StemCell Therapy

Orphan Black, the Canadian science fiction show that revolves around human cloning, will end on Saturday, August 12th after five darkly funny, gory seasons. The show began with a former British street urchin, Sarah Manning (Tatiana Maslany), watching as someone with her exact facial features commits suicide by jumping in front of a train. From there, the show unravels to be about large biotech corporations, conspiracies, and above all, morally questionable science.

Spoilers ahead for all of Orphan Black except the finale.

Science classes teach students early on that human experimentation is ethically wrong if the subjects dont know theyre being experimented on, or exactly what the experiment entails. Orphan Black explores this taboo by giving us villains that love experimenting on unwilling or unwitting people. From installing a secret camera in a womans artificial eye to harvesting the eggs of an eight-year-old girl, the corporate forces on the show are unapologetically sinister and indifferent to basic scientific ethics. The show is both a celebration of science and a reminder that its frightening when used to the wrong ends.

With the end of Orphan Black imminent, were looking at the real world for our fix of real science straddling the world of science fiction. Since the show began airing in 2013, have we gotten any closer to the future of extreme body modifications and human cloning that Orphan Black has so often teased? I spoke with Paul Knoepfler, a biology professor at UC Davis, and John Quackenbush, professor of biostatistics and computational biology at Harvard and the Dana-Farber Cancer Institute, to see how far away we are from some of the shows most outrageous inventions.

GROWING A TAIL

Early in the shows run, Olivier, a body-modification fan whos one of the antagonists overseeing a human cloning project, shows off the pink tail hes grown. Sarah is understandably disgusted. But such body modifications could exist, as humans are already naturally born with primordial tails, Knoepfler says. All youd need to do is stop the pre-programmed cell death of those tail cells, maybe by giving a pregnant woman a drug, Knoepfler says. The most challenging part of getting a functional tail would be finding a way to extend the length of the spine, according to Quackenbush. And even if a tail was successfully constructed, there are more unknowns, says Knoepfler, like what part of the brain would control it, or whether the tail would trip you as youre walking. Granted, that isnt a problem if its this short:

I SPY WITH MY BIONIC EYE

At the end of season 2, Rachel Duncan, a clone whos grown up under the care of large corporations, is stabbed in the eye. She receives an artificial replacement, and after many months, she regains complete sight. Ultimately, though, she decides to tear out her eye, because she learns the man responsible for commissioning it also had a camera installed inside it to spy on her. This leads to a truly creepy cinematic moment where Rachel sneaks into the mans office, looks down at his mysterious tablet, and discovers a live stream of what her eye sees: a screen within a screen within a screen, ad infinitum. I watched you touch yourself in the shower where you think its clean, the man says gleefully in a following episode.

Putting the shows sinister ingenuity aside for a moment, Rachels bionic eye spy-cam and all may be possible, Knoepfler and Quackenbush say. Bionic eyes already exist, but the main challenge is connecting an artificial eye with the optic nerve, which connects the eye to the brain. That nerve probably would have been damaged during Rachels initial injury. Creating a bionic eye poses an additional challenge, as the eye must mimic nature and be able to send and receive the right kinds of signals to be read by the brain, says Quackenbush. But if the eye and optic nerve could be reconnected, the eye could potentially be powered by a battery, and making a camera small enough to fit inside the eye is completely possible with todays current technology. Then Wi-Fi and Bluetooth would give the eye live-streaming capabilities.

POISONOUS BOT IMPLANT

In the penultimate season, Sarah discovers she has a bot implanted inside her cheek, which acts as a tracking device and contains a poison her enemies can release into her bloodstream. Micro-tracking implantations already exist in our world: just take the microchips that are often implanted in dogs and cats, Quackenbush says. The tracking device part of the bot also seems plausible: there are devices today that can draw on nearby Bluetooth devices as a network, Quackenbush says. And even storing a toxin inside the bot isnt just science fiction, given the steady infusion of insulin or other drugs that devices already offer humans today. The problem, however, is the bots power supply: it would have to be significant enough to potentially sustain the bot throughout a human lifetime and no such batteries exist yet.

AND OF COURSE, CLONING

We already have clones; theyre identical twins, says Quackenbush. But there are other, less random methods for achieving human cloning. One way is how Dolly the sheep was cloned, by taking the part of the egg cell that contains genetic information and replacing it with a donors cell nucleus. The egg is then fertilized and grown into a clone. But using this method, called somatic cell nuclear transfer, on humans could be extremely unsafe, because the clone could have serious developmental disorders, Knoepfler says.

Quackenbush imagines another method to approach human cloning: reversing cell aging. Basically, adult stem cells could be reverted into their original state as stem cells, when they possessed the genetic potential to divide and become the heart, liver, skin, and other organs. An embryo, in many ways, is the ultimate stem cell, says Quackenbush. But this method hasnt been tried before.

Orphan Blacks science consultant, Cosima Herter, believes that cloning humans is illegal in North America. Were not allowed to hear about it, because were not allowed to do it, she wrote in a blog post for the show in 2013. This isnt quite right no federal laws, at least in the US, ban human cloning. The US Food and Drug Administration is the regulator that matters for research into cloning humans.

With the end of Orphan Black comes the end of a decently plausible science fiction series. Its given us hints of what the future might have in store. It could even inspire the science to come. I think [science fiction] is part of what got us into this business in the first place, Quakenbush says of himself, and others in the science community, You see the future and you want to try to invent it.

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Orphan Black is ending, but how far has human cloning come? - The Verge

With a jolt from a tiny chip, humdrum skin cells may transform into medical mavericks.

A small electrical pulse blasts open tiny pores in cells and zaps in fragments of DNA or RNA loaded in the chips nanochannels. Those genetic deliveries then effectively reprogram the skin cells to act like other types of cells and repair damaged tissue. In early experiments on mice, researchers coaxed skin cells to act like brain cells. They also restored blood flow to a rodents injured limb by prompting skin cells to grow into new blood vessels.

The technology, published this week in Nature Nanotechnology, is still a long way from confirmed clinical applications in humans. But, the Ohio State researchers behind the chip are optimistic that it may one day perform myriad medical featsincluding healing severe injuries, restoring diseased organs, erasing brain damage, and even turning back the clock on aging tissues.

The researchers, led by regenerative medicine expert Chandan Sen and biomolecular engineer L. James Lee, expect to begin clinical trials next year.

The concept is very simple, Lee said in a press statement. As a matter of fact, we were even surprised how it worked so well. In my lab, we have ongoing research trying to understand the mechanism and do even better. So, this is the beginning, more to come.

Their concept is similar to other cell-based regenerative therapies under development, but it skips some pesky steps. Some other methods explored by researchersand dubious clinicsinvolve harvesting adult cells from patients, reprograming them to revert to stem cells, then injecting those cells back into patients, where they develop into a needed cell type.

But this setup has snags. Researchers often use viruses to deliver the genetic elements that reprogram the cells, which have caused cancer in some animal studies. The method also requires a lot of manipulation of cells in lab, adding complications. Its unclear if the suspect stem cell clinics are even successful at reprogramming cells.

The method used by Lee, Sen, and colleagues ditches the need for a virus and for any cellular handling. The electrical pulse opens pores in cells that allow for direct genetic deliverya process called electroporation. The researchers skipped the need to make stem cells by using preexisting methods of converting one cell type directly into a different one. Generally, this works by introducing bits of genetic material that code for gene regulators key to a specific cell type. Once delivered, these regulators can switch genes on or off so cells can start acting like the different cell type. Such a method has been worked out for creatingliver, brain, and vascular cellsfrom other cell types.

Finally, the researchers method also all takes place on a patch of skin on a living subject, potentially directly where its neededno cell harvesting or lab manipulations are required. (That said, the researchers note that future therapies could use skin patches to generate specific cell types that can then be transferred to other locations in the body if needed.)

So far, the researchers have dabbled with making brain cells and vasculature cells from skin cells. In early experiments, their direct delivery proved effective at converting the cells. The researcher verified that the converted cells mirrored normal brain and vasculature cells' gene expression profilesthe pattern of genes they have turned on and off.

In their ultimate test, the researchers severed leg arteries in ahandful of mice. Then a researcher placed over the injuries nanochips loaded with genetic ingredients for converting skin cells to vasculature cells. The conversion reached cells deep within the skin layers. After a week, the researchers saw more blood flow and less tissue death in the treated mice compared withcontrol animals that werent treated.

Much work still needs to be done to test the idea and prove it's effective for certain treatments. But the researchers are optimistic. They conclude in the study that the technology has the potential to ultimately enable the use of a patients own tissue as a prolific immunosurveilled bioreactor.

Nature Nanotechnology, 2017. DOI: 10.1038/nnano.2017.134 (About DOIs).

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Heal thyself: Skin-zapping chip aims to reprogram cells for tissue repair - Ars Technica

KRAKOW, Poland and RYE BROOK, New York, August 8, 2017 /PRNewswire/ --

Selvita S.A. (WSE: SLV) and The Leukemia & Lymphoma Society (LLS) announced today a partnership to co-fund further preclinical and clinical development of a targeted therapy to treat patients with acute myeloid leukemia (AML). Selvita has discovered and is developing SEL120, a therapy that targets the cyclin-dependent kinase 8 (CDK8) protein, which plays a unique and critical role in gene regulation. Laboratory studies have shown the agent to be effective in certain types of AML cells.

SEL120 is an ATP-competitive and selective inhibitor of CDK8 and a closely related serine kinase, CDK19. CDK8 is a part of a multi-protein complex that regulates gene expression and is distinct from CDK4 or CDK6, which play a role in cell cycle progression. In laboratory experiments, treatment with SEL120 has been shown to result in the death of AML cells especially with elevated phosphorylation of STAT5 and stem cell characteristics, which is significant because AML stem cells are typically resistant to conventional therapies and thereby mediate relapsed disease. Moreover, the status of phosphorylation of STAT5 may provide a useful biomarker for action of the drug. The molecular mechanism of action involves modulation of various oncogenic transcriptional programs that are critical to the survival of AML cells. This unique mechanism, which does not overlap with existing therapies, may allow the development of highly effective combination therapies that may be required to provide long-term control of AML in patients.

SEL120 has shown efficacy in treating AML cells both in vitro (test tube) and in vivo (mouse models). SEL120 has successfully passed a series of non-GLP toxicity studies in mice and monkeys. Selvita initiated Investigational New Drug (IND)-enabling studies for SEL120 in June 2017, a critical step in getting the U.S. Food and Drug Administration's permission to begin in human clinical trials.

Under the terms of the agreement, LLS will provide up to $3.25 million funding over 4 years, through its Therapy Acceleration Program (TAP), in order to help fund further SEL120 IND-enabling studies and a Phase I trial in AML.

"We are very pleased to be partnering with The Leukemia & Lymphoma Society. This partnership constitutes not only a significant validation of the high potential of SEL120 in treatment of AML patients, but also offers a unique opportunity to work with world renowned researchers, specialists in the field of hematological cancers, increasing the chances of bringing a breakthrough treatment to the patients whose treatment options currently remain very limited,"said Krzysztof Brzzka, Ph.D., Chief Scientific Officer at Selvita.

"LLS has developed a comprehensive approach to beat AML, which is one of the leukemias associated with exceptionally high mortality rates. Moreover, very few effective agents are available to control AML, particularly in elderly individuals where the disease commonly occurs," said Lee Greenberger, Ph.D., LLS's Chief Scientific Officer. "LLS is focused on identifying and advancing the most innovative therapeutics to control and/or eradicate blood cancers. LLS's partnership with Selvita understates our commitment to accelerating cures for this deadly disease."

LLS's Therapy Acceleration Program (TAP) funds innovative projects related to therapies, supportive care or diagnostics that have the potential to change the standard of care for patients with blood cancer, especially in areas of high unmet medical need. Further development of the SEL120 project will be co-funded through the Biotechnology Accelerator Division, a strategic initiative to partner directly with biotechnology companies.

About The Leukemia & Lymphoma Society

The Leukemia & Lymphoma Society (LLS) is the world's largest voluntary health agency dedicated to blood cancer. The LLS mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world and provides free information and support services.

Founded in 1949 and headquartered in Rye Brook, New York, LLS has chapters throughout the United States and Canada. Since 1953, LLS has funded over $1 B in blood cancer research through 4000 grants to academic institutions and over 50 therapeutic opportunities through the TAP program.For more information please visit:http://LLS.org/

About Selvita S.A.

Selvita S.A.is a drug discovery company, developing breakthrough therapies in the area of oncology. The company's most advanced program, SEL24, has been licensed to Menarini Group and is currently in Phase I studies in AML.Other projects include SEL120, a first-in-class small molecule inhibitor of CDK8 in preclinical studies, several drug discovery platforms in immuno-oncology, immunometabolism and cancer metabolism, as well as epigenetics, performed independently or in collaboration with global pharma and biotech companies.

Selvita also offers a wide range of integrated drug discovery services, helping biotech and pharma partners discover and develop new drugs.

The company has alliances and partnerships with more than fifty large and medium-sized pharmaceutical and biotechnology companies from USA and Europe, including R&D partnerships with Merck, H3 Biomedicine, Nodthera Therapeutics/Epidarex Capital and Menarini Group.

The company was established in 2007 and currently employs over 400 scientists, among which 30% are PhDs. Selvita is headquartered in Krakow with second research site in Poznan, Poland and international offices located in Cambridge, MA and San Francisco Bay Area, in the US, as well as in Cambridge, UK. Selvita is listed on the Warsaw Stock Exchange (WSE: SLV). More information:http://selvita.com/

SOURCE Selvita S.A.

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Selvita and The Leukemia & Lymphoma Society Announce Partnership to Advance SEL120 Into Phase I for AML Patients - Markets Insider

A new method of isolating lung stem cells could help speed the development of stem-cell based therapies for lung diseases, including cystic fibrosis, according to a University of North Carolina study.

That method is extracting them with a tube from the mouth to the lung rather than surgery. The team has already used the method in their pulmonary fibrosis research work.

The new study, Derivation of therapeutic lung spheroid cells from minimally invasive transbronchial pulmonary biopsies, was published in the journalRespiratory Research.

Doctors can use stem cells to restore injured lungs, but obtaining and maintaining the cells is challenging.

Not only do they need a lot of lung tissue to extract the stem cells, but the way they have obtained the tissue with surgery is highly invasive. This has led to high death rates among patients who have had the biopsy surgery.

Still, isolating the cells for stem cell-based therapies is a good way to treat many lung diseases.

Until recently,University of North Carolina Health Careresearchers used lung tissue biopsies to obtain stem and support cells that they can cultivate for treatments. They discovered thatlung spheroid cells can help regenerate the lungs of mice with pulmonary fibrosis.

The team is now using a relatively non-invasive procedure, called a transbronchial biopsy, to isolate lung spheroid cells while reducing the risks associated with obtaining them by surgery. In this procedure, a lung pneumologist inserts a thin, lighted tube, or bronchoscope, through a patients nose or mouth to collect several pieces of lung tissue.

This is the first time anyone has generated potentially therapeutic lung stem cells from minimally invasive biopsy specimens, Dr. Jason Lobo, an assistant professor of medicine at the university, said in a press release.

We snip tiny, seed-sized samples of airway tissue using a bronchoscope, said Lobo, a co-lead authoer of the study. This method involves far less risk to the patient than does a standard, chest-penetrating surgical biopsy of lung tissue.

They were able to obtain more than 50 million lung spheroid cells from one small piece of isolated tissue. When they injected the cells into mice, they were delighted to find that the cells ended up in the animals lungs.

These cells are from the lung, and so in a sense theyre happiest, so to speak, living and working in the lung, said the other co-lead author, Dr. Ke Cheng. He is an associate professor in the universitys Departments of Molecular Biomedical Sciences and Biomedical Engineering.

In a second study, published in the journalStem Cells Translational Medicine,researchers highlighted lung spheroid cells potential to treat cystic fibrosis. Injecting the cells in rats with cystic fibrosis significantly reduced their lung inflammation and scarring, compared with control animals.

Also, the treatment was safe and effective, whether the lung spheroid cells were derived from the recipients own lungs or from the lungs of an unrelated strain of rats, Lobo said. In other words, even if the donated stem cells were foreign, they did not provoke a harmful immune reaction in the recipient animals, as transplanted tissue normally does.

Scientists have had discussions with theU.S. Food and Drug Administrationabout clinical trials of lung spheroid cells as a pulmonary fibrosis therapy.

Cells isolated from patients own lung tissue would eliminate the risk of the body rejecting the stem cells. Such treatments require a lot cells, however and doctors might opt to harvest some from healthy volunteers and whole lungs obtained from organ donation networks.

Our vision is that we will eventually set up a universal cell donor bank, Cheng said.

The researchers hope that some day their stem cell therapycan be used in other lung diseases, including cystic fibrosis.

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Researchers Use Simpler, Safer Method to Obtain Stem Cells for Treating Lung Diseases - Cystic Fibrosis News Today

Dr. Gabe Mirkin

Sam Shepard was a prolific playwright, actor, screenwriter and director who:

acted in more than sixty films and was nominated for an Academy Award for Best Supporting Actor for his portrayal of pilot Chuck Yeager inThe Right Stuff;

wrote more than 55 plays, often focusing on the serious problems that occur in American family life;

won the most Obie Awards (10) for his off-Broadway writing and directing. In 1979 he received a Pulitzer Prize for his play, Buried Child, andNew York Magazinecalled him the greatest American playwright of his generation.

In his late sixties, he developed amyotrophic lateral sclerosis (ALS), the disease that killed baseball great Lou Gehrig at age 37. Shepard died from complications of ALS on July 27, 2017, at age 73.

A Difficult Life

Sam Shepard

He was born on November 5, 1943, in Fort Sheridan, Illinois. His dysfunctional family served as a basis for characters in many of his plays. His father was a United States Army Air Force bomber pilot during World War II who was also an alcoholic and an abusive husband and father. His loving, supportive mother, a teacher, offset some of the pain and abuse he suffered from his father. In his early years, the family had to move every two years because of army transfers. Later his father left the service and bought an avocado farm in Duarte, California. Shepard briefly studied animal husbandry at nearby Mt. San Antonio College, but soon left school to move to New York City, where he worked as a busboy, played in a psychedelic folk band and tried to break into the theater.

At age 35, his acting career took off when he won a role in Terrence MalicksDays of Heaven, with Richard Gere and Brooke Adams. At the same time, he continued to write successful plays and in 1986 (age 43) he was elected to the American Academy of Arts and Letters.

Amyotrophic Lateral Sclerosis (ALS or Lou Gehrigs Disease)

In his last few years, Shepard suffered privately from ALS, but he described his experience in his last book, The One Inside. One of the characters said that he couldnt get up from bed in the morning and felt as though his limbs werent connected to the motor driving his body. They wont take direction wont be dictated to the arms, legs, feet, hands. Nothing moves. Nothing even wants to. The brain isnt sending signals.

ALS is a progressive disease that destroys the nerves that move voluntary muscles. More than 6,000 people in the United States are diagnosed with ALS each year. Nobody knows the cause and there is no cure. The brain is supposed to send messages to nerves in the spinal cord which transmit messages to the nerves that move muscles. When a muscle loses its nerve control, it starts to twitch and can waste away to nothing. Early symptoms of ALS include

muscle weakness

twitching

slurred speech

inability to chew food

tripping or stumbling.

The first sign could be difficulty buttoning a shirt, writing, or turning a key in a lock. The disease usually does not affect a persons ability to think and reason, so affected people are terribly disturbed by their lack of ability to control their voluntary muscles. As the disease progresses, a person loses the ability to speak, eat, walk and eventually breathe. The most common cause of death is inability to breathe, which typically occurs about 3-5 years after symptoms start. Only about ten percent of affected people live more than ten years after first being diagnosed.

Risk Factors and Diagnosis

The disease usually starts between the ages of 55 and 75, but there are no known specific risk factors. Military veterans appear to be twice as likely as non-veterans to develop ALS. Possible causes could be exposure to occupational or environmental toxins such as lead or pesticides, infections or trauma. Family history does not appear to predict the disease.

There are no specific tests to diagnose ALS. It is usually diagnosed by a history of the symptoms, physical examination and ruling out other causes.

Current Treatments and Research

The U.S. Food and Drug Administration (FDA) has approved riluzole (Rilutek) and edaravone (Radicava) to treat ALS. These drugs offer no hope for a cure, but Riluzole appears to protect nerves by decreasing glutamate, the chemical messenger for nerves that innervate muscles. Intravenous edaravone possibly slows loss of muscle function, but it costs $1,086 per infusion or a yearly cost before government discount of $145,524. Another drug under European review is being developed by French drug maker AB Science SA (ABS.PA). Since there is no cure, all patients should receive physical therapy and speech therapy because inactivity itself causes loss of muscle function.

Since ALS is caused by the death of nerve cells that cause muscles to contract, the most promising line of research is through stem cells. Stem cells are young cells that can become any type of tissue. Treatment in the future may be to program stem cells to become nerve cells that innervate muscles and then inject them into areas where the nerve cells have already died.

Dr. Gabe Mirkin is a Villager. Learn more at http://www.drmirkin.com

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Sam Shepard and Amyotrophic Lateral Sclerosis - Villages-News

Eye doctors are fast-tracking efforts to improve stem cell transplants to save the sight of people blinded in Londons acid attack epidemic, the Standard can reveal.

Research at The Royal Free Hospital aims to boost success rates, particularly where cells are taken from deceased donors at present, three-quarters of such transplants fail.

Corneal stem cell transplants have been used for some time on acid victims, including model Katie Piper.

But they are difficult and risky to perform, with doctors hampered by a shortage of donated eyes.

They are most successful when one eye is damaged and cells can be transplanted from the healthy eye. This works in about seven out of 10 cases.

The success rate is about 25 per cent when both eyes are damaged and cells are harvested from the eye of a deceased donor.

Research: consultant Alex Shortt, right, and student Harley Buck at The Royal Free Hospital

Consultant ophthalmic surgeon Alex Shortt, who is carrying out the research at the Royal Frees institute of immunity and transplantation in Hampstead, said the aim was a success rate of 95 per cent. The work is being funded by the Wellcome Trust and Moorfields Eye Charity.

A total of 454 acid attacks were reported to the Metropolitan police last year, almost three times the number in 2014. Mr Shortt said: The last six to 12 months has seen demand for these treatments rise hugely.

He said the challenge was to remove scar tissue without creating a new scar as the eye healed. A sample of healthy corneal stem cells are grown in the laboratory to form a sheet, which is attached to the surface of the damaged eye to enable the cornea to regenerate.

The success rate is about 68 per cent. It fails in three out of 10 people. They regrow a scar and they go blind again, Mr Shortt added.

We are trying to move to the point where we can use donor cells and prevent the body from rejecting them. Then we can treat patients more cheaply, and have a bank of cells ready to go as soon as we see a severe injury.

Next week NHS rationing body NICE is due to decide whether to approve an 80,000 Italian stem cell treatment, Holoclar, that works for seven in 10 patients. However, it is only effective where cells can be taken from the patients undamaged eye.

NICE is likely to require patients to undergo a cheaper treatment first.

Medics are also appealing for more people to donate their corneas after death. NHS Blood and Transplant said more than one in 10 donors place restrictions on the use of their eyes, the most for any organ.

About 70 corneas a week are needed but 50 are donated. Hundreds of corneas are imported from the US and Europe.

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Surgeons focus on stem cell transplants to help save sight of acid attack victims - Evening Standard

Photo: Arnold Gold / Hearst Connecticut Media

Dr. Steven Gore at the Advanced Cell Therapy Lab at Smilow Cancer Hospital in New Haven, where cells are manufactured that fight a rare form of leukemia.

Dr. Steven Gore at the Advanced Cell Therapy Lab at Smilow Cancer Hospital in New Haven, where cells are manufactured that fight a rare form of leukemia.

Rare leukemia targeted by modifying patients immune cells

NEW HAVEN >> Young patients with a particular type of leukemia who have relapsed after going into remission may find new hope through a treatment that involves modifying a patients own T cells, an important part of the immune system, to destroy cancer cells.

While the therapy, in which genes are inserted into a patients T cells, is expected to receive Food and Drug Administration approval soon for pediatric patients, researchers hope that it will be effective for adult patients as well and for more types of cancers, according to Dr. Steven Gore, director of hematologic malignancies at the Yale Cancer Center.

The cancer thats the focus of this T cell therapy is B-lineage acute lymphoblastic leukemia, which is the most common leukemia in kids and its commonly cured in the 2- to 10-year-old age group, Gore said. He said about 70 percent of children with the cancer are cured.

However, the rest suffer a recurrence of the disease even after treatment with chemotherapy and stem cell transplants.

Its getting to be a difficult situation, Gore said.

There are 3,100 cases of children with B-lineage ALL each year, he said.

B cells, also known as B lymphocytes, are white blood cells that produce antibodies, which fight infection. A characteristic of B cells is that they have a protein on their surface called CD19, which is the key to the new treatment.

The new process, marketed by Novartis and first developed at the University of Pennsylvania, involves harvesting T cells from the patient. Novartis then introduces DNA into these T cells, introducing new genes into the T cells, [which] include a receptor that will recognize CD19, Gore said. The genes that are fused into the T cells are manufactured in the lab but are copies of normal human genes, Gore said. The new cell is called a chimeric antigen receptor T cell, or CAR-T cell.

Normal T cells fight disease, and we know that T cells can attack cancer cells as well, but getting them to do so in the host where the cancer has developed is tricky, Gore said. Cancer cells are very similar [to] normal cells from which they derive.

Turning the T cells into CAR-T cells helps by targeting the CD19 marker on the B cells. CD19 happens to be a pretty good target for cancer technology because its only on B cells, Gore said. These new CAR-T cells latch onto the leukemia cells.

Reproducing cells

Then, once they see that theyre needed, the CAR-T cells are going to make more of themselves. Theyre going to make a whole army-full beside what we gave the patient, Gore said. Other genes in the introduced DNA give the immune system the go-ahead to kill these leukemia cells.

The CAR-T cells target both healthy and malignant B cells, but people live all the time without B cells, Gore said, by relying on drugs such as rituximab.

The treatment is not easy on the patient, however. When this massive influx of these new T cells attack all these leukemia cells, youre basically setting up a jihad in your body, Gore said. People can get very critically ill after this therapy, even needing to be treated in the intensive care unit.

Despite the hardship, the FDAs Oncologic Drugs Advisory Committee voted 10-0 on July 12 to recommend approval of CAR-T therapy, and it is very rare that an ODAC approval does not end up in an FDA approval, Gore said.

In one trial, 41 of 50 patients with relapsed or refractory B-lineage ALL each achieved complete remission after three months, Gore said, and 60 percent of those patients were still in remission six months later.

It will be rapidly opened up to adults as well, theres no question about it, he said. Some people think this therapy may replace stem cell therapy and doctors hope it can be given before a patient relapses, avoiding stem cell transplants.

We dont have long-term follow-up to know if these patients are cured, Gore said. Theyve certainly been rescued from otherwise-certain death.

Gore said the Yale School of Medicine has been approached by Novartis to be one of the rollout sites for this therapy.

While the new treatment targets a relatively rare cancer, its likely to be effective in other cancers involving B cells, including other types of leukemia and lymphoma, Gore said. (Not all lymphomas and leukemias are B cell cancers, however.) This rare leukemia has been the subject of all this investigation because CD19 is such a low-hanging fruit, because we can live without B cells, he said.

But the technology can theoretically be adapted to any kind of tumor, he said. Theoretically, you could make a CAR-T to target any particular kind of cancer provided that that cancer expresses certain proteins that are predominantly limited to the cancer and not important vital organs.

Call Ed Stannard at 203-680-9382.

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Rare leukemia targeted by modifying patients' immune cells - New Haven Register

We lost an American icon Thursday with the death of actor and playwright Sam Shepard. He had ALS (amyotrophic lateral sclerosis), more commonly known in the U.S. as Lou Gehrigs disease. Its an invariably fatal neurological disease that robs individuals of their ability to move muscles, their ability to swallow, and eventually, their ability to breathe.

ALS often starts in a fairly nonspecific way, with weakness in a persons hand or foot. Although I never examined the late Mr. Shepard, even in public photos from 2016, the atrophy of his hand muscle was evidenta hallmark of the loss of muscle that occurs in ALS.

In about 90% of cases diagnosed by neurologists, ALS happens out of the blueits sporadic, and the cause isnt known. About 10% of the time, ALS is inherited through a defective gene; that is, a patient has a family member who also had the disease. We can readily diagnose inherited ALS with a relatively simple blood test.

Five years ago, we learned that even in some patients who have no family history of ALS, a defect in a gene known as C9orf72 underlies the disease. In some patients, the disease may be initially diagnosed incorrectly as a nerve problem in the hands or wrist (carpel tunnel syndrome), or a pinched nerve in the neck or back. But those conditions are commonly associated with painALS is not generally a painful disease.

The weakness typically progressesslowly over many years in some patients, or rapidly over a few months in othersprogressing from one hand to the other, from hand to foot, or foot to hand. Eventually it affects ones ability to chew, swallow, and breathe. The weakness of the breathing muscles is what makes ALS fatal. Unlike cancer, with its rare but real remissions, ALS is always fatal. Patients might choose to have a ventilator artificially breathe for them; that intervention delays death, but not the progressive weakening and paralysis of all muscles.

As treating physicians, we have a paucity of options to slow down the disease and have no real effective drug to halt its relentless progression or to recover functionno cure. ALS is not really one disease, but a combination of different genetic, even environmental, insults, that culminate in this horribly disabling and life-ending malady. Not unlike what we have learned about cancers, there may be many different causesgenetic, molecular, biochemicalthat underlie the disease. In cancers, sampling the actual diseased tissue, commonly through tissue biopsies, has provided a trove of clues about what underlies the basis of the different cancers and how to approach the different forms, sometimes quite successfully. But with ALS, we cannot readily take a chunk of someones brain or spinal cord, so we are often left guessing as to what may underlie the cause of the disease and how to best treat it. That antiquated approach may soon end.

Advances in the generation of stems cells from individual patients provide the most powerful way to generate their own brain cells. We are now able to take a small tube of blood or skin and turn those cells into stem cells (by a procedure that won the Nobel prize several years ago), and then, by adding a few more chemicals and special genes, turn those cells into motor neuronsbrain and spinal cord cells that die in ALS.

This procedure, which in essence creates a biopsy of the brain/spinal cord of ALS patients, will allow us to achieve what has been so successful in cancerto truly understand the different kinds of ALS, to use our patients brain cells to discover their individual disease causes, and to develop a more individualized pathway for drug therapy. We aim to personalize ALS therapywhat we call Answer ALS. That is the hope on the horizon for ALS, along with drugs now already under development or in clinical trials that are specifically targeted to patients with known genetic mutations. How far that horizon is in the distance, we dont know, but we can see it. We only wish Mr. Shepard and all our past patients could have reached that hopeful horizon.

Jeffrey D. Rothstein MD, PhD, a neurologist and professor at Johns Hopkins University, is the director of the universitys Brain Science Institute, ALS clinic and Robert Packard Center for ALS Research.

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Sam Shepard Died of ALS. Here's Why It's so Difficult to Treat. - Fortune

A team of scientists from the UNC School of Medicine and North Carolina State University (NCSU), U.S. have developed promising research towards possible stem cell treatment for several lung conditions, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis, all of which are known to be fatal conditions. In the journal Respiratory Research, the scientists demonstrated that they could harvest lung stem cells from people using a relatively non-invasive, doctors office technique. They were then able to multiply the harvested lung cells in the lab to yield enough cells sufficient for human therapy.

In a second study, published in the journal Stem Cells Translational Medicine, the team showed that in rodents they could use the same type of lung cell to successfully treat a model of IPF a chronic, irreversible, and ultimately fatal disease characterised by a progressive decline in lung function. These diseases of the lung involve the build-up of fibrous, scar-like tissue, typically due to chronic lung inflammation. As this fibrous tissue replaces working lung tissue, the lungs become less able to transfer oxygen to the blood. Patients ultimately are at risk of early death from respiratory failure. In the case of IPF, which has been linked to smoking, most patients live for fewer than five years after diagnosis.

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Lung fibrosis? Stem cell therapy holds promise - The Hindu

CRISPRs original promise appears to be coming to fruition after a potentially fatal hereditary gene was edited out of an embryo.

CRISPR or CRISPR-Cas9, to give it its full name is heralded as an advanced technique that could change the course of medicine by allowing researchers to cut out genetic mutations in embryos that contribute to hereditary conditions.

One of the first steps to this becoming a reality has taken place, with help from a team of international researchers that, for the first time, used CRISPR to correct a mutation that leads to heart conditions in future generations.

In a paper published to Nature, the team revealed that it used the technique on embryos in their earliest stage of development to cut out the genes that lead to the formation of hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in athletes and young people.

Affecting approximately 1 in 500 people, the condition is caused by a dominant mutation in the MYBPC3 gene. Those with the faulty gene have a 50pc chance of passing it on to their children.

To achieve this major breakthrough, the researchers generated stem cells from a skin biopsy from a person with HCM and, using CRISPR, specifically targeted the MYBPC3 gene for repair.

The donors own stem cells were then inserted in place of the mutation during the next round of cell division, by using either a synthetic DNA sequence or the non-mutated copy of the MYBPC3 gene as a template.

Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs, newly fertilised with the donors sperm.

To their surprise, analysis of the repair work was found to be both very safe and efficient. A high percentage of the embryonic cells were repaired, and it did not induce any unintended mutations in other genes.

This might allay of reports on CRISPR over the past few months, whichshowed examples of the technique mutating other genes unrelated to experiments, suggesting it could lead to more damage than good.

Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people, said Juan Carlos Izpisua Belmonte, a professor from the Salk Institute and one of the authors of the paper.

Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.

The team stressed, however, that these are still very preliminary results and more research will need to be done to ensure no unintended effects occur.

This latest news comes just days after a team in the US announced it had changed the DNA of a large number of one-cell embryos, paving the way for a process to correct defective genes that cause inherited diseases.

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CRISPR used to edit out sudden-death gene mutations in major first - Siliconrepublic.com

The secret to healing what ails you lies within your own DNA.(photo credit:DREAMSTIME)

Scientists have, for the first time, corrected a disease-causing mutation in early-stage human embryos using gene editing.

The technique, which uses the CRISPR- Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.

It could pave the way for improved in vitro fertilization outcomes as well as eventual cures for some thousands of diseases caused by mutations in single genes.

The breakthrough and accomplishment by American and Korean scientists, was recently explained in the journal Nature. Its a collaboration between the Salk Institute, Oregon Health and Science University and South Koreas Institute for Basic Science.

Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people, said Prof. Juan Carlos Izpisua Belmonte of Salks gene expression lab and a corresponding author of the paper. Gene editing is still in its infancy, so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations.

Though gene-editing tools have the power to potentially cure a number of diseases, scientists have proceeded cautiously partly to avoid introducing unintended mutations into the germ line (cells that become eggs or sperm).

Izpisua Belmonte is uniquely qualified to speak on the ethics of genome editing because, as a member of the Committee on Human Gene Editing at the US National Academies of Sciences, Engineering and Medicine, he helped author the 2016 roadmap Human Genome Editing: Science, Ethics and Governance.

Hypertrophic cardiomyopathy is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately one in 500 people. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50% chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children but also in their descendants.

The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with Hypertrophic cardiomyopathy and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donors cells own DNA -repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.

Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs that are newly fertilized with donors sperm. All the cells in the early embryos are then analyzed at single-cell resolution to see how effectively the mutation was repaired.

They were surprised by the safety and efficiency of the method. Not only were a high percentage of embryonic cells get fixed, but also gene correction didnt induce any detectable off-target mutations and genome instability major concerns for gene editing.

The researchers also developed an effective strategy to ensure the repair occurred consistently in all the cells of the embryo, as incomplete repairs can lead to some cells continuing to carry the mutation.

Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated, said Jun Wu, a Salk staff scientist and one of the authors.

This was in part because, after CRISPR- Cas9 mediated enzymatic cutting of the mutated gene copy, the embryo initiated its own repairs. Instead of using the provided synthetic DNA template, the team surprisingly found that the embryo preferentially used the available healthy copy of the gene to repair the mutated part.

Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos, said Wu.

The authors emphasized that although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.

Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits, they added.

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Early gene-editing holds promise for preventing inherited diseases - The Jerusalem Post

Invivo Therapeutics (NASDAQ:NVIV) (OTCQB:NVIVD) has paused patient enrollment in the approval trial of its bioresorbable spinal implant, Neuro-Spinal Scaffold, after a third patient in the study died. The company states that all three deaths have been determined to be unrelated to the product or the implantation procedure, used in patients rendered paraplegic by a spinal cord injury, but the company's shares tanked 27%.

Unless Invivo can somehow shake off the product's worrisome reputation - to this end, it is talking with the FDA to see if enrollment criteria ought to be changed or the study altered in other ways - it will have to rely on its one remaining product, an injected spinal cord injury therapy based on neural stem cells. But this is still in animal trials, so Invivo really needs its Neuro-Spinal Scaffold to be vindicated.

This is the second disappointment for the company in its attempt to develop this project. Four years ago the FDA refused to let it file on data from a pilot study, setting the approval date back by some years (InVivo Therapeutics suffers from FDA's timidity on biologic grafts, August 29, 2013).

The Neuro-Spinal Scaffold is made of two polymers, polylactic-co-glycolic acid and poly-L-lysine. It is implanted at the site of a spinal cord injury to provide structural support and a matrix through which the patient's neural tissue can regrow, after which the graft breaks down over several weeks.

The Inspire trial is testing its safety and probable benefit for the treatment of complete spinal cord injury at the T2-T12 and L1 positions - from roughly shoulder level to just above the waist. The primary endpoint is improvement of one or more grades on the on the American Spinal Injury Association impairment scale (AIS) at six months after implantation. The study is slated to enrol 20 patients, according to Clinicaltrials.gov, and is intended to support a filing for US approval via the humanitarian device exemption (HDE) route.

The most recent patient to sign up to the Inspire study underwent implantation in late June but died suddenly at a healthcare facility following discharge from the hospital.

Invivo could hardly be blamed for pointing out that some of the patients in the Inspire trial had had positive outcomes. One had improved from a complete injury (grade A on the AIS) to having some restored sensory and motor function (grade C) one month after treatment. Another had regained sensory but not motor function (grade B) at six months.

One patient who had improved from a complete injury (grade A) to having sensory function (B) at two months reverted to complete injury at three months, but was deemed to have regained this motor function at the six-month point. The company says that of the 16 patients currently in follow-up seven have improved on the AIS, four of whom have recovered both sensory and motor function to reach grade C.

Five further patients had not improved at six months, and four had shown no improvement but had not yet reached this point.

With trial enrollment on hiatus Invivo will have to wait to find out whether these results might be sufficient to get the graft an HDE approval. The company now hopes to complete enrollment in the first half of next year, and to file its FDA approval application in the second half of 2018.

Use of the Neuro-Spinal Scaffold in complete and incomplete spinal cord injury, at cervical and thoracic levels, is forecast to bring Invivo revenues of $268m in 2022, according to EvaluateMedTech's consensus. By 2022 the sellside sees it outsold by Invivo's only other product, a biomaterial-based scaffold used to deliver neural stem cells to help reconnect the spinal cord by re-growing nerves.

But the scaffold is the more advanced product, and Invivo will be relying on revenues from this to fund clinical development of the stem cell therapy. The trial delay puts this in jeopardy, as the company's shareholders are well aware.

Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.

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Third Trial Death Endangers Invivo - Seeking Alpha

Brain stem cells keep us young

Silvia Riccardi/SPL

By Jessica Hamzelou

YOUR brain may be to blame for your ageing body. A small cluster of stem cells in the brain seems to help mice stay young, and injecting extra stem cells helps them live longer. One day anti-ageing drugs might be able to replicate the effect in people.

Ageing is a complicated process, involving DNA damage, chronic inflammation, and worn-out cells, but we dont yet know which of these has the biggest impact on ageing. Dongsheng Cai at the Albert Einstein College of Medicine in New York has been investigating the role of the brain in ageing, since it controls most of our bodily functions.

His team previously found that the hypothalamus, which releases hormones that affect other organs, seems to affect how mice age. By interfering with a molecular pathway in the hypothalamus, the team extended the lifespan of mice by 20 per cent.

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Cais team wondered whether stem cells here might influence ageing. Although stem cells in the hypothalamus create new neurons throughout life, the team noticed that mice start losing them in middle age about 10 or 11 months old. By the time mice are 2 years old around 70 in human years the cells are basically all gone, says Cai.

Mice age faster if these stem cells are destroyed. There was a decline in learning and memory, coordination, muscle mass, endurance and skin thickness, says Cai. The mice died a few months earlier than untreated animals.

But injecting the hypothalamus with extra stem cells, taken from the brains of newborn mice, slowed down this premature ageing, and gave mice an extra two to four months of life (Nature, DOI: 10.1038/nature23282).

First the team had to modify the stem cells so that they kick-started an anti-inflammatory pathway in the mice, otherwise the cells died and the injections didnt work. This suggests that it may be inflammation that usually causes the death of stem cells in the brain as we age.

The team found that the injected stem cells secreted a particularly large amount of microRNAs. These are small molecules that can affect the way genes work, and the types of microRNA in our blood are known to vary according to age. Cai isnt sure how the stem cell microRNAs might be working, but they seem to reduce biological stress and inflammation, he says.

Cai thinks his teams findings could one day lead to a treatment for ageing. Once the microRNAs have been identified, it might be possible to develop drugs that mimic their effects, he says.

This may have the potential to become a therapy in about 30 years, says Richard Faragher at the University of Brighton, UK, who says other teams are already working towards microRNA drug treatments. An alternative strategy would be to target inflammation more generally. I can see us taking multiple approaches, says Faragher.

This article appeared in print under the headline Stem cell boost slows down ageing

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Stem cells in the brain's hypothalamus help mice stay young - New Scientist

Sutro BiopharmasSTRO-001eliminates or significantly slows the growth ofnon-Hodgkin lymphoma and multiple myeloma tumors, studies in mice indicate.

Sutro expects the results to support its investigational new drug application for STRO-001. The U.S. Federal Drug Administration must approve the application before the company can start clinical trials of the therapy. It is planning a Phase 1 trial in early 2018.

STRO-001, an antibody drug conjugate, targets the surface protein CD74. It is found inup to 90 percent of malignant B-cells, but almost no normal tissue. After binding to a cell with CD74, the drug releases a toxic payload that kills the cell.

Sutro tested STRO-001 on tissue samples collected from patients with diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.

The company presented the findings at theAmerican Association for Cancer Research annual meetingin Washington in April. STRO-001 eliminated malignant plasma B-cells in mice with multiple myeloma mice, researchers said. And the mice remained tumor-free through the four-month study, while placebo-treated mice died within 35 days.

Sutro is now reporting that STRO-oo1 eliminates tumor cells or significantly delays tumor growth in mice with large B-cell lymphoma and mantle cell lymphoma.

In addition, the therapy led to mice with mantle cell lymphoma living longer than mice treated with a placebo, whose disease continued to progress.

Combining STRO-001 with the chemotherapies Levact (bendamustine) and Rituxan (rituximab) was more effective against diffuse large B-cell lymphoma tumors than chemo alone, the team added.

They reported the results in June atthe 14th International Conference on Malignant Lymphomain Lugano, Switzerland, and at the 22nd Congress of the European Hematology Associationin Madrid. Thepresentation was titled STRO-001, a Novel Anti-CD74 Antibody Drug Conjugate (ADC) for Treatment of B-Cell Non-Hodgkins Lymphomas (NHL).

STRO-001 also reduced multiple myeloma activity, or even eradicated the cancer, in mice, Sutro said.

In another presentation at the hematology convention, it reported that129 days after receiving STRO-001, none of the mice in a myeloma study had cancer in their bone marrow. In contrast, control animals died within 35 days, with half their bone marrow filled with myeloma cells.

The presentation was titled Targeting CD74 in Multiple Myeloma with a Novel Antibody Drug Conjugate (ADC), STRO-001.

These results are the clearest, most compelling evidence that STRO-001 performs effectively in multiple malignant B-cell lines and animal tumor models, Bill Newell, CEO of Sutro, said in a press release.

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STRO-001 Eliminates or Slows Growth of Myeloma and Lymphoma in Mice, Studies Show - Myeloma Research News

Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries and give physicians new options to combat cardiovascular disease, the worlds leading cause of death.

But new techniques developed at the Morgridge Institute for Research and the University of WisconsinMadison have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modeling and clinical application.

Reporting in the July 10 issue of the journal Proceedings of the National Academy of Sciences, scientists in the lab of stem cell pioneer James Thomson describe methods for generating and characterizing arterial endothelial cells the cells that initiate artery development that exhibit many of the specific functions required by the body.

Further, these cells contributed both to new artery formation and improved survival rate of mice used in a model for myocardial infarction. Mice treated with this cell line had an 83 percent survival rate, compared to 33 percent for controls.

The cardiovascular diseases that kill people mostly affect the arteries, and no one has been able to make those kinds of cells efficiently before, says Jue Zhang, a Morgridge assistant scientist and lead author. The key finding here is a way to make arterial endothelial cells more functional and clinically useful.

Cardiovascular disease accounts for one in every three deaths each year in the United States, according to the American Heart Association, and claims more lives each year than all forms of cancer combined. The Thomson lab has made arterial engineering one of its top research priorities.

New techniques have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modeling and clinical application.

The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, Zhang says.

The research team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signaling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR-Cas9 gene editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.

With this technology, you can test the function of these candidate genes and measure what percentage of cells are generating into our target arterial cells, says Zhang.

The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.

Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery, says Thomson, director of regenerative biology at Morgridge and a UWMadison professor of cell and regenerative biology. This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.

Thomsons team, along with many UWMadison collaborators, is in the first year of a seven-year project supported by the National Institutes of Health on the feasibility of developing artery banks suitable for use in human transplantation.

In many cases with vascular disease, patients lack suitable tissue from their own bodies for use in bypass surgeries. And growing arteries from an individual patients stem cells would be cost prohibitive and take too long to be clinically useful.

The challenge will be not only to produce the arteries, but find ways to ensure they are compatible and not rejected by patients.

Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line, says Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

This article has been republished frommaterialsprovided bythe University of Wisconsin-Madison. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Zhang, J., Chu, L., Hou, Z., Schwartz, M. P., Hacker, T., Vickerman, V., . . . Thomson, J. A. (2017). Functional characterization of human pluripotent stem cell-derived arterial endothelial cells. Proceedings of the National Academy of Sciences, 201702295. doi:10.1073/pnas.1702295114

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Stem Cell Advance Brings Bioengineered Arteries Closer to Reality - Technology Networks

SINGAPORE The use of stem cell treatment to repair liver cirrhosis, or hardening of the liver, will be tested in a clinical trial here involving 46 patients and costing S$2.6 million.

The four-year study, which was launched yesterday, came amid a growing waiting list in Singapore for a liver transplant, which is currently the only cure for patients with end-stage liver cirrhosis.

Conducted by a multi-centre team from several restructured hospitals here, the study is led by the National University Hospital (NUH).

Liver failure is one of the top 20 causes of death in Singapore, but many patients are not suitable for a transplant due to factors such as age and surgical fitness.

Out of every five patients doctors see with end-stage liver disease, only one qualifies for a liver transplant, said Dr Dan Yock Young, principal investigator of the clinical trial and senior consultant at NUHs division of gastroenterology and hepatology.

(A liver transplant) is curative, but it is a complex procedure, and many patients are not suitable for it. For these patients, treatment is limited, but morbidity and mortality rates are high as high as 50 per cent in one year and this is probably worse than many (of the) other terminal illnesses we talk about today, he said.

Animal studies conducted over the last five years have shown that stem cells can reconstruct the micro-environment of a normal liver.

Like how branches are of critical importance in supporting the leaves and fruits of a tree, the endothelial (stem) cells contribute to supporting a nutritious environment for the hepatocyte (liver) cells, Dr Dan explained.

While similar stem-cell studies have been conducted in other centres in Asia, there has been no definitive evidence of the benefits of the treatment for liver patients.

The study will recruit 46 patients aged between 40 and 70 years old, and who are at the terminal stages of chronic liver disease, over three years. It is funded by the National Medical Research Council.

During the clinical trial, patients will be divided into a therapeutic group and a control group.

All patients will receive an injection to stimulate their bone marrow cells as part of the supportive treatment for their liver cirrhosis. However, only patients in the study group will have the stem cells from the bone marrow extracted and deposited directly into their liver for more targeted repair.

Using ones own stem cells will avoid the problem of cell rejection.

The liver tissue will be examined three months later, and an investigation to compare pre- and post-transplant results will be conducted after a year.

Since invasive surgery is not required for stem-cell therapy, the fatality risk is significantly lowered for the patient. However, other risks such as severe bleeding and infections still remain, given the patients weakened condition.

NUH also noted that the stem-cell therapy does not replace liver transplants, and the latter remains the best available treatment for liver cirrhosis.

It is very painful to turn patients away when we cannot offer them a liver transplant, said Dr Dan, adding that this stem cell therapy will serve as an alternative option.

We hope that this is a stepping stone to trials for stem cell candidates, he added.

MORE WAITING FOR A LIVER

The number of people on the waiting list for a liver transplant has been growing in recent years. In June last year, it was reported that there were 54 people on the list, more than double the 24 patients in 2011.

Chronic Hepatitis B remains the primary cause of non-alcoholic fatty liver disease, which refers to a range of liver conditions affecting people who drink little to no alcohol. However, obesity has become a contributing factor to the illness as well.

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New NUH study to test stem cells as treatment for liver disease - TODAYonline

Pancreatic cancer is an especially tough cancer to beat because it usually isn't detected until late in the disease. But a new blood test that uses two protein markers is showing promise for picking it up earlier, researchers report.

The blood test is still in the investigative stages. A new study, published inScience Translational Medicine, finds it works with an 87 percent sensitivity, meaning that's how often it can correctly identify someone with stage 1 or 2 pancreatic cancer. It also had 98 percent specificity, meaning the ability to accurately rule out cancer in a person who doesn't have it.

"What we found is a biomarker panel that's very cheaply, conveniently assayed in the blood and that uses conventional methods used by diagnostic centers around the country. So it could be used to detect pancreatic cancer at stages 1 and 2," study author Kenneth Zaret, director of the Penn Institute for Regenerative Medicine, told CBS News.

The 5-year survival rate for pancreatic cancer patients is only 7 percent, and it's projected to become the second leading cause of cancer death in the United States by 2020.

Zaret worked with Gloria Petersen, from the Mayo Clinic, to identify a pair of biomarkers that physicians could soon use to discover the disease earlier.

Zaret began searching for a way to detect pancreatic cancer earlier after his own mother-in-law passed away from it about 15 years ago.

At the time, scientists were primarily studying late-stage cancer tissues in the lab in order to identify biomarkers for the disease in cells, in the hopes of developing a blood test for pancreatic cancer.

"But I didn't see how that could detect early stage markers," said Zaret, whose expertise is in genetics and stem cell biology, not cancer.

"I came from outside the field and applied genetic reprogramming methods so that's where the novelty is in terms of discovery," he said.

He and colleagues took late stage pancreatic cancer cells and reprogrammed them genetically to a "stem cell-like state" what's called an induced pluripotent stem cell.

"Like an early embryonic stem cell," he said.

Then they let those cells redevelop into differentiated cell types and the cells underwent a progression from early to late stage cancer.

Using those cells, they discovered 107 proteins released from early stage pancreatic cancer cells. From there, they looked for those proteins, which could be found in very low levels in human blood and that would be easy to test for based on current blood lab technologies.

"From those we found a marker called THBS2," said Zaret.

Serum levels of THBS2 were significantly elevated in blood samples from 81 pancreatic cancer patients compared to 80 healthy people who served as the control group.

While the results were promising, "they were not powerful enough to do something statistically with," said Zaret.

So the scientists further improved the test's sensitivity and specificity by combining it with another protein, CA19-9, already being used as a clinical marker. They analyzed samples from 197 cancer patients, 140 healthy people in a control group, and 200 people with pancreatic disorders that weren't linked to cancer.

The combination THBS2 and CA19-9 ratcheted up the test's accuracy to 98 percent. They believe it could serve as a low cost way to screen higher risk people someone with a relative with the disease, or who has diabetes, for example for pancreatic cancer.

"The bottom line is, by looking at two markers and not just the single marker we increased the range of what we could detect in a person with pancreatic cancer," said Zaret.

Combining his background with the expertise of colleagues at the Mayo Clinic made the discovery possible.

"We collaborated with Dr. Gloria Petersen at the Mayo Clinic in Minnesota. She is an expert in obtaining blood samples from pancreatic cancerpatients and controlling for age, sex, and other parameters. So we had a very rigorous study. The extreme care with which we matched patients and controls is part of the strength of our work," he said.

The next step in their work is to use the test in more and more patients, specifically those at higher risk for pancreatic cancer.

"It will let us assess whether our biomarker test will allow us to detect cancer even before it is stage 1," said Zaret "stage negative 1," so to speak.

"Our big goal is to be able to detect pancreatic cancer before it's at the 13 percent survival rate, which is where a stage 1 diagnosis is now."

If that succeeds, doctors would be able to identify more patients earlier, raising hopes of achieving higher survival rates for pancreatic cancer down the road.

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Blood test holds promise for earlier pancreatic cancer detection - CBS News

(Picture: Mercury Press)

On 19 June, Daniel Farbace passed away after contracting parainfluenza, while also battling acute myloid leukaemia. He was just 21 months old.

His mum, Ali Farbace, has shared a photograph of herself kissing her son goodbye as a way to celebrate his life.

His last act was to save us, says Ali, 35, explaining that by passing away, Daniel had saved his parents from the impossible decision to turn off their childs life support.

When people say things like sorry for your loss I dont really like that.

He never lost at anything we think he sacrificed himself for us.

Hes made it a lot easier for us. My feeling was that I wanted him to have quality of life, but it was stacking up against him, it wasnt fair.

We just didnt want him to suffer.

If we had had to make the decision to turn the machine off then we would never have forgiven ourselves. I do think he has saved us from that.

Ali and her husband, Dan, spent nine days with Daniels body after he died, staying to make memories with their child at Demelza Childrens Hospice in Sittingborne Kent from 19 June to 26 June.

On the ninth day, Ali and Dan brought Daniels body home to have a funeral.

It would have broken us to go home straight away with nothing, said Ali. When we got to Demelza it was just perfect. To spend that time with Daniel was lovely.

We sang, and talked to him and read to him. We got so much more time. I didnt want to leave him on his own. He was so beautiful.

He had never spent a day apart from me. He had his own bedroom, he was still a person, and it was so nice to see him without the tubes.

Our friends got to come and visit too, and we really got to say goodbye.

The night before his funeral he came home for the night. We were just glad we could all come home together. To spend our last night together was really nice.

Its cr*p, and wed do anything to have him back, but some children dont get to go home.

Despite being on life support for nine days, Daniels death still came as a surprise.

When he was born on 29 September 2015 at 26 weeks, Daniel had to be resuscitated and was on a ventilator for 16 days. He survived that, went home, but had to return to hospital in April 2016 when his parents noticed pin prick marks on his skin.

Doctors initially thought it could just be a viral rash, but soon lumps developed.

He was admitted to Great Ormond Street Hospital in April, where doctors investigated possibilities of Daniel having leukemia and neuroblastoma.

On 19 April Dan and Ali were told Daniel had leukemia, with an official diagnosis on 21 April.

It was unusual because the leukaemia was presenting as something else, said Ali.

They told us it was treatable, they gave him a 68 to 72 per cent chance he would survive.

It was just awful. Everything gets taken out of your hands. We just wanted our baby.

AML is an aggressive, rare cancer that affects the blood. Stem cells found in bone marrow produce too many immature white blood cells which are called blast cells.

The blast cells are unable to properly fight off infection, and if too many are produced the number of oxygen-carrying red blood cells and platelets, which clot the blood, can be reduced.

Symptoms of the illness include pale skin, tiredness, frequent infections, and breathlessness.

In severe cases AML can make sufferers extremely vulnerable to life-threatening infections. A bone marrow or stem cell transplant may be necessary alongside chemotherapy or radiotherapy to combat the illness.

After four courses of chemotherapy, Daniel seemed to be getting better. He was even able to go home for his first birthday.

But seven months later, the leukemia had returned, this time bringing a lump in Daniels brain with it.

After numerous chemotherapy treatments to battle theacute myloid leukaemia that had spread to Daniels blood and bone marrow, Daniel contracted parainfluenza.

Unable to fight off the infection, he spent nine days on life support before passing away.

He was on life support for nine days, there were so many times when I thought, he was going to die, said Ali.

Then the day he did die we didnt expect it. We just thought, You little b*gger.

I got to carry him across the corridor to the hospital cold room, which was an honour.

Its quite hard coping with death, he was still our baby.

We shared that picture to show the story goes on after death. People have been so supportive.

Dan said that picture looks like when they used to lay warriors to rest and Daniel was a fighter.

He was always happy and always smiling. I know it sounds crazy, but he never really seemed that unwell. When he was sick he was just quiet.

Now, Ali and Dan want to keep their sons legacy alive by using his story to raise awareness about blood and bone marrow donation.

So far, Daniel has helped to raise over 25,000 for charity.

We just want to get the message out about donating blood and bone marrow transplant now, says Ali.

Sometimes Daniel had to wait 12 hours for transfusions. But he would have died a long time ago if it hadnt have been for donors.

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Mum shares heartbreaking photograph kissing her son goodbye after he passed away while battling acute myloid ... - Metro

July 10, 2017 Arterial endothelial cells derived from human pluripotent stem cells express activated NOTCH1 (in red, which is an arterial endothelial cell marker) and CD144 (in white, which is a pan endothelial cell marker). Credit: The Morgridge Institute for Research

Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries and give physicians new options to combat cardiovascular disease, the world's leading cause of death.

But new techniques developed at the Morgridge Institute for Research and the University of Wisconsin-Madison have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modeling and clinical application.

Reporting in the July 10 issue of the journal Proceedings of the National Academy of Sciences (PNAS), scientists in the lab of stem cell pioneer James Thomson describe methods for generating and characterizing arterial endothelial cellsthe cells that initiate artery developmentthat exhibit many of the specific functions required by the body.

Further, these cells contributed both to new artery formation and improved survival rate of mice used in a model for myocardial infarction. Mice treated with this cell line had an 83 percent survival rate, compared to 33 percent for controls.

"The cardiovascular diseases that kill people mostly affect the arteries, and no one has been able to make those kinds of cells efficiently before," says Jue Zhang, a Morgridge assistant scientist and lead author. "The key finding here is a way to make arterial endothelial cells more functional and clinically useful."

Cardiovascular disease accounts for one in every three deaths each year in the United States, according to the American Heart Association, and claim more lives each year than all forms of cancer combined. The Thomson lab has made arterial engineering one of its top research priorities.

The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, Zhang says.

The research team applied two pioneering technologies to the project. First, they used single-cell RNA sequencing to identify the signaling pathways critical for arterial endothelial cell differentiation. They found about 40 genes of optimal relevance. Second, they used CRISPR-Cas9 gene editing technology that allowed them to create reporter cell lines to monitor arterial differentiation in real time.

"With this technology, you can test the function of these candidate genes and measure what percentage of cells are generating into our target arterial cells," says Zhang.

The research group developed a protocol around five key growth factors that make the strongest contributions to arterial cell development. They also identified some very common growth factors used in stem cell science, such as insulin, that surprisingly inhibit arterial endothelial cell differentiation.

"Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery," says Thomson, director of regenerative biology at Morgridge and UW-Madison professor of cell and regenerative biology. "This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing."

Thomson's team, along with many UW-Madison collaborators, is in the first year of a seven-year project supported by the National Institutes of Health (NIH) on the feasibility of developing artery banks suitable for use in human transplantation.

In many cases with vascular disease, patients lack suitable tissue from their own bodies for use in bypass surgeries. And growing arteries from an individual patient's stem cells would be cost prohibitive and take too long to be clinically useful.

The challenge will be not only to produce the arteries, but find ways to insure they are compatible and not rejected by patients.

"Now that we have a method to create these cells, we hope to continue the effort using a more universal donor cell line," says Zhang. The lab will focus on cells banked from a unique population of people who are genetically compatible donors for a majority of the population.

Explore further: Exposure to cardiovascular risk factors linked with arterial distensibility in adolescence

More information: Jue Zhang el al., "Functional characterization of human pluripotent stem cell-derived arterial endothelial cells," PNAS (2017). http://www.pnas.org/cgi/doi/10.1073/pnas.1702295114

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Stem cell advance brings bioengineered arteries closer to reality - Medical Xpress

Australian researchers have successfully turned stem cells from Friedreichs ataxia (FA) patients into heart cells to study molecular anomalies that maycontribute to this disease.

Theseheart cells in a dish provide valuable information for the design of novel treatments.

Their study, Friedreichs ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. appearedin the journal Aging.

FAis caused by low levels of the frataxin protein due to anomalies in the gene sequence encoding this protein repeats of DNA portions within the gene. The higher the number of repeats, the sooner the onset of FAand its associated complications.

Frataxin plays an important role in the mitochondria, the cells powerhouse, so the mutated protein accounts for several symptoms that reflect deficiencies in energy production. The heart is one of the organs affected by this lack of energy.

Cardiomyopathy is detected in two-thirds of individuals with FRDA[Friedreichs ataxia], researchers wrote. Individuals with FRDA generally present with progressive cardiomyopathy of the left ventricle, which is the leading cause of death in FRDA due to arrhythmias and/or heart failure.

Previous studies have shown that death of heart cells, or cardiomyocytes, and fibrosis may contribute to heart complications in FA, but little is known about the diseases impact on the heart.

Researchers generated stem cell cultures using cells from three FA patients with heart complications. They then stimulated the development of these stem cells into cardiomyocytes basically, heart cells in a dish.

The new cardiomyocytes had low levels of frataxin, as expected, but alsoabnormal ionic currents, which are crucial for the normal functioning of these cells. They also had morevariation in their beating rates, which was linked todeficient calcium control, ultimately affecting howthe cardiomyocytes work.

Together, these results pave the way for understanding how FA patients develop abnormal heart activity as well as theuse of induced stem cells to studycardiomyopathy within the context of this disease.

Importantly, our data clearly indicates that FRDA iPSC [stem cells]- derivedcardiomyocytes can be used for screening of compounds able to alter or reverse phenotypes, in human cells, hence providing a novel and unique tool for FRDAresearch, researchers concluded.

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Researchers Create 'Heart Cells in a Dish' to Study FA Heart Disease - Friedreich's Ataxia News