(Picture; Nuthing)

Lets face it, the past few months have been stressful enough were due a break. And frankly summer should be off-season for anything high-maintenance.

Whether you are WFH in August or actually managing a getaway, right now we are all looking for no-fuss makeup, hassle-free hair and stress-free style.

Heres what can help you look and feel your best, with as little effort as possible:

Lots has been written about the importance of Vitamin D in recent months and although were (hopefully) getting sunshine about now it important to keep levels high.

Myprotein makes a convenient spray in both Vitamin D3 and B12 that ensure everyone gets the essential micronutrients and vitamins that we might miss if were in front of a laptop.

Vitamin D3 Spray, 8.99, MyProtein

This award-winning collagen drink supplement is packed with the highest concentration of marine collagen on the market. Its also infused with vitamin C, which works with the collagen to enhance skin rejuvenation and tissue renewal.

A fuss-free and easy addition to your beauty regime, users say that their skin feels softer, more hydrated and firmer.

Comes in 14 ready-mixed 10ml sachets; can be added to hot or cold drinks.

Collagen Drink Supplement For Women, 32.99, Absolute Collagen

Too tired to make your own? These are insta-healthy meals. Purition is 100% whole food shakes, are made from crushed nuts, seeds, fruits and vegetables and come in ordinary or vegan recipe. All are gluten-free and low in sugar.

Flavours include superfood ingredients such as turmeric and beetroot.

Original Discovery Box, 13.50, Purition

Epsom salts have long been hailed by wellness experts for instantly de-bloating and helping with water retention.

These from Westlab do even more. Mixed with essential oils, the Alchemy range helps draw fluid and toxins from the body and can soothe tired, aching, overworked muscles and revive body and mind.

Plus they smell great.

Westlabs Recover Epsom Salts White Willow & Eucalyptus, 5.99, Amazon

A body hack that can help you lose around 5-7 lbs in 5 days and it is actually good for you.

Developed at the Longevity Institute of the University of Southern California (USC) and under the sponsorship of the National Institute for Aging and the National Institute of Health, this five day programme tricks your body into thinking its fasting, and while you get the health benefits, you can continue eating.

Each days complete nutrition arrives in 5 small boxes (one for each day) that include plant-based energy bars, soups, snacks, drinks, and supplements, all carefully designed to nourish your body and promote positive changes in metabolic markers, cellular rejuvenation, reduced inflammation, and healthy aging

ProLon Fasting Mimicking Diet, 200, ProLon

These brand new sauna blankets are built with layers of infrared heating and toxin-free fabrics that lets you feel like youre in a spa without ever leaving home.

You just roll it out on a heatproof surface like your bed and use a handheld controller to begin heating it up. The blanket uses far-infrared heat that makers promise can help detoxify the body, rejuvenate skin, reduce stress, burn calories and give you that relaxed, stress-busting feeling a sauna does.

Benefits also include better blood flow, sleep and of course, there is the calorie burn (who doesnt love a workout you can do lying down watching Netflix?). 30 mins to an 1 hour per session recommended.

Infrared Sauna Blanket, 374, MiHigh UK

Dr Galyna Selezneva, Londons top Body Doctor, gets asked every day about cellulite. If a visit to her or another expert practitioner is not on your summer agenda, she advises to drink more water and move more but the most important thing? Dry Brushing!

Calling it, one of the most underrated and effective ways to beat cellulite, Dr Galyna advises just a few minutes a day, is enough to see results. It improves lymphatic drainage, and fluid retention and lessens cellulite. Results are instant and lasting.

Dr Galyna Selezneva, Rita Rakus Clinic

A sustainable and organic brand created by Danish born US based, make-up artist Kirsten Kjaer Weis, these are the brands hero cream blushes together with a complementary highlighter shade which gives an instant glow.

Minimalist and sleek, the shades work together to create the ultimate bronze and flushed duo for light to medium skin tones and blush and highlight for deeper skin tones.

Kjaer Weis Flush and Glow Duo, 41, Content Beauty Wellbeing

Is lockdown face a real thing?

If youve picked up a bit of puff during all of this, this wonder cream can have you looking sleek and sharp on your zoom call in no time.

Tighter skin, instantly, minus the toxins of injectables. Beloved by cheekbone superior girls like Gwyneth Paltrow, Sienna Miller and Victoria Beckham, its packed with plant extracts and high actives and relies on neuropeptides (naturally derived from algae) to smooth skin. Regularly named as a best natural alternative to Botox by beauty editors.

V-Tox, 105, 99, Linda Meredith

Only sold online, this is a great way to cheat a tan.

Giving your face an instant, natural sun-kissed glow, its packed with ingredients that illuminate, hydrate and perfect the skin.

It comes with a Face Mist and handy Face Lifter Brush that makes it go on really evenly and without staining your hands.

The Bronze & Sculpt Duo, 55.00 Amanda Harrington

The golden glow you love with none of the fuss. Free of odours, orange tones and streaks it gives a great sun-kissed complexion but also sun protection.

Blended with organic sunscreens, it has SPF 50 UVA protection and combines natural gradual technology and instant tanning without clogging pores, allowing the skin to breathe.

Tancream All in One Self Tan, Bronzer and SPF50, Ideal World TV

Tired of scrubbing off old spray tan? Looking to get rid of bronze streaks, while you relax?

This new bath bomb from Lusso Tan is the worlds first tan-removing bath bomb, just relax in a bath filled with essential-oil infused water and watch your tan dissolve before your eyes!

Full of skin-loving ingredients, the Lusso Tan Bath Bomb removes tan in a matter of minutes, while repairing and protecting the skin at the same time. The longer you soak, the better the tan-removing results.

Summer Meadow Bath Bomb, 8.50, Lusso Tan

Specifically designed for the delicate eye area, these little beauties work to stop eyes from looking tired, no matter how little sleep youre getting.

Stick under the eye for around 15 minutes and notice immediate results.

Filled with antioxidant-rich flower extract serum that feels cool to the skin and aims to smooth the look of fine lines and wrinkles, the pack contains 5 x 2 eye pads.

Rose Blossom Glow Hydro-Gel Eye Pads 5 x 2 29.90, Eclat Skin London

Instantly glam up with these beauties.

With eyelash extensions having been on hold because of Covid, award-winning Dollbaby London has come up with a way to boost your lashes that is easy, effective and mess-free.

The UKs first 2-in-1 eyeliner and lash adhesive, the Dollbaby Duo Pen works with any strip (non magnetic) lashes. Simply line the eye with two coats like a regular eyeliner, apply your lashes immediately on top of the liner (no drying time required) and go!

Unlike other eyelash glues, theres drying time and its not sticky or messy. And the pens ultra-fine tip is easy to apply. Vegan and cruelty-free, it comes in black or clear for a more natural look.

To remove, simply peel lashes off and remove eyeliner with normal makeup remover. Will give you approx 30-40 applications

Duo Pen, 19.75, Doll Baby London

Why go to a salon when you can give yourself a 5-minute facial in your own bathroom?

A fantastic do-it-yourself facial peel, skin looks clear, clean and smooth instantly. Made with with dead-cell sloughing glycolic acids, powerful pomegranate enzymes, gentle bamboo scrub grains, purifying salicylic acid and anti-free-radical stem cells from raspberries.

Fruitizyme Five Minute Facial, Beauty Pie Members 10.26, Beauty Pie

Pretty summer dresses can also mean painful, sweaty and chafing thighs in the hot summer sunshine.

Smoovall is a skin contact spray that leaves an invisible protective layer that prevents the soreness and irritation caused by friction (chafing).

Its a non toxic spray and unlike the common roller balms and powders, is non-greasy and invisible.

Skin contact spray, 14.99, Smoovall

A super affordable summer essentials kit packed with everything you need beauty-wise.

New from GlossyBox, it includes everything from an ultra gentle facial peel, a jet lag recovery mask, a coco shimmer body mist, lip balm, nail polish, dry shampoo body cream, tangle teezer and lip balm.

Summer Essentials, (valued over 95, but 30 for subscribers and 35 for non-subscribers), Glossy Box

No time to social distance at a salon? Why not pedi at home?

This 7-day peel sock is the bomb. Just pull these on like socks, tape them around your ankles, wait an hour, wash, and 7 days and some very impressive exfoliation later, youll have feet so soft youll want to show them off.

Ingredients include glycolic and lactic acids, natural fruit extracts of grapefruit, orange and lemon, plus sweet almond and coconut extracts.

Dr Glycolic Soft Feet 7-Day Peel Socks, 3.92 Beauty Pie

This one is a game changer.

Remove & Chill is the first of its kind: an innovative, waterless, acetone-free removal cream that dissolves nail polish, nourishes nails and actually smells good. Its a nail polish remover cream, enriched with hydrating essential oils that removes nail polish in 3 minutes.

Its also travel friendly.

Remove & Chill Nail Polish Eraser Cream, 14.25, Beauty Mart

Want freedom from a hot blow dryer this summer? Who doesnt?

Celebrity stylist Edward James has created a signature treatment that offers smoothness without the hot air. Not to be confused with a Brazilian blow dry, which is made for thicker, stronger Brazilian hair, this one is gentler and suits finer hair.

An ammonia-free glossing oil adds shine and moisture followed by Edwards secret formula a smoothing keratin applied to the frizziest part of the hair with a paint brush.

Its 100, takes 15 minutes, contains no formaldehyde and is heaven in humidity. It lasts for up to 6 weeks, ensuring you will never resemble Monica from Friends even in the hottest days of summer.

British Blow Dry, 100, Edward James London

This is a great dry shampoo that cleans hair and lets you go longer between washes.

It uses Living Proofs triple cleaning technology to absorb and remove dirt, oil and sweat you just leave for 30 seconds and let the cleansing begin.

A time-release fragrances helps hair smell clean- a great way to wash less often protecting your fresh head of colour after your long-awaited salon appointment!

Living Proof Dry Shampoo, 19.99, Living Proof

These seamless clip-ins are amazing. Instantly change and update your look with no effort at all.

They are comfortable and lay flat on the scalp which means no irritating bits poking through your perfect coif.

Their silicone band technology fuses and bonds every single strand of hair at the top of each weft which means there is less shedding and tangling too.

14in Seamless Clip In Human Hair Extensions, 95, Foxy Locks

This 100% vegan friendly, cruelty-free brand makes waxing fun (well, as fun as it can be).

Enriched with things like apricot extract to soothe and moisturise the skin, plus Vitamin E for its antioxidants and anti-ageing effects, the body hair removal jelly is fuss-free and works fast in just 5-10 minutes.

For use on body hair of all lengths. Suitable for sensitive skin Available in 3 scents Strawberry & Watermelon, Pineapple & Coconut and Blueberry & Passionfruit.

Pink Shimmer Hair Removal Jelly, 9.99, Nuthing

Hair takes a beating in the summer and this new range of snazzy hair products are kind to both hair and the environment.

Promising no sulfates, parabens, silicones, or even gluten, the range is vegan and cruelty-free with 100% recyclable sugarcane bottles. They are also affordable and great on hair.

The rescue mask is a summer stand out ideal for colour treated hair, it seals cuticles and repairs split ends and it also has UV protection and a pollution barrier. Ingredients include coconut & yuzu scent, sugar beet extract, and vegetable derived conditioners.

Azure by PFB Rescue & Repair Mask, 10.99, Boots

If your eyebrows are an untamed as theyve ever been enter a summer must-have. This painless eyebrow trimmer looks like a stylish pen and trims eyebrows at the touch of a button.

A precision-engineered shaper, this nifty gadget has a tiny and super-accurate micro-precision trimming head, encased in 18 karat gold plate.

JML Finishing Touch Flawless Brows, 19.97, Amazon

Banish those unwanted hairs once and for all.

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40 Hot Weather Hacks: The lazy girls' hair and beauty product guide to summer - Metro.co.uk

Skin Stem Cells Comments Off on 40 Hot Weather Hacks: The lazy girls’ hair and beauty product guide to summer – Metro.co.uk | August 10th, 2020

Entrepreneur Dave Aspreys end-of-life plans are quite simple, really, even if some of his ambitions sound laughably optimistic to most of us.I want to die at a time and by a method of my own choosing, and keep doing awesome things until that day, he tells me. I dont think its outrageous to believe Ill make it to 180 years old. And if I run out of energy, itll just be because I did too much cool shit for my own good.

Asprey is strolling across his lush property in British Columbia, holding up his phone and pointing out the specimens in this years garden as we chat over Zoom in the midst of the global pandemic. Hes protecting his skin from the sun with a goofy Outdoor Research hat and wearing a long string of beads that he says are each over a hundred years old, from cultures around the world.

Asprey, 48, is the founder of the Bulletproof wellness empire and a vocal champion of the movement to extend human life expectancy beyond 100 years. Hes made millions by experimenting on his own body and packaging his home-brewed discoveries into books, a podcast, consulting services and consumer products (you may have even tried his butter-laced coffee). Asprey, who was a web-security executive before he became the Bulletproof Executive, is just one of a cadre of tech elite who have begun directing their attentionand truckloads of moneytoward the problem of life extension. Jeff Bezos, Peter Thiel, Sergey Brin, Larry Ellisonname a Silicon Valley A-lister and he or she is likely funding longevity research, experimenting with anti-aging interventions or both. These are the masters of the universe who see no reason they cant take the tech industrys optimization obsession and apply it to the ultimate challenge: conquering death itself.

And their efforts appear to be paying off: Thanks to a recent explosion of advances in longevity medicine, Aspreys vision of living healthfully into his second century might not be so crazy. In fact, for people in middle age right now, a handful of therapies in clinical trials have the potential, for the first time in human history, to radically transform what old age looks like. If the life extensionists are right, a person whos 40 today might reasonably expect to still be downhill skiing, running a 10K or playing singles tennis at 100.

Dave AspreyDave Asprey

If you do anti-aging right, Asprey insists, youll have a level of resilience and energy to fight what comes your way. If you get Covid-19, youre less likely to become very sick. The idea is that at a cellular level, youre making yourself very hard to kill.

The most extreme of the controversial interventions Asprey has undergone involved having stem cells extracted from his own bone marrow and fat and then injected into hundreds of locations on his body. Into every joint, between every vertebra and into my cerebrospinal fluid, face and sex organs, he tells me cheerfully. For what I spent on that, I could have bought a really nicely appointed Tesla.

He trots up a flight of stairs to his home office, which sits above a million-dollar lab filled with health gadgets, such as a cryochamber, a hypoxic trainer and an AI-enabled stationary bike. For a wealthy person, investing in your body should be a major part of your Im rich strategy, he explains. Personally, I think you should be spending at least 2 to 3 percent of your net worth on health and longevity. Get a personal chef who can cook you the right food. Its not that hard.

It might be an exaggeration to say BioViva CEO Liz Parrish believes death is optional, but for her, Aspreys goal of living to 180 shows a distinct lack of ambition. If you can reach homeostasis in the body, Parrish says, where its regenerating itself just a little bit faster than its degrading, then what do you die of? An accident or natural disaster, probably. Theres no expiration date at 90 or 100 years old.

Tall, blond and fit, Parrish cuts a strikingly youthful figure at 49one that might convince you to order whatever shes having. But, like Asprey, she has received criticism from the longevity research community for becoming patient zero in her own experimental drug trial, aimed at halting aging at the cellular level. In 2015, Parrish underwent telomerase and follistatin gene therapies in Bogota, Colombia. The procedures involved receiving around a hundred injections of a cocktail of genes and a virus modified to deliver those new genes into her bodys cells. The objective was to prevent age-related muscle loss and lengthen her telomeres: the caps at the end of our chromosomes. Scientists have identified their unraveling as not only a marker of aging but also a potential cause of age-related decline.

Liz ParrishLiz Parrish

Parrish told the media about her clandestine experiment and has published periodic updates on her condition in the five years since, and she reports that she has indeed increased her muscle mass and lengthened her telomeres. Parrishs punk-rock approach stems from her conviction that the medical-research communityboth the Food and Drug Administration (FDA) and researchers who arent business-mindedis moving too slowly, with too much red tape, when it comes to advancing aging therapeutics. But gene therapy is a relatively new area of medicine that brings with it a host of new risks, including cancer, severe immune reactions and infections caused by the viral vector used to deliver the drug.

Parrish downplays such worries. There may be risks, she tells Robb Report. But the known risk is that youre 100 percent likely to die. So you have to decide for yourself if the potential benefit outweighs that.

Humans have always aspired to find the fountain of youth, so people might be skeptical about the fact that anti-aging technologies are working now, says British investor and businessman Jim Mellon. But the fact is that this is finally happening, and we need to seize the moment. Mellon cofounded Juvenescence, a three-year-old pharmaceutical company thats investing in multiple technologies simultaneously to increase the odds of bringing winning products to market.

Mellon, 63, has made his fortune betting on well-timed investment opportunities, and he predicts that a new stock-market mania for life extension is just around the corner. This is like the internet dial-up phase of longevity biotech, he enthuses. If youd invested in the internet in the very early days, youd be one of the richest people on the planet. Were at that stage now, so the opportunity for investors is huge. According to a report by Bank of America Merrill Lynch, hes not wrong: The market for technologies to increase human life span is projected to grow sixfold to $610 billion in just the next five years.

When I talk to Mellon in the late spring, hes sequestered on the rugged coast of the Isle of Man, a tiny spit of land in the Irish Sea. Despite being what he describes as imprisoned there for 15 weeksand countingduring the Covid-19 shutdown, hes jovial and chatty and wants to make it clear that his interest in life extension is much more than financial. Working to extend life is an ethical cause, he says. If we can help people to live healthfully until the end of life, well transform the world completely. Well reduce a huge amount of pressure on failing health-care systems, and well have to reimagine pension and life insurance. This should be the number-one tick in anyones investment portfolio.

If youd like to get on board with this social-impact view of longevity, it helps to understand the trajectory of aging today. In Americas most affluent neighborhoods, the average life span is about 88 years. (Meanwhile, in this countrys poorest, it hovers around a meager 66 because of a raft of inequalities, such as diet, stress, smoking, pollution and health care.) For most people, health starts gradually diminishing in the last 15 years of life with the onset of chronic conditions, including arthritis, neurodegeneration and diabetes. If we could eliminate such diseases of aging, experts say, the US could save an estimated $7.1 trillion in health-care costs over the next 50 years. (Quite where all these sprightly centenarians might live on this already densely populated planet remains to be seen.)

Jim MellonEric Verdin

One of Mellons bets is on a class of drugs called senolytics, which destroy senescent cells: the so-called zombie cells that, for complex reasons, stop dividing as we age. Senescent cells harm the body by secreting compounds that cause inflammation in surrounding tissues. Many age-related conditionsarthritis, diabetes, Alzheimers, cancerhave an inflammatory component, and studies suggest that a buildup of senescent cells is a large part of the problem.

A number of biotech start-ups are devel- oping drugs that target cell senescence, but the furthest along is Unity Biotechnology, a company in South San Francisco that has three drugs in clinical trials to address aging conditions, starting with osteoar- thritis of the knee. Unity raised more than $200 million from such big names as Thiel and Bezos, who chipped in through their investment firms, before going public in 2018. Since then, Mellon has also bought a small stake.

The holy grail of senolytics will be the development of a preventive therapy to wipe out senescent cells in the body before they cause conditions of aging, theoretically extending life span. In June, a team from Sloan Kettering published new breakthrough research showing that CAR T cellstypically used for precision cancer therapycan also be used to target and kill senescent cells. Prescription senolytics for anti-aging therapy are still years away, but unsurprisingly, theres an audience of longevity enthusiasts who want to access such anti-aging miracles yesterdayand no shortage of FDA-unapproved ways to chase after them. For instance, after a few studies examined the senolytic effects of a chemotherapy drug called dasatinib, the website FightAging.org published a step-by-step guide to senolytic self-experimentation using chemotherapeutics.

It doesnt take a Ph.D. in biochemistry to guess that taking off-label chemo drugs might come with harmful side effects, but that hasnt stopped a zealous group of body-hackers from trying it themselves and chronicling their efforts online. The internet is littered with novice longevity adviceand sketchy anti-aging companies eager to separate the hopeful and desperate from their money, like the company that charges $8,000 for transfusions of plasma from the blood of teenagers and early-twentysomethings (yes, just like Gavin Belson on HBOs Silicon Valley). Many of these are at best ineffective and at worst deadly, since the same cellular systems that fuel growth in young people might cause cancer when tipped into overdrive. Imagine the tragic irony of paying tens of thousands for a therapy that promises to help you live longer but actually causes the cancer that kills you.

Adobe

Beyond the obvious red flags of repurposed chemo drugs and the bloodletting of teens, it can be difficult for a layperson to separate the world-changing longevity breakthroughs from the terrible ideas. Enter one of the worlds leading experts on longevity to help make sense of things.

Eric Verdin, 63, is president and CEO of the Buck Institute, a globally renowned center for aging research just outside San Francisco in Marin County. Verdin is bullish on the promise of living healthfully to at least 100. Today. But 180? Dont count on it. My prediction, based on everything we know today, is that getting to 120 is about the best we can do for the foreseeable future. Ill bet my house were not going to see anyone live to 180 for another 200 years, if ever, he says. But making everyone a healthy centenarian, this is something we can do today. And thats something to be excited about.

Verdins own lab at the Buck Institute studies the aging immune system and how its affected by lifestyle factors, such as nutrition and exercise. Informed by this research, Verdin follows a time-restricted diet in which he eats all of his meals in an eight-to-nine-hour window (similar to the Buchinger Wilhelmi process) and gets plenty of exercise mountain biking in Marins steep hills. The good news is that over 90 percent of what causes diseases of aging is environmental, and that means its within your control, he says.

But he emphasizes that responsible management of your health comes with limits, like avoiding experimental therapies. A group of people have decided to try some expensive and dangerous interventions, but there is zero evidence that any of these are going to help them live longer, he says. The problem, according to Verdin, is that the results of aging interventions in mouse trials can look very promising but rarely translate to success in humans. Theres a huge delta between the health of a stressed lab mouse and an optimally healthy mouse, Verdin says. So when you treat lab mice with longevity therapeutics, you see an outsized result that doesnt at all guarantee the same result in humans.

On the other hand, Verdin tells Robb Report, there are definitely new protocols worth getting excited about. Take, for instance, rapalogs, a class of drugs that interact with a protein called mTOR, which serves as a linchpin for multiple critical biological processes, including cell growth and metabolism. Rapalog drugs tamp down mTOR, possibly preventing age-related diseases such as diabetes, stroke and some cancers. The drug rapamycin, the most heavily studied formula, was approved in the US in 1999 to help prevent organ-transplant rejection. Last year the medical journal Aging published a rapturous opinion piece by oncologist Mikhail Blagosklonny in which he made the case that rapamycinin small or intermittent dosesis effective as a preventive treatment to ward off diseases of aging, and that, in the elderly, not taking rapamycin may be even more dangerous than smoking.

Eric VerdinJim Hughes Photography

Later this year, a biotech firm called resTORbio, which was spun out of the Swiss-based Big Pharma company Novartis in 2017, is expected to seek FDA approval for its rapalog RTB101, which clinical trials have shown to slow age-related decline of the immune system and improve immune response in elderly people by more than 20 percent, a key factor in protecting vulnerable aging populations from disease. (It is currently in trials on elderly patients with Covid-19.) This is the furthest-along program of anything in the aging field, Joan Mannick, cofounder and chief medical officer of resTORbio, told MIT Technology Review last year. If health authorities approve this drug well have a product for people to prevent age-related diseases. Not just in our lifetime, but in, you know, a few years.

One of the many effects of rapamycin is that it mimics the mechanisms of calorie restriction. As Verdins lab and others have shown, fasting provides a number of anti-aging benefits, including insulin regulation, reduced inflammation and, to put it colloquially, clearing out the gunky by-products of metabolismpart of the reason Twitter CEO Jack Dorsey and other tech titans eat just a few meals per week. For lesser mortals, fasting is extremely hard to commit to and not much fun, hence the huge interest in calorie-restriction mimetics like rapamycin, which provide all the benefits without the downer not-eating part.

Of all the calorie-restriction mimetics, the one sparking the most excitement among longevity researchers is already on the market: metformin, a decades-old diabetes drug. Metformin became a part of the Silicon Valley health regimen several years ago after an epidemiological study showed that Type 2 diabetics who took the drug lived longer than non-diabetics who didnt. Just about everyone in the longevity industry takes metformin, Verdin tells me. He takes it himself, and nearly everybody I interviewed is taking or has taken it, too.

In April, Nir Barzilai, the renowned endocrinologist who spearheaded research on the anti-aging properties of metformin, announced in an opinion piece he co-authored in the journal Cell Metabolism that his lab is launching a large clinical trial to investigate the anti-aging effects of the drug on non-diabetic populations. Barzilais goal is to prove to the FDA that aging itselfrather than conditions associated with it, like Alzheimers and arthritiscan be targeted as a disease. If Barzilai is successful and the FDA approves aging as a treatment indication, the process of bringing longevity therapies to market would accelerate rapidly.

Just as the FDA was able to move faster to bring Covid-19 therapies to market this year, we will reach a tipping point when public opinion pushes the FDA to approve aging as an indication, and the longevity-research field will make leaps as a result, Mellon says. He has contributed funding to Barzilais metformin research, which he believes will be instrumental in proving that there are compounds that can extend human life across the board.

The fact of the matter is that the US has the best regulatory system for new drug development in the world, Mellon says. Were in the first era ever when humans can be bioengineered to live longer. And in 10 years, well have solutions that are even better than today. Just wait, its coming.

Liz Parrish

Jim Mellon

Diet:Vegetarian.Mindfulness practice:Nightly meditation.

Exercise regimen:30 minutes of cardio and 10 minutes of weights,five days a week.

Anti-aging Rx:Regenerative gene therapies. Im certain most peoplewill take them in the next couple decades.

180th-birthday wish:Solving another critical issue.

Sleep routine:7.5 hours plus a 30-minute nap; in bed by 9 p.m.

Vitamins/supplements/ prescription meds:Vitamins D and B12, metformin.

Exercise regimen:Walk or run minimum 10,000 steps a day;weights three times week.

Anti-aging Rx:Green tea.

100th-birthday wish:Another 25 years.

Dave Asprey

Jim Hughes Photography

180th-birthday wish:Either a cruise to Mars or a 1970 Mustang Fastback,which by then will be 210 years old!

Sleep Routine:Avoid: coffee after 2 p.m., heavy workouts after 6 p.m.,alcohol during the week and heavy eating in the evening.

Vitamins/supplements:Vitamin D, omega fatty acids, NMN, citrus bioflavonoidcomplex, fiber supplement, prebiotic supplement.

Diet:Fasting-mimicking diet once every four to six months;roughly 16:8 intermittent fasting at other times.

Mindfulness practice:Daily meditation.

Anti-aging Rx:I love cooking and eating, so I do not restrict foodon the weekend. Happiness with friends and family is thesurest path to longevity.

100th-birthday wish:A bike tour across the US, from coast to coast.

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Why Silicon Valley Execs Are Investing Billions to Stay Young - Robb Report

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As Cosmetic Skin Care market document has precise and accurate analysis of market trends, future developments, market segments and competitive analysis which suits the needs of all sizes of businesses in the Cosmetic Skin Care industry. This market research report involves a key data and information about the market, emerging trends, product usage, motivating factors for customers and competitors, restraints, brand positioning, and customer behaviour, which is of utmost importance when it comes to achieving a success in the competitive marketplace. A winning Cosmetic Skin Care market report encompasses many vital parameters about market analysis which can be used for the business.

A detailed market study and analysis of trends in consumer and supply chain dynamics cited in this Cosmetic Skin Care market analysis report helps businesses draw the strategies about sales, marketing, and promotion. Company profiles of the key market competitors are analysed with respect to company snapshot, geographical presence, product portfolio, and recent developments. The report also helps to know about the types of consumers, their response and views about particular products, and their thoughts for the step up of a product. Company profiles covered in this Cosmetic Skin Care report can be quite useful for making At present, the market is developing its presence and some of the Global Cosmetic Skin Care Market key players Involved in the study are LOral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation, Johnson & Johnson Services, Inc., Procter & Gamble, Beiersdorf, THE BODY SHOP INTERNATIONAL LIMITED, Shiseido Co.,Ltd., Coty Inc., Bo International, A One Cosmetics Products, Lancme, Clinique Laboratories, llc., Galderma Laboratories, L.P., AVON Beauty Products India Pvt Ltd, Nutriglow Cosmetics Pvt. Ltd, Shree Cosmetics.

Global cosmetic skin care market is set to witness a substantial CAGR of 5.5% in the forecast period of 2019- 2026.

Complete study compiled with over 100+ pages, list of tables & figures, profiling 10+ companies. Ask for Sample @ https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-cosmetic-skin-care-market&SR

Global Cosmetic Skin Care Market Dynamics:

Market Drivers:

Increasing spending on personal care acts as a market driver

Rising prevalence for natural active ingredients based cosmetic among population will also drive the market growth

Growing demand for sun protection products will propel the growth of this market

Market Restraints:

High cost of the skin care products will restrain the market growth

Strict government rules associated with the less usage of antioxidants will also hamper the market growth

Emerging competition in the cosmetic skin care products is another factor impeding the market growth

Important Features of the Global Cosmetic Skin Care Market Report:

1) What all companies are currently profiled in the report?

List of players that are currently profiled in the report- LOral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation, Johnson & Johnson Services, Inc., Procter & Gamble, Beiersdorf, THE BODY SHOP INTERNATIONAL LIMITED, Shiseido Co.,Ltd., Coty Inc., Bo International, A One Cosmetics Products, Lancme, Clinique Laboratories, llc., Galderma Laboratories, L.P., AVON Beauty Products India Pvt Ltd, Nutriglow Cosmetics Pvt. Ltd, Shree Cosmetics.

** List of companies mentioned may vary in the final report subject to Name Change / Merger etc.

2) What all regional segmentation covered? Can specific country of interest be added?

Currently, research report gives special attention and focus on following regions:

North America, Europe, Asia-Pacific etc.

** One country of specific interest can be included at no added cost. For inclusion of more regional segment quote may vary.

3) Can inclusion of additional Segmentation / Market breakdown is possible?

Yes, inclusion of additional segmentation / Market breakdown is possible subject to data availability and difficulty of survey. However a detailed requirement needs to be shared with our research before giving final confirmation to client.

** Depending upon the requirement the deliverable time and quote will vary.

Global Cosmetic Skin Care Market Segmentation:

By Product: Anti-Aging Cosmetic Products, Skin Whitening Cosmetic Products, Sensitive Skin Care Products, Anti-Acne Products, Dry Skin Care Products, Warts Removal Products, Infant Skin Care Products, Anti-Scars Solution Products, Mole Removal Products, Multi Utility Products

By Application: Flakiness Reduction, Stem Cells Protection against UV, Rehydrate the skins surface, Minimize wrinkles, Increase the viscosity of Aqueous, Others

By Gender: Men, Women

Check Complete Report Details of Cosmetic Skin Care Market @ https://www.databridgemarketresearch.com/toc/?dbmr=global-cosmetic-skin-care-market&SR

The Cosmetic Skin Care Market report provides insights on the following pointers:

Major Key Contents Covered in Cosmetic Skin Care Market:

This Cosmetic Skin Care Market Research/analysis Report Contains Answers to your following Questions

Note TheCOVID-19 (coronavirus) pandemic is impacting society and the overall economy across the world. The impact of this pandemic is growing day by day as well as affecting the supply chain. The COVID-19 crisis is creating uncertainty in the stock market, massive slowing of supply chain, falling business confidence, and increasing panic among the customer segments. The overall effect of the pandemic is impacting the production process of several industries. This report onMarket provides the analysis on impact on COVID-19 on various business segments and country markets. The reports also showcase market trends and forecast, factoring theimpact of COVID-19 Situation.

Thanks for reading this article; you can also get individual chapter wise section or region wise report versions like North America, Europe, or Asia Etc.

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Cosmetic Skin Care Market -Product Overview and Scope, Opportunities, Market Volume, Competitive Landscape, Possible Challenges and Forecast to 2026 -...

Skin Stem Cells Comments Off on Cosmetic Skin Care Market -Product Overview and Scope, Opportunities, Market Volume, Competitive Landscape, Possible Challenges and Forecast to 2026 -… | August 10th, 2020

Since sunscreen should be applied every dayyes, every daywhy not consolidate steps by using a sunscreen/moisturizer hybrid? The hydrating formulas give you the benefits of sun protection without the white, streaky aftermath. Plus, it makes it that much easier to apply (aka no more excuses about forgetting to put on sunscreen). Look for moisturizing ingredients like hyaluronic acid, ceramides, or niacinamide that give your skin a drink without leaving it greasy.

And if you're still in the camp of "my skin doesn't get burned," that's not an excuse to skip daily SPF. According to The Skin Cancer Foundation, "no matter your skin type, UV radiation from the sun and other sources can cause dangerous, lasting damage to your skin." Sunscreen isn't just about protecting your skin from a sunburn; it also reduces your risk of developing squamous cell carcinoma (the second most common type of skin cancer) by about 40 percent (again, according to The Skin Cancer Foundation) and lowers your melanoma risk by 50 percent. And if it's aging you're worried about, it has your skin covered there too as it prevents wrinkles, sagging, and age spots as well.

Ghostly white cast turning you off? Say hello to tinted sunscreen! (Keep reading for some favorites.)

To get all these benefits of SPF, you have to make sure you're wearing it correctly: Just remember, you need at least a nickel-size drop of sunscreen or SPF moisturizer to cover your face every morning," says Mona Gohara, MD, dermatologist and Women's Health advisory board member.

Here are the 15 best moisturizers with SPF that you won't mind applying every. Single. Day.

You would never know this natural sunscreen houses a whopping 20% zinc oxide thanks to the blendable tint. (Read: You will not mind applying this every day.) You'll also get antioxidant protection thanks to algae and sunflower sprout extract.

This oil-free, lightweight moisturizer blends right in so fast you'll forget if you even applied it. And if you don't want to listen to WH about wearing sunscreen, maybe you'll take a page out of Rihanna's book: You gotta protect your skin from the sun no matter what your skin color is" she says on the Fenty site. "If you have discoloration, guess what, you can get that from the sun. I think a lot of people with darker skin tones think because theyre not burning that they dont need SPF but we can still get sun damage."

Fenty Skin HYDRA VIZOR INVISIBLE MOISTURIZER SPF 30

Whether you have oily skin or you just prefer a lighter consistency, this lotion will be your new fave. It soaks into skin quickly and is basically weightless after it's been appliedyou might even forget you have it onmaking it ideal for layering. Plus, it's non-comedogenic so acne-prone folks won't have to worry.

Simple Skincare, Protecting Light Moisturizer, SPF 15

Made by Black women for Black women, you can trust that this sunscreen/moisturizer hybrid isn't going to leave any white streaks behind. Avocado, jojoba, and sunflower oil all contribute to the rich, hydrating texture that sinks in without clogging pores or leading to breakouts.

Black Girl Sunscreen SPF 30

$18.99

If you're prone to an oily T-zone, this hydrating sunscreen is for you. Ceramides and niacinamide nourish your skin without making it feel greasy, and the mineral SPF ingredients (it contains both titanium dioxide and zinc oxide) keep you sun safe.

CeraVe Hydrating Sunscreen SPF 50 Face

Moisturizing gold standard hyaluronic acid is paired alongside coconut oil and aloe vera for a refreshing and hydrating formula. And thanks to the tint (there's four shades to choose from), it'll even out your complexion too.

Suntegrity 5-in-1 Tinted Moisturizing Face Sunscreen

Most derms recommend a combination of sunscreen and an antioxidant product (to fight aging free radical damage from UV exposure) for the best daily protection. This lightweight lotion has it all in one. It hydrates, has SPF 30, and contains a combination of blackberry extract and vitamins C and E for an antioxidant boost.

Aveeno Absolutely Ageless Daily Moisturizer SPF 30

Hate the feeling of thick, greasy sunscreen? Meet the complete opposite. This gel sunscreen hydrates (thanks to hyaluronic acid, glycerin, and vitamin E) and protects (thanks to a combo of proven chemical sunscreen ingredients) all while feeling like nothing on your skin.

Neutrogena Hydro Boost Water Gel Lotion SPF 50

This triple threat corrects redness, moisturizes, and protects your skin from UV damage. Centella asiatica (an herb native to Asia) is the hero ingredient that works to protect the skin from environmental stress that can lead to irritated, inflamed skin. While the cream goes on green, it quickly turns into a neutral shade to blend into your skin tone for a more even complexion.

Cicapair Tiger Grass Color Correcting Treatment SPF 30

$18.00

Yes, this is a moisturizer with sunscreen, but if you couldn't tell from the name, it's also packed with plant stem cells (they actually make up 15.5 percent of the formula) that fight free radicals to prevent collagen breakdown, promote firmer looking skin, and help smooth fine lines.

Plant Stem Cell Day Cream SPF 30

$75.00

Ever feel like your sunscreen is leaving your skin looking like an oil slick? Meet your new SPF BFF. Not only does it protect your skin from UVA (what causes aging) and UVB (what causes your skin to burn) rays, it also claims to minimize pores by 54 percent and keeps your skin matte for up to 10 hours.

Oil and Pore Control Mattifier Broad Spectrum SPF 45 PA++++

The combo of chemical sun protection ingredients (avobenzone, homosalate, and octisalate) in this nourishing cream provide your skin safety from UVA and UVB rays. It also contains cerium, a mineral that protects from the blue of your computer screen, television, and phone. So, you're double protected.

Supergoop! Superscreen Daily Moisturizer Broad Spectrum SPF 40 PA+++

Think of this moisturizer with sunscreen like a cup of coffee for your skin. While it protects and nourishes, it also boosts your skin's energy from actual coffee beans (the caffeine is also an anti-irritant). Because who couldn't use a extra jolt in the morning?

Origins Ginzing SPF 40 Energy-Boosting Tinted Moisturizer

Extra oily skin types, meet the moisturizer-SPF face cream that will not leave you looking like a greaseball. It has a whipped texture that absorbs in seconds and leaves a velvety smooth finish that looks great under makeup.

Olay Total Effects Whip Face Moisturizer SPF 25

If you're starting to see hyperpigmentation, then you need to up your SPF game. Stat with a brightening product like L'Oral's. This sunscreen lotion contains SPF 30 to stop new dark spots from forming and a combination of glycolic acid, vitamin C, and retinol to treat any existing discoloration.

L'Oral Paris RevitaLift Bright Reveal Brightening Day Moisturizer SPF 30

$19.98

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15 Best Face Moisturizers With SPF 2020 - Moisturizer With Sunscreen - Women's Health

Skin Stem Cells Comments Off on 15 Best Face Moisturizers With SPF 2020 – Moisturizer With Sunscreen – Women’s Health | August 10th, 2020

Abstract

The emergence of several cell therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective treatment; however, scalable production of these cell therapies has become a bottleneck. To overcome this barrier, three-dimensional (3D) cell culture strategies have been considered for enhanced cell production. Here, we demonstrate a high-throughput 3D culture platform used to systematically screen 1200 culture conditions with varying doses, durations, dynamics, and combinations of signaling cues to derive oligodendrocyte progenitor cells and midbrain dopaminergic neurons from human pluripotent stem cells (hPSCs). Statistical models of the robust dataset reveal previously unidentified patterns about cell competence to Wnt, retinoic acid, and sonic hedgehog signals, and their interactions, which may offer insights into the combinatorial roles these signals play in human central nervous system development. These insights can be harnessed to optimize production of hPSC-derived cell replacement therapies for a range of neurological indications.

Stem cellsincluding adult and pluripotent subtypesoffer tremendous clinical promise for the treatment of a variety of degenerative diseases, as these cells have the capacity to self-renew indefinitely, mature into functional cell types, and thereby serve as a source of cell replacement therapies (CRTs). Human pluripotent stem cells (hPSCs) are of increasing interest for the development of CRTs due to their capacity to differentiate into all cell types in an adult, for which adult tissuespecific stem cells may, in some cases, not exist or may be difficult to isolate or propagate (1). For example, one potential CRT enabled by hPSCs is the treatment of spinal cord injury (SCI) with oligodendrocyte progenitor cells (OPCs). These hPSC-OPCs have recently advanced to a phase 2 clinical trial for the treatment of SCI (2) and are being considered for additional myelin-associated disorders in the central nervous system (CNS), including adrenoleukodystrophy, multiple sclerosis (3, 4), and radiation therapyinduced injury (5). In parallel, hPSC-derived midbrain dopaminergic (mDA) neurons are under consideration for Parkinsons disease therapy (6, 7).

The promise of hPSC-derived therapeutics such as hPSC-OPCs or mDA neurons motivates the development of manufacturing processes to accommodate the potential associated clinical need. For example, approximately 250,000 patients in the United States suffer from some form of SCI, with an estimated annual incidence of 15,000 new patients (8). Human clinical trials involving hPSC-OPCs have used dosages of 20 million cells per patient (9), such that the hypothetical demand would be over 1 trillion differentiated OPCs. It is therefore imperative to develop systems to enable discovery of efficient and scalable differentiation protocols for these therapies.

Differentiation protocols to direct hPSCs into functional OPCs (10, 11) have been developed to approximate the signaling environment at precise positions within the developing spinal cord. Positional identity of cells is guided patterning cues that form intersecting gradients along the dorsoventral axis, such as Sonic hedgehog (SHH), and rostrocaudal axis, such as retinoic acid (RA). In addition, certain cues are present along both axes, such as Wnts (1215). These signaling environments vary over time as the embryo develops (16, 17). However, translating this complex developmental biology to an in vitro culture requires optimization of a large combinatorial parameter space of signaling factor identities, doses, durations, dynamics, and combinations over many weeks to achieve efficient yield of the target cell type, and there remains open questions about the impact of cross-talk between patterning cues on the expression of cellular markers present in OPCs such as transcription factors Olig2 and Nkx2.2 (18). Strategies to derive OPCs and other potential CRTs from hPSCs have shown steady progress, especially with application of high-throughput screening technology (1921); however, current production systems for hPSC-derived CRTs involve two-dimensional (2D) culture formats that are challenging to scale (2228).

More recently, 3D culture systems have demonstrated strong potential for a larger scale and higher yield (29) of hPSC expansion and differentiation than 2D counterparts, as well as compatibility with good manufacturing practice (GMP) standards (3033). While high-throughput systems for screening 3D cell culture environments have been applied to basic biological studies of hPSC proliferation (34), we envision that this technology could additionally be applied toward systematically optimizing production strategies for CRTs to accelerate the pace of their discovery and development toward the clinic while simultaneously uncovering new interactions among signaling cues that affect cell fate. Here, we harness the powerful capabilities of a uniquely structured microculture platform (35, 36), to screen dosage, duration, dynamics, and combinations of several cellular signaling factors in 3D for hPSC differentiation (Fig. 1). The independent control of gel-encapsulated cells (on pillar chip) and media (in well chip) enables simultaneous media replenishment for more than 500 independent microcultures in a single chip. Furthermore, we use custom hPSC reporter cell lines (37) to enable live imaging of proliferation and differentiation of OPCs for over 80 days on the microculture chip. One thousand two hundred combinatorial culture conditions, amounting to 4800 independent samples, were screened while consuming less than 0.2% of the reagent volumes of a corresponding 96-well plate format. Furthermore, the robust dataset enabled statistical modeling to identify relative differentiation sensitivities to, and interactions between, various cell culture parameters in an unbiased manner. Last, we demonstrate the generalizability of the platform by applying it toward a screen for differentiation of tyrosine hydroxylaseexpressing dopaminergic neurons from hPSCs.

(A) A micropillar chip with cells suspended in a 3D hydrogel is stamped to a complementary microwell chip containing isolated media conditions to generate 532 independent microenvironments. One hundred nanoliters of hPSCs suspended in a hydrogel is automatically dispensed onto the micropillars, and 800 nl of media is automatically dispensed into the microwells by a robotic liquid handling robot programmed to dispense in custom patterns. The independent substrate for cells and media enables screens of combinations of soluble cues at various dosages and timings. Scale bar, 1 mm. (B) Timeline of exogenous signals for in vitro 3D OPC differentiation from hPSCs and anticipated cellular marker expression along various differentiation stages.

Initially, we assessed whether hPSCs could be dispensed in the microculture platform system uniformly and with high viability. Quantification of total, live, and dead cell counts across the microchip indicates uniform culture seeding and cell viability at the initiation of an experiment (fig. S1).

We then used a custom-made Nkx2.2-Cre H9 reporter line, which constitutively expresses DsRed protein but switches to green fluorescent protein (GFP) expression upon exposure to Cre recombinase, to longitudinally monitor proliferation and differentiation of hPSCs to Nkx2.2+ oligodendrocyte progenitors in 3D on the microchip platform. A small range of culture conditions from previously published protocols of OPC differentiation were selected for an initial, pilot differentiation experiment, and the GFP expression was quantified after 21 days of differentiation. Cell morphology changes accompanying neural lineage commitment and maturation were clearly observed at later stages in the 3D differentiation (movie S1 and fig. S2) as cultures were maintained and monitored for up to 80 days on the microchip. We then developed fluorescence image analysis pipelines for quantification of nuclear and cytoplasmic marker expression via immunocytochemistry for endpoint analyses at various times (fig. S3). Together, these results support the robust and long-term culture potential and cellular marker expression readout of this miniaturization methodology for hPSC differentiation screening.

hPSC seeding density. We first focused on parameters within the first week of 3D differentiation into OPCs (Fig. 2A). The importance of autocrine, paracrine, and juxtacrine signaling mechanisms among cells in many systems led us to anticipate that the density of cells at the start of differentiation could affect the early neural induction efficiency and, consequently, the efficiency of OPC differentiation. We therefore demonstrated the ability of this microculture platform to test a range of initial hPSC seeding densities on day 2 (fig. S1) and assessed the effect of seeding density on Olig2 expression. We observed notable differences in levels of cell-to-cell adhesion in hPSC cultures by day 0, 2 days after initial seeding (Fig. 2Bi). Then, after 15 days of differentiation, we observed a trend that lower hPSC seeding density, between 10 and 50 cells per pillar, increased OPC specification slightly (Fig. 2Bii).

(A) Timeline of key parameters in the early phase of OPC differentiation. (B) i. Bright-field images of 3D H9 microculture sites at day 0 seeded with varying cell densities and the immunocytochemistry images of Olig2 (red) expression at day 15. Scale bar, 100 microns. ii. Quantification of day 15 Olig2 expression with respect to seeding density and SAG dose. *P value < 0.05 using Tukeys Method for multiple comparisons. (C) i. Montage of 360 fluorescence confocal images representing 90 unique differentiation timelines on a single microchip stained for Hoechst (blue) and Olig2 (red) after 21 days of differentiation. ii. Trends in Olig2 expression at days 15 and 21 in various CHIR and RA concentrations and durations (short CHIR, days 0 to 1; long CHIR, days 0 to 3). Error bars represent 95% confidence intervals from four technical replicates.

Timing of SMAD inhibition relative to RA and Wnt signals. The formation of the neural tube in human development (12) results from cells in the epiblast being exposed to precisely timed developmental signals such as Wnt (38) and RA that then instruct neural subtype specification (39). This led us to hypothesize that the overall differentiation efficiency of hPSCs to OPCs in this 3D context in vitro would be sensitive to the timing at which RA and Wnt signals were introduced during neural induction. Therefore, we induced neuroectodermal differentiation of hPSCs via inhibition of bone morphogenetic protein (BMP) signaling using the dual SMAD inhibition approach (40), with LDN193189 (hereafter referred to as LDN) and SB431542 (hereafter referred to as SB), and tested a range of times (0, 2, and 4 days) at which RA and Wnt signals (by CHIR99021, hereafter referred to as CHIR) were introduced into the culture. We observed a strong correlation between early addition of RA/CHIR and OPC specification such that combined exposure of RA and CHIR signals with SMAD inhibition on day 0 resulted in up to sixfold higher Olig2 expression in some cases (fig. S4), potentially implicating an important role of synchronized exposure of RA and CHIR signals with SMAD inhibition for specifying Olig2+ progenitors. For subsequent experiments, we kept the timing of RA and CHIR addition at day 0 and evaluated how the dose and duration of these signals may affect Olig2+ specification.

Dose and duration of key signaling agonists. We examined the combinatorial and temporal effects of three signaling cues that form gradients across intersecting developmental axes in the neural tube to influence specification of oligodendrocyte progenitors: RA (present along the rostrocaudal axis of the CNS development), SHH (41) (a morphogen that patterns the dorsoventral axis of the developing CNS and is activated by smoothened agonist, hereafter referred to as SAG), and Wnt (present along both the rostrocaudal and dorsoventral axes). Because OPC specification is likely sensitive to the relative concentrations of these cues, for example, given the importance of morphogen gradients in oligodendrocyte differentiation in the developing neural tube (12), we assessed the Olig2 expression resulting from a full factorial combinatorial screen of these cues (fig. S5). Most notably, we observed positive correlations in Olig2 expression in response to increasing RA dose and increasing duration of CHIR exposure from days 0 to 4 of differentiation (Fig. 2C). Without CHIR, an increase in RA from 10 to 1000 nM resulted in a 10-fold increase of Olig2 expression by day 21. A similar 10-fold increase in Olig2 expression was observed at an RA concentration of 100 nM if CHIR was present for the first 3 days of differentiation (Fig. 2C). Analysis of variance (ANOVA) analysis revealed a strong effect size for RA when added early in the differentiation, as well as an interaction between RA dose and longer CHIR duration, in specifying Olig2+ cells in this 3D context (fig. S5), consistent with previous work conducted in 2D in vitro formats (19, 42).

In other developmental systems, the activity of the Wnt signaling pathway was observed to be biphasic (43), whereby activation of the pathway initially enhances cardiac development but later represses it. As this complex signaling profile has been applied to enhance cardiomyocyte differentiation protocols in vitro (44), we analogously investigated whether adding antagonists of key signaling pathways after pathway activation could further enhance the OPC differentiation efficiency by adjusting the dorsoventral and rostrocaudal positioning in vitro. Maintaining the 5 M CHIR for days 0 to 3 from the previous experiment, we used IWP-2 (an inhibitor of the Wnt pathway), GANTT61 (an antagonist of SHH signaling), and DAPT (a Notch pathway antagonist) (Fig. 3A) to inhibit endogenous autocrine/paracrine and/or basal signaling. We used a full factorial analysis of these cues to additionally probe for combinatorial interactions among the pathway inhibitors.

(A) Timing of addition for three inhibitory signaling cuesGANTT61, IWP-2, and DAPTin the OPC differentiation protocol. (B) i. Olig2+, Nkx2.2+, and the proportion of total Olig2+ that are Nkx2.2+/Olig2+ cells in at day 21 in response to full factorial combinations of selected novel signaling antagonists. ii. Immunocytochemistry images of costained Olig2 (red) and Nkx2.2 (green) cells. Scale bar, 100 m. Error bars represent 95% confidence intervals from four technical replicates.

To further refine the markers for OPC specification, we measured Nkx2.2 expression in addition to Olig2 and quantified the proportion of cells coexpressing both OPC markers. Most notably, a significant decrease in %Olig2 was observed in response to Notch inhibitor DAPT across all conditions tested (Fig. 3Bi). The same trend was not observed with respect to %Nkx2.2. This result could point to a role for Notch signaling in maintaining or promoting specification of Olig2+ progenitorsa hypothesis not previously examined to our knowledgeand serves as preliminary evidence to test Notch agonists such as DLL-4 in follow-up studies of OPC optimization. This effect may be mediated by an interaction with the SHH pathway (45).

A slight increase in %Olig2+ cells was detected with increasing Wnt inhibitor IWP-2 dose when no SHH inhibitor GANTT61 was present, as was a slight increase in %Nkx2.2+ cells as a function of increasing IWP-2 and GANTT61 dose, pointing to a potential interaction between these two cues in inducing Nkx2.2 expression. The highest proportion of Olig2+Nkx2.2+ cells was observed at the highest IWP-2 and GANTT61 doses and was not influenced by DAPT exposure (Fig. 3Bii). As CHIR was present between days 0 and 3 in the differentiation, it seems that the role of Wnt signaling changes during the 21-day differentiation window of hPSCs to OPCs in that initially (days 0 to 3) it promotes OPC differentiation but shifts to an inhibitory role at later stages (days 4 to 21). To examine the extent of reproducibility of these findings, we tested the effect of temporal modulation of Wnt signals in a human induced pluripotent stem cell (hiPSC) line, TCTF, and found that the general trend of activation followed by inactivation of Wnt signaling would increase the proportion of Olig2+ cells at day 21 (fig. S6).

Although the levels of key signaling cues may vary temporally within the natural developmental environment of certain target cell types, such as within the neural tube where a dynamic SHH gradient along the dorsoventral axis patterns pMN development (16, 17), the dosage of signaling cues in the media for in vitro stem cell differentiation protocols is often applied at a constant level throughout the culture period. On the basis of this discrepancy, we applied the micropillar/microwell chip to screen through numerous temporal profiles of SAG, as well as RA due to its analogous role along the rostrocaudal axis during spinal cord development, by dividing the signal window into early and late stages that were dosed independently to form constant, increasing, and decreasing dose profiles over time (Fig. 4A). To gain additional insights into OPC marker expression, we measured Tuj1 expression and calculated the proportion of Olig2+ cells that coexpressed Tuj1 to potentially identify any modulators of the balance between Olig2+ cells that proceed down a motor neuron fate (which are both Olig2+ and Tuj1+) versus an oligodendrocyte fate (Olig2+/Nkx2.2+).

(A) Timeline of early and late windows for RA and SAG exposure. (B) i. Hierarchical cluster analysis of standardized (z score) phenotypic responses to temporal changes in RA and SAG dose during OPC differentiation. ii. Representative immunocytochemistry images of each major category of endpoint population phenotype mix of Olig2 (red), Nkx2.2 (green), and Tuj1 (orange) expression. Scale bar, 100 m. iii. Olig2, Nkx2.2, and coexpression of Olig2+Nkx2.2+ and Olig2+Tuj1+ at day 15 in response to time-varying doses of SAG. Error bars represent 95% confidence intervals from four technical replicates. *P value < 0.05.

To consider all measured phenotypes simultaneously, we applied a hierarchical cluster analysis from which we were able to identify several patterns. A broad range of endpoint phenotype proportions of Olig2, Nkx2.2, and Tuj1 was found to result from varying the temporal dosing of only two signaling cues, RA and SAG, pointing to a very fine sensitivity to temporal changes in signal exposure in these populations. Four categories of the endpoint marker expression profiles were created to further interpret the cluster analysis. Categories 1 and 2 are composed of phenotypes ranking low on OPC progenitor fate (low Olig2 and/or Nkx2.2 expression), all of which shared the low dosing of RA at 0.1 M between days 2 and 21 of the differentiation, further emphasizing the strong impact of RA on OPC yield. In contrast, category 3composed of the highest Olig2 and Nkx2.2 expression as well as Olig2+Nkx2.2+ proportioncorrelated with the highest dose of early SAG but had negligible differences across doses of late SAG (Fig. 4Biii, and fig. S7). Last, category 4 points to a biphasic relationship of Nkx2.2 expression as a function of RA dosage, where a high dose of RA of 1 M in the late stage of differentiation resulted in lower Nkx2.2 expression (fig. S8) compared with a consistent RA of 0.5 M throughout the entire differentiation. It appears that Olig2 and Nkx2.2 undergo maxima under different RA dosage profiles (fig. S8), and therefore, the use of coexpressing Olig2+Nkx2.2+ cells as the main metric when optimizing OPC differentiation may be most suitable.

We sought a comprehensive, yet concise, analysis to describe individual and combinatorial effects of all 12 culture parameters (e.g., signal agonist and antagonist dosages and timings) on the results of the more than 1000 unique differentiation conditions involved in this study. To this end, we fit generalized linear models to correlate the expression and coexpression of Olig2, Nxk2.2, and Tuj1 to individual input parameters within the 12 culture parameters involved in this study, and the 132 pairwise interactions between them. First, we identified significant parameters of interest for each phenotype measured using a factorial ANOVA (fig. S9). After applying a Benjamini and Hochberg false discovery rate correction for multiple comparisons (46), we fit an ordinary least squares model of the statistically significant terms to the phenotype of interest. The parameter coefficients were analyzed as a measure of relative influence on the expression of a certain endpoint phenotype, such as Olig2+Nkx2.2+ cells, and could be interpreted as a sensitivity analysis of key parameters on the OPC specification process. The most significant parameters were then sorted by their effect magnitude (Fig. 5B).

(A) Identification of statistically significant culture parameters using a factorial ANOVA of all single and pairwise effects on Nkx2.2 expression subject to the Benjamini and Hochberg false discovery rate (B&H FDR) correction. (B) Effect magnitude of significant culture parameters for i. Nkx2.2 expression, ii. Olig2 expression, iii. and coexpression of Olig2 and Nkx2.2. (C) i. Diagram summarizing results and effect magnitude of significant culture parameters for Olig2 and Nkx2.2 coexpression within the Olig2+ population and ii. effect magnitude of significant culture parameters for Olig2 and Tuj1 coexpression within the Olig2+ population.

RA, a rostrocaudal patterning cue, was among the most impactful parameters in this study for Olig2 and Nkx2.2 expression (Fig. 5Bi and ii). In particular, a high RA dose (1 M) early in the differentiation (days 0 and 1) emerged as the most influential culture parameter in the acquisition of OPC fate (coexpression of Olig2 and Nkx2.2) (Fig. 5Bi to iii). In addition, the dose of SAG from days 4 to 10 of differentiation exerted a markedly more significant impact on OPC fate induction than from days 10 to 21 of differentiation, in line with the previous analysis (Fig. 4). IWP-2 and GANT were observed to correlate positively with coexpression of Olig2 and Nkx2.2 as well. Furthermore, this analysis identified two cases of culture parameters interacting in a synergistic manner to promote OPC differentiation. First, higher doses of RA during days 0 to 2 followed by SAG during days 4 to 10 were found to promote higher Nkx2.2 expression. In addition, longer CHIR duration (from days 0 to 4) along with higher GANT dose promoted coexpression of Nkx2.2 and Olig2.

We created a new differentiation protocol from the parameters isolated in this screen to have the most influence in specifying Olig2+Nkx2.2+ progenitors (Fig. 5Biii) and carried out the differentiation into the later stages of OPC maturation in a larger-scale format to assess the ability of this optimized protocol to create mature oligodendrocytes. The protocol was able to produce platelet-derived growth factor receptor (PDGFR)expressing cells by day 60 across multiple hPSC lines, as well as O4-expressing cells by day 75 and myelin basic protein (MBP) expressing cells and myelination ability at day 100 (fig. S10).

The OPC screening identified new conditions that affect cell differentiation, and we then sought to demonstrate the generalizability of this approach by conducting a different study. Specifically, we screened 90 unique hPSC differentiation protocols for tyrosine hydroxylase+ mDA neurons (Fig. 6). Exposure of CHIR was divided into three periods (early, middle, and late), and dosage for each period was varied independently. This screening strategy uncovered a key window of CHIR competence between days 3 and 7 (early), a negligible effect of CHIR between days 8 and 11 (middle), and an inhibitory effect of CHIR between days 12 and 25 (late) of mDA differentiation. These data further illustrate the existence of biphasic signaling activity during the differentiation process and underscore the need to improve the temporal dosing of several signaling agonists across a range of hPSC-derived CRTs.

(A) Timeline of small-molecule addition for differentiation of mDA neurons from hPSCs. (B) Montage of 90 unique differentiation timeline to test temporal profiles of CHIR dose stained for tyrosine hydroxylase (TH) and Tuj1. Scale bar, 1 mm. (C) Immunocytochemistry images of i. low, ii. medium, and ii. high proportions of TH+ (yellow) neurons (red) dependent on the temporal profile of CHIR exposure. Scale bar, 100 m.

The clinical emergence of several cell-based therapy candidates (47) is encouraging for human diseases/disorders that currently have no effective small molecule or biologic-based therapy. As research and development into CRT candidates continues to progress, cell production has emerged as a bottleneckas delivery vectors recently have in gene therapyand improved tools will be necessary to enable higher quality and yield in cell manufacturing. Although previous studies have reported ~90% hPSC differentiation efficiency into Olig2+ progenitors using 2D culture formats (19), the 2D culture format constrains the space in which cells can expand to the surface area of the culture plate that limits the overall cell yield that can be produced. The adoption of scalable 3D culture formats, which have demonstrated the ability to produce up to fivefold higher quantities of cells per culture volume, shows promise in surpassing limits of 2D cell expansion (2933) and could result in a higher overall production quantity of target cells even if differentiation efficiencies were lower than what has been reported in 2D. Therefore, the 3D screening and analysis strategy presented here is relevant for numerous emerging CRT candidates for which conversion of a stem or progenitor cell, such as a hPSCs (48), to a therapeutically relevant cell type requires searching through a large in vitro design space of doses, durations, dynamics, and combinations of signaling cues over several weeks of culture.

Notably, to emulate a ubiquitous and naturally occurring phenomenon in organismal development (16, 49), we dynamically varied key signaling cues in our screening strategy, tuning dosage over time. These analyses revealed new biological insights into the dynamic process by which cell competence to signals and fate are progressively specified (50). For example, by applying this platform to screen through several dynamic signaling levels simultaneously, we observed that the differentiation toward Nkx2.2+ progenitors is very sensitive to the dose of RA between days 0 and 1 and the dose of SAG between days 4 and 10. After these respective time windows, the effect of each respective signal in producing Nkx2.2+ progenitors is decreased, potentially pointing to a decrease in cellular competence to each of these signals over the course of OPC development. These cases of stage-specific responses to signaling cues, revealed by our screening platform, create a new dimension for future optimization of cell production.

To effectively navigate this enormous parameter space across doses, durations, dynamics, and combinations of signaling cues and resulting differentiation outcomes, we developed a robust sensitivity analysis strategy that can rank effect sizes to reveal which parameters should be the focus of optimization to modulate expression of target markers of interest (49) and, by contrast, which parameters exert minimal impact and can thus be neglected. For example, titration of RA dose will exert a significantly higher impact on differentiation efficiency than several other culture parameters combined. Furthermore, insights from this study could reduce the necessary quantity of SHH agonist by more than 50% to achieve similar levels of OPC differentiation. As these cell production processes translate from bench scale to industrial scale, awareness of key parameters that influence critical quality attributes (18) of the cell therapy product (such as expression of specific cellular markers) will be a necessary step in reliably producing these therapeutic cell types at scale for the clinic (51).

The wealth of combinatorial and temporal signaling patterns identified in this study can be analyzed in the context of CNS development as well. We observed a potential case of biphasic activity for the Wnt signaling pathway as both activation and inhibition appeared to increase expression of OPC markers Nkx2.2 and Olig2. In particular, this effect was seen with initial Wnt activation by CHIR during days 0 to 3 of OPC differentiation followed by inhibition by IWP-2 during days 4 to 21 of OPC differentiation. The Wnt pathway has shown stage-specific activity in cardiac and hematopoietic development (43, 44), which may thus be a conserved feature across several developmental systems. Wnt signals play an important role in the gastrulation of the embryo to form the primitive streak (38), yet in the subsequent stages of spinal cord development, Wnt signals induce a dorsalizing effect (52), whereas oligodendrocytes originate from the motor neuron domain on the ventral side. Therefore, suppressing endogenous Wnt signals in vitro after initial activation of Wnt may better recapitulate the natural developmental signaling environment of developing oligodendrocytes. Alternatively, as Wnt signals also play a role in rostrocaudal patterning of the CNS, these insights may further point toward a rostrocaudal region of the CNS during this developmental window that is optimal to recapitulate in vitro for OPC production. The oligodendrocytes created through this protocol, which expressed OTX2 at day 10 (fig. S2C), may resemble OPCs in the midbrain/hindbrain region. It is conceivable that exposure to the Wnt antagonist, IWP-2, induced a position rostral to the spinal cord during the differentiation window. This biphasic Wnt trend was seen again in our analysis of differentiation of mDA neurons, underscoring that stage-specific responses may be a conserved feature across several differentiation processes aiming to recapitulate a precise cellular position across several axes of patterning signals during natural development.

Furthermore, the statistical model identified an interaction between RA and SAG (an SHH agonist) in the early differentiation windows for specifying Nkx2.2+ progenitors (Fig. 5B), which has not been previously reported to our knowledge. In the developing CNS, RA signaling influences rostrocaudal positional identity, whereas SHH signaling specifies dorsoventral positional identity. Therefore, this statistical interaction found in the screen may represent intracellular cross-talk between the RA and SHH signaling pathways to integrate both patterning dimensions into Nkx2.2+ progenitor identity. This finding builds on what is known about RA and SHH signals for Olig2+ progenitor development in the spinal cord (53, 54).

Additionally, the 3D context of this screening platform enables high-throughput investigation into neurodevelopmental model systems that can offer unique perspectives beyond what is capable in 2D screening platforms, for example, by recapitulating cell-to-cell interactions, cytoskeletal arrangement, and multicellular patterning in 3D. The lumen structures that were observed during the neural induction period (fig. S2B and movie S1) in response to caudalizing conditions (high Wnt and RA) could be the basis of future organoid screening strategies to probe early multicellular arrangement and the effect of lumen size and shape on cell fate determination at various positions along the rostrocaudal and dorsoventral axes.

In conclusion, we demonstrate the versatile capabilities of a unique microculture platform for 3D differentiation screening and optimization of hPSC-derived cell therapies, whereby 1200 unique OPC differentiation timelines, and a total of over 4800 independent samples, were investigated using 0.2% of the reagent volumes required in a standard 96-well plate format. The dense dataset enabled subsequent statistical modeling for empirical optimization of the differentiation process and identified differential sensitivities to various culture parameters across time. These insights are important in developing strong process knowledge for manufacturing stem cell therapeutics as they continue to emerge in the clinic, and therefore, such screening strategies may accelerate the pace of discovery and development. Simultaneously, this combinatorial 3D hPSC differentiation screens may provide new insights on the basic biology of human development.

Human embryonic stem cells (H9s: National Institutes of Health Stem Cell Registry no. 0062) and hiPSCs (TCTFs: 8FLVY6C2, a gift from S. Li) were subcultured in monolayer format on a layer of 1% Matrigel and maintained in Essential 8 medium during expansion. At 80% confluency, H9s were passaged using Versene solution and replated at a 1:8 split.

H9s were dissociated into single cells using Accutase solution and resuspended in Essential 8 medium containing 10 M Y-27632 (ROCK Inhibitor). H9s were counted and resuspended at defined densities in 50% Matrigel solution on ice. While chilled, 100 nl of H9s in 50% Matrigel solution was deposited onto the micropillars at a density of 100 cells per pillar, unless otherwise noted, using a custom robotic liquid handling program and then incubated at 37C for 20 min to promote gelation of 3D cultures. The micropillar chip was then inverted and placed into a fresh microwell chip containing cell culture media (table S1). All liquid dispensing into the microculture platform was performed with a DIGILAB OmniGrid Micro liquid handler with customized programs for deposition patterns. Between days 2 and 0, cells were kept in E8 media supplemented with 10 M ROCK Inhibitor. Between days 0 and 10, cells were kept in differentiation media made of a base of 50% Dulbeccos Modified Eagles MediumF12, 50% Neurobasal, 0.5% penicillin/streptomycin (pen/strep), 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. Between days 10 and 21, cells were kept in differentiation media made of a base of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. After day 21, OPCs were transitioned to maturation media consisting of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, 1:50 N2 supplement, insulin-like growth factor 1 (10 ng/ml), platelet-derived growth factor (PDGF)AA (10 ng/ml), NT-3 (10 ng/ml), and insulin (25 g/ml). Media were changed daily by transferring the micropillar chip into a microwell chip containing fresh media every other day using a custom-made mechanical Chip Swapper for consistent transfer. Technical replicates included two different dispensing patterns to average out positional effects across the microchip.

At the endpoint of the experiment, the micropillar chip was carefully removed from the microwell chip and placed in new microwell chip containing calcein AM, ethidium homodimer, and Hoechst diluted in sterile phosphate-buffered saline (PBS) (dilution details in table S1). The micropillar chip was incubated for 20 min and then transferred to a new microwell chip containing PBS, and individual microenvironments were imaged using fluorescence microscopy.

At the endpoint of the experiment, the micropillar chip was carefully removed from the wellchip and placed into a bath of 4% paraformaldehyde for 15 min to fix cell cultures. Then, the micropillar chip was washed twice in PBS for 5 min each and placed into a bath of 0.25% Triton X-100 + 5% donkey serum in PBS for 10 min to permeabilize cells. After permeabilization, the micropillar chip was washed five times in 5% donkey serum for 5 min each, transferred to a wellchip containing primary antibodies of interest diluted in PBS + donkey serum (dilution details in table S1), and stored overnight at 4C. After primary staining, the micropillar chip was washed twice in PBS for 5 min each, placed into a microwell chip containing the corresponding secondary antibodies (dilution details in table S1), and incubated at 37C for 2 hours. After secondary staining, the micropillar chip was washed twice in PBS for 5 min each and placed into a wellchip containing PBS; individual microenvironments were imaged using fluorescence confocal microscopy.

Stained micropillar chips were sealed with a polypropylene film (GeneMate T-2452-1) and imaged with a 20 objective using a Perkin Elmer Opera Phenix automated confocal fluorescence microscope available in the High-Throughput Screening Facility at University of California, Berkeley. Laser exposure time and power were kept constant for a fluorescence channel within an imaging set. Images were scored for marker expression depending on nuclear or cytoplasmic localization (fig. S3).

Fixed cultures on micropillars at day 15 were stained with 4,6-diamidino-2-phenylindole (DAPI) and imaged using an upright Olympus BX51WI microscope (Olympus Corporation) equipped with swept field confocal technology (Bruker) and a Ti:sapphire two-photon Chameleon Ultra II laser (Coherent) was used. The two-photon laser was set to 405 nm, and images were captured using an electron multiplying charge-coupled device camera (Photometrics). Prairie View Software (v. 5.3 U3, Bruker) was used to acquire images, and ImageJ software was used to create a video of the z-series.

Quantified image data were then imported into Python for statistical data analysis (55) and visualization. For comparisons between datasets acquired across different experimental sessions, raw data were scaled and centered by z score, and descriptive statistics were calculated from four technical replicates. Error bars represent 95% confidence intervals, unless otherwise specified. For the hierarchical cluster model, the Euclidean distance was used to measure pairwise distance between each observation, and the unweighted pair group method with arithmetic mean (UPGMA) algorithm was used to calculate the linkage pattern. A Benjamini and Hochberg false discovery rate correction was applied as needed to correct for multiple comparisons. Code is available upon request.

Acknowledgments: We thank M. West of the High-Throughput Screening Facility (HTSF) at UC Berkeley and E. Granlund of the College of Chemistry machine shop for machining custom parts. In addition, we are grateful to G. Rodrigues, M. Adil, and J. Zimmermann for participating in the discussions on the work. Funding: This research was supported by the California Institute for Regenerative Medicine (DISC-08982) and the NIH (R01-ES020903) and Instrumentation Grant (S10OD021828) that provided the Perkin Elmer Opera Phenix microscope. R.M. was supported in part by an NSF Graduate Research Fellowship. Author contributions: R.M., D.S.C., and D.V.S. conceived various parts of the project and supervised the study. R.M. designed the experiments and managed the project workflows. X.B. created Nkx2.2-Cre H9 reporter lines. R.M., E.T., and E.C. performed the experiments. R.M. conducted statistical modeling, and A.M. aided in statistical testing. R.M., D.S.C., and D.V.S. analyzed and interpreted the data. R.M. wrote the manuscript with revisions from J.S.D., D.S.C., and D.V.S. Competing interests: R.M., D.S.C., and D.V.S. are inventors on a U.S. patent pending related to this work filed by the University of California, Berkeley (PCT/US2020/029553, filed on 23 April 2020). D.V.S. is the inventor on two U.S. patent pendings related to this work filed by the University of California, Berkeley (PCT/US2016/055362, filed on 4 October 2016; no. PCT/US2016/055361, filed on 5 October 2015). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates - Science Advances

Cardiac Stem Cells Comments Off on High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates – Science Advances | August 10th, 2020

Dyne Therapeutics started out last April with a modest $50 million to mine targeted muscle disease therapies from its in-house conjugate technology. The biotech has now convinced more investors that its got gems on its hands, closing $115 million in fresh financing to push its next-gen oligonucleotide drugs into the clinic.

Vida Ventures and Surveyor Capital led the round, joined by a group of other new backers including Wellington Management Company, Logos Capital and Franklin Templeton.

Atlas where Dyne was incubated also returned alongside Forbion and MPM.

Stefan Vitorovic, who co-founded Vida with Arie Belldegrun and others, took the lead on this one. Dynes FORCE platform matches exactly their appetite for bold visions in the future of medicine, with the potential to deliver life-changing outcomes for patients with muscle diseases, he said.

This is how the biotech plans to do it: By linking an antibody to an oligonucleotide, Dynes therapies are engineered to hone in on muscle cells and degrade only disease-causing RNA, thereby avoiding systemic toxicity issues.

Romesh Subramanian, a co-founder of what is now Translate Bio, helped launch the operations as an entrepreneur-in-residence at Atlas. Hes since handed the CEO baton to Joshua Brumm and moved to the CSO post.

When you deliver a naked oligo, very little gets to the muscle, he told C&EN back in 2019.

That means a lack of specificity and potential safety problems for drugs like Sareptas controversial Exondys 51. While Dyne is aiming directly at that market with its Duchenne muscular dystrophy program, its initial focus is on myotonic dystrophy.

Trailing closely is a third therapy for facioscapulohumeral muscular dystrophy, followed by discovery work in the cardiac and metabolic arenas.

How would the approach compare to gene therapies, which are cropping up at Sarepta and other newer players focused on muscle diseases? We didnt get a chance to ask Dyne, which is shying away from interviews this morning perhaps a sign of upcoming plans in a booming biotech IPO market.

Under Braum, Dyne has been on a bit of a hiring spree recently, poaching Susanna High from bluebird to be COO, appointing ex-Celgene exec Daniel Wilson as VP of intellectual property, and scooping Debra Feldman from Sage Therapeutics as head of regulatory.

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Vida Ventures co-leads Dyne's $115M megaround for next-gen oligo therapies aimed squarely at muscles - Endpoints News

Cardiac Stem Cells Comments Off on Vida Ventures co-leads Dyne’s $115M megaround for next-gen oligo therapies aimed squarely at muscles – Endpoints News | August 10th, 2020

Adam Smith (1723-1790) was not who you think he was. I'm talking about the original Adam Smith who wrote The Wealth of Nations (1776) and spent most of his life in Edinburgh, Scotland. The more recent "Adam Smith" - nom de plume of the late George Goodman who wrote The Money Game (1967) - bears much more resemblance to the Adam Smith you think you know.

The first Adam Smith would have had little interest in stock market wisdom because he regarded himself as a moral philosopher rather than an analyst of markets. In fact, he was not even a capitalist. His works do not include the words "capitalist" or "capitalism" because neither came into use in his lifetime. The first mention of "capitalism" in print was in the 1854 novel The Newcomes by William Makepeace Thackeray, whose father had been involved with the East India Company. Karl Marx, oddly enough, helped popularize the term in his classic Das Kapital (1867). The irony is that if Marx did not quite invent the concept of capitalism, he certainly made the term popular in the process of opposing and bashing it.

No one can know what Adam Smith would have thought about free market capitalism as presently practiced, nor can we guess what he would have thought about the aftermarket in shares which we call "the stock market." The first stock exchanges came into being a couple of years after his death and shares were traded in only a small handful of companies including the still extant Bank of New York (NYSE:BK). Security trading over Smith's lifetime was concerned primarily with credit instruments, the exceptions being one-off exchanges organized by and for the British and Dutch East India Companies. So no capitalism, no market opinions from Adam Smith. Sorry to have to tell you.

The primary interest of Adam Smith was the goal which gave his book its full title - an inquiry into the nature and causes of the wealth of nations, in short, the well-being of the general populace. Counterintuitively paired with this was the self-interest which led tradesmen and the early industrialists to seek profit. He used the term "invisible hand" only three times in his writing and just once in The Wealth of Nations, to wit:

The rich consume little more than the poor, and in spite of their natural selfishness and rapacity, though they mean only their own conveniency, though the sole end which they propose from the labours of all the thousands whom they employ be the gratification of their own vain and insatiable desires, they divide with the poor the produce of all their improvements. They are led by an invisible hand to make nearly the same distribution of the necessaries of life which would have been made, had the earth been divided into equal portions among all its inhabitants, and thus without intending it, without knowing it, advance the interest of the society, and afford means to the multiplication of the species...the beggar, who suns himself by the side of the highway, possesses that security which kings are fighting for."

This is the central core of Adam Smith's thinking. It has always interested me that the ultimate goals of Adam Smith and Karl Marx did not differ greatly. The important difference is that Smith believed in freedom of the market while Marx believed that the solution was the top-down mandate of a command economy. We are familiar at this point with the general course of events in top down economies. The 20th Century resolved that question definitively in favor of Smith's view, which we now call capitalism.

Smith, however, never imagined a world with an after-market of securities measured by such things as price earnings ratios and discounted free cash flow. He would have been astonished at the use of these and other forms of analysis central to modern markets including shares of corporations with thousands of shareholders and many millions of shares. The few larger businesses in his day - a few early industrialists and the enormous East India Companies - did not lend themselves to that kind of analysis.

Does that mean that the thinking of Adam Smith is useless in trying to understand value in the modern financial markets? Not at all. Smith's model of the invisible hand contains a clue as to the way he might have valued companies and their shares. In fact, the view of Adam Smith may take us back to the primary purpose of capital markets which focus on start-ups, IPOs, unicorns, perhaps even SPACs, and all companies in their early stages. Such companies seek capital with which they aspire to bring innovations. They hope to profit by serving the unmet and often unrecognized needs of a body of potential customers.

What Smith saw was the intricate interplay between the needs and desires of customers and the self-interest of a risk-taking capitalist. That is the core transaction of the capitalist system. Without so much as a glance at discounted future cash flow, Smith implicitly understood that for a business the important thing was the population for which a business might add value. The issues for the entrepreneur involve the accuracy of their estimate of that market, the share of that market they might expect to win, the revenues they might expect to receive, and the profit margin they might expect to realize on those revenues.

In short, Adam Smith's thinking may not ordinarily be very helpful in the after-market we call "the stock market" but is central to the universe of young and innovative companies. It is directly connected with the way businesses and customers are conjoined. What a business does for its customers, he implies, provides an outline of its ultimate value. For this reason, I see the conjunction of businesses and customers as potentially useful in thinking about leading companies in the current market, especially for those companies which cannot be analyzed usefully by the standard market metrics of sales, margins, earnings, PE, and discounted cash flow.

In Adam Smith terms, a company should be worth a reasonable return for what it contributes to the greater good of the general populace. This single sentence is at the heart of what I am calling the "Adam Smith Model" of valuation. Does it actually work when trying to value innovative companies? Can one make decisions based on this model? To a large degree I think it is the only really helpful approach in valuing companies driven by new products and concepts.

To show how this sort of analysis might work, I will start with my daughter's portfolio of innovative biotech companies, which she put together in the early days of the pandemic. It is a pretty good model of the kind of thing I have always kept a careful distance from. Her surprising success with this portfolio prompted my own internal debate.

My daughter is a bright young woman who will soon turn 50. She has a doctorate in art history from Penn but retrained as a nurse in order to live in the woods in western Massachusetts and raise her children as a single mom close to nature and away from urban centers. Her life is modeled more on Thoreau's Walden than on Ben Graham's The Intelligent Investor. Despite sitting at my dinner table for seventeen years she remained almost entirely ignorant about financial markets until recently. The after-market in stocks seemed to her insufficiently serious to deserve her attention, which might well have been Adam Smith's view had he lived to see it. I confess to having had similar thoughts myself at times but have suppressed them.

In recent years, however, prompted by the realization that she may one day retire and need an income, she has begun to take an interest in markets. Around the beginning of the COVID-19 crisis (on which she had early insight and much sound advice), she put together without telling me a portfolio of biotech companies. She did this on a very small scale. Over four or five months she is up well over 200%, an amount I have never made in anything like that period. Here's an excerpt from an email she sent me on her portfolio:

Yes, that's why I like leronlimab - CytoDyn (OTCQB:CYDY). It has many uses, a high safety profile (I don't give a second glance to drugs with a low safety profile-anyone could have seen that with hydroxychloroquine, and now dexamethasone-which is a broad-target immunosuppressant, hence will never be a commonly used drug for Covid). Leronlimab has a great safety profile and works with a known mechanism vs. the cytokine storm. Anything good for Covid (or the other viruses that are still around: SARS, MERS and Ebola) must not suppress the immune system as a whole (as do all steroids such as dexamethasone). Leronlimab is targeted at the CCR5 receptor-which makes it effective for coronaviruses as well as cancers and autoimmune disease. Amazing for metastatic cancer, including prostate (though the recent studies are on a hard to treat breast cancer), and probably other untreatable but common cancers. It's going to be great for HIV. It's going to work for host vs graft disease (post-transplants, when we go back to doing them). It also appears to work for NASH (non-alchoholic fatty liver disease, which has increased dramatically in numbers, but is silent in most people until it is at a late stage.) It is the next diabetes.

Mesoblast (MESO):

The next wave of medical advances are going to come through better understanding of immunomodulation. Most if not all diseases-including cardiac disease and diabetes--will come to be understood as inflammatory diseases to be manipulated at the cellular level. We will see more and more of these diseases due to our inflammatory (sedentary, antioxidant-deprived) lifestyle and toxic environment. In any case, I'm interested in the companies who are leading the way in specialized research in immunomodulation. Mesoblast is using stem cell technologies to repair the immune system, and applying that technology to many untreatable diseases.

Avalon GloboCare (AVCO):

Same argument as Mesoblast: multiple technologies, targeted immunotherapy. I'm not so interested in any single technology, but they are partnering on several important technologies (stem cells, diagnostic technologies), with broad implications and clinical uses. They are partnering to develop a nasal vaccine for Covid, but again, I'm not as interested in that particular product, but the broader technology. Nasal vaccines are going to be a winner for many reasons-ease of use, global application, and the fact that we will run short on syringes for other vaccines).

Altimmune (ALT):

Same as above: leader in NASH (non-alcoholic fatty liver disease), nasal vaccine technology

Okay, those are my four picks. Amazing for metastatic cancer, including prostate (though the recent studies are on a hard to treat breast cancer). The others, JNJ, Becton Dickinson, and DaVita, you know."

I love the fact that my daughter comes at investing from an angle so different from mine and with a skill set that does not overlap mine at all. I also love that its method combines brains and a good heart - the assumption that a company is worth the sum of what it contributes to human well being. What I find most intriguing is that her natural way of coming at things aligns so closely with the Adam Smith view. Can growth investing possibly have such a simple foundation?

You will probably have guessed that I have never bought anything like these biotech companies nor used anything resembling this kind of analysis. I do not, and could not possibly, recommend any or all of them. They are well outside my areas of knowledge and expertise. The only counsel I was able to give my daughter included the fact that when buying companies like this you should probably buy a basket of them - something which she had already done, intuitively.

By early July she had tripled her money and was beginning to be worried about what felt to her like an overhyped sector of an overpriced market. This was where she thought my advice might be useful. I laughed and said that she should be giving me financial advice instead of vice versa, but if she was nervous she should probably sell down to her comfort level (she's in a low tax bracket so cap gains aren't a problem). Perhaps she should at least sell down to the point at which she was investing with house money. I added that it was okay to leave a few chips on the table and let her long term bet ride. She agreed and did something close to that.

Her insight had been pretty simple. The value of a company should correspond to the amount of value added via the "invisible hand" to the health, happiness, and well-being of its customers - perhaps even to the general populace. You would start by estimating the size of the market for which it provided a product or service. You would then adjust to take into account the competition for that market and finally the probability of your particular company capturing a major part of that market. Then, and only then, you might begin to make rough estimates as to potential revenues and profit margin. The key correlation is not revenue and profit margin, which are well out in the future, but the value the company is likely to add to society. The payoff in small biotechs like these, if it comes at all, is likely to come in a rush when a large pharma company sees the potential and buys them out, fulfilling the Adam Smith projection of appropriate reward for a large service.

When I started to formulate it this way, I realized that I have missed quite a lot in never owning stocks which might be best measured in this way. This includes not just small biotechs and niche technology startups but also giant current market leaders such as Amazon (AMZN), Netflix (NFLX), and Tesla (TSLA). At every point in the lives of these three companies, I have found that the methods by which I have always valued stocks - things like discounted earnings, dividends, and cash flow - made me unable to put together any reasonable argument for owning them.

Had I finally stumbled upon a valuation model that might provide a rationale for buying them? Up to this point, I have not seen a persuasive methodology for thinking about the value of these companies. Could this simple approach account for their unusually high valuations?

Adam Smith implied that the relationship between a business and the population it served was the invisible force behind what we call capitalism. It takes only a small further step to propose that the population served by a business can also be described as an "asset" owned by that business. In some cases, especially young or innovative companies, it is customers acquired that is the central asset. The idea of a business "owning" its customers is not new. I first read about it in a novel at least fifty years ago when a literary agent retires by essentially selling his customers to a rival - a practice that was apparently commonplace even then.

This customer-based approach seems to be the way the founders of these three market leaders looked at the opportunity. Customers weren't just part of the picture. They were the whole thing. Acquiring customers is what these companies set out to do. Everything else could come later. They were determined to do everything it takes to own the largest number of customers, including running their businesses with negative earnings and free cash flow for a long time. The market caught on to their goals and their prices shot up to the stratosphere.

Amazon, Netflix, and Tesla have always sold at ridiculous multiples of earnings and cash flow, if any, and are ridiculously expensive by pretty much every other traditional measure. When you look at them the way my daughter looks at biotechs, however, the picture changes. You set the standard ratios aside and instead ask: what is the value of these companies if measured by the sum of value they provide in service to their actual and potential customers? The transmission of that value to shareholders is initially as invisible as the invisible hand by which value is distributed to the populace. It is nevertheless reflected in the stock price.

Here's how one might do a broad estimate of value for the three companies:

Today, online commerce saves customers money and precious time," writes Bezos. "Tomorrow, through personalization, online commerce will accelerate the very process of discovery. Amazon.com uses the internet to create real value for its customers and, by doing so, hopes to create an enduring franchise, even in established and large markets.

We believe that a fundamental measure of our success will be the shareholder value we create over the long-term. This value will be a direct result of our ability to extend and solidify our current market leadership position. The stronger our market leadership, the more powerful our economic model.

Because of our emphasis on the long-term, we may make decisions and weigh tradeoffs differently than some companies... We will continue to make investment decisions in light of long-term market leadership considerations rather than short-term profitability considerations or short-term Wall Street reactions...We aren't so bold as to claim that the above is the 'right' investment philosophy, but it's ours, and we would be remiss if we weren't clear in the approach we have taken and will continue to take.

From the beginning, our focus has been on offering our customers compelling value," explained Bezos. "We brought [customers] much more selection than was possible in a physical store (our store would now occupy six football fields), and presented it in a useful, easy-to-search, and easy-to-browse format in a store open 365 days a year, 24 hours a day."

That's Amazon's mission statement summed up in a few paragraphs. The guiding purpose to this business model is positioning yourself to "own" more and more customers. This customer-obsession of Bezos amounts to is a manifesto for innovative companies. The second paragraph flows directly from the core principle of Adam Smith. Get first things first, Bezos is saying, meaning understanding the potential market and seizing it. Profitability and measurements commonly used by Wall Street come later.

Amazon is no longer a young company in chronological age, but the vision embedded in its mission statement is to remain a young company forever. A Day 1 company, as Bezos calls it, is always visionary and entrepreneurial in its thinking. What Bezos is saying to investors is: disregard the numbers used by Wall Street analysts. They are important measures only for Day 2 companies (slow-moving, mature companies in stasis, for which the next stage is death). Keep your eyes on the main thing - the growth of your customer base and a high level of customer satisfaction. Facebook (FB) and Alphabet (GOOG)(GOOGL) were like that in early stages but moved fairly quickly to address the question of how to monetize their users, eventually succeeding and becoming measurable by ordinary metrics. They are now ordinary growth companies with moderately high PEs, at least in context of the current market. Bezos rejected early monetization. Have faith, he said. We will monetize our customer base when we get around to it.

The greatest single risk for Amazon is its increasing size, which makes it difficult to remain nimble and full of energy. At some point, it will face the horror which confronts history's great empires - running out of worlds to conquer. Political constraints may have something to do with that, but pure size is the major burden. Summing it up, I would buy Amazon at something like 50-60% of its present price if nothing had gone wrong in the business in the meantime.

2. Elon Musk somehow manages to top Bezos. His manifesto, much of which comes out in random statements and tweets, is that Tesla will one day produce pretty much every car sold in the US, maybe even the world. At the very least it will be the driving force in a new industry. His business has a powerful technological core, but the rational for it is the prospect of capturing much of the total customer base for vehicles. It currently appears to be priced on the assumption that Musk will succeed in this ambition to a large degree.

Musk is confident that Tesla's technology will become the universal standard and squeeze most of the current auto industry into terminal decline. Its panache stems from great aesthetics and the promise of enlisting his customers in the project of slowing climate change and helping save the world. Tesla, he implies, will almost incidentally become highly profitable, an outcome to which Musk himself seems to be personally indifferent but in which his investors might have some interest. If he is right, Tesla will probably look cheap if bought today or tomorrow at 160 times its current (and first annual) positive earnings.

Like Bezos, Musk would have us remember: we don't care about all that. That's the old valuation model. What we care about is a market of 17 million vehicles sold annually in the US and a number around five times that in the world. That's the scale of customers Elon wants to own. Once that happens, he will bite the bullet and monetize.

To own Tesla at anything like the current price you have to make a few audacious assumptions. You have to believe that vehicles will continue to be bought on very large scale and that the overwhelming number of vehicles sold will become electric within a short period of time. You then have to believe that Tesla will become the company that owns most of the customers and sells most of the vehicles. It's not impossible, but there are obstacles to overcome.

If Ford, GM, Toyota, Honda and others launch a modestly successful counterattack, or the whole market shrinks, you will see the earnings and cash flow multiples of Tesla shares contract in the general direction of the valuations of those "Day 2" companies. In other words, if you are an investor, you don't want Tesla to become just another car company, nor do you want it to be the last giant in an industry that is contracting and possibly dying. If one of those things happens, Tesla, as measured by the Adam Smith premise, is likely to be a disappointing investment. This is very broad brush analysis, but that's the only way to really deal with Tesla, a company quite similar to my daughter's biotechs. The risks for Tesla seem high and hard to calculate. These are the problems routinely faced by innovative companies in their early stages, and you must also pay attention to the risk that Tesla could run out of time to overthrow the industry while the industry still exists in its present form.

3. Netflix is a company I have looked at only recently. Until a few months ago I had never used their product - not once. Entertainment is OK - I'm being entertained by writing this, and I dare to hope that you readers are both entertained and stimulated to further thought by it - but I didn't experience Netflix until a millennial step child and her husband spent some time with us and promptly realized that they couldn't live without it. They put it on a couple of our TVs so that they would have some kiddie movies to bribe their 3-year-old to eat dinner plus an hour of decompressing entertainment for themselves before sleep.

A few months ago my wife and discovered that we still had it, linked somehow to their home two thousand miles away, and it turns out that the shows are pretty good. They turned out to be especially valuable during the lockdown. We had run out of old movies, so we started over with Netflix. I started paying attention to articles on Netflix and ultimately took a look at their numbers.

Egads! They have been unprofitable from day one and their negative cash flow has done nothing but increase. Their costs for content are going up and their competition is mounting. On the other hand, Stranger Things is the kind of nitwit escapism that I found that I like after a long hot day teaching tennis (my wife not so much).

How do I put the two views of Netflix together. In this case, the risks and uncertainties make the stock uninvestable for me. For one thing, I am used to having entertainment piped into me for free (I automatically tune out all ads.) The numbers needed are just too daunting for Netflix, the rising costs for content are worrisome, and ultimate limits in a market now sliced several ways implies limits to growth. I am doubtful that Netflix will ever morph into a company I can measure more conventionally. I'm pretty sure I wouldn't renew if our faraway relatives stopped providing it for free. That's the core of it: I'm a customer of sorts, but they don't really own me. I don't own them either, and am not likely to any time soon.

The outperformance of high growth companies over the last decade and most spectacularly over recent months has naturally invited vigorous debate. The catastrophic dot.com crackup exactly two decades ago has receded sufficiently that alt explanations of market behavior are once again beginning to be proposed in earnest. This article is perhaps one of them but exists within the frame of traditional methods.

The dot.com era which reached its peak in 2000 crashed amidst assertions that eyeballs and clicks were better measures of value than earnings or cash flow. I lived through it as a bystander, listening to fellow fitness enthusiasts in the workout room at my tennis club boast about their portfolios, then noticing their absences one by one as the crisis unfolded. I didn't feel schadenfreude, far from it, only relief that I myself had not been ruined.

Valuations are once again at a point which calls ordinary prudence into question. Are the traditional models of valuation no longer worth using? This was suggested recently by BlackRock quant Jeff Shen who argued here that traditional efforts to solve the "mystery" of value are worthless. The Shen view, by the way, derives from this article by another BlackRock analyst, Gerald T Garvey, published in the prestigious Journal of Portfolio Management. The Garvey article comes down firmly on the growth side of the growth/value debate arguing that "elevated percentage value spreads predict higher risk, not higher returns."

In more down to earth terms, Shen and Garvey are saying that companies whose shares haven't been able to grow in this environment are losing ground and possibly dying, and should be avoided. If a stock goes up a lot it is probably safe because the wisdom of crowds is behind its rise. This is the kind of statement that is true until it isn't. Shen goes on to argue that contemporary investors should look for alt indicators and models such as the happiness of a company's employees. That particular idea didn't exactly blow me away, and neither Bezos nor Musk seem to be proponents of using that principle to focus or drive their businesses.

On the other hand, an effort to measure a company's success in terms of the overall value it provides to its customers does seem to me an interesting way to think about growth companies. Most companies trading in the aftermarket for stocks - by now you know that when I use this awkward but accurate phrase I am referring to the "stock market" - are not high growth companies and are probably best analyzed by traditional measures. Ultimately some form of traditional value measurement must appear within the life-cycle of a successful company.

To Jeff Bezos, the moment when traditional cash measures become important to a company is the day that it wakes up as a Day 2 company, a company that does not attempt to reinvent the world afresh every morning. While such a company may still turn out to be a decent investment, it's important for value investors to pay careful attention to their risk of having their business disrupted by new technologies and methods. This is a fairly straightforward way of thinking about the world we now live in, and I have learned to ask the hard questions about everything I own - even companies with seemingly strong moats.

Disruption is a major theme of the contemporary world, and every thoughtful person would do well to put the world together afresh every morning. Even with an open mind, it's hard to anticipate what hidden risks might cause a company's current defenses to collapse. Because of the incredible speed of change and the prevalence of unsuspected collateral effects, this questioning is important in a way that it has never been in the past. That was the important lesson number two from the dot.com event. Buying the disruptors rarely made fortunes, but not being sufficiently cautious about potential disruptees was a good way to lose a fortune.

For these businesses the Adam Smith Model needs to be turned upside down so that it becomes a story about loss of customers. One of the great anecdotal examples was Bill Gates stunning a 1990s gathering of Buffett's value investor pals by using his knowledge of the digital world to inform them that Eastman Kodak (KODK), then a market stalwart, was "toast." The customer criterion proves its importance when inverted. I was unable to estimate the outcome for Amazon - haven't made a nickel directly by buying it - but it was obvious to me instantly that it was going to be the end of the road for many other retailers, as well as many malls and REITs. The history of Sears Roebuck and Walmart were powerful precedents. The only thing not entirely clear was the time frame, which is proving to be much faster than most people expected.

The astonishing thing was how eagerly investors jumped on the Amazon bandwagon, which has many uncertainties, and how slowly the investor mind adjusted to the knock-on effects, which were far more certain. The key to grasping this quickly, is to focus on customers "owned" but sure to slip away, as in the case of Kodak.

The Adam Smith Model is simply one of the ways of making an estimate concerning what the cumulative value should be somewhere down the road at whatever time the company decides to monetize the cash value of owning its customer base. At that point, it will begin to report profits and cash flow, pay dividends, and buy back shares. Apple (AAPL) may be the best current example of this model. It started paying dividends and buying back shares about a year before its growth began to level off. As the dream of perpetual growth disappeared, investors were rewarded by the cold cash that abundantly flowed.

This is the distant event that Bezos' mission statement grudgingly projects. For Bezos, earnings, dividends, and buybacks are Day 2 concerns, and you get the feeling that he would just as soon not live to see them. Being a Day 2 company, is like living a comfortable and happy life: the great second-best award for those who have given up their aspirations to greatness. So Apple was once an innovative company priced on the basis of the Adam Smith Model and has now normalized into a Day 2 company which can be valued by the traditional tools. Who knows, maybe it has a few positive tricks up its sleeve but relentless regular growth is a thing of the past.

Amazon seems to be on the same general course as Apple, but with ordinary shareholder gratification deferred into a less well defined and more distant future. You just have to wait for it, and at an incredibly low discount rate such as the current Treasury rates you are willing to pay up for the ultimate awards now and wait a long time. This is part of the current market infatuation with rapid and persistent growth. If you project very far into the future, the value may approach infinity, or since that concept no longer exists even in physics, you could approximate it by the difficulty Amazon would have if Amazon's business became the major part of the gross product of the planet.

High valuations in the current market can be partially explained by a number of factors including historically low interest rates and the appeal of the tech leaders during a broad public lockdown. It also true, however, that the most optimistic thinking stems from a gambling mentality which is supported by the famous Petersburg Paradox which has come to bear in their valuations. There are a number of recent articles with varied approaches to this subject, and you can sample them by googling Petersburg Paradox.

The Petersburg Paradox is generally credited to Daniel Bernoulli, who published an article on it in 1738, but is sometimes credited to his cousin Nicolaus Bernoulli who talked about it in a letter written in 1713. It is a simple gambling game that doubles your winnings with each successive throw of tails. Its expected return generates an infinite series of events the probability of which decline by the exponential 1/2 to the N power exactly offsetting the exponential increase in winnings (2 to the N power).

Each successive term is exactly 1. The mathematically expected return is the sum of that infinite number of ones. I suppose that this means you max out when the number in dollars is equal to the number of bits (or Planck units) in the universe.

This series, therefore, produces quite large expectation of winnings despite the fact that the probability of large winnings at any particular future point obviously diminishes enormously and becomes very slight after a few coin tosses. It is famous for the contradiction of the expected total return and the relatively small amount that any reasonable person would be willing to wager on that return. A number of mathematicians have attempted to resolve this contradiction - economist and quant Paul Samuelson having been one of them - but their efforts at refutation have been unsatisfying.

Recent articles have related the Petersburg Paradox to investor expectations for stocks with high and persistent earnings growth. An extremely smart and interesting article was published way back in 1957 by David Durand (The Journal of Finance, Vol 12, No 3, Sep 1957, pp 348-363). Durand explored the problem of valuation for growth stocks including the then relatively new approach of using multiple discount rates at various break points in time. The growth numbers are quaint - annual growth at numbers like 5 and 6.5% - chickenfeed compared to growth rates of modern high tech companies.

Durand related the question of pricing long growth periods to the Petersburg Paradox, addressing the infinity problem and the need to truncate the infinite series at some point. This has a parallel to the problem of valuing current growth companies where it is necessary to consider not only forecasts for future earnings growth rates but also the length of waiting time before cash flows and dividends appear. There's also the question of the interest rate used for discounting, which is now virtually nil but has been very significant at times in the past.

The Adam Smith Model happens to dovetail nicely with the distant outcomes of the Petersburg Paradox coin flip game. The further away the payout is from the present the larger the rewards become when you finally throw heads. It's just that in the case of fast growing but not yet profitable companies, you more or less defer the chance of hitting heads early in order to let the reward build exponentially and have the promise of hitting a very large summative outcome in the future. That's where the thinking of investors in Amazon, Tesla, and Netflix must come from, and it's more or less rational if their estimate of the payoff and the time necessary to achieve it are reasonably accurate. It has been pretty accurate in the case of Apple.

There's just one more thing, of course. What if the estimate of Adam Smith value proves to be outright wrong? What if a tough new competitor with a better technology or improved business model appears? What if competition already in place proves to be more formidable than assumed? Even with Amazon these risks must be taken into account, but with Tesla they should be major concerns, and with Netflix they should be very major concerns.

There could also be exogenous risks such as a major rise in interest rates which would wreck the denominator and greatly reduce the value of a distant payoff. That high denominator, by the way, was what drove price earnings ratios in the 1970s down to the single digits. Returns even a few out years were so heavily discounted that no one wanted to look that far into the future. This sort of thinking served to greatly diminish the appeal of growth stocks.

Innovative companies don't always work out. I thought about that a lot around the year 2000, when I attached a 95% probability to my belief that the investing world had lost its collective mind but reserved a 5% probability I was the one who just didn't get it. The odd thing is that some of the new model dot.coms did, in fact, contribute quite a bit to the general welfare. They made all sorts of businesses more efficient, and at the same time made basic communication for everyone cheaper, faster, and better. This is presumably a good thing. In the end, however, it didn't work out well for shareholders who held on long term.

But there's another question. Did their temporarily outrageous valuations represent a magical mechanism for pulling forward a proper reward for founders and the most nimble shareholders despite the fact that the companies themselves were destined to never ultimately earn any money? In a just version of Adam Smith's invisible handsome reward was certainly owed to the founders and early owners who contributed so much to human well being but the mechanism by which they received it is somewhat murky,

So what if that deferred payoff never comes?

Schopenhauer asked a similar question in his Studies in Pessimism, except that he asked it about death, not a sudden gush of cash flow. Calm down, Schopenhauer argued. Why fear death? If you knew it wasn't the end of things, that you would wake up tomorrow morning feeling fine, you wouldn't worry about it much. What about waking up next week? What about next year? What about five or ten years out? What about a thousand years before you wake up? Ten thousand? What about... never? Would it make a difference?

Schopenhauer's courage in the face of non-being is reflected in the large number of investors who seem unworried about the possible absence of cash returns many years into the future. Once you take the Schopenhauer premise, it doesn't matter if the payoff never arrives. The stock is going up today in anticipation of it. That's all that really matters. Shareholders are happy. You can always cash out at your convenience. What is the future anyway but a dwindling infinite series?

It's really more like heaven than death. Both of my grandmothers believed strongly in its existence, although I can't imagine what they really thought it would be like. It probably didn't matter. In both cases, it sustained them over the course of long and productive lives which they lived with great confidence of a wonderful if not precisely defined eternity. Ignorance was bliss.

A business is its customers. Is it as simple as that? The value of a business is the value of the services provided to its present and prospective customers discounted for the distance in time to monetization of those customers but discounted to reflect the possibility of various things that could happen to reduce or wipe out that future payoff. Both new and rapid growth businesses generally defer that payout further into the future than most businesses, especially if the discounting factor is relatively low.

This model produces huge winners and abject losers. We marvel at the winners when we see them without considering survivor bias. We discard the losers even if they have played a major part in the evolution of the economic world and traded at high prices in optimistic moments along the way. In retrospect we wonder why they once traded at such high prices.

In very young industries such as biotechs, the outcome often leaves losers by the way side and rewards just one or two competitors. One way of thinking about this is that at the outset many such companies own a similar probability of surviving but one or two end up "owning" most of the customers and the cash flow bonanza that will eventually come with them. The probability of winning gradually shrinks for most but rises for the winners. For that reason, my daughter's approach of buying a basket of these companies is probably the best way for investors to participate.

This approach may also be very helpful in evaluating growth companies which are not new but remain at some distance from giving investors serious cash rewards. Here the method for selecting a basket of winners draws upon the kind of broad-brush estimates and calculations used in selecting a basket of small biotechs. If looking closely at Amazon, Tesla, and Netflix doesn't help much, it's important to make and constantly update estimates bearing upon the scale and strength of their "ownership" of customers as well as rough estimates of risks. This broad and approximate approach is how Adam Smith would probably have looked at valuation of companies if he was as interested in profits as we sometimes assume him to have been.

Disclosure: I am/we are long JNJ, BDX. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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How Adam Smith Might Have Valued Amazon, Netflix, Tesla, And Tiny Biotechs - Seeking Alpha

Cardiac Stem Cells Comments Off on How Adam Smith Might Have Valued Amazon, Netflix, Tesla, And Tiny Biotechs – Seeking Alpha | August 10th, 2020

August 4, 2020 - More than three years after a clinical trial was prematurely ended for failing to show progress in healing heart attack scars, the European Heart Journal publishing some surprising results showing that the heart cell treatment does benefit patients.[1]

Data from the ALLSTAR study published Tuesday by the European Heart Journal showed that although infusions of allogeneic cardiac cells (called cardiosphere-derived cells or CDCs) did not appear to shrink the infarct scar after a heart attack, other data from the study show a clear benefit.

Compared with patients who received placebo treatment, patients randomized to receive CDC infusions showed a decrease in the volume of blood in the heart before and after it beats, indicating that the heart had not dilated, as it does progressively in heart failure.

"As it develops heart failure, the heart gets bigger and bigger, like a swelling balloon," said the study's lead author, Raj Makkar, M.D., vice president of cardiovascular innovation and intervention for Cedars-Sinai and the Stephen R. Corday, M.D., chair in interventional cardiology. "One way we can measure the health of a heart is to measure the volume of blood it can hold. The bigger the volume, the more damaged the heart."

The newly analyzed data from the ALLSTAR study, which was sponsored by Capricor Therapeutics, showed that patients given a placebo had hearts that continued to swell, holding larger volumes of blood, while the patients who received CDC infusions had smaller hearts with lower volumes.

The new data results include:

The volume of blood held by the heart was essentially unchanged six months after CDC infusion, but increased by more than a teaspoonful in placebo patients.

A blood protein that measures heart failure severity was reduced in patients who had received CDCs, but not in placebo patients.

The chance that these findings were statistical flukes was only 2 percent.

"To me, these data are very reassuring that there really is therapeutic benefit," said Eduardo Marbn, M.D., Ph.D., executive director of the Smidt Heart Institute. "There is a growing body of evidence that this cell treatment does work."

Results from the earlier CADUCEUS trial, published in The Lancet in 2014, showed that injecting CDCs into the hearts of heart attack survivors significantly reduced infarct size. In 2017, however, the multicenter ALLSTAR study was prematurely halted after six months of data showed no decrease in heart attack scar size, but later analyses revealed the beneficial findings reported here.

"We think we may have chosen the wrong endpoint," said Marbn, the Mark S. Siegel Family Foundation Distinguished Professor, whose discoveries and technologies resulted in CDCs. "This happens in science because you have to design the trial a year or more before you begin, and sometimes you bet on the wrong hors... but that doesnt necessarily mean the therapy is ineffective."

The cells used in the study were CAP-1002, Capricor Therapeutics off-the-shelf, cardiosphere-derived cell (CDC) product candidate. Other clinical trials and case series, in which CDCs were used to treat advanced heart failure, Duchenne Muscular Dystrophy, and COVID-19, also demonstrated positive results. And new studies using CDCs are in the planning stages.

"California is known as the stem cell state, but few technologies being tested in California actually were developed here," said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs, dean of the Medical Faculty and professor of Medicine. "Increasing evidence-including the results of the large multicenter ALLSTAR trial-validates the potential utility of a cell product which was conceived by a faculty member at Cedars-Sinai, and first tested clinically here."

Read the complete study published by the European Heart Journal.

Disclosures: Except for the cells used in CADUCEUS, the cardiosphere-derived cells used in these studies were derived from donor hearts and provided by Capricor Therapeutics. Marbn developed the process to grow CDCs when he was on the faculty of Johns Hopkins University; the process was further developed at Cedars-Sinai. Capricor has licensed the process from Johns Hopkins and from Cedars-Sinai for clinical and commercial development. Capricor has licensed additional intellectual property from Cedars-Sinai and the University of Rome. Cedars-Sinai and Marbn have financial interests in Capricor.

Reference:

1. Raj R Makkar, Dean J Kereiakes, Frank Aguirre, et al. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial. European Heart Journal, ehaa541, https://doi.org/10.1093/eurheartj/ehaa541.

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Three Years After Stem Cell Trial for Heart Failure was Abandoned New Evidence Shows it Works - Diagnostic and Interventional Cardiology

Cardiac Stem Cells Comments Off on Three Years After Stem Cell Trial for Heart Failure was Abandoned New Evidence Shows it Works – Diagnostic and Interventional Cardiology | August 10th, 2020

Aug. 9, 2020 / PRZen / SUZHOU, China -- Re-Stem Biotech (Re-Stem or the Company), a biotechnology firm engaged in the research and development of cell therapies targeting osteoarthritis, spinal cord injury and various cancers recently funded in part a study titled "Solid-phase inclusion as a mechanism for regulating unfolded proteins in the mitochondrial matrix". Researchers at The Johns Hopkins University School of Medicine, led by Rong Li, Ph.D., published their findings in the journal "Science Advances" (view full article here: https://advances.sciencemag.org/content/6/32/eabc7288) The study may provide mechanistic insights for mitochondrial dysfunction observed in aging and age-related diseases.

About Mitochondrial DysfunctionMitochondrial dysfunction is a hallmark of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. During aging, damaged/unfolded proteins in mitochondria that are failed to be degraded gradually accumulate. In addition, recent evidence suggests that non-mitochondrial proteins constituting pathological aggregates in neurodegenerative diseases also accumulate in mitochondria and cause mitochondrial dysfunction. However, it remains unclear how excessive damaged proteins are managed within mitochondria when known quality control mechanisms become inadequate, and how they contribute to mitochondrial dysfunction during the aging process.

About the StudyThe researchers discovered that excessive unfolded proteins in the mitochondrial matrix are consolidated into novel structures, which they named Deposits of Unfolded Mitochondrial Proteins (DUMP). DUMP formation is an age-dependent process, while accelerated DUMP formation causes mitochondrial dysfunction and premature aging. They found that DUMP formation was not random, but specific in mitochondria near endoplasmic reticulum (ER), another organelle in cells. The contact sites between mitochondria and ER regulate DUMP formation via transferring lipids between two organelles. Via a series of genetic and live-cell imaging studies, researchers identified key enzymes of mitochondrial lipid metabolism that control DUMP formation. Manipulation of these enzymes modulates DUMP formation, therefore, potentially they could be targets for anti-aging or treating age-related diseases.

About Re-Stem BiotechRe-Stem Biotech (Re-Stem) is a biotechnology firm engaged in the research and development of cell-based therapies and products. Backed by state of the art GMP facilities and an international team of world-leading scientists, doctors and management team, Re-Stem currently has a robust technology platform including four profitable therapies on the market and eight other therapies and products in the pipeline. Incorporated and headquartered in 2012 in Suzhou, China, Re-Stem is focused on the large and aging population of China. It also operates clinics and research and development laboratories in Shenzhen, Beijing, Kunming and Ganzhou. For more information visit Re-Stem Biotech website: https://www.restembio.com/

Forward-Looking StatementsStatements in this press release relating to plans, strategies, trends, specific activities or investments, and other statements that are not descriptions of historical facts and may be forward-looking statements are inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors, which include those regarding our ability to implement objective, plans and strategies for future operations. Forward-looking information may be identified by terms such as "will," "may," "expects," "plans," "intends," "estimates," "potential," or "continue," or similar terms or the negative of these terms. Although Re-Stem believes the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that future results, performance or achievements will be obtained. Re-Stem does not have any obligation to update these forward-looking statements other than as required by law.

Follow the full story here: https://przen.com/pr/33354426

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Re-Stem-Funded Study Targeting Mitochondrial Dysfunction in Aging and Age-Related Diseases Published in Science Advances Journal - Press Release -...

Spinal Cord Stem Cells Comments Off on Re-Stem-Funded Study Targeting Mitochondrial Dysfunction in Aging and Age-Related Diseases Published in Science Advances Journal – Press Release -… | August 10th, 2020

Brazilian researchers announced that a 36-year-old man in Brazil is HIV-free after receiving a cocktail of antiviral drugs.

If true, this unidentified case, detailed at the medical conference AIDS 2020, would be the first instance of long-term remission from HIV without a stem cell or bone marrow transplant.

But the researchers peers are sceptical, since anti-retroviral therapy, which is used to queel HIV and prevent it from developing into AIDS, has been the standard treatment for all HIV-positive people since the treatment was invented in 1995.

There will be a lot of buzz, a lot of controversy about this part everyones going to be sceptical, HIV researcher Dr. Steve Deeks told the New York Times. Am I sceptical? Of course. Am I intrigued? Absolutely.

According to the research team at the Federal University of So Paulo, the man was diagnosed with HIV in 2012 and began taking the typical antiretroviral drugs.

In 2016, he joined a clinical trial where he was given three additional drugs, including maraviroc and nicotinamide, for 11 months, in an aggressive treatment designed to flush the virus out of his body.

The man returned to the standard anti-retroviral therapy after the trial ended, and stopped taking all anti-retroviral drugs in March 2019. Every three weeks since March 2019, his blood has been tested.

The fact that he tested negative for HIV is not remarkable in itself anyone religiously taking anti-retroviral therapy for more than six months will reach an undetectable viral load.

But in this case, the researchers said they found no trace of dormant HIV-infected cells in his system.These latent cells can become active as soon as treatment stops, making people sick again.

The researchers announced that virus-detecting blood tests did not show any remaining traces of HIV in the mans blood. The man also did not show any signs of having antibodies to the virus.

Prior to this, just two people had been cured of HIV.

First was the Berlin Patient, an American man named Timothy Ray Brown, who received a bone marrow transplant in 2007 in Berlin, Germany.

Brown had leukemia, and required a bone marrow transplant to survive. His doctors sought bone marrow from someone with an HIV-resistant gene. Post-transplant, Brown suffered a series of health issues, he needed to be put in a medically induced coma, and nearly died. But not only was his cancer gone, so was his HIV. He is still alive today, with no HIV, and no need for the anti-retroviral therapy that HIV-positive people must take habitually.

In 2019, the London Patient, a man named Adam Castillejo, became the second person ever to enter long-term remission from HIV. Castillejo, who was treated in London, England, had two bone marrow transplants. His recovery process was less intense, assuaging scientists concerns that Brown had only been cured because of the massive destruction to his immune system, which also rid him of HIV.

Deeks said that independent lab results will be needed to confirm these results. The Brazilian research team has offered to send the mans blood samples to other labs.

When HIV enters the body, it inserts genetic material into the DNA of its hosts immune cells. This forces the cells to make copies of the virus. Some active HIV-infected cells are created, and some latent HIV-infected cells are created. These cells are infected with HIV but are not actively producing new HIV, according to the NIH.

But there is a difference between testing negative for HIV, as some people do after taking medication that makes their HIV undetectable, and having zero traces of HIV in your RNA or DNA. In the first instance the virus is controlled within the body, but in the second instance it is entirely removed from the body.

Many researchers have announced they have cured HIV in their patients, only for the disease to return a short while later.

A baby in Mississippi stopped taking antiretroviral medication at 18 months, researchers eagerly announced that the virus was gone, and then two years later, in 2014, researchers detected HIV in the child again. In 2013, two Boston patients received bone marrow transplants, and headlines declared that they had been cured, only for the virus to resurface again.

The So Paulo Patient has gone 66 weeks without showing signs of the virus.

Read more:

Case of HIV patient in remission raises hopes for future AIDS cure

Doctors say experimental treatment may have rid man of HIV

There is no virus there that we can measure. Second HIV patient in remission becomes new hope for a cure

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Scientists say a man with HIV is the first to reach long-term remission without a bone marrow transplant, but their peers are sceptical - Business...

Bone Marrow Stem Cells Comments Off on Scientists say a man with HIV is the first to reach long-term remission without a bone marrow transplant, but their peers are sceptical – Business… | July 10th, 2020

FT819 CAR T-cell Product Candidate Derived from Clonal Master iPSC Line with Novel CD19-specific 1XX CAR Integrated into TRAC Locus

Phase 1 Clinical Study will Evaluate FT819 for Patients with Advanced B-cell Leukemias and Lymphomas

SAN DIEGO, July 09, 2020 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced today that the U.S. Food and Drug Administration (FDA) has cleared the Companys Investigational New Drug (IND) application for FT819, an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. FT819 is the first-ever CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line, and is engineered with several first-of-kind features designed to improve the safety and efficacy of CAR T-cell therapy. The Company plans to initiateclinical investigation of FT819for the treatment of patients with relapsed / refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL).

The clearance of our IND application for FT819 is a ground-breaking milestone in the field of cell-based cancer immunotherapy. Our unique ability to produce CAR T cells from a clonal master engineered iPSC line creates a pathway for more patients to gain timely access to therapies with curative potential, said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. Four years ago, we first set out under our partnership with Memorial Sloan Kettering led by Dr. Michel Sadelain to improve on the revolutionary success of patient-derived CAR T-cell therapy and bring an off-the-shelf paradigm to patients, and we are very excited to advance FT819 into clinical development.

FT819 was designed to specifically address several limitations associated with the current generation of patient- and donor-derived CAR T-cell therapies. Under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, and Head, Gene Expression and Gene Transfer Laboratory at MSK, the Company incorporated several first-of-kind features into FT819 including:

The multi-center Phase 1 clinical trial of FT819 is designed to determine the maximum tolerated dose of FT819 and assess its safety and clinical activity in up to 297 adult patients across three types of B-cell malignancies (CLL, ALL, and NHL). Each indication will enroll independently and evaluate three dose-escalating treatment regimens: Regimen A as a single dose of FT819; Regimen B as a single dose of FT819 with IL-2 cytokine support; and Regimen C as three fractionated doses of FT819. For each indication and regimen, dose-expansion cohorts of up to 15 patients may be enrolled to further evaluate the clinical activity of FT819.

At the American Association for Cancer Research (AACR) Virtual 2020 Meeting, the Company presented preclinical data demonstrating FT819 is comprised of CD8 T cells with uniform 1XX CAR expression and complete elimination of endogenous TCR expression. Additionally, data from functional assessments showed FT819 has antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines that is comparable to that of healthy donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia.

Fate Therapeutics has an exclusive license for all human therapeutic use to U.S. Patent No. 10,370,452 pursuant to its license agreement with MSK1, which patent covers compositions and uses of effector T cells expressing a CAR, where such T cells are derived from a pluripotent stem cell including an iPSC. In addition to the patent rights licensed from MSK, the Company owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.

1 Fate Therapeutics haslicensedintellectual propertyfrom MSK on which Dr. Sadelain is aninventor.As a result of the licensing arrangement, MSK has financial interests related to Fate Therapeutics.

About Fate Therapeutics iPSC Product PlatformThe Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

About Fate Therapeutics, Inc.Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for cancer and immune disorders. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology product candidates include natural killer (NK) cell and T-cell cancer immunotherapies, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens with chimeric antigen receptors (CARs). The Companys immuno-regulatory product candidates include ProTmune, a pharmacologically modulated, donor cell graft that is currently being evaluated in a Phase 2 clinical trial for the prevention of graft-versus-host disease, and a myeloid-derived suppressor cell immunotherapy for promoting immune tolerance in patients with immune disorders. Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Forward-Looking StatementsThis release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 including statements regarding the advancement of and plans related to the Company's product candidates and clinical studies, the Companys progress, plans and timelines for the clinical investigation of its product candidates, the therapeutic potential of the Companys product candidates including FT819, and the Companys clinical development strategy for FT819. These and any other forward-looking statements in this release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk of difficulties or delay in the initiation of any planned clinical studies, or in the enrollment or evaluation of subjects in any ongoing or future clinical studies, the risk that the Company may cease or delay preclinical or clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials or to support regulatory approval, difficulties in manufacturing or supplying the Companys product candidates for clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), the risk that results observed in preclinical studies of FT819 may not be replicated in ongoing or future clinical trials or studies, and the risk that FT819 may not produce therapeutic benefits or may cause other unanticipated adverse effects. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the risks and uncertainties detailed in the Companys periodic filings with the Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report, and from time to time in the Companys press releases and other investor communications.Fate Therapeutics is providing the information in this release as of this date and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.

Contact:Christina TartagliaStern Investor Relations, Inc.212.362.1200christina@sternir.com

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Fate Therapeutics Announces FDA Clearance of IND Application for First-ever iPSC-derived CAR T-Cell Therapy - GlobeNewswire

Bone Marrow Stem Cells Comments Off on Fate Therapeutics Announces FDA Clearance of IND Application for First-ever iPSC-derived CAR T-Cell Therapy – GlobeNewswire | July 10th, 2020

By David Bautz, PhD

NASDAQ:BCLI

READ THE FULL BCLI RESEARCH REPORT

Business Update

KOL Event for Alzheimers Program

On July 8, 2020, BrainStorm Cell Therapeutics, Inc. (NASDAQ:BCLI) conducted a Key Opinion Leader (KOL) webinar to discuss the companys upcoming Phase 2a clinical trial of NurOwn in patients with Alzheimers Disease (AD). The event included presentations by two of the lead investigators for the upcoming trial, Dr. Philip Scheltens, Professor of Cognitive Neurology and Director of the Alzheimer Centre at VU University Medical Center in Amsterdam, Netherlands, and Dr. Bruno Dubois, Professor of Neurology at the Neurological Institute of the Salptrire University Hospital in Paris, France. The presentation can be found here.

The companys Phase 2a trial (BCT-201-EU) is expected to enroll approximately 40 patients with prodromal to mild AD. It will be taking place at medical centers in France and the Netherlands. To be eligible for the trial, patients must have been diagnosed with prodromal to mild dementia at least six months prior to enrollment. In addition, patients must score between 20-30 on the Mini-Mental State Exam (MMSE) and have a Clinical Dementia Rating (CDR) global score of 0.5-1.0. The MMSE is a series of questions that are designed to assess a patients mental skills, with the maximum score being 30 points and a score of 20-24 suggesting mild dementia. The CDR is a scale used to characterize six domains of cognitive and functional performance with a score of 0.5 suggesting very mild dementia and a score of 1.0 suggesting mild dementia.

The primary objective of the trial is to assess the safety and tolerability of three intrathecal injections of NurOwn in AD patients. Following bone marrow aspiration during a 10-week run-in period, patients will be treated three times with NurOwn, with eight weeks between treatments. Follow-up visits will occur 12 and 26 weeks following the final injection of NurOwn for a total trial length of 52 weeks. The following figure gives an overview of the trial design.

Cerebrospinal fluid (CSF) and serum will be collected prior to treatment and again at Weeks 0, 8, and 16 to assess changes in various neurotropic, neurodegenerative, and inflammatory factors (e.g., VEGF, HGF, NfL, NfH, MCP-1, IL-6), markers associated with amyloid deposition (e.g., a40, a42), and markers of tau protein levels (e.g., p-tau, t-tau). Additional clinical outcome measures will be analyzed through administration of the following tests:

Clinical Dementia Rating ScaledSum of Boxes (CDR-SB)

Free and Cued Selective Reminding Test (FCSRT)

Neuropsychological Test Battery (NTB)

Delis-Kaplan Executive Function System (D-KEFS) subtests

Mini Mental State Examination(MMSE)

AmsterdamInstrumentalActivitiesofDailyLivingQuestionnaire-ShortVersion(A-IADL-Q-SV)

Alzheimers Disease

Alzheimers disease (AD) is the most common form of dementia in older adults. The disease is named after Dr. Alois Alzheimer, who identified the first case in a 50-year-old woman named Auguste Deter in 1902. Dr. Alzheimer followed her case until her death in 1906, at which point he first publicly reported on it (Alzheimer, 1907).

After Ms. Deters death, Dr. Alzheimer examined her brain and found many abnormal clumps (now known as amyloid plaques) and tangled bundles of fibers (now known as neurofibrillary tangles). Over the next five years, 11 similar cases were reported in the medical literature, with some of them already using the term Alzheimers disease (Berchtold et al., 1998).

The most common early symptom of AD is a gradually worsening ability to remember new information. This is due to neurons associated with forming new memories dying off first. As neurons in other parts of the brain die, individuals experience different symptoms, which include:

Memory loss that disrupts daily life

Inability to plan or solve problems

Difficulty completing familiar tasks

Confusion with location and time

Difficulty with visual images and spatial relationships

Problems with words in speaking or writing

Withdrawal from social activities

Changes in mood, including apathy and depression

Each person progresses through AD at a different rate, and little is known about how or why there is such a marked variation, thus predicting how it will affect someone is quite difficult. One thing that is common to everyone diagnosed with AD is that his or her cognitive and functional abilities will gradually decline. As the disease progresses symptoms can include confusion, irritability, aggression, mood swings, and long-term memory loss. In the final advanced stage of the disease, people need help with the basic activities of living (e.g., bathing, dressing, eating, and using the restroom), they lose the ability to communicate, fail to recognize loved ones, and eventually become bed bound and reliant on round-the-clock care (Frstl et al., 1999). The inability to move makes them more prone to infections, including pneumonia, which are often a contributing factor to the death of those with AD.

Competing Theories for the Cause of Alzheimers

The root cause of Alzheimers is still unknown; however, it is likely to involve a number of different factors as opposed to being due to one single cause. These factors are likely a combination of genetic, environmental, and lifestyle. There are a number of hypotheses that exist to explain the cause of the disease, with the two dominant hypotheses focused on amyloid and tau.

Amyloid hypothesis: This hypothesis proposes that extracellular beta-amyloid deposits are the fundamental cause of the disease (Hardy et al., 1991). Beta-amyloid is a fragment of the larger protein amyloid precursor protein (APP), mutations of which are known to cause FAD. Several lines of evidence support the amyloid hypothesis: 1) the location of APP is on chromosome 21, while those with Down Syndrome (trisomy 21) almost all show signs of AD by 40 years of age (Lott et al., 2005); 2) APOE4 is a major genetic risk factor for AD, and while apolipoproteins enhance the breakdown of beta-amyloid, some isoforms are less capable of performing this task than others, leading to more beta-amyloid buildup on the brain (Polvikoski et al., 1995); 3) mice that harbor a mutant form of APP develop amyloid plaques and Alzheimers-like pathology (Games et al., 1995). Lastly, amyloid plaques are readily identifiable by microscopy in the brains of AD patients (Tiraboschi et al., 2004). While the brains of many older individuals develop some plaques, the brains of AD patients show severe pathological changes specifically within the temporal neocortex (Bouras et al., 1994).

Tau hypothesis: Tau is a protein located mainly within the axonal compartment of neurons and is an important element in microtubule stabilization and neurite outgrowth. In AD, a proportion of tau protein becomes abnormally phosphorylated, dissociates from axonal microtubules, and accumulates in paired helical filaments inside the neuron (Goedert et al., 1991). When this occurs, the microtubules disintegrate causing the collapse of the neurons transport system (Igbal et al., 2005). Just as with beta-amyloid plaques, tau tangles are readily observable in the brains of those affected by AD.

In addition to amyloid and tau, inflammation has been an underappreciated and often overlooked mediator in patients with AD (Akiyama et al., 2000). A multitude of inflammatory markers are found in AD patients brains and a number of studies have shown a link between chronic inflammation and an increased risk of developing AD (Walker et al., 2017; Tao et al., 2018). Thus, a treatment such as NurOwn that can decrease inflammatory mediators could prove beneficial in AD patients.

On Track to Repot Topline Data from Phase 3 ALS Trial in 4Q20

On July 2, 2020, BrainStorm announced that all doses have been administered in the pivotal Phase 3 trial ofrecen NurOwn in patients with amyotrophic lateral sclerosis (ALS) and that it remains on track to report topline data in the fourth quarter of 2020.

The ongoing randomized, double blind, placebo controlled, multi-dose Phase 3 clinical trial is testing the ability of NurOwn to alter disease progression as measured by the ALSFRS-R (NCT03280056). Cells were extracted once from each patient prior to treatment, with all administrations of NurOwn derived from the same extraction of cells due to a cryopreservation process the company developed for long-term storage of mesenchymal stem cells (MSC). Just as with the companys prior studies, there was a 3-month run-in period prior to the first treatment with two additional NurOwn treatments occurring two and four months following the first treatment. The company is focusing the trial on faster-progressing ALS patients since those patients demonstrated superior outcomes in the Phase 2 trial of NurOwn.

BrainStorm Joins Russell 2000 and Russell 3000; Granted SME Status by EMA

On June 23, 2020, BrainStorm announced that its shares would be included in the Russell 2000 Index and the Russell 3000 Index. The annual reconstitution of the Russell indexes is done to capture the 4,000 largest U.S. stocks by market capitalization.

On June 15, 2020, BrainStorm announced that the company has been granted Small and Medium-Sized Enterprise (SME) status by the European Medicines Agency (EMA). SME status allows the company to participate in a number of financial incentives including a 90-100% reduction in the EMA fee for scientific advice, clinical study protocol design, endpoints and statistical considerations, quality inspections of facilities, and fee waivers for selective EMA pre- and post-authorization regulatory filings, including Orphan Drug and PRIME designations.

Conclusion

Were excited about the potential for NurOwn in AD and we look forward to the initiation of the Phase 2a trial later in 2020. We have recently made a few changes to our model, including the inclusion of NurOwn in AD and lowering of the discount rate from 20% to 15% for all indications. We model for the company to file for approval of NurOwn in AD in 2026 and to be granted approval in 2027. We currently estimate peak sales of over $2 billion for NurOwn in AD in both the U.S. and E.U. Using a 25% probability of approval leads to an NPV of $113 million. Combined with the NPV for NurOwn in ALS ($700 million) and MS ($41 million) along with the companys current cash position and potential cash from warrants leads to a valuation for the company of a bit less than $900 million. Dividing by the companys current fully diluted share count of 35.7 million leads to a valuation of $25 per share.

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BCLI: KOL Event Gives Overview of the use of NurOwn in Alzheimer's Disease; Raising Valuation to $25/Share - Zacks Small Cap Research

Bone Marrow Stem Cells Comments Off on BCLI: KOL Event Gives Overview of the use of NurOwn in Alzheimer’s Disease; Raising Valuation to $25/Share – Zacks Small Cap Research | July 10th, 2020

BOSTON, July 09, 2020 (GLOBE NEWSWIRE) -- Ziopharm Oncology, Inc. (Ziopharm or the Company) (Nasdaq:ZIOP), today announced the initiation of a phase 1 clinical trial to evaluate CD19-specific CAR-T, using its Rapid Personalized Manufacturing (RPM) technology, as an investigational treatment for patients with relapsed CD19+ leukemias and lymphomas. The trial is now open for enrollment at The University of Texas MD Anderson Cancer Center.

In this trial, the Company utilizes its non-viral Sleeping Beauty genetic engineering technology to infuse CAR-T the day after electroporation. Ziopharms RPM CD19-specific CAR-T therapy results from the stable, non-viral insertion of DNA into the genome of resting T cells to co-express the chimeric antigen receptor (CAR), membrane-bound IL-15 (mbIL15) and a safety switch.

We are pleased to expand the scope of our clinical development with MD Anderson, as we seek to evaluate our RPM technology using CD19-specific CAR-T cells, said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of Ziopharm. RPM is a promising manufacturing solution, as T cells from the bloodstream are genetically reprogramed with DNA plasmids from the Sleeping Beauty system and then simply administered the next day.

Our CAR-T therapy can be administered at low cell doses, which may control cytokine release syndrome and is appealing for the treatment of patients including those with CD19-expressing malignancies that have relapsed after allogeneic bone marrow transplantation (BMT). There are limited effective treatment options for such patients as evidenced by the low rate of remission and poor long-term survival, Dr. Cooper added.

Up to 24 patients with advanced CD19+ leukemias and lymphomas who have relapsed after allogeneic BMT will be enrolled in this investigator-initiated trial (NCT03579888). The primary endpoint of the study is to determine the safety and maximum tolerated dose of donor-derived genetically modified CD19-specific T cells manufactured using the RPM process. An additional study is planned through Ziopharms joint venture with Eden BioCell to evaluate the RPM technology using patient-derived (autologous) CD19-specific CAR-T in Greater China.

Research reveals three-year survival for adults with CD19+ acute lymphoblastic leukemia after allogeneic BMT ranges from 30% to 65%.1 For patients with other CD19+ cancers, allogeneic BMT can provide three-year survival rates between 30% to 75%.1 Few patients experience a durable remission following allogeneic BMT, regardless of the treatment modality, with some having a median survival of only 2 to 3 months.2

About Ziopharm Oncology, Inc.Ziopharm is developing non-viral and cytokine-driven cell and gene therapies that weaponize the bodys immune system to treat the millions of people globally diagnosed with a solid tumor each year. With its multiplatform approach, Ziopharm is at the forefront of immuno-oncology with a goal to treat any type of solid tumor. Ziopharms pipeline is built for commercially scalable, cost effective T-cell receptor T-cell therapies based on its non-viral Sleeping Beauty gene transfer platform, a precisely controlled IL-12 gene therapy, and rapidly manufactured Sleeping Beauty-enabled CD19-specific CAR-T program. The Company has clinical and strategic collaborations with the National Cancer Institute, The University of Texas MD Anderson Cancer Center and Regeneron Pharmaceuticals. For more information, please visit http://www.ziopharm.com.

Forward-Looking Statements DisclaimerThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as "may," "will," "could," "expects," "plans," "anticipates," and "believes." These statements include, but are not limited to, statements regarding the progress, design and timing of the Company's research and development programs, the potential benefits of the Companys therapies, and the Companys expectations regarding the number of patients in its clinical trials. Although Ziopharms management team believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Ziopharm, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, changes in our operating plans that may impact our cash expenditures, the uncertainties inherent in research and development, future clinical data and analysis, including whether any of Ziopharms product candidates will advance further in the preclinical research or clinical trial process, including receiving clearance from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies to conduct clinical trials and whether and when, if at all, they will receive final approval from the U.S. FDA or equivalent foreign regulatory agencies and for which indication; the strength and enforceability of Ziopharms intellectual property rights; competition from other pharmaceutical and biotechnology companies as well as risk factors discussed or identified in the public filings with the Securities and Exchange Commission made by Ziopharm, including those risks and uncertainties listed in Ziopharms Quarterly Report on Form 10-Q filed by Ziopharm with the Securities and Exchange Commission. We are providing this information as of the date of this press release, and Ziopharm does not undertake any obligation to update or revise the information contained in this press release whether as a result of new information, future events or any other reason.

Investor Relations Contacts:Ziopharm Oncology:Chris TaylorVP, Investor Relations and Corporate CommunicationsT: 617.502.1881E: ctaylor@ziopharm.com

LifeSci Advisors:Mike MoyerManaging DirectorT: 617.308.4306E: mmoyer@lifesciadvisors.com

Media Relations Contact:LifeSci Communications:Patrick BurseyT: 646.876.4932E: pbursey@lifescicomms.com

1 D'Souza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2018. Available at https://www.cibmtr.org

2 Keil F, Prinz E, Kalhs P, et al. Treatment of leukemic relapse after allogeneic stem cell transplantation with cytotoreductive chemotherapy and/or immunotherapy or second transplants. Leukemia 2001; 15:355-361.

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Ziopharm Oncology Announces Initiation of Phase 1 Trial Evaluating Rapid Personalized Manufacturing CAR-T Technology in Patients with Relapsed CD19+...

Bone Marrow Stem Cells Comments Off on Ziopharm Oncology Announces Initiation of Phase 1 Trial Evaluating Rapid Personalized Manufacturing CAR-T Technology in Patients with Relapsed CD19+… | July 10th, 2020

Embryonic stem cells. The ethical issues associated with stem cell research could be resolved through the use of induced pluripotent stem cells, which are derived from fully committed and differentiated cells of the adult body

The almost miraculous benefits that stem cells may one day deliver have long been speculated on. Capable of becoming different types of cells, they offer huge promise in terms of transplant and regenerative medicine. It is, however, also a medical field that urges caution one that must constantly battle exaggeration. If stem cells do in fact hold the potential to reverse the ageing process, for example, then such breakthroughs remain many years away.

Recently, though, the field has had cause for excitement. In 2006, Japanese researcher Shinya Yamanaka discovered that mature cells could be reprogrammed to become pluripotent, meaning they can give rise to any cell type of the body. In 2012, the discovery of these induced pluripotent stem cells (iPSCs) saw Yamanaka and British biologist John Gurdon awarded the Nobel Prize in Physiology or Medicine. Since then, there has been much talk regarding the potential iPSCs possess, not only for the world of medicine, but for society more generally, too.

A big stepHistorically, one of the major hurdles preventing further research into stem cells has been an ethical one. Until the discovery of iPSCs, embryonic stem cells (ESCs) represented the predominant area of research, with cells being taken from preimplantation human embryos. This process, however, involves the destruction of the embryo and, therefore, prevents the development of human life. Due to differences in opinion over when life is said to begin during embryonic development, stem cell researchers face an ethical quandary.

The promise of significant health benefits and new revenue streams has led some clinics to offer unproven stem cell treatments to individuals

With iPSCs, though, no such dilemmas exist. IPSCs are almost identical to ESCs but are derived from fully committed and differentiated cells of the adult body, such as a skin cell. Like ESCs, iPSCs are pluripotent and, as they are stem cells, can self-renew and differentiate, remaining indefinitely propagated and retaining the ability to give rise to any human cell type over time.

One important distinction to make is that both ESCs and iPSCs do not exist in nature, Vittorio Sebastiano, Assistant Professor (Research) of Obstetrics and Gynaecology (Reproductive and Stem Cell Biology) at Stanford Universitys Institute for Stem Cell Biology and Regenerative Medicine, told The New Economy. They are both beautiful laboratory artefacts. This means that at any stage of development, you cannot find ESCs or iPSCs in the developing embryo, foetus or even in the postnatal or adult body. Both ESCs and iPSCs can only be established and propagated in the test tube.

The reason neither ESCs nor iPSCs can be found in the body is that they harbour the potential to be very dangerous. As Sebastiano explained, these cells could spontaneously differentiate into tumorigenic masses because of their intrinsic ability to give rise to any cell type of the body. Over many years of research, scientists have learned how to isolate parts of the embryo (in the case of ESCs) and apply certain culture conditions that can lock cells in their proliferative and stem conditions. The same is true for iPSCs.

To create iPSCs, scientists take adult cells and exogenously provide a cocktail of embryonic factors, known as Yamanaka factors, for a period of two to three weeks. If the expression of such factors is sustained for long enough, they can reset the programme of the adult cells and establish an embryonic-like programme.

Turning back the clockThere is already a significant body of research dedicated to how stem cells can be used to treat disease. For example, mesenchymal stem cells (usually taken from adult bone marrow) have been deployed to treat bone fractures or as treatments for autoimmune diseases. It is hoped that iPSCs could hold the key for many more treatments.

Global stem cell market:25.5%Expected compound annual growth rate (2018-24)$467bnExpected market value (2024)

IPSCs are currently utilised to model diseases in vitro for drug screening and to develop therapies that one day will be implemented in people, Sebastiano explained. Given their ability to differentiate into any cell type, iPSCs can be used to differentiate into, for example, neurons or cardiac cells, and study specific diseases. In addition, once differentiated they can be used to test drugs on the relevant cell type. Some groups and companies are developing platforms for cell therapy, and I am personally involved in two projects that will soon reach the clinical stage.

Perhaps the most exciting prospects draw on iPSCs regenerative properties. Over time, cells age for a variety of reasons namely, increased oxidative stress, inflammation and exposure to pollutants or sunlight, among others. All these inputs lead to an accumulation of epigenetic mistakes those that relate to gene expression rather than an alteration of the genetic code itself in the cells, which, over time, results in the aberrant expression of genes, dysfunctionality at different levels, reduced mitochondrial activity, senescence and more besides. Although the epigenetic changes that occur with time may not be the primary cause of ageing, the epigenetic landscape ultimately affects and controls cell functionality.

What we have shown is that, if instead of being expressed for two weeks we express the reprogramming factors for a very short time, then we see that the cells rejuvenate without changing their identity, Sebastiano said. In other words, if you take a skin cell and express the reprogramming genes for two to four days, what you get is a younger skin cell.

By reprogramming a cell into an iPSC, you end up with an embryonic-like cell the reprogramming erases any epigenetic errors. If expressed long enough, it erases the epigenetic information of cell identity, leaving embryonic-like cells that are also young.

Slow and steadyAs with any scientific advancement, financial matters are key. According to Market Research Engine, the global stem cell market is expected to grow at a compound annual growth rate of 25.5 percent between 2018 and 2024, eventually reaching a market value of $467bn. The emergence of iPSCs has played a significant role in shaping these predictions, with major bioscience players, such as Australias Mesoblast and the US Celgene, working on treatments involving this particular type of stem cell.

The business potential around stem cell research is huge, Sebastiano told The New Economy. [Particularly] when it comes to developing cell banks for which we have detailed genetic information and, for example, studying how different drugs are toxic or not on certain genetic backgrounds, or when specific susceptibility mutations are present.

Unfortunately, even as the business cases for iPSC treatments increase, a certain degree of caution must be maintained. The promise of significant health benefits and new revenue streams has led some clinics to offer unproven stem cell treatments to individuals. There have been numerous reports of complications emerging, including the formation of a tumour following experimental stem cell treatment in one particular patient, as recorded in the Canadian Medical Association Journal last year. Such failures risk setting the field back years.

The challenge for researchers now will be one of balance. The potential of iPSCs is huge both in terms of medical progress and business development but can easily be undermined by misuse. Medical advancements, particularly ones as profound as those associated with iPSCs, simply cannot be rushed.

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Could induced pluripotent stem cells be the breakthrough genetics has been waiting for? - The New Economy

Skin Stem Cells Comments Off on Could induced pluripotent stem cells be the breakthrough genetics has been waiting for? – The New Economy | July 10th, 2020

New HCPCS Code Enables Facility Reimbursement to Physician Offices Performing Skin Graft Substitute Procedures, Benefiting Wound Patients

RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)-- Merakris Therapeutics, LLC., a leader in innovative approaches for cutaneous wound healing, announces that the Centers for Medicare & Medicaid Services (CMS) has assigned a Healthcare Common Procedure Coding System (HCPCS) product code Q4248 for its topical skin graft substitute, Dermacyte Matrix. The new HCPCS code, effective July 1, 2020, enables physician office reimbursement under Medicare Part B. Dermacyte Matrix is a crosslinked amniotic membrane allograft designed for cutaneous wound applications, commonly used by outpatient surgical, podiatry and dermatology clinics. Dermacyte is available in dehydrated and hydrated configurations with 5 years of shelf stability at room temperature.

This is another milestone for Merakris Therapeutics that the largest healthcare payer, CMS, has recognized Dermacyte Matrix with a unique reimbursement code. This strengthens our position with broader payer coverage for Dermacyte Matrix, says Chris Broderick, CEO of Merakris. We are dedicated to continued leadership in cell-free biologics and have aligned with academic institutions to support its product development and commercial operations while retaining full rights to our intellectual property.

Merakris has developed a novel purification system yielding two separate amniotic biomolecule fractions, one capable of promoting early-stage cutaneous wound healing, and the second fraction promoting late stage wound healing, including epithelialization and re-keratinization. Dr. W. Sam Fagg, MSc., PhD says this technology distinguishes our value proposition to physicians and payers. Merakris has successfully combined these with Dermacyte Matrix to demonstrate improved healing outcomes in cutaneous ulcers. Pursuant to recent FDA guidance, Merakris has completed a pre-IND meeting with the FDA and is preparing an IND to further develop the use of this technology in combination with Dermacyte Matrix.

About Merakris Therapeutics, LLC

Merakris Therapeutics, based in Research Triangle Park, North Carolina, is focused on researching, developing, and actively marketing regenerative healthcare products for wound care, ophthalmology, pain management, and skin rejuvenation. Our vision is to improve global patient care by pioneering commercially scalable biotherapeutic technologies primarily derived from perinatal cells and tissues. The company has filed patents to protect its amniotic fractionation technology, and a novel stem cell co-culture technology that produces an amniotic fluid-like solution targeted for scalable manufacturing for various therapies.

For more information contact Matt Murray at mmurray@merakris.com.

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Merakris Therapeutics, LLC Announces the Commercial Launch of Dermacyte Matrix and CMS Assignment of an HCPCS Code for Use as a Skin Graft Substitute...

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Plasma transfers exercise benefit in mice

Exercise has a broad range of beneficial healthful effects. Horowitz et al. tested whether the beneficial effects of exercise on neurogenesis in the brain and improved cognition in aged mice could be transferred in plasma (blood without its cellular components) from one mouse to another (see the Perspective by Ansere and Freeman). Indeed, aged mice that received plasma from young or old mice that had exercised showed beneficial effects in their brains without hitting the treadmill. The authors identified glycosylphosphatidylinositol-specific phospholipase D1 as a factor in plasma that might, in part, mediate this favorable effect.

Science, this issue p. 167; see also p. 144

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

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Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain - Science Magazine

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Remember Owen Buell of Joliet, the toddler who was diagnosed with a neuroblastoma right before the COVID-19 pandemic began?

His abdomen had doubled in size and his eye looked bruised and was drooping, the story also said.

Since his diagnosis, Owen's had chemotherapy and abdominal surgery to remove a large tumor that had wrapped itself around major blood vessels.

And Tuesday night, Owen, who wont even turn 2 until Aug. 10, had the first of two stem cell treatments.

His health care team is hoping will help to address the hot spots in some of his bones his shoulders and one of his shins places chemo struggles to reach, according to his great-grandmother Jackie Moore of Florida.

The big thing yesterday is that he had very high blood pressure, Moore said. But sometimes thats from too much hydrationonce they put that IV in, he had tons of fluid.

But the family, which includes his parents Brian Buell and Valerie Mitchell, along with his brothers Elliott, age 8, and Bentley, age 5, still needs financial help.

Although the GoFundMe account has raised $20,000 of its $30,000 goal, donations have stalled, Moore said, but the familys needs are still so high.

Brian and Val are exhausted," Moore wrote on the Help for Baby Owen Buell Facebook page. "Val has the weight of the world on her shoulders and it shows on her face. Brian has done so much.

"Now after almost 5 months he is able to give Val a day off from the hospital. Otherwise, they have been there 24/7 with Owen. There are no volunteers right now because of the Covid virus."

No one is working right now and the familys van has taken a toll with the continual trips to Ann & Robert H. Lurie Children's Hospital of Chicago.

The medical bills for all this care has gone over a million dollars, Moore wrote on the Help for Baby Owen Buell Facebook page. Just one of Owen's shots is $6,000.

On top of the financial worries, Owens chemotherapy treatments have been very rough, Jackie said. When his platelet count would plummet, he went to the hospital for transfusions, she added.

Owen requires frequent diaper changes because the chemotherapy is so acid it can burn his skin, Moore said, so his parents have a special cream to use, too.

Doctors could not remove the part of Owens tumor that had wrapped itself around his major blood vessels, Moore said.

They literally would have scraped them off the blood vessels. It was too risky, Moore said. They could have nicked one of those blood vessels and he could have had a major bleed.

Owen required a special chemotherapy before the stem cell transplant. And then he had to be submerged in water every six hours to reduce the likelihood of welts, a reaction from this type of chemo, Moore said.

Sometimes he complains his leg is hurting, Moore said. But he never says his head hurts from the chemotherapy or that he is going to throw up because he doesnt have enough vocabulary for it yet, she added.

He simply throws up.

A nasogastric tube makes it difficult for Owen to eat.

And still he smiles, Moore said. Sometimes not the biggest of smiles.

But about 2 million stem cells were harvested from Owens body. He will stay in the hospital for a month and a parent can remain with him. Then Owen will go to a Ronald McDonald House for two weeks because he will need to stay close to the hospital, Moore said.

And then Owen will repeat the process: two rounds of potent chemo, a second stem cell transplant, a month-long stay in the hospital and two weeks at Ronald McDonald House, Moore said.

Hes at the point where he knows something is wrong, Jackie said. But you cant sit him down like you could to even an 8-year-old and say, Youve got this thing that wants to hurt your body.

People can donate to the GoFundMe page at bit.ly/2S7sPN7 or visit the Help for Baby Owen Buell and His Family Facebook page for updates and detailed instructions on other ways to help the family.

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Whatever happened to baby Owen? - The Herald-News

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Written by Jayashree Narayanan | Pune | Updated: July 9, 2020 6:38:55 pm Lifestyle coach Luke Coutinho on dry fasting and why it matters for your body. (Source: PR Handout)

Dry fasting for good health has raised eyebrows for its complete abstinence from food and water for an extended period, but the trend has been presented as a superior form of fasting and cleansing by Luke Coutinho in his book The Dry Fasting Miracle: From Deprive to Thrive, published by Penguin Random House India.

Coutinho, a holistic lifestyle coach-integrative medicine, who has co-authored the book with Sheikh Abdul Aziz Nuaimi aka Green Sheikh, from UAEs Ajman royal family, advocates dry fasting and intermittent fasting for healthy living. He talks to indianexpress.com on the book, why fasting is for everyone, and how it could be a way to build immunity given the pandemic concerns.

Excerpts:

Why do you think fasting is important?

Fasting in earlier times was built into ones lifestyle; people ate early because there was hardly any light after sunset and their next meal would only be after sunrise. This practice spread to all religions as a discipline due to its health and spiritual benefits. Sickness too was followed by fasting, because it allowed the body to redirect its energy towards healing and repairing. So, fasting is very natural to us, however, we have moved too far away from this concept because of the habit of constant nibbling, an abundance of food and storage options, etc. Our bodies were never designed to eat the amount of food we actually eat today. Overeating turns out to be one of the most common causes of sickness, more so when the quality of food is bad and inappropriate.

Today, science is proving how necessary fasting is for the immune system, digestive system, energy, spirituality, cardiovascular health, obesity, mental health and so much more.

Fasting draws up an image of no food, no water, and basically starving. How is dry fasting different?

Fasting is not starvation. Fasting is not deprivation. Fasting is a discipline where one willingly gives their body and digestive system a break, redirecting the energy towards rejuvenation and detoxification. Fasting is way more disciplined and planned. Skipping meals is not fasting.

Fasting must be practiced around the same time, so our body builds a memory around when it can expect food. Starvation can lead to nutritional deficiencies and acidity, whereas a well-planned fasting schedule eradicates acidity.

Isnt it dangerous for the body to go without food and, more importantly, water for more than 12 hours?

Dry fasting is a cleansing practice that involves complete abstinence from food and water (in any form) for a brief period of time, which could range from 10 hours to 16, 18, 20 hours, depending upon an individuals comfort level.

Our digestive system utilises almost 80 per cent of the energy into digestion, absorption and assimilation with 20 per cent of the energy towards healing, repair, recovery, growth, rejuvenation, detoxification and building the immune system. Too much eating, eating at the wrong timings, overeating can all drain energy, leaving little or no energy for repair and recovery. Fasting gives the digestive system a temporary shutdown, boosting the immune system, stem cell regeneration, hormonal balance, etc.

Dry fasting also sends our body into the autophagy mode (prolonged fasting) wherein its intelligence sacrifices the sickest cells and activates stem cell regeneration. All of this and more can be achieved through fasting, provided its done the right way.

Of course, if someone has a medical condition and cannot fast, they must refrain or modify it according to what their health experts recommend. For example, dry fasting may not suit someone with recurrent UTI infection, so he/she may adopt intermittent fasting. Or someone on water restriction may not be able to do intermittent fasting and can take short fasts under expert guidance only.

Interestingly, the book also mentions hard dry fasting, which means absolutely no contact with water, not just consumption of it but also bathing, washing or cleaning. Is it possible?

Yes, for a brief period of time. Also, hard dry fasting is intense, so its a personal choice whether one is comfortable with fasting by not washing hands, bathing, brushing, or handling water. Not many people are because they go to offices and travel or work and that is absolutely fine. Soft dry fasting (which includes brushing, bathing, etc) if done the right way is powerful in itself.

Fasting is viewed from a religious angle. But in the book, you mention, it is more than that. Can you elaborate?

Fasting does have religious and spiritual significance but its benefits extend beyond that. In fact, it improves the health of an individual from all dimensions physical, mental, emotional, intellectual as well as spiritual.

Fasting is also turning into another fad simply because it is used as a quick fix to achieve health goals, especially losing weight and belly fat.

Fasting is not a solution for weight gain. Use it to instill discipline with reference to eating and constant nibbling, start listening to your body.

Secondly, individuals try to complete with each other on fasting and the number of hours fasted. If someone is doing a 16-hour fast, everyone wants to do a 16 hour fast. Fasting is not a competition. Its what suits you. There is no magic number of hours one should fast.

Lastly, some people claim to be fasting but still have tea/coffee/juices, etc. Such an approach can be detrimental to ones health. Fasting is not a fad.

You mention that the human body is designed for fasting and the simplest way to begin is to have an early dinner. But, people rarely follow that and tend to even eat at odd hours. Is it healthy?

Times may have changed, but not the way the human body functions.While the wisdom of early dinner comes through our grandparents, today, science is proving how late-night meals mess up our digestion, immunity, blood sugar levels, weight, etc. The very fact that the pancreatic cells have melatonin receptors on them proves that our pancreas is meant to shut down when our body starts to secrete melatonin which is when the sun sets. A person who has had a late-night dinner would be able to answer how heavy and uncomfortable it could make one feel the next day and even during the course of the night. Even worse, if the dinner is heavy, because our body is just not designed to digest it at night.

By far, eating an early dinner which is as close to sunset is a powerful lifestyle change. It can result in better immunity, digestion, energy levels, better skin and hair, etc.

Considering each and everyones body systems are different, do you think dry fasting is everyone?

Absolutely. What do you lose by trying? Most people do not fear fasting, they resist moving out of their comfort zones. There are so many people who report literally magical benefits from fasting. If someone is in a dilemma, read about these inspiring stories.At the same time, fasting doesnt have to suit all. Also, if one form of fasting doesnt suit a person, for e.g. dry fasting, in case of a health condition like recurrent UTI, they can adopt intermittent fasting. In the end, its about what suits a person.

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Fasting is not starvation or a fad, it is a discipline: Luke Coutinho - The Indian Express

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Global Stem Cell-Derived Cells market Research presents a Comprehensive scenario Which can be segmented according to producers, product type, applications, and areas. This segmentation will provide deep-dive analysis of the Stem Cell-Derived Cells business for identifying the growth opportunities, development tendencies and factors limiting the development of the marketplace. This report features forecast market information based on previous and present Stem Cell-Derived Cells industry scenarios and growth facets. Each of the Essential regions coated in Stem Cell-Derived Cells report are North America, Europe, Asia-Pacific, South America, Middle East and Africa. The Stem Cell-Derived Cells market share and market prognosis of every region from 2020-2027 are presented within this report. A deep study of Stem Cell-Derived Cells marketplace dynamics will help the market aspirants in identifying the business opportunities that will lead to accumulation of earnings. This segment can efficiently determine the Stem Cell-Derived Cells hazard and key market driving forces.

Request Sample Report @ https://www.persistencemarketresearch.co/samples/28780

The Stem Cell-Derived Cells report is segmented to provide a clear and Precise view of this international Stem Cell-Derived Cells market statistics and market quotes. Stem Cell-Derived Cells report Information represented in the form of graphs, charts, and statistics will show the Stem Cell-Derived Cells growth rate, volume, goal customer analysis. This report presents the significant data to all Stem Cell-Derived Cells business aspirants which will facilitate useful business decisions.

key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

The report covers exhaustive analysis on:

Regional analysis includes

Report Highlights:

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The Stem Cell-Derived Cells report cover following data points:

Part 1: This part enlists the global Stem Cell-Derived Cells marketplace Overview, covering the simple market debut, market analysis by kind, applications, and areas. Stem Cell-Derived Cells industry states and prognosis (2020-2027) is presented in this part. Additionally, Stem Cell-Derived Cells market dynamics saying the chances, market risk, and key driving forces are studied.

Part 2: This part covers Stem Cell-Derived Cells manufacturers profile based On their small business overview, product type, and application. Additionally, the sales volume, Stem Cell-Derived Cells product price, gross margin analysis, and Stem Cell-Derived Cells market share of every player is profiled in this report.

Part 3 and Part 4: This part presents the Stem Cell-Derived Cells competition Based on earnings, earnings, and market share of each producer. Part 4 covers the Stem Cell-Derived Cells market scenario based on regions. Region-wise Stem Cell-Derived Cells sales and growth (2015-2019) is studied in this report.

America and Europes Stem Cell-Derived Cells industry by countries. Under this Stem Cell-Derived Cells revenue, market share of those nations like USA, Canada, and Mexico is provided. Under Europe Stem Cell-Derived Cells report contains, the countries such as Germany, UK, France, Russia, Italy, Russia and their sales and growth is coated.

Part 7, Part 8 and Part 9: These 3 sections covers Stem Cell-Derived Cells The earnings and expansion in these regions are presented in this Stem Cell-Derived Cells industry report.

For any queries get in touch with Industry Expert @ https://www.persistencemarketresearch.co/ask-an-expert/28780

Part 10 and Part 11: This component depicts the Stem Cell-Derived Cells marketplace Share, earnings, sales by product type and application. The Stem Cell-Derived Cells sales growth seen during 2012-2020 is covered in this report.

Related to Stem Cell-Derived Cells market (2020-2027) for every region. The sales channels including indirect and direct Stem Cell-Derived Cells advertising, traders, distributors, and future trends are presented in this report.

Part 14 and Part 15: These components present Stem Cell-Derived Cells market key Research findings and judgment, research methodology, and data sources are covered.

Therefore, Global Stem Cell-Derived Cells report is a complete blend covering all The very important market aspects.

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Stem Cell-Derived Cells Market is Projected to Reach US$XX by the end of 2019 2029 - 3rd Watch News

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The Skin Care Cosmetic market revenue was xx.xx Million USD in 2014, grew to xx.xx Million USD in 2018, and will reach xx.xx Million USD in 2024, with a CAGR of x.x% during 2019-2024. Based on the Skin Care Cosmetic industrial chain, this report mainly elaborates the definition, types, applications and major players of Skin Care Cosmetic market in details. Deep analysis about market status (2014-2019), enterprise competition pattern, advantages and disadvantages of enterprise products, industry development trends (2019-2024), regional industrial layout characteristics and macroeconomic policies, industrial policy has also be included. From raw materials to downstream buyers of this industry will be analyzed scientifically, the feature of product circulation and sales channel will be presented as well. In a word, this report will help you to establish a panorama of industrial development and characteristics of the Skin Care Cosmetic market., The Skin Care Cosmetic market can be split based on product types, major applications, and important regions.

Download PDF Sample of Skin Care Cosmetic Market report @ https://www.arcognizance.com/enquiry-sample/740561

Major Players in Skin Care Cosmetic market are:, Avon Products Inc, Kao Corporation, Procter & Gamble, The Estee Lauder Companies Inc, Beiersdorf AG, Unilever PLC, The Body Shop International PLC, Johnson & Johnson, LOreal S.A.

Major Regions that plays a vital role in Skin Care Cosmetic market are:, North America, Europe, China, Japan, Middle East & Africa, India, South America, Others

Brief about Skin Care Cosmetic Market Report with [emailprotected] https://arcognizance.com/report/global-skin-care-cosmetic-industry-market-research-report

Most important types of Skin Care Cosmetic products covered in this report are:, Sensitive Skin Care, Dry Skin Care, Infants Skin Care, Others

Most widely used downstream fields of Skin Care Cosmetic market covered in this report are:, Stem Cells Protection Against UV, Flakiness Reduction, Rehydrate the Skin Surface, Minimize wrinkles, Increase the viscosity of Aqueous

There are 13 Chapters to thoroughly display the Skin Care Cosmetic market. This report included the analysis of market overview, market characteristics, industry chain, competition landscape, historical and future data by types, applications and regions.

Chapter 1: Skin Care Cosmetic Market Overview, Product Overview, Market Segmentation, Market Overview of Regions, Market Dynamics, Limitations, Opportunities and Industry News and Policies.

Chapter 2: Skin Care Cosmetic Industry Chain Analysis, Upstream Raw Material Suppliers, Major Players, Production Process Analysis, Cost Analysis, Market Channels and Major Downstream Buyers.

Chapter 3: Value Analysis, Production, Growth Rate and Price Analysis by Type of Skin Care Cosmetic.

Chapter 4: Downstream Characteristics, Consumption and Market Share by Application of Skin Care Cosmetic.

Chapter 5: Production Volume, Price, Gross Margin, and Revenue ($) of Skin Care Cosmetic by Regions (2014-2019).

Chapter 6: Skin Care Cosmetic Production, Consumption, Export and Import by Regions (2014-2019).

Chapter 7: Skin Care Cosmetic Market Status and SWOT Analysis by Regions.

Chapter 8: Competitive Landscape, Product Introduction, Company Profiles, Market Distribution Status by Players of Skin Care Cosmetic.

Chapter 9: Skin Care Cosmetic Market Analysis and Forecast by Type and Application (2019-2024).

Chapter 10: Market Analysis and Forecast by Regions (2019-2024).

Chapter 11: Industry Characteristics, Key Factors, New Entrants SWOT Analysis, Investment Feasibility Analysis.

Chapter 12: Market Conclusion of the Whole Report.

Chapter 13: Appendix Such as Methodology and Data Resources of This Research.

Some Point of Table of Content:

Chapter One: Skin Care Cosmetic Introduction and Market Overview

Chapter Two: Industry Chain Analysis

Chapter Three: Global Skin Care Cosmetic Market, by Type

Chapter Four: Skin Care Cosmetic Market, by Application

Chapter Five: Global Skin Care Cosmetic Production, Value ($) by Region (2014-2019)

Chapter Six: Global Skin Care Cosmetic Production, Consumption, Export, Import by Regions (2014-2019)

Chapter Seven: Global Skin Care Cosmetic Market Status and SWOT Analysis by Regions

Chapter Eight: Competitive Landscape

Chapter Nine: Global Skin Care Cosmetic Market Analysis and Forecast by Type and Application

Chapter Ten: Skin Care Cosmetic Market Analysis and Forecast by Region

Chapter Eleven: New Project Feasibility Analysis

Chapter Twelve: Research Finding and Conclusion

Chapter Thirteen: Appendix continued

List of tablesList of Tables and FiguresFigure Product Picture of Skin Care CosmeticTable Product Specification of Skin Care CosmeticFigure Market Concentration Ratio and Market Maturity Analysis of Skin Care CosmeticFigure Global Skin Care Cosmetic Value ($) and Growth Rate from 2014-2024Table Different Types of Skin Care CosmeticFigure Global Skin Care Cosmetic Value ($) Segment by Type from 2014-2019Figure Sensitive Skin Care PictureFigure Dry Skin Care PictureFigure Infants Skin Care PictureFigure Others PictureTable Different Applications of Skin Care CosmeticFigure Global Skin Care Cosmetic Value ($) Segment by Applications from 2014-2019Figure Stem Cells Protection Against UV PictureFigure Flakiness Reduction PictureFigure Rehydrate the Skin Surface PictureFigure Minimize wrinkles PictureFigure Increase the viscosity of Aqueous PictureTable Research Regions of Skin Care CosmeticFigure North America Skin Care Cosmetic Production Value ($) and Growth Rate (2014-2019)Figure Europe Skin Care Cosmetic Production Value ($) and Growth Rate (2014-2019)Table China Skin Care Cosmetic Production Value ($) and Growth Rate (2014-2019)Table Japan Skin Care Cosmetic Production Value ($) and Growth Rate (2014-2019)continued

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NOTE: Our report does take into account the impact of coronavirus pandemic and dedicates qualitative as well as quantitative sections of information within the report that emphasizes the impact of COVID-19.

As this pandemic is ongoing and leading to dynamic shifts in stocks and businesses worldwide, we take into account the current condition and forecast the market data taking into consideration the micro and macroeconomic factors that will be affected by the pandemic.

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Impact Of COVID-19 On Skin Care Cosmetic Market 2020 Industry Challenges, Business Overview And Forecast Research Study 2024 - Owned

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