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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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US

Woman missing for more than 60 years found ‘alive and well’

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Woman missing for more than 60 years found 'alive and well'

A woman in the US who has been missing since 1962 has been found “alive and well”, authorities have said.

Audrey Backeberg left her home in Reedsburg, Wisconsin, in July that year when she was 20 years old, Sauk County Sheriff’s Office said.

Investigators pursued numerous leads over the years but the case eventually went cold.

However, during a review of cold cases earlier this year, a detective reassessed all the case files and evidence, and re-interviewed several witnesses – and found Ms Backeberg.

The 82-year-old was “alive and well” – living outside of the state of Wisconsin, the sheriff’s office said.

Ms Backeberg was married and had two children when she disappeared on 7 July 1962, according to the Wisconsin Missing Persons Advocacy organisation.

She left her home to pick up her salary but never returned, causing her husband to ask family members where she was.

Shortly afterwards their 14-year-old babysitter claimed she and Ms Backeberg had hitchhiked to Wisconsin’s capital city Madison and then caught a bus to Indianapolis, Indiana.

The teenager said when she arrived she became nervous and wanted to go home, while Ms Backeberg refused to return and was last seen walking near a bus stop.

Ms Backeberg’s marriage was troubled and there were allegations of abuse, the Wisconsin Missing Persons Advocacy organisation said, with a criminal complaint having been filed days before she went missing.

Her relatives insisted she would never abandon her children, the organisation added, and her husband passed a polygraph test and maintained his innocence.

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‘We talked for 45 minutes’ – detective

Detective Isaac Hanson, who found Ms Backeberg, said her sister’s Ancestry.com account was vital in helping him locate her address.

“That was pretty key in locating death records, census reports, all kinds of data,” he told local news station WISN.

“So I called the local sheriff’s department, said, ‘Hey, there’s this lady living at this address. Do you guys have somebody, you can just go pop in?’

“Ten minutes later, she called me, and we talked for 45 minutes.”

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‘She sounded happy’

Mr Hanson said Ms Backeberg may have left home due to marital issues, but it was unclear why she had stayed away for so long.

He said he had promised to keep their conversation private.

“I think she just was removed and, you know, moved on from things and kind of did her own thing and led her life,” he said.

“She sounded happy. Confident in her decision. No regrets.”

Sauk County Sheriff’s Office said Ms Backeberg made the choice to leave and her disappearance “was not the result of any criminal activity or foul play”.

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Sports

Jets-Blues Game 7 preview: Key players to watch, final score predictions

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Jets-Blues Game 7 preview: Key players to watch, final score predictions

It all comes down to this. The Presidents’ Trophy-winning Winnipeg Jets host the St. Louis Blues in the 200th Game 7 in Stanley Cup playoffs history Sunday (7 p.m. ET, TBS).

One team will advance to the second round, while the other will get an early start to the offseason — and try to fix what went wrong.

For the Blues, this is the club’s 19th all-time Game 7, the most of any non-Original Six team. They have gone 10-8 in Games 7s, with the most recent one being the 2019 Stanley Cup Final against the Boston Bruins, which they won 4-1.

This version of the Jets has much less Game 7 history on which to draw; their only Game 7 was a second-round victory over the Nashville Predators in 2018.

Who wins this one? We’ve gathered the ESPN hockey family to identify the key players to watch in the contest — as well as their final score predictions.

Who is the one key player you’ll be watching in Jets-Blues?

Ryan S. Clark, NHL reporter: If he plays, it’s Mark Scheifele. The hit in Game 5 from Brayden Schenn and/or Radek Faksa generated quite a bit of conversation about what is arguably the most physically demanding series in the first round. Scheifele’s play this season and this series prior to the hit reinforces what makes him a legit top-line center in this league. We saw how the Jets maneuvered around his absence for the final two periods of Game 5, while Game 6 proved why they need contributions from everyone if he can’t go.

But again, that’s if Scheifele plays. He skated Saturday in a tracksuit, with Scott Arniel saying the center will be a game-time decision Sunday.

Arda Öcal, NHL broadcaster: Connor Hellebuyck is the obvious answer here for me because he’s been “Vezina” at home (especially Game 2) and “Vezina from Temu” on the road.

Hellebuyck has allowed four or more goals in seven straight road playoff games, which ties the second longest such streak in Stanley Cup playoff history. But Game 7 is at home. The pressure is on but he’s in comfortable confines, surrounded by a “Whiteout.” Which version of Hellebuyck do we get Sunday night?

Kristen Shilton, NHL reporter: Connor Hellebuyck, of course. Has there been a Jekyll/Hyde performance like this in recent years?

The Vezina finalist can play lights-out at home and like a fish out of water on the road. Does that trend continue in Game 7? What version of the goalie shows up for this one?

But as a bonus, I’ll toss Pavel Buchnevich into this equation. He’s been driving the Blues’ offense, and if Hellebuyck is on his A-game then St. Louis is going to need Buchnevich to channel his hat trick energy from Game 3 to help the Blues pull off a stunning road win.

Greg Wyshynski, NHL reporter: Jordan Binnington renewed his title as one of the NHL’s most clutch goaltenders with his 31-save performance in Team Canada’s 4 Nations Face-Off championship win over the U.S. — including six saves in overtime. He first earned it in 2019, backstopping the Blues to the Stanley Cup with Game 7 wins over Dallas and Boston.

Now he’s got a chance to reestablish those credentials.

Binnington had a 0.82 goals-against average and a .968 save percentage in those prior Game 7s. While Hellebuyck has been terrible in St. Louis, Binnington hasn’t been much better in Winnipeg, generating an .861 save percentage and a 3.44 goals-against average and giving up four goals in two of the three games. But as 4 Nations showed, Binnington can meet the moment. (Although this time, Kyle Connor will actually be in the lineup for the opposition. Not that we’re bitter or anything.)


The final score will be _____.

Clark: 4-3 Jets. There have been a few themes in this series. The first being that offense hasn’t been an issue — the teams have combined to score more than six goals in all but one game. The second is that the home team has won every game; I say that continues, and the Jets advance.

Öcal: 6-5 Jets. Hellebyuck doesn’t have his best game, but the Jets outscore that challenge, and Kyle Connor scores another third-period goal in this series to win it.

Shilton: 5-4 Jets. The Jets have been too good on home ice to let this one slip away. That’s not to say a St. Louis win would be surprising, but even if Hellebuyck is off, Winnipeg’s offense should be able to provide enough buffer that the Jets can squeak through with a narrow victory to advance.

Wyshynski: 5-3 Jets. The Jets would be toast if this game were played in St. Louis because it’s a demonstrable fact that Hellebuyck is a disaster on the road in the playoffs. He’s slightly below replacement at home in the postseason, but Winnipeg will take that considering his three removals on the road.

The Blues are first in the playoffs in 5-on-5 offense and goals-for percentage at home. But Winnipeg is second in both categories. Hellebuyck calms down, and the offense gets ratcheted up at home, especially now that Nikolaj Ehlers has a game under his belt, having not played since April 12 due to a foot injury.

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Environment

Meet Bodo – the 35 mph electric golf cart that thinks it’s a G-Wagen

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Meet Bodo – the 35 mph electric golf cart that thinks it's a G-Wagen

With a fully-enclosed, G-Wagen-inspired body and an 80 mile electric range, the Bodo G-Wagon golf cart is the NEV you need when you decide it’s time to get serous one-upping the rest of the Palm Beach country clubbers.

If you love the look of the $230,000 Mercedes-Benz G580 off-roader, but think the 579 hp, 6,800 lb. electric 4×4 is probably overkill for occasional trips to the golf course and country club, this G-Wagen-inspired golf cart might be just what you’re looking for.

The shiny black 2024 Bodo G-Wagon sold at Mecum Auctions last month for $31,900, which seems like it might not be a lot of money to the sort of person who decides to take a flyer on a goofy, limited-use EV that ships with real, metal doors, power windows, heating and air conditioning, fully digital instrument cluster and infotainment, and a “posh,” caramel leather interior.

It even has windshield wipers, power steering, and a rear-seat entertainment system that’s built into the front headrests!

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It’s really nice in there

Under the hood, the Bodo packs a 15 kW (20 hp) electric motor drawing power from a 10 kWh li-ion battery that won’t deliver a scorching 0-60 mph time (it only goes 35), but will deliver you and your buddies from one end of any golf course in North America and back several times over, thanks to the G-Wagon’s 80 mile range.

The official Mecum Auctions listing goes into a bit more detail, and I’ve included it here, in case it gets deleted after a while and you’re just finding this for the first time in 2027:

Be the envy of any country club or golf community showing up with this 2024 Bodo G-Wagon Golf Cart. Perhaps more appropriately known as an E-Wagon, this baby G-Wagon is powered by a 15kW motor with a 10kWh lithium battery. Boasting an 80-mile range and a 35 MPH top speed, the Bodo is an enclosed, luxury golf cart that pampers occupants with heating and air conditioning, rear-seat entertainment, power windows, power locks and a posh, caramel-colored interior. With the Bodo fitted with power steering and 4-wheel power disc brakes with brake boost, drivers will think they’re in a full-size G-Wagon, thanks to the multiscreen entertainment cluster, the rearview camera, windshield wipers, turn signals, running lights and so much more.

Finished in black with the right amount of brightwork, the overall vibe is one of jaw-dropping, smile-inducing fun. While the Bodo would be an excellent choice for any golf community, it should also prove to be hugely popular around a race track or car condo community as well, or maybe even a neighborhood with its own airplane runways. Over the past decade in particular, the demand for unique, luxury golf carts has been on the rise, and understandably so. The number of luxury communities with specific interests in sports, aero and auto has also been on the rise, with people buying homes in these exclusive locations to better engage with like-minded people. All too often a golf cart is the perfect way to get around these gated neighborhoods, and this one is enclosed, comes with the amenities of a full-size car and is infinitely more stylish.

MECUM AUCTIONS

You can check out a few more photos of the 2024 Bodo G-Wagon golf cart that sold at Mecum, below – and if you want one for yourself, you’re in luck! I found this brand-new 2025 “G600 E-Wagon” (in white) for $23,900 at Gulf Carts in Santa Rosa Beach, Florida. Head on down to the comments and let us know if you buy it.

SOURCE | LOTS MORE PHOTOS: Mecum Auctions.


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