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By Dr. Chinta Sidharthan Reviewed by Danielle Ellis, B.Sc. Nov 21 2024

Researchers identify gliocidin, a blood-brain barrier-penetrating prodrug, that targets glioblastoma's unique metabolic vulnerability, offering a promising therapeutic strategy and extended survival in preclinical models. Study: Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Image Credit: April stock/Shutterstock.com

In a recent study published in Nature, a team led by researchers from Memorial Sloan Kettering Cancer Center investigated the effects of the compound gliocidin in targeting glioblastoma, an aggressive form of brain tumor.

The study found that gliadin acts on specific cellular pathways to selectively kill glioblastoma cells without harming normal cells. Moreover, the compound can penetrate the blood-brain barrier, which highlights its potential as a treatment option for glioblastoma. Background

Glioblastoma is one of the most lethal forms of brain cancer and is known for its resistance to standard therapies. Despite significant advances in cancer therapies, currently used immunotherapies and targeted therapies have had minimal success in improving survival rates in glioblastoma. This resistance is believed to stem from several challenges unique to glioblastoma, such as its complex cellular heterogeneity and immune-evasive characteristics.

Additionally, crossing the blood-brain barrier to reach tumor cells remains a significant obstacle. Researchers are exploring novel metabolic pathways as potential therapeutic targets. Unlike typical cancer drugs that inhibit cell division, some emerging therapies aim to disrupt cancer-specific vulnerabilities. The use of prodrugs, which are converted into active drugs within the body, is gaining special attention due to their ability to target malignant cells while sparing healthy tissue selectively. About the study

In the present study, the researchers aimed to identify a compound that could selectively target glioblastoma cells. A high-throughput chemical screen of over 200,000 compounds was conducted using low-passage glioblastoma cells derived from genetically engineered mouse models. Compounds toxic to normal replicative cells were excluded. The screening identified gliocidin as a promising candidate due to its selective toxicity against glioblastoma cells.

To investigate the mechanism of action, the team then employed multiple experimental approaches. Genetic analyses were performed using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screens to identify pathways and enzymes essential for the activity of gliocidin.

Pharmacokinetics and biodistribution studies in animal models were used to determine the ability of gliocidin to cross the blood-brain barrier and maintain effective concentrations in the brain. The researchers used glioblastoma-bearing mouse models to test the brain penetration abilities and bioavailability of gliocidin. Drug administration was optimized using intraperitoneal injection, and tissue analysis was used to confirm its presence in the brain.

Additionally, the researchers used liquid chromatography-mass spectrometry (LC-MS) to measure the levels of intermediate compounds and final metabolites in cells and tissues to understand gliocidin metabolism. Related StoriesStudy defines three subtypes of Chiari type-1 malformation to guide treatmentSpecific redox protein identified as a critical regulator of ferroptosisCannabis use linked to brain changes in young adults at risk of psychosis

Structural studies, including cryo-electron microscopy, were also conducted to characterize the interaction between the active form of gliocidin, gliocidin-adenine dinucleotide (GAD), and the enzyme inosine monophosphate dehydrogenase 2 (IMPDH2), to understand the binding mechanisms involved in gliocidin activation and metabolism. Gliocidin was also tested in combination with temozolomide, a standard chemotherapeutic for glioblastoma, to evaluate potential synergistic effects. Results

The study found that gliocidin effectively targeted glioblastoma cells by exploiting specific metabolic vulnerabilities of the cancer cells. Gliocidin was metabolized into GAD within the NAD+ salvage pathway, which then indirectly inhibited IMPDH2, a key enzyme in the purine synthesis pathway. This inhibition was found to lead to a severe reduction in guanine nucleotide levels, causing replication stress and cell death in glioblastoma cells.

Furthermore, the biochemical assays confirmed that gliocidin selectively disrupted guanine nucleotide synthesis in glioblastoma cells without affecting normal cells. The study demonstrated this specificity across multiple glioblastoma cell lines and patient-derived xenograft models. Additionally, the pharmacokinetic studies revealed that gliocidin successfully crossed the blood-brain barrier and accumulated in the brain, ensuring sustained exposure of the cancer cells to the compound.

Moreover, the in vivo studies in glioblastoma-bearing mice also showed that gliocidin monotherapy significantly suppressed tumor progression. When combined with temozolomide, a standard glioblastoma treatment, gliocidin produced synergistic effects, leading to greater tumor reduction and improved survival outcomes. An analysis of tumor samples from treated mice revealed that the combination therapy enhanced glioblastoma cell death by targeting both proliferative and non-proliferative tumor cells.

The researchers also found that gliocidin’s efficacy depended on nicotinamide nucleotide adenylyltransferase 1 or NMNAT1, an enzyme in the NAD+ salvage pathway. Tumors with higher NMNAT1 expression showed greater sensitivity to gliocidin. Interestingly, combination therapy with temozolomide was found to increase NMNAT1 expression further, amplifying the anti-tumor effects of gliocidin. Conclusions

Overall, the results established that gliocidin could selectively kill glioblastoma cells by disrupting critical nucleotide synthesis pathways. Its ability to penetrate the brain highlights its potential as a promising treatment for glioblastoma.

Furthermore, the enhanced efficacy observed when gliocidin was administered in combination with temozolomide further supports the potential of gliocidin as a future therapeutic approach for glioblastoma patients. Journal reference: Chen, Y.J., Iyer, S. V., Hsieh, D.C.C., Li, B., Elias, H.K., Wang, T., Li, J.,… Parada, L.F. 2024. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Nature. doi: 10.1038/s41586-024-08224-z https://www.nature.com/articles/s41586-024-08224-z

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Entertainment

‘I’m shocked at how fragile I am still’: Cumberbatch and Colman on protecting their sanity from perils of social media

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'I'm shocked at how fragile I am still': Cumberbatch and Colman on protecting their sanity from perils of social media

Actor Benedict Cumberbatch says he’s shocked at how “fragile” he still is – despite years in the spotlight and success in the industry.

It might seem like the Doctor Strange star and The Crown actress Olivia Colman have it all when it comes to money and success – but they are also human like the rest of us.

The pair lead the cast of new satirical black comedy The Roses, which sees picture-perfect couple Ivy and Theo Rose – a rising star chef and ambitious architect – raise their two children in California, while chasing their own dreams.

‘I am shocked at how fragile I am’

But behind its dark humour and comic language, the film also looks at the realities of power imbalance, insecurity and wounded pride – in even the strongest of relationships.

And 49-year-old Cumberbatch – whose character faces a major setback in his career – tells Sky News that in real life the glare of social media only intensifies those type of situations.

“I am shocked at how fragile I am still.

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“I don’t go anywhere near it [social media] because of that.

“It’s like walking into a place where people want to marry you or kill you. Those extremes.

“I think we will get to a stage, a corporate culture that’s now manifested around it where people are obliged to do that in order to sell their lives, and therefore their brand and what they do for a living.”

Co-star Colman – who’s long-shunned the online world – agrees.

Cumberbatch and Colman in The Roses. Pic: Jaap Buitendijk/ Searchlight Pictures
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Cumberbatch and Colman in The Roses. Pic: Jaap Buitendijk/ Searchlight Pictures

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“I’m afraid I am very thin-skinned.

“I don’t look at any of it. My husband will look at a review and if it’s nice he’ll show me – but if it’s anything mean he knows to just go ‘don’t look – don’t look.’

“You just have to learn to be thicker-skinned.

“But actually, I think we need people who are sensitive and kind.”

‘Don’t do it… delete it all’

Colman – now 51, and whose leading role in The Favourite bagged her an Academy Award in 2019 – says no amount of experience and success can shield her from criticism.

“My advice to a young’un – sort of dipping their toe into the world of social media for the first time is absolutely don’t do it.

“Delete it all. If you want a happy life, don’t have any of it. I’ve never had it.”

The movie – directed by Meet The Parents’ Jay Roach with The Favourite screenwriter Tony McNamara – also calls into question the notion of success – asking, is it really possible to have it all?

Or is sacrifice inevitable when it comes to spinning the plates of a high-flying career, marriage and parenthood?

Cumberbatch admits “you can’t do it all without there being a cost”.

“You just have to weigh up what those balances are,” he adds.

Colman says “there are I suppose little sacrifices along the way” – from both sides of a relationship.

The comedy drama offers a fresh take on Warren Adler’s novel The War Of The Roses – and the 1989 hit film adaptation- starring Michael Douglas and Kathleen Turner.

Colman and Cumberbatch – both producers on the film – insist they weren’t daunted by that though.

“We wanted to find a project to do together, and we have utter respect for the iconic status of the film and book,” explains Cumberbatch.

“Hopefully this will have its own place in the culture – it’s very different, it’s not a remake – it’s a reimagined jumping-on point.”

“But beyond that, it’s very different,” adds Colman.

Former Doctor Who Ncuti Gatwa and Barbie’s Kate McKinnon also form the cast.

The Roses is out in UK cinemas now.

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Business

How the US trade war is now targeting you from today

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How the US trade war is now targeting you from today

Donald Trump has cancelled a loophole from today that had allowed consumers and businesses to be spared duties for sending low-value goods to the United States.

The so-called de minimis exemption had applied across the world before Trump 2.0 but the president has taken action – and the UK may soon follow suit – as part of his trade war.

The relief had allowed goods worth less than $800 (£595) to enter the US duty-free since 2016.

But now, low-cost packages face the same tariff rate as other, more expensive, goods.

The reasons for the latest bout of protectionism are numerous and the ramifications are country and purpose specific.

What is changing?

It was no accident that China was the first destination to be slapped with this rule change.

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The duty exemption on low-value Chinese goods was ended in May as US retailers, in fact those across the Western world, complained bitterly that they were being undercut by cheap clothing, accessories and household goods shipped by the likes of Shein and Temu.

From today, Mr Trump is expanding the end of the de minimis rule to the rest of the world.

Why is Trump doing this?

Number of de minimis packages imported in to the US since 2018
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Number of de minimis packages imported in to the US since 2018

The president is not acting purely to protect US businesses.

More duties mean more money for his tariff treasure chest, bolstering the goodies already pouring in from his base and reciprocal tariffs imposed on trading partners globally this year.

The Trump administration has also called out “deceptive shipping practices, illegal material and duty circumvention”.

It also believes many parcels claiming to contain low-value goods have been used to fuel the country’s supplies of fentanyl, with the importation of the illegal drug being used by the president as a reason for his wider trade war against allies including Canada.

How will it apply?

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New tariffs threaten fresh trade chaos

Under the new rules, only letters and personal gifts worth less than $100 (£74) will still be free of import duties.

Charges will depend on the tariff regime facing the country from where the goods are sent.

Fox example, a parcel containing products worth $600 would raise $180 in extra duties when sent from a country facing a 30% tariff rate.

It has sparked chaos in many countries, with postal services in places including Japan, Germany and Australia refusing to accept many items for delivery to the US until the practicalities of the new regime become clearer.

What about the UK?

All goods not meeting the £74 exemption criteria now face a 10% charge because that is the baseline tariff the US has slapped on imports from the UK.

We were spared, if you remember, higher reciprocal tariffs under the so-called “trade deal”.

How will the process work?

All shipping and delivery companies will be wading through the changes, with the big international operators such as DHL, FedEx and the like all promising to navigate the challenge.

Royal Mail said on Thursday that it would be the first international postal service to have a dedicated operation.

It said consumers could use its new postal delivery duties paid (PDDP) services both online and at Post Offices.

But it explained that business customers faced different restrictions to individuals.

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Businesses would be charged a handling fee per parcel to cover additional costs and duties would be calculated based on where items were originally manufactured.

While business account customers could be handed an invoice for the duties, it explained that consumers would have to pay at the point of buying postage.

No customs declaration would be required, it concluded, for personal correspondence.

Is the US alone in doing this?

The answer is no, but it remains a fairly widespread relief globally.

The European Union, for example, removed de minimis breaks back in 2021, making all e-commerce imports to the bloc subject to VAT.

It is also now planning to introduce a fee of €2 on goods worth €150 or less to cover the costs of customs processing.

Should the UK do the same?

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July: The value of ‘de minimis’ imports into Britain

The UK has been under pressure for many years to follow suit and drop its own £135 duty-free threshold as retailers battle the cheap e-commerce competition from China we mentioned earlier.

A review was announced by the chancellor in April.

Sky News revealed in July how the total declared trade value of de minimis imports into the UK in the 2024-25 financial year was £5.9bn – a 53% increase on the previous 12-month period.

Any rise in revenue would be welcomed, not only by UK retailers, but by Rachel Reeves too as she looks to fill a renewed black hole in the public finances.

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World

Boy, 8, and girl, 10, killed in US Catholic school shooting named – as father brands attacker ‘a coward’

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Boy, 8, and girl, 10, killed in US Catholic school shooting named - as father brands attacker 'a coward'

The families of two children killed in the US Catholic school shooting have said their “hearts are broken” and branded the attacker a “coward”.

Fletcher Merkel who was eight and 10-year-old Harper Moyski were killed during mass at Annunciation Catholic School in Minneapolis on Wednesday.

Eighteen other people were injured, including children aged between six and 15 and three adults in their 80s.

Police said Robin Westman, a male born as Robert Westman, opened fire with a rifle through the windows of the school’s church as children sat in pews.

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New details released of US school shooting

‘Our hearts are broken’

Harper’s parents, Michael Moyski and Jackie Flavin, remembered her as “a bright, joyful, and deeply loved 10-year-old whose laughter, kindness, and spirit touched everyone who knew her”.

“Our hearts are broken not only as parents, but also for Harper’s sister, who adored her big sister and is grieving an unimaginable loss. As a family, we are shattered, and words cannot capture the depth of our pain,” their statement said.

They urged leaders and communities to “take meaningful steps to address gun violence and the mental health crisis in this country.”

“Change is possible, and it is necessary – so that Harper’s story does not become yet another in a long line of tragedies,” the statement added.

The family of Fletcher Merkel said there was a 'hole in our hearts'. Pic: Family handout/AP
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The family of Fletcher Merkel said there was a ‘hole in our hearts’. Pic: Family handout/AP

‘Fletcher loved his family’

In a statement reported by Sky’s US partner network NBC News, Fletcher’s father Jesse Merkel blamed the “coward” killer for why the boy’s family can’t “hold him, talk to him, play with him, and watch him grow into the wonderful young man he was on the path to becoming”.

He said: “Fletcher loved his family, friends, fishing, cooking, and any sports that he was allowed to play.

“While the hole in our hearts and lives will never be filled, I hope that in time, our family can find healing.”

Mr Merkel also praised “the swift and heroic actions of children and adults alike from inside the church”.

“Without these people and their selfless actions, this could have been a tragedy of many magnitudes more. For these people, I am thankful,” he added.

Families and loved ones reunite at the scene after the shooting. Pic: Reuters
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Families and loved ones reunite at the scene after the shooting. Pic: Reuters

Mayor calls for assault weapon ban

It comes after Minneapolis mayor Jacob Frey called for a statewide and federal ban on assault weapons, a day after the deadly school shooting.

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Minneapolis mayor urges assault weapons ban

“Thoughts and prayers are not going to cut it. It’s on all of us to see this through,” the mayor said at a news conference. “We need a statewide and a federal ban on assault weapons.

“We need a statewide and a federal ban on high-capacity magazines. There is no reason that someone should be able to reel off 30 shots before they even have to reload.

“We’re not talking about your father’s hunting rifle gear. We’re talking about guns that are built to pierce armour and kill people.”

Meanwhile, Minneapolis police chief Brian O’Hara gave an update on the investigation, saying the suspect had fired 116 rifle rounds into the church.

“It is very clear that this shooter had the intention to terrorise those innocent children,” he added, before saying the killer “fantasised” about the plans of other mass shooting attackers and wanted to “obtain notoriety”.

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Thomas Klemond, interim CEO of Minneapolis’s main trauma hospital Hennepin Healthcare, said at an earlier news conference that the hospital was treating nine patients injured in the shooting.

One child at the hospital was in a critical condition, he added.

Children’s Minnesota Hospital also said that three children remain in its care as of Thursday morning.

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