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  • Oracle looks to join an exclusive club as it approaches this financial milestone

    Oracle looks to join an exclusive club as it approaches this financial milestone

    By Britney Nguyen

    Oracle’s stock rose more than 3% on Thursday, moving ever closer to a $700 billion market cap

    Oracle Corp. is getting closer to achieving a feat accomplished by only 13 other U.S. companies.

    With the cloud giant’s stock (ORCL) rising 3.1% on Thursday, Oracle is within a hair of surpassing a $700 billion market capitalization. Its shares clinched a new closing high of $248.75 at the end of the trading day; they need to close at $249.21 to reach the $700 billion mark, according to Dow Jones Market Data.

    Earlier in the day, Oracle’s shares traded as high as $251.60, setting an all-time intraday high, according to the data.

    Oracle’s stock is up 19% in the past month and up 79% over the past year. The rally has added to the wealth of co-founder and Chief Technology Officer Larry Ellison, who on Wednesday regained the No. 2 spot among the wealthiest people in the world, according to the Bloomberg Billionaires Index – topping Meta Platforms Inc. (META) co-founder and Chief Executive Mark Zuckerberg. Ellison, Zuckerberg, and Amazon.com Inc. (AMZN) founder Jeff Bezos have all shuffled in and out of the No. 2 ranking in the past year, though they all lag well behind Tesla Inc. (TSLA) CEO Elon Musk.

    Analysts have been optimistic about Oracle’s cloud-services revenue opportunities, with demand for artificial intelligence only growing.

    Cantor Fitzgerald analysts raised their price target to $271, from $216, in a Wednesday note to clients – noting that they’re boosting estimates after Oracle disclosed a deal in late June that it said would add more than $30 billion in annual revenue starting in fiscal-year 2028. The analysts now expect that the Oracle Cloud Infrastructure (OCI) business will make up 53% of revenue in fiscal 2029, versus their prior estimate of 50%.

    See more: Oracle’s stock is climbing, and these are the big reasons why

    The Cantor analysts said they’re now “slightly” ahead of the consensus view looking at fiscal years 2026 to 2029.

    The analysts did not increase their estimates for Oracle’s Cloud Database Services (CDBS) as “a measure of conservatism,” and said that looking at the company’s core OCI business, excluding CDBS and after increasing their estimates, they still see growth slowing down from 87% in fiscal-year 2026 to 43% in fiscal-year 2029.

    Earlier this week, Evercore ISI analysts also raised their price target for Oracle to $270, from $215. With Oracle’s outlook for fiscal 2026 being “more upbeat than expected” and the $30 billion annual deal getting announced, they said Oracle has solidified its “spot as the ‘fourth’ global hyperscaler.”

    “While Oracle’s massive AI deal is front and center right now in terms of its impact on FY28 growth, we think the longer-term bull case is broader,” the Evercore team wrote.

    OCI’s share of the “multihundred-billion-dollar hyperscaler market” is growing, the analysts said, because of its opportunities with increasing AI workloads and current efforts by governments globally to build out data-center infrastructure for sovereign AI.

    See more: Oracle’s stock is a ‘standout’ in the software sector, these analysts say. Here’s why.

    The Evercore analysts also see potential upside for Oracle as headwinds from its data-cloud and Cerner healthcare-technology businesses subside.

    Meanwhile, Oracle’s applications business is seeing double-digit growth, they added, while its database-maintenance customers are moving to the cloud.

    “Clearly a lot of good news is already priced in, but we think Oracle is set to raise its long-term targets at its October analyst day – and not many other megacap tech names are showing this kind of revenue acceleration at scale,” the Evercore team said.

    -Britney Nguyen

    This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

    (END) Dow Jones Newswires

    07-17-25 1700ET

    Copyright (c) 2025 Dow Jones & Company, Inc.

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  • Scientists extracted water and oxygen from moon dust using sunlight. Could it work on the lunar surface?

    Scientists extracted water and oxygen from moon dust using sunlight. Could it work on the lunar surface?

    Soil excavated from the moon could be used to produce oxygen and methane, which could be used by lunar settlers for breathing and for rocket fuel.

    This is the conclusion of a team of scientists from China who have found a one-step method of doing all this. Whether it is economically viable, however, is up for debate.

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  • Former developer claims Subnautica 2 delay is due to publisher wanting to avoid paying $250 million bonus in new lawsuit

    Former developer claims Subnautica 2 delay is due to publisher wanting to avoid paying $250 million bonus in new lawsuit

    It went from one of 2025’s most anticipated releases to one of the most dramatic public feuds in modern video game history. The announcement that the Early Access launch of Subnautica 2 was being delayed until 2026 was newsworthy enough, but it was revealed that the leadership team of the Subnautica developer Unknown Worlds was being removed as part of the delay. Now, that leadership team is claiming in a new lawsuit that the whole thing is a desperate move by their parent company to avoid paying a $250 million payout to the developers.

    Here is the timeline of events as we know them. Subnautica launched in 2018 and became one of the most popular survival games in history, selling more than 5 million copies and spawning a spin-off in 2021. Obviously, a direct sequel, Subnautica 2, was soon in development at the US-based Unknown Worlds. In October 2021, South Korean publisher Krafton purchased Unknown Worlds. What followed was an underperforming miniature game and a push toward Subnautica 2. That’s where things fell apart between the two companies.

    In July 2025, Subnautica 2 was delayed until 2026 and Unknown Worlds co-founders Charlie Cleveland, Max McGuire, and Ted Gill were all out of the company. Krafton claimed this was because they had not dedicated their efforts toward delivering Subnautica 2. In a post on their homepage, Krafton said that they purchased Unknown Worlds for an initial price of $500 million, with an additional $250 million earn-out compensation expected to go to the developers, 90% of which would go to the executive team of Cleveland, McGuire, and Gill. However, targets were not met and the game was not ready for a 2025 Early Access release, forcing Krafton to make a leadership change at the company.

    Now, Cleveland, McGuire, and Gill are taking aim at Krafton, saying that they delayed the game to 2026 to avoid paying the $250 million bonus to the company, which was tied to earnings reported in 2025. Earnings that would have been met if Krafton hadn’t pushed them out of the company and delayed the game to the following year. Their lawsuit, which was shared by Aftermath, says that Krafton committed “flagrant contractual breaches” in its efforts to avoid paying that bonus and says that Subnautica 2 is ready for Early Access this year as planned. It claims the publisher is “desperate” to avoid paying such a massive payout to the developer.

    In a report from Bloomberg, Krafton claims it is extending the earnings period for that $250 million bonus, which would go to the remaining staff at Unknown Worlds, which seems to undercut the previous executive team’s claims. We won’t know, however, how this will all shake out until the lawsuit is unsealed completely. For now, the gaming industry is watching all the drama around Subnautica 2 as closely as they would the game’s eventual launch.


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  • Citizen Kane sled saved from destruction sells for nearly $15m

    Citizen Kane sled saved from destruction sells for nearly $15m

    A prop central to the celebrated opening scene of Citizen Kane – widely regarded as one of the best films ever made – has sold at auction for $14.75m (£11m).

    The wooden Rosebud sled, one of at least three known to have survived, was long thought to have been lost until it was given to director Joe Dante in 1984, saving it from destruction.

    He went on to use it as a reference for fans (known as an Easter egg) in films he directed, including Gremlins 2: The New Batch.

    It is now the second most expensive piece of memorabilia to have ever been sold – a pair of ruby slippers used in The Wizard of Oz sold for $32m (£23.9) in December.

    “Along with Dorothy’s ruby slippers, the Rosebud sled from Citizen Kane is one of the most iconic objects in Hollywood history,” Joe Maddalena, executive vice president at Heritage Auctions, which held the action, told its magazine the Intelligent Collector.

    The identity of the sled’s buyer was not revealed.

    Other Rosebuds made for the film have been sold in the past, including one to legendary director Steven Spielberg, who later donated it to the Academy Museum of Motion Pictures in Los Angeles.

    However, the version sold on Thursday had not been seen for many years until it ended up in the hands of Dante.

    He told Heritage auctions how he was making the film Explorers in 1984 on the same studio that was formerly owned by RKO Radio Pictures, which produced Citizen Kane.

    Dante said crews were on site clearing out storage areas when one worker, who knew he liked vintage films, asked if he wanted it.

    “I was astonished…Since I am a huge fan of the movie, I said, ‘Yeah, I’ll be glad to take it.”

    “Citizen Kane may be the greatest film ever made, and Rosebud is the linchpin of the story – the whole heart of the plot and the focal point of the mysterious drama in Kane’s life.

    “As a director, to own the prop that represents such a vital element of a cinema treasure is particularly meaningful.”

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  • Bottega Veneta Just Released a New Sneaker With Its Thinnest Sole Yet

    Bottega Veneta Just Released a New Sneaker With Its Thinnest Sole Yet

    Italian fashion house Bottega Veneta is no stranger to the slim-soled sneaker trend. The label was an early adopter, launching its techy, net mesh-adorned Orbit model in 2023. The part Y2K running shoe, part 1970s track sneaker has been the brand’s go-to silhouette over the last two years, withstanding the often brief trend cycles seen in designer footwear. Now, with the look arguably as hot as ever, Bottega Veneta is doubling down on its commitment to the thin-sole look with a new addition known as the Orbit Flash.

    Described on the brand’s e-commerce store as a low-top lace-up sneaker in soft suede and lightweight nylon, the Bottega Veneta Orbit Flash is far from revolutionary, but it’s a tasteful take on a trend that doesn’t appear to be dying off any time soon.

    With a nylon base, the Italian-made Orbit Flash’s upper details include criss-crossing suede overlays which wrap around the toe, heel and side panels of the shoe. Leather trim details are featured on the tongue and eyelets, while a thinner-than-ever rubber outsole completes the look. Like its Orbit predecessor, the Orbit Flash’s sole wraps up the back of the heel several inches. 

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (on-foot).

    Bottega Veneta

    With roots in the post-pandemic rise of the Adidas Samba, the slim-sole movement is an even more exaggerated push toward barely there bottoms. Nearly every brand, from high-end to athletic, has produced their own version of the trending look. Beyond Bottega Veneta, designers including Loewe and Dries Van Noten have issued similar popular sneakers. 

    Despite the popularity, not everyone is a proponent of the trend. Speaking with Footwear News in May, Zach Thomas — better known to YouTube subscribers as Foot Doctor Zach — said the footwear has its drawbacks. “If you want to wear a Samba, if you want to wear a Speedcat or god knows what else, go for it,” Thomas said. “It’s not going to kill you, but throw an orthotic in there, and it’s going to help you so much more.” 

    For its introductory release, the Bottega Veneta Orbit Flash is available in black, abyss/ice/egg yolk and sea salt/black styles. Each pair is priced at $990 and comes in both men’s and women’s sizes.

    The Orbit Flash can be purchased now from bottegaveneta.com, Bergdorf Goodman, Mr Porter, Neiman Marcus and other select retailers. A full look at each color is included below.

    Bottega Veneta Orbit Flash sneakers in black (lateral).

    Bottega Veneta Orbit Flash sneakers in black (lateral).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in black (front).

    Bottega Veneta Orbit Flash sneakers in black (front).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in black (heel).

    Bottega Veneta Orbit Flash sneakers in black (heel).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in black (top).

    Bottega Veneta Orbit Flash sneakers in black (top).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in black (on-foot).

    Bottega Veneta Orbit Flash sneakers in black (on-foot).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (lateral).

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (lateral).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (front).

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (front).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (heel).

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (heel).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (top).

    Bottega Veneta Orbit Flash sneakers in abyss/ice/egg yolk (top).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in sea salt/black (lateral).

    Bottega Veneta Orbit Flash sneakers in sea salt/black (lateral).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in sea salt/black (front).

    Bottega Veneta Orbit Flash sneakers in sea salt/black (front).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in sea salt/black (heel).

    Bottega Veneta Orbit Flash sneakers in sea salt/black (heel).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in sea salt/black (top).

    Bottega Veneta Orbit Flash sneakers in sea salt/black (top).

    Bottega Veneta

    Bottega Veneta Orbit Flash sneakers in sea salt/black (on-foot).

    Bottega Veneta Orbit Flash sneakers in sea salt/black (on-foot).

    Bottega Veneta

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  • Dell’s new Pro Max lineup offers top-tier laptops for sky-high prices

    Dell’s new Pro Max lineup offers top-tier laptops for sky-high prices

    Dell

    Dell launched its new Pro Max laptops Thursday, unveiling three tiers of its top-performing laptops with a combination of high-end hardware: AMD Ryzen AI and Intel Core Ultra processors, and the new Nvidia RTX Pro Blackwell GPUs. 

    Nvidia announced the Blackwell-generation GPUs on its RTX Pro platform earlier this year — first for desktop workstations and servers, then for laptops. The Nvidia RTX PRO Blackwell GPUs use fifth-generation Tensor cores for up to an impressive 4,000 TOPS performance — designed for the pro-user engaged in the most demanding workloads. 

    Also: Nvidia’s latest coup: All of Taiwan on its software

    Dell’s Pro Max laptops are among the first consumer laptops with this new hardware, focused on the enterprise power-user demographic, and designed to bring raw power to accelerated AI and graphics capabilities onto sleek devices. 

    The three tiers of laptops in Dell’s Pro Max lineup include the base Dell Pro Max, the Dell Pro Max Plus (in 16- and 18-inch versions), and the high-end Dell Pro Max Premium. Dell outfitted the base models with either the AMD Ryzen AI 5, 7, or 9 series processors or Intel Core 5 or 7, and the second and third tier models with Intel Core Ultra 7 or 9 chips. 

    The highest-tier laptop, the Dell Pro Max Premium (say that five times fast) comes in a 14- and 16-inch model, and is absolutely stacked with hardware: up to an Intel Core Ultra 9 285H vPro Enterprise CPU, 64GB of memory, and Nvidia’s RTX Pro 2000 GPU. 

    Additionally, both the 14- and 16-inch models can be outfitted with OLED displays, with the 16-inch offering some particularly impressive UHD+, 500nit, 120Hz tandem OLED touch screen with 100% of the DCI-P3 color gamut. 

    Also: This Dell laptop is my top choice for both work and travel – and it’s on sale

    Physically, the base Pro Max and Pro Max Plus look rather nondescript, with sleek, black clamshells, full-sized keyboards, and the usual selection of I/O. The high-end Pro Max Premium, however, retains more physical DNA from the XPS series, with the signature zero-lattice keyboard and upward-firing speakers on either side of the keyboard. 

    All that hardware isn’t exactly feather-light, however, as the Pro Max Premium weighs in at 4.82 pounds and measures almost an inch thick. Similarly, the Dell Pro Max 18 Plus weighs a hefty 7.17 pounds, and features a minimalist, center-aligned trackpad and recessed keyboard that looks a lot like a MacBook M3 Pro Max. 

    These new laptops position Dell favorably in the never-ending AI race, securing market share of a use case the company is already well-established in: enterprise-ready, reliable machines with powerful hardware. 

    Also: I found a 16-inch Windows laptop that could replace my MacBook Pro

    As expected, all of these laptops come with substantial price tags. The lowest-tier model, the 14-inch Dell Pro Max with the AMD Ryzen 5 Pro 340 starts at $2,472, and it goes up from there. 

    There are a great deal of configuration options available for all of these laptops, including support for Linux Ubuntu out of the box. Kitting out the Dell Pro Max, however, brings the price sky-high, upwards of $6,000 for 64GB, an Intel Core Ultra 9 285H, 4TB of storage, and the UHD+ tandem OLED display. 

    Needless to say, this is an exclusive product reserved for the upper tiers of pro creators, engineers, programmers, and designers who leverage on-device AI for complex, demanding tasks and want to go all-in on performance. 

    Get the morning’s top stories in your inbox each day with our Tech Today newsletter.


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  • How China created a chokehold on the rare earths industry : NPR

    How China created a chokehold on the rare earths industry : NPR

    Deep in an underground, World War Two-era vault, investment manager Louis O’Connor guards his firm’s most valuable assets.

    The treasure inside? Rare earth elements.

    “Make no mistake about it, there’s three and a half meter walls and doors and armed security,” says O’Connor, the CEO of Strategic Metals Invest, a firm that lets individual investors buy into stockpiles of rare earths.

    Many so-called rare earth elements are actually quite common, and they are mined globally, but China has a near-monopoly on refining them for use in everyday electronics, like speakers, as well as for crucial defense systems, like fighter jets.

    When China decided to substantially cut off exports of seven types of rare earths this spring, O’Connor says he felt the pinch immediately. One investor touring the company’s vault at the time offered on the spot to buy O’Connor’s entire inventory of terbium and dysprosium, two valuable “heavy” rare earth elements, he says.

    The episode illustrated the power of China’s dominance over the industry.

    “They’re installing what you might call a tap system, where they can turn that tap on and off,” says O’Connor.

    That supply chain chokehold has given China a powerful tool it has wielded in a trade war with the U.S. Within weeks of China requiring foreign companies to apply for a license to buy rare earths, several American and European companies said they were forced to shut down production lines. Regaining access to Chinese rare earths was a central point of contention in US-China trade negotiations this spring.

    But China did not always enjoy such dominance. Developing an export control regime they could minutely control took decades of sometimes painful trial and error.

    Spotting strategic value

    During most of the 20th century, the U.S. was top dog in the rare earths industry, which was then-concentrated around the Mountain Pass mine in California.

    China also recognized the strategic value of rare earths, and starting in the 1960s, Chinese executives came to visit Mountain Pass several times, says Mark Smith, a former CEO at Molycorp, a major rare earths processing company at the Mountain Pass mine.

    “We toured them. We explained what we do, allowed them to take pictures and everything else. They took it back to China,” says Smith.

    Chinese refineries then improved on technology, and taking advantage of cheap electricity in China, hundreds of lucrative mining and processing firms in the country popped up to service mostly domestic demand for rare earths.

    But the industry was highly unregulated and chaotic, as hundreds of small-scale, private mines and refineries competed against one another, undercutting each other’s profits.

    “They drive down the price against themselves,” says Chris Ruffle, an investor who has worked in China for decades, including in the metals industry. “They kill themselves.”

    “China’s rare earths aren’t being sold at a ‘rare’ price but at an ‘earth’ price,” complained Xiao Yaqing, a minister of industry and information technology.

    A dirty business

    As Chinese producers sought an upper hand in rare earths, they also unleashed unrestrained mining that came at great cost to the country’s natural resources.

    In the early 2000s, Ruffles visited a private rare earths refinery in Jiangsu, a province in southern China. “The thick smoke slightly gave it away,” says Ruffles of the facilities. He described huge piles of tailings — toxic, metallic by-products from other industrial processes, sitting on the bare ground.

    Destructive, small-scale mining was especially prevalent in southern China, where the most valuable, natural deposits of “heavy” rare earth elements are.

    “They would mine the side of the hill with their acts and picks and shovels, and then they would dig a hole in the ground, no liners or anything like that at all. Then they poured five gallon buckets of sulfuric acid or hydrochloric acid….let that certain stew for a while,” remember Smith, who frequently visited China during this period. “When the storms come in, all that acid just washes out.”

    The mining left China’s terrain scarred with lasting groundwater and soil pollution. Local residents staged period protests against rare earth mining, but rare earth mining provided local governments with abundant revenue, and they repeatedly ignored central government orders to close down dirty mines.

    “The rare earth industry has the profits of [selling] heroin but without the risks… Rare earth is more addictive than drugs,” wrote two Chinese state media reporters in a 2012 investigation into rare earths mining.

    “There are generally two types of people who can deal with rare earths: the first is someone who has just been released from prison, and the other is someone who can get someone out of prison. Those who are not afraid of death and leading cadres are all involved,” in the journalists wrote.

    Consolidation or bust

    By the late 1990s, Beijing had had enough of the domestic price wars and local pollution. It started imposing production and export quotas to incentivize upstream processing of rare earths, cut down on pollution, and protect the industry from foreign intervention.

    The quotas created two sets of prices, “in effect, two tier pricing, when exports were limited to the rest of the world that resulted in lower rare earth prices for domestic Chinese consumers,” says Rod Eggert, a professor of mineral economics at the Colorado School of Mines.

    There was also a second, unintended consequence to the quotas: they creating a thriving smuggling industry. Up to a third of the country’s rare earth products in the mid-2000s was illegal, smuggled out of China despite state controls, analysts estimate, because of demand from Japan and the U.S.

    Then, American and European companies cried foul over the export quotas, and in 2014, the World Trade Organization ruled China could not use them.

    But China was unfazed. It was already shifting tactics. It would seek global dominance in rare earths not through controlling the volume of outputs, but instead, by controlling which firms could operate.

    A “secret war” to consolidate

    Authorities dubbed the campaign “one plus five:” an ambitious, and often ruthless, effort to winnow down the entire rare earth industry to just six consolidated companies. Authorities called the consolidation their “secret war” against illegal production.

    Starting in 2011, provincial authorities were instructed to mount unannounced audits of mines, to seize contraband ore and byproducts, and when needed, dynamiting and smashing to pieces illegal mining operations.

    “I saw firsthand how the private sector got squeezed out,” says Ruffle, the investor.

    Within four years, China declared victory. It announced the closure of dozens of smaller mining and refining companies and guided the mergers of surviving companies into six supersized, mostly- state-owned firms, nicknamed the Big Six in China.

    Through the Big Six, China could now largely control both supply and price.

    “Whereas before you had a lot more competition from different producers, now you get very homogeneous pricing,” says Jan Giese, a Frankfurt-based rare earth trader. “It’s difficult to have competitive bids.”

    American upstarts

    Unlike metal commodities like nickel or gold, there is no independent exchange for buying and selling rare earth elements.

    Because Chinese companies can cause huge price fluctuations depending on how much they decide to produce or export, investors have been wary of pouring money into new ventures in the U.S..

    That has made raising capital to build refining plants a big challenge for American companies trying to break back into the industry.

    “They’re putting their money into things like Alphabet and, you know, Amazon and, you know, all the high-flying type of investments and just very, very little, if any, is coming into the mining industry,” says Smith, the former CEO of Molycorp.

    Some are still trying. Smith’s new venture, NioCorp, is opening new mines and refining capacity for rare earths in Nebraska.

    Phoenix Tailings, in Massachusetts, is also among a handful of American companies prepared to refine rare earths, by refining the tailings, or leftover waste, from mining companies.

    “We have to be full speed on the gas to make sure we’re successful here,” says Nicholas Myers, one of the co-founders and CEO.

    The company already makes rare earth magnets for automotive and defense companies, and they are currently building a second plant in New Hampshire which the company says can meet about half of the U.S.’ defense needs for rare earth products.

    For years, Myers said his company struggled to attract investment at the magnitude needed to compete with Chinese firms in scale.

    This year, things changed, after China implemented a licensing system for foreign companies which caused rare earth exports to plummet.

    “Definite tone shift,” says Myers, “I think what happened is the end customers, the folks at the big automotive companies or defense primes, realized that they had told their bosses that China would never shut off the supply for them.”

    But this spring, China did shut off that supply.

    The cut off galvanized American investor interest in rare earths, says Myers. Phoenix Tailings garnered a major round of investment in May, and now, for the first time in decades, the U.S. may make rare earth minerals again.

    Aowen Cao contributed research from Beijing.

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  • A Novel CAR T-Cell Therapy Could Pave the Way for Improvements in Advanced ccRCC Management

    A Novel CAR T-Cell Therapy Could Pave the Way for Improvements in Advanced ccRCC Management

    Clear cell RCC | Image by

    Ashling Wahner & MJH Life Sciences Using AI

    Ongoing research with CAR T-cell therapy in clear cell renal cell carcinoma (ccRCC), which builds on successes achieved with this treatment modality in patients with hematologic malignancies, has supported the development of a dual-targeting CAR T-cell therapy for the treatment of patients with advanced ccRCC who have overexpression of CAIX and CD70, according to Wayne A. Marasco, MD, PhD.1

    During a presentation at the 2025 Kidney Cancer Research Summit, Marasco highlighted the goal of evaluating a dual-targeted, fine-tuned, and immune-restoring CAR T-cell therapy for the treatment of patients with CAIX- and CD70-overexpressing ccRCC. He noted that this therapeutic strategy, pending clinical investigation, may be a path toward curing this disease subtype.

    Marasco is a professor of Medicine at Brigham and Women’s Hospital and a principal investigator of Cancer Immunology and Virology at Dana-Farber Cancer Institute, both in Boston, Massachusetts.

    Early CAR T-Cell Therapy Research in RCC

    Following the established role of CAR T-cell therapy for the management of hematologic malignancies, recent work has investigated the CAR T-cell therapy approach in solid tumors, Marasco explained. For example, the phase 1 COBALT-RCC trial (NCT04438083) evaluated CTX130, a novel CD70-targeting CAR T-cell therapy, for the treatment of patients with advanced or refractory ccRCC.2 Of note, dose-limiting toxicities were not observed, and the disease control rate was 81.3%, with 1 patient remaining in durable complete response at 3 years.The study included 16 patients at least 18 years of age who weighed at least 42 kg with unresectable or metastatic RCC that had relapsed on or was refractory to standard of care.2,3 Patients on the trial were also required to have a Karnofsky performance status of at least 80% and adequate renal, liver, cardiac, and pulmonary organ function.3

    Furthermore, the phase 1 TRAVERSE trial (NCT04696731) evaluated the CAR T-cell therapy ALLO-316 for the treatment of patients with advanced or metastatic ccRCC following lymphodepletion comprising fludarabine and cyclophosphamide with or without ALLO-647.4 Early data from the study demonstrated that among 44 patients, the overall response rate was 20% in patients treated with the lymphodepletion regimen (n = 6/30) who had CD70-positive tumors. Treatment-emergent adverse effects (TEAEs) occurred in 96% of patients, with grade 3 or higher TEAEs observed in 84% of patients. Patients included on the study were at least 18 years of age with advanced ccRCC, an ECOG performance status of 0 or 1, and disease progression following immune checkpoint inhibition and VEGF-targeted therapy.

    “What’s different about what we’re trying to do here is our target,” Marasco said in reference to the study of CAIX/CD70-directed CAR T-cell therapy in RCC.1 “Our CAR T cells are dual-targeted, and the affinity is fine-tuned to improve safety. We do immune-restoring capabilities at the tumor site to change the tumor microenvironment [TME].”

    Specifically, the dual-targeting aspect of the CAIX/CD70-directed CAR T-cell product aims to improve efficacy, whereas the fine-tuned aspect aims to improve safety by targeting only high-density antigen expressed on the tumor cells without targeting low density antigen on healthy tissues. Moreover, the immune-restoring aspect changes the TME by locally secreting checkpoint blockade inhibitors to restore antitumor immunity.

    Preclinical Efficacy and Safety of CAR T-Cell Therapy in ccRCC

    Early efficacy data from a preclinical study demonstrated that CD70 is not universally expressed on RCC cells, and therefore, some targets were CD70-negative, Marasco explained.

    “[However,] all tumors express CAIX, which is still the molecule that is most desirable. The killing data in the immunofluorescence [analysis] show the specificity of the dual-targeted CAR [T-cell therapy] for both targets. In humanized animal studies, the [respective] CAR T-cell therapy effectively cured the animals from the tumors, and in these animals, we don’t even see the tumors after the therapy,” he said.

    Although preliminary efficacy data have shown promise, safety data have been the most significant concern, notably due to CAIX overexpression, Marasco added.

    “We spent over a decade working this out to be able to develop high-avidity, low-affinity antibodies as the targeting moiety. Why would you want that? Well, we certainly don’t want to target CAIX if it’s in limited quantities, because a high-affinity targeting residue will bind to it,” he said. “Therefore, you want only targeting molecules that are recognized with high density, and that’s what we engineered.”

    Most notably, the immune-restoring aspect of this therapy is “the most important part of this change in the TME,” according to Marasco.

    “If we [administer] CAR T-cell therapy without delivering a payload to the tumor site, we do not ever cure the animals of tumors,” Marasco emphasized. “If we deliver monoclonal antibodies at the tumor sites, which is what we’re doing, we secrete antibodies [and] checkpoint blockade inhibitors locally at the tumor site, [and] we can get complete cures.”

    Future Steps for Examining CAR T-Cell Therapy in RCC

    The investigational dual-targeted CAR T-cell therapy in development by Marasco and colleagues targets CAIX and CD70 and delivers an anti–PD-1 and -CTLA4 bispecific antibody at the tumor site, Marasco reported. Currently, ongoing preclinical studies with this product are nearing finishing stages, which will guide the next step of GMP manufacturing and subsequently submitting an investigational new drug (IND) application to the FDA, he explained.

    “We’re on schedule to be able to complete this [preclinical research] and file an IND sometime, hopefully in September or October [2025],” Marasco concluded.

    References

    1. Marasco WA. Redesigning CAR T cells for solid tumors: a new path toward cures of ccRCC. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.
    2. Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024;14(7):1176-1189. doi:10.1158/2159-8290.CD-24-0102
    3. A safety and efficacy study evaluating CTX130 in subjects with relapsed or refractory renal cell carcinoma (COBALT-RCC). ClinicalTrials.gov. Updated January 8, 2025. Accessed July 17, 2025. https://www.clinicaltrials.gov/study/NCT04438083
    4. Srour SA, Chahoud J, Drakaki A, et al. ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): updated results from the phase 1 TRAVERSE study. J Clin Oncol. 2025;42 (suppl 16):4508. doi:10.1200/JCO.2025.43.16_suppl.4508

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  • Clinicians Take Heed—High BP Merits Quick Action, Data Suggest

    Clinicians Take Heed—High BP Merits Quick Action, Data Suggest

    Patients whose hypertension diagnosis is delayed are less likely to get the drugs they need and face higher CV risks over the years.

    Approximately one in seven patients with hypertension don’t receive a prompt diagnosis, and with such delays, these individuals are less likely to initiate treatment for their high blood pressure and are more vulnerable to experiencing an adverse CV outcome over the next 5 years, new research suggests.

    It’s not that clinicians are intentionally disregarding hypertension, John E. Brush Jr, MD (Sentara Health, Virginia Beach, VA), one of the lead researchers, told TCTMD. Possible drivers of their results instead include the fragmented nature of healthcare in the United States, as well as information overload.

    “In practice, you might get a blood pressure that’s measured in the primary care office and you might get another one that’s measured a month or two later in someone else’s office,” noted Brush. “It’s not that easy for a practitioner who’s busy and trying to just get through the day to make the connection.” This is where electronic health records (EHR), the source of data for the current analysis, might be of assistance, by helping “physicians put two and two together,” he added.

    Delayed diagnoses have fairly immediate effects, Brush pointed out. “It’s not like it’s 30 years later you have a problem,” he said. “No, it’s in a relatively short period of time.”

    Patients in the study whose diagnoses came more than a year late had a 30% higher chance of experiencing a CV event within 5 years. “Treating somebody’s high blood pressure is important—everyone knows that—but it’s also important to get started on treating it right away. Don’t delay,” Brush stressed.

    The Longer the Delay, the Worse the Impact

    For the study published this week in JAMA Network Open, which included first author Yuan Lu, ScD (Yale New Haven Hospital, CT), the group analyzed data from EHR for 311,743 adults with at least two outpatient BP readings ≥ 140/90 mm Hg that were recorded at least 30 days apart between 2010 and 2021. All were treated through a large nonprofit integrated healthcare system with 12 hospitals, 566 outpatient sites, and over 1,300 clinicians in Virginia and North Carolina.

    Within this cohort, 14.6% of patients were diagnosed with hypertension after their second BP elevation. Their mean age was 57.9 years, 53.3% were women, and 69.6% were non-Hispanic white (24.9% were non-Hispanic Black, 2.4% Hispanic or Latino, and 1.7% non-Hispanic Asian).

    Get started on treating it right away. Don’t delay. John E. Brush Jr

    Lu et al took several steps to overcome bias in their observational analysis—in clinical encounters with multiple readings, for example, they only counted the last measurement as a precaution against “white coat hypertension.” They also adjusted for factors such as age, sex, race/ethnicity, comorbidities, and baseline BP.

    Patients who received a hypertension diagnosis only after two measurements, compared with after the first test, were less likely to be prescribed antihypertensive drugs within 30 days of the diagnosis (30.6% vs 75.2%; P < 0.001). Treatment rates became progressively lower with lengthier delays.

    With a delayed diagnosis, patients also faced a greater risk of cardiovascular events (hospitalization for acute MI, hospitalization for heart failure, and clinically diagnosed ischemic stroke during an inpatient or emergency department visit). The impact was larger when delays were longer, and the associations were most pronounced for heart failure hospitalization.

    Patients Diagnosed With Hypertension After Two BP Elevations

    Length of Delay

    Prescribed Antihypertensives

    5-Year CV Event Risk

    (HR; 95% CI)

    0-90 Days

    54.5%

    1.04 (0.95-1.13)

    91-365 Days

    32.4%

    1.11 (1.04-1.19)

    > 365 Days

    26.4%

    1.29 (1.23-1.36)

    Longer delays were more common in younger compared with older patients, women compared with men, and Asian or Black patients compared with white. These demographic differences in diagnosis point to the possibility of “implicit bias, differences in symptom presentation, or variability in clinician-patient interactions,” according to researchers.

    The findings suggest that “missed clinical opportunities” are at the root of the delays, not “patient disengagement from care,” they say. For example, those with a delayed diagnosis had a similar number of outpatient and primary care visits before the second elevated BP reading as those who were diagnosed earlier. These patients also continued to interact with the healthcare system after the second reading, with a longer diagnostic delay linked to more outpatient and doctor’s visits. 

    Patients, and sometimes clinicians, want to first try lifestyle changes to address hypertension, though “that hardly ever works,” said Brush. Patients also may be concerned that acknowledging the disease could impact other areas of life, such as their ability to buy life insurance.

    While it may be valid to take some time to be sure BP measurements are consistent and accurate enough to reach a diagnosis, the study shows that waiting too long to act can have consequences for patients, he emphasized.

    The investigators propose several ways to hasten diagnosis, such as EHR-decision support tools as well as expanded roles for nonphysicians.

    “Pharmacists, as integral members of team-based care models, can contribute significantly to BP screening, medication initiation and titration, follow-up monitoring, and patient education, especially in outpatient and community settings,” they suggest. “Similarly, nurses can contribute to BP rechecks, patient education, and referral for confirmatory testing.”

    Embedding these efforts into primary care practices could help encourage a team approach and distribute the workload, they note.


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  • Investigational Neoantigen Vaccines Target RCC Mutations and Drive Durable T-Cell Activity

    Investigational Neoantigen Vaccines Target RCC Mutations and Drive Durable T-Cell Activity

    ccRCC | Image by Ashling Wahner &

    MJH Life Sciences Using AI

    Early data with personalized neoantigen vaccines demonstrate their promising immune activation and durable antitumor activity in select patients with kidney cancer, laying the groundwork for further investigation of this treatment approach in the adjuvant setting, according to David A. Braun, MD, PhD.1

    During a presentation at the 2025 Kidney Cancer Research Summit, Braun described the rationale and design of a phase 1 trial (NCT02950766) investigating the efficacy of personalized neoantigen vaccines in patients with high-risk, resectable clear cell renal cell carcinoma (ccRCC); key antitumor strengths of this vaccine; and why the minimal residual disease (MRD) setting may be most optimal for developing therapeutic vaccines for patients with kidney cancer and other diseases with relatively low mutational burdens.

    Braun is an assistant professor of medicine (medical oncology) and the Louis Goodman and Alfred Gilman Yale Scholar at the Yale School of Medicine, and a member of the Center of Molecular and Cellular Oncology at Yale Cancer Center in New Haven, Connecticut.

    Spotlighting the Promise of Neoantigen Vaccines in RCC

    Braun framed his presentation with a glance at the mechanisms of antitumor immunity in kidney cancer. He used the analogy of a car, explaining that the goal of cancer therapy is to drive CD8-positive T cells toward the tumor as quickly and accurately as possible. He noted that historically, this goal has been achieved through immune activation strategies, such as immune checkpoint inhibitors, which he likened to releasing the brakes of the car, as well as novel cytokine and immune agonists, which are comparable to pressing the gas pedals. However, he emphasized that propelling the next generation of kidney cancer therapies will rely on immune navigation approaches, such as antigen-directed therapies, which steer the immune system in the optimal direction.

    “Personalized cancer vaccines are an ideal example of how to do that,” Braun stated.

    Braun and colleagues saw the potential for neoantigens as effective targets for antitumor immunity and T-cell response based on the previously reported performance of neoantigen-directed treatment approaches across tumor types, including melanoma, pancreatic cancer, and glioblastoma. However, Braun explained that neoantigen-targeting treatment presents a heightened challenge in kidney cancer, which, although immunogenic, has a modest mutation burden and therefore a lower number of targetable neoantigens. Nevertheless, acknowledging the dearth of effective RCC therapies in the adjuvant setting, Braun and colleagues aimed to design a personalized vaccine that could target the neoantigens present in kidney cancer.

    Defining the Ideal Patient Population

    This small study enrolled 9 patients with high-risk, resectable (stage III or IV) ccRCC who had undergone complete tumor resection.1,2 The investigators created personalized vaccines for these patients through tumor sequencing and neoantigen prediction. These vaccines were composed of synthetic long peptides that contained up to 20 personal neoantigens present in each tumor. These peptides were divided into 4 pools to decrease competition with local lymph nodes in the event of certain epitopes presenting as immunodominant, Braun stated in a question-and-answer session following his presentation.1

    Regarding the later-stage patient population, when asked how neoantigen-directed vaccines might perform in earlier-stage tumors, Braun explained, “The immune composition is different in those early-stage tumors, so I don’t think we’ll know until we try. At the same time, some of those earlier-stage tumors tend to have excellent outcomes, so it’s not that [these vaccines] would be for every early-stage tumor, but if we can identify ones that are higher risk, those will be the ones to think about how to target.”

    In another answer, he noted that the most convincing levels of success with cancer vaccines have been shown in settings of MRD, such as the adjuvant setting in kidney cancer. Therefore, he expressed that although the vaccines currently in development may not be advanced enough to elicit meaningful responses in the metastatic setting—at least when used alone—he and co-investigators hypothesized that this type of therapy would be most effective in patients with minimal, manageable disease that is nevertheless at high risk of recurrence.

    Outlining the Trial Design and Feasibility Analysis

    The vaccines were administered with or without ipilimumab (Yervoy) in 2 phases: a priming phase to activate and prime the T cells, followed by a boost phase to facilitate long-lasting T-cell memory.1,2

    Regarding the feasibility of manufacturing a neoantigen-directed vaccine for a disease with a low mutational burden, the investigators found that despite the low prevalence of coding mutations in the patient population, they could create a multi-epitope vaccine directed at single nucleotide variants and frameshift insertion deletions that corresponded with kidney cancer driver mutations.

    Highlighting the Durable Efficacy of Personalized RCC Vaccines

    From there, Braun explained that the second goal of the study was to determine the immunological efficacy of these vaccines.1

    “The basic question was: Are the T cells reacting to these neoantigens and capable of recognition?” He asked.

    Prior to vaccination, most patients had barely detectable or undetectable levels of neoantigen immunity.1,2 However, after vaccination, neoantigen-specific responses were observed in the peripheral T cells of all treated patients. For instance, at baseline, one patient had no detectable immunity for 3 of the 4 vaccine peptide pools. However, during the vaccination period, this patient exhibited strong peripheral T-cell responses.

    When analyzing which neoantigens were associated with responses, Braun reported that, surprisingly, these results were not random. Instead, the investigators saw the most effective immune responses against known kidney cancer driver mutations, such as those in PIK3CA, PBRM1, KDM5C, BAP1, and VHL.

    To determine the durability of these responses, the investigators tracked levels of vaccine-specific T-cell clones in the peripheral blood. At baseline, these levels were undetectable or near the lower limit of detection. However, upon vaccination, these levels rose rapidly, persisting through the boost phase. Additionally, Braun spotlighted that in some patients, vaccine-reactive T-cell clones were still observed months to years after vaccination, indicating the durable T-cell immunity elicited by this treatment.

    Furthermore, the investigators conducted an in vitro assessment of the antitumor activity of these vaccines by placing vaccine-expanded T cells back on top of the corresponding patients’ tumors. In total, 7 of the 9 patients had generated detectable levels of vaccine-specific T cells that reacted against the autologous whole-tumor cells.

    Overall, at a median follow-up of 40.2 months from the time of surgery, none of the enrolled patients had a recurrence of RCC.2 Moreover, no dose-limiting toxicities were reported.

    “We’re encouraged by the fact that all 9 patients, despite having high-risk disease, remained free of kidney cancer throughout the study,” he emphasized, noting that 1 patient died of unrelated causes during the study.1,2

    Acknowledging How the Study’s Limitations Give Way to Further Research

    Braun noted that the small sample size is a key limitation of this research that warrants follow-up studies to determine the clinical relevance of these findings.1

    “These neoantigen vaccines are feasible for kidney cancer,” Braun concluded. “They can elicit effective T-cell responses and antitumor activity. At least this preliminary signal of clinical activity sets up [the phase 2] INterpath-004 [trial (NCT06307431)], the next study that will hopefully demonstrate some clinical activity.”

    Notably, the phase 2 INterpath-004 trial (NCT06307431) is investigating adjuvant treatment with the mRNA-based personalized cancer vaccine intismeran autogene (V940) plus pembrolizumab (Keytruda) vs placebo plus pembrolizumab in patients with RCC.3

    References

    1. Braun DA. Personalized vaccines in kidney cancer: a journey from concept to clinic. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025. Boston, Massachusetts.
    2. Braun DA, Moranzoni G, Chea V, et al. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature. 2025;639(8054):474-482. doi:10.1038/s41586-024-08507-5
    3. A study of adjuvant intismeran autogene (V940) and pembrolizumab in renal cell carcinoma (V940-004). (INTerpath-004). ClinicalTrials.gov. Updated May 13, 2025. Accessed July 17, 2025. https://clinicaltrials.gov/study/NCT06307431

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