Tyrosine kinase inhibitors are a type of targeted cancer medicine that can attack specific types of cancer cells and prevent them from multiplying. Although these inhibitors, called TKIs, can be very useful in fighting certain cancers, they also cause serious inflammatory side effects that limit their use. A Japanese research team has discovered the underlying mechanism that causes this inflammation. This study revealed the underlying mechanism by which the TKIs cause inflammation, and therefore provides the molecular basis that is essential to overcome the inflammatory-based side effects."
Atsushi Matsuzawa, Professor at the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
The team's findings were published in The Journal of Immunology on February 6, 2023.
These TKIs are essential anticancer drugs. However, the use of TKIs frequently initiates inflammation in the body, such as the lung disease interstitial pneumonitis. From their earlier studies, the team had learned that a representative TKI called Gefitinib (GF) causes lung inflammation. GF is a helpful cancer medication used in treating certain breast, lung, and other cancers. It works by targeting the epidermal growth factor receptors. When the GF is used to treat the cancer, it can also cause inflammation in the patient's lungs, through the NLRP3 inflammasome. The NLRP3 inflammasome is part of the body's immune system and plays an important role in innate immunity. But when the NLRP3 inflammasome is improperly activated, it can contribute to the development of a wide range of inflammatory diseases.
Until now, scientists have not fully understood why the NLRP3 inflammasome is activated, but the evidence seems to point to mitochondrial dysfunction. When mitochondria are healthy, they work like batteries, producing energy in the body's cells. Mitochondrial dysfunction happens when the mitochondria do not work as they should because of disease. In their earlier study, the team learned that the GF activated the NLRP3 inflammasome through mitochondrial damage that led to the interstitial pneumonitis in patients. However, they had not understood how GF initiates the mitochondrial damage and whether or not other TKIs also shared this mechanism. Cancer Research eBook Compilation of the top interviews, articles, and news in the last year. Download a free copy
To conduct their study, the team looked at the tyrosine kinases, those enzymes that work as a kind of "on" and "off" switch in many of the cells' functions. They specifically studied the Src family kinases, called SFKs. The SFKs are nonreceptor tyrosine kinases that regulate many cell processes. There are 11 types of SFKs in the human genome. Some of these SFKs are in the mitochondria and they play an essential role in the function of the mitochondria. The team found that all the TKIs they tested inhibit the kinase activity of the SKFs in the mitochondria which is responsible for the NLRP3 inflammasome.
The team's comprehensive analysis of the TKIs they tested revealed that these TKIs act as powerful agonists. In addition, the team observed off-target activity that could contribute to the side effects. "As an important finding, all TKIs we tested share a common off-target activity against the mitochondrial SFKs. Therefore, blocking the access of TKIs to mitochondria is a good way to prevent the inflammation," said Matsuzawa. They also noted that the other TKIs that do not affect the activity of the mitochondrial SFKs may overcome the inflammatory-based side effects. As another approach, when effective inhibitors of the NLRP3 inflammasome are developed, administering the TKIs at the same time as the NLRP3 inhibitors can counteract the side effects. The team's results provide insight into both the biological and the clinical significance of the NLRP3 inflammasome and the SFKs.
Looking ahead, the team's next step is to propose a new approach to avoid the inflammatory-based side effects of TKIs. They hope to lead in the development of new TKIs that do not initiate inflammation.
The research team includes Yuto Sekiguchi, Saya Takano, Takuya Noguchi, Tomohiro Kagi, Ryuto Komatsu, Maoko Tan, Yusuke Hirata, and Atsushi Matsuzawa from the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan. Source:
Tohoku UniversityJournal reference:
Sekiguchi, Y., et al. (2023) The NLRP3 inflammasome works as a sensor for detecting hypoactivity of the mitochondrial Src family kinases. The Journal of Immunology. doi.org/10.4049/jimmunol.2200611.
YouTuber-turned-boxer Jake Paul has defeated one of the greatest-ever fighters, former heavyweight world champion Mike Tyson, who’s more than twice his age.
The bout was won on a unanimous points decision at the AT&T Stadium in Arlington, Texas – home of the Dallas Cowboys and the biggest NFL stadium in the US.
The fight was already controversial but then arguably failed to live up to the hype. Boos were heard from the crowd in the final two rounds, after a perceived lack of action.
Boxing careers compared
This was not Paul’s first professional fight. The 27-year-old American YouTube star made his debut in 2020 with his most high-profile clash against Tyson Fury’s brother Tommy Fury last year, which he lost by a split decision.
The so-called “Problem Child” has since defeated former UFC contender Nate Diaz, professional boxer Andre August, former Gold Gloves champion Ryan Bourland and most recently MMA fighter Mike Perry.
In contrast, “Iron Mike” Tyson, 58, was ranked among the best heavyweight boxers of all time.
More on Jake Paul
Related Topics:
During his career, he knocked out 44 opponents – retiring from professional boxing in 2005 after defeat against Kevin McBride.
He returned to the ring in 2020 for a bout against fellow boxing icon Roy Jones, which ended in an unofficial draw.
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‘Someone’s getting put to sleep’
Earlier this week, Paul said he believed the bout would not go the distance. “No, someone’s getting put to sleep,” he said. “It’s going to be a war, and we’re both heavy hitters. It’s not going the full 16 minutes.”
Tyson was more reflective: “I’ve been through so many ups and downs since my last fight with Kevin McBride,” he said.
“I’ve been in rehab. I’ve been in prison, been locked up. Never in a million years did I believe I’d be doing this.”
Several states would not allow the bout to go ahead, and the Texas Athletic Commission only agreed to the fight if there were changes, due to Tyson’s age.
It limited the contest to eight rounds lasting a maximum of two minutes instead of three. Both boxers were also required to wear heavier gloves, designed to lessen the force of punches.
The fight was initially scheduled for 20 July, but was postponed when Tyson suffered an ulcer flareup.
Taylor defends title
Meanwhile, among the undercard fights, Irish boxer Katie Taylor successfully defended her super lightweight world title against Puerto Rico’s Amanda Serrano.
But it was tight. Taylor claimed the rematch 95-94 for all three judges in an epic battle.
The bout came two and a half years after the pair fought at Madison Square Garden, which Taylor won on a split decision.
Bout suffered from buffering
Earlier in the evening thousands of Netflix users in the US reported problems seeing the coverage, with some posting on social media about buffering.
At one point, more than 98,000 people had reported issues according to Downdetector, which tracks outages.
This breaking news story is being updated and more details will be published shortly.
Please refresh the page for the fullest version.
You can receive Breaking News alerts on a smartphone or tablet via theSky News App. You can also follow@SkyNews on X or subscribe to ourYouTube channel to keep up with the latest news.
YouTuber-turned-boxer Jake Paul has defeated one of the greatest-ever fighters, former heavyweight world champion Mike Tyson, who’s more than twice his age.
The bout was won on a unanimous points decision at the AT&T Stadium in Arlington, Texas – home of the Dallas Cowboys and the biggest NFL stadium in the US.
The fight was already controversial but then arguably failed to live up to the hype. Boos were heard from the crowd in the final two rounds, after a perceived lack of action.
Boxing careers compared
This was not Paul’s first professional fight. The 27-year-old American YouTube star made his debut in 2020 with his most high-profile clash against Tyson Fury’s brother Tommy Fury last year, which he lost by a split decision.
The so-called “Problem Child” has since defeated former UFC contender Nate Diaz, professional boxer Andre August, former Gold Gloves champion Ryan Bourland and most recently MMA fighter Mike Perry.
In contrast, “Iron Mike” Tyson, 58, was ranked among the best heavyweight boxers of all time.
More on Jake Paul
Related Topics:
During his career, he knocked out 44 opponents – retiring from professional boxing in 2005 after defeat against Kevin McBride.
He returned to the ring in 2020 for a bout against fellow boxing icon Roy Jones, which ended in an unofficial draw.
Advertisement
‘Someone’s getting put to sleep’
Earlier this week, Paul said he believed the bout would not go the distance. “No, someone’s getting put to sleep,” he said. “It’s going to be a war, and we’re both heavy hitters. It’s not going the full 16 minutes.”
Tyson was more reflective: “I’ve been through so many ups and downs since my last fight with Kevin McBride,” he said.
“I’ve been in rehab. I’ve been in prison, been locked up. Never in a million years did I believe I’d be doing this.”
Several states would not allow the bout to go ahead, and the Texas Athletic Commission only agreed to the fight if there were changes, due to Tyson’s age.
It limited the contest to eight rounds lasting a maximum of two minutes instead of three. Both boxers were also required to wear heavier gloves, designed to lessen the force of punches.
The fight was initially scheduled for 20 July, but was postponed when Tyson suffered an ulcer flareup.
Taylor defends title
Meanwhile, among the undercard fights, Irish boxer Katie Taylor successfully defended her super lightweight world title against Puerto Rico’s Amanda Serrano.
But it was tight. Taylor claimed the rematch 95-94 for all three judges in an epic battle.
The bout came two and a half years after the pair fought at Madison Square Garden, which Taylor won on a split decision.
Bout suffered from buffering
Earlier in the evening thousands of Netflix users in the US reported problems seeing the coverage, with some posting on social media about buffering.
At one point, more than 98,000 people had reported issues according to Downdetector, which tracks outages.
This breaking news story is being updated and more details will be published shortly.
Please refresh the page for the fullest version.
You can receive Breaking News alerts on a smartphone or tablet via theSky News App. You can also follow@SkyNews on X or subscribe to ourYouTube channel to keep up with the latest news.
According to a court filing, Elon Musk said that the proposed initial coin offering (ICO) “would simply result in a massive loss of credibility for OpenAI.”