Tag: 18/11/24

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Resistance to Artemisinin Found in African Children with Severe Malaria

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Indiana University School of Medicine researchers, in collaboration with colleagues at Makerere University in Uganda, have uncovered evidence of partial resistance to artemisinin derivatives – the primary treatment for malaria – in young children with severe, or “complicated,” malaria. 

Earlier studies have shown partial resistance to artemisinin in children with uncomplicated malaria, but the new study, published in the Journal of the American Medical Association (JAMA), is the first to document such resistance in African children with well-defined signs of severe disease from malaria. 

“Artemisinin-based therapies have been quintessential in the fight against malaria for the past 20 years,” said corresponding author Chandy C. John, MD, the professor of paediatrics at the IU School of Medicine. “Growing evidence of artemisinin partial resistance in African children with uncomplicated malaria has led to concerns that new therapies, like triple artemisinin combination therapies, may be needed in uncomplicated malaria. The findings of artemisinin partial resistance in children with severe or complicated malaria, as well as the findings of a high rate of recurrent malaria with current standard treatment in these areas raise the question of whether new treatments are needed for severe malaria as well.”

Led by John and co-authors Ruth Namazzi, MBChB, MMEd, and Robert Opoka, MD, MPH, of Makerere University; Ryan Henrici, MD, PhD, of the University of Pennsylvania; and Colin Sutherland, PhD, MPH, of the London School of Tropical Medicine and Hygiene, the study examined 100 Ugandan children aged 6 months to 12 years who were undergoing treatment for severe malaria complications caused by Plasmodium falciparum, the deadly malaria parasite transmitted by mosquitos. 

In the study, 10 children had parasites with genetic mutations previously associated with artemisinin partial resistance. The most common mutation, which was seen in eight of these children, was associated with a longer parasite clearance half-life — the time it takes the parasite’s burden in the body to reach half of its initial level. The study also showed that 10% of children returned within 28 days of treatment with an infection from the same malaria strain they had during their original admission. These were all children who had received complete intravenous and then oral treatment for severe malaria, and all had cleared the parasite by microscopic examination. John said these findings suggest that the standard intravenous and oral treatment lowers the parasite level to where it cannot be detected by microscopy, but it does not completely eliminate the parasite in some children.   

Reports of artemisinin resistance first surfaced in Southeast Asia in 2008 before emerging in East Africa, a trend the IU research team unexpectedly observed through their ongoing work in Uganda. While studying why severe malaria develops in children, the researchers noticed slower responses to artemisinin in some of their Ugandan study participants, prompting the present study. 

“The study findings point to a need for more data on artemisinin resistance and recurrence of clinical malaria in children with severe malaria,” John said. “If our study findings are confirmed in other areas, that would suggest that treatment guidelines for severe malaria may require revision.”  

John presented the study’s results at the Annual Meeting of the American Society of Tropical Medicine and Hygiene on Nov. 14 in New Orleans, Louisiana.

Source: Indiana University

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Antiseizure Drugs during Pregnancy may Affect Neurodevelopment

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Children whose mothers have taken antiseizure drugs during pregnancy are more likely than others to receive a neuropsychiatric diagnosis. This is according to a comprehensive study by researchers at Karolinska Institutet and elsewhere, published in Nature Communications. However, the researchers emphasise that the absolute risk is low.

Antiseizure drugs are used to treat epilepsy and to stabilise mood in certain psychiatric conditions. However, some of these drugs, such as valproate, are known to affect the foetus if used during pregnancy. 

The current study included data from over three million children in the UK and Sweden, 17 495 of whom had been exposed to antiseizure drugs during pregnancy. 

As expected, children exposed to valproate were more likely to be diagnosed with autism, intellectual disability or ADHD compared to children not exposed to antiseizure drugs. Children exposed to topiramate had a 2.5-fold increased risk of intellectual disability, while those exposed to carbamazepine had a 25 per cent increased risk of being diagnosed with autism and a 30 per cent increased risk of intellectual disability. 

No increased risk with lamotrigine 

However, the researchers found no evidence that taking the antiseizure drug lamotrigine during pregnancy increases the risk of neuropsychiatric diagnoses in the child. 

“Our findings suggest that while certain medications may pose some risk, lamotrigine may be a less risky option, but active monitoring of any antiseizure medication is critical to ensure safety and effectiveness, particularly during pregnancy,” says Brian K. Lee, Professor at Drexel University Dornsife School of Public Health, USA, and affiliated researcher at the Department of Global Public Health, Karolinska Institutet, Sweden. 

The researchers emphasise that the absolute risk of the child receiving a neuropsychiatric diagnosis is low and that there may also be risks associated with not taking antiseizure medication during pregnancy. 

“If you’re pregnant or trying to become pregnant, and taking one of these medications, it may be worth talking with your physician to make sure you’re taking the best medicine for your needs, while minimising risk to future children,” says Viktor H. Ahlqvist, researcher at the Institute of Environmental Medicine, Karolinska Institutet, and joint first author with Paul Madley-Dowd at the University of Bristol, UK. 

The results support previous findings from smaller studies that found links between antiseizure drugs during pregnancy and the risk of neuropsychiatric diagnoses in the child. One difference is that the new study found no statistically significant association between topiramate or levetiracetam and ADHD in the child. 

Source: Karolinska Institutet

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Telltale Chemical in the Breath can Warn of Lung Cancer

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Exhaled breath contains chemical clues to what’s going on inside the body, including diseases like lung cancer. And devising ways to sense these compounds could help doctors provide early diagnoses — and improve patients’ prospects. In a study in ACS Sensors, researchers report the development of ultrasensitive, nanoscale sensors that in small-scale tests distinguished a key change in the chemistry of the breath of people with lung cancer.

Besides carbon dioxide, people also exhale other airborne compounds. Researchers have determined that declines in one exhaled chemical — isoprene — can indicate the presence of lung cancer. However, to detect such small shifts, a sensor would need to be highly sensitive, capable of detecting isoprene levels in the parts-per-billion (ppb) range. It would also need to differentiate isoprene from other volatile chemicals and withstand breath’s natural humidity. Previous attempts to engineer gas sensors with characteristics like these have focused on metal oxides, including one particularly promising compound made with indium oxide. A team led by Pingwei Liu and Qingyue Wangset out to refine indium oxide-based sensors to detect isoprene at the level at which it naturally occurs in breath.

The researchers developed a series of indium(III) oxide (In2O3)-based nanoflake sensors. In experiments, they found one type, which they called Pt@InNiOx for the platinum (Pt), indium (In) and nickel (Ni) it contains, performed best. These Pt@InNiOx sensors:

  • Detected isoprene levels as low as 2ppb, a sensitivity that far surpassed earlier sensors.
  • Responded to isoprene more than other volatile compounds commonly found in breath.
  • Performed consistently during nine simulated uses.

More importantly, the authors’ real-time analysis of the nanoflakes’ structure and electrochemical properties revealed that Pt nanoclusters uniformly anchored on the nanoflakes catalyzed the activation of isoprene sensing, leading to the ultrasensitive performance.

Finally, to showcase the potential medical use of these sensors, the researchers incorporated the Pt@InNiOx nanoflakes into a portable sensing device. Into this device they introduced breath collected earlier from 13 people, five of whom had lung cancer. The device detected isoprene levels lower than 40 ppb in samples from participants with cancer and more than 60 ppb from cancer-free participants. This sensing technology could provide a breakthrough in non-invasive lung cancer screening and has the potential to improve outcomes and even save lives, the researchers say.

Source: American Chemical Society

Categories : Cancer Immune SystemTags : Leave a comment

Chronic Activation of the Innate Immune System can Unleash Cancer

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Along with defending against pathogens, the body’s innate immune system helps to protect the stability of our genomes in unexpected ways that have important implications for the development of cancer, researchers at Memorial Sloan Kettering Cancer Center (MSK) are discovering.

In a pair of recent papers, scientists in the lab of molecular biologist John Petrini, PhD, showed that innate immune signaling plays a key role in maintaining genome stability during DNA replication. Furthermore, the researchers showed that chronic activation of these immune pathways can contribute to tumour development in a mouse model of breast cancer.

Not only do the findings add vital insights to our understanding of fundamental human biology, says Dr Petrini, they may also shed new light on tumour initiation and present potential opportunities for new therapies.

“Living organisms have evolved complex pathways to sense, signal, and repair damaged DNA,” he says. “Here we’re learning new things about the role of the innate immune system in responding to that damage – both in the context of cancer and also in human health more generally.”

How Chronic Activation of the Innate Immune System Can Lead to Cancer

The newest paper, led by first author Hexiao Wang, PhD, a postdoctoral fellow in the Petrini Lab, and published in Genes & Development, reveals a connection between innate immune signaling and tumour development in breast tissue. And, Dr Petrini says, the data suggest that when instability arises in the genome, chronic activation of the innate immune system can greatly increase the chances of developing cancer.

The study focused on a protein complex called the Mre11 complex, which plays a pivotal role in maintaining the stability of the genome by sensing and repairing double-strand breaks in DNA.

To study how problems with the Mre11 complex can lead to cancer, the team manipulated copies of the protein in mammary tissue organoids (miniature lab-grown model organs) and then implanted them into laboratory animals.

When oncogenes (genes known to drive cancer) were activated in these mice, tumors arose about 40% of the time, compared with about 5% in their normal counterparts. And the tumors in the mice with mutant Mre11 organoids were highly aggressive.

The research further showed that the mutant Mre11 led to higher activation of interferon-stimulated genes (ISGs). Interferons are signaling molecules that are released by cells in response to viral infections, immune responses, and other cellular stressors.

They also found that the normally tightly controlled packaging of DNA was improperly accessible in these organoids — making it more likely that genes will get expressed, when they otherwise would be inaccessible for transcription.

“We actually saw differences in the expression of more than 5600 genes between the two different groups of mice,” Dr Petrini says.

And strikingly, these profound effects depended on an immune sensor called IFI205.

When the organoids were further manipulated so they would lack IFI205, the packaging of DNA returned almost to normal, and the mice developed cancer at essentially the same rate as normal mice.

“So what we learned is that problems with Mre11 – which can be inherited or develop during life like other mutations – can create an environment where the activation of an oncogene is much more likely to lead to cancer,” Dr Petrini says. “And that the real lynch pin of this cascade is this innate immune sensor, IFI205, which detects that there’s a problem and starts sending out alarm signals. In other words, when problems with Mre11 occur, chronic activation of this innate immune signaling can significantly contribute to the development of cancer.”

New Understandings Could Pave the Way for Future Treatments

The work builds on a previous study, led by Christopher Wardlaw, PhD, a former senior scientist in the Petrini Lab, that appeared in Nature Communications.

That study focused on the role of the Mre11 complex in maintaining genomic integrity. It found that when the Mre11 complex is inactive or deficient, it results in the accumulation of DNA in the cytoplasm of cells and in the activation of innate immune signaling. This research primarily looked at the involvement of ISG15, a protein made by an interferon-stimulating gene, in protecting against replication stress and promoting genomic stability.

“Together, these studies shed new light on how the Mre11 complex works to protect the genome when cells replicate, and how, when it’s not working properly, it can trigger the innate immune system in ways that can promote cancer,” D. Petrini says.

By shedding light on the interrelationships between these complex systems and processes, the researchers hope to identify new strategies to prevent or treat cancer, he adds, such as finding ways to short-circuit the increased DNA accessibility when Mre11 isn’t working properly.

Source: Memorial Sloan Kettering Cancer Center