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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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Premier League clubs at risk of legal action over unlicensed casino sponsors

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Premier League clubs at risk of legal action over unlicensed casino sponsors

Casinos sponsoring two Premier League clubs are accepting UK customers without a licence, putting club officers at risk of prosecution, Sky News has learned.

The gambling websites, BC.Game and DEBET, are the matchday shirt sponsors of Leicester City and Wolverhampton Wanderers, respectively.

But an investigation by anti-gambling advert campaigners, shared with Sky News, suggests the casinos have continued to accept UK customers – despite this becoming unlawful after they lost their licences to operate in the UK.

DEBET lost its licence on 15 May, while BC.Game lost its licence in December 2024.

Neither club has indicated that they intend to end the sponsorships, despite criticism from campaigners and warnings from the Gambling Commission.

With the end of the 2024/25 season this weekend, both clubs are now half-way through two-year sponsorship deals with the casinos – putting them in a difficult position for next season.

The campaign group Coalition to End Gambling Ads (CEGA) told Sky News it was able to make deposits on both gambling websites, despite the sites having no licence to accept UK customers.

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CEGA also successfully deposited cash on Burnley FC sponsor 96.com. Burnley are due to be promoted to the Premier League next season.

The findings come one week after the Gambling Commission warned five football clubs, including Wolverhampton and Burnley, that their officers “may be liable to prosecution and, if convicted, face a fine, imprisonment or both if they promote unlicensed gambling businesses that transact with consumers in Great Britain”.

The Commission had issued a similar warning to Leicester City in February.

It made clear then that the clubs must either cut ties with the casinos or ensure they are not accessible to UK customers “by any means” – including virtual private networks (VPNs) – software used to hide a user’s real location.

Other than the need to use a VPN, CEGA director Will Prochaska says it “really wasn’t very difficult” to access the sites.

The Gambling Commission declined to be interviewed by Sky News, but said that “where we have evidence that meets the standard for criminal prosecution we will take appropriate action”.

Head of enforcement at the Commission John Pierce previously said the body would “conduct ongoing spot checks as necessary to ensure they are not accessible to consumers in Great Britain by any means”.

Mr Prochaska, however, said the Commission was taking “far too long” to take action.

“Far too many children, far too many football fans, are seeing these adverts every day,” he said. “It’s got to stop.”

Leicester City’s sponsor has had no UK licence for almost six months

The three sites that appear on the matchday shirts of Leicester, Wolves and Burnley were previously licensed by TGP Europe, a company based on the Isle of Man.

On 15 May, TGP Europe surrendered its UK gambling licence to avoid a £3.3m fine, leaving DEBET and 96.com unable to legally accept UK customers.

Leicester City sponsor BC.Game has been unlicensed in the UK since it parted ways with TGP Europe in December 2024 – almost six months ago.

Jamie Vardy celebrating scoring for Leicester City last December.
Pic: PA
Image:
Jamie Vardy celebrating scoring for Leicester City last December.
Pic: PA

Mr Prochaska said he contacted Leicester City on 13 March to alert them that BC.Game was still accepting UK customers.

“In fact, it was one of the easiest for me to gamble on – there were very few checks whatsoever,” he says. “But Leicester don’t seem to have done anything about it, and it’s still on the front of their shirts.”

Leicester City FC did not respond to a request for comment.

Sky News was able to sign up to every single site

Bournemouth, Fulham and Newcastle United are also sponsored by casinos that were formerly licensed by TGP Europe, but have been unlicensed since 15 May.

These casinos (bj88, SBOTOP and FUN88) are no longer able to legally accept UK customers.

However, Sky News was able to use a VPN to sign up to all three casinos, as well as those sponsoring Leicester City, Wolverhampton and Burnley.

On all six websites, Sky was able to access QR codes for making cryptocurrency deposits. Sky News did not attempt to make any deposits.

All six casinos are forbidden by law from accepting UK customers.

Yet Burnley sponsor 96.com allowed Sky News to sign up using a Telegram account registered to a UK phone number.

The other websites all required phone numbers to be entered upon registration, which could be used as an additional layer of security to filter out UK customers.

However, most of the websites did not check whether the phone number provided was genuine.

Only one website, Leicester City sponsor BC.Game, did check.

However, after confirming the phone number’s authenticity, BC.Game allowed registration to proceed – even though Sky News had provided a UK phone number.

Sky News presented these findings to the football clubs concerned, to TGP Europe and to the Gambling Commission, but did not receive any comment.

Anyone concerned about their gambling, or that of a loved one, can visit BeGambleAware.org for free, confidential advice and support, or The National Gambling Helpline is available on 0808 8020 133 and operates 24 hours a day, seven days a week.


The Data and Forensics team is a multi-skilled unit dedicated to providing transparent journalism from Sky News. We gather, analyse and visualise data to tell data-driven stories. We combine traditional reporting skills with advanced analysis of satellite images, social media and other open source information. Through multimedia storytelling we aim to better explain the world while also showing how our journalism is done.

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Former BBC executive and presenter Alan Yentob dies

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Former BBC executive and presenter Alan Yentob dies

Alan Yentob, the former BBC presenter and executive, has died aged 78.

A statement from his family, shared by the BBC, said Yentob died on Saturday.

His wife Philippa Walker said: “For Jacob, Bella and I, every day with Alan held the promise of something unexpected. Our life was exciting, he was exciting.

“He was curious, funny, annoying, late, and creative in every cell of his body. But more than that, he was the kindest of men and a profoundly moral man. He leaves in his wake a trail of love a mile wide.”

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Yentob joined the BBC as a trainee in 1968 and held a number of positions – including controller of BBC One and BBC Two, director of television, and head of music and art.

He was also the director of BBC drama, entertainment, and children’s TV.

Yentob launched CBBC and CBeebies, and his drama commissions included Pride And Prejudice and Middlemarch.

Alan Yentob with former BBC director general Tony Hall in 2012. Pic: Reuters.
Image:
Alan Yentob (left) with former BBC director general Tony Hall in 2012. Pic: Reuters.

The TV executive was made a Commander of the Order of the British Empire (CBE) by the King in 2024 for services to the arts and media.

In a tribute, the BBC’s director-general Tim Davie said: “Alan Yentob was a towering figure in British broadcasting and the arts. A creative force and a cultural visionary, he shaped decades of programming at the BBC and beyond, with a passion for storytelling and public service that leave a lasting legacy.

“Above all, Alan was a true original. His passion wasn’t performative – it was personal. He believed in the power of culture to enrich, challenge and connect us.”

BBC Radio 4 presenter Amol Rajan described him on Instagram as “such a unique and kind man: an improbable impresario from unlikely origins who became a towering figure in the culture of post-war Britain.

“I commend his spirit to the living.”

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Mother and three children who died in house fire in London named by police

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Mother and three children who died in house fire in London named by police

A mother and three of her children who died in a house fire in northwest London have been named by police.

Warning: This article contains pictures of a fire in which people died

Detectives say Nusrat Usman, 43, Maryam Mikaiel, 15, Musa Usman, eight, and Raees Usman, four, died following the fire in Stonebridge, near Wembley, in the early hours of Saturday.

A woman in her 70s was taken to hospital but has since been released. A 13-year-old girl remains in hospital in a critical condition.

A 41-year-old man was arrested at the scene and has since been bailed. He was subsequently detained under the Mental Health Act.

A 43-year-old woman and three children died at the scene in Brent, northwest London.
Image:
The blaze gutted two homes in Stonebridge


Flowers and a blue teddy bear have been left near the scene, where crews wearing helmets and respiratory equipment were seen building scaffolding against the burnt-out buildings.

Neighbour Cecilia Marquis, 60, said she was “stunned by the devastation”.

“This will leave a devastating impact,” Ms Marquis, who witnessed the fire, said.

A 43-year-old woman and three children died at the scene in Brent, northwest London.

Witness Mohamed Labidi, 38, said he “can’t even look at the house right now”.

“We used to socialise together.

“They’re very good people, no problems on their side at all. It’s really shocking. It’s a really strong community here, we look after each other.”

The inferno that claimed the lives of a mother and her three children

A neighbour, who asked not to be named, said: “It’s horrible, we saw people running outside.

“It’s hard to process. I only just moved in, so it’s hard to think about it.”

Read more from Sky News:
Police officer fighting for life after on-duty traffic incident named
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Emergency services on the scene. Pic: PA
Image:
Emergency services on the scene. Pic: PA

Eight fire engines and around 60 firefighters responded to the blaze, London Fire Brigade (LFB) said.

Two terrace houses, each with three floors, were severely damaged in the fire, which was under control by around 3.25am, the fire service added.

Superintendent Steve Allen, from the Met’s local policing team in northwest London, said: “Our thoughts go out to all those impacted by what has happened.

“Specialist officers are continuing to support the wider family who have asked for privacy at this deeply upsetting time.

“Local officers are working closely with officers from the Specialist Crime Command on what continues to be a very complex investigation.”

Mayor of London Sadiq Khan said in a post on X: “This is devastating news and my thoughts are with the family, friends and wider community of the four people who sadly have lost their lives.

“I remain in close contact with the London Fire Brigade and Metropolitan Police as they work to establish the cause of the fire and offer support to all those impacted.”

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