Updated March 17, 2017 13:31:00

Queensland researchers have used stem cells to create a beating human heart muscle, as well as heart tissue that is able to repair itself.

Doctors James Hudson and Enzo Porello from the University of Queensland worked with German researchers to create the samples in a laboratory, and will use them to study cardiac biology and diseases.

"The patented technology enables us to now perform experiments on human heart tissue," Dr Hudson said.

Up until now researchers have had no "living" tissue to study, but now scientists have a viable, functioning heart muscle to work on.

Dr Hudson said it would help them model the cardiovascular disease, screen new drugs and investigate heart repair.

"Immature tissues were found to have the ability to regenerate following injury something that did not occur naturally for adults," he said.

"In the laboratory we used dry ice to kill part of the tissue while leaving the surrounding muscle healthy and viable.

"We found that when we injured those tissues in contrast to what happens normally in the heart where you get a 'dead' patch muscle function fully recovered because the cells regenerate.

"Our goal is to use this model to potentially find new therapeutic targets to enhance or induce cardiac regeneration in people with heart failure."

While the researchers have grown samples of beating heart tissue, they are not full size.

Dr Hudson said they were about 1 centimetre long and 1 millimetre wide.

He said about 54,000 Australians had heart attacks each year, with an average of about 23 deaths a day.

"Current pharmaceuticals can help those people in the shorter term, however some of those patients still progress to heart failure," Dr Hudson said.

"The holy grail goal of all this is to come up with new regenerative therapeutics to cure those patients."

The research team hopes to commercialise the technology, which it believes will help save lives.

The project has been supported by the National Health and Medical Research Council (NHMRC) and the National Heart Foundation.

Topics: medical-research, health, diseases-and-disorders, heart-disease, science-and-technology, research, qld, university-of-queensland-4072, australia

First posted March 17, 2017 13:11:06

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Aired 3/16/17 on KPBS News.

A research team led by UC San Diego scientists have created a lab-grown model of the anorexic brain using stem cells derived from patients with the eating disorder.

Researchers led by San Diego scientists have created a lab-grown model of the anorexic brain using stem cells derived from patients with the eating disorder. They say the results provide further evidence for understanding anorexia as largely genetically based, rather than primarily as a socially conditioned behavior.

"There's a stigma regarding eating disorders that it's something social," said UC San Diego researcher Alysson Muotri. "But in fact, our results point to a strong genetic factor. And moreover, it suggests there's a specific pathway in the brain that is altered."

For the study published Tuesday in the journal Translational Psychiatry, Muotri and his colleagues took skin cells from seven anorexia patients and then converted them into stem cells in the lab. They then coaxed those stem cells into brain cells, providing scientists with a new model for studying the eating disorder.

Muotri, who has developed similar models for other diseases, said the "disease-in-a-dish" approach is great for studying neurological disorders. Scientists wanting to study these diseases "can't just open the skull and look through the brain cells," he said.

The researchers compared anorexic brain models with other models built from cells taken from four non-anorexic people, most of them relatives of the anorexic patients. The researchers found a difference in the TACR1 gene between the two groups.

Muotri admits the number of patients studied was small, but says these results support "the idea that anorexia has a fundamental biological basis on the perception of fat in the body."

Anorexia experts not involved in the study told KPBS this is another step toward understanding the underlying biology of a misunderstood and often deadly disease.

Walter Kaye, director of the UCSD Eating Disorder Research and Treatment Program, said in an email to KPBS that the findings establish an interesting link between anorexia and a genetic pathway known to play a role in anxiety and fat metabolism.

"This may be a very important clue to understanding puzzling symptoms in anorexia nervosa, such as why food is often associated with anxiety, and why patients see themselves as fat and tend to avoid fat-containing foods," Kaye wrote.

Christina Wierenga, co-director of the eating disorder research program at UCSD, wrote in an email to KPBS, "Although the sample size is small, this elegant study is the first of its kind to examine gene expression in neurons derived from individuals with anorexia and sheds new light on possible causes of anorexia. Of course, replication in larger samples is needed."

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Luxembourg (Scicasts) Stem cells are unspecialized cells that can develop into any type of cell in the human body. So far, however, scientists only partially understand how the body controls the fate of these all-rounders, and what factors decide whether a stem cell will differentiate, for example, into a blood, liver or nerve cell. Researchers from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg and an international team have now identified an ingenious mechanism by which the body orchestrates the regeneration of red and white blood cells from progenitor cells. "This finding can help us to improve stem cell therapy in future," says Dr. Alexander Skupin, head of the "Integrative Cell Signalling" group of LCSB. The LCSB team has published its results in the scientific journal PLOS Biology.

Although all cells in an organism carry the same genetic blueprints -- the same DNA -- some of them act as blood or bone cells, for example, while others function as nerve or skin cells. Researchers already understand quite well how individual cells work. But how an organism is able to create such a diversity of cells from the same genetic template and how it manages to relocate them to wherever they are needed in the body is still largely unknown.

In order to learn more about this process, Alexander Skupin and his team treated blood stem cells from mice with growth hormones and then watched closely how these progenitor cells behaved during their differentiation into white or red blood cells. The researchers observed that the cells' transformation does not occur in linear, targeted fashion, but rather more opportunistically. Each progenitor cell adapts to the needs of its environment and integrates itself into the body where new cells are needed. "So, it is not as though the cell takes a ticket at the beginning of its differentiation and then travels straight to its destination. Rather, it gets off frequently to look around and see which line is best to take," Alexander Skupin explains. By this clever mechanism, a multicellular organism can adapt the regrowth of new cells to its current needs. "Before progenitor cells differentiate once and for all, they first lose their stem cell character and then check, as it were, which cell line is currently in demand. Only then do they develop into the cell type that best suits their characteristics and which prevails in their environment," Alexander Skupin says.

The researcher likens this step to a game of roulette, where the different types of cells can be thought of as the differently numbered slots in the roulette wheel that catch the ball. "When the cells lose their stem cell character, they are quasi thrown into the roulette wheel, where they first bounce around aimlessly. Only when they have found the right environment do the cells then drop into that niche - like the roulette ball falling into a numbered slot - and differentiate definitively." This way, the body can orchestrate its cell regeneration and at the same time prevent stem cells from being misdirected too early. "Even if a cell takes a wrong turn, it is ultimately sorted out again if its characteristics are unsuitable for the niche, or slot, it has landed in," says Skupin.

With their study, Alexander Skupin and his team have shown for the first time that a progenitor cell's fate is not clearly predetermined and does not follow a straight line. "This observation contradicts the current doctrine that stem cells are programmed to follow a certain lineage from the beginning," Alexander Skupin says. The researcher is furthermore convinced that the processes are similar for other progenitor cells. "In the lab, we have observed the same differentiation pattern in so-called iPS cells, or induced pluripotent stem cells, which can transform into many different types of cells."

This knowledge can help the researchers to improve the effectiveness of therapies in future. Stem cell therapy involves administering a patient his or her own body's stem cells in order to replace other cells that have died as a result of an affliction such as Parkinson's disease. While this promising treatment method has been intensively researched over many years, there has so far been only limited practical success in endogenous stem cell therapy. It is also highly controversial, since it is frequently accompanied by severe side effects and it cannot be ruled out that some cells might degenerate and lead to cancer. "Because we now have a better understanding of how the body influences the direction in which stem cells differentiate, we can hopefully control this process better in future," Alexander Skupin concludes.

Article adapted from a University of Luxembourg news release.

Publication: Cell Fate Decision as High-Dimensional Critical State Transition. Mitra Mojtahedi et al. PLoS Biol. (2016): Click here to view.

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A retina with macular degeneration. (Image: University of Iowa)

An unproven stem cell therapy conducted by a Florida clinic has blinded three patients in an apparent clinical trial gone horribly wrong. The incident showcases the extent to which unscrupulous clinics will take advantage of desperate patientsand how the lack of government oversight contributes to the problem.

As reported in the New England Journal of Medicine, the clinical trialif it can be called thatinvolved three women between the ages of 72 and 88 who were suffering from macular degeneration, a common progressive disease of the retina that leads to loss of vision. The women, all of whom were experiencing various degrees of vision loss, sought the help of a Florida clinic, which claimed to be testing a stem cell procedure designed to treat macular degeneration. Sometime in 2015, a week after stem cells were injected into their eyes, the women became blind. Two years later, doctors say theres virtually no chance the womens vision will be restored.

The authors of the new report, ophthalmologists Jeffrey Goldberg from Stanford University School of Medicine and Thomas Albini from the University of Miami, said the unfortunate incident serves as a call to awareness for patients, physicians and regulatory agencies of the risks of this kind of minimally regulated, patient-funded research.

Stem cells are undifferentiated cells that havent quite decided what they want to be when they grow up. Under the right conditions, these immature cells can be transformed into virtually any kind of cell found in the body, which is why theyve proven useful in regenerative medicine.

Eventually, scientists hope to be able to use stem cells to regenerate damaged tissue and organsand possibly even repair the effects of macular degenerationbut were not there yet. The only truly effective clinical application of stem cells to date has been in bone marrow transplants, in which stem cells extracted from a donors bone marrow are used to produce a fresh blood system for patients suffering from blood disorders such as leukemia. A recent study showed that there are nearly 600 clinics peddling unproven stem-cell procedures in the United States for a wide range of conditions, including arthritis, autism, cerebral palsy, stroke, muscular dystrophy, and cancer.

As noted in the NEJM report, two of the three patients learned about the stem cell trial for macular degeneration on ClinicalTrials.gov, a registry run by the US National Library of Medicine. The listings on this site arent fully scrutinized for scientific efficacy. The patients were reportedly under the assumption that they were participating in a bonafide clinical trial, but the consent form and other materials made no mention of a trial. Tellingly, each patient had to pay $5,000 for the procedure. This is highly unorthodox for a clinical trial, and it should have been cause for alarm. Im not aware of any legitimate research, at least in ophthalmology, that is patient-funded, Albini said in a statement.

The NEJM study didnt identify the Florida clinic responsible, but (conveniently) the authors provided the name of the trial: Study to assess the safety and effects of cells injected intravitreal in dry macular. A quick Google search calls the trial up, along with the name of the company responsible: Bioheart Inc., otherwise known as US Stem Cell. As the ClinicalTrials.gov page indicates, the study has been withdrawn prior to enrollment. According to Goldberg and Albini, the company is no longer performing the procedure, but it is still seeing patients.

The trial itself was a joke, lacking in all the components of a properly designed test. It wasnt based on prior laboratory experiments, no control group was assigned, no data was collected, and no plans were made for follow-ups.

During the procedure, the patients had some of their fat cells (i.e. adipose tissue) removed, along with a standard blood withdrawal. The fat tissues were then processed with an enzyme to draw out stem cells. Once plasma was isolated from the blood and added to the stem cells, the mixture was injected into both eyes of each patientyes, both eyes. Again, another serious clinical no-no; normally, only one eye would be injected for an experimental procedure like this in the event that something should go wrong. The entire procedure lasted less than an hour.

A week later, all three women were blind. As noted in the NEJM report, the blindness was accompanied by detached retinas and hemorrhaging.

The patients severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, and lens dislocation. After one year, the patients visual acuity ranged from 20/200 to no light perception.

Goldberg and Albini say the preparation of the stem cells was likely shoddy, and the injections may have been contaminated. Once in the eye, the stem cells could have changed into myofibroblasts, a type of cell associated with scarring.

The Florida clinic, it would appear, was appealing to the desperation of their patients, while taking advantage of a regulatory loophole. As the authors write in their report:

Adipose tissuederived stem cells have been increasingly used by stem-cell clinics because of the relative ease of obtaining and preparing these cells. Many of the clinics that provide these stem-cell therapies have done so under the auspices of patient-funded, institutional review boardapproved research, and the research is listed on ClinicalTrials.gov without an investigational new drug filing with the FDA.

At the time, the procedure was not subject to FDA approval because the cells werent transferred between patients, and because the cells were considered minimally processed. The FDA has since revised its requirements, and it now needs approval for these types of procedures. In addition to updating its regulations, the FDA is also clamping down on stem cell clinics.

Thats obviously a good thing, but its a little too late for the women involved. This incident shows what happens when regulations and oversight are weak, and how shady companies will take risks with their patients health. Certainly food for thought as Trump and his cronies start to recreate the FDA in their own image.

Update: We reached out to US Stem Cell Clinic for comment and they responded with this statement:

Founded in 1999, U.S Stem Cell, Inc. has been committed to the research and development of effective cell technologies to treat patients with a variety of diseases and injuries. Since 2001, our clinics have successfully conducted more than 7,000 stem cell procedures with less than 0.01% adverse reactions reported. We are unable to comment further on specific cases due to patient confidentiality or legal confidentiality obligations. Neither US Stem Cell nor US Stem Cell Clinic currently treats eye patients.

[New England Journal of Medicine]

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Adam Krief, a Jewish cancer patient whose search for a bone marrow donor captured the attention of social media and celebrities including Kim Kardashian, Mayim Bialik and Jason Biggs, has died.

Krief, a father of three from Los Angeles, died Tuesday, a family friend confirmed to JTA. He was 31.

Krief was diagnosed with primary myelofibrosis, a rare form of blood cancer that is likely fatal if a stem cell transplant match is not found. To find an HLA, or gene complex match for Krief something more difficult to track down than a blood type match drives were held around the world, including in North America, Israel, France and Mexico.

Kardashian posted about Krief on Facebook in September, saying he was a friend of a friend.

A bone-marrow donor was found last December seven matches were found, in fact, through the donor drives organized for him.

This is what cloud 9 looks like Im so grateful to let you all know that a donor has been found, Krief wrote at the time, sharing a video with two of his children.

The Hope 4 Adam Facebook page on March 8 called for a Worldwide Unity Shabbat for March 11 and March 18 for the recovery of Krief, asking followers to Help us bring about a miracle.

On Monday, the Eretz Kabbalah Facebook page of the Los Angeles-based Eretz Cultural Center posted a call for followers to recite Tehillim, or psalms, on behalf of Krief.

After a long search for a bone-marrow match to save his life, he finally received one. However, after some complications, he is said to only have a few hours to live, the post said.

Krief is survived by his wife, Lia, and his young children.

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American Jewish father of 3 whose bone marrow search inspired celebrities dies - Jerusalem Post Israel News

Bone Marrow Stem Cells Comments Off on American Jewish father of 3 whose bone marrow search inspired celebrities dies – Jerusalem Post Israel News | March 15th, 2017

Researchers decipher how the body controls stem cells Science Daily "In the lab, we have observed the same differentiation pattern in so-called iPS cells, or induced pluripotent stem cells, which can transform into many different types of cells." This knowledge can help the researchers to improve the effectiveness of ... and more »

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Targeting cancer stem cells may be a more effective way to overcome cancer resistance and prevent the spread of squamous cell carcinoma the most common head and neck cancer and the second-most common skin cancer, according to a new study by cancer researchers at the UCLA School of Dentistry.

Head and neck squamous cell carcinoma is a highly invasive form of cancer and frequently spreads to the cervical lymph nodes. Currently, cisplatin is the standard therapeutic drug used for people with HNSCC. Yet, more than 50 percent of people who take cisplatin demonstrate resistance to the drug, and they experience a recurrence of the cancer. The five-year survival rates remain sorely low and researchers still dont understand the underlying mechanisms behind head and neck squamous carcinoma. Therefore, said UCLA cancer biologist Dr. Cun-Yu Wang, who led the study, theres an urgent need to understand why people with this type of cancer are resistant to therapy and to develop new approaches for treating it.

Wangs researchis published online today in the peer-reviewed journal Cell Stem Cell.

Cancer stem cells are known to be responsible for tumor formation and development; they also self-renew and tend to be unresponsive to cancer therapy. These cells have been found in head and neck squamous cell carcinoma. Given the unique challenges that cancer stem cells pose for oncologists, it remains unclear what the optimal therapeutic strategy is for treating HNSCC.

To address this, Wang, who holds the Dr. No-Hee Park Endowed Chair in Dentistry at UCLA and holds a joint appointment in the UCLA Department of Bioengineering, and his research team first developed a mouse model of head and neck squamous cell carcinoma that allowed them to identity the rare cancer stem cells present in HNSCC usingin vivolineage tracing, a method to identify all progeny of a single cell in tissues.

The researchers found that the cancer stem cells expressed the stem cell protein Bmi1 and had increased activator protein-1, known as AP-1, a transcription factor that controls the expression of multiple cancer-associated genes. Based on these new findings, the UCLA team developed and compared different therapeutic strategies for treating head and neck squamous cell carcinoma. They found that a combination of targeting cancer stem cells and killing the tumor mass, consisting of high proliferating cells, with chemotherapy drugs resulted in better outcomes.

The team further discovered that cancer stem cells were not only responsible for squamous cell carcinoma development, but that they also cause cervical lymph node metastasis.

This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice, said Wang, who is a member of the UCLA Jonsson Comprehensive Cancer Center and of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.

With this new and exciting study, Dr. Wang and his team have provided the building blocks for understanding the cellular and genetic mechanisms behind squamous cell carcinoma, said Dr. Paul Krebsbach, dean of the UCLA School of Dentistry. The work has important translational values. Small molecule inhibitors for cancer stem cells in this study are available or being utilized in clinical trials for other diseases. It will be interesting to conduct a clinical trial to test these inhibitors for head and neck squamous cell carcinoma.

Additional authors of the study include Demeng Cheng, first author and postdoctoral scholar in Wangs lab; Mansi Wu, Yang Li, Dr. Insoon Chang, Yuan Quan, Mari Salvo, Peng Deng, Dr. Bo Yu, Yongxin Yu, Jiaqiang Dong, John M. Szymanski, Sivakumar Ramadoss and Jiong Li who are all from the laboratory of molecular signaling in the division of oral biology and medicine at the UCLA School of Dentistry.

This work was supported in part by the National Institute of Dental and Craniofacial Research grants R37DE13848, R01DE15964 and R01DE043110.

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Robert Clayton Robbins, head of the Texas Medical Center, was named Tuesday as top choice for president of the University of Arizona.

The Board of Regents selected Robbins in Phoenix following interviews with him and one other candidate Monday.

Robbins will meet the campus community and the public at a forum Wednesday afternoon. The regents will vote next week formally to make him an offer, and contract negotiations will begin. A final vote on the contract is expected April 6, based on a timeline the regents released last week.

Robbins, who serves as president and chief executive officer at the Texas Medical Center, said at a press conference Tuesday he was eager to get on the road to Tucson. He said his top priority will be the UA's students.

"I look forward to meeting them, working with them, and helping them be prepared for this new world that were living in now," he said. "Its changing rapidly, and as the university family weve got to treat each one of them like our own children and help them be prepared for not just the four years they spend on campus, but the next 40 years of their life."

The announcement was delayed by more than an hour late Tuesday afternoon as members of the Board of Regents met privately to select their top candidate. Regent Bill Ridenour, who headed the search committee, said the delay was not a sign of disagreement.

"We just wanted to be very thorough," Ridenour said. "When you get nine people in a room that have differing thoughts, you want to make sure that you give those people every opportunity because its important, we think, that we be unanimous. So we are, and we are, and were excited."

Robbins is a cardiac surgeon who joined the Texas Medical Center as its president and CEO in 2012. In that time, he introduced five research initiatives centered on innovation, genomics, regenerative medicine, health policy and clinical research. The Texas Medical Center is the largest medical complex in the world, a press release said.

Dr. Robbins comprehensive experience as both a visionary leader and highly-respected physician, as well as his evident talent for advancing research, innovation, entrepreneurship and economic development will serve the University of Arizona and our state well, regents' President Eileen Klein said in a press release.

As a surgeon, Robbins has focused on acquired cardiac diseases with a special expertise in the surgical treatment of congestive heart failure and cardiothoracic transplantation. His research work includes the investigation of stem cells for cardiac regeneration.

The other finalist was Sethuraman Panch Panchanathan, executive vice president and chief research and innovation officer at Arizona State University.

Current UA President Ann Weaver Hart will step down after her successor is chosen. Hart will take a one-year sabbatical leave and return to the UA as a professor in the College of Education.

She became the university's first female president in 2012 and announced last year she would not seek renewal of her contract in 2018.

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Cardiac Stem Cells Comments Off on Robert Clayton Robbins Top Choice for UA President – Arizona Public Media | March 9th, 2017

MILPITAS, Calif.--(BUSINESS WIRE)--Applied StemCell (ASC), a leading stem cell and genome-editing company with a goal to advance genome editing and stem cell technologies for biomedical research and clinical applications, welcomes Dr. Michele Calos as a member of the companys Scientific Advisory Board (SAB).

Dr. Michele Calos is a Professor of Genetics at the Stanford University School of Medicine, Vice President of the American Society of Gene and Cell Therapy, and has served as an Advisory Committee member for the US FDA, grant review panels for the NIH and NSF, and on numerous editorial review committees of scientific journals. She is a leader in the field of molecular genetics and has developed several novel vector systems for genetic manipulation of mammalian cells. In particular, she developed novel methods for sequence-specific integration in mammalian cells using the C31 phage integrase system. A similar integrase system was also successfully used in site-specific integration in human ES and iPS cells. For this work, Dr. Calos holds a joint patent application with Applied StemCells Chief Scientific Officer, Dr. Ruby Yanru Chen-Tsai and several other Stanford researchers. Dr. Calos pioneering work with C31 integrase also set the scientific stage for ASCs TARGATT integrase technology, which was co-developed by Dr. Chen-Tsai and Dr. Liqun Luo of Stanford University for gene modification in mouse models.

We are extremely pleased to have Dr. Calos join as a member of our scientific advisory board. With her impressive background in integrase gene modification technology and gene therapy, Dr. Calos will be an invaluable guide in furthering expansion of our genome editing platforms and our gene/cell therapy pipeline, said Ruby Yanru Chen-Tsai, Ph.D., Co-founder and Chief Scientific Officer of Applied StemCell.

Dr. Calos and her research team are currently focused on gene therapy and genome engineering for the treatment of Duchenne and Limb Girdle Muscular Dystrophies and developing further novel strategies for gene and cell therapy.

About Applied StemCell, Inc.

Applied StemCell, Inc. is a leading stem cell and gene-editing company focused on the development of products and therapeutics that are enabled by its proprietary gene editing platform technologies TARGATT and CRISPR/Cas9. For more information, please visit http://www.appliedstemcell.com.

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An HIV-positive bone marrow transplant recipient at the Mayo Clinic experienced prolonged viral remission lasting nearly 10 months longer than the so-called Boston patients after interrupting antiretroviral therapy (ART), according to a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle. Although his viral load eventually rebounded, his HIV reservoirs appeared to be reduced.

The only person known to be cured of HIV Timothy Ray Brown, known as the 'Berlin Patient' stopped ART when he received a bone marrow transplant to treat leukaemia and has not had detectable virus for ten years. Brown received a transplant from a donor with a double CCR5-delta-32 mutation, meaning they lack the CCR5 co-receptors most types of HIV use to enter T-cells. It is unclear whether his sustained remission is attributable to the donor's CCR5 mutation, the strong chemotherapy conditioning regimen used to kill off cancerous blood cells, a graft-versus-host reaction or multiple factors.

Bone marrow transplantation is apparently not sufficient to eradicate HIV. A few years ago, Timothy Henrich reported on two HIV-positive bone marrow transplant patients in Boston who got stem cells from 'wild-type' donors without the CCR5-delta-32 mutation, received a milder conditioning regimen and experienced acute graft-versus-host disease (GVHD). Both men maintained undetectable viral load longer than expected after interrupting ART, but eventually they experienced viral rebound at three and eight months after stopping HIV treatment.

The latest case, presented by Nathan Cummins of the Mayo Clinic in Rochester, Minnesota, and colleagues, involved a 55-year-old man who was diagnosed with HIV in 1990 and started combination ART in 1999 with a CD4 T-cell count of 300 cells/mm3. He stopped treatment between 2004 and 2009 for unexplained reasons, then restarted ART consisting of ritonavir-boosted atazanavir (Prezista) plus tenofovir disoproxil fumarate (DF) and emtricitabine (the drugs in Truvada).

In April 2013 the man was diagnosed with B-cell acute lymphoblastic leukaemia. In anticipation of chemotherapy, his ART regimen was switched to raltegravir (Isentress), etravirine (Intelence), and tenofovir DF/emtricitabine. In October 2013 he underwent reduced intensity conditioning followed by an allogeneic stem cell transplant from a CCR5 'wild-type' donor.

At the time of transplantation the man had an HIV viral load of 25 copies/ml and a CD4 count of 288 cells/mm3, and he stayed on ART without interruption. After the transplant he developed opportunistic infections (E. coli septicaemia and pneumocystis pneumonia) and experienced GVHD at four months post-transplant.

The man continued on ART for more than two years after transplantation, mostly with detectable plasma viral load levels. HIV RNA was also undetectable in gut biopsy samples. HIV DNA in his peripheral blood cells became undetectable by day 56, and repeated leukapheresis procedures showed significant reductions in HIV RNA and DNA reservoir size.

In addition, that man's HIV antibody levels decreased, as indicated by weaker Western blot bands. However, single genome sequencing and phylogenetic analysis identified identical HIV clones at day 142, possibly due to homeostatic proliferation, or replication of latently infected cells, while he had GVHD.

After having such low HIV levels for a prolonged period, the man underwent an analytic treatment interruption, or carefully monitored discontinuation of ART. His plasma HIV RNA levels were tested every two weeks for the first 12 weeks of ART interruption, then every four weeks.

At day 288 9.6 months after stopping ART he was found to have low-level viral rebound to 60 copies/ml. This rose to 1640 copies/ml by day 293, requiring that he restart HIV treatment. The man had no evidence of drug resistance and his viral load was re-suppressed within a month.

"Allogeneic peripheral blood stem cell transplantation in the setting of HIV is associated with significant reductions in HIV reservoir size by multiple measures, including prolonged combination ART-free remission," the researchers concluded.

They added that stem cell transplantation in the setting of suppressed viral replication may be associated with loss of HIV-specific immunity, and hypothesised that "immune activation in the setting of GVHD without anti-HIV specific immunity may cause homeostatic proliferation of latently infected cells, decreasing the chance of HIV eradication."

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Bone Marrow Stem Cells Comments Off on Researchers report case of bone marrow transplant patient off ART for 288 days without HIV rebound – aidsmap | March 6th, 2017

An Edmonton police officer is counting on the city he serves to help save his sons life.

Brady Mishio, 8, has an aggressive form of leukemia and needs a bone marrow transplant. His dad Terry desperately hopes someone who is a match will hear his plea.

Bradys family received the news of his illness in November after they took him for treatment of a persistent fever and flu.

You become that family that's searching for hope and have all these dreams and things for your children, and then one day, one day it's taken away from you so quickly, said Mishio.

The diagnosis was a form of cancer that starts in blood stem cells called acute myelogenous leukemia (AML). It is the most common leukemia found in adults but is less common in children. Brady began chemotherapy right away.

Four days into chemo he had a reaction to some of the drugs that they were giving him and he quit breathing and had a seizure, said Mishio, a 20-year veteran of the Edmonton Police Service who was once forced off work for a year with a brain injury after being kicked while making an arrest.

Bradys doctors found a drug combination that worked and the boy just finished his third round of treatment. He is in an isolation unit in hospital and the next step is a bone marrow transplant.

It gives Brady a second chance at life, at cleaning out his bone marrow and hopefully eliminating the cancer, said his father, while fighting tears.

Bradys family is not a match and Mishio is reaching out publicly, hoping he can help his child by finding a suitable donor. The test is a simple mouth swab. Donors must be between 17 and 35 and be in relatively good health, says Robyn Henwood, a stem cell territory manager for Canadian Blood Services. Younger people have fewer antibodies in their blood, lowering the risk of rejection.

Once registered, potential donors stay in the agencys registry until they are 60 years old.

Less than 25 per cent of patients find a bone marrow match in their own family, says Henwood.

So every single person we add to our database is giving hope to those who are looking for a match or who are likely going to die if we don't find them one.

In most cases, the process to donate bone marrow is much like giving blood and takes four to six hours to complete.

A clinic is being held Thursday, March 9 from 4 p.m. to 8 p.m. at Holy Cross Ukrainian Catholic Church. Interested donors who cant make that clinic can be tested at the Canadian Blood Services clinic next to University Hospital or register at blood.ca to be mailed a swab kit.

Mishio is amazed by the bravery of his son through this battle.

He's a fighter and there's many days where he'll be rubbing my back and kind of telling me it's going to be OK, and that's when I'm like, 'I got to be strong for him.'

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Xconomy Texas

San Antonio StemBioSys, the life sciences company with a system for growing stem cells, has licensed an experimental technology from University of Texas Health San Antonio that may help identify healthy young adult stem cells among large pools of other cells.

Theres plenty of research examining how to possibly use adult stem cells as treatments for medical conditions, ranging from cardiac disease to metabolic disorders, but current uses are rather limited to therapies like bone-marrow transplants for blood disorders, especially in children. Treatments that use patients own stem cells may be safer than using stem cells from someone else because they might reduce the potential for an immune response, according to StemBioSys CEO Bob Hutchens. Thats still theoretical, he says.

Finding large quantities of usable adult stem cells is difficult, though. StemBioSys believes its new technology can potentially identify a few thousand high-quality, young stem cells from a sample of tens of thousands of cells taken from a patient, Hutchens sayspotentially being a key word.

The research is quite earlythe technology has only been studied in animal models and in vitro, and StemBioSys is in the process of applying for federal grants to take the research into animal trials. If StemBioSys new intellectual property can successfully isolate the stem cells, Hutchens says they could grow more of them with StemBioSys core product.

StemBioSys sells a so-called extracellular matrix product made of proteins that provide a hospitable environment for stem cells, helping them divide and produce more stem cells.

Whats intriguing to us is that its a really interesting application of our technology, Hutchens says. You take this combination of identifying this very small population of young healthy cells in elderly people, and use our technology to expand it.

If the company can indeed find the young stem cells of a single patient and replicate them, it would give researchers and physician an accessible pool of the cells that theyd want for potential stem cell transplants and other treatments, Hutchens says.

Terms of the deal werent disclosed. StemBioSys, which was founded based on other University of Texas System research, acquired a portfolio of issued and pending patents. Famed MIT researcher and Xconomist Robert Langer is on the companys board of directors.

Again, theres plenty to prove out with this early stage research, so it will take time before any potential commercialization comes to fruition. Travis Block, the researcher who helpeddevelopthe technology while earning his PhD. last year at the University of Texas Health Science Center at San Antonio, will help shepherd the project along and other regenerative medicine work as StemBioSyss senior scientist.

David Holley is Xconomy's national correspondent based in Austin, TX. You can reach him at dholley@xconomy.com

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Shreveport, La. - Jasmine Sewell was diagnosed with bone caner in February of 2014. She and her fiance, Marcus Price, had planned their wedding for September of 2017 but moved up the date after Jasmine was given a prognosis in 2016 of less than a year to live.

Jasmine and Marcus were married February 11, 2017 and many of their guests gave a present to Jasmine by registering as bone marrow donors.

Jasmine has stopped responding to treatments and now needs a bone marrow or stem cell transplant to survive.

Be the Match signs people up to be bone marrow and stem cell donors but there is a shortage of minority donors. The match between the donor and recipient is largely based on genetics an ancestry so the likelihood of a non minority donor being able to help Jasmine is very slim.

The sign up is easy, just a cheek swab, and the donation of stem cells is a process similar to giving blood. Infant recipients can need actual bone marrow which is taken from the bone with a needle but the patient is sedated and most people only feel a bit sore after the procedure.

Jasmine is asking anyone not registered to sign up, and act as if it were their loved ones that needed the transplant.

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February 24, 2017

Orlando- In a significant advance in improving the safety of donor stem cell transplants, a major clinical trial led by researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital (BWH) has shown that a novel agent can protect against the most common viral infection that patients face after transplantation.

The results represent a breakthrough in a decade-long effort to identify an effective drug for the prevention of CMV infection in transplant patients that doesn't produce side effects that negate the benefit of the drug itself, the study authors said.

The findings, from an international phase 3 clinical trial of the drug letermovir for preventing cytomegalovirus (CMV) infection in transplant patients, will be presented at the 2017 Bone Marrow Transplant Tandem Meetings of the American Society for Blood and Marrow Transplantation (ASBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) in Orlando, Florida, February 22, 2017.

The study, which involved 565 adult patients at 67 research centers in 20 countries, compared letermovir to placebo in preventing an active CMV infection following transplant with donor stem cells. The patients, who were undergoing transplant as treatment for blood-related cancers or other disorders, all carried a CMV infection from earlier in life that had been wrestled into dormancy by their immune system. Twenty-four weeks after completing up to 14 weeks of treatment, 61 percent of the patients receiving a placebo had developed a CMV infection serious enough to require treatment or had discontinued the trial. By contrast, only 38 percent of those treated with letermovir developed that level of CMV infection or did not complete the trial.

Unlike other drugs able to forestall active CMV infection in stem cell transplant patients, letermovir did so without producing unacceptable toxicities. Most of the side effects associated with letermovir were tolerable, including mild cases of nausea or vomiting, and some swelling, investigators found. Letermovir also conferred a survival benefit: at the 24-week mark, 15 percent of the placebo patients had died, compared to 10 percent of those receiving letermovir.

"For the first time, we seem to have a drug that is a true safe and effective preventive for CMV infection in stem cell transplant patients," said the study's lead author, Francisco Marty, MD, an infectious disease specialist at Dana-Farber and BWH. "Letermovir will allow many patients to avoid infection, usually with no or mild side effects, and seems to provide a survival benefit in the first six months post-transplant."

Transplantation of donor hematopoietic stem cells - which give rise to all types of blood cells, including white blood cells of the immune system - is used to treat blood-related cancers such as leukemia, lymphoma, and myeloma, as well as several types of non-cancerous blood disorders. Patients typically receive chemotherapy to wipe out or reduce the bone marrow, where blood cells are formed, followed by an infusion of donor stem cells to rebuild their blood supply and reconstitute their immune system.

While refinements in transplant techniques have sharply improved the safety of the procedure, the reactivation of CMV infection following a transplant has been a longstanding problem.

Infection with CMV, a type of herpes virus, is one of the most common viral infections in the world. In the United States, it's estimated that over 50 percent of people are infected before adulthood. In other parts of the world, infection rates can be significantly higher. The effects of CMV infection can range from no symptoms to a flu-like fever or mononucleosis ("mono") syndrome. Once the immune system has brought the infection under control, the virus persists unobtrusively in the body.

The jolt of a stem cell transplant - the rapid erasure or diminishment of the immune system produced by pre-transplant chemotherapy, as well as measures to prevent graft-versus-host disease - can give CMV a chance to reawaken and run amok before the newly reconstituted immune system takes hold. In the early years of bone marrow transplant therapy, 60 to 70 percent of transplant recipients developed CMV infection, Marty recounts. Of those, 20 to 30 percent contracted CMV pneumonia, and of those, 80 percent died of the disease.

In previous clinical trials, several drugs aimed at preventing CMV infection in stem cell transplant patients either were not effective or produced intolerable side effects. In the absence of safe preventive drugs, physicians worked out a "surveillance" approach in which they provide treatment only when patients develop CMV infection, and only for a short period of time. This strategy has largely been a success: patients now have just a 2 or 3 percent chance of getting CMV disease affecting the lungs or other organs. Still, the often harsh side effects of current drugs were reason to continue the search for a useful preventive agent.

Letermovir works by a different mechanism from previously tested agents, which block an enzyme known as DNA polymerase, which viruses use to duplicate their DNA. (Human cells use the same process to replicate their own DNA.) By contrast, letermovir blocks a process by which CMV is "packaged" inside infected cells - a wrapping that allows it to go on and infect other cells. The fact that this process does not occur in human cells may explain in part why letermovir usually gives rise to only mild side effects, researchers say.

In the trial, patients received letermovir or a placebo beginning an average of nine days after transplant. "The goal was to suppress the virus before it has a chance to become active," Marty remarked. "The results of this trial offer encouragement that letermovir can offer a new strategy for donor stem cell transplant patients in preventing the emergence of CMV infection following transplant."

Explore further: Novel drug prevents common viral disease in stem-cell transplant patients, study finds

A new drug can often prevent a common, sometimes severe viral disease in patients receiving a transplant of donated blood-making stem cells, a clinical trial led by researchers at Dana-Farber Cancer Institute and Brigham ...

A single blood test and basic information about a patient's medical status can indicate which patients with myelodysplastic syndrome (MDS) are likely to benefit from a stem cell transplant, and the intensity of pre-transplant ...

Patients with hepatitis C virus infection who received an antiviral drug around the time they underwent liver transplantation saw a high rate of sustained virologic response, according to a Northwestern Medicine phase II ...

Recent studies on a small number of patients with leukemia treated with bone marrow transplantation have suggested that the presence of the common cytomegalovirus (CMV) in patients or their donors may protect against relapse ...

(HealthDay)Umbilical cord blood may work as well as current alternatives for adults and children with leukemiaor even better in some cases, according to a study published in the Sept. 8 issue of the New England Journal ...

Letermovir keeps the ubiquitous Cytomegalovirus in check for weakened immune systems of infected transplant patients.

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New antiviral drug cuts cytomegalovirus infection and improves survival in patients - Medical Xpress

Bone Marrow Stem Cells Comments Off on New antiviral drug cuts cytomegalovirus infection and improves survival in patients – Medical Xpress | February 25th, 2017

A girl of eight whose rare brain disorder is likely to lead to her death when she is in her teens is taking part in pioneering stem cell research in a bid to save others with same condition.

Lily Harrisss skin cells will first be turned into stem cells and then into brain cells by researchers at University College London as they seek treatments or a cure.

About 100 to 200 cases of BPAN beta-propeller protein-associated neurodegeneration are known worldwide, although this is believed to be an underestimate.

Children often suffer delayed development, sleep problems, epilepsy and lack of speech and their symptoms can be mistaken for other conditions.

Lily, from Luton, was diagnosed when she was five. She has very limited communication skills and uses a wheelchair. She wakes four or five times a night and needs drugs to control seizures.

However, she loves swimming and her father Simon said she has recently began singing on car journeys.

Shes laughed and giggled her way through everything, and shes been through a lot, he said.

Shes a beautiful little girl who can be quite naughty sometimes. Were giving her the best time we can while shes here. We have a beautiful little girl and its just so cruel.

Young people with BPAN develop abnormal muscle tone, symptoms of Parkinsons disease and dementia.

Mr Harriss and his wife Samantha, who work for an airline, know that as Lilys condition progresses she may have difficulty swallowing and require pain management.

Mr Harriss said: Lily can point to things she wants, she uses a little sign language and she can say a few words, like mummy, daddy, hello and goodbye.

Medical research like this for children is just absolutely vital.

We know we wont get a cure for Lily but, as parents, we need to be bigger than that. Other children might benefit through Lily. We are so proud of her.

The UCL study is being funded by 230,000 from childrens charity Action Medical Research and the British Paediatric Neurology Association. Lead researcher Dr Apostolos Papandreou hopes his research will lead to trials of treatments.

He said: The parents Ive met understandably feel devastated at the prospect of their children having a progressive disorder. However, theyre really keen to explore new avenues and participate in research projects.

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Girl, eight, with rare brain disorder in pioneering UCL stem cell research - Evening Standard

Skin Stem Cells Comments Off on Girl, eight, with rare brain disorder in pioneering UCL stem cell research – Evening Standard | February 23rd, 2017

If we cut off the tail of a lizard, it grows back. If we cut off the hand of a human being, it does not grow back. Why not? This question has perplexed scientists for a long time. Recently scientists at the Translational Genomics Research Institute (TGen) and Arizona State University (ASU) in the US identified three tiny RNA switches (known as microRNAs) which turn genes on and off and are responsible for the regeneration of tails in the green lizard. Now researchers are hoping that using the next generation genomic DNA and computer analysis will lead to discoveries of new therapeutic approaches to switch on similar regenerative genes in human beings.

Micro RNAs are able to control many genes at the same time. They have been compared to an orchestra conductor controlling and directing many musicians. Hundreds of genes (musicians playing the orchestra of life), controlled by a few micro RNA switches, have been identified that are responsible in the regenerative process. This may well mark the beginning of a new era in which it may be possible to regenerate cartilage in knees, repair spinal cords and amputated limbs.

Tissue regeneration has become an attractive field of science, triggered by exciting advances in stem cell technologies. Stem cells are undifferentiated biological cells that are then converted into various types of cells such as heart, kidney or skin through a process known as differentiation. They can divide into more stem cells and provide a very effective mechanism for repair of damaged tissues in the body. The developing embryo contains stem cells which are then transformed into specialised cells as the embryo develops. They can be obtained by extraction from the bone marrow, adipose tissue or blood, particularly the blood from the umblical cord after birth.

Stem cells are now finding use in a growing number of therapies. For instance leukaemia is a cancer of the white blood cells. To treat leukaemia, one approach is to get rid of the diseased white blood cells and replace them with healthy cells. This may be done by a bone marrow transplant through which the patients bone marrow stem cells are replaced with those from a healthy, matching donor. If the transplant is successful, the stem cells migrate into the patients bone marrow resulting in the production of new, healthy white blood cells that replace the abnormal cells. Stem cells can now be artificially grown and then transformed (differentiated) into the heart, kidney, nerve or other typed of cells.

The field of regenerative medicine is developing at a fast pace. It involves the replacement, engineering or regeneration of human tissues and organs so that their normal function can be restored. Tissues and organs can also be grown in the laboratory if the body cannot heal itself. If the cells of the organ being grown are derived from the patients own cells, the possibility of rejection of the transplanted organ is minimised. Stem cells may also be used to regenerate organs.

Each year about 130,000 organs, mostly kidneys, are transplanted from one human being to another. The process of growing organs artificially has been greatly accelerated by the advent of 3D bioprinting. This involves the use of 3D printing technologies through which a human organ, liver or kidney, is produced by printing it with cells, layer-by-layer. This became possible when it was discovered that human cells can be sprayed through the nozzles of an inkjet printer without destroying or damaging them. Tissues and organs can thus be produced and transplanted into humans. Joints, jaw bones and ligaments can also be produced in this manner.

Initially, the work was confined to animals when ears, bones and muscle tissues were produced by bioprinting and then successfully transplanted into animals. Even prosthetic ovaries of mice were produced and transplanted so that the recipient mice could conceive and give birth later. While gonads have not been produced by bioprinting in humans, blood vessels have already been produced by the printing process and successfully transplanted into monkeys. Considerable work is also going on in the production of human knee cartilage pads through the bioprinting process. Wear and tear of the cartilage results in difficulties in walking, particular in older age groups, and often requires knee replacement through surgeries. The development of technologies to replace the damaged cartilages with new cartilages made by bioprinting could prove to be invaluable.

Another area of active research in this field is the production of human skin by bioprinting which may be used for treating burns and ulcers. Technologies have been developed to spray stem cells derived from the patient directly on the areas of the body where the skin is needed. In this way, stem cells help skin cells regrow under suitable conditions. Similar progress is being made in generating liver, kidney and heart tissues so that the long waiting time for donors can be circumvented.

When will we be able to print entire human organs? It has been estimated that complete human kidneys and livers should become commercially available through the bioprinting process within five to seven years. Hearts will probably take longer because of their more complex internal structure. However, one thing is clear: a huge revolution is now taking place in the field of regenerative medicine, triggered by spectacular advances in stem cell research. This presents a wonderful opportunity for learning and developing expertise in this field for us in our country.

In Pakistan a number of important steps have been taken in this fast evolving field. One of them is the establishment of a first rate facility for stem cell research in the Dr Panjwani Centre for Molecular Medicine and Drug Research (PCMD) in the University of Karachi. This institution has already earned an international reputation because of its outstanding publications in this field.

A second important development is that plans to set up an Institute for Translational Regenerative Medicine at PCMD so that Pakistan remains at the cutting edge in this fast emerging field are now under way.

Such initiatives can however only contribute to the process of socio-economic development if they operate under an ecosystem that is designed to promote the establishment of a strong knowledge economy.

Pakistan spends only about 0.3 percent of its GDP on science and about two percent of its GDP on education, bringing the nations ranking to the lowest 10 countries in the world. This is largely due to the stranglehold of the feudal system over our democracy. It is only by tapping into our real wealth our children that Pakistan can emerge from the quagmire of illiteracy and poverty and stand with dignity in the comity of nations.

The writer is chairman of UN ESCAP Committee on Science Technology & Innovation and former chairman of the HEC. Email: [emailprotected]

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Amazing medicine - The News International

Bone Marrow Stem Cells Comments Off on Amazing medicine – The News International | February 22nd, 2017

Feb. 20--Kevin Wise doesn't know the man who donated the bone marrow that helped rid his body of leukemia a year ago.

But that didn't stop the Stanislaus Consolidated Fire Protection District battalion chief and a few of his colleagues from organizing two bone marrow registry drives -- even before he underwent his transplant -- in hopes of helping others like him.

As Wise said, it was a way to "pay it forward."

It paid off quickly.

Last week, one of Wise's fellow firefighters, one of nearly 200 people who registered during the drive, donated his bone marrow to a 53-year-old man.

"I feel like it was a once-in-a-lifetime experience," said volunteer firefighter Richard Gleaves. "I am lucky I got to do it. I would do it again if I had the chance."

The chances of a match are pretty slim. In fact, only 1 in every 430 Americans on the registry will actually donate.

Gleaves doesn't know anything about the recipient. He doesn't know what disease he has, whether he has children or where he is from. He just hopes that, like with Wise, the bone marrow will save the man's life and that someday he can meet him.

Gleaves, who lives in Oakdale, said he had no hesitation when he was contacted as a potential match a few months ago. He was even excited despite thinking that donating would require anesthesia and surgery to have bone removed from his hip. He'd been through it before when a foot injury required a fusion from bone that was taken from his hip. He said the recovery was painful, but the memory of it didn't deter him.

He went to a local clinic to have blood drawn for additional testing and eventually was determined to be the best genetic match for the recipient. Then Gleaves learned that his donation wouldn't require a surgery but rather a peripheral blood-stem donation, which is the method used by 70 percent of transplant facilities.

It wasn't a pain-free process and it required a bit of his time, but Gleaves said representatives from Be The Match went above and beyond to make it easier for him and his wife, paying for travel and hotel expenses near Stanford Medical Center and thoroughly explaining all the potential side effects.

The donation required five days of injections of a medication that causes the stem cells to leave the bone marrow where they're produced and enter the bloodstream.

Gleaves said he experienced the bone and joint pain about which he was counseled. It became most uncomfortable two nights before the procedure. But he received additional medication to cope with the pain.

The donation procedure took about six hours. Blood was removed from one of Gleaves' arms, run through a machine that extracts the bone marrow, then put back into his body though the other arm, he said. Gleaves said he was exhausted afterward but felt normal the next day.

He encourages others to sign up for the registry to increase the chance of survival for those with blood cancers.

"What you are doing for people -- what I have done and what the person did for Kevin -- it is life. It's the absolute best hope you are giving for someone. So who cares if you have to take a little time off of work," Gleaves said, joking that the worst part was the traffic getting to and from the Bay Area.

Of his recipient, Gleaves said, "I hope I get to meet the guy ... it would be nice to shake each other's hand."

Be The Match, the organization that manages the marrow registry, allows for donors and recipients to apply to meet each other a year to three years after the recipient received the transplant, depending on the country the people are from.

That requirement is in place, representatives have said, because the outcome for the recipient and his or her family is not always positive. There is the possibility the cancer will return or an even higher chance the recipient will suffer an infection or his or her body will reject the donor's bone marrow, resulting in an attack on the patient's organs. The chances of those decrease with time.

Last month, Wise, who lives in Modesto, celebrated one year since his transplant, a milestone that means the chance the leukemia will return decreased from a range of 40 percent to 60 percent to 10 percent, he said. After two years, he will be officially cured.

Wise has defied many odds in his recovery, such as returning to work six months early. He even has been cleared by his doctor to participate in a firefighter stair climb in Seattle next month that benefits the Leukemia and Lymphoma Society. Wise will climb 69 flights of stairs in full turnout, gear and an oxygen mask. Contributions can be made at his fundraising page.

Last month, Wise applied to meet his donor and is awaiting a response.

Erin Tracy: 209-578-2366

___ (c)2017 The Modesto Bee (Modesto, Calif.) Visit The Modesto Bee (Modesto, Calif.) at http://www.modbee.com Distributed by Tribune Content Agency, LLC.

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February 21, 2017 by Mark Derewicz Top Row: Heart arteries in normal mice, diabetic mice, and normal mice with deleted IRS-1 gene. Bottom row: when artery is wounded, diabetic mice with less IRS-1 and normal mice with deleted IRS-1 gene show much greater blockage due to over-proliferation of smooth muscle cells. Credit: Clemmons Lab, UNC School of Medicine

People with diabetes are at high risk of developing heart disease. Despite knowing this, scientists have struggled to trace the specific biology behind that risk or find ways to intervene. Now, UNC School of Medicine researchers have hunted down a possible culprit - a protein called IRS-1, which is crucial for the smooth muscle cells that make up veins and arteries.

According to a study published in the Journal of Biological Chemistry, too little of IRS-1 causes cells to revert to a "dedifferentiated" or stem-cell like state, and this may contribute to the buildup of plaque in the heart's arteries, a condition known as atherosclerosis, which increases the risk of heart attack, stroke, and other forms of heart disease.

"When diabetes is poorly managed, your blood sugar goes up and the amount of this protein goes down, so the cells become subject to abnormal proliferation," said senior author David R. Clemmons, MD, Sarah Graham Kenan Professor of Medicine at the UNC School of Medicine. "We need to conduct more studies, but we think this cell pathway may have significant implications for how high blood glucose leads to atherosclerosis in humans."

The research could bring scientists one step closer to finding drugs to help stave off heart disease in people with diabetes, who are twice as likely to have heart disease or experience a stroke, as compared to people without diabetes. People with diabetes also tend to experience major cardiac events at a younger age.

The study focused on the cells that form the walls of veins and arteries, known as vascular smooth muscle cells. The main function of these cells is to contract whenever the heart beats, helping to push oxygen-rich blood to the body's tissues. When plaque builds up along the arterial walls, these cells gradually lose their ability to contract.

In their previous work, Clemmons and colleagues discovered that diabetes can trigger an abnormal cell signaling pathway that causes vascular smooth muscle cells to proliferate, which contributes to atherosclerosis. But their attempts to correct the abnormal signaling pathway didn't seem to completely solve the problem, leading them to suspect another factor.

In the new study, the team found that IRS-1 acts as an inhibitor of the abnormal signaling pathway thereby keeping the vascular smooth muscle cells differentiated, or specialized. In the absence of IRS-1, the cells revert to a stem-cell like state, which in turn activates the abnormal signaling pathway and promotes cell proliferation.

In people with diabetes, the presence of IRS-1 is strongly influenced by how well - or how poorly - blood sugar is kept in check. Previous studies have shown that patients who frequently or consistently have high blood sugar show dramatic reductions in IRS-1. The new study is the first to link this reduction with a predisposition for heart disease.

"The study suggests that you can't just inhibit the abnormal signaling, which we've already figured out how to do," Clemmons said. "Our work suggests you probably have to restore the normal signaling pathway, at least to some extent, in order to completely restore the cells to normal cell health, differentiation, and functioning."

As a next step, the Clemmons lab will look for things that might stimulate the synthesis of this protein even in the presence of high blood glucose.

To prove that IRS-1 acts as a brake on the abnormal signaling pathway that leads to cell proliferation, the team conducted experiments in three different types of mice: healthy mice, diabetic mice, and nondiabetic mice that were genetically engineered to produce no IRS-1. The scientists made a small incision in the blood vessels of the animals and then watched to see how the vascular smooth muscle cells reacted. In healthy mice, the incision stimulated wound healing but little cellular proliferation. In both the diabetic animals and the nondiabetic IRS-1 deficient animals, the researchers observed a marked increase in abnormal cellular proliferation.

The findings suggest that it may be possible to counteract the deleterious effects of high blood sugar on atherosclerosis by developing drugs that boost IRS-1.

Clemmons said the activities of IRS-1 might also play a role in other diabetes complications, such as eye and kidney disease. The researchers plan to study those potential links.

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A process using human stem cells can generate the cells that cover the external surface of a human heartepicardium cellsaccording to a multidisciplinary team of researchers.

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According to the American Heart Association, approximately 2,200 Americans die each day from heart attacks, strokes and other cardiovascular diseases. The most common cause is blocked blood vessels that can no longer supply ...

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Patients with diabetes and metabolic syndrome are at increased risk of atherosclerosis and subsequent heart disease. It is not fully understood why atherosclerosis is increased with diabetes, but it has been proposed that ...

Scientists have implicated a type of stem cell in the calcification of blood vessels that is common in patients with chronic kidney disease. The research will guide future studies into ways to block minerals from building ...

People with diabetes are at high risk of developing heart disease. Despite knowing this, scientists have struggled to trace the specific biology behind that risk or find ways to intervene. Now, UNC School of Medicine researchers ...

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A new study by researchers at King's College London has found that patients with diabetes suffering from the early stages of kidney disease have a deficiency of the protective 'anti-ageing' hormone, Klotho.

Why do some people get Type 2 diabetes, while others who live the same lifestyle never do?

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I was diagnosed with type 2 Diabetes and put on Metformin on June 26th, 2016. I started the ADA diet and followed it 100% for a few weeks and could not get my blood sugar to go below 140. Finally i began to panic and called my doctor, he told me to get used to it. He said I would be on metformin my whole life and eventually insulin. At that point i knew something wasn't right and began to do a lot of research. On August 13th I found Lisa's diabetes story (google " HOW EVER I FREED MYSELF FROM THE DIABETES " ) I read that article from end to end because everything the writer was saying made absolute sense. I started the diet that day and the next morning my blood sugar was down to 100 and now i have a fasting blood sugar between Mid 70's and the 80's. My doctor took me off the metformin after just three week of being on this lifestyle change. I have lost over 30 pounds and 6+ inches around my waist in a month

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Researchers implicate suspect in heart disease linked to diabetes - Medical Xpress

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Slacking off in ALS? Mutant SOD1 may partially close the SLACK ion channel resulting in increased excitability in some neurons (Zhang et al., 2017).[Image: NIGMS.]

Increased activity in the motor cortex of the brain may occur in most forms of ALS (see September 2015 news). But whether this hyperexcitability contributes to the disease remains an open question.

Now, researchers at Yale University make the case that ALS-linked mutant SOD1 may downregulate a key sodium-gated potassium ion channel, known as SLACK, through an apoptosis signal-regulatingkinase1 (ASK1)-based mechanism (Zhang et al., 2017).

The findings may help explain how motor neuron hyperexcitability occurs in ALS. These changes in excitability may contribute to disease pathogenesis and may underlie fasciculations, one of the earliest clinical manifestations of the disease.

The question is whether this pathway is the primary way that SOD1 mutations cause disease, said Steve Vucic of the University of Sydney, who was not involved in the study. If so, [there] is a tremendous opportunity for developing treatments against these kinase pathways.

The study is published on January 24 in the Journal of Neuroscience.

Excitement builds

Neuronal hyperexcitability emerged in recent years as an early and potentially unifying stepin ALS, due to its detection in a number of sporadic and genetic forms. While the evidence is still not yet conclusive, some studies suggest that this prolonged excitation can lead to toxicity, strengthening the case that these changes in excitability may contribute to the disease (Fritz et al., 2013; Hadzipasic et al., 2014).

How hyperexcitability occurs in ALS remains unclear. But a growing number of studies suggest that mutant SOD1 may be involved, at least in some cases of the disease (Wainger et al., 2014; van Zundert et al., 2008).

Researchers at Yale University, led by Leonard Kaczmarek and Arthur Horwich, wondered whether mutant SOD1 could trigger hyperexcitability in motor neurons by downregulating a key membrane-bound ion channel called SLACK (sequence like a calcium-activated K channel), also known as KCNT1 or KNa1.1.

SLACK is a key regulator of excitability that helps neuronsreturn to the resting state upon firing. Its widely expressed in the CNS and its dysfunction has also been implicated in neurological diseases including Fragile X and epilepsy (Barcia et al., 2012; Heron et al., 2012; Martin et al., 2014).

Hyperexcitability in the bag. Researchers use sea slug bag cell neurons to study underlying hyperexcitability mechanisms. [Image: Kabir et al., 2001 under a CC-BY-NC-SA license.]

To investigate this question, first co-authors Yalan Zhang and Weiming Ni turned to the neuronalmodel system, the sea slug Aplysia. The system gained recognition in the 1960s for its role in providing Eric Kandel Nobel Prize-winning insights into learning and memory formation.

The approachinvolves the manipulation and study of bag cell neurons, very large neuroendocrine cells in the sea slugs abdomen that control egg laying. The really big advantage is that, because of their size, you can inject materials into them and then use a very fine microelectrode to record changes in excitability, all without any disturbance of the cytoplasm, Kaczmarek said.

The researchers compared the activity of potassium channels in bag cell neurons in the presence or absence of wild-type or mutant SOD1, including soluble oligomers of increasing size. They found that SOD1 or mutant SOD1 G85R monomers had no effect. But when they injected SOD1 G85R oligomers, they observed a reduction in outward potassium currents by 20-30%. This drop occured within 10 minutes and increased with larger oligomer size.

Whats more, SOD1 G85R oligomers increased excitability of these neurons. Injection of these soluble 300 kDa protein complexes decreased the neurons resting membrane potential and increased its susceptibility to firing in response to applied stimuli, they found.

Further experiments identified the SLACK channel as the one most likely to have been affected by mutant SOD1, because neurons pretreated with siRNA against SLACK mitigated the effect of these protein complexes in these neurons.

Together, the results suggest that soluble mutant SOD1 oligomericcomplexes may lead to hyperexcitability due to partial closure of SLACK, a key sodium-gated potassium channel that helps neurons return to their resting state upon firing.

ASK1ing for trouble

How could mutant SOD1 downregulateSLACK? The researchers suspected that these effects may be triggered by ASK1, a key kinase that has been previously implicated in the destruction of motor neurons in the disease (Raoul et al., 2002).

ASK1 has been shown to mediate key effects of mutant SOD1 in mouse models of the disease including ER stress and disruption of axonal transport (Lee et al., 2016; Song et al., 2013). In addition, inhibitingthis pathway appears to extend the survival of a SOD1 G93A mouse model of the disease (Fujisawa, et al. 2016).

To investigate this possibility, the researchers blocked ASK1 signaling and determined the impact of SOD1 oligomeric complexes on potassium channel activity. They found that the suppression of outward potassium current could be abolished by pre-treatment with an inhibitor of the apoptosis signaling regulating kinase ASK1. Similar effects were achieved with an inhibitor of one of ASK1s downstream targets, JNK.

The results, Kaczmarek said, suggest that mutant SOD1 oligomericcomplexessuppressSLACK channels in neurons through a ASK1-based mechanism, causing hyperexcitability.

Its an attractive idea, says Massachusetts General Hospitals Brian Wainger, who was not involved in the study. The findings may provide a potentially direct mechanistic connection between mutant SOD1 and motor neuron hyperexcitability in ALS.

Mind your Potassium and KCNQs. Researchers are evaluating Kv 7.2 potassium channel activators including retigabine (orange) in hopes to reduce hyperexcitability in people with the disease. More specific channel modulators are being developed. One such activator, AUT00063, is being evaluated at the phase 2a stage by the London startup Autifony Therapeutics to treat hearing disorders. [Miceli et al., 2011 under CC BY 4.0 license.]

But a change in excitability may not be the only or even the most important consequence of SLACK down regulation, according to Kaczmarek. SLACK may act as an activity sensor, providing a direct link between neuronal firing and protein synthesis.

His teamhas previously shown that SLACK channel activity plays a role in synaptic development, through its ability to regulateactivity-dependent protein synthesis (Brown et al., 2010; Zhang et al., 2012). When you precipitate the channel from mammalian brain, it pulls down several messenger RNAs, he pointed out, and mutations that cause channel overactivity are associated with epilepsy (Barcia et al., 2012; Kim et al., 2015).

In fact, Kaczmarek added, it may not be the hyperexcitability of motor neurons that is toxic in ALS, but rather its proposed (but not yet tested) consequences on protein synthesis. A rapid change in the activity of these channels, as we saw here, is likely going to alter protein synthesis, and that can produce much longer-lasting effects, potentially more consistent with a late-onset disease.

This was an extremely elegant study, and an ingenious way to approach the issue of hyperexcitability, said Steve Vucic, who, in collaboration with University of Sydneys Matthew Kiernan in Australia helped identify these neuronal changes as an early sign of ALS in people with the disease. The goal now will be to see if this same pathway is affected in the mammalian models, or in human ALS iPS cells.

Brian Wainger agrees. The key questions, according to Wainger, are whether these findings hold up in mammalian models, and whether these findings can be generalized to other forms of the disease.

Searching for ALS-linked gene variants in SLACK or related ion channels might also provide insight into its relevance for the human disease, added Vucic.

Approaching the clinic

Hyperexcitability is clearly a clinical feature of many forms of familial and sporadic ALS, explains Wainger. Thats why it is attractive as a convergent mechanism for many forms of ALS. But one of the challenges is to determine to what extent an increase in firing is relevant for disease pathogenesis, rather than, as some argue, being a compensatory mechanism. Directly modulating excitability is one of the clearest ways of answering that question directly, he added.

If motor neuron hyperexcitabilitydoes hold up as a driver of disease, however, it may be a good target for therapy, according to Kaczmarek. I see this as very much a therapeutic possibility.

The reason is because opening up these potassium ion channels may help motor neurons in people with ALS return to their resting state and thereby, reduce hyperexcitability in the disease.

Finding magneto. Researchers are using transcranial magnetic stimulation to evaluate in part whether mexiletine and retigabine reduce hyperexcitability in people with the disease.[Image: NIH].

Kaczmareks team is now hoping to do just that by developing a SLACK activator. The project is ongoing.

In the meantime, clinicians are aiming to reduce hyperexcitability in people with ALS by repurposing existing medicines in hopes to treat the disease. Brian Wainger is leading an effort to determine whether the epilepsy drug retigabine may be helpful in ALS. The drug, identified by Wainger as a potential treatment while in the laboratory of Kevin Eggan, may help normalize the activity of motor neurons by opening up Kv7 potassium channels in people with the disease (see April 2016 news; ; Wainger et al., 2014).

Across the US, the University of Washingtons Michael Weiss is taking a different approach. He is evaluating whether mexiletine, a sodium channel blocker, may reduce hyperexcitability in people with the disease (see March 2016 news). Both strategies are currently at the phase 2 stage.

In a disease that has a selective neuronal vulnerability like ALS, says Wainger, I think it is likely that the electrophysiological properties of the neuron are going to be related to the degenerative nature of the disease. So normalizing those properties may have a good chance of being helpful.

References

Zhang Y, Ni W, Horwich AL, Kaczmarek LK. AnALS-associatedmutantSOD1rapidlysuppressesKCNT1 (Slack) Na+-activated K+ channels in Aplysia neurons. J Neurosci. 2017 Jan 24. pii: 3102-16. [PubMed]

Fritz E, Izaurieta P, Weiss A, Mir FR, Rojas P, Gonzalez D, Rojas F, Brown RH Jr, Madrid R, van Zundert B. MutantSOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability. J Neurophysiol. 2013 Jun;109(11):2803-14. 2013 Mar 13. [PubMed].

Hadzipasic M, Tahvildari B, Nagy M, Bian M, Horwich AL, McCormick DA. Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16883-8. [PubMed].

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ.Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1-11.[PubMed]

van Zundert B, Peuscher MH, Hynynen M, Chen A, Neve RL, Brown RH Jr, Constantine-Paton M, Bellingham MC. Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Neurosci.2008 Oct 22;28(43):10864-74. [PubMed].

Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova JL, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012 Nov;44(11):1255-9. [PubMed].

Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012 Nov;44(11):1188-90. [PubMed].

Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, Copley RR, Rimmer A, Barcia G, Fleming MR, Kronengold J, Brown MR, Hudspith KA, Broxholme J, Kanapin A, Cazier JB, Kinoshita T, Nabbout R; WGS500 Consortium., Bentley D, McVean G, Heavin S, Zaiwalla Z, McShane T, Mefford HC, Shears D, Stewart H, Kurian MA, Scheffer IE, Blair E, Donnelly P, Kaczmarek LK, Taylor JC. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet. 2014 Jun 15;23(12):3200-11. [PubMed].

Raoul C, Estvez AG, Nishimune H, Cleveland DW, deLapeyrire O, Henderson CE, Haase G, Pettmann B. Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. Neuron. 2002 Sep 12;35(6):1067-83. [PubMed].

LeeS, Shang Y, Redmond SA, Urisman A, Tang AA, Li KH, Burlingame AL, Pak RA, Jovii A, Gitler AD, Wang J, Gray NS, Seeley WW, Siddique T, Bigio EH,LeeVM, Trojanowski JQ, Chan JR, Huang EJ. Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis. Neuron. 2016 Jul 6;91(1):41-55. [PubMed].

Song Y, Nagy M, Ni W, Tyagi NK, Fenton WA, Lpez-Girldez F, Overton JD, Horwich AL, Brady ST. Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5428-33. [PubMed].

Fujisawa T, Takahashi M, Tsukamoto Y, Yamaguchi N, Nakoji M, Endo M, Kodaira H, Hayashi Y, Nishitoh H, Naguro I, Homma K, Ichijo H. The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. Hum Mol Genet. 2016 Jan 15;25(2):245-53. [PubMed].

Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci. 2010 Jul;13(7):819-21. [PubMed].

Zhang Y, Brown MR, Hyland C, Chen Y, Kronengold J, Fleming MR, Kohn AB, Moroz LL, Kaczmarek LK. Regulation of neuronal excitability by interaction of fragile X mental retardation protein with slack potassium channels. J Neurosci. 2012 Oct 31;32(44):15318-27. [PubMed].

Kim GE, Kronengold J, Barcia G, Quraishi IH, Martin HC, Blair E, Taylor JC, Dulac O, Colleaux L, Nabbout R, Kaczmarek LK. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep. 2014 Dec 11;9(5):1661-72. [PubMed].

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IPS Cell Therapy Comments Off on A key ion channel may SLACK off in ALS – ALS Research Forum | February 20th, 2017

Asterias Biotherapeutics (AST) continues to generate excitement and buzz around its stem cell treatment for catastrophic spinal cord injury (SCI). I wrote about this historic event back in September. Thats when the company first released results about this transformative medical breakthrough.

Asterias has now released follow-up data. This was gathered at six and nine months after six quadriplegics received treatment. All six continue to show improvement in motor function and sensation. This is truly wonderful news for those with SCI.

There are also broader medical implications and these should be of great interest to investors.

The difference between this stem cell therapy and traditional drug therapies is huge. Drug therapies have specific and mechanistic impacts. But stem cells derived from embryonic cells work a different way. They draw on the massive DNA databanks in their nuclei. They then use these genetic programs to interact with their surroundings and repair damaged structures.

The Asterias oligodendrocyte progenitor cells were derived from a single unused embryo (from an IVF procedure in the late 1990s). Such embryos are often discarded. But this one was donated to create an unlimited number of therapeutic cells. Both the Bush and Obama Administrations approved the cell line.

When injected into the site of a spinal cord injury, these cells create healthy new spinal cord structures. They restore myelin sheaths (which are like an insulating material on nerves) and repair the lesions caused by injury. They send chemical signals that stimulate the growth of nerve cells. They also generate blood vessels that deliver oxygen and nutrients (and clear out toxic substances).

In works of science fiction, you may have read about nanobots. These are theoretical nanomachines that can fix profound biological damage. But the truth is that we all have this type of device in our bodies at the embryonic stage of development. Each uses the complex repair systems that can be found in the human genome.

These are the cells (AST-OPC1) that were given to patients in the SCI trial. The result is that patients who could not breathe on their own can now perform complex physical tasks. We have seen them lift weights, text, and type 35 words a minute and they continue to improve.

Most people assume this therapy must be the most modern of biotechnologies. In truth, its quite old in modern scientific terms. Dr. Michael West oversaw the creation of this therapy over two decades ago as Gerons chief science officer.

When that company stumbled, he brought the clinical trial and Gerons IP into BioTime (*see disclosure below) as Asterias Biotherapeutics. When I spoke to Asterias CEO Steve Cartt, his excitement was palpable. Heres why.

Each year, about 17,000 people experience the kind of spinal cord injuries targeted by the current trial. AST-OPC1 would be the only approved treatment for this condition.

Cartt is now considering plans to extend clinical trials to those who have suffered less serious spinal cord injuries. This means the patient population for AST-OPC1 cells would expand a great deal.

These cells might also be used to treat other neurological diseases. Multiple sclerosis, for example, also involves the deterioration of the myelin nerve sheath. But this is just the tip of iceberg for pluripotent stem cell therapies. Many of our worst diseases can be addressed by these biological nanobots.

If spinal cords can be repaired, so can the connective tissue deterioration that leads to arthritis and joint failures. Im convinced we will see simple injections of stem cells to repair hip, knee, and other joints in the future.

BioTime has also done extensive research into stem cell therapies for heart muscle and cardiovascular repair. In fact, Dr. West has converted some of my cells to embryonic status. He then engineered them to become my heart muscle cells. There have been animal studies as well. The results indicate that these types of cells will repair the damage done by heart attacks.

Next up, though, is blindness. A BioTime subsidiary in Israel, Cell Cure Neurosciences, is in a phase 1/2a trial to treat dry age-related macular degeneration (dry-AMD). Israeli government grants have helped fund this project.

Based on animal trials, it seems that the companys retinal pigment epithelial cells will be successful in treating the leading cause of adult blindness. Dry-AMD is an attractive target because there is no effective treatment. From what Ive learned, I think that these cells will treat the wet form of macular degeneration and other causes of blindness as well.

This is the real importance of the Asterias SCI trial. Right now, were seeing the proof of concept for a biotechnology that will disrupt the entire healthcare market. I've written about this extensively in Tech Digest (subscribe here for free).

This change will happen sooner than you think. Japan has already revised its Pharmaceutical Affairs Act to speed up the approval of stem cell therapies. And on the home front, several of President Trump's candidates for FDA chief have endorsed similar reforms.

(*Disclosure: The editors or principals of Mauldin Economics have a position in BioTime (BTX) which has significant ownership of Asterias stock. They have no plans to sell their position at this time. There is an ethics policy in place that specifies subscribers must receive advance notice should the editors or principals intend to sell.)

This weekly newsletter by biotech expert Patrick Cox highlights research that is much more advanced than most people know, and the profit potential for investors is vast. Read about the latest breakthroughsfrom new, non-invasive cancer treatments to age-reversing nutraceuticals and vaccines that kill any virusas well as the innovative companies that work on them. Get Tech Digest free in your inbox every Monday.

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A Breakthrough in Stem Cell Treatment? - Equities.com

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