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.
“Terrible”, “weird”, “peculiar” and “baffling” – some of the adjectives being levelled by observers at the Donald Trump administration’s peace plan for Ukraine.
The 28-point proposal was cooked up between Trump negotiator Steve Witkoff and Kremlin official Kirill Dmitriev without European and Ukrainian involvement.
It effectively dresses up Russian demands as a peace proposal. Demands first made by Russia at the high watermark of its invasion in 2022, before defeats forced it to retreat from much of Ukraine.
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Ukrainian support for peace plan ‘very much in doubt’
The suspicion is Mr Witkoff and Mr Dmitriev conspired together to choose this moment to put even more pressure on the Ukrainian president.
Perversely, though, it may help him.
There has been universal condemnation and outrage in Kyiv at the Witkoff-Dmitriev plan. Rivals have little choice but to rally around the wartime Ukrainian leader as he faces such unreasonable demands.
The genesis of this plan is unclear.
Was it born from Donald Trump’s overinflated belief in his peacemaking abilities? His overrated Gaza ceasefire plan attracted lavish praise from world leaders, but now seems mired in deepening difficulty.
The fear is Mr Trump’s team are finding ways to allow him to walk away from this conflict altogether, blaming Ukrainian intransigence for the failure of his diplomacy.
Mr Trump has already ended financial support for Ukraine, acting as an arms dealer instead, selling weapons to Europe to pass on to the invaded democracy.
If he were to take away military intelligence support too, Ukraine would be blind to the kind of attacks that in recent days have killed scores of civilians.
Europe and Ukraine cannot reject the plan entirely and risk alienating Mr Trump.
They will play for time and hope against all the evidence he can still be persuaded to desert the Kremlin and put pressure on Vladimir Putin to end the war, rather than force Ukraine to surrender instead.
Over 200 students have been kidnapped from a Catholic boarding school in western Nigeria – the second mass abduction in the country this week.
Gunmen took 215 students and 12 teachers from St Mary’s School in Agwara, Niger state, early on Friday, according to the Christian Association of Nigeria.
Daniel Atori, a spokesperson for the Niger state chapter of the association, said he met parents of the abducted children “to assure them that we are working with the government and security agencies to see that our children are rescued and brought back safely”.
St Mary’s is a secondary school that has students aged 12 to 17, but the institution is attached to an adjoining primary school with more than 50 classrooms and dormitory buildings.
Dauda Chekula, 62, said that four of his grandchildren, ranging in age from seven to 10, were among those abducted.
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“We don’t know what is happening now, because we have not heard anything since this morning,” Mr Chekula said.
“The children who were able to escape have scattered, some of them ran back to their houses and the only information we are getting is that the attackers are still moving with the remaining children into the bush.”
On Monday, 25 schoolgirls were kidnapped from a boarding school in neighbouring Kebbi state, northwest Nigeria.
Police said men armed with rifles stormed the Government Girls Comprehensive Secondary School in the town of Maga at around 4am local time (3am UK time), arriving on motorcycles in an apparently well-planned attack.
Student escapes from kidnappers
A 15-year-old student who was among those abducted from the boarding school in Kebbi state’s Danko-Wasagu area managed to escape.
She said she found refuge at a teacher’s house.
Image: The Government Girls Comprehensive Secondary School in the town of Maga was attacked on Monday. Pic: AP
Image: Police at the school compound to investigate the kidnapping. Pic: Africa Independent Television/Reuters
It was not immediately clear who was to blame for either of the abductions.
Abubakar Usman, the secretary to the Niger state government, said in a statement that the latest kidnapping occurred despite a prior intelligence warning of heightened threats.
“Regrettably, St Mary’s School proceeded to reopen and resume academic activities without notifying or seeking clearance from the state government, thereby exposing pupils and the staff to avoidable risk,” it read.
A security staffer was “badly shot” during the early-morning attack on the school, the Catholic Diocese of Kontagora said.
Image: Blood stains on the floor of the Government Girls Comprehensive Secondary School. Pic: AP
Ransom demand for worshippers
Separately, gunmen attacked a church in Kwara state on Monday, killing at least two people.
A church official said 38 worshippers were also kidnapped by the gunmen, who have since issued a ransom demand of 100 million naira (£52,660) for each person.
Kebbi, Kwara and Niger states border one another.
Image: Worshippers run for cover after hearing gunshots in Kwara state, Nigeria. Pic: Reuters
The attacks have highlighted insecurity in Nigeria and forced President Bola Tinubu to postpone foreign trips.
At least 1,500 students have been abducted in the region since Boko Haram extremists seized 276 Chibok schoolgirls more than a decade ago.
No group has claimed responsibility for the attacks in Niger and Kebbi state, but analysts say gangs often target schools in kidnappings for ransom.
Nigeria was recently thrust into the spotlight after Donald Trump singled the country out, claiming that Christians are being persecuted – an allegation that the government rejected.
The Eurovision Song Contest is changing its voting system, following allegations of “interference” by Israel’s government this year.
Israeli singer Yuval Raphael received the largest number of votes from the public in the contest in May, ultimately finishing as runner-up after the jury votes were counted.
But a number of broadcasters raised concerns about Israel’s result.
After the final, Irish broadcaster RTE requested a breakdown in voting numbers from contest organiser the European Broadcasting Union (EBU), while Spain’s public broadcaster, Radio Television Espanola (RTVE), called for a “complete review” of the voting system to avoid “external interference”.
In September, Dutch public broadcaster AVROTROS said it could no longer justify Israel‘s participation in the contest, due to the Israel-Hamas war in Gaza.
It went on to say there had been “proven interference by the Israeli government during the last edition of the Song Contest, with the event being used as a political instrument”. The statement did not elaborate on the means of “interference”.
Sky News has contacted the Israeli government for comment.
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In early December, the EBU will hold its winter general assembly, with members due to consider the changes, and if not satisfied, vote on Israel’s participation.
Key changes to next year’s competition include:
• Clearer rules around promotion of artists and their songs • Cap on audience voting halved • The return of professional juries to semi-finals • Enhanced security safeguards
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Will Eurovision boycott Israel?
Sanctions threat
The EBU said the tightening of rules around promotion was to “discourage disproportionate promotion campaigns… particularly when undertaken or supported by third parties, including governments or governmental agencies”.
It said that “any attempts to unduly influence the results will lead to sanctions”.
Contest director Martin Green said “no broadcaster or artist may now directly engage with or support campaigns by third parties – including governments or their agencies – that could distort the vote”.
He said the reduction in the number of votes that can be made online, or via SMS or phone call, from 20 to 10 was “designed to encourage more balanced participation”.
He said that “although the number of votes previously allowed did not unduly influence the results of previous contests, there were concerns expressed by participating broadcasters and fans alike”.
Professional juries in semi-finals – and younger jurors
It was also announced that professional juries in the semi-finals would be restored for the first time since 2022, with an expansion to the range of professions from which jurors can be chosen.
The EBU said this will give roughly 50-50 percentage weight between audience and jury votes.
At least two jurors aged 18-25 will be present in every jury, to reflect the appeal of the contest with younger audiences.
Also mentioned were enhanced technical safeguards designed to “protect the contest from suspicious or coordinated voting activity” and strengthen security systems that “monitor, detect and prevent fraudulent patterns”.
Politics making itself heard over Europop lyrics
Mr Green said that the neutrality and integrity of the competition is of “paramount importance” to the EBU, its members, and audiences, adding that the event “should remain a neutral space and must not be instrumentalised”.
Image: Israel’s 2024 representative, Eden Golan. Pic: AP
Russia was banned from the competition in 2022 following its invasion of Ukraine.
Israel has competed in Eurovision for more than 50 years and won four times, but there have been ongoing calls to block their participation over the conduct of Prime Minister Benjamin Netanyahu’s government in the Hamas-Israel war.
Israel denies targeting civilians in Gaza and has said it is being unfairly demonised abroad.
In September, Spain, the Netherlands, Ireland, Iceland, and Slovenia threatened to withdraw their participation in Eurovision unless Israel is excluded from the competition.
There were also demonstrations against Israel’s inclusion in Basel, Switzerland, when the 2025 competition took place.
‘Step in right direction’
Responding to the changes, Iceland’s official broadcaster RUV told Sky News they were “a step in the right direction”, and they would be discussing them with their “sister stations in the Nordic countries” ahead of the EBU meeting in December.
Ireland’s official broadcaster RTE told Sky News: “Clearly, events in the Middle East are unfolding day by day. As previously confirmed by the EBU, the issue of participation in the 2026 Eurovision Song Contest has been included on the agenda of the EBU Executive Board’s ordinary Winter General Assembly.”
Sky News has also contacted the official broadcaster for the Netherlands (AVROTROS), Spain (RTVE), Slovenia (RTVSLO), and Israel (Kan) for comment.
The chief executive of Kan, Golan Yochpaz, has previously said the event should not become political and that there is “no reason” why Israel should not be part of it.
Image: Israeli Prime Minister Benjamin Netanyahu. Pic: Reuters
Netanyahu praised Israeli entrant
Earlier this year, Israeli Prime Minister Benjamin Netanyahu told Israel’s 2025 Eurovision entrant Yuval Raphael she had brought the country “a lot of honour” after she finished in second place, adding “you’re the real winner. Statistically, it’s true… You entered the hearts of a huge portion of the public in Europe.”
The year before he told entrant Eden Golan: “I saw that you received almost the highest number of votes from the public and this is the most important thing, not from the judges but from the public, and you held Israel’s head up high in Europe.”
In October, a ceasefire deal was put in place, aimed at bringing an end to the two-year war in the Middle East.
The war began when Hamas stormed into Israel on October 7 2023, killing around 1,200 people and taking 251 hostage.
Israel invaded Gaza in retaliation, with airstrikes and ground assaults devastating much of the territory and killing more than 67,000, according to the Hamas-run health ministry.
Its figures do not differentiate between civilians and combatants, but it says around half of those killed were women and children.
The world’s largest live music event, next year’s contest will be held in Vienna, Austria, in May and will celebrate 70 years of Eurovision.