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Reviewed by Emily Henderson, B.Sc. Mar 17 2023

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.

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Sports

Source: USC flips Ducks’ Topui, No. 3 DT in 2026

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Source: USC flips Ducks' Topui, No. 3 DT in 2026

USC secured the commitment of former Oregon defensive tackle pledge Tomuhini Topui on Tuesday, a source told ESPN, handing the Trojans their latest recruiting victory in the 2026 cycle over the Big Ten rival Ducks.

Topui, ESPN’s No. 3 defensive tackle and No. 72 overall recruit in the 2026 class, spent five and half months committed to Oregon before pulling his pledge from the program on March 27. Topui attended USC’s initial spring camp practice that afternoon, and seven days later the 6-foot-4, 295-pound defender gave the Trojans his pledge to become the sixth ESPN 300 defender in the program’s 2026 class.

Topui’s commitment gives USC its 10th ESPN 300 pledge this cycle — more than any other program nationally — and pulls a fourth top-100 recruit into the impressive defensive class the Trojans are building this spring. Alongside Topui, USC’s defensive class includes in-state cornerbacks R.J. Sermons (No. 26 in ESPN Junior 300) and Brandon Lockhart (No. 77); four-star outside linebacker Xavier Griffin (No. 27) out of Gainesville, Georgia; and two more defensive line pledges between Jaimeon Winfield (No. 143) and Simote Katoanga (No. 174).

The Trojans are working to reestablish their local recruiting presence in the 2026 class under newly hired general manager Chad Bowden. Topui not only gives the Trojans their 11th in-state commit in the cycle, but his pledge represents a potentially important step toward revamping the program’s pipeline to perennial local powerhouse Mater Dei High School, too.

Topui will enter his senior season this fall at Mater Dei, the program that has produced a long line of USC stars including Matt Leinart, Matt Barkley and Amon-Ra St. Brown. However, if Topui ultimately signs with the program later this year, he’ll mark the Trojans’ first Mater Dei signee since the 2022 cycle, when USC pulled three top-300 prospects — Domani Jackson, Raleek Brown and C.J. Williams — from the high school program based in Santa Ana, California.

Topui’s flip to the Trojans also adds another layer to a recruiting rivalry rekindling between USC and Oregon in the 2026 cycle.

Tuesday’s commitment comes less than two months after coach Lincoln Riley and the Trojans flipped four-star Oregon quarterback pledge Jonas Williams, ESPN’s No. 2 dual-threat quarterback in 2026. USC is expected to continue targeting several Ducks commits this spring, including four-star offensive tackle Kodi Greene, another top prospect out of Mater Dei.

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Environment

SunZia Wind’s massive 2.4 GW project hits a big milestone

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SunZia Wind’s massive 2.4 GW project hits a big milestone

GE Vernova has produced over half the turbines needed for SunZia Wind, which will be the largest wind farm in the Western Hemisphere when it comes online in 2026.

GE Vernova has manufactured enough turbines at its Pensacola, Florida, factory to supply over 1.2 gigawatts (GW) of the turbines needed for the $5 billion, 2.4 GW SunZia Wind, a project milestone. The wind farm will be sited in Lincoln, Torrance, and San Miguel counties in New Mexico.

At a ribbon-cutting event for Pensacola’s new customer experience center, GE Vernova CEO Scott Strazik noted that since 2023, the company has invested around $70 million in the Pensacola factory.

The Pensacola investments are part of the announcement GE Vernova made in January that it will invest nearly $600 million in its US factories and facilities over the next two years to help meet the surging electricity demands globally. GE Vernova says it’s expecting its investments to create more than 1,500 new US jobs.

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Vic Abate, CEO of GE Vernova Wind, said, “Our dedicated employees in Pensacola are working to address increasing energy demands for the US. The workhorse turbines manufactured at this world-class factory are engineered for reliability and scalability, ensuring our customers can meet growing energy demand.”

SunZia Wind and Transmission will create US history’s largest clean energy infrastructure project.

Read more: The largest clean energy project in US history closes $11B, starts full construction


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Stablecoin issuer Circle files for IPO as public markets open to crypto

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USDC stablecoin issuer Circle files for IPO as public markets open to crypto

Jeremy Allaire, Co-Founder and CEO, Circle 

David A. Grogan | CNBC

Circle, the company behind the USDC stablecoin, has filed for an initial public offering and plans to list on the New York Stock Exchange.

The prospectus, filed with the SEC on Tuesday, lays the groundwork for Circle’s long-anticipated entry into the public markets.

JPMorgan Chase and Citigroup are serving as lead underwriters, and the company is reportedly aiming for a valuation of up to $5 billion. It will trade under ticker symbol CRCL.

It marks Circle’s second attempt at going public. A prior merger with a special purpose acquisition company (SPAC) collapsed in late 2022 amid regulatory challenges. Since then, Circle has made strategic moves to position itself closer to the heart of global finance, including the announcement last year that it would relocate its headquarters from Boston to One World Trade Center in New York.

Circle reported $1.68 billion in revenue and reserve income in 2024, up from $1.45 billion in 2023 and $772 million in 2022. The company reported net income last year of about $156 million., down from $268 million a year earlier.

Read more about tech and crypto from CNBC Pro

A successful IPO would make Circle one of the most prominent pure-play crypto companies to list on a U.S. exchange. Coinbase went public through a direct listing in 2021 and has a market cap of about $44 billion.

Circle will be trying to hit the public markets at a volatile moment for tech stocks, with the Nasdaq having just wrapped up its steepest quarterly drop since 2022. The tech IPO market has been mostly dry for over three years, though there are signs of life. Online lender Klarna, digital health company Hinge Health and ticketing marketplace StubHub have all filed their prospectuses recently. Late last week, artificial intelligence infrastructure provider CoreWeave held the biggest IPO for a U.S. venture-backed tech company since 2021. But the company scaled back the offering and the stock had a disappointing first two days of trading before rebounding on Tuesday.

Circle is best known as the issuer of USD Coin (USDC), the world’s second-largest stablecoin by market capitalization.

Pegged one-to-one to the U.S. dollar and backed by cash and short-term Treasury securities, USDC has roughly $60 billion in circulation and makes up about 26% of the total market cap for stablecoins, behind Tether‘s 67% dominance. Its market cap has grown 36% this year, however, compared with Tether’s 5% growth.

The company’s push into public markets reflects a broader moment for the crypto industry, which is enjoying political favor under a more crypto-friendly U.S. administration. The stablecoin sector specifically has been ramping up as the industry gains confidence that the crypto market will get its first piece of U.S. legislation passed and implemented this year, focusing on stablecoins. President Donald Trump has said he hopes lawmakers will send stablecoin legislation to his desk before Congress’s August recess.

Stablecoins’ growth could have investment implications for crypto exchanges like Robinhood and Coinbase as they become a bigger part of crypto trading and cross-border transfers. Coinbase also has an agreement with Circle to share 50% of the revenue of its USDC stablecoin, and Coinbase CEO Brian Armstrong said on the company’s most recent earnings call that it has a “stretch goal to make USDC the number 1 stablecoin.” 

The stablecoin market has grown about 11% so far this year and about 47% in the past year, and has become a “systemically important” part of the crypto market, according to Bernstein. Historically, digital assets in this sector have been used for trading and as collateral in decentralized finance (DeFi), and crypto investors watch them closely for evidence of demand, liquidity and activity in the market.

WATCH: Circle CEO on launching first stablecoin in Japan

Circle CEO on launching the first stablecoin in Japan

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