StemCell Therapy

Cancer is not just an adult problem.

Whether it's a health fightin the public's eye or in private, children across the world claw, scratch and rip away in theirbattle with "The Big C."

An American Cancer Society report last year estimated2019 would seemore than 11,000 children between the ages of 1 and 14 diagnosed with some form of cancer. Of them, 1,190 would not survive.

Abilene is no safe haven. Those youngsters who are diagnosed must deal with more than just their fragile and failing health.

For them, cancer isn't just a disease. There's also a social element becausethey're in school when not undergoing treatment or at checkups.

Third-grade student, Ciara Husing'sdiagnosis was a death sentence. Not for her body, but for her standing in the social circles.

"They (fellow classmates)would be rude," said Ciara, now 10. "One girl told me 'You know you're going to die.'"

First, it was relief. Then reality set in for McKenzie Husing.

On a typically hot August afternoon in 2018, alone in her vehicle, Husing heldan envelope in her hands.She began to cry.

Its contents weretest results after a mass was removed from the knee of her daughter, Ciara.

Breathing in, she tore it. Two years of struggle, fighting, pain and anguishnot justCiara's but also her own channeled into that motion. She reached in.

It's contents read, "Synovial sarcoma."

Not cancer, she thought.

Then reality hit hard. It most certainly is cancer, and Ciara, then 8, was in the fight for her life.

Sarcomas are cancers of soft tissue, according to Dr. Douglas Harrison, center director of the pediatrics department at University of Texas MD Anderson Cancer Center in Houston.

Synovial, Harrison said, refers to the long bones that the cancerous soft tissue is attached to.

While synovial sarcoma is one of the most common forms of sarcomas in terms of diagnosis, it's not typical in children, Harrison said.

"A pediatric (cancer) diagnosis is a pretty rare phenomenon," Harrison said. "And (specific types) getrarer and rarer. It's extremely rare to be diagnosed with synovial sarcoma (in a pediatric case). So, it's not great that it's synovial sarcoma."

The most common diagnosis for children is acute lymphoblastic leukemia, he said. That's a cancer of the blood-forming tissue. Children nextare most susceptible to brain cancer, then soft tissue cancers, including but not limited to sarcomas.

It was 2016. Ciara Husing, a kindergarten student, complained about a bump on her left knee. It hurt to the touch, McKenzie Husing recalledher daughter saying.

"I thought it was growing pains, at first," Husing said. To be safe, the family took Ciara to the hospital for an x-ray. It came back normal.

But Ciara's pain didn't go away. Neither did the bump. In fact, the bump got bigger. And bigger.

Eventually, after several doctor visits, the diagnosis came back. Ciara had developed a condition called Osgood-Schlatter Disease. Or so the family was told.

Ciara Husing, 10, plays basketball during a league practice at First Baptist Church Dec. 5. She was excited to be playing again after the fight for her life. Ciara was diagnosed with synovial sarcoma, a tissue cancer found in the body's extremities, in August 2018.(Photo: Ronald W. Erdrich/Reporter-News)

"This was her tag," Husing said. "As a mom, I thought, 'Finally we had a diagnosis.' I didn't second guess the doctors. And her pain was real."

According to the Mayo Clinic's website, Osgood-Schlatter manifests asa bony bump on the shin directly below the knee cap and associated most often with young athletes as they undergo growth spurts. It's typical among girls ages 10-13. Boys develop it at a slightly older age.

Ciara was 6.

MORE: Ward Elementary teacher in Abilene is a Life Changer, like it or not

In hindsight, itwasclue No. 1 that something was terribly wrong with the determination. There would be others.

Ciara's "diagnosis" came in September 2016. By December, Ciara was in the waiting room of an orthopedic doctor. Combined with Husing's input, the doctor fitted Ciara with a knee brace.

But that was just a stop-gap measure.

By the time Ciara started first grade the next summer, she was leaving the brace at home while at school. It never really helped her much anyway, Husing said.

And the bump kept getting bigger. So Husing sent her daughter to school with knee pads on under her clothes. It led to some confidence problems as some teasing came along with the bulging joints.

Under normal circumstances, Osgood-Schlatter has specific symptoms. The bump, medical reports say, is not painful to the touch. And the inflammation tends to subside with enough rest.

Clue Nos. 2 and 3, Husing said.

Yet the Osgood-Schlatter disease diagnose continued.

Emergency room trips, visits to Cook Children's Hospital in Fort Worth and local doctor visits piled up, each doctor confirming what the previous one said despite the abnormal presentation. And each bill dropping the family deeper down a rabbit hole.

Ciara kept complaining about pain. Nothing was being done about it.

"I tried everything over-the-counter, everyhome remedy," Husing said. "Nothing worked."

So Ciara's father suggested they go to the doctor every time she complained about anything.

Jack Marcelain, left, survived a benign brain tumor diagnosed in 2005, when Marcelain was 6 years old. He's now a social work student at Abilene Christian University, studying to one day help families who are enduring what he and his suffered through. His mother, Tammy Marcelain, right, supports him through his journey.(Photo: Ronald W. Erdrich/Reporter-News)

In 2005, 6-year-old Jack Marcelain was diagnosed with a type of benign brain cancer called pilocytic astrocytoma.

It was his last month of kindergarten, his mother said. Surgery at Children's Medical Center Dallas removed about 96 percent of the tumor. However,the 4 percent that remained, in Jack's brain stem, was acting as the heart of the tumor.

Tammy Marcelain, his mother, remembers it well. Jack? Not so much.

"I was so young at that point," he said, "I knew what cancer was, but I never really knew the whole gravity of the situation."

Though it's all burned into her synapses, what Tammy Marcelain remembers most is the immediate aftermath of the surgery. The danger of operating on the brain, especially the brain of a 6-year-old, became reality.

For four weeks, Jack was unable to use his eyes. He was unable to speak. He was unable to walk. His parents moved him into Our Children's House in Dallas while Jack was recovering.

You're mad, scared, petrified (in the moment). But you can't live like that. You have to know where he went and know where we're going. We have faith in our religion and our God.

At 9, after years of the tumor regenerating, Jack endured radiation treatment, aimed at addressing that tumor's heart in his brain stem. It resulted in two things: the right side of Jack's face is paralyzed and the tumor eventually was halted.

With that one caveat, mission accomplished.

"That was what eventually stopped the tumor from growing," Tammy Marcelain said. "Once he was cancer-free, he progressed like a pretty normal kid."

Jack Marcelain, now a social work student at Abilene Christian University, hopes to translate that experienceat least, what he remembers from being a young childhood cancer patient and survivorinto a career helping families in situations similar to were his family found itself all those 15 years ago.

He has singled out the pediatric hospital setting as his focus. He just wants to make sure future him can help in any way possible anyone avoid some of the struggles his family endured making sure he was receiving the proper care.

"Social work was never something I knew what it was," Marcelain said. "I knew you helped people. As I was coming into college, I had narrowed down my focus to between that and ministry. I knew I wanted to work with people and found this was a really good way to help people .... andmake that time a little less stressful."

In March 2018, Ciara was climbing on her bed with her siblings when she fell.

Thump! She landed on the bump. The noise she made was unlike anything Husing said she'd ever heard from her daughter.

It was questionable Ciara Husing, 10, would ever play sports again after she was diagnosed with synovial sarcoma. But she runs circles around people now, despite a large scar on her left leg.(Photo: Ronald W. Erdrich/Reporter-News)

Still, there was no change in the diagnosis. But the doctor prescribed crutches for Ciara.

"We know now that she had a tumor on her nerve and she hit the dang thing," Husing said.

In April, they finally were able to convince the hospital to order an MRI on Ciara's knee. It came back with an irregularity: a bursa, doctors said, had formed as a result of the Osgood-Schlatter disease.

The family argued with doctors, sick of hearing the same diagnosis. At this point, they were self-made experts and they knew their daughter had something, and it wasn'tOsgood-Schlatter.

"We argued, we yelled," Husing said. "Some bad words were said. But as we were scrolling through the images from the MRI, I saw a flash of something. When I pointed it out, it looked like a crescent moon, but when I pointed to it, the doctor said it could be the bursa."

A bursa is a fluid-filled sac that develops near joints due to friction.

Finally, there was a light at the end of a darktunnel, Husing said. While they had no idea what actually was happening, they knew there was a foreign body affecting her knee.

Again, Ciara's pain and struggle was justified.

'I knew something was wrong'

With the bursa identified, it was time to remove it. Surgery.

It happened in August. Husing said they were told it would take 20-30 minutes.

Hours ticked by.

Finally, the surgeon camethrough the doors. Husing said her stomach dropped.

"My heart stopped," she said. "I thought she'd died. I mean, that's what you see in movies when the doctor comes out."

When you hear those words, you don't know who to call. There is no speed dial for when you're told your kid has cancer. You pray about it but you don't know who to call.

Once she was able to move, they were ushered into Ciara's recovery room.

The surgeon sat between mom and dad and looked them in the eye. He told them they did a good thing getting her to surgery. He told them she needed him to cut into their daughter.

He told them he found a massof some kind.

"He said he'd never seen anything like it before," Husing said. "He said he got it out of her, cut it open and it was black inside."

That's where Husing's imagination took over. She kept thinking about the doctor's words. As she got home, she jumped on Google and searched out phrases like "pediatric knee mass."

The results weren't what she wanted.

"I thought it couldn't be cancer," she said. "But in my mind, I knew."

It's one of the worst feelings in the world, Husing said.

"When you hear those words, you don't know who to call," Husing said. "There is no speed dial for when you're told your kid has cancer. You pray about it but you don't know who to call."

Eventually, she called Ciara's pediatrician, one of the many doctors who, up to this point, classified it as Osgood-Schlatter disease. There was an apology, Husing said. And an offer to put her in touch with a child life specialist.

I was so young at that point, I knew what cancer was, but I never really knew the whole gravity of the situation.

Husing refused.

In her anger, she refused to allow anyone but herself deliver the information to her daughter and the rest of her family. Hours after opening the envelope, she sat with Ciara and began her explanation.

It didn't go well, Husing said.

"The cry she let out was awful," she said.

At that point, she hadn't slept much. Less sleep came in the next few days as she waited for test results on the mass to come back.

That's when she opened the envelope in her car. That's when reality confirmed both her worst-case scenario and her daughter's story.

Within 45 days of Ciara's diagnosis, the child had seen more of the United States than she ever thought possible.

Aside from the trips to Cook Children's in Fort Worth, they flew to Cincinnati in September 2018. There, she had a lymph node biopsy done to see if the cancer had spread. Nine days later, Ciara had traveled to the East Coast, inBoston for an official consultation.

She was going in for surgery.

There, she met with the man who helped change her young life around: Dr. Ernest "Chappie" Conrad III.

Specializing in both adult and pediatric sarcomas, Conrad was able to save Ciara's leg.

It's called limb salvage surgery, a procedure Conrad excels at and has pioneered.

Essentially, Conrad removed a section of herleg and replaced the missing piece witha donor bone.

Since that surgery, Husing and her daughter have been to Houston tomeet with Conrad, who serves as a professor of medicine in the University of Texas McGovern Medical School at MD Anderson Cancer Center.

Thomas Elementary School students released balloons in November 2012 to honor Rex Fleming, 10, who died earlier that week after a two-year bout with brain cancer. Students and football teams at Abilene Christian University, where his father was employed, and at Abilene High had rallied around Rex.

(Photo: Joy Lewis/Reporter-News)

When Jill Fleming sees pink pom-poms at football games, or National Football League players wearing pink cleats in October, she gets frustrated.

Here is the original post:
'I was scared': Abilene parents and children remember their pediatric cancer struggles - Abilene Reporter-News

With triple the number of sepsis cases in Australia, small cap biotech company Cynata Therapeutics (ASX:CYP) hopes to wage a new war on blood infections.

Last Friday the world learned blood infections were on the rise, with researchers showing in the international medical journal The Lancet that sepsis infections had increased 201 per cent Down Under.

Young children, the elderly, indigenous or those with compromised immune systems are at risk of sepsis.

Lancets Global Burden of Disease study of 195 countries and territories was based on records such as Australian death certificates, rather than just what medical professionals put on their paperwork, and showed a dramatic increase in cases from previous estimates.

The study showed that in 2017 there were about 55,000 cases of sepsis in Oz more than three times the number of cases than the 18,000 incidences previously estimated.

The death count that year from the infection was 8,700 people in Australia. It was a dramatic 74 per cent increase on the 5,000-deaths estimated previously.

Some people experience multiple cases of sepsis in a year but mortality rates are still grim.

A 2016 study by the Canadian Institute for Health Information and the Canadian Patient Safety Institute found that the mortality rate for sepsis was 20 to 30 per cent in Western nations.

Sepsis is a life-threatening blood infection that people can rapidly lose their lives to.

Its a threat taken seriously in medical facilities across the globe, and a challenge Cynata hopes to address with stem cells to put peoples immune response in check.

Cynata researchers have shown its Cymerus mesenchymal stem cells (MSCs) can work well in battling blood infections in animals.

The company wants to expand its research to human studies, Cynata managing director and CEO Dr Ross Macdonald told Stockhead.

The recent feature article in the highly respected medical journal The Lancet and the worldwide media attention it garnered outlines the chilling reality of just how devastating, prevalent and widespread sepsis is, Dr Macdonald said.

It is now acknowledged as one the most common and lethal conditions faced in medicine and which existing treatments are not capable of addressing.

Cynatas very promising findings in the recent pre-clinical study of its Cymerus mesenchymal stem cells provide a new potential treatment option for this exceedingly challenging problem.

Cynatas early-stage research out of Ireland effectively showed its stem cells calm down the animals immune system, Macdonald explained.

Known as the silent killer, sepsis is seen by some as an overreaction of the immune system to infection.

The Lancets study found the number of cases of sepsis worldwide had doubled to 49 million a year.

Deaths from the condition stood at 11 million people, equating to one in five deaths globally.

Researchers called it the leading cause of death worldwide.

Australian Sepsis Network (ASN) founder Professor Simon Finfer from The George Institute for Global Health was one of The Lancet studys authors and said it was concerning so many lives were lost to a largely preventable condition.

People need to act fast with sepsis, which can quickly damage a persons tissues and organs and lead to shock, organ failure and death.

Australia has good systems in place to treat people early but more needs to be done, according to Professor Finfer.

We urgently need a coordinated national approach that addresses pre-hospital and in-hospital recognition and treatment, to address the significant death and disability caused by sepsis in Australia, he said.

ASN is housed at the George Institute and has $1.5m in federal government backing to develop treatment guidelines and run public awareness campaigns.

Current treatments can include antibiotics given within an hour of medics suspecting sepsis, intravenous fluid therapy, vasopressordrugs to support organ systems, mechanical ventilation and renal replacement therapy.

More females than males experienced sepsis, while 40 per cent of cases are in kids.

The most affected regions worldwide are sub-Saharan Africa, the South Pacific islands near Australia and South-East Asia.

Cynata is not the only ASX-listed company looking at sepsis.

Recce Pharmaceuticals (ASX:RCE) has an antibiotic known as RECCE 327 that targets sepsis and blood infection.

The company raised about $7m last October to progress the drug through early stage clinical trials to test its safety and work out the right doses.

Medtech Uscom (ASX:UCM) is targeting the monitoring market with a non-invasive medical device to measure heart flow that can be used in sepsis patients.

Resources company Surefire Resources (ASX:SRN) had a sepsis program that it licensed from the University of Western Australia in the mid-naughties, when it was known as Genesis Biomedical (ASX:GBL).

Genesis opted to terminate the program in 2006 and become Black Ridge Mining (ASX:BRD) before rebranding to Surefire.

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Sepsis has tripled in Australia and these small caps are tackling it head on - Stockhead

Wow, you survived cancer? What's your secret to health care?

As absurd as that sounds, its a question many Americans who get sick are still asking as we ring in the year 2020. Getting health care in this country is still so circuitous it often does feel like a secret a maze deciphered in private that's never quite mastered. The reward for solving it? Perhaps your life; perhaps the loss of your life savings. And thats if youre lucky.

Even with the Affordable Care Act, almost 30 million are without health insurance in the U.S. And if youve perused plans on the ACA marketplace, youll know why. Theyre pricey, and a new year brings fears that insurance premiums are once again rising. (Who knew the inflation rates on a pap smear were that high?!) Meanwhile, 14 Republican-led states are still refusing to expand Medicaid as stipulated in the ACA, even though the federal government would pay for 90 percent of the cost. Why? Something about repeal and replace or socialism. Its hard to keep track.

Even with the Affordable Care Act, almost 30 million are without health insurance in the U.S. And if youve perused plans on the ACA marketplace, youll know why.

I traveled to three states, each with their own unique health care access challenges, for my new MSNBC special "Red, White, and Who? Between Texas, New York and Utah there are major differences in how easy it is to see a doctor without going bankrupt. But every single person I spoke with regardless of job, socioeconomic status or even political affiliation had one identical anxiety: healthcare in one of the most advanced countries in the world is ridiculously, hopelessly complicated.

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Im retired, but I feel like a have a job, Larry Chiuppi told me sitting outside at an RV park in Houston, blocks from one of the top cancer treatment hospitals in the country. Larry has been caring for his wife Nancy Raimondi, who has blood cancer, for over a year. During that time, he himself was diagnosed with prostate cancer. Even with her Medicare and his private health plan under the ACA, navigating the billing systems for the endless hospital visits, specialists and tests each with their own separate charges requires a huge amount of time and vigilance. He tells me they once got a $14,000 bill for a stem cell transplant because someone forgot to link Nancys Medicare. Larry imagined many people wouldve just tried to pay it. And most Americans dont have a retirees free time and Larrys persistence to help them through the bureaucracy, an added burden of getting well.

We also dont all have a mother like Sandra Stein. She and her family live in New York, a state where the uninsured population is less than five percent, and 6.5 million are on Medicaid. I met Sandra on a street corner in upper Manhattan, where activists were flyering for the New York Health Act, a bill that would give every New Yorker state-funded care. Sandra believes in single-payer healthcare because she has experienced the mind-numbing labyrinth that is the private insurance system firsthand.

When her son was nearly three, he developed a rare neurological disease that left him unable to walk or speak. At the time, she and her husband had private insurance, which was relatively good insurance, according to Sandra. But that didnt make things easier. When they first went to the hospital in an ambulance, the doctors there didnt take their insurance even though the hospital did. Her son ultimately stayed in three different hospitals over the course of 15 months.

When we got home it was my job to figure out the pile of bills and the collections threats, she told me. Its been eight years, but Sandras voice cracked like the memory happened yesterday. I couldnt imagine how hard it mustve been to be afraid for your childs life while collections agents breathed down your neck. Sandra says the billing department sought her out even while her son was in the ICU, and that there were so many billing errors that she ultimately asked for an audit.

And yet, Sandra, Larry and Nancy are the lucky ones. They have health insurance, and they have the time and resources to be able to make their way through the bureaucratic hall of mirrors and toward a fighting chance at getting well.

Its this cruel opacity of the private insurance system, on top of the rising monthly costs of just having a plan, that can be the difference between life and death. And it keeps a surprising number of Americans away from the system altogether. Like a rodeo cowboy I met in Texas, whose story youll just have to watch (Im not spoiling it all!). Its also led Americans like Sandra to believe that a massive simplification of our health care system is far overdue.

For many, that simplification comes in the form of cutting out the profit motive and moving toward government-funded insurance, like Medicare for All, which Big Pharmas enemy number one Sen. Bernie Sanders and I hashed out over bagels in a New York City deli.

Ultimately what became clear through my travels is that healthcare in America is often overpriced and even dysfunctional, but its the lack of transparency that can be the most insidious. You pretty much have to be a health care policy expert, or have a loved one who can quit their job to become one, in order to ensure proper help.

Its also strange that in a country that loves the free market as much as we do, we the consumer have no idea how much anything costs when we walk into a hospital. Why would we? Our health is priceless, so we are simply at the mercy of an ineffective system. That is, unless we fight for something different.

Red, White, and Who premieres on MSNBC on Dec. 29 at 9 p.m. E.T.

Francesca Fiorentini is journalist and comedian. She is the host of "Red, White and Who?" on MSNBC and Newsbroke on AJ+. Follow her @franifio.

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Health care in America is dysfunctional but its lack of transparency is downright dangerous - NBC News

No matter how packed with all that makes the game greata golf year might be and Id contend that theres never been a year that wasnt it wont stand out in history unless it has one extra special moment. And 2019 had that.

Golfs broad strokes rarely cut as wide a swath through culture as the Big 3 team sports, but Tiger Woods victory at the Masters was voted The Associated Presss top sports story of the year. Its importance may come to be considered greater than his 1997 Masters victory, or his U.S. Open wins at Pebble Beach in 2000 and Torrey Pines in 2008. And as a comeback from adversity, Woods first major victory in 11 years at least rivals and arguably surpasses not only Ben Hogans 1950 U.S. Open, but ANY sports comeback ever. It was extra special.

But so much else happened in 2019. What to make of the rest?

Well, lets start with Woods. Its easy to forget that a lot of things had to go just right on Sunday for Tiger to win at Augusta. And that as much as the place is considered his sweet spot, he hadnt won there since 2005. For me, the singular moment that meant more going forward was the Zozo Championship in November. Not because it became Woods record-tying 82nd career. And despite the tournament being a limited field, off-season event over a short golf course in a faraway land.

Was there any doubt? For our No. 1 Storyline of the Year, we look back on Tiger Woods' 15th major title at the Masters Tournament.

It was the WAY that Tiger played with a return to an ease and smoothness in his action that not only recalled much earlier days, but which promises repeatability and consistency. As well as on the right occasions dominance.

Next on the hit parade the education of Rory McIlroy. The four-time major winner added important elements to his game namely better putting and overall ball control to set the foundation for another sustained run of greatness in his 30s.

But it was also a year of searching. McIlroy came into 2019 reflective and open to new ideas. He said meditation, juggling and several self-help books had led him to decide that he would no longer allow my score to define who I am as a person. His consistency improved and he impressively won The Players in March. But McIlroy also had several flattish Sundays with chances to win, and the Masters where he continues to chase the career Grand Slam didnt go so well.

Prior to the U.S. Open, McIlroy roared to a seven-shot win in Canada. But he tied for ninth at Pebble Beach. Expectations were again high at Portrush, a short car ride from his boyhood home and where he had shot the course record of 61 at age 16. He opened The Open with a nervous 79 and missed the cut. The next week he got boat-raced by winner Brooks Koepka in a final Sunday pairing at the WGC-FedEx in Memphis.

It was again time to reassess.

After winning the FedExCup at East Lake, this time outplaying Koepka in the last group in what he would later call the highlight of his year, McIlroy revealed having committed to a harder and more self-aware competitive edge.

I think one of the biggest things is sometimes Ive tried to treat Sundays the same as a Thursday or Friday, and theyre not, said McIlroy, who would go on to win WGC-HSBC in Shanghai in November for his fourth victory of the year. Ive gone into them maybe a little too relaxed, but its not the same, and its about trying to get yourself in the right mindset. I guess thats the ultimate compliment I can give Brooks is that I wanted to be a little bit more like him.

McIlroy on Koepka rivalry: Feels good to take down No. 1

Speaking of Big Game Brooks, his ruthless march through the major championships since 2017 has been undervalued. In the last 30 years, only Woods, McIlroy and Nick Faldo have had such prolonged periods of excellence in the biggest events.

This year, Koepka showed true dominance in building a seven-stroke lead through three rounds in his victory at the PGA at Bethpage. That he bookended that performance with seconds at the Masters and at the U.S. Open got short shrift. And after he finished fourth at Portrush, when his putter uncharacteristically failed him (and he was being bothered by a torn patella tendon in his left knee that required stem cell treatment and from which he is still recovering), too many acted as though his reign had ended.

That impression was strengthened when McIlroy was chosen as PGA Tour Player of the Year by a vote of his peers. In the last couple of years, Koepka has used relatively small slights for fuel. But going into 2020 and turning 30 in May, he will be on a mission to strengthen his hold on world No. 1 and outdo McIlroy in the process. Koepka betrayed some saltiness in October by pointing out that, Ive been out here for what, five years. Rory hasnt won a major since Ive been on the PGA Tour. So I dont view it as a rivalry.

Sounds like a rivalry.

Although Jon Rahm, who enters 2020 at No. 3 in the world, is expected to intrude.

The 25-year-old Spaniard earns the description beast in the same way as team sport athletes who appear physically overwhelming. Along with his nine combined victories on the PGA and European tours, Rahm has also validated his combination of power and touch with a relentless consistency in his first 89 official worldwide professional starts, Rahm has 44 top-10s, only one less than Woods in his first 89. As he continues to mature and he got married just this month expect a calmer, more controlled Rahm to be even more dangerous.

In the womens game, Jin Young Ko was by far the best player of the year, winning two majors and two other events in only her second season on the LPGA tour. In a gracious acceptance speech for year-end honors at the tours awards banquet, the 24-year-old South Koreans accented, but precise English reflected the same discipline and exactitude that is so evident in her game. The current Rolex No. 1 knows thats been a precarious perch over the last decade in womens golf, and she seems determined to change the cycle. This is not the end, she told the gathering, but only the beginning.

Ok, thats the highest profile stuff. But there was also a pervasive theme that permeated 2019. In so many ways, it was an extraordinarily feel-good year.

Usually in these end-of-the-year assessments, what sticks with me most and reinforces my generally tragic sense of competitive golf are the deeply wounding, self-induced losses brought on by late implosions. You know, Phil Mickelson at Winged Foot, Adam Scott at Royal Lytham & St. Annes, and Jordan Spieth at the 2016 Masters with plenty of other examples to stuff into the hurt locker. But as I remember 2019, only two players caused such sadness, Francesco Molinari at the Masters and Lizette Salas at the Womens British Open. Molinari, the seemingly unflappable ball-striking machine led by two strokes on the 12th tee Sunday at the Masters before mishitting an 8-iron into Raes Creek, opening the door for Woods. Salas, who played the best golf of her life with a closing 65 at Woburn, missed a 5-foot birdie putt on the 72nd hole, and then watched Hinako Shibuno win it with a 20-footer.

Instead of a bevy of heartbreak, we got a full complement of Capra-esque moments.

Winning putt: Pettersen clinches the Solheim Cup for Europe

Suzann Pettersen, after making an 8-footer on the final green in the last match that spelled the difference between winning and losing the Solheim Cup, announced her retirement at age 38. One of the great walk-offs ever in professional sports. Pettersen said she reached the decision spontaneously with the thought, This is it. This is the peak.

Shane Lowry, as an underachiever scarred by a Sunday failure at the 2016 U.S. Open, shouldering the immense mental load before thousands of home fans in a land that hadnt held the Open Championship since 1951, and winning by six. The panorama on Portrushs 72nd hole, with fansrunning up the fairway behind Lowry, some waving Irish flags in the rain amid a constant roar, was one of pure cathartic release.

Shibuno winning the Womens British Open at Woburn in her first professional tournament outside Japan. A babe in the woods at 20, she was bolstered by innocence and a constant, infectious smile, even as she four-putted early in the final round. Shibunocaught fire and closed with a 31 on the final nine, her final putt rammed in with a blissful freedom, to become the second Japanese player to win a major championship.

The scene at the inaugural Augusta National Womans Amateur, where the image of women striding the hallowed grounds was a transformative moment for the game. The impressive brand of head-to-head power golf played by winner Jennifer Kupcho and runner-up Maria Fassi was the icing on the cake.

The effervescent Helen Alfreddson winning the second U.S. Senior Womens Open at Pine Needles, the most joyous, about time and appreciated championship in golf. Love of the game is never more palpable than among too-long-ignored 50-and-over LPGA veterans, and Alfreddsons passion and exuberance spoke for them all.

Cameron Champ won the Safeway Open in October while dedicating his play to his gravely ill African-American grandfather, Mack, who started him in the game. The 24-year-old bombers calm as he garnered his second victory was reminiscent of Ben Crenshaws march to the 1995 Masters after being a pallbearer at the funeral of his teacher, Harvey Penick, earlier that week.

In the most exciting finish of the year, Matthew Wolff he of the fascinatingly powerful swing and unofficial leader of the games latest youth movement in only his third pro start, won the 3M Championship with an eagle on the 72nd hole to beat Bryson DeChambeau, who had also eagled the last, by one.

Finally and excuse my darkness Koepka and Rahm saving big victories after blowing huge Sunday leads. For some reason, nothing makes me happier (or more accurately relieved) than seeing a player who has gone from the zone to full meltdown, and then reverse what suddenly looks like his or her inevitable and awful fate in the nick of time. Koepka dug to the very bottom of his deep reservoir of poise to do it at Bethpage after four straight bogeys on the final nine had him lose all but one of his seven-stroke lead. Rahm had a five shot lead with 10 to play at the DP World in Dubai, but it was all gone thanks especially to a couple of knuckleheaded three-putts from inside 25 feet when he reached the 72nd hole. Hell remember that birdie with a smile and a shudder for the rest of his life.

Adding additional poignancy to our main theme, it was also the year of journeymen each capable, but with a history of struggle at the highest level seizing the day.

There is a fine line between success and slump in professional golf. It took only one swing to send Brendon Todd over that line and years to make it back.

Brendan Todd ran away with this category, returning from nearly four years in the wilderness that included a stretch of missing 37 of 41 cuts, to win back-to-back at Bermuda and Mayakoba, and then nearly won again at the RSM. The 34-year-old, who won the Byron Nelson in 2014, came down with a nightmare dose of the swing yips (the lose-it-way-right strain) that by late-2018 had him on the verge of giving up pro golf and opening a pizza franchise. Instead, Todd got some help from swing coach and former player Bradley Hughes and pulled off one of the great turnarounds in golf history.

And consider this roll call of others who went through storybook lost-and-found cycles to convert a week of magic into first victories that take them into 2020 with transformed lives: Max Homa (Wells Fargo Championship), JT Poston (Wyndham Championship), Nate Lashley (Rocket Mortgage), Lanto Griffin (Houston Open), Tyler Duncan (RSM Classic), Adam Long (Desert Classic). Inspirations all.

And at the risk of belaboring the feel-good point, it seemed that just about every level of pro golf ended the year on a happy note.

At the PGA Tours finale at East Lake, McIlroy spread much joy in Ponte Vedra, with one fell swoop validating the wisdom of the Tours more compressed and earlier finishing schedule, getting the new staggered start scoring system at the Tour Championship off on the right foot, and winning in the final group in another showdown with Koepka.

The LPGAs season ended on a high note with Sei Young Kim making a 22-foot birdie putt on the last hole to win the richest first-place prize ever in the womens game $1.5 million at the CME Group Tour Championship. A new format had been questioned for seeming to put sheer money over an equitable reward for season-long performance, but Kims stature as a top player and the cliffhanger nature of her victory over Charley Hull made for a satisfying result.

The PGA Tour Champions season ended with a bang when Jeff Maggert holed out from 123 yards for eagle to win the Charles Schwab Cup Championship in sudden-death.

And at the last big event of the year, the Presidents Cup, Woods was fittingly triumphant as both captain and player. And, as he has done more with age, a strong display of emotion spread the joy.

So finally, did something happen that set the tone for all this happiness? Was there a beginning?

Amy Bockerstette, a 20-year-old golfer with Down syndrome, got to play the iconic 16th hole at the Waste Management Phoenix Open and made par with Gary Woodland watching.

To say there wasnt would be to underestimate the impact of Amy Bockerstette, a 20-year-old collegiate golfer and Special Olympics athlete with Down syndrome, who in January played the 16th hole with Gary Woodland at the pro-am of the Waste Management Phoenix Open. Ill admit it, tears fill my eyes each time I watch the 2-minute and 50-second video, which has reached double-digit million views.

Seeing the way Bockerstette, clearly thrilled to meet her playing partners, Woodland and Matt Kuchar, reveled so genuinely as the center of attention on golfs iconic stadium hole, and then stepped up, assertively telling herself, I got this, is irresistible. She hit a good tee shot, followed with a deft bunker shot, and then, again repeating her mantra out loud, drilled the 10-footer for par with Nicklausian poise.

One guess at the phrase Woodland told himself before pulling off the shot of the year a perfectly clipped 60-degree wedge off the 17th green at Pebble Beach that carried and spun to within 4 feet and a crucial par.

Said Woodland of Bockertette: Theres nobody that Ive seen be in the moment as much as she is.

In a particularly feel-good year, it might have been the most extra special moment of all.

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All the feels: From start to finish, a year of emotional stories - Golf Channel

When ESPN reporter Edward Aschoff died, he had been diagnosed with multifocal pneumonia and a rare disease known as HLH, his fiance tweeted.

Aschoff was first admitted to the hospital and diagnosed with pneumonia in many parts of his lungs but was brought back to the emergency room when antibiotic treatment failed and he got worse, Katy Berteau said.

HLH, hemophagocytic lymphohistiocytosis, is a rare disease that affects the immune system.

She did not provide any further details about the manner of Aschoff's death, which occurred on his 34th birthday.

Other people, including Aschoff himself, expressed surprise about the seriousness of the illness in a young man in apparently good health.

"Anyone ever had multifocal (bilateral) pneumonia in their early 30s as some who never gets sick and has a very good immune system? Asking for two friends ... my lungs," he tweeted on December 5.

More questions have come up about his second diagnosis, HLH. It is unclear if Aschoff had HLH or pneumonia first, if one came from the other, and exactly how he died so quickly.

Here is what we know about the diseases Aschoff's had:

Pneumonia is when air sacs in the lungs fill with fluid or pus. It can be caused by a virus, bacteria or a fungus, causing a fever and respiratory problems.

It can occur in one or both lungs, and multifocal means the pneumonia occurs in multiple places.

Thousands of people die around the world each year of pneumonia, but most healthy people can fight it off, especially with antibiotics and antiviral medications. The people most at risk are the young, elderly, frail or immune-compromised.

What is HLH?

HLH is a rare disease that affects the immune system, making certain white blood cells attack other blood cells and enlarging the spleen and liver, according to Johns Hopkins Medicine.

It can be inherited or acquired, Johns Hopkins said. About a quarter of cases are passed down through families, and the rest come from infections, a weakened immune system and cancer.

Is it dangerous?

There is treatment for HLH, and acquired forms may clear when properly treated, Johns Hopkins said. If familial HLH goes untreated, it is usually fatal.

Treatments include chemotherapy, immunotherapy, steroids, antibiotic drugs and antiviral drugs. Stem cell transplants can cure HLH in most cases if drug treatments don't work, Johns Hopkins said.

There is no way to prevent HLH, the medical center said.

The-CNN-Wire& 2019 Cable News Network, Inc., a WarnerMedia Company. All rights reserved.

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ESPN reporter Edward Aschoff diagnosed with pneumonia and HLH before he died - WPVI-TV

Sickle cell disease is a genetic condition in which red blood cells, which should be circular, adopt a crescent shape and are sticky and rigidALAMY

The first patients to receive gene-editing treatments for inherited blood diseases will enter the new year free of agonising symptoms.

The experiments suggest that altering DNA could treat sickle cell disease (SCD) and beta thalassemia, conditions both caused by faulty genes that hamper the bloods ability to carry oxygen.

The companies behind the trials said that a patient in the US with SCD had been well since July. A thalassemia patient in Germany had been free of symptoms for nine months. Previously she had 16 blood transfusions a year.

British patients could be offered similar experimental therapies next year. The treatment for both conditions involved a high-precision gene-editing tool called Crispr-Cas9. It was used to alter the DNA of some of the cells of Victoria

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Sickle cell patient is pain free after geneediting trial altered her DNA - The Times

Kirollos S. Hanna, PharmD, BCPS, BCOP

The National Comprehensive Cancer Network MM panel prefers triplet therapy over doublet as the standard of care for all patients because of improved response rates, depth of response, and rates of progression-free survival (PFS) or overall survival.3 The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and a corticosteroid remains the cornerstone of frontline treatment for patients, regardless of eligibility for autologous stem cell transplant (ASCT). As an example, the bortezomib/lenalidomide/dexamethasone regimen is a preferred category 1 recommendation for transplant-eligible and -ineligible patients.3

Many agents administered as frontline therapy for patients with MM are used in the relapsed/refractory setting. Choice of therapy is influenced by what was used in the frontline setting, patient comorbidities and organ function, response assessment from prior treatment, tolerability of prior therapy, and time to relapse. Despite numerous treatment combinations, the primary goals of therapy for all patients with MM are disease control, improved quality of life, and prolonged survival. MM remains incurable to date. This article reviews select novel treatments that have recently expanded the therapeutic landscape for patients with MM and highlights others in the pipeline.

Daratumumab as Frontline Treatment for MMDaratumumab (Darzalex), an anti-CD38 monoclonal antibody, was initially approved on November 16, 2015, for the treatment of patients with relapsed/refractory MM.4 The FDA recently approved 2 daratumumab combination regimens as frontline treatment for patients with MM.

The MAIA trial (NCT02252172), an open-label, randomized (1:1), active-controlled phase 3 study, compared daratumumab 16 mg/kg, in combination with lenalidomide (Revlimid), and low-dose dexamethasone (DRd) with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed MM who were ineligible for ASCT.5 A total of 737 patients were randomized, 368 to the DRd arm and 369 to the Rd arm. MAIA demonstrated an improvement in PFS in the DRd arm compared with the Rd arm. The median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (HR, 0.56; 95% CI, 0.43-0.73; P <.0001), representing a 44% reduction in the risk of disease progression or death in patients treated with DRd. In responders, the median time to response was 1.05 months (range, 0.2-12.1) in the DRd group and 1.05 months (range, 0.3-15.3) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI, 30.8not estimable [NE]) in the Rd group. In patients with newly diagnosed MM who received DRd, the most frequent (20%) adverse ef fects (AEs) were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea, and cough.

The CASSIOPEIA trial (NCT02541383), an open-label, randomized, active-controlled phase 3 study, compared induction and consolidation treatment withbortezomib, thalidomide, and dexamethasone (DVTd) with treatment with bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed MM who were eligible for ASCT.6 A total of 1085 patients were randomized, 543 to the DVTd arm and 542 to the VTd arm. CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm compared with the VTd arm. At a median follow-up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared with VTd alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). In patients with newly diagnosed MM who received DVTd, the most frequent (20%) AEs were infusion reactions, periph eral sensory neuropathy, constipation, asthenia, nausea, peripheral edema, neutropenia, thrombocytopenia, pyrexia, and paresthesia. AEs that occurred with 5% frequency in the DVTd arm were infusion reactions, nausea, neutropenia, thrombocytopenia, lymphopenia, and cough. No significant differences were observed in the number or type of serious AEs between the 2 treatment arms.

Selinexor for Relapsed/Refractory MMSelinexor (Xpovio) offers a novel mechanism of action as a first-in-class selective inhibitor of nuclear export 1 (XPO1).7 XPO1 inhibition leads to accumulation of tumor suppressor proteins in the nucleus; reductions in several oncoproteins, such as cMyc and cyclin D1; cell cycle arrest; and apoptosis of cancer cells. Selinexor in combination with dexamethasone is indicated for adult patients with relapsed/refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 PIs, at least 2 IMiDs, and an anti-CD38 monoclonal antibody.4

Investigators evaluated the efficacy of selinexor plus dexamethasone in the STORM trial (NCT02336815), a multicenter, singlearm, openlabel study.7,8 In STORM part 2, 122 patients were treated with selinexor 80 mg in combination with dexamethasone 20 mg on days 1 and 3 of every week. The overall response rate (ORR) was 25.3% (95% CI, 16.4-36.0), with 1 stringent complete response, no complete responses, 4 very good partial responses, and 16 partial responses. The median time to first response was 4 weeks (range, 1-10).

The median duration of response was 3.8 months (95% CI, 2.3-NE). Common AEs reported in at least 20% of patients included thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

It is important to note the first dose reduction is administered as 100 mg once weekly, followed by 80 mg and 60 mg once weekly for subsequent reductions.7 Patients should receive antiemetic therapy prior to doses of selinexor.

Ongoing Clinical TrialsInvestigators continue to evaluate novel drug mechanisms and therapeutic combinations, aiming to optimize treatment outcomes and safety for patients throughout all stages of disease. B-cell maturation antigen (BCMA) targeting has demonstrated efficacy in treating MM.9 Anti-BCMA chimeric antigen receptor T-cell therapies, such as idecabtagene vicleucel, received FDA breakthrough therapy designation for treating relapsed/refractory MM based on data from the phase 1 CRB-401 trial. Antibody-drug conjugates such as belantamab mafodotin have demonstrated an ORR of 60% with a median duration of response >1 year, based on findings from the phase I DREAMM-1 trial.10

The treatment landscape of MM is extremely bright, with novel agents and combinations in various clinical trial phases. Importantly, clinicians should remain up-to-date on novel therapies to provide optimal and safe therapeutic options for patients in all phases of treatment.

REFERENCES

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Updates in the Management of Multiple Myeloma - Pharmacy Times

NEW DELHI: An image of the black hole, the stuff of science fiction down the decades, was at the centre of a year that saw science breaching new frontiers with exciting firsts such as the development of a quantum computer that can outperform its classical counterparts and artificial embryos.

Cutting edge innovations in research and technology celebrated science and forwarded humankind's understanding of complex realities of the universe. The year will also be remembered as the year of testing biological and ethical limits in the laboratory, helping researchers find new avenues in the treatment of critical diseases.

In April, the International Event Horizon Telescope collaboration, consisting of a global network of radio telescopes, unveiled the first actual image of a black hole, a place in space where gravity pulls so much that even light cannot escape.

To produce the image, the researchers combined data from a network of radio telescopes to take simultaneous readings from around the world.

Science magazine named the image of the supermassive black hole situated at the centre of the Messier 87 galaxy, 54 million light years away, as the 2019 Breakthrough of the Year.

The imaging of the black hole is a fantastic revelation that is simultaneously a validation and a celebration of science, Ayan Banerjee, from the Indian Institute of Science Education and Research (IISER) in Kolkata, told PTI.

Although it does not uncover something that we did not know earlier, it does convert science fiction into science -- which is crucial for the acceptance of science in the daily lives of human beings, and the generation of future scientists, Banerjee said.

In a year that marked the 50th anniversary of the Apollo Moon landings, lunar exploration was high on the agendas of space agencies.

In January, China's Chang'e-4 probe became the first spacecraft to land safely on the far side of the Moon. Its rover Yutu-2 continues to roll across the dusty soils of Von Karman crater on the lunar body.

Other attempts to explore the Earth's natural satellite were not so successful.

To produce the image, the researchers combined data from a network of radio telescopes to take simultaneous readings from around the world. In April, an Israeli-led effort to put the first private spacecraft on the Moon's surface ended in a crash landing. The same fate was met by India's ambitious Chandrayaan-2 Vikram lander in September.

The ongoing Mars missions returned a host of results. In April, NASA announced that its robotic Mars InSight lander had recorded a marsquake for the first time ever.

The marsquake' is the first recorded trembling that appears to have come from inside the planet, as opposed to being caused by the forces above the surface, such as wind.

There were many firsts in the micro world of laboratories too.

US researchers restored cellular function in 32 pig brains that had been dead for hours, opening up a new avenue in treating brain disease -- and shaking our definition of brain death to its core.

Announced in April in the journal Nature, the researchers at the Yale University School of Medicine devised a system roughly analogous to a dialysis machine, called BrainEx, that restores circulation and oxygen flow to a dead brain.

In another out-of-body experiment, scientists grew monkey embryos in a dish for nearly three weeks -- longer than primate embryos have ever been grown in the laboratory before.

The advance raised ethical concerns of whether lab-grown human embryos should be allowed to develop beyond 14 days, a restriction imposed in most countries.

In September, researchers at the University of Michigan in the US provided a possible circumvention of the 14-day limit by using human stem cells to make artificial embryos' that mimic the early development of a real human embryo.

Our stem cell structures that mimic embryos can help fill critical gaps in knowledge about early human development, and that could lead to a lot of good, Jianping Fu, an associate professor at Michigan, who led the study, said in a statement.

In October, Google took a quantum leap in computer science. Using its state-of-the-art quantum computer, called Sycamore, the tech giant claimed "quantum supremacy" over the most powerful supercomputers in the world by solving a problem considered virtually impossible for normal machines.

The quantum computer completed the complex computation in 200 seconds. That same calculation would take even the most powerful supercomputer approximately 10,000 years to finish, according to researchers from the University of California, Santa Barbara, who published their results in the journal Nature.

A fantastic discovery has been that of Google's 53 qubit quantum computer ('quantum supremacy), Banerjee said.

And for the first time in July, an artificial intelligence (AI) bot beat human champions at multiplayer poker.

The AI programme developed by Carnegie Mellon University in the US in collaboration with Facebook AI defeated leading professionals in six-player no-limit Texas hold'em poker, the world's most popular form of poker.

The AI, called Pluribus, defeated poker professional Darren Elias, who holds the record for most World Poker Tour titles, and Chris Ferguson, winner of six World Series of Poker events.

In August, researchers from Oxford University and IBM Research made the first-ever ring-shaped molecule of pure carbon in the lab by using an atomic-force microscope to manipulate individual molecules.

Carbon can be arranged in a number of configurations. For example when each of its atoms is bonded to three other carbon atoms, it's relatively soft graphite.

A ring of carbon atoms, where each atom is bonded to just two others, and nothing else has eluded scientists for 50 years. Their best attempts have resulted in a gaseous carbon ring that quickly dissipated.

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From the image of a black hole to 'artificial embryos', 2019 was the year of many firsts in science - Economic Times

1. A decrease in circulating progenitor cells during exercise stress-testing in patients with stable coronary artery disease is associated with worse outcomes than the presence of myocardial ischemia.

Evidence Rating Level:2 (Good)

Risk stratification for stable coronary artery disease (CAD) typically involves the measurement of stress-induced myocardial ischemia, often using single-photon emission computed tomography (SPECT) myocardial perfusion imaging. However, given the cost and radiation exposure associated with this technique, efforts are being focused towards the identification of surrogate biomarkers. Recent evidence suggests that levels of circulating progenitor cells (CPCs) and resident stem cells may be decreased in patients with myocardial ischemia, however, the impact on adverse cardiovascular events is unknown. In this prospective cohort study, 454 patients with stable CAD were studied to investigate the association between the change in CPC counts during stress testing and the risk of adverse cardiovascular events, specifically, cardiovascular death and myocardial infarction (MI). CPCs were enumerated with flow cytometry as CD34+mononuclear cells, with additional evaluation of subsets co-expressing the chemokine receptor 4 (CXCR4+), at rest and 45 minutes after stress testing. Stress-induced myocardial ischemia was measured with SPECT myocardial perfusion imaging at rest and 30 to 60 minutes after stress testing. At baseline, 76% of patients were men, and 31.3% had stress-induced ischemia by SPECT. Researchers found that those with stress-induced ischemia had a decrease in circulating CD34+/CXCR4+cells (median decrease 20.2%, IQR -45.3 to 5.5, p<0.001), whereas those without stress-induced ischemia experienced a cell count increase (median increase 3.2%, IQR -20.6 to 35.1, p<0.001). After adjusting for demographic variables and comorbidities, every unit increase in the ischemic defect was found to be associated with a 13% decrease in CD34+cell counts after exercise stress. During a median follow-up of 3 years, 5.2% of patients experienced adverse events (12 cardiovascular deaths, 12 MIs). Stress-induced ischemia was significantly associated with adverse events after adjustment for covariates (HR 2.79, 95% CI 1.55 to 5.03). Furthermore, each 50% decrease in the CD34+/CXCR4+count after stress testing, was found to be significantly associated with adverse outcomes, even after adjusting for presence of ischemia (HR 1.84, 95% CI 1.34 to 3; HR 2.59, 95% CI 1.15 to 5.32, respectively). In summary, this study suggests that a decreased CPC count during and after exercise is an even stronger predictor of adverse outcomes in patients with stable CAD than stress-induced myocardial ischemia. Thus, further research on the prognostic implications of increasing CPC mobilization are warranted.

Click to read the study in JAMA Cardiology

Image: PD

20192 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from2 Minute Medicine, Inc. Inquire about licensinghere. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

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DetailsCategory: Small MoleculesPublished on Monday, 23 December 2019 16:05Hits: 504

NEW YORK, NY, USA and LONDON, UK I December 23, 2019 I Akari Therapeutics, Plc (Nasdaq:AKTX), a biopharmaceutical company focused on innovative therapeutics to treat orphan autoimmune and inflammatory diseases where the complement and/or leukotriene systems are implicated, announces that a U.S. Food and Drug Administration (FDA) investigational new drug application (IND) is open for its multicenter Phase III study for the treatment of pediatric HSCT-TMA with nomacopan, allowing clinical sites to open in the first quarter of 2020.

With the pediatric HSCT-TMA IND now open we look forward to starting the pivotal Phase III study of nomacopan in HSCT-TMA, a potential treatment for a high risk pediatric population that suffer very high death rates and for which there are currently no approved therapies. If successful, we expect HSCT-TMA to be a gateway into a range of other poorly treated orphan TMAs, commented Clive Richardson, CEO of Akari Therapeutics. In addition, following the recent successful completion of our Phase II bullous pemphigoid study, we expect data from our Phase I/II atopic keratoconjunctivitis trial in early 2020 and interim data from our Phase III paroxysmal nocturnal hemoglobinuria trial in the first half of 2020.

HSCT-TMA is an orphan hematological condition that occurs in up to 30% of patients who have received a hematopoietic stem cell transplant (HSCT). There are no approved treatments for pediatric HSCT-TMA, and it has an estimated mortality rate of more than 80% in children with the severe form of the disease1. It is this severe form that is being targeted with nomacopan which is a bifunctional inhibitor of complement C5 and leukotriene B4 (LTB4). Following the recent end-of-Phase II meeting with the FDA, Akari has now opened an IND to initiate its pivotal pediatric HSCT-TMA study based on a single arm responder-based design. Recruitment will be focused on specialist pediatric sites in the U.S. and Europe where treatment tends to be concentrated in specialist centres.

Whilst the role of complement inhibition is understood to play an important role in pediatric HSCT-TMA, the Company believes LTB4 may also be an important target in reducing epithelial activation in both TMA and graft versus-host disease2 (GVHD) which often occur simultaneously. The Company believes daily dosing with nomacopan may also be of particular advantage in facilitating more complete complement suppression, especially in HSCT-TMA patients with high transfusion requirements.

As previously announced, this two-part pivotal Phase III study of nomacopan in pediatric patients with HSCT-TMA is based on guidance from the Companys end-of-Phase II meeting with the FDA. Part A of the trial is a dose confirmation study. Part B of the trial is a single arm responder-based efficacy study that will follow an interim analysis of Part A and a meeting with the FDA. Akari has both FDA fast track and orphan status for this program.

1 Sonata Jodele, et al. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation associated thrombotic microangiopathy. Transfus Apher Sci . 2016 April; 54(2): 181190

2 Takatsuka, et al. Predicting the severity of intestinal graft-versus-host disease from leukotriene B4 levels after bone marrow transplantation. Transplantation 2000, 26: 1313-1316

About Akari Therapeutics

Akari is a biopharmaceutical company focused on developing inhibitors of acute and chronic inflammation, specifically for the treatment of rare and orphan diseases, in particular those where the complement (C5) or leukotriene (LTB4) systems, or both complement and leukotrienes together, play a primary role in disease progression. Akari's lead drug candidate, nomacopan (formerly known as Coversin), is a C5 complement inhibitor that also independently and specifically inhibits leukotriene B4 (LTB4). Nomacopan is currently being clinically evaluated in four indications: bullous pemphigoid (BP), atopic keratoconjunctivitis (AKC), thrombotic microangiopathy (TMA), and paroxysmal nocturnal hemoglobinuria (PNH). Akari believes that the dual action of nomacopan on both C5 and LTB4 may be beneficial in AKC and BP. Akari is also developing other tick derived proteins, including longer acting versions.

SOURCE: Akari Therapeutics

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Akari Therapeutics Announces Initiation of Pivotal Phase III Trial of Nomacopan in Pediatric Hematopoietic Stem Cell Transplant-Related Thrombotic...

Of all blood cancers, leukaemia and lymphoma are among the most curable.

However, many people, including doctors, still believe the disease leads to immediate death.

This is no longer true today as they are not fatal.

With optimal treatment, the majority of patients go into remission and are considered cured.

These two cancers have been more extensively studied than other forms of cancer, due to the ease in obtaining samples from blood, bone marrow or lymph nodes, spurring the advent of novel targeted therapies for a cure, says consultant haematologist Dr Ng Soo Chin.

Most blood cancers start in the bone marrow, where blood is produced.

Bone marrow contains stem cells, which mature and develop into red blood cells, white blood cells or platelets.

In most blood cancers, normal cell development is interrupted by the uncontrolled growth of an abnormal type of a particular blood cell.

These abnormal blood cells, which are cancerous, prevent your blood from performing many of its functions, like fighting off infections or preventing serious bleeding.

Leukaemia or white blood is classified into acute and chronic disease, which is then divided further into subtypes: acute lymphocytic leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML).

The presentation between acute and chronic leukaemia differs.

The acute person will tell you he was well a week ago and is now down with symptoms such as lethargy, anaemia and recurrent infection.

Suddenly, he may look pale, so we check his blood count for any abnormalities. A bone marrow exam will further confirm whether it is acute.

With chronic leukaemia, the patient can be unwell for a couple of months.

We are increasingly picking up cases early because of blood test availability.

The survival rate has improved tremendously for acute leukaemia, with more than 50% fully cured because bone marrow transplants are easily available in the country.

For CLL and CML, 95% of patients are alive at the 10-year mark, says Dr Ng.

Generally, chronic leukaemia patients belong to the older age group (50 years and above), but acute leukaemia can occur in all ages.

Leukaemia symptoms are often vague and not specific, so its easy to overlook them as they may resemble symptoms of the flu and other common illnesses.

In fact, chronic leukaemia may initially produce no symptoms and can go unnoticed or undiagnosed for years.

Lymphomas, a type of blood cancer that begins in a subset of white blood cells called lymphocytes, can be classified into Hodgkins and non-Hodgkins.

The main difference between Hodgkins and non-Hodgkins lymphoma is the specific lymphocyte each involves.

Lymphocytes are an integral part of your immune system, which protects you from germs.

Five-year survival rates are high with Hodgkins lymphoma at 86% and non-Hodgkins lymphoma at 70%.

You can beat the disease even if it is detected at a late stage.

Multiple myeloma, which is the third kind of blood cancer, forms in a type of white blood cell called a plasma cell.

Patients often complain of bone pain, and unfortunately, this type of cancer has no cure.

Blood cancers typically involve abnormal white blood cells and can affect paople of all ages, depending on the type of cancer. 123rf.com

Fear of treatment

Chemotherapy is a much dreaded word among cancer patients.

But with advances in medicine, newer chemotherapy-free treatments are now available.

Dr Ng says, Traditionally, cancer is treated via surgery or radiation the layman says we fry and poison them, which is not far from the truth!

Radiation means burning the cancerous area, but a lot of times, the cancer can also be present elsewhere, so there is limitation to this treatment.

With chemotherapy, we use cytotoxic (cell-killing) drugs they go in and knock off both cancer and normal cells.

The short-term effects include vomiting, hair loss, appetite loss and weight loss.

But as doctors, we are looking at a different perspective. We are more worried about white cells dropping (neutropenia) because the patient can pick up an infection that can potentially kill him.

Neutropenia is a condition that results when the body does not have enough neutrophils, a type of white blood cell that is an essential first line of defence against infections.

Thats one risk of chemotherapy, although we can now improve neutropenia by giving a growth factor injection.

But for certain cancers, we need to step up the drugs.

He adds: We are scared of neutropenia, but patients are more concerned about bodily changes.

The older ones get upset over losing hair because they cannot take it when others ask them what has happened to their hair.

Young people are not as concerned with hair loss because it can be trendy.

We understand that chemotherapy is less than pleasant and strong doses can impair fertility in young patients, especially women.

Despite current technology, only one-third of patients are successful in freezing their eggs.

What he is concerned about is that chemotherapy can actually increase the patients risk of getting another cancer, especially blood cancer.

It can happen the day after! says Dr Ng.

Most experts believe chemotherapy damages stem cells, so if youre unlucky, you might get acute myeloid leukaemia after undergoing chemotherapy for breast cancer.

Its just like crossing the road there is always a risk of being knocked down.

All our cells have a biological clock and there is an orderly exchange of old and new cells.

But with blood cancers such as leukaemia, there is a clone of abnormal cells.

Cancer cells have an advantage over normal cells because they can survive longer.

Chemotherapy is still needed to treat most acute blood cancers, although if the mutation is known, targeted therapies can be applied.

For chronic blood cancers, there is no need for chemotherapy. Oral drugs are enough to combat the disease.

Eventually, many patients are able to wean off the drugs.

As we may be aware, immunotherapy is the buzzword in cancer treatment today.

Also called biologic therapy, it is a type of cancer treatment that boosts the bodys natural defences to fight cancer.

It uses substances made by the body or in a laboratory to improve or restore immune system function.

One of the latest treatment modalities is the CAR T-cell therapy, a form of immunotherapy that uses specially altered T cells a part of the immune system to fight cancer.

A sample of a patients T cells are collected from the blood, then modified to produce special structures called chimeric antigen receptors (CARs) on their surface.

When these CAR T-cells are reinfused into the patient, the new receptors enable them to latch onto a specific antigen on the patients tumour cells and kill the cells.

At the moment, this intravenous therapy is available in the United States and hasnt reached our shores yet. It has to be properly regulated first, says Dr Ng.

A volunteer is having his head shaved to donate hair to make wigs for cancer patients in this filepic. Hair loss is one of the side effects of chemotherapy that affect patients the most.

Following natural remedies

The consultant haematologist errs on the side of caution when patients ask about natural cancer remedies, or the dos and donts during treatment.

We always believe there should be a scientific approach to the problem.

If patients are doing okay while undergoing treatment and there is no weight loss, I tell them to go ahead and do what they always do.

However, just be particular about food hygiene, as there is a chance you may get food poisoning.

If youre undergoing chemotherapy, then youll land yourself in hospital, and if your luck is bad, you may even land up in the ICU (intensive care unit).

So make sure the food is cooked and not left overnight to reduce your chances of infection.

Eat a balanced diet, he advises.

When it comes to exercise, he says to work out within your limit.

Instead of pushing the body and running marathons or climbing mountains, go for walks.

Dr Ng says, Life should go on, but be sensible.

Dont go to crowded places because you may pick up an infection, but dont be withdrawn either. All humans need social interaction.

With the billion-dollar dietary supplements industry, companies are constantly trying to lure customers into buying their products.

A lot of supplements are just glorified vitamins in different packaging.

The more expensive they are, the more people will buy them, thinking they are good.

There are people with good intentions, but unfortunately, there are also a lot of scammers out there that is life.

For the amount you spend on supplements, why not keep the money aside and go for a trip once your treatment is over? he suggests.

Often, the late diagnosis is due to preference for alternative treatment.

These alternative treatments are like fashion shows, after some time, they go out of trend.

For me, youre wasting valuable time because cancer is not your friend.

Yes, chemotherapy is tough, but with the latest chemo-free regimen, patients are more willing to come forward.

The earlier it is treated, the higher your chances of recovering, he says.

To share his 30-odd years of knowledge and experience in the field, Dr Ng has written his third book titled Understanding Blood Disorders.

Intended for patients, caregivers and healthcare professionals, proceeds from the sales of the 270-page book will go to the newly set-up Faith Hope Love Hospice Care Malaysia in Petaling Jaya, Selangor.

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Leukaemia and lymphoma have a good survival rate - The Star Online

Two piglets recently born in China look like average swine on the outside, but on the inside, they are (a very small) part monkey.

A team of researchers generated the pig-primate creatures by injecting monkey stem cells into fertilized pig embryos and then implanting them into surrogate sows, according to a piece by New Scientist. Two of the resulting piglets developed into interspecies animals known as chimeras, meaning that they contained DNA from two distinct individuals in this case, a pig and a monkey.

"This is the first report of full-term pig-monkey chimeras," co-author Tang Hai, a researcher at the State Key Laboratory of Stem Cell and Reproductive Biology in Beijing, told New Scientist. Eventually, Hai and his colleagues aim to grow human organs in animals for use in transplant procedures. For now, the team plans to stick with monkey cells, as developing human-animal chimeras presents a slew of "ethical issues," the authors noted in a report published Nov. 28 in the journal Protein & Cell.

To create pig-primate chimeras, Hai and his co-authors first grew cells from cynomolgus monkeys (Macaca fascicularis) in lab dishes. The team then altered the cells' DNA by inserting instructions to build a fluorescent protein, which caused the cells to glow a bright green. These luminescent cells gave rise to equally radiant embryonic stem cells, which the researchers then injected into prepared pig embryos. These glowing spots allowed the researchers to track the monkey cells as the embryos grew into piglets.

Related: The 9 Most Interesting Transplants

In total, 4,000 embryos received an injection of monkey cells and were implanted in surrogate sows. The pigs bore 10 piglets as a result of the procedure, but only two of the offspring grew both pig and monkey cells. By scanning for spots of fluorescent green, the team found monkey cells scattered throughout multiple organs, including the heart, liver, spleen, lungs and skin.

In each organ, between one in 1,000 and one in 10,000 cells turned out to be a monkey cells in other words, the interspecies chimeras were more than 99% pig.

Although low, the ratio of monkey to pig cells still outnumbered the maximum amount of human cells ever grown in a human-animal chimera. In 2017, scientists created human-pig chimeras that grew only one human cell for every 100,000 pig cells. The interspecies embryos were only allowed to develop for a month for ethical reasons, including the concern that humans cells might grow in the chimera's brain and grant the animal human-like consciousness, according to New Scientist.

Despite these ethical qualms, the same team of researchers went on to create human-monkey chimeras earlier this year, according to a July report from the Spanish newspaper El Pas. The results of the controversial experiment have not yet been reported, but the scientists said that no human-primate embryos were allowed to develop for more than a few weeks, the paper reported.

Hai and his co-authors may have avoided the ethical issues involved with human-animal chimeras, but one expert wasn't impressed with their interspecies piglets. Stem-cell biologist Paul Knoepfler of the University of California, Davis, told New Scientist that the low ratio of monkey to pig cells seems "fairly discouraging." Additionally, the two chimeras and all eight other piglets died shortly after being born, he noted.

The exact reason for the piglets' death remains "unclear," Hai told New Scientist, but he said that he suspects the deaths are linked to the in vitro fertilization (IVF) procedure rather than the injection of monkey DNA. Other scientists have also found that IVF doesn't consistently work in pigs, according to a 2019 report in the journal Theriogenology.

In the immediate future, Hai and his colleagues aim to increase the proportion of monkey cells to pig cells in future chimeras, and eventually, grow entire monkey organs in their pigs, Hai told New Scientist. In their paper, the authors noted that their work in pigs could help "pave the way" toward the "ultimate goal of human organ reconstruction in a large animal."

Originally published on Live Science.

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First Pig-Monkey Chimeras Were Just Created in China - Livescience.com

This article highlights some of the most recent drug target discoveries that could be used to develop and design a treatment for pancreatic cancer.

Scientists investigating pancreatic cancer have identified new targets which, with further research, could be the basis for developing future therapies. Listed below are five of the most recent target discoveries, in order of their journal publication dates, with the newest first.

Scientists at the Queen Mary University of London, UK and Zhengzhou University, China have developed a personalised vaccine system that may be able to delay the onset of pancreatic cancer.

Cells taken from mice, mutated chemically into pancreatic cancer cells and then infected with Adenovirus (AdV) as a prime or Vaccinia virus (VV) as a boost, create a vaccine product. The virus kills the cancerous cells in such a way that their antigens are released and are therefore able to prime the immune system to prevent pancreatic cancer returning.

Injection of the virus-infected cells into mice destined to develop pancreatic cancer doubled their survival rate, compared to their unvaccinated counterparts. The vaccine also delayed the onset of the condition in these mice.

Using cells from the recipient of the vaccine enables the immune system to respond to the exact antigens seen in tumour cells of the individual, resulting in a vaccine regime tailored to them.

Through this international collaboration, we have made progress towards the development of a prophylactic cancer vaccine against pancreatic cancer, said Professor Yaohe Wang, leader of the study, from Queen Mary University of London and the Sino-British Research Centre at Zhengzhou University in China.

Researchers at Sanford Burnham Prebys Medical Discovery Institute in the US have identified that a combination of two anti-cancer compounds, already approved for use to treat other cancers, shrank pancreatic tumours in mice.

Our study identifies a potential treatment combination that can immediately be tested against these aggressive tumours. We are already meeting with oncologists at Oregon Health & Science University, US to discuss how to advance this discovery into clinical evaluation, explained Dr Zeev Ronai, a professor in Sanford Burnham Prebys Tumor Initiation and Maintenance Program, also senior author of the study.

Scientists used L-asparaginase to starve pancreatic tumours of asparagine, an amino acid required by cells for protein synthesis. However, the tumour cells did not die, instead switching on a stress response pathway whereby they could produce asparagine themselves. Scientists then used an MEK inhibitor to block the stress response pathway, causing the pancreatic tumour to shrink.

L-asparaginase is already US Food and Drug Administration (FDA) approved to treat leukaemias and similarly the MEK inhibitor is approved for the treatment of solid tumours, including melanoma skin cancer.

This research lays the basis for the inhibition of pancreatic tumour growth by a combined synergistic attack based on asparagine restriction and MAPK signalling inhibition, says Dr Eytan Ruppin, chief of the Cancer Data Science Library at the National Cancer Institute (NCI) and co-author of the study.

Scientists from the Max Planck Institute for Biology of Ageing, Germany have identified that YME1L, a protease in the membrane of mitochondria, is activated when a cell uses glycolysis to produce energy anaerobically.

scientists were able to reduce tumour growth by switching off the glycolysis signalling pathway in the mitochondria

Cells adapt to oxygen deficiency by switching their energy supply to glycolysis, which ferments sugar without oxygen. This switch is often necessary in old age, as the cells in the body become poorly supplied with oxygen and nutrients.

Cancer cells can also face this problem; prior to angiogenesis, tumours are poorly perfused and so the tissue is deprived of oxygen. Oxidative stress in tumours drives the switch-on of multiple pathways. This includes the glycolysis pathway that alters the behaviour of the mitochondria to provide tumour cells with energy despite being starved of oxygen.

Scientists found that the YME1L protease is activated during the conversion to glycolysis. YME1L appears altered and breaks down various proteins in the organelles, preventing the formation of new mitochondria and causing the remaining organelles to change their metabolism. This process eventually stops as YME1L begins to degrade itself at high activity.

Researchers examined cancer cells originating from patients with pancreatic tumours and were able to reduce tumour growth by switching off the glycolysis signalling pathway in the mitochondria, with reproducible results both in the petri dish and in pancreatic tumours in mice.

There is currently no treatment available for pancreatic cancer. I believe that this protease can be a very interesting therapeutic target because we have seen that the signalling pathway is also active in human patients with pancreatic cancer, explained Thomas Langer, the Max Planck Director, continuing: However, there are no known substances that have an effect on this protease.

Researchers at the Crick Institute have identified cancer stem cells as a driver of pancreatic cancer growth. These cells can metastasise and differentiate into different tumour types to continue the spread of cancer.

Cancer stem cells appear at all stages of cancer growth so being able to identify where they are present could be vital in both targeting cancer and developing new treatments, according to the researchers. Analysis of gene expression in the cancer stem cells identified a protein, CD9, is present on tumour surfaces during development and when it is more established. This protein could therefore be used as a marker to help locate these cells.

A further development of the study established that this protein is not just a marker of cancer stem cells, but also promotes their malignant behaviour. By altering the amount of CD9 in tumour cells in mice, researchers found that reduced levels of this protein caused smaller tumours to form and increasing levels of CD9 created more aggressive cells able to form large tumours quickly.

These cells are vital to pancreatic cancer and if even just a few of them survive chemotherapy, the cancer is able to bounce back. We need to find effective ways to remove these cells and so stop them from fuelling cancer growth. However, we need more experiments to validate the importance of CD9 in human pancreatic cancer, says Victoria Wang, lead author and member of the Adult Stem Cell Laboratory at the Crick Institute.

A look into cancer stem cell metabolism also revealed CD9 increases the rate tumour cells take up glutamine, an amino acid which helps provide energy for cancer growth.

Now we know this protein is both linked to cancer stem cells and helps cancer growth, this could guide the development of new treatments that are targeted at the protein and so cut off the supply of glutamine to cancer stem cells, effectively starving the cancer, says Axel Behrens, corresponding author and group leader in the Adult Stem Cell Laboratory at the Crick Institute.

Scientists at Tel Aviv University, Israel have found that PJ34, a small molecule, causes human pancreatic cancer cells to self-destruct. The researchers tested PJ34 on xenografts (transplants) of human pancreatic tumours in mice.

this mechanism also exists in other types of cancer and therefore the treatment could be valuable for use on those resistant to current therapies

The mice were treated with a molecule called PJ34, which is permeable in the cell membrane but affects human cancer cells exclusively. This molecule causes an anomaly during the duplication of human cancer cells, provoking their rapid cell death. Thus, cell multiplication itself resulted in cell death in the treated cancer cells, explains Professor Malca Cohen-Armon, project lead at Tel Aviv Universitys Sackler Faculty of Medicine.

The treatment consisted of daily PJ34 injections for 14 days and four weeks later there was a relative drop of 90 percent in the number of cancer cells within the tumours of the mice. Cohen-Armon also noted there were no adverse side-effects observed in the mice.

This mechanism similarly exists in other types of cancer and therefore the treatment could be valuable for use on those resistant to current therapies. The molecule PJ34 is being tested in pre-clinical trials according to FDA regulations before clinical trials begin.

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Five recent drug target discoveries for pancreatic cancer - Drug Target Review

NEW YORK--(BUSINESS WIRE)--CurePSP, the foundation for prime of life neurodegeneration, has issued four Venture Grants totaling $300,000 for research in progressive supranuclear palsy (PSP) and the related disease, corticobasal degeneration (CBD). The studies will investigate the mechanisms of toxic tau protein aggregation in the brain.

Tau is a normal brain protein that, when folded on itself in an abnormal way, forms clumps called neurofibrillary tangles that are toxic to some types of brain cells. In the cases of PSP and CBD, the brain cells involved are important in the control of movement, behavior, and thinking. Unlike many other disorders of tau aggregation, PSP and CBD are pure tauopathies, which means that no other proteins are clumping along with tau. This makes these disorders good subjects for studying the pathology involved in many other and often more common neurodegenerative conditions, including Alzheimers disease, which afflicts some six million people in the U.S. alone.

Lawrence I Golbe, MD, CurePSP Director of Scientific Affairs, said, We are pleased to be able to fund these talented investigators whose studies will advance our understanding of the key role that tau protein aggregation plays in neurodegeneration.

The grants will fund the following studies:

Lukasz Joachimiak, The University of Texas Southwestern Medical Center, Dallas

The Mary Jane Semcer Legacy Study

Structural basis for tau strain conformation in CBD and PSP

In the brain, the tau protein can form an altered shape that clumps together in an aggregated form. This study will isolate the tau protein from healthy PSP and CBD patient brain tissues. Specialized research tools will be applied to determine how the abnormally folded shape of tau differs from the tau from healthy brains. Understanding the fine details of how the tau protein changes from a normal shape to the different bad forms found in disease will provide the blueprint for designing new methods to detect and prevent these devastating diseases in patients.

David Butler, Neural Stem Cell Institute, Rensselaer, NY

Bifunctional intrabodies to lower tau

The goal of this project is to develop therapeutic agents that will prevent tau accumulation and associated death of brain cells with novel antibody-based reagents (termed intrabodies). Intrabodies are antibodies expressed within brain cells, while antibodies produced by the immune system or administered by vein do not penetrate brain cells. These antibodies are highly selective for tau, and they have been engineered to target tau for degradation using the cells normal clearing process. The studys central hypothesis is that targeted degradation of tau protein will reduce the amount of tau available to misfold and thus reduce cell death.

J. Mark Cooper, University Hospital, London

The influence of TRIM11 on tau, aggregation, release, and propagation

This study will investigate the effects of a protein known as TRIM11 on toxic tau protein aggregation in the brain. TRIM11 is believed to play a role in regulating the levels of some proteins within the cell, in particular proteins that may form aggregates. To identify how changes to TRIM11 may influence PSP, the study will use models of brain cells grown in the laboratory to focus on how changes to TRIM11 influence tau protein regulation, in particular, its tendency to aggregate. These findings may help to identify potential therapeutic targets to modify PSP disease progression.

K. Matthew Scaglione, Duke University, Durham, NC

Small-molecule regulation of a protein quality-control E3 to treat PSP

The protein Hsc70, or CHIP, accelerates the removal of tau from the brain. This project intends to identify compounds that stimulate CHIP functions. One important such function is as an E3 enzyme, which is an important part of one of the brain cells garbage disposal mechanisms called the ubiquitin-proteasome system (UPS). E3 allows the UPS to recognize specific proteins for appropriate disposal. Finding new compounds to stimulate this function is an important first step toward developing small (that is, orally dosable) molecules to slow or prevent the progression of PSP and CBD.

CurePSPs Venture Grants program provides seed funding for early-career investigators who want to test their innovative ideas. Grant applications are reviewed by CurePSPs eminent international Scientific Advisory Board (SAB) chaired by Dr. Golbe. CurePSPs Venture Grants program is one of the few sources of funding for early stage research into PSP and CBD.

About CurePSP

CurePSP is the nonprofit organization for prime of life neurodegenerative diseases, a spectrum of fatal brain disorders that often strike during a person's most productive and rewarding years. Since it was founded in 1990, CurePSP has funded more than 180 research studies and is a leading source of support and advocacy for patients, families, and other caregivers and education and information for doctors and allied healthcare professionals. CurePSP is based in New York City. Please visit http://www.curepsp.org for more information.

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CurePSP Funds Four Venture Grants for the Study of Neurodegenerative Diseases - Business Wire

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced that KEYTRUDA, Mercks anti-PD-1 therapy, showed improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) as monotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 (tumor proportion score [TPS] 1%), regardless of KRAS mutational status. These findings, which are based on an exploratory analysis of the pivotal Phase 3 KEYNOTE-042 trial, were presented today in a proffered paper presentation (Abstract #LBA4) at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2019 in Geneva, Switzerland.

KRAS mutations occur in approximately 20% of people with non-small cell lung cancer, and some previous studies have suggested that these mutations are associated with a poorer response to treatment, said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. It was therefore encouraging to see in this exploratory analysis that KEYTRUDA monotherapy was associated with a survival benefit in certain patients with metastatic nonsquamous non-small cell lung cancer, regardless of KRAS mutational status.

The objective of the exploratory analysis was to assess the prevalence of KRAS mutations and their association with efficacy in the KEYNOTE-042 trial. Of the 1,274 untreated patients with metastatic nonsquamous NSCLC whose tumors expressed PD-L1 (TPS 1%) enrolled in KEYNOTE-042, 301 patients had KRAS evaluable data (n=232 without any KRAS mutation; n=69 with any KRAS mutation, including n=29 with the KRAS G12C mutation). Tissue tumor mutational burden (tTMB) and KRAS mutational status were determined by whole-exome sequencing (WES) of tumor tissue and matched normal DNA (blood). Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks (Q3W) (n=637) or investigators choice of chemotherapy (pemetrexed or paclitaxel) (n=637). Treatment continued until progression of disease or unacceptable toxicity. The primary endpoint was OS with a TPS of 50%, 20% and 1%, which were assessed sequentially. The secondary endpoints were PFS and ORR.

Findings from this exploratory analysis showed that KEYTRUDA monotherapy was associated with improved clinical outcomes, regardless of KRAS mutational status, in patients with metastatic nonsquamous NSCLC versus chemotherapy. In this analysis, KEYTRUDA reduced the risk of death by 58% (HR=0.42 [95% CI, 0.22-0.81]) in patients with any KRAS mutation and by 72% (HR=0.28 [95% CI, 0.09-0.86]) in patients with the KRAS G12C mutation compared to chemotherapy. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with metastatic NSCLC.

Additional efficacy results from this exploratory analysis showed:

With Any KRASMutation

With KRAS G12CMutation

Without Any KRAS Mutation

KEYTRUDA Mono-therapy

(N = 30)

Chemo-therapy

(N = 39)

KEYTRUDA Mono-therapy(N = 12)

Chemo-therapy(N = 17)

KEYTRUDA Mono-therapy

(N = 127)

Chemo-therapy(N = 105)

OS, median, mo(95% CI)

28 (23-NR)

11 (7-25)

NR (23-NR)

8 (5-NR)

15 (12-24)

12 (11-18)

OS, HR(95% CI)

0.42 (0.22-0.81)

0.28 (0.09-0.86)

0.86 (0.63-1.18)

ORR, %(95% CI)

56.7

18.0

66.7

23.5

29.1

21.0

PFS, median, mo(95% CI)

12 (8-NR)

6 (4-9)

15 (10-NR)

6 (4-8)

6 (4-7)

6 (6-8)

PFS, HR(95% CI)

0.51 (0.29-0.87)

0.27 (0.10-0.71)

1.00 (0.75-1.34)

Data from an exploratory analysis of KEYNOTE-189 (Abstract #LBA5), which evaluated KRAS mutations and their association with efficacy outcomes for KEYTRUDA in combination with pemetrexed and platinum chemotherapy, were also presented in a mini-oral session today at the ESMO Immuno-Oncology Congress 2019. KEYNOTE-189 was conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. Lung cancer can also be characterized by the presence of different biomarkers, including PD-L1, KRAS, ALK, EGFR and ROS1. KRAS mutations occur in about 20% of NSCLC cases. Between 2008 and 2014, the five-year survival rate for patients diagnosed in the U.S. with advanced NSCLC was only 5%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [CPS 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

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Data from Exploratory Analysis Show Merck's KEYTRUDA (pembrolizumab) Improved Overall Survival as Monotherapy for the First-Line Treatment of...

Abstract

IFN- produced by T cells directly induces intestinal stem cell death upon inflammation-induced intestinal injury (see the related Research Article by Takashima et al.).

Intestinal regeneration upon tissue damage is fueled by intestinal stem cells (ISCs) residing in the crypt bottom of the epithelium and marked by the gene Lgr5 (1, 2). There is growing evidence that tissue repair is at least partially mediated by a regenerative inflammatory response (3, 4). How inflammation-induced intestinal injury influences ISCs and their microenvironment (stem cell niche) remains poorly understood. In this issue of Science Immunology, Takashima et al. (5) explore the changes in the ISC niche in vivo upon T cellmediated injury as a model of graft-versus-host disease (GVHD) and in vitro using organoid T cell cocultures. Although earlier studies already implicated interferon- (IFN-) as a negative regulator of intestinal epithelial homeostasis (68), Takashima et al. now demonstrate that IFN- directly acts on ISCs by triggering apoptosis.

In an allogeneic bone marrow transplant (BMT) model, Takashima and colleagues found that ISC numbers per intestinal crypt were markedly reduced in mice receiving bone marrow alone or bone marrow and T cells when compared with normal control mice. While the ISCs in the mice receiving only bone marrow recovered 7 days later, the ISC numbers remained reduced in those mice also transplanted with donor T cells. Of note, Paneth cell numbers were also reduced after ISC depletion. The numbers of organoids established from the intestines of mice 10 days after BMT recovered back to that of control mice, whereas the organoid forming capacity from crypts of mice after combined transplantation of bone marrow and T cells remained significantly lower. Similar in vivo and in vitro results were obtained when autoreactive T cells were transplanted, pointing to a common feature of T cellmediated intestinal injury.

As seen by three-dimensional confocal microscopy, intraepithelial T cells (CD3+ IELs) preferentially localized to the villus region, whereas lamina propriaassociated T cells (CD3+ LPLs) were equally distributed along the crypt-villus axis of control mice (Fig. 1A). Conversely, mice receiving bone marrow and allogeneic T cells showed a progressive increase in the density of both CD3+ LPLs and CD3+ IELs in the crypt region.

To identify signaling molecules that cause the loss of ISCs in this model, Takashima and colleagues performed several elegant murine and human epithelial organoid coculture experiments. Murine nave allogeneic T cells did not impair murine intestinal organoid numbers, whereas alloreactive T cells effectively reduced organoid numbers. Likewise, human allogeneic cytotoxic T cells robustly inhibited human intestinal organoid forming efficiency. Even bead-activated autologous T cells suppressed human intestinal organoid growth. The authors then proceeded to screen for potential pathways mediating cytotoxicity. Organoids cocultured with T cells in the presence of antiIFN- neutralizing antibodies showed normal growth. Although IFN- receptor (IFN-R)depleted T cells were still able to affect organoid viability, IFN-Rdepleted organoids were resistant to T cellmediated killing. Organoid toxicity by IFN- was also observed in the absence of T cells. Live imaging confirmed the progressive ISC depletion upon organoid exposure to IFN-. Treatment of organoids with the immunosuppressive JAK1/2 inhibitor ruxolitinib robustly preserved numbers of both organoids and ISCs in the presence of IFN-, irrespective of whether the organoids were cultured alone or together with T cells. The authors additionally demonstrated that JAK1-depleted organoids are resistant to IFN- treatment. Further downstream, ruxolitinib prevented STAT1 phosphorylation by IFN- in intestinal crypts, and, in line, STAT1-depleted organoids were resistant to growth suppression in response to IFN- treatment.

IFN-treated organoids showed reduced expression of ISC marker genes. ISCs underwent apoptosis in vitro in a direct response to IFN-. Next, the authors confirmed in vivo that ISC numbers did not change upon transplanting allogeneic bone marrow and T cells when treating mice with IFN- neutralizing antibodies. Likewise, ruxolitinib treatment protected ISCs from T cellmediated killing in vivo. Donor T cells, particularly T helper 1 cells, were activated and IFN-+. Transplanting IFN-depleted allogeneic T cells robustly reduced the ISC loss and allowed epithelial cell proliferation to increase.

Takashima and colleagues lastly investigated whether IFN- directly induces ISC apoptosis. Using tissue-specific depletion of IFN-R1, the authors found that epithelial loss of the receptor protects from the immune-mediated GVHD phenotype. IFN-R1 is expressed by both ISCs and Paneth cells, the epithelial component of the ISC niche (9). However, Paneth celldeficient organoids remained sensitive to both IFN- and allogeneic T cellmediated cytotoxicity. Likewise, T cells were able to reduce the number of organoids containing IFN-R1deficient Paneth cells, whereas organoids containing IFN-R1deficient ISC were protected from cytotoxicity. The authors demonstrated in further experiments that IFN- directly induces ISC apoptosis independent of Paneth cells (Fig. 1, B and C).

The study by Takashima et al. extends our knowledge on signaling between ISCs and immune cells, identifying ISCs as direct targets of IFN- secreted by T cells in immune-mediated intestinal damage (as caused by GVHD). In the 2015 study by Lindemans et al., this group already identified that interleukin-22 (IL-22) secreted by group 3 innate lymphoid cells (ILC3s) directly stimulates ISCs to proliferate and regenerate the intestinal epithelium upon inflammation-induced intestinal injury (4). Modulating the effects of T cellderived IFN- on ISC, for instance, by suppressing JAK/STAT signaling via ruxolitinib treatment, may provide a new therapeutic avenue to reducing GVHD-induced damage of the intestinal epithelium (10).

(A) ISCs maintain adult homeostasis of the intestinal epithelium. T lymphocytes patrol the intestine. (B) Takashima et al. show that in GVHD as modeled by BMT and aberrant activation of T lymphocytes, T cellderived IFN- directly acts on ISCs and induces apoptosis via JAK/STAT signaling. (C) Disease progression results in marked intestinal damage due to loss of ISCs and their niche.

Acknowledgments: Funding: K.K. is a long-term fellow of the Human Frontier Science Program Organization (LT771/2015). Competing interests: H.C. and K.K. are named inventors on patents or patents pending on Lgr5 stem cellbased organoid technology.

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IFN-: The T cell's license to kill stem cells in the inflamed intestine - Science

Pigs engineered to have a small amount of monkey cells have been brought to full term and were even born alive, surviving for a few days after birth. Although the piglets died, it is claimed the experiment - performed in China - marks a major milestone for the future of lab-grown organs.

"This is the first report of full-term pig-monkey chimeras," Tang Hai of the State Key Laboratory of Stem Cell and Reproductive Biology in Beijing told New Scientist.

The research is part of an ongoing effort to develop animals - whether they are sheep or pigs - that can grow human organs we could then harvest for transplants, a process called xenogeneic organogenesis.

Research has been done on both pig and sheep embryos with transplanted human stem cells; in both cases, the embryos continued to develop until the experiment was deliberately terminated.

That's because, due to ethical concerns, these chimeras - organisms that incorporate the genetic material of another species - cannot be cultivated or studied in the later stages of embryonic development. Some scientists worry that some of the human stem cellscould end upin other parts of the animal or even in its brain, with unintended consequences.

For that reason, in this experiment the team used stem cells from crab-eating macaques (Macaca fascicularis). These were imbued with fluorescent proteins so that they would glow under fluorescent light, and derived to produce fluorescing embryonic cells.

These cells were then injected into over 4,000 five-day-old pig embryos fertilised using IVF; the modified pig embryos were subsequently implanted into sows.

This fiddly and painstaking work produced just 10 piglets that made it to full term and were born alive. And only two of these were chimeric, with between one in 1,000 and one in 10,000 functional monkey cells to pig cells.

The monkey cells had migrated to the heart, liver, lungs, spleen and skin of the piglet hosts, but were not found in other organs, such as testes and ovaries, due to the low rate of chimerism, the researchers said.

Sadly, before a week was out, the piglets died - not just the two chimeras, but the other eight normal piglets, too. Because all the pigs died, Hai told New Scientist, the cause of death likely had less to do with chimerism, and more to do with IVF - a procedure that is notoriously tricky in pigs.

The low chimerism rate is also somewhat discouraging. However, the researchers remain optimistic. Although the birth rate was low, and the pigs didn't survive, the team now has a wealth of data they can apply to future experiments.

The scientists are planning to try again, increasing the chimeric cell ratio. And they believe their data may help other scientists working in the field.

"Here, we have used monkey cells to explore the potential of reconstructing chimeric human organs in a large animal model," they wrote in their paper.

"We believe this work will facilitate the development of xenogeneic organogenesis by providing a better understanding of the processes of xenogeneic recognition, fate determination, and the proliferation and differentiation of primate stem cells during porcine development.

"The findings could pave the way toward overcoming the obstacles in the re-engineering of heterogeneous organs and achieve the ultimate goal of human organ reconstruction in a large animal."

The research has been published in Protein & Cell.

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Pig-Monkey Chimeras Have Been Brought to Term For The First Time - ScienceAlert

BOSTON and LONDON, Dec. 08, 2019 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, will be presenting new registrational data from multiple programs at the 61st American Society of Hematology (ASH) Annual Meeting being held December 7-10, 2019 in Orlando, FL.

On Sunday, December 8, 2019, investigators will describe ongoing clinical progress for two lead development programs in the companys primary immune deficiencies portfolio: OTL-103, an investigational gene therapy in development for the treatment of Wiskott-Aldrich syndrome (WAS) at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy; and OTL-101, an investigational gene therapy in development for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID).

In addition, on Monday, December 9, 2019, investigators will deliver an oral presentation featuring updated data from the ongoing clinical proof-of-concept study of OTL-203, an investigational gene therapy in development for the treatment of mucopolysaccharidosis type I (MPS-I) at SR-Tiget.

To learn more about Orchards approach to ex vivo, autologous, hematopoietic stem cell (HSC) based gene therapy, conference attendees can visit booth #2228 in the Exhibition Hall.

Full presentation details are below:

Poster Presentation Details

Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Wiskott-Aldrich Syndrome (WAS): Up to 8 Years of Follow up in 17 Subjects Treated Since 2010Publication Number: 3346Session: 801. Gene Therapy and Transfer: Poster IIDate and time: Sunday, December 8, 6:00-8:00pm ET

Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded CohortPublication Number: 3345Session: 801. Gene Therapy and Transfer: Poster IIDate and time: Sunday, December 8, 6:00-8:00pm ET

Oral Presentation Details

Extensive Metabolic Correction of Hurler Disease by Hematopoietic Stem Cell-Based Gene Therapy: Preliminary Results from a Phase I/II TrialPublication Number: 607Session: 801. Gene Therapy and Transfer: Gene Therapies for Non-Malignant DisordersDate and time: Monday, December 9, 7:00am ET

About ADA-SCID and OTL-101Severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID) is a rare, life-threatening, inherited disease of the immune system caused by mutations in the ADA gene resulting in a lack of, or minimal, immune system development.1-4 The first symptoms of ADA-SCID typically manifest during infancy with recurrent severe bacterial, viral and fungal infections and overall failure to thrive, and without treatment the condition can be fatal within the first two years of life. The incidence of ADA-SCID is currently estimated to be one in 500,000 live births in the United States and between one in 200,000 and one in 1 million in Europe.3 OTL-101 is an autologous, ex vivo, hematopoietic stem cell-based gene therapy for the treatment of patients diagnosed with ADA-SCID being investigated in multiple clinical trials in the United States and Europe, including a registrational trial at the University of California, Los Angeles (UCLA). OTL-101 has received orphan drug designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ADA-SCID, and Breakthrough Therapy Designation from the FDA.

About WAS and OTL-103Wiskott-Aldrich Syndrome (WAS) is a life-threatening inherited immune disorder characterized by autoimmunity and abnormal platelet function and manifests with recurrent, severe infections and severe bleeding episodes, which are the leading causes of death in this disease. Without treatment, the median survival for WAS patients is 14 years of age. Treatment with stem cell transplant carries significant risk of mortality and morbidities. OTL-103 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy developed for the treatment of WAS that Orchard acquired from GSK in April 2018 and has been developed at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. The global incidence of WAS is estimated to be about 100-260 births per year, with a global prevalence of 2,900-4,700 patients.

About MPS-I and OTL-203Mucopolysaccharidosis type I (MPS-I) is a rare inherited neurometabolic disease caused by a deficiency of the IDUA (alpha-L-iduronidase) lysosomal enzyme required to break down glycosaminoglycans (also known as GAGs or mucopolysaccharides). The accumulation of GAGs across multiple organ systems results in the symptoms of MPS-I including neurocognitive impairment, skeletal deformity, loss of vision and hearing, hydrocephalus, and cardiovascular and pulmonary complications. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births.5 There are three subtypes of MPS-I; approximately 60 percent of MPS-I patients have the severe Hurler subtype and, when untreated, these patients rarely live past the age of 10.Id Treatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have significant limitations. Though early intervention with enzyme replacement therapy has been shown to delay or prevent some clinical features of the condition, it has only limited efficacy on neurological symptoms. OTL-203 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MPS-I. Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the gene therapy program for the treatment of MPS-I developed by the San Raffaele-Telethon Institute for Gene Therapy in Milan, Italy.

About Orchard Orchard Therapeutics is a fully integrated commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies.

Orchards portfolio of ex vivo, autologous, hematopoietic stem cell (HSC) based gene therapies includes Strimvelis, a gammaretroviral vector-based gene therapy and the first such treatment approved by the European Medicines Agency for severe combined immune deficiency due to adenosine deaminase deficiency (ADA-SCID). Additional programs for neurometabolic disorders, primary immune deficiencies and hemoglobinopathies are all based on lentiviral vector-based gene modification of autologous HSCs and include three advanced registrational studies for metachromatic leukodystrophy (MLD), ADA-SCID and Wiskott-Aldrich syndrome (WAS), clinical programs for X-linked chronic granulomatous disease (X-CGD), transfusion-dependent beta-thalassemia (TDT) and mucopolysaccharidosis type I (MPS-I), as well as an extensive preclinical pipeline. Strimvelis, as well as the programs in MLD, WAS and TDT were acquired by Orchard from GSK in April 2018 and originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy initiated in 2010.

Orchard currently has offices in the UK and the U.S., including London, San Francisco and Boston.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release, Orchards expectations regarding the timing of regulatory submissions for approval of its product candidates, including the product candidate or candidates referred to in this release, the timing of announcement of clinical data for its product candidates and the likelihood that such data will be positive and support further clinical development and regulatory approval of these product candidates, including any cryopreserved formulations of such product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchards product candidates, including the product candidate or candidates referred to in this release, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchards ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, the delay of any of Orchards regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchards ability to commercialize its product candidates, if approved. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards annual report on Form 20-F for the year ended December 31, 2018 as filed with the U.S. Securities and Exchange Commission (SEC) on March 22, 2019, as well as subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

1Orphanet. SCID due to ADA deficiency. 2Whitmore KV, Gaspar HB. Front Immunol. 2016;7:314. 3Kwan A, et al. JAMA. 2014;312:729-738. 4Sauer AV, et al. Front Immunol. 2012;3:265. 5Beck et al. The Natural History of MPS I: Global Perspectives from the MPS I Registry. Genetics in Medicine 2014, 16(10), 759.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaMolly CameronManager, Corporate Communications+1 978-339-3378media@orchard-tx.com

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Orchard Therapeutics Showcases Clinical Data at the 61st American Society of Hematology Annual Meeting - BioSpace

Organ donation involves removing a healthy organ from a donor and transplanting it into the body of a recipient who has a diseased organ that has failed irreversibly. The recipients survival often depends on getting an organ transplant.

There is a large need for organs by people affected with end-stage ailments, like diseases of the liver, lung, heart and kidney. A major obstacle to treating such people is that there arent enough donated organs around the world. In many countries, including in the West, the number of patients in the waiting list for organ transplants has progressively increased compared to the number of donor organs available.

And while the number of donors per million people is very low in many parts of the world, about 20-30 per million, its many times lower than this in India: less than 0.5 donor per million. Experts have estimated that a few lakh organs are required per year in India, although no more than 2-3% of this requirement is really met. The severe shortfall may need more effective propaganda, retrieval and use of donated organs.

There are also personal, religious and cultural barriers that make it hard for people to accept the idea of organ donation. Most religions dont appear to oppose organ donation, but people are often uncertain about these recommendations and so they are reluctant to donate. Judaism and Islam prohibit the desecration of corpses and stress on a complete body, timely rituals and burial within 24 hours after death. People may not prefer to donate organs of their near and dear after death, due to the mutilating effect of dissecting the body and removing its parts.

There are often logistical issues as well. Due to a lack of awareness of the donation procedure and its consequences, most people prefer receiving organs from live, instead of recently deceased, donors.

* * *

Organ donation came to be thanks to advances in surgical procedures that allowed doctors to replace a diseased or dying organ with a healthy foreign organ. These advances reflected the rise of the exchangeability of body parts. That is, clinicians began to view the body as a collection of organs and independent entities, such that they could be removed from one body and placed in another. By contrast, the older and more traditional view of the body regarded it as a complex, indivisible whole interacting with its environment. As the idea of exchangeability gained traction, organs became commodities with market value.

Also read:The Seamy Underbelly of Organ Transplantation in India

The advent of organ transplantation was a landmark in the history of medicine. Researchers had developed transplantation surgeries for small animals such as dogs, pigs and goats well before the 20th century. The organs in the human body that doctors most transplant are the kidney, heart and liver.

Murray and Merrill performed the first kidney transplant in the 1950s, from one monozygotic twin to another. Since the twins were genetically identical, they survived and lived for eight years after the procedure.

The first heart and liver transplants were undertaken in the mid-1960s. Christian Bernard, the famous South African surgeon, performed the first heart transplant in 1967, from a 25-year-old who was brain dead after an accident and to a 50-year-old man suffering from heart failure. In the same year, other doctors performed more than 100 heart transplants around the world, but the recipients in these transplants didnt live for more than a few days after. There were problems related to the health of the transplanted organs and the aftereffects of surgery.

An American surgeon named Thomas Starzl performed the first liver transplant in the mid-1960s. The first patient died immediately and after the surgery; a few more patients who received transplanted organs also died from infections and other illnesses within a few weeks.

Corneal grafts are a very well-known and effective form of organ or tissue donation. The cornea, which is the transparent structure on the front of the eye, consists of multiple layers of cells designed to be transparent. The cornea refracts light towards the eyes lens, located just behind it. Its relatively simpler to transplant cornea because it lacks blood vessels (i.e. since one doesnt need to restore blood vessels in the grafted tissue).

Another advantage is that the cornea is in a state of immune privilege: it is relatively protected from immune responses. So persons who undergo a corneal transplant dont need lifelong treatment with systemic drugs to suppress the immune system.

Corneal donation and transplantation have continuously evolved in theory and practice, and have a high rate of success. Franz Reisinger first attempted corneal grafts in the early 19th century, trying to transplant animal corneas into humans. He failed in repeated attempts. Reisinger also coined the term keratoplasty, which means surgery to the cornea.

Also read:Why Moral Exhortations Alone Will Not Boost Organ Donation in India

Only a few years later, Samuel Bigger, an Irish surgeon, treated a gazelle that had been blinded by a corneal scar by transplanting cornea from another gazelle.

A Viennese ophthalmologist named Edward Zirm performed the first successful corneal graft between two humans in the early 20th century.

* * *

One possible reason why organ transplants often dont have long-term success is the recipient. A person who is already sick due to a failed heart or liver is not likely to respond well to major surgery, and may have difficulty recovering from it. Similarly, an older patient may not be able to withstand the effects of surgery.

Another important factor is the recipients immune system, which could reject the donated organ. In 1979, doctors who just performed a liver transplant used a drug called cyclosporine to dampen the bodys immune response and thus spare the transplanted organ from attack. This occasion was a new step in the history of liver transplants. Cyclosporine improved the survival of over 70% of patients up to at least one year after surgery, and many patients survived for up to five yrs. Doctors have followed up with newer, better drugs to improve patients health outcomes since.

A third issue relates to an ethical question that researchers have flagged: a living donor has to undergo a major surgical procedure to donate an organ, and such procedures carry their own risks. Moreover, close relatives of a patient may be under pressure to agree to donate their organs, so they may not be necessarily free to decide for themselves. Another issue regards commercialisation: its very easy to provide monetary incentives to the poor and convince them to donate an organ in return. In such circumstances, the decision to donate an organ will not have been the result of free choice where it should be.

Such a market for kidneys is all too visible in India, where one finds advertisements for the sale of kidneys with hospitals involved in the business. Often, poor people are ready to donate their organs to make a lakh or two. Apart from theft and the black market for organs, monetary compensation for organs is legal in some parts of the world.

* * *

An alternative to overcome the shortage of organs for transplants is a xenotransplant: transplanting animal organs into humans. The principal animals that can potentially donate to humans are monkeys, since theyre most closely related to humans.

However, due to differences between the sizes of monkey and human organs, researchers have also considered pigs, whose organs are closer in dimensions as well as because pigs are easy to breed. Researchers are currently exploring these procedures in experiments.

Also read:Why Does Spain Lead the World in Organ Donation?

Another alternative for intact organs is stem cells, which scientists can grow in controlled environments, such as in a laboratory, and develop into miniature organs, or organoids. Using bioengineering techniques, they removed cells from an intact organ, such as a lung or trachea, such that the cells retain a skeleton of proteins and carbohydrates. Next, they populate these cells with stem cells and maintained them in a laboratory so that different types of cells grow inside the container. For example, scientists have grown multilayered corneas in a dish using a culture of stem cells and certain biomolecules.

Such advances in preserving and engineering tissues are help plug the gap between the demand for and supply of organs.

* * *

Its very important to preserve and properly store organs to ensure theyre in the best possible condition and retain their nature following transplantation. One particular concern here stems from the time and temperature of storage, which need to be carefully controlled to remain within specific limits depending on the organ and the type of death. Maintaining the right conditions ensures the organ remains viable after the recipient has received it. A heart may be stored for up to four hours, the lungs for up to six hours and the kidneys for longer periods, up to 18 hours.

A critical question to be addressed with regard to organ donation is the distinction between brain death and cardiac, or circulatory, death. A brain-dead patient will still have a functioning heart and may be on life support. However, brain-death means brain function has been completely and irreversibly lost.

For an organ donor, a criterion of either brain death or cardiac death may be taken under the definition of death. Indian law mentions two possibilities. One is in the Registration of Births and Deaths Act and the other, in the Transplantation of Human Organs and Tissues (THOT) Act. The former defines death as the permanent disappearance of all evidence of life at any time after live-birth has taken place. The THOT Act, on the other hand, defines a deceased person as one in whom permanent disappearance of all evidence of life occurs, by reason of brain stem death or in a cardiopulmonary sense, at any time after live-birth has taken place.

In many countries, both forms of death are considered acceptable for organ donation.

Chitra Kannabiranleads research on molecular genetics at the L.V. Prasad Eye Institute, Hyderabad.

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The Ins and Outs of Organ Donation - The Wire

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SebergFrench New Wave actress Jean Seberg is targeted by the FBI for her political and romantic involvement with civil-rights activist Hakim Jamal during the 1960s in this fact-based drama. With Kristen Stewart, Anthony Mackie, Jack OConnell, Margaret Qualley, Zazie Beetz, Vince Vaughn. Written by Joe Shrapnel, Anna Waterhouse. Directed by Benedict Andrews. (1:36) R.

6 UndergroundRyan Reynolds stars in this Michael Bay action flick about a globe-trotting team of untraceable operatives dedicated to saving the world. With Mlanie Laurent, Corey Hawkins, Adria Arjona, Dave Franco. Written by Paul Wernick, Rhett Reese. (2:05) R.

Uncut GemsAdam Sandler stars as a desperate New York City jeweler juggling numerous deals in this crime thriller. With Lakeith Stanfield, Julia Fox, Kevin Garnett, Idina Menzel, Eric Bogosian, Judd Hirsch. Written by Josh Safdie, Benny Safdie, Ronald Bronstein. Directed by the Safdies. (2:15) R.

What She Said: The Art of Pauline KaelDocumentary on the longtime firebrand film critic of the New Yorker. With Alec Baldwin, Quentin Tarantino, David O. Russell, Francis Ford Coppola and Sarah Jessica Parker as the voice of Kael. Directed by Rob Garver. (1:38) NR.

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Movies opening in L.A. this week: 'Bombshell,' 'Jumanji: The Next Level' and more - Los Angeles Times