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Sealed Air Corp (NYSE:SEE) Expected to Announce Quarterly Sales of $1.30 Billion – Slater Sentinel

Analysts forecast that Sealed Air Corp (NYSE:SEE) will post sales of $1.30 billion for the current quarter, according to Zacks. Three analysts have made estimates for Sealed Airs earnings, with the highest sales estimate coming in at $1.30 billion and the lowest estimate coming in at $1.29 billion. Sealed Air reported sales of $1.26 billion in the same quarter last year, which would suggest a positive year over year growth rate of 3.2%. The business is expected to announce its next quarterly earnings report on Thursday, February 6th.

On average, analysts expect that Sealed Air will report full-year sales of $4.79 billion for the current financial year, with estimates ranging from $4.78 billion to $4.80 billion. For the next financial year, analysts expect that the business will report sales of $5.01 billion, with estimates ranging from $4.91 billion to $5.20 billion. Zacks Investment Researchs sales calculations are an average based on a survey of research analysts that follow Sealed Air.

Sealed Air (NYSE:SEE) last posted its quarterly earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share (EPS) for the quarter, topping the Thomson Reuters consensus estimate of $0.62 by $0.02. The firm had revenue of $1.22 billion for the quarter, compared to analyst estimates of $1.23 billion. Sealed Air had a net margin of 7.55% and a negative return on equity of 135.60%. The firms quarterly revenue was up 2.7% compared to the same quarter last year. During the same quarter in the previous year, the business posted $0.61 earnings per share.

In other news, CFO James M. Sullivan bought 5,000 shares of the stock in a transaction on Thursday, November 7th. The shares were purchased at an average price of $38.75 per share, for a total transaction of $193,750.00. Following the completion of the purchase, the chief financial officer now directly owns 17,028 shares of the companys stock, valued at approximately $659,835. The purchase was disclosed in a filing with the SEC, which is available through this link. 0.53% of the stock is currently owned by company insiders.

Several institutional investors and hedge funds have recently bought and sold shares of the company. Evoke Wealth LLC bought a new stake in shares of Sealed Air in the 3rd quarter valued at approximately $1,469,000. Man Group plc increased its stake in shares of Sealed Air by 91.7% during the 3rd quarter. Man Group plc now owns 125,245 shares of the industrial products companys stock worth $5,199,000 after purchasing an additional 59,911 shares during the last quarter. Michael & Susan Dell Foundation increased its stake in shares of Sealed Air by 28.7% during the 3rd quarter. Michael & Susan Dell Foundation now owns 14,760 shares of the industrial products companys stock worth $613,000 after purchasing an additional 3,294 shares during the last quarter. Squarepoint Ops LLC bought a new position in shares of Sealed Air during the 3rd quarter valued at $4,082,000. Finally, Voloridge Investment Management LLC increased its holdings in shares of Sealed Air by 391.5% during the 3rd quarter. Voloridge Investment Management LLC now owns 41,538 shares of the industrial products companys stock valued at $1,724,000 after acquiring an additional 33,087 shares during the last quarter. 94.05% of the stock is owned by institutional investors.

Shares of NYSE:SEE opened at $38.26 on Friday. The companys fifty day moving average is $38.61 and its two-hundred day moving average is $41.11. The company has a market cap of $5.91 billion, a P/E ratio of 15.30, a price-to-earnings-growth ratio of 1.31 and a beta of 1.03. Sealed Air has a 12-month low of $34.92 and a 12-month high of $47.13.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air Corp (NYSE:SEE) Expected to Announce Quarterly Sales of $1.30 Billion - Slater Sentinel

Recommendation and review posted by Bethany Smith

Sealed Air Corp (NYSE:SEE) Receives Average Recommendation of Hold from Brokerages – Riverton Roll

Sealed Air Corp (NYSE:SEE) has been assigned an average rating of Hold from the fourteen brokerages that are currently covering the stock, MarketBeat reports. Three research analysts have rated the stock with a sell rating, eight have assigned a hold rating and two have given a buy rating to the company. The average twelve-month price objective among analysts that have issued a report on the stock in the last year is $44.61.

Several research firms recently issued reports on SEE. Robert W. Baird reaffirmed a buy rating and set a $50.00 price target on shares of Sealed Air in a research note on Monday, November 18th. ValuEngine downgraded shares of Sealed Air from a sell rating to a strong sell rating in a research note on Thursday. KeyCorp raised shares of Sealed Air from an underweight rating to a sector weight rating in a research note on Wednesday, November 6th. They noted that the move was a valuation call. Wells Fargo & Co reaffirmed a hold rating on shares of Sealed Air in a research note on Monday. Finally, Citigroup dropped their price target on shares of Sealed Air from $45.00 to $42.00 and set a neutral rating on the stock in a research note on Thursday, October 17th.

In related news, CFO James M. Sullivan acquired 5,000 shares of the firms stock in a transaction on Thursday, November 7th. The stock was bought at an average cost of $38.75 per share, with a total value of $193,750.00. Following the acquisition, the chief financial officer now directly owns 17,028 shares in the company, valued at $659,835. The acquisition was disclosed in a document filed with the Securities & Exchange Commission, which is available through this link. 0.53% of the stock is owned by company insiders.

A number of hedge funds have recently made changes to their positions in the business. Motco acquired a new position in shares of Sealed Air in the 2nd quarter valued at about $29,000. Doyle Wealth Management acquired a new position in shares of Sealed Air in the 2nd quarter valued at about $40,000. CSat Investment Advisory L.P. boosted its holdings in shares of Sealed Air by 34.1% in the 2nd quarter. CSat Investment Advisory L.P. now owns 1,234 shares of the industrial products companys stock valued at $53,000 after buying an additional 314 shares during the period. Penserra Capital Management LLC boosted its holdings in shares of Sealed Air by 556.0% in the 3rd quarter. Penserra Capital Management LLC now owns 1,804 shares of the industrial products companys stock valued at $74,000 after buying an additional 1,529 shares during the period. Finally, Massey Quick Simon & CO. LLC acquired a new position in shares of Sealed Air in the 3rd quarter valued at about $96,000. 94.07% of the stock is owned by institutional investors.

Sealed Air stock traded down $0.16 during midday trading on Friday, hitting $38.54. 30,675 shares of the stock were exchanged, compared to its average volume of 972,233. Sealed Air has a 1 year low of $32.33 and a 1 year high of $47.13. The firm has a market cap of $5.99 billion, a P/E ratio of 15.42, a P/E/G ratio of 1.41 and a beta of 1.00. The company has a 50 day moving average price of $39.18 and a two-hundred day moving average price of $41.51.

Sealed Air (NYSE:SEE) last released its quarterly earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share (EPS) for the quarter, topping the Thomson Reuters consensus estimate of $0.62 by $0.02. Sealed Air had a net margin of 7.55% and a negative return on equity of 135.60%. The firm had revenue of $1.22 billion for the quarter, compared to the consensus estimate of $1.23 billion. During the same quarter in the previous year, the firm posted $0.61 EPS. The firms quarterly revenue was up 2.7% on a year-over-year basis. On average, equities research analysts anticipate that Sealed Air will post 2.78 EPS for the current fiscal year.

The business also recently disclosed a quarterly dividend, which will be paid on Friday, December 20th. Shareholders of record on Friday, December 6th will be issued a dividend of $0.16 per share. This represents a $0.64 annualized dividend and a yield of 1.66%. The ex-dividend date is Thursday, December 5th. Sealed Airs dividend payout ratio is currently 25.60%.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air Corp (NYSE:SEE) Receives Average Recommendation of Hold from Brokerages - Riverton Roll

Recommendation and review posted by Bethany Smith

Sealed Air (NYSE:SEE) Stock Rating Reaffirmed by Wells Fargo & Co – Riverton Roll

Sealed Air (NYSE:SEE)s stock had its hold rating restated by analysts at Wells Fargo & Co in a report issued on Monday, December 9th, AnalystRatings.com reports.

A number of other analysts have also weighed in on SEE. KeyCorp upgraded Sealed Air from an underweight rating to a sector weight rating in a report on Wednesday, November 6th. They noted that the move was a valuation call. Citigroup reduced their price target on Sealed Air from $45.00 to $42.00 and set a neutral rating on the stock in a research report on Thursday, October 17th. ValuEngine raised Sealed Air from a strong sell rating to a sell rating in a research report on Tuesday, November 19th. Finally, Robert W. Baird reaffirmed a buy rating and set a $50.00 price target on shares of Sealed Air in a research report on Monday, November 18th. One equities research analyst has rated the stock with a sell rating, eight have given a hold rating and three have given a buy rating to the companys stock. Sealed Air currently has a consensus rating of Hold and an average price target of $44.33.

Sealed Air stock traded down $0.61 during mid-day trading on Monday, reaching $38.26. 1,144,692 shares of the company were exchanged, compared to its average volume of 989,617. The business has a fifty day moving average of $38.61 and a 200 day moving average of $41.11. The firm has a market cap of $5.91 billion, a P/E ratio of 15.30, a PEG ratio of 1.31 and a beta of 1.03. Sealed Air has a 12-month low of $34.92 and a 12-month high of $47.13.

Sealed Air (NYSE:SEE) last posted its earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share for the quarter, topping analysts consensus estimates of $0.62 by $0.02. The company had revenue of $1.22 billion during the quarter, compared to analyst estimates of $1.23 billion. Sealed Air had a negative return on equity of 135.60% and a net margin of 7.55%. Sealed Airs revenue was up 2.7% on a year-over-year basis. During the same quarter in the prior year, the business earned $0.61 earnings per share. As a group, equities research analysts predict that Sealed Air will post 2.78 EPS for the current fiscal year.

In other news, CFO James M. Sullivan bought 5,000 shares of the businesss stock in a transaction that occurred on Thursday, November 7th. The shares were purchased at an average cost of $38.75 per share, with a total value of $193,750.00. Following the transaction, the chief financial officer now directly owns 17,028 shares in the company, valued at $659,835. The transaction was disclosed in a legal filing with the Securities & Exchange Commission, which is accessible through this link. 0.53% of the stock is owned by corporate insiders.

Several hedge funds and other institutional investors have recently added to or reduced their stakes in SEE. FMR LLC increased its position in shares of Sealed Air by 3.1% in the 1st quarter. FMR LLC now owns 88,646 shares of the industrial products companys stock valued at $4,083,000 after acquiring an additional 2,697 shares during the period. Steward Partners Investment Advisory LLC acquired a new stake in Sealed Air during the 2nd quarter worth about $152,000. Los Angeles Capital Management & Equity Research Inc. grew its position in Sealed Air by 4.6% during the 2nd quarter. Los Angeles Capital Management & Equity Research Inc. now owns 143,346 shares of the industrial products companys stock worth $6,132,000 after purchasing an additional 6,285 shares during the period. First Trust Advisors LP acquired a new stake in Sealed Air during the 2nd quarter worth about $3,762,000. Finally, Aperio Group LLC grew its position in Sealed Air by 1.7% during the 2nd quarter. Aperio Group LLC now owns 64,135 shares of the industrial products companys stock worth $2,743,000 after purchasing an additional 1,064 shares during the period. 94.05% of the stock is currently owned by hedge funds and other institutional investors.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air (NYSE:SEE) Stock Rating Reaffirmed by Wells Fargo & Co - Riverton Roll

Recommendation and review posted by Bethany Smith

Genetic Testing Leads to End of Protections for Grand Canyon Snail – Courthouse News Service

(CN) When the U.S. Fish and Wildlife Service takes a species off the endangered list, the move is typically greeted with effusive praise from wildlife conservation groups and offered as proof that conservation in concert with recovery programs works.

But the delisting of the Kanab ambersnail, which makes its home in the Grand Canyon, is different.

The snail was delisted not because its numbers have rebounded dramatically, but because scientists have concluded the creature in question is likely not that genetically different from other ambersnails distributed throughout the high deserts of southern Utah and northern Arizona.

Available genetic evidence suggests that at least one population identified as Kanab ambersnail is more closely related to other nearby Oxyloma populations than it is to the other two Kanab ambersnail populations, the service said in the final act document released Friday.

In other words, at least one of the Kanab ambersnail populations, which was historically found in three distinct springs in Utah and Arizona, is more related to another ambersnail population found outside the region in question than they are to each other. Oxyloma is the scientific name for ambersnails, which are characterized by translucent shells that appear amber when empty.

They were first discovered by biologist James Ferriss in 1909. Biologists at the time believed the ambersnails in question were genetically distinct but acknowledged more research was required to establish their taxonomic independence.

When the Kanab ambersnails were first listed under the endangered species act in 1992, they were thought to only exist in three separate spots Kanab Creek Canyon and Three Lakes in Utah as well as Vaseys Paradise in Arizona.

Vaseys Paradise is a small spring or seep located about 33 miles downstream from Lees Ferry on the Colorado River. Located squarely within Grand Canyon National Park, it has been protected from development and copious groves of poison ivy deter potential visitors.

But the snail has struggled due to frequent flooding, sometimes caused by water managers releasing large amounts of water from the Glen Canyon Dam situated just upstream.

In Utah, livestock managers entirely depleted a small spring at the Kanab Creek Canyon location outside of the small town, causing the local extinction of the snail there. The species at Three Lakes near Kanab has fared better.

Kanab is a small town on the eastern flank of Zion National Park and on the doorstep of the Grand Staircase-Escalante National Monument, serving as a headquarters for tourists to explore the spectacular scenery of Utahs unique high desert.

While the species recovered somewhat in both places and was introduced to Upper Elves Canyon, also located in the Grand Canyon National Park about 83 miles downstream from Vaseys Paradise, their recovery isnt the reason for delisting as much as additional scientific studies have raised doubt as to whether the Kanab ambersnail is actually distinct from other ambersnail populations that flourish throughout the region.

Specifically, a research team studied the morphology and mitochondrial DNA patterns of the three distinct populations in questions and compared it with those of eight other populations found in Utah and Arizona.

The authors concluded that the three populations of Kanab ambersnail are not a valid subspecies of Oxyloma haydeni and should instead be considered part of the same taxa as ambersnails from the eight other populations of Oxyloma in Utah and Arizona that were sampled for comparison, the service wrote.

The delisting of species on taxonomic reasons is rare but not unheard of. The International Union for Conservation of Nature recognizes such delistings as non-genuine reasons rather than genuine reasons involving the reduction of threats and the introduction of conservation measures such as habitat restoration.

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Genetic Testing Leads to End of Protections for Grand Canyon Snail - Courthouse News Service

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Tech’s Biggest Leaps From the Last 10 Years, and Why They Matter – Singularity Hub

As we enter our third decade in the 21st century, it seems appropriate to reflect on the ways technology developed and note the breakthroughs that were achieved in the last 10 years.

The 2010s saw IBMs Watson win a game of Jeopardy, ushering in mainstream awareness of machine learning, along with DeepMinds AlphaGO becoming the worlds Go champion. It was the decade that industrial tools like drones, 3D printers, genetic sequencing, and virtual reality (VR) all became consumer products. And it was a decade in which some alarming trends related to surveillance, targeted misinformation, and deepfakes came online.

For better or worse, the past decade was a breathtaking era in human history in which the idea of exponential growth in information technologies powered by computation became a mainstream concept.

As I did last year for 2018 only, Ive asked a collection of experts across the Singularity University faculty to help frame the biggest breakthroughs and moments that gave shape to the past 10 years. I asked them what, in their opinion, was the most important breakthrough in their respective fields over the past decade.

My own answer to this question, focused in the space of augmented and virtual reality, would be the stunning announcement in March of 2014 that Facebook acquired Oculus VR for $2 billion. Although VR technology had been around for a while, it was at this precise moment that VR arrived as a consumer technology platform. Facebook, largely fueled by the singular interest of CEO Mark Zuckerberg, has funded the development of this industry, keeping alive the hope that consumer VR can become a sustainable business. In the meantime, VR has continued to grow in sophistication and usefulness, though it has yet to truly take off as a mainstream concept. That will hopefully be a development for the 2020s.

Below is a decade in review across the technology areas that are giving shape to our modern world, as described by the SU community of experts.

Dr. Tiffany Vora | Faculty Director and Vice Chair, Digital Biology and Medicine, Singularity University

In my mind, this decade ofastounding breakthroughs in the life sciences and medicinerests on the achievement of the$1,000 human genome in 2016.More-than-exponentially falling costs of DNA sequencinghave driven advances in medicine, agriculture, ecology, genome editing, synthetic biology, the battle against climate change, and our fundamental understanding of life and its breathtaking connections. The digital revolution in DNA constituted an important model forharnessing other types of biological information, from personalized bio data to massive datasets spanning populations and species.

Crucially, by aggressively driving down the cost of such analyses, researchers and entrepreneurs democratized access to the source code of lifewith attendantfinancial, cultural,andethical consequences. Exciting, but take heed: Veritas Geneticsspearheaded a $600 genomein 2019, only to have to shutter USA operations due to amoney trail tangled with the trade war with China. Stay tuned through the early 2020s to see the pricing of DNA sequencing fall even further and to experience the many ways that cheaper, faster harvesting of biological data will enrich your daily life.

Alex Gladstein | Chief Strategy Officer, Human Rights Foundation

The past decade has seen Bitcoin go from just an idea on an obscure online message board to a global financial network carrying more than 100 billion dollars in value. And were just getting started. One recent defining moment in the cryptocurrency space has been a stunning trend underway in Venezuela, where today, the daily dollar-denominated value of Bitcoin traded now far exceeds the daily dollar-denominated value traded on the Caracas Stock Exchange. Its just one country, but its a significant country, and a paradigm shift.

Governments and corporations are following Bitcoins success too, and are looking to launch their own digital currencies. China will launch its DC/EP project in the coming months, and Facebook is trying to kickstart its Libra project. There are technical and regulatory uncertainties for both, but one thing is for certain: the era of digital currency has arrived.

Pascal Finnette | Chair, Entrepreneurship and Open Innovation, Singularity University

For me, without a doubt, the most interesting and quite possibly ground-shifting development in the fields of entrepreneurship and corporate innovation in the last ten years is the rapid maturing of customer-driven product development frameworks such as Lean Startup, and its subsequent adoption by corporates for their own innovation purposes.

Tools and frameworks like the Business Model Canvas, agile (software) development and the aforementioned Lean Startup methodology fundamentally shifted the way we think and go about building products, services, and companies, with many of these tools bursting onto the startup scene in the late 2000s and early 2010s.

As these tools matured they found mass adoption not only in startups around the world, but incumbent companies who eagerly adopted them to increase their own innovation velocity and success.

Ramez Naam | Co-Chair, Energy and Environment, Singularity University

The 2010s were the decade that saw clean electricity, energy storage, and electric vehicles break through price and performance barriers around the world. Solar, wind, batteries, and EVs started this decade as technologies that had to be subsidized. That was the first phase of their existence. Now theyre entering their third, most disruptive phase, where shifting to clean energy and mobility ischeaper than continuing to useexistingcoal, gas, or oil infrastructure.

Consider that at the start of 2010, there was no place on earth where building new solar or wind was cheaper than building new coal or gas power generation. By 2015, in some of the sunniest and windiest places on earth, solar and wind had entered their second phase, where they were cost-competitive fornewpower. And then, in 2018 and 2019, we started to see the edge of the third phase, as building new solar and wind, in some parts of the world, wascheaper thanoperatingexisting coal or gas power plants.

Liz Specht, Ph. D | Associate Director of Science & Technology, The Good Food Institute

The arrival of mainstream plant-based meat is easily the food tech advance of the decade. Meat analogs have, of course, been around forever. But only in the last decade have companies like Beyond Meat and Impossible Foods decided to cut animals out of the process and build no-compromise meat directly from plants.

Plant-based meat is already transforming the fast-food industry. For example, the introduction of the Impossible Whopper led Burger King to their most profitable quarter in many years. But the global food industry as a whole is shifting as well. Tyson, JBS, Nestle, Cargill, and many others are all embracing plant-based meat.

Jody Medich | CEO, Superhuman-x

The breakthrough moment for augmented and virtual reality came in 2013 when Palmer Lucky took apart an Android smartphone and added optic lenses to make the first version of the Oculus Rift. Prior to that moment, we struggled with miniaturizing the components needed to develop low-latency head-worn devices. But thanks to the smartphone race started in 2006 with the iPhone, we finally had a suite of sensors, chips, displays, and computing power small enough to put on the head.

What will the next 10 years bring? Look for AR/VR to explode in a big way. We are right on the cusp of that tipping point when the tech is finally good enough for our linear expectations. Given all it can do today, we cant even picture whats possible. Just as today we cant function without our phones, by 2029 well feel lost without some AR/VR product. It will be the way we interact with computing, smart objects, and AI. Tim Cook, Apple CEO, predicts it will replace all of todays computing devices. I cant wait.

Alix Rbsaam | Faculty Fellow, Singularity University, Philosophy of Technology/Ethics of AI

The last decade has seen a significant shift in our general attitude towards the algorithms that we now know dictate much of our surroundings. Looking back at the beginning of the decade, it seems we were blissfully unaware of how the data we freely and willingly surrendered would feed the algorithms that would come to shape every aspect of our daily lives: the news we consume, the products we purchase, the opinions we hold, etc.

If I were to isolate a single publication that contributed greatly to the shift in public discourse on algorithms, it would have to be Cathy ONeils Weapons of Math Destruction from 2016. It remains a comprehensive, readable, and highly informative insight into how algorithms dictate our finances, our jobs, where we go to school, or if we can get health insurance. Its publication represents a pivotal moment when the general public started to question whether we should be OK with outsourcing decision making to these opaque systems.

The ubiquity of ethical guidelines for AI and algorithms published just in the last year (perhaps most comprehensively by the AI Now Institute) fully demonstrates the shift in public opinion of this decade.

Ola Kowalewski | Faculty Fellow, Singularity University, Data Innovation

In the last decade we entered the era of internet and smartphone ubiquity. The number of internet users doubled, with nearly 60 percent of the global population connected online and now over 35 percent of the globe owns a smartphone. With billions of people in a state of constant connectedness and therefore in a state of constant surveillance, the companies that have built the tech infrastructure and information pipelines have dominated the global economy. This shift from tech companies being the underdogs to arguably the worlds major powers sets the landscape we enter for the next decade.

Darlene Damm | Vice Chair, Faculty, Global Grand Challenges, Singularity University

The biggest breakthrough over the last decade in social impact and technology is that the social impact sector switched from seeing technology as something problematic to avoid, to one of the most effective ways to create social change. We now see people using exponential technologies to solve all sorts of social challenges in areas ranging from disaster response to hunger to shelter.

The worlds leading social organizations, such as UNICEF and the World Food Programme, have launched their own venture funds and accelerators, and the United Nations recently declared that digitization is revolutionizing global development.

Raymond McCauley | Chair, Digital Biology, Singularity University, Co-Founder & Chief Architect, BioCurious; Principal, Exponential Biosciences

CRISPR is bringing about a revolution in genetic engineering. Its obvious, and its huge. What may not be so obvious is the widespread adoption of genetic testing. And this may have an even longer-lasting effect. Its used to test new babies, to solve medical mysteries, and to catch serial killers. Thanks to holiday ads from 23andMe and Ancestry.com, its everywhere. Testing your DNA is now a common over-the-counter product. People are using it to set their diet, to pick drugs, and even for dating (or at least picking healthy mates).

And were just in the early stages. Further down the line, doing large-scale studies on more people, with more data, will lead to the use of polygenic risk scores to help us rank our genetic potential for everything from getting cancer to being a genius. Can you imagine what it would be like for parents to pick new babies, GATTACA-style, to get the smartest kids? You dont have to; its already happening.

Neil Jacobstein | Chair, Artificial Intelligence and Robotics, Singularity University

The convergence of exponentially improved computing power, the deep learning algorithm, and access to massive data resulted in a series of AI breakthroughs over the past decade. These included: vastly improved accuracy in identifying images, making self driving cars practical, beating several world champions in Go, and identifying gender, smoking status, and age from retinal fundus photographs.

Combined, these breakthroughs convinced researchers and investors that after 50+ years ofresearch and development, AI was ready for prime-time applications. Now, virtuallyevery field of human endeavor is being revolutionized by machine learning. We still have a long way to go to achieve human-level intelligence and beyond, but the pace of worldwide improvement is blistering.

Hod Lipson | Professor of Engineering and Data Science, Columbia University

The biggest moment in AI in the past decade (and in its entire history, in my humble opinion) was midnight, Pacific time, September 30, 2012: the moment when machines finally opened their eyes. It was the moment when deep learning took off, breaking stagnant decades of machine blindness, when AI couldnt reliably tell apart even a cat from a dog. That seemingly trivial accomplishmenta task any one-year-old child can dohas had a ripple effect on AI applications from driverless cars to health diagnostics. And this is just the beginning of what is sure to be a Cambrian explosion of AI.

Divya Chander | Chair, Neuroscience, Singularity University

If the 2000s were the decade of brain mapping, then the 2010s were the decade of brain writing. Optogenetics, a technique for precisely mapping and controlling neurons and neural circuits using genetically-directed light, saw incredible growth in the 2010s.

Also in the last 10 years, neuromodulation, or the ability to rewire the brain using both invasive and non-invasive interfaces and energy, has exploded in use and form. For instance, the Braingate consortium showed us how electrode arrays implanted into the motor cortex could be used by paralyzed people to use their thoughts to direct a robotic arm. These technologies, alone or in combination with robotics, exoskeletons, and flexible, implantable, electronics also make possible a future of human augmentation.

Image Credit: Image by Jorge Guillen from Pixabay

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Tech's Biggest Leaps From the Last 10 Years, and Why They Matter - Singularity Hub

Recommendation and review posted by Bethany Smith

The best paperbacks coming out in January | Saturday Review – The Times

Fleetwood Macs Stevie Nicks: Did she help to inspire Daisy Jones and the Six?GETTY IMAGES

FICTION

Frankissstein: A Love Story by Jeanette Winterson A trans woman doctor starts an affair with the scientist Victor Stein, who is planning to reanimate the head of a man frozen in a cryonics facility. The recently divorced Ron Lord is marketing talking sex dolls for lonely men. And in 1816 Mary Shelley is plotting a new novel . . . This fast-paced tale has fun with the Frankenstein story.Vintage, 8.99

Daisy Jones and the Six by Taylor Jenkins Reid A rocknroll soap opera. The rise and drug-addled fall of a fictional pop group definite shades of Fleetwood Mac told in glorious Seventies detail.Arrow, 8.99

Reasons to be Cheerful by Nina Stibbe Nina Stibbe won the Bollinger Everyman Wodehouse prize for comic literature

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Pills, Powder and Smoke by Antony Loewenstein a war waged against human nature

How the Brain Lost its Mind by Allan Ropper and BD Burrell when science was left in two minds

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The best paperbacks coming out in January | Saturday Review - The Times

Recommendation and review posted by Bethany Smith

Cardio Round-up: Look Back at 2019, The Importance of Sleep, and More – DocWire News

This weeks Cardio Round-up features a look back at what you may have missed during the holidays, as well as some of the big 2019 cardiology stories.

The past year saw some big stories like the Apple Heart study, presented at ACC.19, which essentially validated the ability of a wearable device (an Apple iWatch) equipped with a tachogram-tracking algorithm was able to detect pulse irregularities associated with atrial fibrillation. Icosapent ethyl also featured prominently, gaining an FDA approval for the reduction of cardiovascular disease risk as an add-on to statin therapy in high-risk patients with hypertriglyceridemia. Dapagliflozin (highlighted in the DAPA-HF study) also was shown to be an effective treatment for heart failure in both diabetic and non-diabetic patients.

2019 In Cardiology: Apple Heart Study Lands; Icosapent Ethyl Gets FDA Nod for New Indication; Dapagliflozin For Nondiabetics; and More

A new observational study published inEuropacesuggests it is possible to monitor and predict individual progression ofatrial fibrillation (AFib) using pacemakers or defibrillators.We aimed to study the progression of AER in individual patients with implantable devices and AFib episodes, the paper authors wrote. The study results indicated that the slope of AAR changes during the progression of AFib showed patient-specific patterns correlating with the time-to-completion of AER (R2 = 0.85). This technology opens up enormous possibilities in personalized medicine for AFib patients because it allows us to determine the progression rate of the arrhythmia in each individual and to optimize the timing of medical intervention with current treatment options, one of the researchers said in a press release.

Personalized Medicine for AFib: How Electric Activity in the Heart Can Predict Individual Progression of Atrial Fibrillation

A research team, publishing the study in the Journal of Molecular and Cellular Cardiology, worked on converting adipogenic mesenchymal stem cells, which reside within fat cells, into cardiac progenitor cells. The ensuing cardiac progenitor cells can be programmed to aid heartbeats as a sinoatrial node (SAN), which is part of the electrical cardiac conduction system.We are reprogramming the cardiac progenitor cell and guiding it to become a conducting cell of the heart to conduct electrical current, said study co-author Bradley McConnell, associate professor of pharmacology, in a press release. Results of this study show that the SHT5 combination of transcription factors can reprogram CPCs into Pacemaker-like cells.

The Next Generation of Biologic Pacemakers? New Discovery in Stem Cells from Fat Creates Another Alternative Treatment

Diabetes mellitus is an independent predictor for heart failure, according to the findings of a study published inMayo Clinic Proceedings. In this study, using the Rochester Epidemiology Project, researchers assessed the long-term impact ofdiabeteson the development of heart failure by including 116 study subjects with diabetes, who were matched 1:2 based on age, hypertension, sex, coronary artery disease and diastolic with 232 participants without diabetes. The results showed that that diabetes is an independent risk factor for the development of heart failure. Over the duration of 10 years, 21% of participants with diabetes developed heart failure, independent of other causes. The researchers observed that by comparison, only 12% of patients without diabetes developed heart failure. The key takeaway is that diabetes mellitus alone is an independent risk factor for the development of heart failure, wrote one of the authors.

Diabetes is an Independent Predictor for Heart Failure

A new study suggests that regularly getting a good nights sleep isnt just a helpful overall health recommendation but is also an essential way to keep risk for heart disease and stroke down. The paper, published in theEuropean Journal of Cardiology, included more than 300,000 participants initially free of cardiovascular disease (CVD) from UK Biobank. According to the results, there were 7,280 documented cases of incident CVD (4,667 coronary heart disease and 2,650 stroke) cases. Participants with a sleep score of 5 had a 35% reduced risk for CVD, a 34% reduced risk for coronary heart disease, and a 34% reduced risk for stroke when compared to participants with a score of 0-1.As with other findings from observational studies, our results indicate an association, not a causal relation, one of the authors said in a press release. However, these findings may motivate other investigations and, at least, suggest that it is essential to consider overall sleep behaviors when considering a persons risk of heart disease or stroke.

Getting Quality Sleep, and the Right Amount, Can Offset Genetic Susceptibility for Heart Disease and Stroke Risk

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Cardio Round-up: Look Back at 2019, The Importance of Sleep, and More - DocWire News

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ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa – Ottawa Sun

Colleen LeCours lay in a hospital bed at the General campus of The Ottawa Hospital on August 12, 2016, waiting for the only thing that could save her life a stem cell transplant from a stranger.

The donor could be anywhere in the world if a related blood donor cant be found, the call to find a match goes out to registries all over the globe and the donated stem cells are rushed across international borders.

What LeCours didnt know is that her donor, an 18-year-old Carleton University student named Timothy White, was just one floor below. Similarly, White didnt know that his recipient was in the same hospital.

There are currently more than 450,000 people on the Canadian Blood Services Stem Cell Registry formerly known as OneMatch and 36 million on affiliated international registries. Still, some people never find a match. There are more than 900 Canadians in need of a transplant who have not found a match anywhere in the world.

What were the odds that the match for LeCours, now 57, would be found in the same city?

Astronomical, she said.

The chances that White would even ever be asked to donate were also very low only about one in a thousand. After he agreed to donate, he was not told where the recipient might be. I was told the recipient could be anywhere. They could be in Africa, said White, now 22 and a recent graduate in computer science.

White had signed up for the registry through a cheek swab booth at ComiCon less than six months earlier. A smart place to recruit would-be stem cell donors, he notes. The optimal donor is a male between the age of 17 and 35 and thats the ComiCon demographic.

He decided to register as a potential donor because he grew up in the scouting movement. One of the main philosophies is to do a good turn every day, he said.

The donation was a non-surgical procedure in which Whites blood was removed though a needle, the stem cells were separated from his blood and the remaining blood components returned to his body through another needle. The procedure started at about 8 a.m. and was over by about 5 p.m.

I figured if I gave someone a day for a thousand more days (of life) then I felt it was a fair trade. I have many years of life. Why not spend one day? said White.

LeCourss medical journey started in 2009 with an emergency room visit for abdominal pain. She was eventually diagnosed with Stage 4 follicular lymphoma, a blood cancer that affects infection-fighting white blood cells. At the time, LeCours was working for Gov.-Gen. Michalle Jean and was able to stay on the job most of the time during her six months of treatment.

Four years later, the lymphoma returned. It was back again two years after that, in a more aggressive form. The only treatment was stem cell transplant.

There are two main kinds of stem cell transplants autologous and allogenic. In an autologous transplant, stem cells are collected from a patients own blood and reintroduced after being treated to remove cancer cells. In an allogenic stem cell transplant, the stem cells come from a donor.

At this point, LeCours was a candidate for an autologous transplant. Once again, she underwent aggressive chemotherapy. A year later, the cancer returned.

Doctors told LeCours there wasnt much else they could do and advised her to get her affairs in order. But the hospitals transplant team felt she could be a candidate for an allogenic transplant. Theres risk rejecting donated stem cells can be fatal to the patient.

LeCours learned that her brother was a match. But the medical work-up would last about three months and she couldnt wait that long.

I wasnt sure I wanted to do it but I didnt have much choice, she said. They said, We have someone waiting in the wings.

And I said, He probably has wings.

After the transplant, LeCours recovered as an outpatient in the home of her brother and sister-in-law. It took three months to rebuild her immune system. Her only rejection symptoms were a bit of skin irritation.

In January 2018, LeCours received an email asking if she would like to exchange contact information with her donor. She replied that she would.

A few months later, she got a message with Whites co-ordinates and was astonished to find that her donor was in Ottawa. It took her a few weeks to formulate an email.

I didnt want to scare him. I just wanted him to know how incredibly grateful I was. And I wanted to pay it forward, said LeCours.

After careful consideration, she sent White an email on Oct. 8, 2018.

Today, being Thanksgiving, I have so much to be thankful for, namely you giving your stem cells and saving my life and the success of the stem cells grafting to my bone marrow, LeCours wrote. I cant thank you enough for your wonderful selfless act.

Stem cell donor 18-year-old Carleton University student Timothy White at The Ottawa Hospital, General campus, donating stem cells for Colleen LeCours in August 2016. At the time he did not know that LeCours would be the recipient. Courtesy Timothy White.jpg

She added that she didnt know anything about him except for his name and email address, and asked if they could meet. They got together for the first time over lunch in a burger restaurant.

As soon as I saw him, I broke down, said LeCours.

It has been three and a half years since the transplant and LeCours remains in remission. She invited White to her familys Thanksgiving this year, and the two meet to catch up every few months. Its one of the quirks of stem cell donation that the recipient assumes the blood type of the donor. LeCours, once O-positive, now has blood type A-negative, like White.

Im a grandmother. The fact that my grandson has his moma is huge.

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ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa - Ottawa Sun

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more – CNBC

Military personnel walk past the Raytheon Missile stand.

Carl De Souza | AFP | Getty Images

Check out the companies making headlines in midday trading:

Raytheon, Lockheed Martin, L3Harris Equity of major aircraft and weapons manufacturers Raytheon, Lockheed Martin and L3Harris rose 1.6%, 3.8% and 3.3%, respectively, in midday trading as U.S.-Iranian tensions flare in the Middle East. The U.S. confirmed it was responsible for a drone strike in Baghdad on Friday that killed Iranian Gen. Qasem Soleimani, Tehran's top military commander and a prominent political fixture in the region.

Incyte Shares of Incyte plunged 10% Friday after the company announced that a Phase III study showed one of its developmental drugs failed to show results that were statistically superior to a placebo. The drug was aimed at treating a disease that arises when donated bone marrow or stem cells attack their new host.

Tesla Tesla's stock climbed 3.8% on Friday after the automaker reported better-than-expected deliveries for its most recent quarter. The electric car company delivered 112,000 vehicles during the fourth quarter, topping consensus estimates of 106,000. Tesla delivered roughly 367,500 vehicles for the full year, a 50% increase from 2018 and within the range that it had given as guidance.

Bank of America Shares of the top U.S. bank fell 1.5% in afternoon trading after BMO Capital Markets downgraded the equity to market perform from outperform, telling clients its valuation re-rating has "run its course." Analyst James Fotheringham added that Bank of America shares now trade at a premium to their long-term average and suggested investors look to cheaper names like Citi and Morgan Stanley in the big-bank space.

Concho Resources, Apache, Devon Energy Shares of Concho, Apache and Devon all traded higher, following crude prices, after the U.S. killed a top Iranian military leader in an airstrike. Concho and Apache each traded higher by more than 1% while Devon advanced 0.8%.

L Brands Shares of L Brands rose nearly 8% after Bank of America upgraded the retail and apparel company to buy from neutral. The bank's analysts cited a strong Bath & Body Works business, potential for a more stable Victoria's Secret and a high dividend yield as reasons for the upgrade. The bank also raised its price target on the stock to $25 per share from $21, which would be a 49% increase from where the stock closed on Thursday.

Humana Humana rose 1.5% after Goldman Sachs added the health care company to its "Conviction Buy" list and told clients it sees sizable upward revisions to earnings estimates due to the recent repeal of a fee on health insurers.

CNBC's Fred Imbert and Jesse Pound contributed to this report.

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more - CNBC

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Targeted deletion of PD-1 in myeloid cells induces antitumor immunity – Science

INTRODUCTION

Programmed cell death protein 1 (PD-1) is a major inhibitor of T cell responses expressed on activated T cells. It is also expressed on natural killer cells, B cells, regulatory T cells, T follicular helper cells, and myeloid cells (1). The current model supports that a key mechanism dampening antitumor immune responses is the up-regulation of PD-1 ligands in cancer cells and antigen-presenting cells (APCs) of the tumor microenvironment (TME), which mediate ligation of PD-1 on tumor-infiltrating CD8+ T cells, leading to the development of T incapable of generating antitumor responses (2). Therapeutic targeting of the PD-1 pathway with antibodies blocking the PD-1 receptor or its ligands induces expansion of oligoclonal CD8+ tumor-infiltrating lymphocytes that recognize tumor neoantigens (3). Thus, in the context of cancer, PD-1 is considered a major inhibitor of T effector cells, whereas on APC and cancer cells, emphasis has been placed on the expression of PD-1 ligands. PD-1 ligand-1 expression in the TME is often a prerequisite for patient enrollment to clinical trials involving blockade of the PD-1 pathway. However, responses do not always correlate with PD-L1 expression, and it remains incompletely understood how the components of the PD-1:PD-L1/2 pathway suppress antitumor immunity.

Recent studies indicated that PD-1 can be induced by Toll-like receptor (TLR) signaling in macrophages (M) and negatively correlates with M1 polarization (4). PD-1 expression in macrophages plays a pathologic role by suppressing the innate inflammatory response to sepsis (5) and inhibiting Mycobacterium tuberculosis phagocytosis in active tuberculosis (6). Our knowledge about the function of PD-1 on myeloid cells in the context of cancer is very limited. However, similar to its role in infections, PD-1 expression inversely correlates with M1 polarization and phagocytic potency of tumor-associated M (TAM) against tumor (7, 8). The mechanisms of PD-1 expression in myeloid cells and the role of PD-1expressing myeloid cells in tumor immunity remain unknown.

The rapid increase in myeloid cell output in response to immunologic stress is known as emergency myelopoiesis. Terminally differentiated myeloid cells are essential innate immune cells and are required for the activation of adaptive immunity. Strong activation signals mediated by pathogen-associated molecular pattern or danger-associated molecular pattern molecules lead to a transient expansion and subsequent differentiation of myeloid progenitors to mature monocytes and granulocytes to protect the host. In contrast, during emergency myelopoiesis mediated by continuous low-level stimulation mediated by cancer-derived factors and cytokines, bone marrow common myeloid progenitors (CMPs) but, predominantly, granulocyte/macrophage progenitors (GMPs) undergo modest expansion with hindered differentiation, and a fraction of myeloid cells with immunosuppressive and tumor-promoting properties, named myeloid-derived suppressor cells (MDSCs), accumulates. MDSCs suppress CD8+ T cell responses by various mechanisms (9). In the mouse, MDSCs consist of two major subsets, CD11b+Ly6ChiLy6G (thereafter named CD11b+Ly6C+) monocytic (M-MDSC) and CD11b+Ly6CloLy6G+ (hereafter named CD11b+Ly6G+) polymorphonuclear (PMN-MDSC) (10). These cells have similar morphology and phenotype to normal monocytes and neutrophils but distinct genomic and biochemical profiles (9). In humans, in addition to M-MDSC and PMN-MDSC, a small subset of early-stage MDSC has been identified (10).

Although PMN-MDSCs represent the major subset of circulating MDSC, they are less immunosuppressive than M-MDSC when assessed on a per cell basis (1113). Current views support the two-signal requirement for MDSC function. The first signal controls MDSC generation, whereas the second signal controls MDSC activation, which depends on cues provided by the TME and promotes MDSC differentiation to TAM (14). Proinflammatory cytokines and endoplasmic reticulum stress response in the TME contribute to pathologic myeloid cell activation that manifests as weak phagocytic activity, increased production of reactive oxygen species and nitric oxide (NO) and expression of arginase-1 (ARG1), and convert myeloid cells to MDSC (9). MDSCs are associated with poor outcomes in many cancer types in patients and negatively correlate with response to chemotherapy, immunotherapy, and cancer vaccines (1519).

In the present study, we examined how PD-1 regulates the response of myeloid progenitors to cancer-driven emergency myelopoiesis and its implications on antitumor immunity. We determined that myeloid progenitors, which expand during cancer-driven emergency myelopoiesis, express PD-1 and PD-L1. PD-L1 was constitutively expressed on CMPs and GMPs, whereas PD-1 expression displayed a notable increase on GMPs that arose during tumor-driven emergency myelopoiesis. PD-1 was also expressed on tumor-infiltrating myeloid cellsincluding M-MDSCs and PMN-MDSCs, CD11b+F4/80+ M, and CD11c+major histocompatibility complex class II-positive (MHCII+) dendritic cells (DCs) in tumor-bearing miceand on MDSCs in patients with refractory lymphoma. Ablation of PD-1 signaling in PD-1 knockout (KO) mice prevented GMP accumulation and MDSC generation and resulted in increase of Ly6Chi effector monocytes, M and DC. We generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared with T cellspecific ablation of PD-1, myeloid-specific PD-1 ablation more effectively decreased tumor growth in various tumor models. At a cellular level, only myeloid-specific PD-1 ablation skewed the myeloid cell fate commitment from MDSC to effector Ly6Chi monocytes M and DC and induced T effector memory (TEM) cells with improved functionality. Our findings reveal a previously unidentified role of the PD-1 pathway and suggest that skewing of myeloid cell fate during emergency myelopoiesis and differentiation to effector APCs, thereby reprogramming T cell responses, might be a key mechanism by which PD-1 blockade mediates antitumor function.

For our studies, we selected the murine B16-F10 melanoma tumor model because it has been informative in dissecting mechanisms of resistance to checkpoint immunotherapy (20). First, we examined whether B16-F10 induces tumor-driven emergency myelopoiesis similarly to the MC17-51 fibrosarcoma, a mouse tumor model well established to induce cancer-driven emergency myelopoiesis (21). We assessed the expansion of myeloid progenitors in the bone marrow and the increase of CD11b+CD45+ myeloid cells in the spleen and tumor (figs. S1 and S2). Both tumor types induced increase of myeloid progenitors in the bone marrow and systemic increase of CD45+CD11b+ myeloid cells (fig. S3), providing evidence that B16-F10 melanoma is an appropriate tumor model to study tumor-driven emergency myelopoiesis and its consequences in tumor immunity. In the spleen of nontumor-bearing mice, few myeloid cells constitutively expressed very low levels of PD-L1, whereas PD-1 was very low to undetectable (Fig. 1, A and B). In B16-F10 tumor-bearing mice, expression of PD-1 and PD-L1 was up-regulated on myeloid cells of the spleen (Fig. 1, C to F). PD-1 and PD-L1 were also expressed on myeloid cells at the tumor site (Fig. 1, G to I). All subsets of myeloid cells expanding in tumor-bearing mice including M-MDSCs, PMN-MDSCs, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs expressed PD-1 (Fig. 1, D and G). Kinetics studies of PD-1 expression on myeloid cells in the spleen of tumor-bearing mice showed a gradual increase over time (Fig. 1, J to M).

(A and B) Expression of PD-1 and PD-L1 on CD11b+Ly6C+ monocytes and CD11c+MHCII+ DC in the spleen of nontumor-bearing C57BL/6 mice. FMO, fluorescence minus one. (C) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and at the indicated time points, expression of PD-1 was examined by flow cytometry in the spleen after gating on the indicated myeloid populations; contour plots depicting the percentage of positive cells are shown. On day 16 after tumor inoculation, expression of PD-1 and PD-L1 was assessed in the spleen (D) and the tumor site (G) after gating on the indicated myeloid populations. (D and G) Fluorescence-activated cell sorting (FACS) histograms and contour plots depicting the percentage of positive cells and bar graphs (E, F, H, and I) of mean SEM positive cells. Results are representative of 12 independent experiments with six mice per group. (J to M) Kinetics of PD-1 up-regulation on CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ of the spleen after tumor inoculation. **P < 0.01, ***P < 0.005, ****P < 0.001.

Because myeloid cells that give rise to MDSC and TAM are generated from myeloid progenitors in the bone marrow during tumor-driven emergency myelopoiesis, we examined PD-1 and PD-L1 expression in these myeloid progenitors. In nontumor-bearing mice, PD-1 was detected at very low levels on GMPs (Fig. 2A), whereas PD-L1 was constitutively expressed in CMPs but mostly on GMPs (Fig. 2B). In tumor-bearing mice, PD-L1 was up-regulated in CMPs and GMPs, and its expression levels remained elevated during all assessed time points (Fig. 2, F to J). PD-1 expression was induced on CMPs but more prominently on GMPs (Fig. 2, C to I). Kinetics studies showed that PD-1 expression on GMPs peaked early after tumor inoculation (Fig. 2, C, E, and I), at a time point when tumor growth was not yet measurable. Thus, induction of PD-1 expression in myeloid progenitors is an early event during tumor development.

(A and B) Expression of PD-1 and PD-L1 on CMPs and GMPs of nontumor-bearing mice. (C to J) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and expression of PD-1 and PD-L1 on CMPs and GMPs was examined on days 9, 12, 14, and 16 after implantation. FACS histograms (C and F) and contour plots (D, E, G, and H) indicating the percentage of positive cells and bar graphs of mean SEM positive cells (I and J) are shown. Results are representative of four independent experiments with six mice per group. (K and L) Kinetics of PD-1 (K) and PD-L1 (L) expression on CMPs (blue) and GMPs (orange) during tumor-driven emergency myelopoiesis. Results are representative of four separate experiments with six mice per group. *P < 0.05, ***P < 0.005, ****P < 0.001.

To determine whether PD-1 expression on GMPs was mediated by growth factors regulating emergency myelopoiesis, we cultured bone marrow cells from nontumor-bearing mice with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony growth factor (GM-CSF), and the TLR4 ligand lipopolysaccharide. PD-1 that was constitutively expressed at low levels in GMPs was up-regulated by culture with each of these factors (fig. S4A), consistent with our findings that PD-1 expression was rapidly induced on GMPs of tumor-bearing mice in vivo (Fig. 2, C, E, and I). Quantitative polymerase chain reaction (qPCR) in purified Linneg bone marrow cells showed that PD-1 mRNA was constitutively expressed in myeloid progenitors and was up-regulated by culture with G-CSF or GM-CSF (fig. S4B). Together, these in vivo and in vitro studies provide evidence that PD-1 expression on myeloid progenitors is regulated by a direct cell-intrinsic effect of factors driving cancer-mediated emergency myelopoiesis.

To examine whether PD-1 was expressed in MDSCs in humans, we used samples from healthy donors and patients with malignant non-Hodgkins lymphoma (NHL) (figs. S5 and S6). A high level of PD-1expressing M-MDSCs was detected in the peripheral blood of three patients with treatment-refractory NHL but not in two patients who responded to treatment or five healthy donors (fig. S6). These results show that PD-1 expression is detected in human MDSCs and serve as a paradigm, suggesting that PD-1 expression in MDSCs of patients with cancer might be a clinically relevant event.

To examine whether PD-1 might have an active role in tumor-induced stress myelopoiesis, we used PD-1deficient (PD-1/) mice. PD-1 deletion, which resulted in decreased tumor growth (Fig. 3, A and B), substantially altered tumor-induced stress myelopoiesis (Fig. 3, C to E). Although accumulation of CMPs was comparable, accumulation of GMPs was significantly diminished in PD-1/ mice (Fig. 3, C and D), indicating that GMPs might be a key target on which PD-1 mediated its effects on myeloid progenitors (Fig. 3E). Kinetics studies showed sustained GMP expansion in wild-type (WT) tumor-bearing mice. In contrast, in PD-1/ tumor-bearing mice, GMPs displayed a rapid expansion and subsequent decline (fig. S7). In parallel, in PD-1/ mice, there was an increase of differentiated CD11b+Ly6Chi monocytic cells not only in the tumor (Fig. 3H) but also in the spleen and the small intestine, which also displayed an increase in CD11c+MHCII+ DCs (Fig. 3, F and G). Moreover, at these sites, there was a significant increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 3, I to K), indicating a shift of myelopoiesis output toward monocytic lineage dominance. These Ly6Chi monocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs in PD-1/ tumor-bearing mice expressed interferon (IFN) regulatory factor 8 (IRF8), and all myeloid subsets had elevated expression of the retinoic acid receptor-related orphan receptor (RORC or ROR) (Fig. 3, L to N, and fig. S8). Similar results were observed in two additional tumor models, the MC38 colon adenocarcinoma and the MC17-51 fibrosarcoma model (fig. S9), both of which induced cancer-driven emergency myelopoiesis (fig. S3).

(A and B) WT and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). Mice were euthanized on day 16, and tumor weight was measured (B). Data shown are means SEM of six mice per group and are representative of six independent experiments. (C) Mean percentages SEM of LSK (Linneg, Sca1pos, CD127neg, c-kitpos) and LK (Linneg, Sca1neg, CD127neg, c-kitpos) hematopoietic precursors, CMP, and GMP in the bone marrow of nontumor-bearing and tumor-bearing WT and PD-1/ mice. GMPs in PD-1/ mice were significantly lower compared with GMPs in WT mice (**P < 0.01). (D) Representative contour plots of FACS analysis for CMP and GMP in the bone marrow of tumor-bearing WT and PD-1/ mice. (E) Schematic presentation of myeloid lineage differentiation. The arrowhead indicates GMP, the key target population of PD-1 during emergency myelopoiesis. HSC, hematopoietic stem cells; MPP, multi-potent progenitor; MDP, monocyte/macrophages and DC precursors; CDP, common dendritic cell progenitors; CLP, common lymphoid progenitors. (F to H) Mean percentages of CD45+CD11b+, CD11b+Ly6C+, CD11b+Ly6G+, and CD11c+MHCII+ in the spleen (F), small intestine (G), and B16-F10 site (H) of tumor-bearing WT and PD-1/ mice. (I to K) Representative plots of FACS analysis for CD11b+Ly6Chi and CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen (I), small intestine (J), and B16-F10 site (K). (L to N) Mean percentages SEM of RORC and IRF8 expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD45+CD11b+ gate in the spleen (L), small intestine (M), and B16-F10 site (N). Data from one representative experiment of three independent experiments with six mice per group are shown. (O and P) Diminished suppressive activity (O) and NO production (P) of CD11b+Ly6C+ cells isolated from PD-1/ tumor-bearing mice. CD11b+Ly6C+ cells were isolated from tumor-bearing WT and PD-1/ mice and cultured at various ratios with OTI splenocytes stimulated with OVA257264. Data show means SEM of one representative of two experiments (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001).

IRF8 regulates myeloid cell fate to monocyte/macrophage and DC differentiation versus granulocyte differentiation (22, 23), explaining the increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio that we observed in tumor-bearing PD-1 KO mice. IRF8 is designated as one of the terminal selectors that control the induction and maintenance of the terminally differentiated state of these myeloid cells (22, 23). Moreover, IRF8 shifts the fate of myeloid cells away from immature MDSC, which are characterized by a restriction in IRF8 expression (24, 25). Retinoid-related orphan nuclear receptors not only are required for myelopoiesis and are mediators of the inflammatory response of effector Ly6Chi monocytes and macrophages (21, 26) but also can be expressed by MDSC (21). For these reasons, we examined the functional properties of CD11b+Ly6C+ cells in PD-1/ tumor-bearing mice. A key mechanism by which CD11b+Ly6C+ M-MDSCs mediate suppression of T cell responses involves the production of NO (27). We assessed the immunosuppressive function and found diminished NO production and diminished suppressor capacity of CD11b+Ly6C+ myeloid cells isolated from tumor-bearing PD-1/ mice compared with their counterparts isolated from tumor-bearing WT control mice (Fig. 3, O and P). Thus, PD-1 ablation switches the fate and function of myeloid cells away from immunosuppressive MDSC and promotes the generation of differentiated monocytes, M, and DC. The expansion of CD11b+Ly6Chi monocytes, the increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio, and the up-regulation of RORC in myeloid cells of the spleen of PD-1/ mice were already observed on day 9 after tumor inoculation, when tumors were not yet measurable, and on day 12, when tumors in WT and PD-1/ mice had comparable size (fig. S10). These results indicate that the effects of PD-1 ablation on the myeloid compartment of PD-1/ tumor-bearing mice preceded the differences in tumor growth.

To determine the potential therapeutic relevance of these findings, we examined whether changes in the myeloid compartment might be detected during treatment with PD-1blocking antibody. Compared with the control treatment group, mice receiving antiPD-1 antibody (fig. S11A) had diminished accumulation of GMP in the bone marrow (fig. S11B) and increased expansion of Ly6C+ monocytes and DC in the tumor site (fig. S11D), with effector features characterized by the expression of RORC, IRF8, and IFN- (fig. S11, E to G and I). In contrast, cells expressing interleukin-4 receptor (IL-4Ra), a marker of MDSC (10, 28), were significantly decreased (fig. S11H). Thus, treatment with antiPD-1blocking antibody promotes the differentiation of myeloid cells with effector features while suppressing expansion of MDSC in tumor-bearing mice.

To determine whether these changes on myeloid cell fate in PD-1/ mice were mediated by myeloid cellintrinsic effects of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) (fig. S12A) and crossed them with mice expressing cre recombinase under the control of the lysozyme (LysM) promoter to induce selective ablation of the Pdcd1 gene in myeloid cells (PD-1f/fLysMcre) or with mice expressing cre recombinase under the control of the CD4 promoter to induce selective ablation of the Pdcd1 gene in T cells (PD-1f/fCD4cre) (fig. S12, B and C). In PD-1f/fLysMcre mice, tumor growth was significantly diminished (Fig. 4, A and B), indicating that despite the preserved PD-1 expression in T cells, myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice was sufficient to inhibit tumor growth. Tumor-driven emergency myelopoiesis was selectively affected in PD-1f/fLysMcre mice. Although myeloid-specific PD-1 ablation resulted in expansion of CMPs, accumulation of GMPs was prevented (Fig. 4C). In contrast, no change on cancer-driven emergency myelopoiesis was detected in PD-1f/fCD4cre mice, which had comparable expansion of CMP and GMP to PD-1f/f control mice (Fig. 5A).

(A and B) PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). After mice were euthanized, tumor weight was measured (B). (C) Mean percentages SEM of CMP and GMP in the bone marrow of tumor-bearing PD-1f/f and PD-1f/fLysMcre mice. (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen of tumor-bearing mice. (E) Mean percentages SEM of CD11b+CD45+, CD11b+Ly6C+, and CD11b+Ly6G+ cells and (F) representative contour plots of FACS analysis for CD11b+CD45+ and CD11b+Ly6C+ cells at the tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (G) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, and CD80+ cells and IFN-expressing myeloid cell subsets within the CD45+CD11b+ gate in B16-F10 tumors from PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (H) Mean percentages SEM and (I) FACS histograms of IL-4Ra, CD206, and ARG1 expression in CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD11b+CD45+ gate in the spleen of tumor-bearing PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. Data are from one representative of three independent experiments with six mice per group are shown in all the panels (*P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001).

PD-1f/f and PD-1f/fCD4cre mice were inoculated with B16-F10 melanoma. (A) On day 16, mice were euthanized, and bone marrow CMPs and GMPs were examined by flow cytometry. Mean percentages SEM of CMP or GMP are shown. (B and C) Tumor size was assessed every other day from inoculation (B). On the day of euthanasia, tumor weight was measured (C). (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+ and CD11b+Ly6G+ populations within the CD11+CD45+ gate in the spleen. (E) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ cells within the CD11b+CD45+ gate in the tumor site. (F) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, CD80+, and IFN- expression in the indicated myeloid subsets (CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+) within the CD11b+CD45+ gate in the tumor site. (G to J) Mean percentages SEM of CD4+ and CD8+ TCM and TEM (G), as well as IFN-, IL-2, and IL-17 (H to J) expression in CD4+ and CD8+ TEM and TCM at the tumor site, and respective contour plots (K to M). Results are from one representative of two independent experiments with six mice per group are shown (*P < 0.05 and **P < 0.01).

Myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice not only shifted the differentiation of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid subsets and increased the CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen and tumor site as in PD-1/ mice (Fig. 4, D to F) but also resulted in a notably different immunological profile of CD11b+Ly6C+ monocytic myeloid cells, consistent with effector myeloid function as indicated by the expression of effector myeloid cell markers including CD80, CD86, CD16/32 (Fc receptor II/III), and CD88 (C5aR) (Fig. 4G). Consistent with the improved function of myeloid cells, PD-1f/fLysMcre mice also had higher levels of IFN-expressing CD11b+Ly6Chi monocytes and CD11b+F4/80+ Ms (Fig. 4G and fig. S13, A and B) and increase of IRF8+ and RORC+ CD11b+Ly6Chi monocytes (fig. S13, C and D). In contrast, cells expressing IL-4Ra, CD206, and ARG1which are markers of MDSC, immunosuppressive neutrophils, and tolerogenic DCs (2933)were diminished (Fig. 4, H and I). Thus, myeloid-intrinsic PD-1 ablation skews the fate of myeloid cells away from immunosuppressive MDSCs; promotes the differentiation of functional effector monocytes, Ms, and DCs; and has a decisive role in systemic antitumor immunity despite PD-1 expression in T cells.

We studied antitumor responses in mice with T cellspecific PD-1 ablation and found that PD-1f/fCD4cre mice had diminished antitumor protection (Fig. 5, B and C). Consistent with the causative role of myeloid cellspecific PD-1 targeting in the differentiation and function of myeloid cells, T cellspecific PD-1 ablation did not induce expansion of CD11b+CD45+ leukocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs and increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 5, D and E) or immunological features of functional effector myeloid cells (Fig. 5F) in PD-1f/fCD4cre tumor-bearing mice, compared with control tumor-bearing mice. Moreover, despite PD-1 ablation, tumor-bearing PD-1f/fCD4cre mice did not have quantitative differences in tumor-infiltrating TEM cells compared with control tumor-bearing mice (Fig. 5G) or features of enhanced effector function as determined by assessment of cytokine-producing cells (Fig. 5, H to M).

Similar outcomes to those observed with B16-F10 tumor in the differentiation of myeloid cells toward myeloid effectors versus MDSC were obtained when PD-1f/fLysMcre and PD-1f/fCD4cre mice were inoculated with MC38 colon adenocarcinoma cells (Fig. 6, B to I). Moreover, PD-1f/fLysMcre but not PD-1f/f CD4cre mice inoculated with MC38 had functional differences in tumor-infiltrating TEM and T central memory (TCM) cells compared with control tumor-bearing mice (Fig. 6, J to L). In the context of this highly immunogenic tumor, PD-1 ablation in myeloid cells resulted in complete tumor eradication, whereas mice with PD-1 ablation in T cells showed progressive tumor growth (Fig. 6A). Together, these results suggest that by preventing the differentiation of effector myeloid cells and promoting generation of MDSC, myeloid-specific PD-1 expression has a decisive role on T cell function. Thus, although PD-1 is an inhibitor of T cell responses (2, 34, 35), ablation of PD-1 signaling in myeloid cells is an indispensable requirement for induction of systemic antitumor immunity in vivo.

(A) PD-1f/f, PD-1f/fCD4cre, and PD-1f/fLysMcre mice were inoculated with MC38 colon adenocarcinoma, and tumor size was monitored daily. Mice were euthanized on day 21, and mean percentages SEM of CD45+CD11b+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen (B) and tumor site (C) were determined. (D) Mean percentages SEM of RORC- and IRF8-expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F/480+, and CD11c+MHCII+ myeloid cells and (E) mean percentages SEM of ARG1, IL-4Ra, CD88, and CD80 cells within the same myeloid subsets in the spleen. (F and G) Representative flow cytometry plots for RORC and IRF8 expression. (H) Mean percentages SEM and (I) representative flow cytometry plots of IFN- and ARG1-expressing CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells at the tumor site. (J to L) Mean percentages SEM of CD4+ and CD8+ TCM and TEM cells (J) and IFN-expressing CD4+ and CD8+ TEM and TCM at the tumor site (K) and respective contour plots (L). Data are from one representative of three experiments with six mice per group (*P < 0.05, **P < 0.01, and ***P < 0.001).

To further investigate the direct effects of PD-1 on myeloid cell fate in the absence of T cells, we used recombination activating gene 2 (RAG2) KO mice (lacking mature T cells and B cells). Treatment of RAG2 KO tumor-bearing mice with antiPD-1blocking antibody resulted in decreased accumulation of GMPs during tumor-driven emergency myelopoiesis (fig. S14A), myeloid cell expansion in the spleen and tumor site (fig. S14, B and C), and enhanced generation of effector myeloid cells (fig. S14, D to G), providing evidence that blockade of PD-1mediated signals skews myeloid lineage fate to myeloid effector cells in a myeloid cellintrinsic and T cellindependent manner. In RAG2 KO mice treated with antiPD-1 antibody, despite the absence of T cells, a decrease of tumor growth was also observed (fig. S14, H and I), suggesting that ablation of PD-1 signaling promotes myeloid-specific mechanisms that induce tumor suppression, one of which might involve increased phagocytosis (8).

To understand mechanisms that might be responsible for the significant differences of myeloid cell fate commitment induced by myeloid-specific PD-1 targeting, we examined whether PD-1deficient bone marrow myeloid progenitors might have distinct signaling responses to the key hematopoietic growth factors that mediate cancer-driven emergency myelopoiesis, which also induced PD-1 expression in GMP during in vitro culture. To avoid any potential impact of bone marrowresiding PD-1/ T cells or mature myeloid cells on the signaling responses of myeloid progenitors, we used Linneg bone marrow from PD-1f/fLysMcre mice because LysMcre is expressed in CMPs and GMPs (36), allowing us to take advantage of the selective deletion of PD-1 in these myeloid progenitors. PD-1deficient GMPs (fig. S15) had enhanced activation of extracellular signalregulated kinase 1/2 (Erk1/2), mammalian target of rapamycin complex 1 (mTORC1), and signal transducer and activator of transcription 1 (STAT1) in response to G-CSF, a main mediator of emergency myelopoiesis (37, 38). These results are notable because each of these signaling targets has a decisive role in the differentiation and maturation of myeloid cells while preventing the generation of immature immunosuppressive MDSC (3942). These findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis.

Metabolism has a decisive role in the fate of hematopoietic and myeloid precursors. Stemness and pluripotency are regulated by maintenance of glycolysis (43). Switch from glycolysis to mitochondrial metabolism and activation of oxidative phosphorylation and trichloroacetic acid (TCA) cycle are associated with differentiation (44). This is initiated by glycolysis-mediated mitochondrial biogenesis and epigenetic regulation of gene expression (43). The structural remodeling of the mitochondrial architecture during differentiation is characterized by increased replication of mitochondrial DNA to support production of TCA cycle enzymes and electron transport chain subunits, linking mitochondrial metabolism to differentiation (45).

We examined whether PD-1 ablation, which promoted the differentiation of myeloid cells in response to tumor-mediated emergency myelopoiesis, might affect the metabolic properties of myeloid precursors. Linneg bone marrow myeloid precursors were cultured with the cytokines G-CSF/GM-CSF/IL-6 that drive tumor-mediated emergency myelopoiesis in cocktail (Fig. 7, A and B) or individually (Fig. 7, C and D). Hematopoietic stem cell differentiation was documented by decrease of Linneg, which was more prominent in the cultures of PD-1deficient bone marrow cells, and coincided with increase of CD45+CD11b+ cells (Fig. 7, A and B). Ly6C+ monocytic cells dominated in the PD-1f/fLysMcre cultures, whereas Ly6G+ granulocytes were decreasing compared with PD-1f/f control cultures (Fig. 7, C and D), providing evidence for a cell-intrinsic mechanism of PD-1deficient myeloid precursors for monocytic lineage commitment. Glucose uptake, but more prominently, mitochondrial biogenesis, was elevated in PD-1deficient CMP and GMP (Fig. 7, E and F). Bioenergetics studies showed that PD-1deficient cells developed robust mitochondrial activity (Fig. 7G) and increase of oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio during culture (Fig. 7H), indicating that mitochondrial metabolism progressively dominated over glycolysis. This bioenergetic profile is consistent with metabolism-driven enhanced differentiation of hematopoietic and myeloid precursors (45, 46).

(A and B) Linneg bone marrow from PD-1f/f and PD-1f/fLysMcre mice was cultured with GM-CSF, G-CSF, and IL-6 for the indicated time intervals. Mean percentages SEM of CD11b+CD45+ (A) and Linneg cells (B) are shown. (C and D) Bone marrow cells purified as in (A) and (B) were cultured with the indicated growth factors, and mean percentages SEM of CD11b+Ly6C+ and CD11b+Ly6G+ cells were examined after 48 hours of culture. (E to H) Bone marrow cells were prepared and cultured as in (A) and (B), and at 48 hours of culture, glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) (E), and mitochondrial biogenesis was assessed by MitoGreen staining and flow cytometry (F). (G) At 24, 48, and 72 hours of culture, OCR and ECAR were measured by a Seahorse extracellular flux analyzer, and mitostress responses at each time point of culture were examined. (H) OCR/ECAR ratio was measured at these time points, and the increase of OCR/ECAR ratio during stimulation was calculated. (I) Linneg bone marrow cells from PD-1f/f and PD-1f/fLysMcre mice were cultured with G-CSF and GM-CSF for 48 hours, and metabolite analysis was performed by mass spectrometry. The unsupervised hierarchical clustering heat map of the top 50 metabolites is shown. (J) At 24, 48, and 72 hours of culture with G-CSF and GM-CSF, mRNA was extracted and analyzed for the expression of the indicated genes by qPCR. Results of the 48-hour culture are shown and are presented as the fold increase over the mRNA level expressed by PD-1f/f cells. Results are from one of three independent experiments. (K to M) At 24 hours of culture with GM-CSF, G-CSF, or IL-6, the content of neutral lipid droplets, including triglycerides and cholesterol esters, was assessed by flow cytometry using boron-dipyrromethene (BODIPY) 493/503. Mean percentages SEM (K) of BODIPY 493/503positive cells within the CD11b+CD45+ gate, representative contour plots (L), and histograms of FACS analysis (M) are shown. (N) PD-1f/f and PD-1f/fLysMcre DC were differentiated in the presence of B16-F10 tumor supernatant, and the content of neutral lipids was assessed. Mean percentage SEM of BODIPY 493/503positive DC within the CD45+CD11b+ gate is shown. Results are representative of three experiments. *P < 0.05, **P < 0.01, and ***P < 0.005.

We performed unbiased global metabolite analysis to determine whether PD-1deficient myeloid precursors developed a distinct metabolic program. Compared with control, PD-1deficient cells had elevated metabolic intermediates of glycolysis and pentose phosphate pathway (PPP), acetylcoenzyme A (coA), and the TCA cycle metabolites citrate and -ketoglutarate, but the most prominent difference was the elevated cholesterol (Fig. 7I, figs. S16 and S17, and table S1). Abundant cytosolic acetyl-coA can be used for fatty acid and cholesterol biosynthesis (fig. S17) (43). Moreover, mTORC1 activates de novo cholesterol synthesis via sterol regulatory element-binding protein 1 (SREBP1), which regulates transcription of enzymes involved in cholesterol synthesis (47, 48). Because acetyl-coA was elevated (Fig. 7I and fig. S17) and mTORC1 activation was enhanced in PD-1deficient myeloid progenitors in response to growth factors driving emergency myelopoiesis (fig. S15), we examined whether activation of the mevalonate pathway that induces cholesterol synthesis (fig. S18A) might be involved. In PD-1deficient myeloid progenitors cultured with growth factors of emergency myelopoiesis, mRNA of genes regulating cholesterol synthesis and uptake was increased, mRNA of genes promoting cholesterol metabolism was decreased (Fig. 7J and fig. S18B), whereas cellular cholesterol and neutral lipid content was elevated (Fig. 7, K to M). PD-1deficient DC not only differentiated in vitro in the presence of B16-F10 tumor supernatant but also had a significant increase of cholesterol and neutral lipids compared with similarly differentiated DC from control mice (Fig. 7N). Consistent with these in vitro findings, glucose uptake and content of cholesterol and neutral lipids were elevated in GMPs of tumor-bearing PD-1 KO mice compared with control mice at days 7 or 9 after tumor inoculation, respectively, when tumors were not yet detectable or tumors in WT and PD-1 mice had equal size (fig. S19). Thus, features associated with metabolism-driven differentiation of myeloid progenitors are enhanced early in tumor-bearing PD-1 KO mice.

In addition to cholesterol synthesis, mevalonate also leads to the synthesis of isoprenoids, including geranylgeranyl pyrophosphate (GGPP) (fig. S17), which is required for protein geranylgeranylation catalyzed by geranylgeranyltransferase and has an active role in the up-regulation of RORC expression (49). Our metabolite analysis showed increased GGPP (Fig. 7I), providing a mechanistic explanation for the up-regulation of RORC in PD-1deficient myeloid cells. Cholesterol accumulation is associated with skewing of hematopoiesis toward myeloid lineage and monocytosis, induces a proinflammatory program in monocytes/macrophages and DC, and amplifies TLR signaling (5052). Together, these results unravel a previously unidentified role of PD-1 targeting in regulating myeloid lineage fate commitment and proinflammatory differentiation of monocytes, macrophages, and DC during tumor-driven emergency myelopoiesis, through metabolic reprogramming.

Previously, it was determined that monocyte/macrophage terminal differentiation is controlled by the combined actions of retinoid receptors and the nuclear receptor peroxisome proliferatoractivated receptor (PPAR), which is regulated by cholesterol and promotes gene expression and lipid metabolic processes, leading to terminal macrophage differentiation (26, 53). Because our in vitro studies showed that PD-1deficient myeloid progenitors developed a distinct metabolic program with elevated cholesterol metabolism, we examined whether PD-1 ablation might alter the expression of PPAR in addition to RORC. We found that the expression of PPAR was elevated in CD11b+Ly6C+ monocytic cells and M isolated from tumors of PD-1/ and PD-1f/fLysMcre mice (Fig. 8, A to C). Because PD-1deficient myeloid progenitors developed robust mitochondrial activity during culture in vitro (Fig. 7, G and H) and PPAR is involved in mitochondrial function (53), we examined whether myeloid cells in tumor-bearing mice have improved mitochondrial metabolism, a feature that has an important role in supporting antitumor function of other immune cells (54). Monocytes, M, and DC isolated from tumor of PD-1/, and PD-1f/fLysMcre mice had increased mitochondrial membrane potential compared with myeloid cells from control tumor-bearing mice, consistent with enhanced mitochondrial metabolism (Fig. 8, D to G).

(A to C) Expression of PPAR in myeloid cells at the B16-F10 site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by flow cytometry. Mean percentages SEM (A), representative histograms (B), and contour plots (C) of PPAR-expressing CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets. (D to G) Mitochondrial metabolic activity of myeloid cells at the B16-F10 tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by assessing mitochondrial membrane potential using MitoRed. Mean fluorescence intensity (MFI) SEM of MitoRedpositive CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets within the CD45+CD11b+ gate (D to F) and representative plots of FACS analysis (G) are shown. (H to L) In parallel, expression of IFN-, IL-17A, IL-2, IL-10, RORC, and ICOS in CD8+ TCM and TEM isolated from B16-F10bearing PD-1f/f and PD-1f/fLysMcre mice was assessed by flow cytometry. Representative histograms (H), contour plots (I and K), and mean percentages SEM (J, L, and M) within the CD44hiCD62Lhi gate (for TCM) and CD44hiCD62lo gate (for TEM) cells are shown. Data are from one representative of four independent experiments (*P < 0.05, **P < 0.01, and ***P < 0.005).

We investigated whether these significant immunometabolic changes of myeloid cells, induced by myeloid-specific PD-1 targeting, affected immunological properties of T cells that have key roles in their antitumor function. Compared with control PD-1f/f tumor-bearing mice, PD-1f/fLysMcre tumor-bearing mice had no quantitative differences in CD4+ or CD8+ TEM and TCM cells (fig. S20A) but had significant functional differences. There was an increase of IFN-, IL-17, and IL-10producing CD8+ TEM cells and IL-2producing CD8+ TCM cells (Fig. 8, H to J). Inducible T cell costimulator (ICOS) and lymphocyte-activation gene 3 (Lag3) were elevated in T cells from PD-1f/fLysMcre tumor-bearing mice but cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and mucin domain 3 (Tim3), CD160, and PD-1/PD-L1 were comparable in T cells from PD-1f/f and PD-1f/fLysMcre tumor-bearing mice (Fig. 8, K to M, and fig. S20B). These findings are significant because IL-17producing T helper cell 17 (TH17)/ T cytotoxic cell 17 (Tc17) cells have enhanced antitumor function and mediate durable tumor growth inhibition (55). Moreover, T cells with a hybrid phenotype producing both IFN- and IL-17 might have superior antitumor properties by combining the enhanced effector function of TH1/Tc1 and the longevity and stemness of TH17/Tc17 cells (56). In our studies, these properties of TEM cells correlated with improved antitumor function in PD-1f/fLysMcre mice.

To examine experimentally whether PD-1deficient myeloid cells differentiated in tumor-bearing mice in vivo have improved capacity of inducing antigen-specific T cell responses, we assessed responses of the same primary CD4+ or CD8+ T cells to antigen-loaded DCs isolated from PD-1/ or control mice bearing B16-F10 tumors (fig. S21A). DCs isolated from the spleen of tumor-bearing WT and PD-1/ mice were pulsed with ovalbumin (OVA) and cocultured with OVA-specific CD4+ or CD8+ T cells from OTI or OTII T cell receptor (TCR)transgenic mice. DCs from tumor-bearing PD-1/ mice had superior ability to induce OTI and OTII T cell proliferation and IFN- expression (fig. S21, B and C). Together, our data provide evidence that myeloid cellintrinsic PD-1 ablation induces potent antitumor immunity by decreasing accumulation of MDSC and promoting proinflammatory and effector monocytic/macrophage and DC differentiation, thereby leading to enhanced effector T cell responses.

Our present studies reveal a previously unidentified role of the PD-1 pathway in regulating lineage fate commitment and function of myeloid cells that arise from tumor-driven emergency myelopoiesis. These outcomes are mediated by myeloid-intrinsic effects of PD-1 ablation, leading to altered signaling and metabolic reprogramming of myeloid progenitors characterized by enhanced differentiation and elevated cholesterol synthesis. Consequently, the accumulation of immature immunosuppressive and tumor-promoting MDSC is diminished, and the output of differentiated, inflammatory effector monocytes, M, and DC is enhanced. These immunometabolic changes of myeloid cells promote the differentiation of TEM cells and systemic antitumor immunity in vivo despite preserved PD-1 expression in T cells.

We found that PD-1deficient myeloid progenitors had enhanced activation of Erk1/2 and mTORC1 in response to G-CSF. These results indicate that Erk1/2 and mTORC1, a downstream mediator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which are major targets of PD-1 in T cells (2), are subjected to PD-1mediated inhibition in myeloid cells. These results are revealing because Erk1/2 phosphorylation subverts MDSC-mediated suppression by inducing M-MDSCs differentiation to APC (39). Erk and PI3K regulate glycolysis in response to G-CSF (57). PI3K/Akt/mTORC1 signaling is critical in myeloid lineage commitment. Expression of constitutively active Akt in CD34+ cells induces enhanced monocyte and neutrophil development, whereas a dominant negative Akt has the opposite effect (58). mTORC1 is necessary for the transition of hematopoietic cells from a quiescent state to a prepared alert state in response to injury-induced systemic signals (59), for G-CSFmediated differentiation of myeloid progenitors (40), and for M-CSFmediated monocyte/macrophage generation (41). mTORC1 stimulates translation initiation through phosphorylation of 4E (eIF4E)binding protein 1 (4E-BP1) and ribosomal S6 kinases and has a decisive role in the expression of glucose transporters and enzymes of glycolysis and PPP (47). Consistent with these, our studies showed that PD-1deficient myeloid progenitors had elevated expression of glycolysis and PPP intermediates after culture with emergency cytokines in vitro and enhanced monocytic differentiation in tumor-bearing mice in vivo. Together, our findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis. Further studies will identify how receptor-proximal signaling events mediated by hematopoietic growth factors are targeted by PD-1 in a manner comparable to PD-1mediated targeting of signaling pathways in T cells (2, 34, 35).

Our metabolite analysis showed that a notable difference of PD-1deficient myeloid progenitors was the increased expression of mevalonate metabolism enzymes and the elevated cholesterol. mTORC1 activates SREBP1, which induces transcription of enzymes involved in fatty acid and cholesterol synthesis (48), thereby leading to glycolysis-regulated activation of the mevalonate pathway. Our signaling studies showing enhanced mTORC1 activation and our metabolic studies showing enhanced mitochondrial metabolism and increased cholesterol content in PD-1deficient myeloid cells provide a mechanistic link between the altered differentiation of PD-1deficient myeloid progenitors and the altered immunophenotypic and functional program of PD-1deficient monocytes, M, and DC in tumor-bearing mice. Cholesterol drives myeloid cell expansion and differentiation of macrophages and DC (50, 51, 60) and promotes antigen-presenting function (61). These properties are consistent with the metabolic profile and the increased cholesterol of PD-1deficient myeloid progenitors; the inflammatory and effector features of differentiated monocytes, M, and DC; and the enhanced T effector cell activation in tumor-bearing mice with myeloid-specific PD-1 ablation that we identified in our studies. By such mechanism, PD-1 might centrally regulate antitumor immunity, independently of the expression of PD-1 and its ligands in the TME. Our studies showed that PD-1 expression on myeloid progenitors is an early event during tumor-mediated emergency myelopoiesis and indicate that PD-1 blockade at early stages of cancer might have a decisive effect on antitumor immunity by preventing MDSC generation from myeloid progenitors and inducing the systemic output of effector myeloid cells that drive antitumor T cell responses.

In addition to its expression in myeloid progenitors, in the bone marrow, we found that PD-1 is expressed in all myeloid subsets including M-MDSC, PMN-MDSC, CD11b+F4/80+ M, and CD11c+MHCII+ DC in the tumor and the spleen of tumor-bearing mice, albeit at different levels. This difference might be related to gradient of tumor-derived factors responsible for PD-1 induction such as G-CSF and GM-CSF that we found to induce PD-1 transcription in myeloid progenitors. This possibility would be consistent with the gradual up-regulation of PD-1 expression in splenic myeloid cells, determined by our kinetics studies, which correlates with tumor growth that might be responsible for the increase of systemic levels of tumor-derived soluble factors that induce PD-1. Other cues of the TME known to mediate the activation step of MDSC (14) might also be responsible for the induction of higher PD-1 expression level in the tumor versus the splenic myeloid cells. Our findings unravel a previously unidentified role of PD-1 in myeloid cell fate commitment during emergency myelopoiesis, a process that is involved not only in antitumor immunity but also in the control of pathogen-induced innate immune responses and sterile inflammation (62).

An additional important finding of our studies is that the nuclear receptors RORC and PPAR are up-regulated in myeloid cells by PD-1 ablation. RORs were initially considered retinoic acid receptors but were subsequently identified as sterol ligands. RORC not only is induced by sterols and isoprenoid intermediates (49) but also serves as the high-affinity receptor of the cholesterol precursor desmosterol (63, 64), a metabolic intermediate of cholesterol synthesis via the mevalonate pathway that regulates inflammatory responses of myeloid cells (52, 60). Desmosterol and as sterol sulfates function as endogenous RORC agonists and induce expression of RORC target genes (63, 64). Our studies showed that, in addition to cholesterol, the mevalonate metabolism product GGPP that has an active role in the up-regulation of RORC expression (49) was elevated in PD-1deficient myeloid cells, providing a mechanistic basis for our finding of the elevated RORC expression. Retinoid receptors and PPAR together regulate monocyte/macrophage terminal differentiation (26). Although initially thought to be involved in proinflammatory macrophage differentiation, it was subsequently understood that PPAR predominantly promotes macrophage-mediated resolution of inflammation by inducing expression of the nuclear receptor liver X receptor and the scavenger receptor CD36, thereby regulating tissue remodeling (65). PPAR also regulates macrophage-mediated tissue remodeling by efferocytosis and production of proresolving cytokines (66), which can suppress cancer growth (67). The combined actions of RORC and PPAR induced by myeloid-specific PD-1 ablation might be involved in the antitumor function by promoting both proinflammatory and tissue remodeling properties of myeloid cells. Future studies will dissect the specific role of each of these nuclear receptors on the antitumor immunity induced by myeloid cellspecific ablation of PD-1.

In conclusion, our results provide multiple levels of evidence that myeloid-specific PD-1 targeting mediates myeloid cellintrinsic effects, which have a decisive role on systemic antitumor responses. This might be a key mechanism by which PD-1 blockade induces antitumor function. Recapitulating this immunometabolic program of myeloid cells will improve the outcome of cancer immunotherapy.

immunology.sciencemag.org/cgi/content/full/5/43/eaay1863/DC1

Materials and Methods

Fig. S1. Gating strategy of hematopoietic and myeloid precursors in the bone marrow.

Fig. S2. Gating strategy of myeloid subsets in the spleen and tumor site.

Fig. S3. Cancer-induced emergency myelopoiesis in three different mouse tumor models.

Fig. S4. PD-1 expression is induced on myeloid progenitors by emergency cytokines.

Fig. S5. Gating strategy for identification of MDSC in human blood samples.

Fig. S6. PD-1 expression in human MDSC.

Fig. S7. PD-1 ablation alters tumor-driven emergency myelopoiesis.

Fig. S8. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in response to tumor-driven emergency myelopoiesis.

Fig. S9. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in mice-bearing MC38 or MC17-51 tumors.

Fig. S10. PD-1 ablation increases the output of RORChi effector-like myeloid cells at early stages of tumor growth.

Fig. S11. Therapeutic targeting of PD-1 increases effector features of myeloid cells and decreases tumor growth.

Fig. S12. Myeloid-specific and T cellspecific PD-1 deletion.

Fig. S13. Myeloid-specific PD-1 ablation promotes expansion of IRF8hi and RORChi monocytes and IFN-producing monocytes and macrophages in the tumor site.

Fig. S14. Tumor-induced emergency myelopoiesis and myeloid effector differentiation in Rag2-deficient mice treated with PD-1 antibody.

Fig. S15. PD-1 ablation reduces the threshold of growth factormediated signaling in GMP.

Fig. S16. Myeloid-specific PD-1 ablation induces a distinct metabolic profile characterized by elevated cholesterol.

Fig. S17. Metabolic pathways linking glycolysis to PPP, fatty acid, and cholesterol synthesis.

Fig. S18. Schematic presentation of the mevalonate pathway.

Fig. S19. Increase of glucose uptake and neutral lipid content in PD-1deficient myeloid progenitors early after tumor implantation.

Fig. S20. Myeloid-specific PD-1 deletion alters the immunological profile of CD8+ TEM cells.

Fig. S21. PD-1 ablation enhances antigen presentation ex vivo by tumor-matured DC.

Table S1. List of significantly different metabolites.

Table S2. List of antibodies used for surface staining.

Table S3. List of antibodies used for intracellular staining.

Table S4. List of antibodies used for phenotype of human MDSC.

Table S5. Raw data in Excel spreadsheet.

References (6871)

Acknowledgments: Funding: This work was supported by NIH grants CA183605, CA183605S1, and AI098129-01 and by the DoD grant PC140571. Author contribution: L.S. participated in the conceptualization of the project and experimental design, performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. M.A.A.M. performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. J.D.W., N.M.T.-O., A.C., R.P., Q.W., and M.Y. participated in various steps of the experimental studies. J.A. participated in the experimental design of metabolite studies and the formal analysis and the validation of the data and participated in the preparation of the manuscript. N.P. participated in the conceptualization of the project, designed and performed the bioenergetics studies, and participated in experiments, the analysis and validation of the data, and the preparation of the manuscript. V.A.B. had the overall responsibility of project conceptualization, experimental design, investigation, data analysis and validation, and preparation of the manuscript and figures. Competing interests: V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

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Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

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Energy sector planning needs to be flexible enough to deal with an uncertain future – The National

As the chief executive of a big German utility told me, in the 1970s, the future of his countrys energy was going to be nuclear. In the 1980s, it was brown coal. Today it is renewables solar and wind. Looking out on a new decade, as modellers confidently predict energy to 2050, do we really have a good idea what is coming?

International agencies, ministries, oil companies, banks, consultancies and environmental campaigners all put out their long-term forecasts, whether predictions or aspirations. Popular end dates seem to be 2030 or 2035, though 2030 is effectively tomorrow as far as major energy policies and infrastructure are concerned. Long-range forecasts mostly stop in 2050 apart from the ones studying climate change effects, where 2100 is the horizon to show more of the damage we are inflicting on the environment. The next century may seem unimaginably far-off, yet it should be well within the lifespan of children born today, and certainly of our monuments.

The underlying assumptions in these models are fairly similar. Growth of the world population and economy will continue but slow down, with economic expansion in the range 2.5-3.5 percent annually at first before settling at 1.5-2.5 percent. Essentially, the same large countries and global political and economic system will remain. Emerging Asian economies will grow faster than the West and dominate in overall size, but remain poorer per capita, while Africa catches up only slowly. Energy efficiency and technology will improve steadily, but no dramatic new technologies will appear either in energy production or use.

So energy consumption rises, although in some cases of high efficiency it might peak in the 2030s and then fall slowly. The models more attuned to climate and environment phase out coal and oil in favour of renewable energy and battery vehicles, and petroleum consumption goes into decline somewhere in the 2030s. Some oil company forecasts show still-rising demand into the 2040s and beyond, but oil use becomes concentrated in aviation and petrochemicals. Nuclear generally shrinks a little.

Think if we could have made such confident predictions going back eight decades instead of forwards.

Eighty years ago, the world was descending into the full horrors of the Second World War. The US was barely emerging from the Great Depression, the Soviet Union was ruled by a totalitarian Communist state, and all of Africa and much of Asia were in the grip of colonial empires. Some 2.3 billion people, a third of todays level, inhabited this world, and the economy was less than 4 percent the size it is now. The power of the atom, the jet engine and electronics were just emerging; the world was powered by coal supplemented by oil, wood and horses; steaming from England to Australia took a month; and space travel was science fiction.

New methods for producing and using energy, and entirely new political and social phenomena, will surely emerge up to 2050 and 2100. We can imagine five areas of development, which might overlap or might define entirely new paradigms.

In a world of virtualisation and miniaturisation, we might live much more within our minds and within computers. Three-dimensional printing and nanotechnology would produce highly efficient and tailored goods with a minimum of waste, while centralised industry and conventional bricks-and-mortar retail disappears. Vertical farms powered by low-carbon energy, and artificial meat grown without animals, would feed humanity.

Life extension would change demographics. Genetic engineering, manufactured and tailor-grown organs, and artificial intelligence could take life-spans regularly beyond 125 years. Birth-rates may drop but populations rise more as wealthy people live much longer, exacerbating inequality and generational divides.

Super-globalisation would see the hypercharging of our interconnected yet competitive world. The importance of nation states would diminish in favour of self-selecting personal networks, unanchored corporations and activist groups, and supranational unions.

Self-driving electric vehicles and ships, delivery drones and hypersonic planes usher in a new era of mobility. Space travel would be routine, and much industry would be located in orbit. A wealth of unimagined energy-using devices, including universal helper robots, would emerge. Energy consumption could rise much faster than anticipated, even if most of it comes from ubiquitous solar cells, super-compact batteries, hydrogen and small advanced nuclear or fusion reactors, instead of fossil fuels.

Planetary stewardship would demand the repair of our damaged and impoverished environment. Unprecedented global cooperation would see huge areas of land returned to the wild, extinct species and ecosystems resurrected. Biological and technological methods would remove carbon dioxide from the atmosphere while carefully calibrated geoengineering slows global warming.

Finally, there is the prospect of defeat by the forces of entropy and chaos. Ever-worsening climate change would combine toxically with other problems: a slowing and ageing world economy, growing inequality, the dystopian effects of social media and mass surveillance, the confrontation between China and the US, failed states in parts of the Middle East and Africa. Lands made uninhabitable by drought, sea-level rise, wildfires and heat waves, mass migration, militarised borders, conflict and new totalitarian systems would send the global economy into a permanent and deepening depression. Energy demand would fall but be very dirty as countries fall back on coal and oil.

Much that is familiar will remain alongside much that seems bizarre or inconceivable today. Its hard for energy companies or energy-rich states to build a strategy in the face of such uncertainties. But it is a reminder that whatever we do today should be robust and flexible, not wedded to a single vision of the future however seductive.

Robin M Mills is CEO of Qamar Energy, and author of The Myth of the Oil Crisis

Updated: December 30, 2019 07:49 AM

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Energy sector planning needs to be flexible enough to deal with an uncertain future - The National

Recommendation and review posted by Bethany Smith

Better Buy: CRISPR Therapeutics vs. Sangamo Therapeutics – The Motley Fool

If you're considering investing in the gene editing sector, it's worth taking some time to look through all the main players in this small but promising biotech market. At the moment, there are just a few noteworthy companies in this space, all of them still at early clinical stages despite commanding market valuations well into the billions of dollars.

CRISPR Therapeutics (NASDAQ:CRSP) is likely the first gene editing stock to come to mind, and it's considered by many to be the leading company in the market, if only by market cap. However, smaller companies, like Sangamo Therapeutics (NASDAQ:SGMO), also have plenty of promise.

If you're wondering which of these two stocks is the better buy, then read below to find out all the details.

Image source: Getty Images.

While different gene editing companies target their own specific conditions, investors will notice that many tend to coalesce around the area of blood disorders. Both CRISPR and Sangamo are working on drug candidates that target sickle cell disease and transfusion-dependent beta thalassemia (TDT), which are disorders that hinder the ability of hemoglobin to carry oxygen around the body.

CRISPR is working on CTX001, which has been used to treat two different patients, one with sickle cell disease and the other with beta thalassemia. Both patients have shown a complete reversal of all key symptoms, with more patients now undergoing CTX001 treatment.

Unlike CTX001, Sangamo has two separate drug candidates, each targeting only one of the blood disorders mentioned above. ST-400 is Sangamo's beta thalassemia drug, while BIVV003 is its sickle cell candidate. Both are being developed alongside Sanofi, which has partnered with Sangamo to develop these drugs.

While BIVV003 is still undergoing early clinical testing, with investors still waiting to see the preliminary results, ST-400 has proven to be an early success so far. Sangamo released data in early December regarding the first three patients treated with ST-400 for TDT, with all of them showing encouraging results with few side effects. Further results are expected to come out in 2020.

Sangamo has a pretty diverse portfolio of drug candidates that are either in preclinical or clinical stages of development, totaling 15 separate projects in comparison to CRISPR's nine. Five of those are in early phase 1/2 trials. Besides Sangamo's sickle cell and beta thalassemia treatments, Sangamo is working on treatments for Fabry disease, Hemophilia A, and Hunter syndrome (also known as mucopolysaccharidosis type 2 or MPS II).

The Hemophilia A treatment, SB-525, showed strong results in its phase 1/2 study earlier this year. Patients with this blood disorder, who experience a lack of a key blood-clotting factor, showed significant improvements in levels of this clotting factor after taking SB-525.

Even patients with severe cases of hemophilia A, which is extremely hard to treat, showed impressive improvements in the levels of this clotting factor. Pfizer, which is partnered with Sangamo to develop SB-525, is now moving toward a new phase 3 trial, which is expected to begin sometime in 2020.

Sangamo's Fabry treatment, ST-920, is still undergoing its own early-stage clinical trials, with little information available at present. The only setback for Sangamo has been in its MPS II drug, SB-913, which ended up failing to significantly help patients with the rare genetic disorder. While the company hasn't given up on SB-913 yet, it's definitely the weak link in an otherwise strong drug portfolio.

CRISPR's drug portfolio is a bit narrower, with only two drugs in clinical testing in comparison to Sangamo's five. Besides the previously mentioned CTX001, CRISPR has a fairly strong cancer immunology lineup. CTX110, CTX120, and CTX130 are its selection of immunology candidates, although CTX110 is the only one in clinical testing at the moment.

Cancer immunology is a massive market that's estimated to reach $127 billion by 2026, and a home run in this area would be a major win for CRISPR. CTX110 is a CAR-T (chimeric antigen receptor T-cell) therapy, a type of treatment in which immune cells are extracted from a patient, retrained outside the body, and later reintroduced into the patient's system in hopes they will perform better. While it's not the only CAR-T therapy being developed, CRISPR's treatment could prove to be much cheaper than current treatments, which cost hundreds of thousands of dollars for a single patient.

CRISPR has had a strong fiscal third quarter, reporting $138.4 million in net income on revenues of $211.9 million. But in 2019, CRISPR has so far only reported $36.3 million in net income, as the earlier quarters reported losses. While it's nice that CRISPR is reporting a profit, something very few early-stage biotech companies can boast, it's still a very small figure considering CRISPR's $3.9 billion market cap.

Sangamo's financials look a lot different. Besides being a fraction of CRISPR's size with a market cap of $970 million, Sangamo's Q3 2019 revenues came in at $21.9 million, while reporting a net loss of $27.4 million for the quarter. However, the company has an impressive $408.3 million in cash and equivalents, enough to last for around four years at the current rate of expenses.

In terms of traditional valuation metrics, it's hard to evaluate clinical-stage biotech stocks by looking at ratios, as their financial figures can change dramatically if a drug candidate receives approval. Currently, CRISPR trades at 16.7 its price to sales (P/S) ratio, but in July, the company was trading at an astronomical 1,800 P/S ratio, meaning that investors were willing to pay extraordinarily high amounts for what little revenue it was making that quarter. In comparison, Sangamo is more moderately priced, with a 12.2 P/S ratio.

Both companies are compelling investments if you're looking for exposure to the gene editing sector. While Sangamo has a broader pipeline of projects, I still think CRISPR is the better choice if you had to pick just one of these companies. CRISPR has not only shown positive clinical results for CTX001 and CTX110, but is also reporting a profit for this most recent quarter, which is pretty rare for early-stage biotech stocks. Meanwhile, Sangamo isn't expected to turn a profit anytime soon.

However, gene-editing drugs are still at an early stage of clinical development, and plenty of things can change over the coming years. Both CRISPR and Sangamo are promising investments for someone who's comfortable buying into early-stage biotech stocks.

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Better Buy: CRISPR Therapeutics vs. Sangamo Therapeutics - The Motley Fool

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Duke Researchers Garner Over $6 Million in NIH Funding to Fight Genetic Diseases – Duke Today

Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the sourcebut significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common Funds Somatic Cell Genome Editing (SCGE) program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing both new CRISPR systems for gene regulation and to regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in using AAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about the Duke Center for Advanced Genomic Technologies.

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Duke Researchers Garner Over $6 Million in NIH Funding to Fight Genetic Diseases - Duke Today

Recommendation and review posted by Bethany Smith

The Advances that Will Shape Life Sciences in the 2020s – The Scientist

The 2010s brought major advancements in every aspect of the life sciences and ushered in an era of collaboration and multidisciplinary approaches. The Scientist spoke with Steven Wiley, a systems biologist at Pacific Northwest National Laboratory and member of TSs editorial board, about what he thinks the recent past indicates about the upcoming decade of research.

Wiley: The next year will be a continuation of the scientific breakthroughs that were present the last couple of years, and whats happened the last couple of years will fundamentally transform the next decade. There are two areas that I think are really posed for an explosive growth, and one is single-cell biology. . . . The second one people know is transformative . . . is CRISPR technologies.

Wiley: Single-cell sequencing, single-cell proteomics, single-cell imagingthese are all part of this new area of single-cell biology which is really going to impact a whole slew of different fields. We'll see a lot of breakthroughs driven by that in the next year, but well see the full impact of this playing out over the next decade.

[Single-cell biology] started [out] driven by single-cell sequencing, and very near on the horizon is going to single-cell proteomics. And then, of course, that complements a lot of the imaging work thats been done, developing a new generation of probes to be able to query whats happening at the single-cell level.

This really brings to the fore the idea that cells in a population are very heterogeneous, and what we see at the population level is a reflection of what the individual cells are doing. And until we understand what the individual cells in a population are doing, we cant deal with issues of, for example, mathematically modeling whats going on in cells.

[Researchers developing] both sequencing technologies and proteomics technology in the last decade have been working on increased sensitivity and speed and precision. This increase in speed and precision and increasingly small sample size has gotten down to a point where now we can look at things like cancer heterogeneity. That is . . . when you treat a cancer you can kill 95 percent of the tumor but theres 5 percent left and that is whats going to come back, and you have a recurrence of the cancer or metastasis. So its the small parts that really cause the problem, and until you can actually understand why those resistant cells are different, youre never going to do things like develop a completely effective cancer treatment.

Now the technology is thereboth sequencing technology and mass spectrometry technologies. It opens up new worlds of what we can look at, and I think thats why this is really being very transformative. Were now at the level where we can look at individual cells. Thats amazing.

Wiley: CRISPR technologieseveryone touts them as a way of editing the genome, which is true. But the true power of that, I believe . . . is the fact that it provides a way of tagging endogenous genes. So for example, you see a number of different papers come out in which people have used CRISPR technologies to insert fluorescent markers into genes. You can look at the dynamics and localization and expression of individual genes and individual cells.

The second thing that CRISPR is really good at is perturbations, being able to turn up genes and down genes, altering the expression of individual genes up and down in a cell with incredible specificity. For example, [with] a genetic disease or in cancer, most of the really significant impactful genetic changes are at the level of increased expression or decreased expression. So the way we think about changing gene expression is: [in] one cell type, the gene is off, [and in] another cell type, the gene is on. But thats not actually true. There are subtle changes in abundance and localization and disposition of individual genes that have enormous regulatory impact on the cells. But weve lacked good tools to [investigate] that.

The ability to manipulate the expression level of genes, to tag them, to make modifications in the individual genes and cells opens up a toolbox of experimental technologies that are just revolutionary.

Editors note: Answers have been edited for length and clarity.

Emma Yasinski is a Florida-based freelance reporter. Follow her on Twitter@EmmaYas24.

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The Advances that Will Shape Life Sciences in the 2020s - The Scientist

Recommendation and review posted by Bethany Smith

CRISPR Therapeutics AG [CRSP] A Healthcare stock that is highly – The Dwinnex

CRISPR Therapeutics AG [NASDAQ: CRSP] gained by 1.21% on the last trading session, reaching $60.04 price per share at the time. CRISPR Therapeutics AG represents 57.50M in outstanding shares, while the company has a total market value of $3.41B with the latest information.

The CRISPR Therapeutics AG traded at the price of $60.04 with 803450 shares were bought and sold during the latest trading session. Over the period of the last 3 months, the average trading volume of CRSP shares recorded 1.08M.

Its stock price has been found in the range of 27.50 to 74.00. This is compared to its latest closing price of $59.32.

Pay attention to the next-scheduled financial results for this company to be released, which is slated for Mon 24 Feb (In 52 Days).

Now lets turn to look at profitability: with a current Operating Margin for CRISPR Therapeutics AG [CRSP] sitting at -5087.80, this companys Net Margin is now -5.30%. These metrics indicate that this company is not generating as much profit, after accounting for expenses, compared to its market peers.

This companys Return on Total Capital is -54.81, and its Return on Invested Capital has reached -40.70%. Its Return on Equity is -56.89, and its Return on Assets is -43.40. These metrics suggest that this CRISPR Therapeutics AG does a poor job of managing its assets, and likely wont be able to provide successful business outcomes for its investors in the near term.

What about valuation? This companys Enterprise Value to EBITDA is -22.31. The Enterprise Value to Sales for this firm is now 16.31. CRISPR Therapeutics AG [CRSP] has a Price to Book Ratio of 3.78.

Shifting the focus to workforce efficiency, CRISPR Therapeutics AG [CRSP] earns $16,617 for each employee under its payroll. Similarly, this companys Receivables Turnover is 2.30 and its Total Asset Turnover is 0.01. This publicly-traded organizations liquidity data is also interesting: its Quick Ratio is 16.81 and its Current Ratio is 16.81. This company, considering these metrics, has a healthy ratio between its short-term liquid assets and its short-term liabilities, making it a less risky investment.

CRISPR Therapeutics AG [CRSP] has 57.50M shares outstanding, amounting to a total market cap of $3.41B. Its stock price has been found in the range of 27.50 to 74.00. At its current price, it has moved down by -18.86% from its 52-week high, and it has moved up 118.33% from its 52-week low.

This stocks Relative Strength Index (RSI) is at 42.19. This RSI score is good, suggesting this stock is neither overbought or oversold.

Shares of CRISPR Therapeutics AG [CRSP], on the whole, present investors with both positive and negative signals. Wall Street analysts have mixed reviews when it comes to the 12-month price outlook, and this companys financials show a combination of strengths and weaknesses. Based on the price performance, this investment is somewhat risky while presenting reasonable potential for ROI.

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CRISPR Therapeutics AG [CRSP] A Healthcare stock that is highly - The Dwinnex

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Year in Review: The Top Science Stories of 2019 – WTTW News

2019 has seen some astonishing scientific breakthroughs, from the creation of the first ever image of a black hole a feat once thought impossible to the use of DNA splicing technology to treat sickle cell disease.

As the year comes to an end, three of our regular science contributors Daniel Holz of the University of Chicago, Rabiah Mayas of the Museum of Science and Industry and Mark Hammergren of the Adler Planetarium share what they regard as the most significant science stories of the year.

Here are the stories they selected.

Daniel Hotz: First ever image of a black hole

Using the Event Horizon Telescope, scientists obtained an image of the black hole at the center of galaxy M87, outlined by emission from hot gas swirling around it under the influence of strong gravity near its event horizon. (Credits: Event Horizon Telescope collaboration et al.)

In April, an international astronomical team called the Event Horizon Telescope Collaboration produced an image of a black hole for the first time.

Because not even light can escape from the immense gravity well that is a black hole, the idea of imaging a one was once thought impossible. Holz explained that the image the Event Horizon Telescope team produced is actually of super-heated matter about to fall into the black hole.

We are not looking at the black hole itself, what we are doing is seeing stuff fall into the black hole and that stuff gets very, very hot superheated because of the strong gravity and then it glows, said Holz. And what we are seeing is that glow but in the center nothing is glowing and thats because theres a black hole there.

Mayas noted the years of hard work and international collaboration that created what has already become an iconic image. The team used telescopes around the world to, in effect, create one huge telescope the size of the Earth to create the image.

There were scientists and engineers and astronomers from across the globe that came together to generate this image, said Mayas. The shear technology and the instrumentation and the collaboration that led to that is another example of what a career in STEM can look like for young people.

Rabiah Mayas: Gene-edited cells used to treat sickle cell disease

Researchers at the Sarah Cannon Research Institute in Nashville, Tennessee, announced in November that they had used genetically edited cells to treat sickle cell disease a painful and until now incurable condition that impacts millions of people in the United States and around the world.

Doctors used cells from a patients bone marrow that had been modified using CRISPR cas9 gene-splicing technology and reintroduced the cells back into the patients body.

CRISPR cas9 is something that was identified in bacteria as part of a bacterias natural immunity, said Mayas. The way that CRISPR works is that it looks for specific regions of DNA so the genetic information in the cells of many organisms and recognizes the particular sequence. And cas9 is an enzyme that can cut it. So it cuts the DNA, makes a break, and then your cell can put those ends back together.

CRISPR in this case was used to genetically modify the version of hemoglobin which is the protein that is malformed in Sickle Cell and turn it into a different form that is functional, said Mayas.

Within a month, those cells were producing healthy hemoglobin.

Mark Hammergren: Artemis moon mission

NASA is returning to the moon much sooner than it originally planned.

At the direction of President Donald Trump, NASA has been asked to accelerate its Artemis mission and return humans to the moons surface by 2024. The original Artemis schedule would have put humans back on the moon by 2028.

President Trump and his administration have proposed accelerating this return to the moon and came out and said we are going to land humans on the moon a man and a woman on the moon by 2024. And that is the directive given to NASA, said Hammergren. Regardless of what you think of these plans this is a directive to NASA that NASA has to follow.

Mayas noted that although the Artemis mission is to the moon, it is also regarded as a way to answer key questions and test and prove technology that could one day take humans to Mars.

What does it mean to spend time on another solar body? What does it mean to look for water and develop systems on a place that is not Earth in preparation for Mars?

All: Climate change

Activists on the evening of Monday, Oct. 7, 2019 closed down the streets in front of Chicago City Hall and the James R. Thompson Center as they called on Mayor Lori Lightfoot and Gov. J.B. Pritzker to declare a climate emergency. (WTTW News)

Climate change is the defining challenge of our time, according to United Nations Secretary-General Antonio Guterres.

Guterres noted in an introduction to the latest report of the UNs Science Advisory Group, released in September, that the climate is already changing and highlights the far-reaching and dangerous impacts that will unfold for generations to come.

All three of our scientific contributors believe that climate change is one of the top science stories of the year.

I think young people have been telling us for years that they have been concerned about climate change, said Mayas. Young people from indigenous cultures around the world, from black and other marginalized communities in this country and elsewhere have been screaming for a while about climate change in part because we know from data that certain communities suffer the consequences of climate change more than others.

Hammergren said that as a planetary scientist we have to consider the Earth as a system as a whole and that he had seen directly the increase in carbon dioxide in the atmosphere in his astronomical observations.

Holz noted the evidence for global warming was overwhelming at this point.

The last few years have shown just look at the news the wildfires, the storms, the rising sea levels its just this whole parade of disasters. And this is just the beginning, said Holz. I fear for the future.

But Holz also noted that its not yet too late to try and address some of the worst impacts of climate change, particularly as young people around the world have rallied around this issue.

Its not too late, we can all get involved theres lots of things to do and the fact that young people are rising up. It really impacts them the most and we should listen to them, said Holz. Its somewhat embarrassing that we have to have the young, the next generation, to hold us to task.

Related stories:

Field Museums New Meteorite Contains Stardust That Predates the Solar System

Astronomers Take First-Ever Picture of a Black Hole

Climate Simulations Are Mostly Accurate, Study Finds

Climate Activists: The Oceans Are Rising, And So Are We

Excerpt from:
Year in Review: The Top Science Stories of 2019 - WTTW News

Recommendation and review posted by Bethany Smith

Ventilation Abnormalities Are Unlikely Random Among Patients With Asthma – Pulmonology Advisor

In contrast to previous in silico modeling studies, ventilation abnormalities do not appear randomly distributed among patients with asthma, and may persist in the same lung regions during a prolonged period. These findings were published in CHEST.

In a case study, researchers prospectively followed-up nonidentical female adult twins with lifelong asthma for 2 study visits between January 2010 and March 2017. Pulmonary magnetic resonance imaging, computed tomography imaging, and pulmonary function tests were used to prospectively evaluate the patients during this 7-year period.

Twins had parents who were heavy tobacco smokers in the home, and both parents had a history of airway disease. Different asthma specialists independently prescribed the twins 400 g daily budesonide combined with formoterol (patient 1: once-daily 200/6 g 2 puffs; patient 2: twice-daily 200/6 g 1 puff). Both patients reported weak to moderate controller medication adherence.

At baseline, each twin demonstrated spatially identical focal ventilation defects, and both twins showed left-sided upper lobe ventilation abnormalities at follow-up. Patients had a similar subsegmental airway wall area percentage at follow-up (71% in patient 1 and 75% in patient 2), which the researchers found substantially abnormal, based on the published literature.

Fewer airways were found in patient 2 vs patient 1 (166 vs 202, respectively), as demonstrated in airway number by airway tree generation distal to left-sided upper lobe apicoposterior bronchopulmonary segment and right-sided upper lobe apical bronchopulmonary segment.

Limitations of the study included using only 2 time points for evaluation and the lack of adjustment for shared genetics or in utero events.

If ventilation defects occur randomly in patients with asthma, the researchers wrote, the probability of this occurring in both patients in the same location, twice over 7 years, is approximately one in 130,000 people.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors disclosures.

Reference

Eddy RL, Matheson AM, Svenningsen S, et al. Nonidentical twins with asthma: spatially matched CT airway and MRI ventilation abnormalities. CHEST. 2019;156(6):e111-e116.

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Ventilation Abnormalities Are Unlikely Random Among Patients With Asthma - Pulmonology Advisor

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‘I want to be real’: Ricki Lake debuts shaved head after years of struggling with ‘debilitating’ hair loss – Yahoo Style

Ricki Lake has opened up about about her private struggle with hair loss in a candid post to social media.

The 51-year-old actress and producer rang in the New Year feeling liberated and free after debuting a shaved head. In a lengthy post onFacebook, Lake detailed her nearly 30-year history of hair loss, in hopes that her story will help those who suffer in silence feel less alone.

I have been struggling with hair loss for most of my adult life, Lake wrote. It has been debilitating, embarrassing, painful, scary, depressing, lonely, all the things. There have been a few times where I have even felt suicidal over it. Almost no one in my life knew the level of deep pain and trauma I was experiencing. Not even my therapists over the years knew my truth.

Lake, who landed her first role in the 1988 film Hairspray by director John Waters, says her journey from Hairspray to hairless was likely caused by years of yo-yo-dieting, taking birth control, pregnancy, genetics and stress. The former Ricki Lake Show host relied on hair extensions and wigs to mask her hair loss.

(Photo by Amy Sussman/Getty Images)

It all felt fake and I was super self-conscious and uncomfortable, she said. Ive been to many doctors, gotten steroid shots in my head, [have taken] all the supplements and then some. My hair would recover and then shed again. It was maddening.

ALSO SEE: Model Iskra Lawrence shows off her curves in nude pregnancy shoot

Lake is not alone in her struggle with female hair loss. According to theCanadian Dermatology Association, 40 per cent of women will experience thinning hair and hair loss by the age of 50. In the United States,approximately30 million women experience noticeable hair loss including female pattern baldness and different forms of alopecia.

Ricki Lake. Image via Facebook/MsRickiLake. Photo by Amanda Demme.

Whilemost female hair loss occurs over the age of 40, women of any age can notice an increase of shedding and thinning hair. Genetics, tight or frequent hair styling, extreme stress, hormonal changes, chemotherapy and some medications all contribute to female hair loss.

An extreme diet that resulted in a rapid weight loss of 20 pounds in six weeks lead to a noticeable increase in hair loss, prompting Lake to take control of the situation and set herself free. She decided to forego hair extensions and hair colour, and shave her head.

Story continues

ALSO SEE: 'Sometimes we want to give up': Justin Bieber gets candid about mental health struggles

It is a New Year and a new decade and a new me...I buzzed my hair off and it feels so good! she wrote, giving thanks to her friends and partner Jeff Scult for their support.

(Photo by JB Lacroix/WireImage)

While she notes that she will continue to play with hair for fun, any changes to her look in the future will be done by choice, and not out of shame.

I am liberated. I am free. I am releasing and letting go. I am brave. I am beautiful. I am love, Lake told followers. For 2020 and beyond, I want to be real.

Let us know what you think by commenting below and tweeting @YahooStyleCA!Follow us onTwitterandInstagram.

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'I want to be real': Ricki Lake debuts shaved head after years of struggling with 'debilitating' hair loss - Yahoo Style

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Free Gene Therapy Available for Patients with Alzheimer’s – HealthITAnalytics.com

January 03, 2020 -Maximum Life Foundation (MaxLife), a non-profit organization focused on aging research, is providing a promising free gene therapy for ten patients with Alzheimers disease.

According to the Alzheimers Association, Alzheimers disease is the sixth leading cause of death in the US. Over five million Americans have the condition, leading to costs of $277 billion a year.

With this gene therapy, researchers have seen improvements in Alzheimers symptoms and the recovery of normal brain functions in experiments with mice. In human cell experiments, the therapy had the same effects through the rejuvenation of microglia, the brains first line of defense against infection, and neurons.

In August 2018, a patient received a low dose of the therapy with no adverse side effects. To date, the patients disease hasnt progressed.

MaxLife will grant 100 percent of the therapy costs to help bring pioneering gene therapy to cure this disease and make Alzheimers disease a thing of the past, said David Kekich, MaxLifes CEO.

Studies have proven that aging is the leading factor in many life-threatening diseases, including Alzheimers. This new gene therapy aims to treat the cellular degeneration caused by aging.

The new treatment is offered by Integrated Health Systems, a gene therapy facilitator that is seeking to treat other adult aging-related diseases with no known cure, including sarcopenia, chronic kidney disease, and atherosclerosis.

This technology could halt many of the big age-associated killers in industrialized countries, said Kekich. Compassionate care helps patients with no other option to get access to experimental therapies that may benefit both themselves and society as a whole.

Other healthcare organizations have stressed the need to leverage gene therapies and precision medicine to improve treatment for Alzheimers and other diseases. A recent study published in Frontiers in Aging Neuroscience discussed how precision medicine tactics will help improve cognitive disease treatment.

Taking a precision medicine approach, the question is no longer Does treatment work? but Who does treatment work for? Identifying the characteristics of non-responders becomes as important as responders in understanding the impact of a particular intervention, the team said.

Such an approach may result in considerable health benefits by allowing more effective selection of individuals for treatments based ona prioriknown profiles of disease risk and their potential response to treatment.

Researchers at Massachusetts General Hospital (MGH) also recently discovered that certain genetic variants may help protect individuals against Alzheimers disease, a finding that could hold important implications for precision medicine therapies.

The team studied a patient who carried a mutation in a gene known to cause early onset Alzheimers but didnt show signs of mild cognitive impairment until her seventies. This is nearly three decades after the typical age of onset. Evaluating this patient, and patients like her, could help researchers understand more about the progression of Alzheimers.

This single case opens a new door for treatments of Alzheimers disease, based more on the resistance to Alzheimers pathology rather than on the cause of the disease. In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology, said Yakeel T. Quiroz, PhD, clinical neuropsychologist and neuroimagingresearcher at MGH.

With the new gene therapy, MaxLife will add to the growing body of research exploring the use of precision medicine and genetics in chronic disease treatment.

If we can prove a benefit to patients that have no other option now, we can potentially treat Alzheimers disease in people in early to mid-stage Alzheimers, finally creating effective medicine at the cellular level, states Kekich. If successful, this treatment could potentially be used on other diseases such as Parkinsons and ALS.

To apply for a free therapy or for more information, click here.

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Free Gene Therapy Available for Patients with Alzheimer's - HealthITAnalytics.com

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Duke researchers land $6M in federal grants to advance gene editing – WRAL Tech Wire

DURHAM Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the source but significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common FundsSomatic Cell Genome Editing (SCGE)program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

Duke engineers improve CRISPR genome editing with biomedical tails

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Duke researchers: Single CRISPR treatment provides long-term benefits in mice

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing bothnew CRISPR systems for gene regulationandto regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in usingAAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about theDuke Center for Advanced Genomic Technologies.

(C) Duke University

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New Batten Research Key to Informing Potential Therapies, Review Says – Batten Disease News

New research has deepened the understanding of the underlying causes of Batten disease, including organs and cell types affected as well as crucial molecular mechanisms, which can help the design of novel therapies, a review study reports.

Researchers believe these new insights will be key to inform the targeting, timing, and strategies for future treatments.

The study, Pathomechanisms in the neuronal ceroid lipofuscinoses, was published in the journal Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease.

Batten disease, also known as neuronal ceroid lipofuscinoses (NCLs), is a group of inherited neurodegenerative disorders that share certain clinical symptoms. The various forms of the disease are caused by different mutations and distinguished in part by the age at which symptoms appear.

All are lysosomal storage disorders (LSDs) characterized by the abnormal accumulation of fatty substances, known as ceroid and lipofuscin, inside cells in compartments called lysosomes, which are responsible for breaking down and recycling cell materials.

This buildup is particularly toxic to nerve cells (neurons) and leads to progressive deterioration of the brain, even though other tissues can also be affected.

Novel clinical and preclinical findings have deepened scientists understanding of what causes Batten disease and how these disorders progress over time.

The study reviews these insights, which could facilitate the development of new treatments that target each disease type.

Major advances have been made in therapies targeting the central nervous system, or CNS (comprising the brain and spinal cord), but NCLs should be considered diseases that can affect multiple organ systems, and not just the brain as has been the traditional view, the researchers wrote.

Evidence shows that multiple organs can be affected, with disease spreading to other body regions depending on disease type. Mapping all the tissues affected will be important to refine therapeutic delivery and timing, the researchers said.

Shrinkage, or atrophy, of the brain, accompanied by enlargement of the lateral ventricles (cavities within the brain filled with cerebrospinal fluid) is a common finding in Batten disease. But as the proteins affected in Batten disease are widely expressed in various tissues and cell types, it is likely that other organs are also affected by these disorders.

Observations in animal models and patients, for instance, suggest that the spine, as well as vision, the heart, and the bowel, are likely affected in multiple NCLs.

Identifying and targeting all organs and tissues involved, which so far have been overlooked, is important and could provide added benefit to treatment approaches for Batten disease, the scientists said.

Specific populations of neurons are more vulnerable to Batten disease. Early in the disease, interneurons neurons that connect sensory and motor neurons within the CNS are lost in several regions in the brain. Moreover, a type of neuron involved in controlling motor movement, called Purkinje cells, also seem to be particularly vulnerable.

While the reasons for this are still unclear, the unique biological and electrical properties of these neurons and their greater dependence on lysosomes could explain why they are more vulnerable to Batten disease.

Researchers have also been reconsidering the role played by glial cells, which are cells of the nervous system that provide protection and support to neurons.

Although Batten disease has been considered a disease of neurons, the abnormal accumulation of fatty and proteic substances that mark these disorders occurs in various cell types across the body, in addition to the nervous system.

A growing body of evidence suggests that the activation of astrocytes and microglia two types of glial cells precedes and more accurately predicts where neuronal loss is going to occur, when compared to the actual measurement of fatty material accumulation.

In cell models of CLN1 (known as infantile Batten disease) and CLN3 (known as juvenile Batten disease), astrocytes and microglia were seen to cause neuronal loss, which suggests that they have an important role in the development of Batten disease.

There is also evidence for an antibody-mediated immune response in Batten disease, with a possible autoimmune component a harmful immune response that attacks the bodys own tissues especially in CLN3.

In addition to their role in degrading cell waste, lysosomes are involved in other processes such as sensing nutrients and balancing the levels of calcium and metals, as well as the transport and communication between nerve cells.

Likely related to that is the fact that various Batten disease models are characterized by synaptic dysfunction a malfunction of the synapse, or the junctions between two nerve cells that allow them to communicate.

Other cellular pathways linked to lysosomes including autophagy (the self-eating waste disposal system of cells) and gene activation routes may also be abnormal in Batten disease and contribute to its development.

This information sheds light on potential mechanisms by which NCL mutations may lead to disease, beyond the role of lysosomes.

Various investigational therapies have gone through preclinical tests, including immunomodulatory agents, modulators of lysosomal function, agents that mimic the deficient enzyme in a particular NCL, and inhibitors of glutamate receptor (cell receptors important for transmitting signals between neurons). All these approaches have had varying degrees of success, the review stated.

Some medicines have been tested in patients, such as the immunosuppressive agent mycophenolate mofetil, sold under the brand name CellCept, which was evaluated in a Phase 2 study for CLN3 (NCT01399047).

Cystagon, a molecule that mimics PPT1 (the protein deficient in CLN1), has also been clinically tested in a Phase 4 clinical trial (NCT00028262). However, the benefits of both treatments have been only modest in patients.

This has further highlighted the importance of targeting [disease mechanisms] that are specific to each form of the disease, the researchers wrote.

They believe that targeting the known common defects in neuroinflammation and autophagy may help to develop add-on therapies that could greatly improve the therapeutic efficacy as compared to single-therapy strategies.

Moreover, the discovery of disease manifestations at unexpected sites within or outside the CNS will necessitate the development of therapies that can be targeted to these tissues successfully, the researchers wrote.

Defining the timing of disease in these different tissues, in relation to events in the CNS, will provide important information about effective therapeutic windows and is currently informing the design of various gene therapy clinical trials.

These include ongoing Phase 1/2 clinical trials at the Nationwide Childrens Hospital, in Ohio, testing Amicus Therapeutics gene therapies: AAV-CLN6 for CLN6 disease (NCT02725580) and AAV9-CLN3 for CLN3 (NCT03770572).

To evaluate a gene therapy for CLN2, safety and efficacy studies (NCT00151216, NCT01414985, and NCT01161576) are being conducted at Weill Cornell Medical College in New York.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.

Total Posts: 14

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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New Batten Research Key to Informing Potential Therapies, Review Says - Batten Disease News

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What Does 2020 Have in Store for the Life Sciences? – BioSpace

With the books being closed on 2019, its time to prognosticate about what the next year will hold in the biotech and pharmaceutical industry. And, to paraphrase a famous song from the 1980s, grab a set of shades, because the future looks bright.

BioSpace spoke to leaders from various corners of the industry who provided their insights into what the coming year is likely to hold for their particular sphere. Below are predictions for three spheres within the industry for the coming year.

Oncology

Immuno-oncology has been one of the research cornerstones in cancer research and that will continue. However, in 2020, traditional targeted therapies will continue to be of importance. Stephen Gately, chief executive officer of TD2 (Translational Drug Development), an oncology-focused contract research organization, said there are still roles for traditional targeted therapeutics for specific indications. Following Mercks acquisition of ArQule, Inc. and its kinase inhibitor discovery and development programs for cancer treatment, predicted the industry might see a refocus on understanding cancer and how it can respond to different drugs. He said Merck would not have spent $2.7 billion for ArQules Phase II Brutons tyrosine kinase inhibitor ARQ 531 if there was not a potential upside for the therapy, particularly as a treatment for B-cell cancers. If trial protocols are well-established and there are stricter guidelines for patient selections, Gately said the use of certain inhibitors are vastly superior to immunotherapies in development.

When it comes to clinical trials, Gately predicted there could be a change in how those are organized. He said the goal for companies is to attempt to get their assets into trials as quickly as possible but noted there is a heated and competitive battle for trial sites. As companies attempt to elbow their way to the front of the line, Gately said it is possible that the industry will begin to see more opportunities for economic incentives used to convince the clinical trial sites to take up trials sooner. If that is established, Gately said it will become a game-changer.

Cell and Gene Therapies

This past year saw the approval of gene therapies that can address devastating diseases. And that is likely to continue in 2020. But, safety will still be paramount. Ena Cratsenburg, chief business officer of Ginkgo Bioworks, said over the course of the next year, we will see drug developers use synthetic biology to improve their ability to develop therapeutics with unprecedented levels of activity and control. In 2020, synbio companies will solidify their positions as key enablers in bringing the most innovative medicines to consumers, Cratsenburg said.

Mark Sawicki, chief commercial officer at Cryoport, developer of the first shippers certified for the delivery of human advanced therapies, said that as the cell and gene therapies continue to show their importance for treating new diseases, 2020 will usher in a record year for biologics license applications and marketing authorization applications. Sawicki suggested that over the course of the coming year, eight or nine companies will file such applications to gain regulatory approval of their products. In addition to the high number of filing companies, he suggested that there will be multiple new products launching with three or four generating revenues in 2020. By 2023, Sawicki predicts there will be at least 22 commercial launches in the space.

Jason Steiner, vice president of business development and strategy at gene editing company Synthego, said in 2020, the gap between the pace of innovation in the cell and gene therapy landscape and the infrastructure required for commercialization and deployment will continue to widen before it converges again.Steiner said the development of engineered cell therapies will continue to move toward non-viral approaches in order to boost engineering sophistication while decreasing the time and cost of traditional engineering. He added that manufacturing consideration of cell and gene therapies will continue to move farther upstream. They will be more tightly integrated with early development to avoid commercialization bottlenecks that are being caused by a rapid increase in the pace of development and regulatory approval cycles.

Real World Evidence

The importance of Real World Evidence (RWE) will continue to grow in 2020. Jane Reed, director of life sciences at U.K.-based Linguamatics, said the industry will continue to harness RWE in its drug development programs. RWE was not a topic of conversation in the industry 10 years ago, Reed said, but now there is significant value seen from what RWE brings to the table. RWE relates to the collection of information about a drugs safety and efficacy outside the structure of a clinical trial. The data can be collected from a variety of sources, including electronic health records, wearable devices, lab tests and more. The pharma industry will need to not only continue to collect the data, but learn to use it in a way that improves the outcomes of the patients it serves. Reed said the industry has to show they are listening to the patient community and be flexible. From there, the industry will need to feed that patient-driven data into drug discovery efforts. To boost the collection of RWE, Reed said the use of targeted social media research will also increase the amount of data that companies have at their fingertips. As companies within the pharmaceutical industry continue to dig into the depths of disease states, particularly those of rare diseases, Reed said the use of RWE will prove to be increasingly important.

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What Does 2020 Have in Store for the Life Sciences? - BioSpace

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Cell and Advanced Therapies Supply Chain Management Industry Report, 2019-2030 – GlobeNewswire

Dublin, Jan. 03, 2020 (GLOBE NEWSWIRE) -- The "Cell and Advanced Therapies Supply Chain Management Market, 2019-2030: Focus on Technological Solutions" report has been added to ResearchAndMarkets.com's offering.

Cell and Advanced Therapies Supply Chain Management Market: Focus on Technological Solutions, 2019-2030 report features an extensive study of the growing supply chain management software solutions market.

The focus of this study is on software systems, including cell orchestration platforms (COP), enterprise manufacturing systems (EMS), inventory management systems (IMS), laboratory information management systems (LIMS), logistics management systems (LMS), patient management systems (PMS), quality management systems (QMS), tracking and tracing software (TTS), and other such platforms that are being used to improve / optimize various supply chain-related processes of cell and advanced therapies.

One of the key objectives of the report was to understand the primary growth drivers and estimate the future size of the supply chain management software solutions market. Based on multiple parameters, such as number of cell and advanced therapies under development, expected pricing, likely adoption rates, and potential cost saving opportunities from different software systems, we have developed informed estimates of the evolution of the market, over the period 2019-2030.

In addition, we have provided the likely distribution of the current and forecasted opportunity across:

Advanced therapy medicinal products, such as cell and gene therapies, have revolutionized healthcare practices. The introduction of such treatment options has led to a paradigm shift in drug development, production and consumption. Moreover, such therapies have actually enabled healthcare providers to treat several difficult-to-treat clinical conditions.

In the past two decades, more than 30 such therapy products have been approved; recent approvals include Zolgensma (2019), RECELL System (2018), AmnioFix (2018), EpiFix (2018), EpiBurn (2018), Alofisel (2018), LUXTURNA (2017), Yescarta (2017), and Kymriah (2017). Further, according to a report published by The Alliance for Regenerative Medicine in 2019, more than 1,000 clinical trials are being conducted across the globe by over 900 companies.

In 2018, around USD 13 billion was invested in this domain, representing a 73% increase in capital investments in this domain, compared to the previous year. It is worth highlighting that, based on an assessment of the current pipeline of cell therapies and the historical clinical success of such products, it is likely that around 10-20 advanced therapies are approved by the US FDA each year, till 2025.

The commercial success of cell and advanced therapies is not only tied to whether they are capable of offering the desired therapeutic benefits, but also on whether the developers are able to effectively address all supply chain requirements. The advanced therapy medicinal products supply chain is relatively more complex compared to the conventional pharmaceutical supply chain. As a result, there are a number of risks, such as possible operational inefficiencies, capacity scheduling concerns, process delays leading to capital losses, and deliverable tracking-related issues, which need to be taken into consideration by therapy developers.

This has generated a need for bespoke technological solutions, which can be integrated into existing processes to enable the engaged stakeholders to oversee and manage the various aspects of the cell and advanced therapies supply chain, in compliance to global regulatory standards. Over the years, several innovative, software-enabled systems, offering supply chain orchestration and needle-to-needle traceability, have been developed.

The market has also recently witnessed the establishment of numerous partnerships, most of which are agreements between therapy developers and software solutions providers. Further, given the growing demand for cost-effective personalized medicinal products, and a myriad of other benefits of implementing such software solutions, the niche market is poised to grow significantly in the foreseen future.

Amongst other elements, the report features:

In order to account for the uncertainties associated with some of the key parameters and to add robustness to our model, we have provided three market forecast scenarios portraying the conservative, base and optimistic tracks of the industry's evolution.

The opinions and insights presented in this study were influenced by discussions conducted with several stakeholders in this domain. The report features detailed transcripts of interviews held with the following individuals:

Key Topics Covered

1. PREFACE1.1. Scope of the Report1.2. Research Methodology1.3. Chapter Outlines

2. EXECUTIVE SUMMARY

3. INTRODUCTION3.1. Context and Background3.2. An Introduction to Cell and Advanced Therapies3.2.1. Classification of Advanced Therapy Medicinal Products3.2.2. Current Market Landscape3.3. Cell and Advanced Therapies Supply Chain3.3.1. Key Processes3.3.2. Challenges Associated with the Cell and Advanced Therapies Supply Chain3.4. Software Solutions for Cell and Advanced Therapies Supply Chain Management3.4.1. Cell Orchestration Platform3.4.2. Enterprise Manufacturing System3.4.3. Inventory Management System3.4.4. Laboratory Information Management System3.4.5. Logistics Management System3.4.6. Patient Management System3.4.7. Quality Management System3.4.8. Tracking and Tracing System3.5. Growth Drivers and Roadblocks3.6. Emergence of Digital Technologies in Supply Chain Management3.6.1. Blockchain Technology3.6.2. Internet of Things3.6.3. Augmented Reality3.6.4. Big Data Analytics3.6.5. Artificial Intelligence

4. CURRENT MARKET LANDSCAPE4.1. Chapter Overview4.2. Cell and Advanced Therapies Supply Chain Management: Overall Market Landscape4.2.1. Analysis by Type of Software Solution4.2.2. Analysis by Key Specification and Benefit4.3.3. Analysis by Application4.3.4. Analysis by End User4.3.5. Analysis by Mode of Deployment4.3.6. Analysis by Scale of Management4.3.7. Analysis by Regulatory Certifications / Accreditations4.3. Cell and Advanced Therapies Supply Chain Management: Developer Landscape4.2.1. Analysis by Year of Establishment4.2.2. Analysis by Location of Headquarters4.2.3. Analysis by Size of Company4.3.4. Analysis by Support Services Offered4.3.5. Leading Developers: Analysis by Number of Software Solutions

5. COMPANY COMPETITIVENESS ANALYSIS5.1. Chapter Overview5.2. Methodology5.3. Assumptions and Key Parameters5.4. Competitiveness Analysis: Overview of Supply Chain Management Software Solution Providers5.4.1. Small-sized Companies5.4.2. Mid-sized Companies5.4.3. Large Companies

6. CORE SUPPLY CHAIN MANAGEMENT SOFTWARE SOLUTIONS: COMPANY PROFILES6.1. Chapter Overview6.2. Brooks Life Sciences6.2.1. Company Overview6.2.2. Financial Information6.2.3. BiobankPro: Software Description6.2.4. Recent Developments and Future Outlook6.3. Cryoport6.3.1. Company Overview6.3.2. Financial Information6.3.3. Cryoportal: Software Description6.3.4. Recent Developments and Future Outlook6.4. MasterControl6.4.1. Company Overview6.4.2. MasterControl Platform: Software Description6.4.3. Recent Developments and Future Outlook6.5. SAP6.5.1. Company Overview6.5.2. Financial Information6.5.3. SAP S/4HANA: Software Description6.5.4. Recent Development and Future Outlook6.6. Savsu Technologies6.6.1. Company Overview6.6.2. Financial Information6.6.3. evo Cold Chain 2.0: Software Description6.6.4. Recent Development and Future Outlook6.7. TraceLink6.7.1. Company Overview6.7.2. Financial Information6.7.3. Digital Supply Chain Platform: Software Description6.7.4. Recent Developments and Future Outlook

7. CELL ORCHESTRATION PLATFORMS: EMERGING TRENDS AND PROFILES OF KEY PLAYERS7.1. Chapter Overview7.2. Supply Chain Orchestration Platforms7.2.1. Key Functions of Supply Chain Orchestration Platforms7.2.2. Advantages of Supply Chain Orchestration Platforms7.2.3. Supply Chain Orchestration Platform Implementation Strategies7.3. Supply Chain Orchestration Platform: Trends on Twitter7.3.1. Scope and Methodology7.3.2. Historical Trends in Volume of Tweets7.3.3. Popular Keywords7.4. Key Industry Players7.4.1. Be The Match BioTherapies7.4.2. Clarkston Consulting7.4.3. Haemonetics7.4.4. Hypertrust Patient Data Care7.4.5. Lykan Bioscience7.4.6. MAK-SYSTEM7.4.7. sedApta Group7.4.8. Stafa Cellular Therapy7.4.9. Title 21 Health Solutions7.4.10. TrakCel7.4.11. Vineti

8. FUNDING AND INVESTMENT ANALYSIS8.1. Chapter Overview8.2. Types of Funding8.3. Cell and Advanced Therapies Supply Chain Management: Recent Funding Instances8.3.1. Analysis by Number of Funding Instances8.3.2. Analysis by Amount Invested8.3.3. Analysis by Type of Funding8.3.4. Analysis by Number of Funding Instances and Amount Invested across Different Software Solutions8.3.5. Most Active Players: Analysis by Amount Invested8.3.6. Most Active Investors: Analysis by Participation8.3.7. Geographical Analysis by Amount Invested8.4. Concluding Remarks

9. PARTNERSHIPS AND COLLABORATIONS9.1. Chapter Overview9.2. Partnership Models9.3. Cell and Advanced Therapies Supply Chain Management: Recent Collaborations and Partnerships9.3.1. Analysis by Year of Partnership9.3.2. Analysis by Type of Partnership9.3.3. Analysis by Partner's Focus Area9.3.4. Analysis by Type of Software Solution9.3.5. Most Active Players: Analysis by Number of Partnerships9.3.6. Analysis by Regions

10. PLATFORM UTILIZATION USE CASES10.1. Chapter Overview10.2. Cell and Advanced Therapies Supply Chain Management: Recent Platform Utilization Use Cases10.2.1. Analysis by Year of Utilization10.2.2. Analysis by User's Focus Area10.2.3. Analysis by Type of Software Solution10.2.4. Most Active Players: Analysis by Number of Utilization Instances10.2.5. Most Active Players: Regional Analysis by Number of Utilization Instances

11. VALUE CHAIN ANALYSIS11.1. Chapter Overview11.2. Cell and Advanced Therapies Value Chain11.2. Cell and Advanced Therapies Value Chain: Cost Distribution11.3.1. Donor Eligibility Assessment11.3.2. Sample Collection11.3.3. Manufacturing11.3.4. Logistics11.3.5. Patient Verification and Treatment Follow-up

12. STAKEHOLDER NEEDS ANALYSIS12.1. Chapter Overview12.2. Cell and Advanced Therapies Supply Chain Management: Needs of Different Stakeholders12.2.1. Comparison of Stakeholder Needs

13. COST SAVINGS ANALYSIS13.1. Chapter Overview13.2. Key Assumptions and Methodology13.3. Overall Cost Saving Potential of Supply Chain Management Software Solutions, 2019-203013.3.1. Cost Saving Potential in Donor Eligibility Assessment, 2019-203013.3.2. Cost Saving Potential in Sample Collection, 2019-203013.3.3. Cost Saving Potential in Manufacturing, 2019-203013.3.4. Cost Saving Potential in Logistics, 2019-203013.3.5. Cost Saving Potential in Patient Verification and Treatment Follow-up, 2019-2030

14. MARKET FORECAST14.1. Chapter Overview14.2. Key Assumptions and Forecast Methodology14.3. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market, 2019-203014.3.1. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by Application14.3.2. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by End User14.3.3. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by Type of Software Solution14.3.4. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by Mode of Deployment14.3.5. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by Geography14.4. Overall Cell and Advanced Therapies Supply Chain Management Solutions Market: Distribution by Application, Type of Software Solution and Mode of Deployment14.4.1. Cell and Advanced Therapies Supply Chain Management Solutions Market for Donor Eligibility Assessment, 2019-203014.4.2. Cell and Advanced Therapies Supply Chain Management Solutions Market for Sample Collection, 2019-203014.4.3. Cell and Advanced Therapies Supply Chain Management Solutions Market for Manufacturing, 2019-203014.4.4. Cell and Advanced Therapies Supply Chain Management Solutions Market for Logistics, 2019-203014.4.5. Cell and Advanced Therapies Supply Chain Management Solutions Market for Patient Verification and Treatment Follow-up, 2019-2030

15. EXECUTIVE INSIGHTS15.1. Chapter Overview15.2. Thermo Fisher Scientific15.2.1. Company Snapshot15.2.2. Interview Transcript: Bryan Poltilove, Vice President and General Manager15.3. Cell and Gene Therapy Catapult15.3.1. Company Snapshot15.3.2. Interview Transcript: Jacqueline Barry, Chief Clinical Officer15.4. McKesson15.4.1. Company Snapshot15.4.2. Interview Transcript: Jill Maddux, Director, Cell and Gene Therapy Product Strategy, and Divya Iyer, Senior Director, Corporate Strategy and Business Development15.5. TrakCel15.5.1. Company Snapshot15.5.2. Interview Transcript: Martin Lamb, Chief Business Officer

16. CONCLUDING REMARKS16.1. Chapter Overview16.2. Key Takeaways

17. APPENDIX 1: LIST OF ADDITIONAL SUPPLY CHAIN MANAGEMENT SOFTWARE SOLUTIONS

18. APPENDIX 2: TABULATED DATA

19. APPENDIX 3: LIST OF COMPANIES AND ORGANIZATIONS

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Cell and Advanced Therapies Supply Chain Management Industry Report, 2019-2030 - GlobeNewswire

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BLA Submitted for Gene Therapy to Treat Hemophilia A – Hematology Advisor

Home Topics Bleeding Disorders

BioMarin has submitted a Biologics License Application (BLA) to the Food and Drug Administration (FDA) for valoctocogene roxaparvovec (BMN 270) for the treatment of hemophilia A in adults. This is the first marketing application submission for a gene therapy product for any type of hemophilia.

Valoctocogene roxaparvovec is an investigational adeno-associated virus (AAV) gene therapy that is administered as a single infusion to produce clotting factor VIII. The BLA submission is supported by interim analysis of a phase 3 study and 3-year phase 1/2 data. Results from the ongoing phase 1/2 study showed that bleed rate control and reduction in factor VIII usage was maintained for a third year following a single administration of valoctocogene roxaparvovec.

The FDA previously granted Breakthrough Therapy and Orphan Drug designations to valoctocogene roxaparvovec. The Company anticipates the BLA review to commence in February 2020.

We look forward to working with the FDA as we seek marketing authorization for the potential first gene therapy for hemophilia A, said Hank Fuchs, MD, President, Global Research and Development at BioMarin. Our hope is one day very soon to deliver a transformative treatment that has the potential to change the way hemophilia A is treated.

For more information visit biomarin.com.

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Top 10 ALS Stories of 2019 – ALS News Today

Throughout 2019, ALS News Today brought you daily coverage of key findings, treatment developments, clinical trials, and other events related to amyotrophic lateral sclerosis (ALS).

As a reminder of what mattered most to you in 2019, here are the top 10 most-read articles of last year with a brief description of what made them interesting and relevant to the ALS community.

We look forward to reporting more news to patients, family members, and caregivers dealing with ALS during 2020.

A tale of two preclinical studies showed that a gene therapy candidate targeting a key ALS mutation in the C9orf72 gene was able to lessen the buildup of toxic RNA clumps and reduce the activity of the mutated gene in cells collected from a patient with frontotemporal dementia (FTD) and a mouse model of ALS.

Developed by uniQure,the therapy is designed to silence thedisease-causing gene. It works by delivering microRNAs (miRNAs) RNA molecules that regulate gene expression that target the mutated C9orf72s RNA for degradation. The results supported the continuation of uniQures gene therapy program in ALS and FTD, the company said.

In the summer, a small study discovered an altered composition of gut microbes in people with ALS, which could drive digestive problems in those with the disease.

Using genetics, a research team in China found that fecal samples of people with ALS have an increase in harmful microbes of the phylum Firmicutes and a decrease in beneficial microorganisms called Bacteroidetes. The resulting poor gastrointestinal health may lead to a decline in the guts digestion and metabolism functions.

At the beginning of the year, U.S. biopharmaceutical MediciNova received a notice of allowance stating that its request for a patent covering a combination of its investigational therapy ibudilast (MN-166) plus Rilutek (riluzole) was being consideredby the U.S. Patent and Trademark Office.

Ibudilast is a small molecule that reduces the activity of immune cells in the brain while supporting the growth of motor neurons, those lost in people with ALS. In a Phase 2 trial (NCT02238626), the treatment was found to work well in combination with Sanofis approved therapy Rilutek, improving patients functional activity, quality of life, and muscle strength.

The notice of allowance was the final step toward patent registration. Such registration will provide patent protection until November 2035 to the combination, for use in treating ALS and other neurodegenerative diseases.

In June, MediciNova launched a Phase 2b/3 clinical trial to continue studying ibudilast as an add-on therapy to Rilutek. The multicenter, double-blind study (NCT04057898) will recruit approximately 230 participants, who will be randomly selected to receive either ibudilast plus Rilutek or a placebo plus Rilutek for 12 months.

The trials main goal is to study ibudilasts impact on ALS progression and functional disability by determining changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score between the beginning and end of the treatment period. Secondary objectives include changes in patients muscle strength, quality of life, and respiratory function. The study also will evaluate the safety and tolerability profile of ibudilast.

Just a few months earlier, MediciNova had received approval from the U.S. Food and Drug Administration (FDA) to initiate this trial. Eligible patients must have had the disease for no more than 18 months and present just mild disability.

During the trial, patients will receive Rilutekfor at least 30 days before starting a regimen of either 100 mg per day of ibudilast or a placebo for a period of 12 months. Participants may then enter an extension phase in which they will be offered the ibudilast combination for an additional six months. Top-line data is expected by December 2021.

The Phase 3 trial evaluatingBrainStorm Cell Therapeuticss cell therapy candidateNurOwn completed patient enrollment in October. The 200 participants will receive three administrations of NurOwn, or a placebo, into the spinal canal every two months. The primary goals are to demonstrate the therapys safety and its ability to slow disease progression.

A cell-based therapy, NurOwn works by removing specific stem cells from patients and converting them to cells that produce molecules that promote nerve tissue growth and survival. The modified cells are then returned to the patient to stimulate nerve tissue growth. NurOwn aims to safely improve abilities like swallowing, speech, handwriting, and walking in people with ALS.

A long-term Phase 2/3 study examining vitamin B12 as a treatment for ALS found that ultra-high doses of methylcobalamin, the physiologically active form of this vitamin, may extend survival and slow the decline in functional capacity, compared with a placebo.

The study included 373 patients, diagnosed fewer than three years earlier, across 51 sites in Japan. However, the benefits were only seen in patients diagnosed less than one year before taking the supplements, and only a trend was observed.

Results from a Phase 1 clinical trial (NCT02870634) showed that CuATSM a small molecule able to selectively deliver copper to cells with damaged mitochondria slowed disease progression and improved the respiratory and cognitive function of people with ALS.

Damaged mitochondria are considered a hallmark of several neurodegenerative diseases, including ALS, and delivering copper is thought to restore the health of these organelles. Developer Collaborative Medicinal Development (CMD) began testing CuATSM in patients with sporadic and familial ALS in 2016.CMD is now planning to launch a randomized, placebo-controlled clinical trial for CuATSM to confirm these results.

In March, a study discovered several species of bacteria and fungi living in the central nervous system (CNS) of people with ALS, suggesting that patients have coexisting bacterial and fungal infections.

The study built on prior research suggesting that ALS might be caused by a fungal infection. Researchers then examined frozen CNS tissue from 11 ALS patients to assess whether bacterial infections accompany fungal infections. Bacterial DNA was found in different regions of the CNS and the presence of bacteria was confirmed in neural tissue samples.

Our most-read article of 2019reported that small nerve damage may serve as an ALS trigger. Such damage may accelerate motor symptoms in rats carrying a mutation in the SOD1 gene,one of the 40 genes associated with ALS development in humans.

While rats without the mutation completely recovered leg function four weeks after induced damage to the sciatic nerve, located in the leg, SOD1-mutated animals were unable to fully recover. These rats also lost function in the uninjured leg, likely as a consequence of sustained immune activation and more severe neurodegeneration.

The induced nerve damage mimics head injury and trauma in human patients, which could explain the higher prevalence of the disease among war veterans and professional athletes.

***

At ALS News Today, we hope these stories and our regular reporting throughout 2020 contribute to informing and improving the lives of everyone affected by ALS.

We wish all our readers a happy 2020.

Total Posts: 6

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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Top 10 ALS Stories of 2019 - ALS News Today

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