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How early cancer detection startup Earli survived its founder’s death

From his house in Portola Valley, California, Sanjiv Gambhir logged on to an essential assembly for his startup one afternoon in April 2020. He stored the video digital camera off.

This was uncommon, not least as a result of he cherished face-to-face connections and was obsessive about visibility. A pioneer of molecular imaging and the director of Stanford’s Canary Heart for Early Cancer Detection, Gambhir, generally known as Sam, had spent many years making an attempt to make small, hidden tumors contained in the physique simpler to see. Practically 600,000 individuals within the U.S. die from cancer yearly, principally as a result of we are inclined to catch tumors after they’re too late to successfully deal with.

“Cancer doesn’t must be a death sentence,” Gambhir would inform the researchers in his lab, as he reminded them of the particular sufferers they had been making an attempt to save lots of. By the point he was 50, his breakthroughs in early detection—together with growing the reporter genes utilized in positron emission tomography, or PET scans—had led to 3 startups, hundreds of thousands in seed funding, and 40 patents.

His newest startup, Earli, was the fruits of a decade’s-worth of analysis into whether or not you might drive tumors to indicate themselves, by having them ship out a sign that might be detected in blood checks or PET scans. If that labored, you might open up a brand new frontier in cancer detection. Gambhir had pioneered the expertise, however cofounder Cyriac Roeding, an lively e-commerce entrepreneur had satisfied him to show it into an organization. By the beginning of 2020, that they had already raised $19.5 million in enterprise funding to gasoline the commercialization of their expertise.

However in 2019, medical doctors had detected one thing inside Gambhir. A tumor of unknown origin was quietly spreading in his bones. The irony of cancer sneaking up on him was as brutal because the prognosis: After discovering such metastasis, the median survival time is three to 4 months. However Gambhir turned his cancer and his experimental therapies—each few weeks in Munich—right into a studying alternative for himself and his colleagues. Now, a 12 months after his analysis, he was bedridden and weak from the therapies. However he was decided to be on this name.

For 3 hours, Gambhir and the remainder of the five-person board—together with Jorge Conde, a biotech veteran and accomplice on the outstanding enterprise capital agency Andreessen Horowitz—mentioned manufacturing challenges, the seek for additional cash, and the outcomes of a latest examine the corporate had completed in mice. “He was sharp as a tack. I imply, for God’s sake, the man was nonetheless pulling aside the science,” says Earli cofounder and chief scientific officer David Suhy. “However you might hear in his voice, he was bodily weak.”

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Sanjiv Gambhir [Photo: courtesy of Earli]Gambhir was typically reminding his cofounders how bedeviling biology might be, how resistant it was to commercialization. “The world of biology will all the time discover a solution to screw you over,” he’d warned Roeding as they had been founding the corporate in 2018. After establishing Stanford’s Multimodality Molecular Imaging Lab in 2003, Gambhir had helped develop an armory of futuristic advances for recognizing tumors, together with a sensible bra to repeatedly monitor for breast cancer and a sensible rest room for detecting colon cancers. However a lot of the tech was nonetheless experimental.

As Gambhir pursued this analysis, his spouse, Aruna, battled again breast cancer—twice. Then, in 2013, biology reared its head in one other, horrible manner: Their 15-year-old son, Milan, was recognized with a uncommon type of probably the most aggressive sort of mind cancer, the very kind of tumor Gambhir’s lab had been finding out. Gambhir’s have to translate his work from lab to observe had by no means been extra pressing. However Milan’s cancer proved faster than the tempo of drugs. He died in 2015, on the age of 16.

5 years later, as a tumor unfold in his personal physique, Gambhir felt a unique sort of urgency. “The issue is, he knew an excessive amount of, even with Milan,” says Aruna. Now Gambhir’s concepts and multi-disciplinary insights into molecular imaging—his one-of-a-kind data of the sphere—would wish to go to the scientists and medical doctors who may take advantage of it, even in his absence.

When President Nixon launched the conflict on cancer 50 years in the past, Sidney Farber, the president of the American Cancer Society, declared that with sufficient assets, scientists may conquer cancer in seven years. As a substitute it has been a protracted conflict with a roving goal. Regardless of tons of of billions of {dollars} spent on analysis, cancer is now vying with coronary heart illness to be the primary reason for death within the U.S. “Since 1970, there’s perhaps 50% enchancment in cancer survivors,” says Leland Hartwell, an advisor to Earli whose work on cell development earned him a Nobel Prize in Biology. “Given all the trouble, it’s not nice.”

The hope now isn’t a remedy, however discovering the proper mixture of diagnostics and coverings to handle it. And after years of comparatively miniscule authorities funding, detection is getting extra consideration. The race to catch cancer earlier has given rise to a $168 billion industry touting a brand new class of checks that promise to detect tiny indicators of cancers in your blood or stool. Most are pursuing an strategy generally known as “liquid biopsy,” utilizing a blood take a look at to search for irregular items of DNA shed by cancer cells.

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Discovering bits of cancer cell sheddings, nonetheless, is notoriously exhausting. Earli’s strategy compels tiny tumors to supply new alerts, sending out flares—naturally-occurring proteins—that may be extra simply detected in a blood take a look at or illuminated for an imaging scan. A dependable diagnostic that might be administered annually by a physician to search out and pinpoint very early, aggressive tumors in apparently wholesome individuals may have a profound influence on healthcare and its prices.

“As soon as you discover [a tumor] and you may localize it, you possibly can act on it, after which it turns into safety, not simply detection,” Roeding says. Sometime, Earli’s “artificial biopsy” platform may even be helpful for concentrating on cancer cells with personalised medication, immunotherapies, or mRNA vaccines. Already the corporate has proven a capability to detect sure cancers in mice and canine; in June, it started dosing its first human sufferers as a part of a medical trial. However it nonetheless has an extended solution to go.

Again on the board assembly, Roeding reviewed the outcomes of their first trial in mice. The artificial biomarker they had been utilizing to tag tumor cells had proven up in PET scans of cancerous mice—slightly glowing lighthouse in a sea of uncertainty. Suhy and Roeding had been ecstatic. Gambhir was circumspect. “He requested us 4 questions,” Roeding remembers. Did the take a look at really detect cancer? Did it have a low false adverse charge? Was it differentiating between malignant and benign? Might it decide the stage of cancer?

The trial was promising, however Gambhir wanted greater than guarantees. In June 2020, three months after the board assembly—and the day after receiving Stanford’s Dean’s Medal, its highest honor—he died at house on the age of 57.

For the sphere of early cancer detection, the loss was devastating. Tributes poured in from researchers world wide, and colleagues held a string of educational symposia devoted to his legacy. Final September, the Journal of Nuclear Medication bucked a 55-year custom for the duvet, buying and selling its typical medical imagery for a full-page portrait of Gambhir.

His firm, in the meantime, is forging forward and confronting one other massive query: Can they manifest a expertise with out the visionary who dreamt it up? “We’re engaged on a really low likelihood, however probably excessive influence factor,” says Roeding. “It’s a moonshot. There’s little question about it.”

Gentle-haired and boyish, Roeding was born in Germany, and but is the archetypical energetic Silicon Valley entrepreneur-investor. A veteran of enterprise consulting, smartphone-era startups, and enterprise capital, he can repeat a well-rehearsed pitch verbatim and by no means sound scripted—expertise that helped him construct up the in-store low cost app Shopkick and promote it for $250 million to the most important telecom firm in South Korea.

In 2016, a pair years after that deal, Roeding was within the Bay Space in search of his subsequent startup thought. An curiosity in brain-computer interfaces introduced him to Stanford’s campus, which in flip led him down the rabbit gap of precision medication. However the deeper he obtained, the extra confused he turned. Right here had been all these scientists saying they every had the answer to the world’s numerous greatest issues. “I’m not a biologist,” says Roeding. “I didn’t know who was unsuitable.”

By Thanksgiving, three months into his search, Roeding was feeling deflated. That morning, his spouse handed him a duplicate of Stanford’s alumni journal and prompt he learn the duvet story, a few outstanding radiologist’s battle to save lots of his son from metastatic mind cancer. The piece shook him, and early that afternoon he despatched an electronic mail to its topic, Gambhir. “I can solely think about how exhausting particularly holidays like right now’s are for you and your spouse,” Roeding wrote. “However maybe simply on a day like this, it’s price remembering that Milan, your journey to attempt to save him, and the highly effective concepts which have come from this journey, have impressed others like me.” Roeding launched himself, and stated he, too, was all in favour of well being monitoring. “Maybe there are methods we may work collectively.”

Two months later, they met on a sun-drenched Saturday at a small restaurant in Portola Valley, a city close to Palo Alto. They talked about innovation and science and the yawning chasm between academia and business medication. After years of navigating the bureaucracies of biomedical analysis, Gambhir was drawn to Roeding’s left-field considering. The lunch turned the primary of many Saturday conferences. Gambhir agreed to show Roeding biology (“largely in useless,” says Roeding) and launched him to much more scientists. However Roeding was extra keen to listen to what Gambhir was engaged on. When Gambhir instructed him about his lab’s work round utilizing biomarkers to catch tumors sooner than different diagnostics, Roeding was hooked.

They used $400,000 of their very own cash to get began, incorporating the corporate in June 2018. They negotiated a licensing take care of Stanford for Gambhir’s associated patents and tapped Suhy, who beforehand led gene therapies at Australian biopharma Benitec, to function chief scientific officer. Gambhir can be a scientific advisor and Roeding turned CEO.

Earli cofounders Cyriac Roeding, Sanjiv Gambhir, and David Suhy [Photo: courtesy of Earli]Roeding was an uncommon option to helm a breakthrough biotech firm. He remembers asking Gambhir: “Ought to somebody with my background hassle the world of biology with my presence?” The sector of biology has a surplus of consultants and no generalists, stated Gambhir, and few individuals who knew tips on how to run a startup. On high of that, he stated, biology is fickle: organic exploration will all the time take longer and be more durable than you assume. He argued that having the ability to transfer quick—and, sure, fail quick—may assist the corporate resist the inertia of experiments, trials, and laws.

Initially, Roeding’s aggressive targets raised eyebrows amongst buyers. “We stated, we wish to be in people inside three years, they usually sort of chuckled,” says Roeding. Most weren’t satisfied, however the pitch caught the eye of Andreessen Horowitz’s Conde, who’s a biotech trade veteran. Earlier than the 12 months was out, Gambhir and Roeding had secured simply shy of $19.5 million in seed funding from a gaggle led by Andreessen Horowitz that included Salesforce founder Marc Benioff, Menlo Ventures, and Chinese language enterprise agency ZhenFund.

Even with buy-in from the likes of Andreessen and Benioff, the founders knew their operation confronted an uphill battle. Diagnostics that require injecting sufferers face a phalanx of medical trials, a course of that takes years even with the large assets of large pharmaceutical corporations. Whereas Earli had proven some promise within the lab, there wasn’t a assure it might translate to animals. And scientists had by no means examined artificial biomarkers in people: There have been more likely to be uncommon regulatory hurdles to getting a medical trial permitted.

For the primary 12 months, Suhy and Roeding met with Gambhir each 4 to 6 weeks to speak in regards to the firm’s progress. They managed day-to-day operations, however Gambhir may discover the holes of their considering and minor successes—a useful perspective in setting the course till their subsequent assembly. Because the hours wore on, their conversations would inevitably give solution to heady discussions on the state of science.

In late spring of 2019, Roeding obtained a name from Gambhir. His voice sounded humorous. He instructed Roeding that he was sitting on the sofa along with his spouse. They’d simply came upon that he had cancer, and it wasn’t clear the place it had began. By definition, it was metastatic and nearly unimaginable to deal with. In the event that they didn’t know the place it originated, they couldn’t know what they had been preventing.

Roeding tried to remain optimistic. “It’s battle time,” he instructed his cofounder. Gambhir stated there have been attainable therapies, however he was additionally clear-eyed. They agreed that they wanted to arrange the corporate for a world with out Gambhir.

“Now we have to be sure that our science is superior sufficient in order that we are able to transfer ahead with out having to depend on his enter at a deep stage repeatedly,” Roeding remembers realizing. “For us, actually the principle query turned, does Earli have sufficient escape velocity in order that we are able to change into what [Gambhir] desires us to be?”

The largest victories within the conflict on cancer have been scored through anti-smoking campaigns and cigarette taxation. They’re largely liable for the 27% drop in deaths from cancer within the U.S. between 2009 and 2019, in accordance with the Heart for Illness Management and Prevention (in lung cancer, advances in focused therapies additionally performed a job). Nonetheless, little has progressed in screening, which scientists see as the very best alternative to search out cancer earlier than it will get uncontrolled.

Likelihood is, you’ve been by way of a number of cancer screenings: mammograms, pap smears, colonoscopies, when a physician takes a have a look at the bizarre mole in your again. Lengthy-time people who smoke over 50 years previous may get a CT scan. For sure cancer sorts, these screens, which principally depend on seeing bodily adjustments, can save lives.

However there are many types of cancers that may’t be screened for: ones which can be too small to see or that haven’t essentially triggered any bodily adjustments. Tumors mutate and evolve in distinctive methods, so every individual’s cancer is slightly totally different. A tumor that’s benign in a single physique might be lethal in one other. “What we’re confronted with is simply monumental variety,” says Earli advisor Hartwell.

Consequently, cancer therapy has change into extra personalised, with scientists tailoring dosage and kind of therapeutic to the genetic make-up of a cancer’s cells. However some scientists, together with Hartwell, assume that growing higher earlier detection strategies will provide a far much less invasive—and way more reasonably priced—path to decreasing cancer deaths. Up to now, nonetheless, early detection has proceeded in suits and begins. “The fee per advance shouldn’t be spectacular,” he says.

[Photo: courtesy of Earli]The newest and best instruments in cancer diagnostics are genetic testing and liquid biopsy checks. Genetic testing alerts medical doctors to potential genes which can be related to an elevated danger of cancer, like BRCA-1 and BRCA-2 for breast cancer. Liquid biopsies capitalize on advances in machine studying to investigate blood samples for the tiniest clues of cancer, by detecting and analyzing fleeting fragments of cells that tumors shed. These can embrace DNA, RNA, proteins, and different items of cancer cells that flow into within the physique and typically comprise clues about their location.

Menlo Park-based Grail—one among dozens of corporations that Gambhir suggested—now sells a liquid biopsy take a look at referred to as Galleri, which purports to search out 50 varieties of cancers in apparently wholesome individuals. The take a look at, at $950, shouldn’t be lined by insurance coverage, however that might change after full FDA approval, which Grail intends to hunt in 2023. One other California firm, Redwood-based Guardant Well being, is at present operating trials of its early-stage colorectal cancer take a look at, eyeing a marketplace for early detection that’s anticipated to succeed in $280 billion by 2027.

Not everyone seems to be so bullish on liquid biopsies, nonetheless. “I ought to be cautious what I say. I may make myself persona non grata,” says Judy Garber, Director of the Heart for Cancer Genetics and Prevention at Dana-Farber Cancer Institute and board member to Earli. A number of liquid biopsy corporations, she says, “wish to discover all cancer without delay, which I agree can be nice. However I believe that hasn’t been what the information helps, and but they appear to be on this enormous rush to promote their take a look at.”

Essentially the most compelling latest data confirmed that Grail’s take a look at may positively establish stage I to III cancer greater than 67% of the time in a set of twelve cancers together with head and neck, liver, and pancreatic circumstances. Total, the take a look at had a false optimistic charge of 0.5%, and was capable of establish the tumors’ organ websites 88.7% of the time. However its capability to detect different cancers was decrease: It recognized lower than 20% of thyroid, kidney, and prostate cancer circumstances, as an illustration.

[Photo: courtesy of Earli]One main problem with in search of pure biomarkers, like cell sheddings, is that younger tumors produce far fewer of those fragments. Even when these cancer bits do make it into the bloodstream, they spend much less time in circulation, making it exceedingly tough to drag them out in a pattern.

Earli’s diagnostic takes a extra proactive strategy to the seek for tumors. The platform consists of an injectible compound that carries a reporter gene, engineered to activate on the faintest hints of tumor cells, wherever they’re. As soon as it’s tapped into the mobile pathways driving the tumor’s uncontrolled development, the gene is designed to specific an artificial biomarker, successfully “boosting” the cancer’s sign. For its biomarker, Earli selected an enzyme that sometimes solely seems throughout embryonic improvement. (A Cambridge-based startup referred to as Glympse is growing artificial biomarkers to establish liver illness, although cancer detection can be on its roadmap.)

The strategy has a number of obvious benefits over present liquid biopsy applied sciences. As a result of it makes use of an artificial biomarker, Earli can extra simply management the amplitude of the sign. The place liquid biopsy corporations use the genetic code of cancer fragments to attempt to decide a tumor’s location within the physique, Earli pinpoints the tumor itself. This might additionally assist physicians higher monitor the success of ongoing therapies, and result in novel therapies: With an extra molecule designed to set off an immune response in cancer cells, Earli’s surveillance platform may finally be harnessed to kill elusive tumors too.

Hartwell remembers listening to Earli’s idea for the primary time, and being struck by it as “extremely good.” “You form of marvel why it took us so lengthy to consider it,” he says. “However that’s not what makes a profitable firm.” If Earli goes to be “an organization slightly than only a analysis venture,” he stresses, it must rapidly establish—and market—an software of its expertise. “That’s a race you can’t predict.”

When Gambhir died, the corporate was nonetheless in semi-stealth. Earli barely had an online presence, save for a recruiting web site, and had fascinating, however nascent progress in mice. It wanted additional cash, to rent extra scientists, double down on pre-clinical analysis, and begin constructing out a brand new lab.

Earlier than Gambhir’s final board assembly, the corporate started getting suggestions from his longtime colleagues and buddies, a Who’s Who of cancer pioneers: Hartwell and Garber, but additionally Nobel Prize-winning cancer researcher Jim Allison, Moderna founder Bob Langer, Charlie Rudin, who heads up thoracic oncology at Memorial Sloan Kettering, and Aruna, who now runs one other firm associated to her husband’s analysis referred to as CellSight, which is engaged on expertise that acknowledges if cancer therapy is working.

In fall 2019, Langer dashed off an electronic mail to investor Vinod Khosla, founding father of Khosla Ventures, introducing him to Earli and laying out the way it differed from liquid biopsy corporations. Khosla had for years handed on high-flying biotech investments, however says he was drawn to Earli’s “orthogonal strategy” to early detection, versus the “incremental” efforts of different ventures. Khosla likens Earli to Cambridge-based Commonwealth Fusion Programs, one among his greatest investments, which is aiming for the moonshot of nuclear fusion. “In our fund, we form of say, ‘giant influence, giant expertise breakthroughs that trigger a big influence’—in the event you do this, the cash will comply with.”

Dr. Michael Kent, pictured along with his canine Danson, helps Earli conduct trials at his canine lab at UC Davis [Photo by Don Preisler/UCDavis]In January 2020, Khosla Ventures led Earli’s $40 million sequence A, alongside Andreessen Horowitz. The board now contains Conde, Justin Kao, who led Khosla’s funding, and Marc Andreessen, who serves as a board observer.

“It’ll by no means be fairly nearly as good as if Sam was engaged on it himself,” Khosla admits, “however they’re at a proof level that’s considerably decrease danger right now than it was two years in the past.” He pointed to “a cadre of world-class scientists” that Earli has recruited as advisers. “If it may be completed, I believe this group can do it.”

With the funds, Earli went on a hiring spree: 29 researchers now work at its headquarters in South San Francisco. And Roeding and Suhy determined to pursue a proof of idea in canine. The corporate labored with the Comparative Cancer Heart on the College of California Davis Faculty of Veterinary Medication, which connects sick canine with medical trials. Collectively they studied the biomarker at 4 totally different doses in a complete of 23 canine to see if it might present up in blood work.

Roeding and members of the Earli analysis group [Photo: courtesy of Earli]Michael Kent, director of the middle, says that Earli’s compound was nicely tolerated, with only some canine growing a quick and low-grade fever. Full trial outcomes of the trial will likely be revealed later this 12 months, however the outcomes had been favorable. “This isn’t going to be in your physician’s workplace subsequent 12 months, however this might be game-changing,” Kent says. In contrast to the liquid biopsy tech Kent has examined, Earli doesn’t rely on serendipity to identify cancer. “You’ve one thing making a transparent sign and saying, ‘Hey, I’m right here!” That’s distinctive.” Earli is now funding subsequent trials with dozens of canine.

Demonstrating that the take a look at was unhazardous for canine was essential in getting the Australian authorities to conform to let Earli start its first human trials within the nation, which started this previous September. Up to now, two individuals have been dosed, and one other is on monitor. The intention is to detect advanced-stage lung cancer in already recognized sufferers—and to amass the information Earli might want to persuade the U.S. Meals and Drug Administration to let it proceed with a U.S. trial of its novel expertise.

Suhy says he’s inspired by the velocity with which the FDA permitted mRNA vaccines through the pandemic. That implies regulators are amenable to novel medical expertise like Earli’s diagnostic. Nonetheless, he notes, these approvals had been based mostly on years of knowledge. And even when Earli achieves FDA approval, it might want to persuade medical doctors so as to add a novel diagnostic to their workflow.

Nora Pashayan, a professor of Utilized Cancer Analysis at College Faculty London who shouldn’t be affiliated with Earli, calls its idea “wonderful.” However says “it may take a very long time” for Earli to come back to market. And its strategy faces a number of urgent questions, she says, associated to the design of the biomarker, how typically it’s deployed, and in whom.

These components—how and who—matter, as a result of opposite to standard medical knowledge, early detection doesn’t all the time save lives. The issue is that medical doctors can’t all the time inform the distinction between a benign or malignant tumor and due to this fact could deal with a tumor out of an abundance of warning. “Aside from the psychological burden [of diagnosis], there are unintended effects of therapy—going into chemotherapy, endotherapy, or surgical procedure,” says Pashayan. “So the harms are rather more than the advantages, [if] this cancer was not going to do something.”

A failed public well being effort in South Korea serves as a cautionary tale. Between 2000 and 2011, due to a authorities suggestion, medical doctors within the nation began screening everybody for thyroid cancer. Unsurprisingly there was a surge in thyroid cancer diagnoses and surgical procedure to take away these tumors. Nonetheless, after ten years, deaths from thyroid cancer remained secure. The screening marketing campaign wasn’t stopping death. If something, it was creating issues for individuals who had been experiencing problems from pointless surgical procedure. For corporations like Earli, the protocols round a diagnostic matter as a lot as whether or not it really works.

The higher scientific analysis group nonetheless believes that early detection instruments, like Earli’s, are vital. Cancer medicine deal with, however don’t remedy—and are immensely costly. The hope is that discovering cancer early, figuring out the tumor profile, and stopping it earlier than it spreads may sooner or later make getting cancer a comparatively anxiety-free expertise. “What we have to present are the success circumstances of what it means to search out it, do away with it, and reside on,” says Roeding. “And with a view to do this, we have to discover extra early stage cancers.”

Greater than 1,600 individuals logged into Gambhir’s memorial service, which was held on the peak of the pandemic, in July 2020. Colleagues described his generosity and far-sightedness. “It will not be totally correct to say that Sam introduced a ‘imaginative and prescient’ for the sphere of molecular imaging, as a result of that sounds slightly like the weather of the imaginative and prescient had been on the market and others had been additionally conscious of it,” stated Norbert Pelc, Stanford College professor emeritus of radiology. “Sam created the imaginative and prescient after which articulated it. He was in a position to do this: See a path forward a few years forward of his time and clarify it to an viewers at a variety of ranges.”

“He gave you confidence in that future,” says Christina Zavaleta, an assistant professor of biomedical engineering at USC and one among Gambhir’s tons of of former college students. Sam could not get to see the place all of his concepts will journey, however “he was already there in his thoughts,” she says. “We’re those that should catch up.”

[Photo: courtesy of Earli]Gambhir’s expertise is sure to introduce new conundrums, about if and tips on how to deal with beforehand hidden tumors. Even when Roeding and Suhy can efficiently render Gambhir’s novel early detection expertise right into a marketable diagnostic, it gained’t finish our battle with cancer. Nonetheless, if they’ll pull it off, it may give sufferers and medical doctors the luxurious of selection, one thing that Sam and Milan Gambhir didn’t have.

“It’s a merciless irony that Sam’s personal cancer was solely detected after it had unfold to his bones,” Aruna, Sam’s spouse, stated at his memorial, her voice breaking. “Maybe if a few of the instruments in precision well being had been in place, he would have had an opportunity to reside and contribute much more. He instructed me in the direction of the top days that he felt he had one other decade of productive work left in him. Think about what that might have meant for humanity.”

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