StemCell Therapy

Appiah rang Leukaemia Cares helpline from the point of diagnosis until well after the end of her daughters life. Sometimes Id call them as a means of support, she says, when things got really rough, when her medications were really powerful, and the chemo made her so unwell. She rang when she had panic attacks; an NHS psychologist had told her that these were likely, and that she should breathe into a brown paper bag, but Appiah found speaking to a person more soothing.

With a laugh, Appiah notes that shed ring the helpline at other times, too: Sometimes Id be out with Imogin, and shed be in the pram, being naughty, and all of my patience was going down the drain, and Id phone Leukaemia Cares nurses, and say: Look, Im feeling so depressed, my daughters shouting, I dont know what to do!

But I might also say: Nurse, Im actually feeling good today.

Appiah says the support of an independent person was invaluable: When your child is so ill, you need to speak to someone who doesnt know your name you need an outsider you can unload to. I didnt want anyone thinking: Here Sheila comes again!

You become self-conscious about your situation and dont want to be a burden on your friends and family. With the helpline, you wont be judged: they just listen. You get it out of your system and then go do the shopping at Sainsburys.

When Imogin was well, shed go to school. But she also spent weeks at a time in isolation in St Georges Hospital, with her mother by her side. Once, she had a bad reaction to a medication and went into cardiac arrest. She was crying and saying, Please, please! and they were giving her all sorts of medicine. The doctors were battling to keep her stable and I dived into the bed with her and told her: Youre going to be OK. I lay down with her and I started singing with her. And then, once she stabilised, she said: Now can I watch High School Musical?"

Appiah shakes her head, laughing: Thats what she was like: I was on thedoor of death, but I have something else planned. I want to watch my video and none of you are going to stop me!

Charities sent the pair to Disneyland Paris twice. The first time was fantastic, says Appiah, the second time Imogin was in and out of consciousness. But they said we should go, to make memories, Appiah explains. Imogin got to be a celebrity for a day and went to Hamleys in a limousine to get anything she wanted.

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'My daughter's death took me to the darkest place, but I've learned it's possible to come back' - Telegraph.co.uk

GammaDelta Therapeutics is a company that focusses on utilizing the unique properties of gamma delta () T cells to develop novel immunotherapies for patients.Through their research, the companys scientists have discovered a number of targets and antibodies that have the potential to modulate the activity of T-cells in situ. Therefore, GammaDelta Therapeutics recently announced the formation of Adaptate Biotherapeutics, a spin-out company that will focus on research in this area.

Technology Networks spoke with Natalie Mount, CEO of Adaptate BioTherapeutics, to learn more about the company's aims and the challenges faced when developing immunotherapies and advancing them into clinical studies.

Molly Campbell (MC) Please can you tell us more about T-cell based cell therapy products and their potential applications?Natalie Mount (NM): T cells play an increasingly appreciated critical role in immune surveillance, being able to recognize malignant/transformed cells through a pattern of stress markers. The recognition mechanism is not major histocompatibility complex (MHC) restricted and not dependent on a single antigen.

T cells therefore have potential in a range of disease indications, including both hematological and solid malignancies and a positive correlation between T cell infiltration and prognosis/survival in patients has been determined in a range of oncology indications in studies published in the literature by other groups. Additionally, as a cell therapy, T cells can be used in an allogeneic setting (ie, T cells can be used for unrelated recipients without a requirement for matching).

Both Adaptate Biotherapeutics and GammaDelta Therapeutics are focussed on harnessing the potential of T cells, in particular the V1 subtype which is the predominant T cell type in tissue.This is based on data originating from the labs of Professor Adrian Hayday of Kings College London and the Crick Institute, supported by Cancer Research Technology and also from Professor Bruno Silva Santos of Institute for Molecular Medicine at the University of Lisbon, Portugal.

Previous clinical trials conducted by other groups/companies targeting or using T cells in cancer have focussed on the V2 subtype which is predominant in the blood. These trials have demonstrated safety, but efficacy has been limited.Compared to V2 cells, V1 cells, which are the focus of work at Adaptate Biotherapeutics and GammaDelta Therapeutics, are less susceptible to exhaustion and activation induced cell death. Expansion of donor derived V1 has been shown to be a positive prognostic indicator for acute myeloid leukemia patients following hematopoietic stem cell transplant.

MC: Why are current immunotherapy treatment approaches limited?NM: Immunotherapy approaches have had very significant success and impact in Oncology recently, however, challenges and unmet needs remain.One challenge is effective treatment of solid tumors. The hypoxic, low nutrient tumor environment provides a challenge for successful infiltration and activation of T cells. However, V1 T cells have real potential as they are naturally tissue resident and hence primed for this environment. In addition, their ability to recognize malignant cells by a pattern of markers expressed by dysregulated, transformed cells rather than one specific antigen presented by the MHC provides an additional advantage for both specificity of response and maintenance of efficacy.

T cells act as orchestrators of an immune response and, following recognition of a cell as malignant, they induce maturation of monocytes and signal to alpha beta T cells, hence increasing immunogenicity of the tumor and providing a sustained response, with potential even in tumors with low mutational load which have proven challenging with other immunotherapies.

MC: The new spin-out company, Adaptate Biotherapeutics, will build on GammaDelta's knowledge to modulate T-cell activity using therapeutic antibodies. Why have you decided to create a spin-out focusing on this area of research?NM: GammaDelta Therapeutics was formed in 2016 to harness the unique properties of T cells, and since then has gained extensive knowledge of T-cell biology. In addition to gaining insight into cell growth and isolation, the companys scientists have also discovered a number of targets and antibodies that have potential to modulate the activity of T-cells in situ.

GammaDelta Therapeutics now has a pipeline of cell therapy products progressing into clinical development under the guidance of CEO, Dr Paolo Paoletti.

Adaptate Biotherapeutics will be developing antibodies which will be administered to cancer patients to modulate activity of the patient's gamma delta T cells in situ.

Delivery of cell therapy and antibody therapeutics each needs focus and specific skillsets and formation of two independent entities will facilitate this. The two companies share a common goal to harness the potential of T cells to bring effective therapies to patients. Both benefit from support of the scientific founding team and have common investors, Abingworth and Takeda Pharmaceuticals.MC; Your goal is to develop targets and antibodies that can modulate the activity of T-cells and advance them into clinical studies. What challenges exist here, and how do you hope to overcome them?

Our assets at Adaptate Biotherapeutics are currently at the pre-clinical stage and therefore face the non-clinical development risks for a novel therapy. However, these risks are mitigated by biology understanding from our scientific founders and the work at GammaDelta Therapeutics to date.

One of our challenges is in selecting the most suitable patient population for initial trials. There is potential for opportunity for our therapeutics in multiple indications but the utility of animal models in modelling the human immune compartment and human tumor setting is limited. Therefore in vitro and ex vivo models are important, in addition to the learnings from other clinical studies.

MC: GammaDelta Therapeutics formed in 2016 to gain extensive knowledge of T-cell biology and to developing a portfolio of investigational cell therapies. Some of these cell therapies are poised to enter clinical development. Can you tell us any further information about these therapies?NM: GammaDelta was set up to develop cell-based therapy utilizing ex-vivo expanded tissue resident gd T cells. Subsequent acquisition of Lymphact SAS allowed GammaDelta to augment its capabilities with a platform for ex-vivo expansion of blood derived V1 cells. GammaDelta is focussed on progressing ex-vivo expanded skin and blood derived V1 cells to the clinic both in unengineered and engineered formats. Clinical trials are currently on track to commence in the next 12-18 months.

MC: Your press release states: "The two companies will continue sharing their insights into T-cell biology as they work towards developing different therapeutic modalities". How will you continue to share insights here?NM: Antibodies and cells represent complementary approaches to realizing the potential of T cell activity for patients with solid and haematological malignancies.

The two companies will work together in areas of common interest in the biology of these fascinating cells, such as understanding the phenotype and behavior of T cells in tumors and mechanisms of cell regulation as well as the effects of antibody on the T cells.

We have deliberately established a contractual framework that allows efficient collaboration between scientists of both the companies via formal and informal meetings.

MC: What are your hopes for the future of Adaptate Biotherapeutics?NM: This is a remarkable time in the development of new immune therapies, and the role of "non-conventional" cell types of the immune system is coming to the fore as we recognize the successes achieved to date and the needs of patients and related scientific challenges that remain.

Both GammaDelta Therapeutics and Adaptate Biotherapeutics are at the lead of translating our increasing understanding of T cell biology and its potential into therapies to address these unmet needs.

Adaptate Biotherapeutics has a fantastic opportunity to build and accelerate a portfolio of antibody-based approaches in this novel area and I look forward to the successful translation of this science into therapies with the support of our investors at Abingworth and Takeda Pharmaceuticals.

Dr Natalie Mount, CEO of Adaptate Biotherapeutics was speaking with Molly Campbell, Science Writer, Technology Networks.

Read more here:
Harnessing Gamma T Cells To Bring Effective Therapies to Patients - Technology Networks

Bradley J. Fikes, an ever-on-the move ball of energy who roamed the labs of San Diego as the Union-Tribunes biotech writer, chronicling scientists efforts to find ways to alleviate human suffering, died on Wednesday. He was 61.

His family said he passed away of natural causes at his home in Grantville. He had been dividing his time between poring through medical journals and exploring his two other great loves, the San Diego Zoo and Safari Park in Escondido.

Fikes who was part Dr. Dolittle, part Inspector Gadget was especially excited earlier this week as he pulled together a story about two extremely rare platypuses that are being introduced at the zoo.

He talked about it almost non-stop as we drove back and forth between the zoo, said Michelle Guerrero, a Union-Tribune illustrator and graphics reporter. He knew how animals evolve, their relationship with humans, and how they ended up at zoos.

He had the wonderment of a child, the complexity of a scientist and an artful way of coming up with the words to explain it all.

This is the last known photograph of Bradley J. Fikes, the Union-Tribunes biotech writer

(Howard Lipin/The San Diego Union-Tribune)

Fikes was forever in the middle of things, in a literal and figurative sense.

Every Friday, he staked out a table at Bella Vista, a heavily-trafficked cafe between the Salk Institute and UC San Diego. In science, anybody whos anybody and everybody who wants to become somebody hangs out at Bella and networks.

Fikes listened in, took notes, then speed-wrote stories that were devoured by the biotech brigade. Fikes could talk non-stop for 30 minutes about the nature of pluripotent stem cells, then do another half-hour on telomeres and wrap up with some thoughts on chimeras.

He also hung at Bella because of the food. He loved the comfort fare. He loved it so much that Bellas owner, Amanda Caniglia, named a spaghetti dish after him. She called it Il Journalista.

Fikes was impossible to miss. By his own admission, he was a walking fashion disaster. He wore odd-colored business shirts that clashed with his suspenders, and slacks that never made contact with an iron. At times, cellphone cables hung out of his pockets like limp licorice. He feared not having enough power to use his cellphone to watch Black Sabbath and Van Halen videos on YouTube.

People lovingly teased him, hoping for a retort. He often snapped his own suspenders, smiled, and asked, Are you jealous?

News of his death elicited a wave of sorrow and praise Thursday from the countys science industry, whose denizens knew Fikes as a deliciously quirky figure who understood the arcane language of science and the people who are drawn to it.

I always prepped scientists who were meeting him for the first time not to be fooled by the red suspenders and taped glasses, said Chris Emery, communications director at Scripps Research in La Jolla. Bradley is the most legit science reporter youll encounter.

Fikes also was lauded for highlighting the needs and interests of patients, particularly Theresa Blanda and Nancy Davidson, a pair of Orange County women who suffered from debilitating blood cancers.

He followed their cases closely as they sought experimental drugs that might keep them alive. Blanda also supported the biotech companies who were willing to pursue fresh alternatives, even though the outlook was grim.

Blanda later died. But UC San Diego cancer specialist Catriona Jamieson, who helped with the womens treatment, said Fikes was invaluable in telling their stories.

Bradley championed their cause by telling their stories clearly, said Jamieson. He was a serious advocate for patients. He persevered and got difficult stories right. Ive always been a big fan of Bradley.

He was also very keen on gender diversity in life science, said Dawn Barry, president and co-founder of LunaDNA. We lost such a warm, engaged, important San Diego citizen.

Bradley Joseph Fikes was born in San Diego on Jan. 30, 1958, the son of Garland Fikes, a blueprinter, and Trudy Fikes, a nurse who worked at Mercy Hospital.

He learned to read and comprehend difficult information early, which led to a life-shaping moment when he was roughly 6 years old.

Fikes discovered a medical encyclopedia that captivated his attention. One afternoon, he shared the book with neighborhood children, which alarmed their parents because it showed explicit images of the human body.

It was just anatomy; there was nothing wrong with it, said Vanessa Dimalanta, one of Fikes three sisters. That was Brad. Always reading, always sharing with others.

His obsession with science deepened while he was attending San Diego High School and it grew at San Diego State University, where he found his calling journalism.

Like hundreds before him, Fikes joined the Daily Aztec, the campus newspaper, which operated in a raucous newsroom that had male mannequin legs hanging from the ceiling.

This is where he found his tribe, said Karla Peterson, a Union-Tribune columnist who also was part of the Aztec staff.

He loved the work and was at it all of the time. He had so much energy. When we threw parties, Bradley was always the first to arrive and the last to leave. He was happy. He knew how to enjoy life.

Union-Tribune theater critic James Hebert said, He struck me as a total original from the moment I met him like our own slightly mellower answer to Hunter S. Thompson. And it was always resoundingly clear just from being around him that he loved what he did.

After graduating from San Diego State in 1984, Fikes worked as a freelance writer and then spent three years as a staff writer for the Chula Vista Star-News. In 1990, he joined the staff of the San Diego Business Journal, where he worked for six years. Then he spent another year covering business for the San Diego Daily Transcript.

Because of the deep connections he had built in the local business community, Fikes took a brief career detour into corporate communications for a high-tech firm in 1997. He quickly realized his mistake. Despite the higher salary, Fikes missed working as a newspaper journalist. In 1997, he contacted then-North County Times business editor Pam Kragen looking for a staff-writing job. He was hired immediately.

Brad had a bit of the nutty professor about him when it came to style, but his brain worked like a computer, Kragen said.

He was able to store vast amounts of information and call on it to write knowledgeably, accurately, quickly and prolifically. After returning to the newspaper business, I remember Brad telling me that all he ever really wanted to do was to be a journalist because he loved the process of discovering something new and then sharing it with readers. He was very proud to work at the Union-Tribune.

He loved the job and the newsroom was his home.

Union-Tribune Publisher and Editor Jeff Light said, Bradley had a rare combination of intellect, curiosity and character. It made him a wonderful journalist.

By character, I mean the strength to be true to himself. But he also had a vulnerability that made you feel protective of him. He was a beloved figure. Our newsroom will miss him terribly.

Fikes is survived by three sisters, Sue Tate of San Diego; Vanessa Dimalanta of San Diego, and Kimberley Cross of San Diego.

Originally posted here:
Union-Tribune biotech writer Bradley J. Fikes, beloved by colleagues, dies at 61 - The San Diego Union-Tribune

Science has identified in the plant kingdom the "missing link" of cellular immortality between human and single-celled animals, according to a new study led by scientists from Arizona State University and Texas A&M University.

"This is the first time that we have identified the detailed structure of the telomerase component from plants," said co-author Dr. Julian Chen, a professor of biochemistry at Arizona State University. The study was published Monday in the Proceedings of the National Academy of Sciences journal.

Telomerase is the enzyme that creates the DNA of telomeres, the compound structures located at the tips of our chromosomes. Telomeres protect our cells from aging as they multiply.

"So in terms of fundamental research, this is a really big breakthrough because now finally we have a way to study telomerase in plants and to understand how different or similar they are from animals," Chen said.

Could the discovery possibly lead to humans one day living as long as the fabled "Methuselah" tree, a bristlecone pine species that can live over 5,000 years? Maybe one day.

"This is really basic research. The application to humans is really a long way away," Chen said.

In the meantime, however, experts like University of California at San Francisco's Elizabeth Blackburn are bullish. Blackburn won the 2009 Nobel Prize in Physiology or Medicine -- along with Johns Hopkins' Carol Greider and Harvard's Jack Szostak -- for their discoveries on telomeres and telomerase.

"Excitingly, this paper reports how plants fill in the missing links of telomerase RNA's eventful evolutionary history ... from our simplest forebears," Blackburn said. "This fundamental new understanding may pave the way to new routes to optimizing telomere maintenance for human health."

Think of telomeres as the plastic caps on the ends of your shoelaces. High levels of telomerase keep those telomeres long, thus allowing them to continue to protect our cells from damage as they divide.

Most of the cells in our body have very low levels of telomerase, and thus age as they divide (picture the shoelace tips wearing away until they are gone). Aging cells equal an aging body, with cells no longer functioning normally.

However, when the cell's ends are protected by telomeres, only a piece of the telomere, or cap, is lost as the cell divides, and the important DNA is left undamaged. Considering a typical cell divides about 50 to 70 times, having no protective cap could lead to chromosome instability or cells that stop dividing.

In humans, for example, egg, sperm and stem cell chromosomes contain high levels of telomerase, and so can continue to divide over and over and avoid rapid aging.

Yet even telomeres do not have eternal life. Each time a cell replicates, about 20 base pairs are lost from the telomere, or shoelace cap. We can lose even more -- 50 to 100 base pairs per cell division -- when our bodies are in oxidative stress.

We put our bodies into oxidative stress by smoking, eating a poor diet, stress and other harmful lifestyle behaviors. Between normal wear and tear and the oxidative stress of our lifestyles, even long telomeres are worn away.

But if science could harness the secret of the telomerase enzyme, it's possible that we could prolong the life of telomeres, slowing the aging process.

We might be able to reverse diseases in which telomeres are shortened, such as pulmonary fibrosis.

And here's another key benefit to unraveling this mystery: Cancer cells contain high levels of telomerase, allowing them to continue replicating themselves until they form tumors.

Switching off telomerase activity in cancer cells would shorten their telomeres, whittling them down to a nub called a "critical length," which then triggers programmed cell death.

The ultimate goal: stopping cancer cold.

When Blackburn, Greider and Szostak won the Nobel Prize in 2009, it was for their groundbreaking discoveries on telomeres and telomerase. They extracted telomere DNA from a single-celled organism in pond scum, showed how it protected chromosomes in yeast, and identified and named the enzyme telomerase that builds the DNA of telomeres and extends their lives.

Since then, telomerases have been found to exist almost universally across species, but in complicated ways.

"This enzyme action is similar from the simplest organisms to humans," Blackburn said. "Yet, the telomerase RNA part of telomerase has long presented a mystery because it is surprisingly different between different evolutionary branches of life."

Each species has unique elements to their telomere RNA, and not all appear to protect against aging. For example, some species with longer telomeres have shorter life spans than those with shorter telomeres.

Scientists continue to explore the role of telomeres and the enzyme telomerase in aging, and now believe that they may only be one part of the aging process, at least in animals.

"If cells have telomerase, they will live longer, but these cells are just part of your body," Chen said. "Whether it can delay the entire individual's aging or increase their life span, that's a different story. "

Now science has an entire new kingdom of telomerase to dissect: Plantae, consisting of more than 2,500 species.

"Maybe telomerase activity is different in plants than in animals," Chen said. "We know that some of the core is similar, but you might have some additional features that plants acquire to be plant specific.

"We're hoping to learn something from their regulation, mechanisms or structures that can apply to human telomerase," Chen said. "So in terms of basic research, this is really exciting because it's a brand new kingdom that we can explore as to how telomeres do their jobs in plants."

Read the rest here:
Breakthrough discovery in plants' DNA may lead to slowing aging process in humans - WAAY

Maggie L. Shaw

Researchers aim to eliminate leukemia stem cells safely.

Its like removing the tree, but leaving the roots that can sprout new shoots, they said in a statement.

Because stem cells are responsible for cell self-renewal and differentiation, Lacorazza and his team set out to better understand the LSC self-renewal process, hoping to pinpoint possible new options to target that activity, prevent relapses, and lead to treatment-free remission. Their results appeared recently in Blood, the official publication of the American Society of Hematology.

Knowing that Krppel-like factor 4 (KLF4) plays an essential part in carcinogenesisalthough it has also been shown to have antitumor activitythe study investigators removed KLF4 to see if it was necessary also for LSCs to survive. The result? Loss of LSC/progenitor cells and increased levels of tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) protein.

According to the authors, A major change in the absence of KLF4 was an increase in the production of kinase DYRK2, an enzyme involved in protein stability, cell cycle control, and apoptosis.

Stabilizing levels of this protein, then, could be a possible solution. To do this, they inhibited ubiquitin E3 ligase SIAH2 by introducing menadione (vitamin K3), as this has been shown to stimulate cell death in human CML stem/progenitor cells and increase levels of DYRK2. The drawback to this approach is that vitamin K3 can be toxic. To remedy this, the authors suggest SIAH2 inhibitors with lower hematological toxicity, evaluating the safety of that inhibition, and developing alternatives to activating DYRK2 in CML LSCs. In other words, stabilize or increase DYRK2 levels to inhibit LSCs.

Having set out to better their understanding of LSC renewal for new inroads to treatment-free survival and relapse prevention, Lacarozza and colleagues did just that. They identified the DYRK2 checkpoint in LSC/progenitor cell survival and self-renewal, showing there are 2 ways to increase its levels: (1) remove the Klf4 gene or (2) inhibit the ubiquitin ligase SIAH2 pharmacologically.

At present, they continue to search for ways to accomplish this that will not harm patients with CML, who today must take TKIs for life. We envision that targeting the bulk of leukemia with tyrosine kinase inhibitors plus a new drug that targets the stem cells might be a future strategy for patients to reach drug-free remission.

Reference

Park CS, Lewis A, Chen T, et al. KLF4 represses DYRK2 inhibition of self-renewal and survival through c-Myc and p53 in leukemia stem/progenitor cells [published online September 12, 2019]. Blood. doi: 10.1182/blood.2018875922.

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Treatment-free Remission at Heart of New CML Study - AJMC.com Managed Markets Network

Dr Pascoal Carvalho addressed the 21st convention of Indias Catholic nurses in Mumbai. He spoke about the ethical aspects of genetic engineering, citing the doctrine of the Church towards human cloning and stem cells. Respect for human dignity must prevail from conception to natural death.

Mumbai (AsiaNews) Medical innovation, which increasingly uses modern technologies to improve life, should not attempt to artificially replicate creation, said Dr Pascoal Carvalho, a doctor from Mumbai and a member of the Pontifical Academy for Life, speaking at the 21st convention of Catholic nurses (8-10 November).

In his address on 9 November, he referred to therapeutic cloning, stem cells and modified human DNA before an audience of more than 200 Catholic health workers.

"[W]e can rest assured in the wisdom of the Church," he said, because for her, The dignity of a person must be recognized in every human being from conception to natural death.

Some areas of medical research that raise serious moral and ethical questions touch stem cells, embryos and DNA.

In his view, today There is a growing threat of overestimating genetic modification techniques and underestimating the repercussions of cloning and human gene therapy.

On the one hand, we have the positive results of therapeutic cloning aimed at organ and tissues reconstructed in laboratory for transplanting into patients to reduce the risk of rejection; on the other, reproductive cloning, like in the case of Dolly the sheep, seeks to reproduce living beings.

He warns against research that leads to alterations in an organisms DNA, like the famous case of the Chinese scientist who in 2018 said that he had created two twins in the laboratory immune to the HIV virus. This kind of experiment can reduce life expectancy and increase susceptibility to other, and perhaps more common, diseases.

The doctor cites the Dignitas Personae, which defines any attempt at human cloning as unacceptable, because it represents a serious offense to the dignity of the person and fundamental equality between men.

As for therapeutic cloning, To create embryos with the intention of destroying them, even with the intention of helping the sick, is completely incompatible with human dignity, because it makes the existence of a human being at the embryonic stage nothing more than a means to be used and destroyed. It is gravely immoral to sacrifice a human life for therapeutic ends.

Citing the doctrine of the Church, Dr Carvalho stresses the importance of the method with which stem cells are taken. In his view, Methods which do not cause serious harm to the subject from whom the stem cells are taken are to be considered licit.

This is generally the case when tissues are taken from: a) an adult organism; b) the blood of the umbilical cord at the time of birth; c) foetuses who have died of natural causes.

Overall, the doctor believes that modern gene technologies raise new moral questions, whilst attempts to create a new type of human being contains an ideological element in which man tries to take the place of his Creator.

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INDIA Indian doctor: Medical innovation should not try to replace the Creator - AsiaNews

Laura Beil was skeptical when Wondery called her two years ago. The sensationalistic podcast hitmaker behind Dirty John needed a host for its new series about Christopher Duntsch, the infamous Dallas neurosurgeon accused of maiming his patients. Beil, a veteran Dallas Morning News medical reporter, hadn't listened to a true crime podcast in full, let alone reported one. She'd certainly never heard of Wondery. "I said, 'I'm a print journalist,'" she tells ELLE.com. "Why are you calling me?" With some hesitation, she agreed to do it. Today, she's grateful she did.

Since airing last September, Dr. Death has been downloaded more than 50 million times and ordered as a television series. On the heels of its massive success, Wondery greenlit a second Beil-led podcast, Bad Batch, now available on Apple Podcasts and Spotify. In the six-part investigative series, she takes listeners through the crazy, complicated world of stem cell medical treatment. Like Dr. Death, there's a narrative arc (corrupt system, suspicious CEO, unsuspecting victims); unlike Dr. Death, she says, it serves a real purpose. "The chances of you coming across a horrible neurosurgeon are pretty slim," she says, "but the chances of you or someone you love wanting to spend a bunch of money on stem cells because you're promised a miracle cure? That's much higher. This has a greater chance of having an impact on listeners."

Bad Batch has already garnered 3 million listeners since it debuted three weeks ago, and is now the fourth most popular show on Apple podcasts, ahead of rival My Favorite Murder.

On the phone, Beil and I discuss her transition to audio from print journalism, the future of true crime content in a frenetic digital age, and her secret sauce to producing a hit podcast.

Apparently a Dirty John listener had emailed Wondery saying, "Hey, have you heard of Christopher Duntsch?" They wanted a journalist who had knowledge of the healthcare system in Dallas, where Duntsch practiced, to look into him, and that's a pretty short list. When they called, I hadn't even heard of Wondery. But I decided to take a chance on it.

Journalism is journalism. There are some things I had to get used to, of course. For example, in print journalism, if you need something else, you can go back and get it from a source. You'll email or you'll text somebody to follow up as you find out you need more details. With audio, you just have one shot. It's a lot harder to go back and reinterview someone. You have to make the one interview really count, and that means asking the same question over and over again in a different way, to get details that draw people out. It's something that I'm still learning how to do, frankly.

The feedback about my voice has been all over the place. I didn't get so much with Dr. Death, but for Bad Batch I am. Listeners will say, "Oh, the narrator's too dramatic." And then someone else will say, "Oh, the narrator's too robotic." It's all conflicting. My favorite bit of feedback was from a listener who said they preferred the host of Dr. Death to Bad Batch.

I don't see true crime being dethroned anytime soon. It will always dominate, because people love it. That said, Bad Batch doesn't necessarily fit in the true crime box. There wasn't really a crime, and nobody died. What you need, just like in a print piece, is a good central narrative to hang your story off. The stem cell story is complicated, because you can't just say it's all a big con job. There's legitimate stem cell research going on. The business is growing so much and most of the information about it is coming from people trying to sell it. There's a lot to explore and explain.

In this business, so much is contracting, like newspapers, so it's nice to see one aspect of journalism that's expanding. To see more demand for audio journalism is heartening. It's reviving a lot of the long-form storytelling that's been cut in other places. Dr. Death had 50 million downloads. The same story was told in print on ProPublica, which is a hugely popular website, and yet the response from our audio was so much greater. A lot of things that we're told people want nowadaysshorter stories that are more clickable and scannablewell, you can't do that with a podcast. I can't explain it, but people can't get enough of podcasts.

I do enjoy doing the audio stuff, but I have to say, in my heart of hearts, I'm still a print writer. If I had to give up one or the other, I'd give up the audio.

[Laughs] With two number one podcasts out in a row, Wondery is like, "Do you have anything else?" After Dr. Death, I had so many emails from people saying, "Here's another horrible doctor to look into." It was depressing. I don't want to do another bad doctor story, I want to do something completely different. I want it to be the right story. It'll be something medical of course.

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'Dr. Death' and 'Bad Batch' Host Laura Beil on the Future of Podcasts - ELLE.com

Heart failure (HF) is the most frequent cardiovascular diagnosis and exacts significant health and financial costs around the globe. It is estimated that at least 26 million people worldwide are living with HF, including nearly 6 million in the United States.1, 2 One in nine U.S. deaths in 2009 included heart failure as a contributing cause and about 50 percent of people in the U.S. with HF die within five years of diagnosis.2 The annual cost of HF-related healthcare services, medication and missed days of work is estimated at $40 billion in the United States and $108 billion globally.3, 4 Quality of life in HF patients is frequently worse than many other chronic diseases and comorbidities are common.5-7 The challenges of HF are expected to grow, as it is estimated that more than 8 million people in the United States alone will have HF by 2030.2 Current therapies improve quality of life in the short-term and have improved long-term survival but a significant number of patients have Class 3 HF despite optimal medical and device therapy. These patients have limited treatment options beyond heart transplant and left ventricular assist devices (LVAD). New therapeutic approaches that address the underlying causes of HF are needed to improve patient outcomes.

Heart failure is a complex disease process and multiple pathways contribute to its development and progression. Myocardial ischemia is frequently an issue in both ischemic and non-ischemic cardiomyopathy as well as HF with preserved and/or reduced ejection fraction. Myocardial ischemia results in insufficient oxygen and nutrients and leads to hypoxia, cardiomyocyte and fibrosis, which all contribute to the progression of heart failure. More effective angiogenesis may prevent this progression. Cell homing also plays a critical role, as injured cardiac tissue secretes factors that lead to the recruitment, proliferation, migration and differentiation of progenitor cells that can help repair tissue damage. Stromal cell-derived factor (SDF)-1 has been shown to play an important role in cardiac repair by mediating cell homing.10 Mitochondrial energy generation is also impaired in HF, leading to decreased contractility and adverse changes to cardiac architecture.11 Scar tissue formed in response to cardiomyocyte injury or death can compromise the hearts mechanical strength or electrical signaling results in myocardial infarction. Inflammatory responses to cardiac tissue damage can promote inappropriate and chronic inflammation and the expression of pro-inflammatory molecules that lead to pathologic changes to cardiac architecture.12, 13

These pathways offer a variety of potential new targets for therapeutic intervention to prevent the development and progression of HF. This opens the door to the development of novel therapies that address the underlying molecular and cellular causes of disease rather than treating HF symptoms alone.

After decades of development, gene-based therapies are now validated therapeutic modalities for the treatment of inherited retinal disorders and cancer and are undergoing clinical evaluation in a variety of inherited, acute and chronic diseases. Nearly two dozen single gene-based therapies for HF have been evaluated in clinical trials.14 Genes evaluated as monogenic gene therapy for HF in clinical trials include vascular endothelial growth factor (VEGF) and fibroblast growth factor type 4 (FGF4) to promote angiogenesis; adenylyl cyclase type 6 (AC6) and sarco/endoplasmic reticulum Ca2+-ATPase type 2 (SERCA2) to improve cardiac calcium homeostasis, which plays a critical role in the contraction and relaxation of heart muscle; and stromal cell-derived factor-1 (SDF-1) to improve cell homing and promote cardiac tissue repair. Late-stage trials of single gene therapies have yielded conflicting results, raising the question as to whether positively impacting a single pathway can be sufficient to overcome detrimental activity of other pathways that contribute to the development and progression of HF. Other potential limitations to HF therapies evaluated in clinical trials to date include the method of delivery, dose and the potency of vectors and gene products.

Given the multiple molecular and cellular pathways active in HF, a multi-gene approach to HF gene therapy may be needed. Simultaneously delivering multiple genes that target diverse HF-related pathways has the potential to improve cardiac biology and function. A triple gene therapy approach (INXN-4001, Triple-Gene LLC, a majority-owned subsidiary of Intrexon Corporation) is currently in clinical development, with each of the genes targeting a specific HF-related pathway. The investigational drug candidate INXN4001 vector expresses: the S100A1 gene product, which regulates calcium-controlled networks and modulates contractility, excitability, maintenance of cellular metabolism and survival; SDF-1a which recruits stem cells, inhibits apoptosis and supports new blood vessel formation; and VEGF-165 which initiates new vessel formation, endothelial cell migration/activation, stem cell recruitment and tissue regeneration. The hypothesis is that the simultaneous delivery of multiple genes in a single vector would more effectively improve multiple aspects of cardiac function compared with single gene therapy. It is delivered by retrograde coronary sinus infusion of a triple effector plasmid designed with a self-cleaving linker to constitutively express human S100A1, SDF-1a and VEGF 165. This route is designed to allow for delivery of a dose to the ventricle which may help achieve improved therapeutic effect.

Several preclinical studies have set the foundation on which to advance a triple gene therapy for HF into the clinic.15-17 Using in vitro studies, transfecting cells derived from patients with dilated cardiomyopathy with a triple gene combination demonstrated improvement in contraction rate and duration, to the levels demonstrated by the control cells and did not result in increased cell death compared to controls.15 Studies in an Adriamycin-induced cardiomyopathy rodent model demonstrated triple gene therapy increased fractional shortening and myocardial wall thickness compared to controls.16 In addition, retrograde coronary sinus infusion of INXN-4001 in a porcine model of ischemic HF resulted in a cardiac-specific biodistribution profile.17

A Phase 1 clinical study has been initiated to evaluate the safety of a single dose of triple gene therapy in stable patients implanted with a LVAD for mechanical support of end-stage HF. An independent Data and Safety Monitoring Board agreed to proceeding to the second cohort following review of the data from the first cohort in the multi-site study.18 The study is ongoing and final results will help to inform our understanding of the potential that multi-gene therapy may play in the treatment of HF.

The recent FDA approvals of gene therapies for an inherited retinal disease and cancer are evidence that gene therapy is a valid therapeutic strategy. Realizing the potential of gene therapy in HF will require appropriately designed clinical trials, but several interesting approaches currently in development may prove to be effective. The results of the initial investigational drug INXN-4001 Phase 1 trial should provide insight into the safety of combining S100A1, SDF-1a and VEGF-165. Evaluation of additional multi-gene combinations will also be important for understanding which targeted pathways yield the greatest effects with respect to relevant clinical endpoints. Continued refinement and optimization of vector design and delivery methods will also be important for advancing further HF gene therapies from bench to bedside.

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The Heart of the Matter: Leveraging Advances in Cardiac Biology to Innovate Gene-Based Therapies for Heart Failure - Physician's Weekly

Diabetes is a major public health crisis that is approaching epidemic proportions around the globe and growing at an alarming rate. According to the International Diabetes Federation (IDF), over 425 million adults are currently living with diabetes. That number is expected to rise to 629 million by 2045.

The disorder, which occurs when the pancreas does not produce enough insulin (the hormone that regulates blood sugar) or when the body cannot use its produced insulin, has become so deadly, that the International Diabetes Federation said it was responsible for four million deaths in 2017 alone. The World Health Organization estimated diabetes to be the seventh leading cause of death globally in 2016.

Over 350 million people are at risk of developing Type 2 diabetes, when the body becomes to resistant to insulin due to lifestyle facts such as excess weight gain, while more than 1.1 million children are living with Type 1 diabetes, the disorder that occurs when the bodys immune system attacks cells of the pancreas that produce insulin, according to the International Diabetes Federation.

World Diabetes Day, marked annually on November 14 to honor the co-discoverer of insulin Canadian Dr. Frederick Banting, born on that day in 1891, aims to raise awareness of the impact of this disease while promoting its management, care, and prevention. For the past two years (including in 2019,) the theme of World Diabetes Day has been The Family and Diabetes promoting the familys role in awareness and education of the disorder.

To mark the day, NoCamels is taking a closer look at Israels role in advancing diabetes research and treatment as well as some of the companies with cutting-edge technology that stand out in the field.

Dr. Irit Yaniv, a general manager at Accelmed Ventures II, a new $100 million venture early-stage health tech fund for medical device and digital health startups and co-founder and chairperson of Type 2 diabetes medical device startup Digma Medical, calls diabetes the most dangerous global epidemic. Israel is no exception, she says, citing half a million people living with the disease in the country.

Additionally, about 300,000 are prediabetic, a condition manifesting as borderline high blood sugar levels and an increased risk to progress to diabetes Type 2 within a few years, she explains.

Dr. Yaniv says life science entrepreneurs address the challenges presented by the epidemic in a number of ways, including creating companies and projects aimed at reducing the risk of developing the diseases, development of novel drug delivery methods for diabetes drugs, and unique medical devices for managing the disorder.

SEE ALSO: 6 Israeli Companies At The Forefront Of Diabetes Care, Prevention, and Treatment

There are a few interesting examples such as oral insulin and nasal insulin delivery systems that were developed in Israel, Yaniv says. A recent success story is Nutrino, [an Israeli] software company for the management of diabetes that was acquired by Medtronic.

Treatment for Type 2 diabetes has been focused on lifestyle changes and pharmacologic solutions. Both have challenges including patient compliance and adverse effects such as weight gain, hypoglycemia, and other reactions, Yaniv says. More than 50 percent of the patients arent able to control the disease, even with combination therapeutics.

The medical device industry has made many efforts in recent years to address this need, Yaniv says, Companies such as GI Dynamics have paved the way for new therapeutic alternatives. Digma Medical has demonstrated initial positive clinical data with its unique duodenal ablation system.

Yaniv founded Digma Medical in 2013 with Ilan Ben Oren. Backed by leading venture capital firms such as Arkin Holdings and Peregrine Ventures, the company is dedicated to the development of its DiaGone device to treat insulin resistance. DiaGone is an endoscopic, disposable device, that uses innovative laser technology to treat the duodenum, a segment of the small intestine, without an implant. The Duodenal Glycemic Control procedure is a one-time 30 minute GI procedure, in which the gastroenterologist uses DiaGone to treat the duodenum for restoring the natural ability of the body to control glucose levels, said to provide long term remission from Type 2 diabetes and other metabolic syndrome-related diseases.

For Rami Epstein, who assumed the role of CEO at stem cell company Kadimastem in May 2019, a need exists to find a better solution for the management of diabetes in order to decrease the morbidity, mortality, and costs linked to it and its medical-related care, he tells NoCamels. This method is more than just controlling insulin levels in the body. It is controlling the dose of insulin administered to the body.

All Type 1 diabetes and 30 percent of Type 2 diabetes patients depend on the daily administration of insulin in order to control their glucose levels in the blood. This is not ideal since patients have to calculate insulin dosages and take into account meal times and portions, physical activity, and other parameters, he explains. Unfortunately, many patients do not manage to stabilize their blood glucose levels properly, thereby risking complications that arise from episodes of hypoglycemia or hyperglycemia,

Through Kadimastems groundbreaking stem-cell therapy technology, developed by the companys chief scientist Professor Michel Revel at the Weizmann Institute of Science and used as the basis for the companys founding in 2009, the Ness Ziona-based firm has developed and manufactured an off-the-shelf cell product for the treatment of insulin-dependent diabetes based on its proprietary tech platform. The tech platform has been used to treat multiple diseases, including ALS, through the expansion and differentiation of Human Embryonic Stem Cells (hESCs) into clinical-grade functional cells.

The product, called IsletRx, is currently in pre-clinical trials. Its goal is to free patients from continuous monitoring of blood sugar levels and repeated insulin injections. The drug contains an endless source of pancreatic functional islet cells, which produce and secrete insulin and glucagon in response to external glucose levels.

Meanwhile, Tel Aviv-based clinical-stage pharmaceutical company Oramed, which is focused on the development of oral drug delivery systems, announced this week that Phase IIb trial evaluating the efficacy and safety of its lead oral insulin candidate, ORMD-0801, has had positive results.

The study was a 90-day, double-blind, randomized, multi-center trial designed to evaluate the safety and efficacy of ORMD-0801 as a treatment for patients with type 2 diabetes, Oramed said in a statement. The primary efficacy endpoint was a reduction in Hemoglobin A1c (A1C, also known as HbA1c, is a key clinical measure of blood glucose control) at Week 12, with no weight gain.

Israeli scientists are taking diabetes management solutions one step further and adding machine learning and AI to the mix. DreaMed Diabetes, a medical tech startup founded in 2014 to develop these types of personalized solutions, announced in September that it had received clearance from the US Food and Drug Administration (FDA) as well as a CE Mark for its DreaMed Advisor Pro, an AI-based insulin dosing decision support software. The software is for patients with Type 1 diabetes using insulin pump therapy with continuous glucose sensors and blood glucose meters (BGMs)

The decision-support platform uses proprietary algorithms to process data from a range of connected devices, including insulin pumps and self-management glucometers. The data is then analyzed to provide an optimized insulin dosing treatment plan to maintain a balanced glucose level.

SEE ALSO: Israeli AI Startup Can Predict Which Diabetes Patients Will develop Kidney Disease

This clinical and technological advance leverages the power of artificial intelligence to optimize insulin administration in a streamlined and cost-effective manner, the company said in a statement.

This year I am more optimistic that a change will happen in how we manage diabetes. We see more technology adopted in all markets, more sharing of data between patients providers and industry all for the benefit of offering better care for patients, the companys CEO Eran Atlas tells NoCamels in an email. DreaMed is happy to be part of the leaders in this effort, by offering a unique artificial intelligence technology that can analyze data and recommend in only a few seconds how to optimize the technology. With such technology, the proliferation of expert care can be achieved even in emerging markets.

Another key player operating in artificial intelligence in the diabetes management market is Sweetch. Founded in 2013, Sweetch offers an AI-based platform that aims to identify those at high risk of developing Type 2 diabetes. The company calls itself the first AI-powered therapeutics solution to help people with the disorder and comes with a mobile app and a wireless Bluetooth-connected scale. The early prevention platform announced last year that it will partner with US-based integrated healthcare system WellSpan Health and provide its app to 15,000 employees, including 200 primary care and specialty physicians, as well as advanced practice clinicians in central Pennsylvania and northern Maryland.

In 2016, the startup raised $3.5 million in a Series A round led by equity crowdfunding platform OurCrowd and Philips.

Diabetes can cause circulation problems and related conditions such as peripheral arterial disease (PAD) which occurs when plaque builds up in the arteries and reduces blood flow to the limbs. For some patients, high levels of blood glucose can damage blood vessels and cause plaque build-up affecting healthy blood flow.

The northern Israel-based startupElastiMedhas developed a wearable medical device that doesnt treat diabetes patients directly but can help the patient improve his or her circulation.

It cant treat the disease directly, but it can treat some of its symptoms, says Elastimed CEO and founder Omer Zelka.

Compression socks improve circulation by squeezing the foot and calf muscles, which straightens out the vein walls to a better working state, says Advanced Tissue, the leading wound care supply provider. Compression therapy is particularly beneficial for diabetes patients because they improve circulation in a non-invasive manner, helping to maintain the right amount of pressure in feet and legs.

ElastiMeds sock uses battery-operated technology to activate a smart material that compresses and massage the legs to stimulate circulation. The pulses mimic contractions in the calf muscles that in turn increase blood flow.

The sock provides patients with a comfortable, easy-to-wear, highly effective, and cost-effective treatment option to prevent symptoms such as swelling, blood clots, leg ulcers and reduce athletes recovery time.

ElastiMed is currently finishing an ongoing clinical study to demonstrate the safety and the feasibility of this device and its ability to increase venous blood flow. The study is led by Dr. Vered Shuster Ben-Yosef, R&D Lab Manager of the company and is currently taking place at Hillel Yaffe Medical Center in Hadera. The company currently has a working prototype and aims to get the product on the market in early 2021.

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These Israeli Companies Are Finding Innovative Ways To Improve Diabetes Care, Treatment | Health News - NoCamels - Israeli Innovation News

This is the tear-jerking moment a dad shares a hug with the woman who saved his life.

James O'Donnell, from Burnage, feared the worst after being diagnosed with a blood disorder similar to leukaemia in 2016.

Usual treatments were failing and James was undergoing a blood transfusion every week while battling constant infections, the Liverpool Echo reports.

James was running out of options and despaired at the pain his death could cause his eight-year-old son, Harrison.

But in a stunning stroke of fortune, his saviour was only the other side of the M62 - LiverpoolCouncil admin worker Leah McDougall.

The 29-year-old mum, from Bootle, had taken the time to sign up to the register of potential stem cell donors on her lunch break at a pop-up stall, organised by blood cancer charity DKSM, the previous year.

James, who despite his Manc heritage is an avid Liverpool FC fan, told staff at the charity that he would be up for meeting his donor, who could have been anyone from a number of European countries using the register.

James, along with his wife Andrea and young Harrison, got the chance to meet Leah for the first time at a DKSM charity gala in London on Wednesday last week (November 6).

James, who says he finally feels like himself after a long period of illness, told the ECHO: "I was just getting chest infections and water infections all the time.

"I am quite a healthy person, and I was in good shape and I knew I should not be getting ill all the time."

He said after a few weeks of tests his was invited to take a bone marrow biopsy and was told the devastating news on his 40th birthday.

The disease meant James' bone marrow was not producing enough white blood cells, but doctors told him a treatment called anti-thymocite globulin (ATG) had a "75% chance" of success.

However, when that failed, fear and doubt began to creep in.

He said: "We are always saying I would get through this, we were thinking I would get better. But I started to think it's not happening, it's not going to be for me, this.

"I thought, I have been good in life, I need some luck. We were having a really hard time.

"My son was four or five then, and it was hard for him having a dad going from playing football with him to being in hospital."

Eventually doctors revealed the only option was for James to have a bone marrow transplant.

The O'Donnell's went through further disappointment when tests on his three siblings revealed none were a match, so the waiting game to find a suitable donor began.

But on a March day in 2017, he got a call to say: "We have got a perfect match, a 10 out of 10."

The operation was a success and after four weeks doctors told James the new bone marrow cells were taking effect.

He said: "We were so lucky to find a donor only about 25 miles away. Some people never find one and we had one on our doorstep."

The powerful emotion of meeting Leah last week is summed up by James: "It was the second best moment of my life after my son being born.

"What she has done means that I can see my son growing up and that he has a father."

Leah did not hesitate to agree to help a total stranger when she was asked by DKSM.

Describing the moment she met James and his family, she told the ECHO: "We were both speechless. When I walked on stage we were just hugging each other for ages.

"It is weird, we felt like we had known each other for years, I felt like I had known him my whole life.

"It just takes five minutes out of your time to sign up to the register; that's like going to the kitchen to make a drink.

"You just think about the impact it is going to have on someone, it is saving someone's life. I feel lucky to have been able to give something back."

James says his family and Leah are planning to meet up again, possibly at a Liverpool FC game.

He said: "Without her, I wouldn't have a future."

DKSM has urged anyone aged 17-55, and in general good health, to sign up to the register here.

Dr Manos Niklolousis, Haematologist at University Hospital Birmingham NHS Foundation Trust, said:"Blood stem cells can be used to treat a wide range of blood cancers and blood disorders and we urgently need more people to come forward as donors.

"Currently, only 2% of the UK population are registered so matching donors with patients isnt easy within a growing multicultural population.

"Many of those in need are unable to find a sibling match and so rely on the generosity of strangers, and a blood stem cell transplant can be some patients only hope of survival.

"As a doctor who treats people with blood cancer or disorders, it is upsetting to know that some patients could have been saved if only more potential donors were registered and available to donate.

"I look forward to the day when there will be a donor for every patient in need."

Excerpt from:
Heartbreaking moment dad meets the woman who saved his life - he feared his son would grow up without a father - Manchester Evening News

"Blood test for sepsis could save lives of thousands of children," reports the Mail Online.

Researchers in the US have developed a test for 5 proteins, which they say allows them to identify people with sepsis who have a high, medium or low risk of dying from the condition. They hope this will eventually help doctors identify the best treatments for individual patients.

Sepsis, sometimes called blood poisoning, is when the body's immune system over-reacts to an infection, causing inflammation and damage to the body's own tissues and organs. Anyone with an infection can get sepsis, although it is more common in babies and people over 75.

One of the challenges in treating sepsis is that symptoms can develop and worsen extremely quickly. So, a test that can confirm a diagnosis of sepsis before this happens should help reduce the risk of serious complications and, in some cases, deaths.

The test is still experimental. However, early experiments in mice suggest people at a high risk of dying from sepsis might benefit from higher doses of antibiotics than would normally be given.

Sepsis is a medical emergency. Find out more about the symptoms and what to do if you think someone may have sepsis.

The researchers who contributed to the study came from 16 institutions in the US, mainly children's hospitals. The research was led by Cincinnati Children's Hospital Medical Center. It was funded by grants from the US National Institutes of Health and Cincinnati Children's Hospital. The study was published in the peer-reviewed journal Science Translational Medicine.

The Mail Online did a good job of reporting a complicated study.

The researchers carried out a series of experiments, testing children with sepsis and then experimenting on mice to explore the results further. This is early-stage experimental research that may one day result in better treatment, but there is much more research to be done.

In earlier experiments, researchers had identified 5 proteins created by the body during sepsis, plus a measure of platelets (components in blood that make clots). They hoped the test, called Persevere II, would work to predict who was at highest risk of dying from sepsis.

They used the test on 461 children admitted to hospitals with sepsis, and divided them into 3 groups high, medium and low risk of death within 28 days. They then looked to see how accurately the test predicted what happened to the children. All children were treated as normal for sepsis in their admitting hospital.

The researchers then developed a mouse equivalent of the test, to see whether it would also predict survival in mice given sepsis in a laboratory experiment. They later investigated whether the higher-risk mice had more inflammation or more bacteria than low-risk mice. In 2 further experiments, they tested whether giving the high-risk mice steroids for inflammation, or higher-dose antibiotics to fight bacteria, changed their chances of survival. They also checked to see whether blocking 1 of the 5 proteins produced by the body and measured in the test affected the outcome.

Finally, researchers checked the results of the children with sepsis. They wanted to see if those classified as high risk by the Persevere II test were more likely to have had bacteria in their blood tests.

The researchers found the Persevere II test worked well to identify the risk level of children with sepsis. Almost all of the patients categorised as low risk survived, while just over half (55%) of those categorised as high risk survived. The test correctly identified as high risk 86% of those who did not survive (86% sensitivity) and correctly identified as low risk 69% of those who survived (69% specificity).

The test also worked well when predicting mice at high and low risk. Further experiments on mice showed high-risk mice had more signs of inflammation in the lungs and throughout the body as well as bigger colonies of bacteria from their infection.

Tests also showed that giving high-risk mice the anti-inflammatory drug dexamethasone or placebo made no difference to their survival, but they were more likely to survive if given high-dose antibiotics.

Mice given a drug to block 1 of the proteins used in the test were more likely to survive for 10 days, but the difference was small enough that the results could have come about by chance.

The researchers found that children who had been identified as high risk by the Persevere II test were more likely to have had bacteria cultured from their blood. While this is not a direct measure of the size of the bacteria colony, larger colony sizes are more likely to be able to be cultured after blood tests.

The researchers said: "On the basis of our findings, we suggest that Persevere II might identify a subgroup of children with septic shock [sepsis] who will benefit most from targeted therapeutic drug monitoring to ensure optimal dosing of antibiotics."

Because little is known about why sepsis happens after some infections, and how exactly it develops, it is hard to develop new treatments. Treatments have stayed the same for many years, and sepsis is a life-threatening condition.

This study is the first for many years to make some progress in our understanding of sepsis. It opens up possibilities for research into potential drugs that could be used in the future. This study also suggests ways in which the Persevere II test could be used to identify people at high risk of life-threatening sepsis, so they can be treated quickly and with the most appropriate dose of antibiotics.

However, this is very early-stage research. Just because a treatment works for mice does not mean it will work for humans. Translating results from a species to another, as the researchers do in this study, does not always work. Higher-dose antibiotics have not been tested for children identified as at high risk of life-threatening sepsis. Higher than usual doses could have damaging effects.

The Persevere II test is still being worked on, so is not yet generally available for doctors to use. In a media interview, a researcher said it is about 2 years away from being made available.

Sepsis can be hard to spot. There are lots of possible symptoms.

Find out more about spotting the signs of sepsis.

Analysis by BazianEdited by NHS Website

See more here:
New blood test could lead to better treatment for sepsis - NHS Website

Stock image.

Miami, FL R.J. Reynolds and Philip Morris were hit with a $42.5 million total verdict in a retrial over the 1996 cancer death of a Florida smoker. Gloger v. R.J. Reynolds and Philip Morris, 2011-CA-23377.

The award includes $15 million in compensatories awarded Friday, as well as an $11 million punitive award imposed against Philip Morris and $16.5 million in punitives imposed against Reynolds Wednesday for the responsibility jurors found the companies bore for Irene Glogers lung cancer.

Gloger, who had smoked for decades, died at 47, about a year after she quit smoking. Her family contends a tobacco industry-wide conspiracy to hide the dangers of smoking throughout much of the 20th century hooked Gloger to cigarettes and ultimately led to her fatal cancer.

The verdictmore than doubles the $17.5 million jurors awarded in a 2018, CVN-covered trial of the case. That verdict was thrown out in March by Floridas Third District Court of Appeal, which found the trial court had not not properly limited Kenneth Glogers testimony concerning conversations he had with his wifes doctors.

The Gloger case is among thousands that stem from Engle v. Liggett Group Inc., a 1994 Florida state court class-action lawsuit against Philip Morris and other tobacco companies. The state's supreme court ultimately decertified the class, but ruled that so-called Engle progeny cases may be tried individually. Plaintiffs are entitled to the benefit of the jury's findings in the original verdict, including the determination that tobacco companies placed a dangerous, addictive product on the market and conspired to hide the dangers of smoking.

However, in order to be entitled to those findings, plaintiffs must prove the smokers at the heart of their cases suffered from nicotine addiction that caused a smoking-related illness.

The origin of Glogers cancer, as well as what, if any responsibility she bore for her smoking, served as key battle lines in the 12-day trial.

During Fridays closings in the trials first phase, on Engle class membership, King & Spaldings Cory Hohnbaum, representing Reynolds, challenged the claim that Gloger had smoking-related lung cancer, and argued that a mass was never found in Glogers lung. He also contended doctors could not agree on the cell-type of Glogers cancer.

There is confusion, massive confusion among the pathologists about what this was, Hohnbaum said, noting Gloger saw several pathologists during her treatment. You dont need to go talk to multiple pathologists if the pathology is clear. It was never clear.

Arnold & Porters Keri Arnold, representing Philip Morris, added that, regardless of the cancers origin, Gloger knew the dangers of cigarettes, yet chose to continue smoking. Arnold noted that Gloger had been smoking for years by the time she began smoking Philip Morris brand cigarettes. She was an adult, she was married, she had a family, she was a medical professional. She had all the maturity and information she needed to make her own decisions about her own smoking and her own health, Arnold said.

But the Gloger familys attorney, The Ratzan Law Groups Stuart Ratzan, argued Gloger was heavily addicted to cigarettes and unable to stop in time to avoid her cancer. Ratzan walked jurors through Glogers smoking history, which included numerous failed quit attempts. Theres no reason no reason at all for a person to coat their lungs every 30 or 40 minutes, a pack-and-a-half a day for 30 years, if its not for nicotine, Ratzan said. Its the only reason.

And Ratzan argued medical records and pathology reports showed Glogers treating physicians concluded she had lung cancer. He noted one pathology report, on fluid taken from around Glogers lungs, found she had non-small cell carcinoma. It means lung cancer, Ratzan said. And I defy anybody to determine otherwise.

Email Arlin Crisco at acrisco@cvn.com.

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Jury Hands Down $42.5M Total Verdict Against Philip Morris and RJR in Retrial Over Smoker's Cancer Death - CVN News

These heart cells were grown from mouse stem cells.

Stem cells have captured the public's attention because of their potential to revolutionize ourtreatment of many debilitating diseases and injuries. Using stem cells, we may someday be able to repair spinal cord injuries or replace diseased organs, although such therapeutic treatments are probably a long way off. The study of stem cells is relatively newthey were discovered in 1976, and human embryonic stem cells finally isolated in 1998so scientists still have much to learn about them.

Right now, researchers are still learning how to generate and grow stem cells. But simply knowing how to culture the cells in the lab isnt enough. Scientists also need to understand and control how stem cells differentiate to become specific cell types. If researchers can decode the signals that govern differentiation, they may be able to take charge of the process, directing a culture of cells to become a specific cell typeheart, neuron, skin, liver, or whatever kind is needed.

Cultivation of stem cells from days-old embryos

Progress....and hurdles

Treatments for a few particular diseases have emerged as exciting possibilities on the forefront of stem cell research. Parkinsons results from the death of a specific type cell in the brain. Scientists have succeeded in easing the condition in rats by injecting them with embryonic stem cells that then turned into the missing neurons. Researchers hope to develop a similar treatment for diabetes, which is caused by the destruction of insulin-producing cells in the pancreas.

Though there has been progress in developing new stem cell-based therapies, researchers caution that many hurdles remain. For example, its unclear whether implanted stem cells can, after differentiating, revert to their previous state and then cause cancer. Another problem involves our natural immune response to foreign cells in the body. Patients currently receiving stem cell treatments, such as bone marrow transplants, must take drugs to prevent their immune system from attacking the newly introduced cells. Scientists may be able to address this problem by creating banks of embryonic stem cells, each of which is slightly different genetically. The cells best suited to a patients genetic makeup would then be used to grow new cells for transplantation, in hopes that this would lessen the immune response.

Embryonic stem cells can be grown in culture dishes. A pinkish solution provides the sugars and other compounds the cells need to grow.

Next: Looking forward

Go here to read the rest:
Microscope Imaging Station. Stem Cells: Cells with potential.

The Central Nervous System

The mature mammalian central nervous system (CNS) is composed of three major differentiated cell types: neurons, astrocytes and oligodendrocytes. Neurons transmit information through action potentials and neurotransmitters to other neurons, muscle cells or gland cells. Astrocytes and oligodendrocytes, collectively called glial cells, play important roles of their own, in addition to providing a critical support role for optimal neuronal functioning and survival. During mammalian embryogenesis, CNS development begins with the induction of the neuroectoderm, which forms the neural plate and then folds to give rise to the neural tube. Within these neural structures there exists a complex and heterogeneous population of neuroepithelial progenitor cells (NEPs), the earliest neural stem cell type to form.1,2 As CNS development proceeds, NEPs give rise to temporally and spatially distinct neural stem/progenitor populations. During the early stage of neural development, NEPs undergo symmetric divisions to expand neural stem cell (NSC) pools. In the later stage of neural development, NSCs switch to asymmetric division cycles and give rise to lineage-restricted progenitors. Intermediate neuronal progenitor cells are formed first, and these subsequently differentiate to generate to neurons. Following this neurogenic phase, NSCs undergo asymmetric divisions to produce glial-restricted progenitors, which generate astrocytes and oligodendrocytes. The later stage of CNS development involves a period of axonal pruning and neuronal apoptosis, which fine tunes the circuitry of the CNS. A previously long-held dogma maintained that neurogenesis in the adult mammalian CNS was complete, rendering it incapable of mitotic divisions to generate new neurons, and therefore lacking in the ability to repair damaged tissue caused by diseases (e.g. Parkinsons disease, multiple sclerosis) or injuries (e.g. spinal cord and brain ischemic injuries). However, there is now strong evidence that multipotent NSCs do exist, albeit only in specialized microenvironments, in the mature mammalian CNS. This discovery has fuelled a new era of research into understanding the tremendous potential that these cells hold for treatment of CNS diseases and injuries.

Neurobiologists routinely use various terms interchangeably to describe undifferentiated cells of the CNS. The most commonly used terms are stem cell, precursor cell and progenitor cell. The inappropriate use of these terms to identify undifferentiated cells in the CNS has led to confusion and misunderstandings in the field of NSC and neural progenitor cell research. However, these different types of undifferentiated cells in the CNS technically possess different characteristics and fates. For clarity, the terminology used here is:

Neural Stem Cell (NSCs): Multipotent cells which are able to self-renew and proliferate without limit, to produce progeny cells which terminally differentiate into neurons, astrocytes and oligodendrocytes. The non-stem cell progeny of NSCs are referred to as neural progenitor cells.

Neural Progenitor Cell: Neural progenitor cells have the capacity to proliferate and differentiate into more than one cell type. Neural progenitor cells can therefore be unipotent, bipotent or multipotent. A distinguishing feature of a neural progenitor cell is that, unlike a stem cell, it has a limited proliferative ability and does not exhibit self-renewal.

Neural Precursor Cells (NPCs): As used here, this refers to a mixed population of cells consisting of all undifferentiated progeny of neural stem cells, therefore including both neural progenitor cells and neural stem cells. The term neural precursor cells is commonly used to collectively describe the mixed population of NSCs and neural progenitor cells derived from embryonic stem cells and induced pluripotent stem cells.

Prior to 1992, numerous reports demonstrated evidence of neurogenesis and limited in vitro proliferation of neural progenitor cells isolated from embryonic tissue in the presence of growth factors.3-5 While several sub-populations of neural progenitor cells had been identified in the adult CNS, researchers were unable to demonstrate convincingly the characteristic features of a stem cell, namely self-renewal, extended proliferative capacity and retention of multi-lineage potential. In vivo studies supported the notion that proliferation occurred early in life, whereas the adultCNS was mitotically inactive, and unable to generate new cells following injury. Notable exceptions included several studies in the 1960s that clearly identified a region of the adult brain that exhibited proliferation (the forebrain subependyma)6 but this was believed to be species-specific and was not thought to exist in all mammals. In the early 1990s, cells that responded to specific growth factors and exhibited stem cell features in vitro were isolated from the embryonic and adult CNS.7-8 With these studies, Reynolds and Weiss demonstrated that a rare population of cells in the adult CNS exhibited the defining characteristics of a stem cell: self-renewal, capacity to produce a large number of progeny and multilineage potential. The location of stem cells in the adult brain was later identified to be within the striatum,9 and researchers began to show that cells isolated from this region, and the dorsolateral region of the lateral ventricle of the adult brain, were capable of differentiating into both neurons and glia.10

During mammalian CNS development, neural precursor cells arising from the neural tube produce pools of multipotent and more restricted neural progenitor cells, which then proliferate, migrate and further differentiate into neurons and glial cells. During embryogenesis, neural precursor cells are derived from the neuroectoderm and can first be detected during neural plate and neural tube formation. As the embryo develops, neural stem cells can be identified in nearly all regions of the embryonic mouse, rat and human CNS, including the septum, cortex, thalamus, ventral mesencephalon and spinal cord. NSCs isolated from these regions have a distinct spatial identity and differentiation potential. In contrast to the developing nervous system, where NSCs are fairly ubiquitous, cells with neural stem cell characteristics are localized primarily to two key regions of the mature CNS: the subventricular zone (SVZ), lining the lateral ventricles of the forebrain, and the subgranular layer of thedentate gyrus of the hippocampal formation (described later).11 In the adult mouse brain, the SVZ contains a heterogeneous population of proliferating cells. However, it is believed that the type B cells (activated GFAP+/PAX6+ astrocytes or astrogliallike NSCs) are the cells that exhibit stem cell properties, and these cells may be derived directly from radial glial cells, the predominant neural precursor population in the early developing brain. NPCs in this niche are relatively quiescent under normal physiological conditions, but can be induced to proliferate and to repopulate the SVZ following irradiation.10 SVZ NSCs maintain neurogenesis throughout adult life through the production of fast-dividing transit amplifying progenitors (TAPs or C cells), which then differentiate and give rise to neuroblasts. TAPs and neuroblasts migrate through the rostral migratory stream (RMS) and further differentiate into new interneurons in the olfactory bulb. This ongoing neurogenesis, which is supported by the NSCs in the SVZ, is essential for maintenance of the olfactory system, providing a source of new neurons for the olfactory bulb of rodents and the association cortex of non-human primates.12 Although the RMS in the adult human brain has been elusive, a similar migration of neuroblasts through the RMS has also been observed.13 Neurogenesis also persists in the subgranular zone of the hippocampus, a region important for learning and memory, where it leads to the production of new granule cells. Lineage tracing studies have mapped the neural progenitor cells to the dorsal region of the hippocampus, in a collapsed ventricle within the dentate gyrus.10 Studies have demonstrated that neurogenic cells from the subgranular layer may have a more limited proliferative potential than the SVZ NSCs and are more likely to be progenitor cells than true stem cells.14 Recent evidence also suggests that neurogenesis plays a different role in the hippocampus than in the olfactory bulb. Whereas the SVZ NSCs play a maintenance role, it is thought that hippocampal neurogenesis serves to increase the number of new neurons and contributes to hippocampal growth throughout adult life.12 Neural progenitor cells have also been identified in the spinal cord central canal ventricular zone and pial boundary15-16, and it is possible that additional regional progenitor populations will be identified in the future.

In vitro methodologies designed to isolate, expand and functionally characterize NSC populations have revolutionized our understanding of neural stem cell biology, and increased our knowledge of the genetic and epigenetic regulation of NSCs.17 Over the past several decades, a number of culture systems have been developed that attempt to recapitulate the distinct in vivo developmental stages of the nervous system, enabling theisolation and expansion of different NPC populations at different stages of development. Here, we outline the commonly used culture systems for generating NPCs from pluripotent stem cells (PSCs), and for isolating and expanding NSCs from the early embryonic, postnatal and adult CNS.

Neural induction and differentiation of pluripotent stem cells: Early NPCs can be derived from mouse and human PSCs, which include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), using appropriate neural induction conditions at the first stage of differentiation. While these neural differentiation protocols vary widely, a prominent feature in popular embryoid body-based protocols is the generation of neural rosettes, morphologically identifiable structures containing NPCs, which are believed to represent the neural tube. The NPCs present in the neural rosette structures are then isolated, and can be propagated to allow NPC expansion, while maintaining the potential to generate neurons and glial cells. More recently, studies have shown that neural induction of PSCs can also be achieved in a monolayer culture system, wherein human ESCs and iPSCs are plated onto a defined matrix, and exposed to inductive factors.18 A combination of specific cytokines or small molecules, believed to mimic the developmental cues for spatiotemporal patterning in the developing brain during embryogenesis, can be added to cultures at the neural induction stage to promote regionalization of NPCs. These patterned NPCs can then be differentiated into mature cell types with phenotypes representative of different regions of the brain.19-24 New protocols have been developed to generate cerebral organoids from PSC-derived neural progenitor cells. Cerebral organoids recapitulate features of human brain development, including the formation of discrete brain regions featuring characteristic laminar cellular organization.25

Neurosphere culture: The neurosphere culture system has been widely used since its development as a method to identify NSCs.26-29 A specific region of the CNS is microdissected, mechanically or enzymatically dissociated, and plated in adefined serum-free medium in the presence of a mitogenic factor, such as epidermal growth factor (EGF) and/or basic fibroblast growth factor (bFGF). In the neurosphere culture system, NSCs, as well as neural progenitor cells, begin to proliferate in response to these mitogens, forming small clusters of cells after 2 - 3 days. The clusters continue to grow in size, and by day 3 - 5, the majority of clusters detach from the culture surface and begin to grow in suspension. By approximately day seven, depending on the cell source, the cell clusters, called neurospheres, typically measure 100 - 200 m in diameter and are composed of approximately 10,000 - 100,000 cells. At this point, the neurospheres should be passaged to prevent the cell clusters from growing too large, which can lead to necrosis as a result of a lack of oxygen and nutrient exchange at the neurosphere center. To passage the cultures, neurospheres are individually, or as a population, mechanically or enzymatically dissociated into a single cell suspension and replated under the same conditions as the primary culture. NSCs and neural progenitor cells again begin to proliferate to form new cell clusters that are ready to be passaged approximately 5 - 7 days later. By repeating the above procedures for multiple passages, NSCs present in the culture will self-renew and produce a large number of progeny, resulting in a relatively consistent increase in total cell number over time. Neurospheres derived from embryonic mouse CNS tissue treated in this manner can be passaged for up to 10 weeks with no loss in their proliferative ability, resulting in a greater than 100- fold increase in total cell number. NSCs and neural progenitors can be induced to differentiate by removing the mitogens and plating either intact neurospheres or dissociated cells on an adhesive substrate, in the presence of a low serum-containing medium. After several days, virtually all of the NSCs and progeny will differentiate into the three main neural cell types found in the CNS: neurons, astrocytes and oligodendrocytes. While the culture medium, growth factor requirements and culture protocols may vary, the neurosphere culture system has been successfully used to isolate NSCs and progenitors from different regions of the embryonic and adult CNS of many species including mouse, rat and human.

Adherent monolayer culture: Alternatively, cells obtained from CNS tissues can be cultured as adherent cultures in a defined, serum-free medium supplemented with EGF and/or bFGF, in the presence of a substrate such as poly-L-ornithine, laminin, or fibronectin. When plated under these conditions, the neural stem and progenitor cells will attach to the substrate-coated cultureware, as opposed to each other, forming an adherent monolayer of cells, instead of neurospheres. The reported success of expanding NSCs in long-term adherent monolayer cultures is variable and may be due to differences in the substrates, serum-free media andgrowth factors used.17 Recently, protocols that have incorporated laminin as the substrate, along with an appropriate serum-free culture medium containing both EGF and bFGF have been able to support long-term cultures of neural precursors from mouse and human CNS tissues.30-32 These adherent cells proliferate and become confluent over the course of 5 - 10 days. To passage the cultures, cells are detached from the surface by enzymatic treatment and replated under the same conditions as the primary culture. It has been reported that NSCs cultured under adherent monolayer conditions undergo symmetric divisions in long-term culture.30,33 Similar to the neurosphere culture system, adherently cultured cells can be passaged multiple times and induced to differentiate into neurons, astrocytes and oligodendrocytes upon mitogen removal and exposure to a low serum-containing medium.

Several studies have suggested that culturing CNS cells in neurosphere cultures does not efficiently maintain NSCs and produces a heterogeneous cell population, whereas culturing cells under serum-free adherent culture conditions does maintain NSCs.17 While these reports did not directly compare neurosphere and adherent monolayer culture methods using the same medium, growth factors or extracellular matrix to evaluate NSC numbers, proliferation and differentiation potential, they emphasize that culture systems can influence the in vitro functional properties of NSCs and neural progenitors. It is important that in vitro methodologies for NSC research are designed with this caveat in mind, and with a clear understanding of what the methodologies are purported to measure.34-35

Immunomagnetic or immunofluorescent cell isolation strategies using antibodies directed against cell surface markers present on stem cells, progenitors and mature CNS cells have been applied to the study of NSCs. Similar to stem cells in other systems, the phenotype of CNS stem cells has not been completely determined. Expression, or lack of expression, of CD34, CD133 and CD45 antigens has been used as a strategy for the preliminary characterization of potential CNS stem cell subsets. A distinct subset of human fetal CNS cells with the phenotype CD133+ 5E12+ CD34- CD45- CD24-/lo has the ability to form neurospheres in culture, initiate secondary neurosphere formation, and differentiate into neurons and astrocytes.36 Using a similar approach, fluorescence-activated cell sorting (FACS)- based isolation of nestin+ PNA- CD24- cells from the adult mouse periventricular region enabled significant enrichment of NSCs(80% frequency in sorted population, representing a 100-fold increase from the unsorted population).37 However, the purity of the enriched NSC population was found to be lower when this strategy was reevaluated using the more rigorous Neural Colony-Forming Cell (NCFC) assay.38-39 NSC subsets detected at different stages of CNS development have been shown to express markers such as nestin, GFAP, CD15, Sox2, Musashi, CD133, EGFR, Pax6, FABP7 (BLBP) and GLAST40-45. However, none of these markers are uniquely expressed by NSCs; many are also expressed by neural progenitor cells and other nonneural cell types. Studies have demonstrated that stem cells in a variety of tissues, including bone marrow, skeletal muscle and fetal liver can be identified by their ability to efflux fluorescent dyes such as Hoechst 33342. Such a population, called the side population, or SP (based on its profile on a flow cytometer), has also been identified in both mouse primary CNS cells and cultured neurospheres.46 Other non-immunological methods have been used to identify populations of cells from normal and tumorigenic CNS tissues, based on some of the in vitro properties of stem cells, including FABP7 expression and high aldehyde dehydrogenase (ALDH) enzyme activity. ALDH-bright cells from embryonic rat and mouse CNS have been isolated and shown to have the ability to generate neurospheres, neurons, astrocytes and oligodendrocytes in vitro, as well as neurons in vivo, when transplanted into the adult mouse cerebral cortex.47-50 NeuroFluor CDr3 is a membrane-permeable fluorescent probe that binds to FABP7 and can be used to detect and isolate viable neural progenitor cells from multiple species.42-43

Multipotent neural stem-like cells, known as brain tumor stem cells (BTSCs) or cancer stem cells (CSCs), have been identified and isolated from different grades (low and high) and types of brain cancers, including gliomas and medulloblastomas.51-52 Similar to NSCs, these BTSCs exhibit self-renewal, high proliferative capacity and multi-lineage differentiation potential in vitro. They also initiate tumors that phenocopy the parent tumor in immunocompromised mice.53 No unique marker of BTSCs has been identified but recent work suggests that tumors contain a heterogenous population of cells with a subset of cells expressing the putative NSC marker CD133.53 CD133+ cells purified from primary tumor samples formed primary tumors, when injected into primary immunocompromised mice, and secondary tumors upon serial transplantation into secondary recipient mice.53 However, CD133 is also expressed by differentiated cells in different tissues and CD133- BTSCs can also initiate tumors in immunocompromised mice.54-55 Therefore, it remains to bedetermined if CD133 alone, or in combination with other markers, can be used to discriminate between tumor initiating cells and non-tumor initiating cells in different grades and types of brain tumors. Recently, FABP7 has gained traction as a CNS-specific marker of NSCs and BTSCs.42-43, 57

Both the neurosphere and adherent monolayer culture methods have been applied to the study of BTSCs. When culturing normal NSCs, the mitogen(s) EGF (and/or bFGF) are required to maintain NSC proliferation. However, there is some indication that these mitogens are not required when culturing BTSCs.57 Interestingly, the neurosphere assay may be a clinically relevant functional readout for the study of BTSCs, with emerging evidence suggesting that renewable neurosphere formation is a significant predictor of increased risk of patient death and rapid tumor progression in cultured human glioma samples.58-60 Furthermore, the adherent monolayer culture has been shown to enable pure populations of glioma-derived BTSCs to be expanded in vitro.61

Research in the field of NSC biology has made a significant leap forward over the past ~30 years. Contrary to the beliefs of the past century, the adult mammalian brain retains a small number of true NSCs located in specific CNS regions. The identification of CNS-resident NSCs and the discovery that adult somatic cells from mouse and human can be reprogrammed to a pluripotent state,62-68 and then directed to differentiate into neural cell types, has opened the door to new therapeutic avenues aimed at replacing lost or damaged CNS cells. This may include transplantation of neural progenitors derived from fetal or adult CNS tissue, or pluripotent stem cells. Recent research has shown that adult somatic cells can be directly reprogrammed to specific cell fates, such as neurons, using appropriate transcriptional factors, bypassing the need for an induced pluripotent stem cell intermediate.69 Astroglia from the early postnatal cerebracortex can be reprogrammed in vitro to neurons capable of action potential firing, by the forced expression of a single transcription factor, such as Pax6 or the pro-neural transcription factor neurogenin-2 (Neurog2).70 To develop cell therapies to treat CNS injuries and diseases, a greater understanding of the cellular and molecular properties of neural stem and progenitor cells is required. To facilitate this important research, STEMCELL Technologies has developed NeuroCult proliferation and differentiation kits for human, mouse and rat, including xenofree NeuroCult-XF. The NeuroCult NCFC Assay provides a simple and more accurate assay to enumerate NSCs compared to the neurosphere assay. These tools for NSC research are complemented by the NeuroCult SM Neuronal Culture Kits, specialized serum-free medium formulations for culturing primary neurons. Together, these reagents help to advance neuroscience research and assist in its transition from the experimental to the therapeutic phase.

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Neural Stem Cells - Stemcell Technologies

Inside your body, red blood cells are constantly on the move. They deliver oxygen to every tissue in every part of your body. These blood cells also cart away waste. So their work is crucial to your survival. But all that squeezing through tiny vessels is tough on red blood cells. Thats why they last only about four months.

Where do their replacements come from? Stem cells.

These are a very special family of cells. When most other cells divide, the daughter cells look and act exactly like their parents. For example, a skin cell cant make anything but another skin cell. The same is true for cells in the intestine or liver.

Not stem cells. Stem cells can become many different types. That is how an embryo grows from a single fertilized egg into a fetus with trillions of specialized cells. They need to specialize to make up tissues that function very differently, including those in the brain, skin, muscle and other organs. Later in life, stem cells also can replace worn-out or damaged cells including red blood cells.

The remarkable abilities of stem cells make them very exciting to scientists. One day, experts hope to use stem cells to repair or replace many different kinds of tissues, whether injured in accidents or damaged by diseases. Such stem cell therapy would allow the body to heal itself. Scientists have found a way to put specialized cells to work repairing damage, too. Together, these cell-based therapies might one day make permanent disabilities a thing of the past.

One unusual type of stem cell offers special promise for such therapeutic uses. For the recent development of this cell type, Shinya Yamanaka shared the 2012 Nobel Prize in medicine.

Meet the family

Blood stem cells live inside your bones, in what is called marrow. There, they divide over and over. Some of the new cells remain stem cells. Others form red blood cells. Still others morph into any of the five types of white blood cells that will fight infections. Although blood stem cells can become any one of these specialized blood cells, they cannot become muscle, nerve or other types of cells. They are too specialized to do that.

Another type of stem cell is more generalized. These can mature into any type of cell in the body. Such stem cells are called pluripotent (PLU ree PO tint). The word means having many possibilities. And its not hard to understand why these cells have captured the imaginations of many scientists.

Until recently, all pluripotent cells came from embryos. Thats why scientists called them embryonic stem cells. After an egg is fertilized, it divides in two. These two cells split again, to become four cells, and so on. In the first few days of this embryos development, each of its cells is identical to all the others. Yet each cell has the potential to develop into any specialized cell type.

When the human embryo reaches three to five days old, its cells start to realize their potential. They specialize. Some will develop into muscle cells or bone cells. Others will form lung cells or maybe the cells lining the stomach. Once cells specialize, their many possibilities suddenly become limited.

By birth, almost all of a babys cells will have specialized. Each cell type will have its own distinctive shape and function. For example, muscle cells will be long and able to contract, or shorten. Red blood cells will be small and plate-shaped, so they can slip through blood vessels with ease.

Hidden among all of these specialized cells are pockets of adult stem cells. (Yes, even newborns have adult stem cells.) Unlike embryonic stem cells, adult stem cells cannot transform into any and every cell type. However, adult stem cells can replace several different types of specialized cells as they wear out. One type of adult stem cell is found in your marrow, making new blood cells. More types are found in other tissues, including the brain, heart and gut.

Among naturally occurring stem cells, the embryonic type is the most useful. Adult stem cells just arent as flexible. The adult type also is relatively rare and can be difficult to separate from the tissues in which it is found. Although more versatile, embryonic stem cells are both difficult to obtain and controversial. Thats because harvesting them requires destroying an embryo.

Fortunately, recent discoveries in stem cell research now offer scientists a third and potentially better option.

The search for answers

In 2006, Shinya Yamanaka discovered that specialized cells like those in skin could be converted back into stem cells. Working at Kyoto University in Japan, this doctor and scientist induced or persuaded mature cells to become stem cells. He did this by inserting a specific set of genes into the cells. After several weeks, the cells behaved just like embryonic cells. His new type of stem cells are called induced pluripotent stem cells, or iP stem cells (and sometimes iPS cells).

Yamanakas discovery represented a huge leap forward. The iP stem cells offer several advantages over both embryonic and adult stem cells. First, iP stem cells are able to become any cell type, just as embryonic stem cells can. Second, they can be made from any starting cell type. That means they are easy to obtain. Third, in the future, doctors would be able to treat patients with stem cells created from their own tissues. Such cells would perfectly match the others, genetically. That means the patients immune system (including all of its white blood cells) would not attack the introduced cells. (The body often mounts a life-threatening attack against transplanted organs that come from other people because they dont offer such a perfect match. To the body, they seem foreign and a potentially dangerous invader.)

Scientists the world over learned of the technique developed by Yamanaka (who now works at the Gladstone Institutes which is affiliated with the University of California, San Francisco). Many of these researchers adopted Yamanakas procedure to create their own induced pluripotent stem cells. For the first time, researchers had a tool that could allow them to make stem cells from people with rare genetic diseases. This helps scientists learn what makes certain cell types die. Experts can also expose small batches of these diseased cells to different medicines. This allows them to test literally thousands of drugs to find out which works best.

And in the future, many experts hope induced stem cells will be used to replace adult stem cells and the cells of tissues that are damaged or dying.

Therapies take patients and patience

Among those experts is Anne Cherry, a graduate student at Harvard University. Cherry is using induced stem cells to learn more about a very rare genetic disease called Pearson syndrome. A syndrome is a group of symptoms that occur together. One symptom of Pearson syndrome is that stem cells in bone marrow cannot make normal red blood cells. This condition typically leads to an early death.

Cherry has begun to study why these stem cells fail.

She started by taking skin cells from a girl with the disease. She placed the cells in a test tube and added genes to turn them into stem cells. Over several weeks, the cells began to make proteins for which the inserted genes had provided instructions. Proteins do most of the work inside cells. These proteins turned off the genes that made the cells act like skin cells. Before long, the proteins turned on the genes to make these cells behave like embryonic stem cells.

After about three months, Cherry had a big batch of the new induced stem cells. Those cells now live in Petri dishes in her lab, where they are kept at body temperature (37 Celsius, or 98.6 Fahrenheit). The scientist is now trying to coax the induced stem cells into becoming blood cells. After that, Cherry wants to find out how Pearson syndrome kills them.

Meanwhile, the patient who donated the skin cells remains unable to make blood cells on her own. So doctors must give her regular transfusions of blood from a donor. Though life-saving, transfusions come with risks, particularly for someone with a serious disease.

Cherry hopes to one day turn the girls induced stem cells into healthy new blood stem cells and then return them to the girls body. Doing so could eliminate the need for further transfusions. And since the cells would be the girls own, there would be no risk of her immune system reacting to them as though they were foreign.

Sight for sore eyes

At University of Nebraska Medical Center in Omaha, Iqbal Ahmad is working on using stem cells to restore sight to the blind. A neuroscientist someone who studies the brain and nervous system Ahmad has been focusing on people who lost sight when nerve cells in the eyes retina died from a disease called glaucoma (glaw KOH muh).

Located inside the back of the eye, the retina converts incoming light into electrical signals that are then sent to the brain. Ahmad is studying how to replace dead retina cells with new ones formed from induced pluripotent stem cells.

The neuroscientist starts by removing adult stem cells from the cornea, or the clear tissue that covers the front of the eye. These stem cells normally replace cells lost through the wear and tear of blinking. They cannot become nerve cells at least not on their own. Ahmad, however, can transform these cells into iP stem cells. Then, with prodding, he turns them into nerve cells.

To make the transformation, Ahmad places the cornea cells on one side of a Petri dish. He then places embryonic stem cells on the other side. A meshlike membrane separates the two types of cells so they cant mix. But even though they cant touch, they do communicate.

Cells constantly send out chemical signals to which other cells respond. When the embryonic stem cells speak, the eye cells listen. Their chemical messages persuade the eye cells to turn off the genes that tell them to be cornea cells. Over time, the eye cells become stem cells that can give rise to different types of cells, including nerve cells.

When Ahmads team implanted the nerve cells into the eyes of laboratory mice and rats, they migrated to the retina. There, they began replacing the nerve cells that had died from glaucoma. One day, the same procedure may restore vision to people who have lost their sight.

Another approach

In using a bodys own cells to repair injury or to treat disease, stem cells arent always the answer. Although stem cells offer tremendous advances in regenerating lost tissue, some medical treatments may work better without them. Thats thanks to the chemical communication going on between all cells all of the time. In some situations, highly specialized cells can act as a conductor, directing other cells to change their tune.

In 2008, while working at the University of Cambridge in England, veterinary neurologist Nick Jeffery began a project that used cells taken from the back of the nose. But Jeffery and his team were not out to create stem cells. Instead, the scientists used those nasal cells to repair damaged connections in the spinal cord.

The spinal cord is basically a rope of nerve cells that ferry signals to and from the brain and other parts of the body. Injuring the spinal cord can lead to paralysis, or the loss of sensation and the inability to move muscles.

Like Ahmad, some researchers are using stem cells to replace damaged nerve cells. But Jeffery, now at Iowa State University in Ames, doesnt think such techniques are always necessary to aid recovery from spinal injuries. Stem cell transplantation, points out Jefferys colleague, neuroscientist Robin Franklin, is to replace a missing cell type. In a spinal injury, the nerve cells arent missing. Theyre just cut off.

Nerve cells contain long, wirelike projections called axons that relay signals to the next cell. When the spine is injured, these axons can become severed, or cut. Damaging an axon is like snipping a wire the signal stops flowing. So the Cambridge scientists set out to see if they could restore those signals.

Jeffery and his fellow scientists work with dogs that have experienced spinal injuries. Such problems are common in some breeds, including dachshunds. The team first surgically removed cells from the dogs sinuses or the hollow spaces in the skull behind the nose. These are not stem cells. These particular cells instead encourage nerve cells in the nose to grow new axons. These cells help the pooches maintain their healthy sense of smell.

The scientists grew these sinus cells in the lab until they had reproduced to large numbers. Then the researchers injected the cells into the spinal cords of two out of every three doggy patients. Each treated dog received an injection of its own cells. The other dogs got an injection of only the liquid broth used to feed the growing cells.

Over several months, the dogs owners repeatedly brought their pets back to the lab for testing on a treadmill. This allowed the scientists to evaluate how well the animals coordinated their front and hind feet while walking. Dogs that had received the nasal cells steadily improved over time. Dogs that received only the liquid did not.

This treatment did not result in a perfect cure. Nerve cells did reconnect several portions of the spinal cord. But nerve cells that once linked to the brain remained disconnected. Still, these dog data indicate that nasal cells can aid in recovering from a spinal cord injury.

Such new developments in cellular research suggest that even more remarkable medical advancements may be just a few years away. Yamanaka, Cherry, Ahmad, Jeffery, Franklin and many other scientists are steadily unlocking secrets to cellular change. And while you cant teach an old dog new tricks, scientists are finding out that the same just isnt true of cells anymore.

cornea The clear covering over the front of the eye.

embryo A vertebrate, or animal with a backbone, in its early stages of development.

gene A section of DNA that carries the genetic instructions for making a protein. Proteins do most of the work in cells.

glaucoma An eye disease that damages nerve cells carrying signals to the brain.

immune cell White blood cell that helps protect the body against germs.

molecule A collection of atoms.

neuron (or nerve cell) The basic working unit of the nervous system. These cells relay nerve signals.

neuroscientist A researcher who studies neurons and the nervous system.

paralysis Loss of feeling in some part of the body and an inability to move that part.

retina The light-sensitive lining at the back of the eye. It converts light into electrical impulses that relay information to the brain.

sinus An opening in the bone of the skull connected to the nostrils.

spinal cord The ropelike collection of neurons that connect the brain with nerves throughout the body.

tissue A large collection of related, similar cells that together work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues. And brain tissue will be very different from bone or heart tissue.

transfusion The process of transferring blood into one person that had been collected from another.

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Stem cells: The secret to change | Science News for Students

Arecent studyis providing new supportfor an old adage: "death is only the beginning." According to the research, some cells in the body fight to live long after the organism dies.

In some cases, cell activity actually increases following death. The research suggests that the death of a living organism is a multi-step process that continues long after the final heartbeat;findings from this research could have implications foreverything from cancer research to life extension.

The study, now published online in the journal Open Biology, revealed just how many cells remain alive and thriving after an organisms death. For example, stem cells in particular were found to be most active after death, fighting to stay alive and attempting to repair themselves for days, and in some cases weeks, after death. In addition, a process known as gene transcription, that Seeker explained as a cellular behavior associated with stress, immunity, inflammation,and cancer, also increased following death. Although the research was conducted on zebrafish and mice, they believe the same cellular activity could be observed in all living creatures.

Read: 'How Long Will I Live?' Your Lifespan Depends On Cellular Death And Progress Of Future Science

Not all cells are 'dead' when an organism dies," senior author Peter Noble told Seeker. "Different cell types have different life spans, generation times and resilience to extreme stress."

In the "Twilight of Death," many cells continue to live and thrive once the body has technically died. Photo Courtesy of Pixabay

The fascinating discovery has been dubbed the Twilight of Death, and refers to the time period between death and decomposition where not all of the bodys cells are yet dead. The study researchers noted that their findings suggest death is more like a slow shutdown process and not the simple off-switch many imagine it to be. Whats more, better understanding of what happens when the body dies could lead to medical interventions aimed at delaying this process.

Not only does this researchhelp us better understand how a body dies, (and perhaps how to delaythis process), but it could also have real-life implications for organ transplant. Past research has suggested that patients have increased chances of developing cancer after they receive an organ transplant. For example, a 2011 study from the National Institutes of Health, found that U.S. organ transplant recipients had a high risk for develop 32 different types of cancer. The highest risks being non-Hodgkin lymphoma (14.1 percent of all cancers in transplant recipients), lung cancer (12.6 percent), liver cancer (8.7 percent), and kidney cancer (7.1 percent).

Although the reason for this remains unclear, the new study suggests it may be connected to the increased cellular activity observed in this Twilight of Death. Whats more, Noble suggested that there may even be something we can do about this, and proposed that prescreening transplant organs for increased cancer gene transcripts could help lower this risk.

Source: Pozhitkov AE, Neme R, Domazet-Loo T, et al. Tracing the dynamics of gene transcripts after organismal death. Open Biology. 2017

See Also:

Legal Definition Of 'Death' May Not Be Enough To Pinpoint When We Medically Kick The Bucket

The Evolutionary Reason Humans Die Despite The Inclination To Survive

See more here:
Life After Death, According To Science: Cells Fight To ...

Boss Stem Cells (or simply Boss Cells) are permanent items that increase the difficulty of the game when active. The first one is acquired by beating the Hand of the King with no Boss Stem Cells active, the second by beating him with one active, and so on. However, the fifth Boss Stem Cell is obtained by beating the Giant with four active.

Boss Stem Cells can be injected and removed at the start of the game in the Tube. Each one makes the game significantly harder by increasing enemy tier, density, variety, and limiting healing options. On the other hand, higher difficulty levels also increase cells dropped from enemies and the level of the Legendary Forge, and allow access to new blueprints and bonus doors scattered through the levels. The doors show the number of Boss Stem Cells required to enter and shine blue if enough are currently active. The fifth Boss Cell is special in that it doesn't modify anything compared to the fourth until the Throne Room, where it grants access to a secret biome, the Astrolab, and the hidden final boss of the game in the Observatory.

- Reduce number of health fountains (only available every other level); transition areas without health fountains will instead give a mini recharge that will refill one use of health flask

+ Improves the level of the Legendary Forge by allowing you to increase the frequency of ++ items up to 100%

+ Unlocks a door in Prison Depths that goes to the Ancient Sewers

+ Allows you to collect the next Boss Stem Cell

- Removes all health fountains, but gain one mini recharge after each boss

+ Improves the level of the Legendary Forge by allowing you to increase the frequency of S items up to 25%

+ Multiplies the amount of dropped cells by 2 (effect also applies to cells found in containers)

+ Unlocks a door in Slumbering Sanctuary that goes to the Cavern

+ Unlocks a door in Forgotten Sepulcher that goes to Guardian's Haven

+ Allows you to collect the next Boss Stem Cell

- Removes all health fountains (individual flask recharges can only be bought in Food shops)

+ Improves the level of the Legendary Forge by allowing you to increase the frequency of S items up to 50%

+ Multiplies the amount of dropped cells by 2 (effect also applies to cells found in containers)

+ Improves Legendary items by having them grant +1 to all Stats

+ Unlocks a door in Ramparts that goes to the Insufferable Crypt

+ Allows you to collect the next Boss Stem Cell

- Removes all health fountains (individual flask recharges can only be bought in Food shops)

- Taking hits always causes Malaise

- Increases detection range of mobs and gives most of them the ability to teleport next to your position

- Some of the food found in levels is infected by the Malaise

+ Improves the level of the Legendary Forge by allowing you to increase the frequency of S items up to 100%

+ Improves Legendary items by having them grant +1 to all Stats

+ Multiplies the amount of dropped cells by 3 (effect also applies to cells found in containers)

- Removes all health fountains (individual flask recharges can only be bought in Food shops)

- Taking hits always causes Malaise

- Increases detection range of mobs and gives most of them the ability to teleport next to your position

- Some of the food found in levels is infected by the Malaise

- No Collector in transitions areas (collected blueprints are unlocked when you go past where Collector was standing)

+ Improves the level of the Legendary Forge by allowing you to increase the frequency of S items up to 100%

+ Improves Legendary items by having them grant +1 to all Stats

+ Multiplies the amount of dropped cells by 3 (effect also applies to cells found in containers)

+ Gives access to the Astrolab and the Observatory (Rise of the Giant DLC content)

Follow this link:
Boss Stem Cell - Official Dead Cells Wiki

JavaScript is disabled on your browser. Please enable JavaScript to use all the features on this page.Abstract

Mesenchymal stem cells are the new generation of medicine for treating numerous vascular diseases and tissue defects because of their ability to secrete therapeutic factors. Poor cellular survival in an oxidative diseased tissue, however, hinders the therapeutic efficacy. To this end, we hypothesized that tethering the surface of stem cells with colloidal particles capable of discharging antioxidant cargos in response to elevated levels of hydrogen peroxide (H2O2) would maintain survival and therapeutic activity of the stem cells. We examined this hypothesis by encapsulating epigallocatechin gallate (EGCG) and manganese oxide (MnO2) nanocatalysts into particles comprising poly(d,l-lactide-co-glycolide)-block-hyaluronic acid. The MnO2 nanocatalysts catalyzed the decomposition of H2O2 into oxygen gas, which increased the internal pressure of particles and accelerated the release of EGCG by 1.5-fold. Consequently, stem cells exhibited 1.2-fold higher metabolic activity and 2.8-fold higher secretion level of pro-angiogenic factor in sub-lethal H2O2 concentrations. These stem cells, in turn, performed a greater angiogenic potential with doubled number of newly formed mature blood vessels. We envisage that the results of this study will contribute to improving the therapeutic efficacy of a wide array of stem cells.

Mesenchymal stem cells

Epigallocatechin gallate

Manganese oxide nanocatalysts

Colloidal particles

Surface tethering

Hydrogen peroxide

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2019 Elsevier Ltd. All rights reserved.

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Untreated pig brain at left shows lots of death and few neurons (green) hours after death, but the image on the right shows a brain connected to a system called BrainEx that Yale researchers report kept more neurons alive. Source.Stefano G. Daniele and Zvonimir Vrselja, Sestan Laboratory, Yale School of MedicineUntreated pig brain at left shows lots of death and few neurons (green) hours after death, but the image on the right shows a brain connected to a system called BrainEx that Yale researchers report kept more neurons alive. Source.Stefano G. Daniele and Zvonimir Vrselja, Sestan Laboratory, Yale School of Medicine

Its been a cool week for stem cell and other associated kinds of research. In this post I have a series of links to a variety of interesting developments and papers.

Gene therapy cures bubble boy infants. William Wan over at the WaPo on this good news. Nope, this wasnt done with CRISPR, but rather with a viral transgene approach (not TALENs as I mistakenly had originally written here).

The pigs were dead. But four hours later, scientists restored cellular functions in their brains.This reminds me of a post I did on a biotech claiming oddly to reverse death ofhuman brain cells at least in part with a laser. In this new report, Yale researchers have a system called BrainEx that purportedly keeps brain cells alive for hours. Note in the image at left that the untreated brain is 8 hours post-death while the image of treated brain is only four hours after death. Still, it seems like a striking difference, but I cant help but feel a bit skeptical about how much meaning this report really has. Well see.

Researchers discover crucial link between brain and gut stem cells. The gut is very tied to overall health in many ways and was also recently found to be a novel reservoir of hematopoietic stem cells in people too.

To protect stem cells, plants have diverse genetic backup plans. Yes, plants have stem cells and they arent just made by nature to go into sketchy anti-aging cremes.

Kind of a first-person piece in the NYT, The Lifesaving Power in Stem Cells on cord blood by Susan Gubar. It has this in your face kind of subtitle in reference to stem cell clinics, Liars and thieves should not be allowed to detract from legitimate scientific research that has made umbilical cord blood mystic in its regenerative powers.

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Weekend reads: reversing death of pig brain cells, brain ...

There are many ways in which human stem cells can be used in research and the clinic. Studies of human embryonic stem cells will yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become the differentiated cells that form the tissues and organs. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A more complete understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Predictably controlling cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. While recent developments with iPS cells suggest some of the specific factors that may be involved, techniques must be devised to introduce these factors safely into the cells and control the processes that are induced by these factors.

Human stem cells are currently being used to test new drugs. New medications are tested for safety on differentiated cells generated from human pluripotent cell lines. Other kinds of cell lines have a long history of being used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. The availability of pluripotent stem cells would allow drug testing in a wider range of cell types. However, to screen drugs effectively, the conditions must be identical when comparing different drugs. Therefore, scientists must be able to precisely control the differentiation of stem cells into the specific cell type on which drugs will be tested. For some cell types and tissues, current knowledge of the signals controlling differentiation falls short of being able to mimic these conditions precisely to generate pure populations of differentiated cells for each drug being tested.

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including maculardegeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

Figure 3. Strategies to repair heart muscle with adult stem cells. Click here for larger image.

2008 Terese Winslow

For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stromal cells, transplanted into a damaged heart, can have beneficial effects. Whether these cells can generate heart muscle cells or stimulate the growth of new blood vessels that repopulate the heart tissue, or help via some other mechanism is actively under investigation. For example, injected cells may accomplish repair by secreting growth factors, rather than actually incorporating into the heart. Promising results from animal studies have served as the basis for a small number of exploratory studies in humans (for discussion, see call-out box, "Can Stem Cells Mend a Broken Heart?"). Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells (Figure 3).

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease, stroke, and congestive heart failure, has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic. Nearly 2,600 Americans die of CVD each day, roughly one person every 34 seconds. Given the aging of the population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes, CVD will be a significant health concern well into the 21st century.

Cardiovascular disease can deprive heart tissue of oxygen, thereby killing cardiac muscle cells (cardiomyocytes). This loss triggers a cascade of detrimental events, including formation of scar tissue, an overload of blood flow and pressure capacity, the overstretching of viable cardiac cells attempting to sustain cardiac output, leading to heart failure, and eventual death. Restoring damaged heart muscle tissue, through repair or regeneration, is therefore a potentially new strategy to treat heart failure.

The use of embryonic and adult-derived stem cells for cardiac repair is an active area of research. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells including mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated as possible sources for regenerating damaged heart tissue. All have been explored in mouse or rat models, and some have been tested in larger animal models, such as pigs.

A few small studies have also been carried out in humans, usually in patients who are undergoing open-heart surgery. Several of these have demonstrated that stem cells that are injected into the circulation or directly into the injured heart tissue appear to improve cardiac function and/or induce the formation of new capillaries. The mechanism for this repair remains controversial, and the stem cells likely regenerate heart tissue through several pathways. However, the stem cell populations that have been tested in these experiments vary widely, as do the conditions of their purification and application. Although much more research is needed to assess the safety and improve the efficacy of this approach, these preliminary clinical experiments show how stem cells may one day be used to repair damaged heart tissue, thereby reducing the burden of cardiovascular disease.

In people who suffer from type1 diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient's own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for persons with diabetes.

To realize the promise of novel cell-based therapies for such pervasive and debilitating diseases, scientists must be able to manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment. The following is a list of steps in successful cell-based treatments that scientists will have to learn to control to bring such treatments to the clinic. To be useful for transplant purposes, stem cells must be reproducibly made to:

Also, to avoid the problem of immune rejection, scientists are experimenting with different research strategies to generate tissues that will not be rejected.

To summarize, stem cells offer exciting promise for future therapies, but significant technical hurdles remain that will only be overcome through years of intensive research.

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Stem Cell Basics VII. | stemcells.nih.gov