all brain vessels, rather than looking one spot at a time as the traditional methods. This provides a richer metric representative of the entire brain.

“The ability to measure how pulsatility is transmitted through the brain’s arteries could revolutionise our approach to neurological diseases, and support research in vascular damage hypotheses” explained Mr. Dempsey. “Our method allows for a detailed assessment of the brain’s vascular health, which is often compromised in neurodegenerative disorders.”

The study also highlighted the potential to enhance clinical assessments and research on brain health. By integrating this new metric into routine diagnostic procedures, healthcare providers can offer more precise and personalised care plans for individuals at risk of or suffering from cognitive impairments.

In addition to its implications for patient care, the researchers have made their tools publicly available, integrating them into pre-existing open-source software. This enables scientists and clinicians worldwide to adopt the advanced methodology, fostering further research and collaboration in the field of neurology.

The research team is planning further studies to explore the applications of this technique in larger and more diverse populations, beginning with the “Digital Twin Dementia Study” starting at Mātai later this month. Results from the initial study of the metric also identified important sex differences in vascular dynamics which has initiated a new study focussing on sex-related dynamics which is anticipated to begin at Mātai and the Centre for Advanced MRI (CAMRI) in November.

Depending on the threat, innate immune sensors can assemble complexes such as inflammasomes or PANoptosomes. The inflammasome can be thought of like an emergency broadcast system that is activated quickly, while the PANoptosome is more like an emergency response unit that generally integrates more signals and components to respond to the threat. How innate immune sensors work — what triggers them to act — has been a mystery, which researchers have been chipping away at for decades.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are a large family of important molecules involved in inflammatory signaling. They are generally thought to function as innate immune sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential in energy production, triggers NLRC5-mediated cell death through PANoptosis.

“One of the biggest questions in the fields of immunology and innate immunity is what the various members of the NLR family are sensing, and what their functions are,” said corresponding author Thirumala-Devi Kanneganti, PhD, St. Jude Department of Immunology vice chair. “NLRC5 was an enigmatic molecule, but now we have the answer — it is acting as an innate immune sensor and cell death regulator, driving inflammatory cell death, PANoptosis, by forming a complex.”

Identifying the NLRC5 trigger

Scientists in the Kanneganti lab conducted a rigorous screen to get to the bottom of what threats trigger NLRC5. This included looking at pathogens such as bacteria and viruses, as well as pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) that can be released by or mimic an infection or the cause of an injury or illness, as well as other danger signals such as cytokines (immune signaling molecules).

The researchers also looked at heme, the component of hemoglobin responsible for carrying oxygen. Infections or disease can cause red blood cells to rupture in a process called hemolysis. This releases hemoglobin into the bloodstream. When hemoglobin breaks down into its components, it releases free heme, which is known to cause significant inflammation and organ damage. The researchers tested many different combinations of pathogens, PAMPs and DAMPs to see if NLRC5 was required for a response.

“Among all the combinations we tested, we identified that the combination of heme plus PAMPs or cytokines specifically induces NLRC5-dependent inflammatory cell death, PANoptosis,” said co-first author Balamurugan Sundaram, PhD, St. Jude Department of Immunology. “Our results showed for the first time that NLRC5 is central to responses to hemolysis, which can occur during infections, inflammatory diseases and cancers.”

Energy depletion triggers NLRC5 function

Upon identifying the heme-containing PAMP, DAMP and cytokine combinations that trigger NLRC5-dependent inflammatory cell death, the researchers further investigated how NLRC5 is regulated. They found that NAD levels drive NLRC5 protein expression. If NAD is depleted, that sounds an alarm that there is a threat the immune system should recognize. The researchers found that depletion of NAD is sensed by NLRC5, triggering PANoptosis.

“By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis,” said co-first author Nagakannan Pandian, PhD, St. Jude Department of Immunology. “Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases.”

The researchers also discovered that NLRC5 is in an NLR network with NLRP12, which come together with other cell death molecules and form an NLRC5-PANoptosome complex that triggers inflammatory cell death. The finding builds on previous research by the Kanneganti lab showcasing the role of NLRP12 in PANoptosis.

A promising target for therapeutic development

NLRs are associated with diseases related to infection, inflammation, cancers and aging. This makes them intriguing targets for the development of novel therapeutics. The work of the Kanneganti lab shows that deleting Nlrc5 can provide protection against inflammatory cell death through PANoptosis and prevent disease pathology in hemolytic and inflammatory disease models, making NLRC5 an exciting therapeutic prospect.

“The fundamental knowledge that we have gained into how innate immune sensing works can be translated to numerous diseases and conditions,” Kanneganti said. “Aging, infectious disease, inflammatory disorders — things for which there are no targeted therapies, this could be an option.”

Authors and funding

The study’s other authors are Emily Alonzo, Department of Research and Development at Cell Signaling Technology; and Hee Jin Kim, Hadia Abdelaal, Omkar Indari, Roman Sarkar, Rebecca Tweedell, Jonathan Klein, Shondra Pruett-Miller and Peter Vogel, all of St. Jude, and Raghvendra Mall, formerly of St. Jude now of the Technology Innovation Institute, Abu Dhabi.

The study was supported by grants from the National Institutes of Health (AI101935, AI124346, AI160179, AR056296 and CA253095) and ALSAC, the fundraising and awareness organization of St. Jude.

Male reproductive disorders are a growing issue due to the global decrease in sperm count and quality. Concerningly, chemicals like DEHP, which can be found in food storage containers, pharmaceuticals, and building materials, have been found to be one of the contributing factors. The toxicity of DEHP is due to its ability to mimic the hormones in our bodies, leading to long-term effects on health.

“The scientific community is aware of the fact that the current generation of men produce half as much sperm compared to the previous one,” said CheMyong Jay Ko (EIRH), a professor of veterinary medicine. “Although it is shocking, not much attention is paid to understanding the causes.”

The researchers used the Barker hypothesis as a guiding principle for their study. Proposed by the British physician and epidemiologist David Barker, the hypothesis argued that the nine months in utero are one of the most critical periods in a person’s life and can shape their future health trajectories.

“The Barker hypothesis primarily focuses on nutrition and we wanted to test whether the mother’s diet could change the health of the next generation,” Ko said. “Additionally, unlike the previous generation, we are constantly exposed to chemicals like DEHP, which can alter how our bodies function. We wanted to ask whether the exposure to both these factors can cause growing babies to have lesser functioning reproductive systems.”

In the past, both the Ko lab and other research groups have shown that prenatal exposure to DEHP decreases testosterone levels and causes fertility defects in male mice. Additionally, scientists have shown that maternal high-fat diet can also decrease sperm counts in male offspring. However, the effects of both together had not been studied.

The researchers used four groups of pregnant mice; one was a control and the other three were either exposed to DEHP, or a high-fat diet, or a combination of the two. They then followed each litter, which contained an average of 6 male and 6 female pups.

“Surprisingly, we found that a high-fat diet had a more damaging effect on the male reproductive systems compared to DEHP alone and the pups born from mothers who had been treated with both had the worst outcomes,” Ko said.

The researchers measured the weight of the body and different reproductive organs in pups during different stages of growth and puberty. They found that although the body weight of pups born from moms on a high-fat diet alone or in combination with DEHP was higher than the other pups, the weight of the reproductive organs was lower. They also found that these mice produced less sperm and had lower testosterone levels. By staining the tissues, the researchers found that the reproductive organs had abnormal cells, which were contributing to the gonadal dysfunction.

“In our studies, we used these mice as a model. Although we need to confirm these results in humans, this study should serve as a warning to our generation that we need to be careful about our environment and diet during pregnancy,” Ko said.

In the study, which appears June 14 in Nature Medicine, the researchers showed that they could train a machine learning model, a type of artificial intelligence platform, to detect circulating tumor DNA (ctDNA) based on DNA sequencing data from patient blood tests, with very high sensitivity and accuracy. They made successful demonstrations of the technology in patients with lung cancer, melanoma, breast cancer, colorectal cancer and precancerous colorectal polyps.

“We were able to achieve a remarkable signal-to-noise enhancement, and this enabled us, for example, to detect cancer recurrence months or even years before standard clinical methods did so,” said study co-corresponding author Dr. Dan Landau, a professor of medicine in the division of hematology and medical oncology at Weill Cornell Medicine and a core faculty member of the New York Genome Center.

The study’s co-first author, and co-corresponding author, was Dr. Adam Widman, a postdoctoral fellow in the Landau Lab who is also a breast cancer oncologist at MSK. The other co-first authors were Minita Shah of NYGC, Dr. Amanda Frydendahl of Aarhus University, and Daniel Halmos of NYGC and Weill Cornell Medicine.

Liquid biopsy technology has been slow to realize its great promise. Most approaches to date have targeted relatively small sets of cancer-associated mutations, which are often too sparsely present in the blood to be detected reliably, resulting in cancer recurrences that go undetected.

Several years ago, Dr. Landau and colleagues developed an alternative approach based on whole-genome-sequencing of DNA in blood samples. They showed that they could gather much more “signal” this way, enabling more sensitive — and logistically simpler — detection of tumor DNA. Since then, this approach has been increasingly adopted by liquid biopsy developers.

In the new study, the researchers leapt ahead again, using an advanced machine learning strategy (similar to that of ChatGPT and other popular AI applications) to detect subtle patterns in sequencing data — in particular, to distinguish patterns suggestive of cancer from those suggestive of sequencing errors and other “noise.”

In one test, the researchers trained their system, which they call MRD-EDGE, to recognize patient-specific tumor mutations in 15 colorectal cancer patients. Following the patients’ surgery and chemotherapy, the system predicted from blood data that nine had residual cancer. Five of these patients were found — months later, with less sensitive methods — to have cancer recurrence. But there were no false negatives: none of the patients MRD-EDGE deemed free of tumor DNA experienced recurrence during the study window.

MRD-EDGE showed similar sensitivity in studies of early-stage lung cancer and triple-negative breast cancer patients, with early detection of all but one recurrence, and tracking of tumor status during treatment.

The researchers demonstrated that MRD-EDGE can detect even mutant DNA from precancerous colorectal adenomas — the polyps from which colorectal tumors develop.

“It had not been clear that these polyps shed detectable ctDNA, so this is a significant advance that could guide future strategies aimed at detecting premalignant lesions,” said Dr. Landau, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Lastly, the researchers showed that even without pre-training on sequencing data from patients’ tumors, MRD-EDGE could detect responses to immunotherapy in melanoma and lung cancer patients — weeks before detection with standard X-ray-based imaging.

“On the whole, MRD-EDGE addresses a big need, and we’re excited about its potential and working with industry partners to try to deliver it to patients,” Dr. Landau said.

The research in this story was supported in part by the National Cancer Institute, part of the National Institutes of Health, through grant number R01 CA266619.