Connect with us

Published

on

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

Continue Reading

Entertainment

Police foil bomb plot targeting Lady Gaga’s biggest-ever show on Copacabana beach

Published

on

By

Police foil bomb plot targeting Lady Gaga's biggest-ever show on Copacabana beach

Brazilian police say they foiled a bomb attack planned for a Lady Gaga concert on Rio de Janeiro’s Copacabana beach that attracted an estimated 2.1 million people.

The plot was orchestrated by a group promoting hate speech and the radicalisation of teenagers, including self-harm and violent content as a form of social belonging, according to the Civil Police of Rio de Janeiro, which worked in coordination with the country’s justice ministry.

“The suspects were recruiting participants, including minors, to carry out coordinated attacks using improvised explosives and Molotov cocktails,” the force said.

The justice ministry said the recruiters identified themselves as Gaga’s fans, known as “Little Monsters”.

It said Operation Fake Monster was based on a report by the ministry’s cyber operations lab following a tip-off from Rio state police intelligence, which uncovered digital cells encouraging violent behaviour among teenagers using coded language and extremist symbolism.

Authorities carried out over a dozen search and seizure warrants, and a man described as the group’s leader was arrested in the southern state of Rio Grande do Sul for illegal possession of a firearm, and a teenager was detained in Rio de Janeiro for storing child abuse images.

Lady Gaga performing at the huge open-air concert. Pic: Reuters
Image:
Lady Gaga performing at the huge open-air concert. Pic: Reuters

Gaga’s biggest ever show

Some 500,000 tourists travelled to watch the concert, which was paid for by the city in an attempt to boost the struggling economy.

Saturday night’s two-hour show, which marked Gaga’s biggest ever, marked the first time she had played in Brazil since 2012, having cancelled an appearance at the Rock in Rio festival in 2017 over health issues.

Gaga, who released her seventh studio album, Mayhem, in March, opened with a dramatic, operatic edition of her 2011 track Bloody Mary, before launching into Abracadabra, a recent track.

Lady Gaga performs during her free concert on Copacabana Beach in Rio de Janeiro, Saturday, May 3, 2025. (AP Photo/Silvia Izquierdo)
Image:
Pic: AP

Lady Gaga, centre, performs during her free concert on Copacabana Beach in Rio de Janeiro, Saturday, May 3, 2025. (AP Photo/Silvia Izquierdo)
Image:
Pic: AP

“Brazil! I missed you. I missed you so much,” she exclaimed, before launching into Poker Face, one of her biggest hits.

The American pop star drew in a similar crowd to Madonna’s in May last year, who performed at the same beach, which is transformed into an enormous dance floor for the shows.

Addressing the crowd in English and through a Portuguese translator, Gaga became emotional as she said: “I’m so honoured to be here with you tonight.

People attend Lady Gaga's open concert at Copacabana beach in Rio de Janeiro, Brazil, May 3, 2025. REUTERS/Tita Barros
Image:
Gaga addresses the crowd. Pic: Reuters

Gaga seen performing on giant screens set up across the beach. Pic: Reuters
Image:
Gaga seen performing on giant screens set up across the beach. Pic: Reuters

“Tonight we’re making history, but no one makes history alone. Without all of you, the incredible people of Brazil, I wouldn’t have this moment. Thank you for making history with me.

“The people of Brazil are the reason I get to shine today. But of all the things I can thank you for, the one I most am grateful for is this: that you waited for me. You waited more than 10 years for me.”

She said it took so long to come back because she was “healing” and “getting stronger”. The pop sensation cancelled many of her shows in 2017 and 2018 due to her fibromyalgia condition, which can cause pain and fatigue.

It is estimated Gaga’s show will have injected around 600 million reais (£79.9m) into the economy, nearly 30% more than Madonna’s show.

People gather to attend Lady Gaga's open concert, in Copacabana beach in Rio de Janeiro, Brazil May 3, 2025. REUTERS/Pilar Olivares
Image:
Pic: Reuters

Read more:
John Lithgow on JK Rowling’s trans stance backlash
Why are the band Kneecap controversial?

The large-scale free shows are set to continue annually until at least 2028, always taking place in May, which is considered the economy’s “low season”, according to the city’s government.

A hefty security plan was in place, including the presence of 3,300 military and 1,500 police officers, along with 400 military firefighters.

‘A dream come true’

Fans find a spot to watch the show. Pic: AP
Image:
Pic: AP

The city has been swarmed with Gaga fans since her arrival on Tuesday, with some even keeping vigil outside of the hotel she has been staying at.

Many arrived at the beach at the crack of dawn on Saturday to secure good spots on the beach, despite the show not starting until 9.45pm.

An aerial view shows fans gathering on Copacabana beach ahead of Lady Gaga's arrival. Pic: Reuters
Image:
An aerial view shows fans gathering on Copacabana beach ahead of Lady Gaga’s arrival. Pic: Reuters

Ana Lara Folador, who attended with her sister, said it was “a dream come true”, and that Gaga had “really shaped a part of my personality, as a person and an artist”.

Ingrid Serrano, a 30-year-old engineer who made a cross-continent trip from Colombia to Brazil to attend the show, turned up in a T-shirt featuring Lady Gaga’s outlandish costumes over the years.

“I’ve been a 100% fan of Lady Gaga my whole life,” she said, adding the 39-year-old megastar represented “total freedom of expression – being who one wants without shame”.

A fan dons an unusual face mask. Pic: AP
Image:
A fan dons an unusual face mask. Pic: AP

A fan strikes a pose. Pic: AP
Image:
A fan strikes a pose. Pic: AP

Matheus Silvestroni, 25, an aspiring DJ and a Gaga fan since the age of 12, endured an eight-hour bus ride from Sao Paulo for the show.

He said it was Gaga who had inspired him to embrace his sexuality and pursue his dream of becoming an artist.

“I was bullied because I was a fat, gay kid, so I was an easy target,” he said. “Gaga was very important because she sent a message that everything was okay with me, I wasn’t a freak, because I was ‘Born This Way’.”

Rio is known for holding massive open-air concerts, with Rod Stewart holding a Guinness World Record for the four million-strong crowd he drew to Copacabana beach in 1994.

Continue Reading

Entertainment

John Lithgow on JK Rowling’s trans stance backlash: ‘She’s handled it fairly gracefully’

Published

on

By

John Lithgow on JK Rowling's trans stance backlash: 'She's handled it fairly gracefully'

John Lithgow is a man well aware of cancel culture and its ability to destroy careers in the blink of an eye.

The Oscar-nominated actor tells Sky News: “It is terrible to be so careful about what you say. Even in an interview like this. It goes into the world, and you can get misconstrued and misrepresented and cancelled in [the click of a finger].”

Pic: Johan Persson
Image:
Roald Dahl is the subject of West End play Giant, by Mark Rosenblatt. Pic: Johan Persson

It’s a theme that runs parallel with his latest work – the stage show Giant – which through the lens of one explosive day in children’s author Roald Dahl‘s life, poses the question, should we look for moral purity in our artists?

The writer of great works including The Witches, Matilda and The BFG, Dahl revolutionised children’s literature with his irreverent approach, inspiring generations of readers and selling hundreds of millions worldwide. But his legacy is conflicted.

Lithgow describes Dahl as “a man with great charm, great wit and literary talent. A man who really cared about children and loved them. But a man who carried a lot of demons.”

Specifically, the play – which explores Palestinian rights versus antisemitism – deals with the fallout from controversial comments the children’s author made over the Israeli invasion of Lebanon in 1982. Its themes couldn’t be more timely.

Lithgow explains: “Things are said in the play that nobody dares to say out loud… But God knows this is a complicated and contradictory issue.”

More on Jk Rowling

Pic: Johan Persson
Image:
John Lithgow plays Dahl – a man capable of ‘great compassion’ and ‘enormous cruelty’. Pic: Johan Persson

‘It didn’t start as an idea about Roald Dahl at all’

So controversial are some of the play’s themes, the 79-year-old star admits his own son warned him: “Prepare yourself. There’ll be demonstrations in Sloane Square outside the Royal Court Theatre.”

Indeed, the play’s first run carried an audience warning flagging “antisemitic language; graphic descriptions of violence; emotional discussion of themes including conflict in the Middle East, Israel and Palestine; and strong language”.

But it didn’t put audiences off. Following a sold-out run at the Royal Court, the role won Lithgow an Olivier. Now, it’s transferring to London’s West End.

The play was written by Mark Rosenblatt, a seasoned theatre director but debut playwright.

He tells Sky News: “It didn’t start as an idea about Roald Dahl at all. It was about the blurring of meaningful political discourse with racism, specifically when, in 2018, the inquiry into antisemitism in the Labour Party started to come out.”

Rosenblatt describes Dahl’s Revolting Rhymes and Dirty Beasts as the “wallpaper” of his childhood, and says he had no desire to “smash the Roald Dahl pinata”.

But despite the fond recollections, he was conflicted: “Understanding that [Dahl] also, possibly, didn’t like someone like me because I’m Jewish felt complicated.” It was Rosenblatt’s exploration of “how you hold those two things at the same time” that led to Dahl becoming the play’s focus.

Elliot Levey plays Dahl's Jewish publisher, and Aya Cash plays an American Jewish sales executive. Pic: Johan Persson
Image:
Elliot Levey plays Dahl’s Jewish publisher, and Aya Cash plays an American Jewish sales executive. Pic: Johan Persson

‘He’s not cancelled in our home’

Rosenblatt describes him as “a complex man, capable of great compassion, great passionate defence of oppressed people, and also capable of enormous cruelty and manipulation. He was many things at once”.

And as for Dahl’s place in his life now? Rosenblatt says: “I still read his books to my kids. He’s certainly not cancelled in our home.”

It’s likely that Dahl’s comments, if uttered today, would lead to swift social media condemnation, but writing in a pre-social media age, the judgment over his words came at a much slower pace.

Dahl died in 1990, and his family later apologised for antisemitic remarks he made during his lifetime. But the debate of whether art can be separated from the artist is still very much alive today.

Earlier this month, Lithgow found himself drawn into a different row over artists and their opinions – this time concerning author JK Rowling.

Author and Lumos Foundation founder J.K. Rowling attends the HBO Documentary Films premiere of ...Finding the Way Home" at 30 Hudson Yards on Wednesday, Dec. 11, 2019, in New York. (Photo by Evan Agostini/Invision/AP)
Image:
JK Rowling in 2019. Pic:AP

‘A matter of nuance’

Soon to play Dumbledore in the Harry Potter TV series, he has been criticised by some fans for working with the author known for her gender critical beliefs.

Lithgow told Sky News: “It’s a question I’m getting asked constantly. I suppose I should get used to that, but JK Rowling has created an amazing canon of books for kids…

“I have my own feelings on this subject. But I’m certainly not going to hesitate to speak about it. Just because I may disagree… It’s a matter of nuance… I think she’s handled it fairly gracefully.”

The actor ignored calls not to take the role.

He goes on: “Honestly, I’d rather be involved in this than not. And if I’m going to speak on this subject, I’m speaking from inside this project and very much a partner with JK Rowling on it.”

Demanding an eight-year commitment and a move to the UK for the part, the stakes are high.

And with a legion of Harry Potter fans watching on from the wings, only time will tell if the Lithgow-Rowling partnership will prove a magical one.

Giant is playing at the Harold Pinter Theatre in London until Saturday, 2 August.

Continue Reading

Entertainment

Lorraine Kelly says she will undergo surgery to remove ovaries

Published

on

By

Lorraine Kelly says she will undergo surgery to remove ovaries

Lorraine Kelly has revealed she is undergoing surgery to remove her ovaries and fallopian tubes.

The 65-year-old TV presenter posted a video of her in a hospital bed on Instagram, and said “I’ve not been feeling all that well for a little while”.

Kelly added she “had a little scan and I have to have my ovaries and my tubes taken out” with keyhole surgery.

She said that the procedure is “purely preventative,” and that “I’m going to be totally fine, see you soon”.

According to the NHS, keyhole surgery – also called laparoscopic surgery – is carried out using several small incisions.

The procedure can take between one and two hours, and doctors recommend staying off work for two to four weeks after the surgery.

In the caption, the ITV presenter wrote she felt “very lucky to be treated so well” and thanked gynaecologist Dr Ahmed Raafat and hospital staff.

More on Lorraine Kelly

Good Morning Britain presenter Susanna Reid said she was “sending you all the love in the world”, while TV presenter Julia Bradbury added: “Wishing you a speedy recovery Lorraine, and good luck with the post op rehab.”

Read more from Sky News:
Trump posts AI image of himself as pope
‘I’m a brain surgeon – here’s what we earn’

Woman dies after bomb explodes in her hands

Kelly has been in television since 1984, starting her career on TV-am as an on-screen reporter covering Scottish news.

In 1990, she began her presenting career on Good Morning Britain, before hosting her own show, Lorraine, from 2010.

Continue Reading

Trending