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Lucknow: In a first, 26-yr-old DMD patient in UP survives with stem cell therapy – ETHealthworld.com

By daniellenierenberg

Lucknow: Duchenne Muscular Dystrophy (DMD) is a deadly genetic disorder, 99.9 per cent people suffering from which, die between the age of 13 to 23 years. However, in a first, a 26-year-old patient from Lucknow has survived DMD by regularly taking stem cells for the last five years.

Children, suffering from DMD, usually die of cardio-respiratory failure. But with the stem cell therapy, this patient has not lost muscle power in last five years and heart and lung muscles and the upper half of the body are working well.

Dr. B.S Rajput, the surgeon who is treating this patient, said, "DMD is a type of muscular dystrophy and being a genetic disorder, it is very difficult to treat. Autologous (from your own body) bone marrow cell transplant or stem cell therapy in such cases was started in Mumbai about 10 years back.

Dr Rajput, who was recently appointed as visiting professor at GSVM Medical College, Kanpur, said he has treated several hundred DMD patients and recently this combination protocol was published in the international Journal of Embryology and stem cell research.

According to Dr Rajput, this disease is endemic in eastern UP, especially Azamgarh, Jaunpur, Ballia and some of the adjoining districts of Bihar, and one out of every 3,500 male child, suffers from the disease.

Yet the disease is not given as much attention as it should be.

Dr Rajput, who is consultant bone cancer and stem cell transplant surgeon from Mumbai, said though patients in Uttar Pradesh and Bihar get financial support from the Chief Minister's Relief Funds, the treatment of autologous bone marrow cell transplant is not included in the package list of Ayushman Bharat scheme, which deprives many from getting the treatment.

The doctor further informed that efforts are being made to establish the department of regenerative medicine in the medical college, where bone marrow cell transplant and stem cell therapy would be done even for other intractable problems like spinal cord injury, arthritis knee and motor neurone disease.

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‘I’ve potentially saved a stranger’s life by donating my blood stem cells and it was painless’ – inews

By daniellenierenberg

NewsReal LifeLydia Burgess-Gamble has helped a sick woman in her twenties after they were genetically matched

Tuesday, 22nd October 2019, 10:38 am

Lydia Burgess-Gamble felt a lump in her throat when she got the letter saying her stem cells were a match for someone sick.

The 42-year-old had signed up to the register to be a donor almost three years earlier and hadn't given it much thought since.

Ahead of her 40th birthday, she'd wanted to do something altrusistic. Now she had the chance to potentially save someone's life who was battling a blood cancer or blood disorder.

Donating stem cells today is almost as easy as giving blood. "It was a straightforward and painless process and being able to relax and read a book for a few hours was a luxury," she said.

Patients face difficult odds

Every 20 minutes someone in the UK is diagnosed with a blood cancer, such as leukaemia, myeloma or lymphoma. That's more than 30,000 people a year. Worldwide, it's one every 30 seconds.

Patients suffering with these types of cancers can have their bone marrow damaged by the cancer itself, or from chemotherapy and radiation treatments. A stem cell transplant lets the new stem cells take over from the damaged marrow so the body can produce healthy, cancer-free blood cells.

Even though there are over 27 million people on the worldwide register, this isnt enough, according to charity DKMS. At any one time there are around 2,000 people in the UK in need of a transplant.

Matching donors and patients isnt easy because it's determined by tissue type, not blood group. There are thousands of different human leukocyte antigen (HLA) characteristics, in millions of combinations. Doctors look to relatives for a match but two out of three of those in need are unable to find one, and so must rely on the generosity of strangers.

Most donations are day cases at hospital

Lydia, an environmental research scientist from Brighton, became aware of the process involved through a Facebook post. "A friend shared an appeal for a loved one who needed a donor," she said. "I remember watching a documentary about donating bone marrow in the 90s and I hadn't realised it mainly doesn't involve an invasive procedure until I read this post."

The donation usually involves a nonsurgical procedure called peripheral blood stem cell (PBSC) donation for around 90 per cent of all cases, which is the method Lydia used.

With this method, blood is taken from one of the donors arms and a machine extracts the blood stem cells from it. The donors blood is then returned to their body through their other arm. It is an outpatient procedure that usually takes four to six hours.

'I had no side effects, other than I felt a little more tired than usual the next day'

Lydia Burgess-Gamble

This procedure doesn't "deplete" a donor's supply of stem cells, as a donor's stem cells will completely replenish themselves within two to four weeks afterwards.

"I had no side effects, other than I felt a little more tired than usual the next day but within 24 hours I was completely back to normal," said Lydia.

"All I know about my recipient is that it's a woman in her twenties who lives in Turkey. I'd love to make contact one day. I'm not expecting anything but I'm hoping she gets well and we may be able to meet."

The other 10 per cent of donations are made through bone marrow, where donors give cells from the bone marrow in their pelvis. This is under general anaesthetic so that no pain is experienced. The collection itself takes one to two hours and most donors return to their regular activities within a week. Two weeks after donation, your bone marrow will have recovered fully, and the hip bone will have fully healed within six weeks.

Donating: the process

To become a potential blood stem cell donor first check your eligibility on the DKMS website and request a swab kit for your cheek.

Complete the swabs posted to you at home and send them back. Then yourtissue type will be analysed and your details will be added to the UK stem cell registry. Your details can be searched for a genetic match for people all over the world who need a second chance at life.

The odds are you may never be called upon, but if you are, you will have a blood test at your local GP or hospital and will be asked to complete a medical questionnaire and consent form. If you're deemed fit and healthy enough, you'll have a further medical assessment and consultation at a specialist collection centre (where you will later donate your blood stem cells).

It's important to read about the methods used to collect blood stem cells PBSC and bone marrow donation because if youre on the register, you should be willing to donate in either way. The method will be determined by what the doctors believe will be best for the patient. However, you will of course always have the final decision on whether you are happy to proceed.

When a donor is matched with a patient, DKMS will cover the costs (including any travel, meals, or accommodation expenses that may be necessary and lost wages if you are not covered by your employer).

Your blood stem cells will never be stored, they last for around 72 hours and are delivered straight to the person in need by a special courier.

You will be allowed to meet the patient, if they consent, eventually UK guidelines state this can happen two years after the donation (and tules vary by country).Contact through anonymous letters can be established before this time via DKMS.

You will stay on the register until your 61st birthday.

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Orchard Therapeutics Presents Data from OTL-200 in Patients with Metachromatic Leukodystrophy Using Cryopreservation – BioSpace

By daniellenierenberg

BOSTON and LONDON, Oct. 22, 2019 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, today announced initial results from a clinical trial with a cryopreserved formulation of OTL-200, a gene therapy in development for the treatment of metachromatic leukodystrophy (MLD) at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. The initial data show that cellular engraftment with OTL-200 using a cryopreserved formulation is similar to that observed using a fresh formulation with the longest patient having 12 months of follow-up since treatment. The data are being featured this week in a poster session at the European Society of Gene & Cell Therapy (ESGCT) Annual Congress in Barcelona, Spain.

MLD is a devastating and rapidly progressing disease with no standard treatment options. In its most severe forms, patients will not survive beyond their first decade of life.

These data compare the initial results of OTL-200 in the first four MLD patients treated using a cryopreserved formulation to a previously presented integrated analysis of 29 patients treated with a fresh formulation that demonstrated meaningful clinical outcomes. Hematopoietic stem cells are collected, purified and transduced in the same way for both formulations. For the cryopreserved formulation, following transduction, the gene-corrected cells are placed in a specific medium that allows them to be stably frozen. After successful testing and release, the cryopreserved cells are shipped to the site of care where they are thawed and administered to patients who have received conditioning.

Presenting the first supportive data on OTL-200 using a cryopreserved formulation represents a cross-functional effort involving our clinical, CMC and regulatory teams as we prepare for the upcoming European regulatory submission for MLD followed by a BLA in the U.S., said Mark Rothera, president and chief executive officer of Orchard. If approved, a cryopreserved formulation of OTL-200 would more readily facilitate global commercialization and patient access efforts, which are key elements in our mission to deliver potentially curative therapies to patients suffering from often-deadly rare diseases.

Mr. Rothera continued, With over 40 patients now treated using a cryopreserved formulation across our pipeline of six clinical-stage programs, we are confident our approach is supported by a robust set of evidence.

Study Results At the time of the analysis, four early-onset MLD patients (two late infantile and two early juvenile) have been treated with the cryopreserved formulation of OTL-200. All patients are alive and were followed for a minimum of one month, with the longest follow-up out to 12 months in the first patient treated (median follow-up of 0.38 years). The age at the time of treatment ranged from seven months to 42 months.

The initial results in patients receiving the cryopreserved formulation (n=4) demonstrated the following:

Figure 1. Profiles of VCN in bone marrow CD34+ cells: OTL-200 cryopreserved vs. OTL-200 fresh

https://www.globenewswire.com/NewsRoom/AttachmentNg/83f41457-927b-4b1b-9ac2-9d48ac10353a

Figure 2. ARSA activity profile in peripheral blood: OTL-200 cryopreserved vs. OTL-200 fresh

https://www.globenewswire.com/NewsRoom/AttachmentNg/393ca5f0-98ad-47f8-b723-35c5c6c08d8f

c = cryopreserved; f = fresh; Sbj. = subject

We are pleased that these initial data suggest that using gene-corrected cells that have been cryopreserved has a similar impact on clinical biomarkers for early-onset MLD patients as the OTL-200 fresh formulation, said Dr. Valeria Calbi, a hematologist at San Raffaele Scientific Institute and SR-Tiget and an investigator of the study. The four treated patients showed good levels of engraftment of gene-corrected cells and reconstitution of ARSA activity at multiple time points, as well as encouraging early trends in GMFM scores that we look forward to evaluating with additional follow-up. We believe that these data further support the positive benefit / risk profile of OTL-200 as a therapy with potential lifelong benefit for patients with MLD.

Next Steps for OTL-200 Orchard remains on track to submit a marketing authorization application, or MAA, in Europe for MLD in the first half of 2020, as well as a biologics licensing application, or BLA, in the U.S. approximately one year later.

About MLD and OTL-200Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, the gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged and patients with MLD will experience neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures, finding it more and more difficult to move, talk, swallow, eat and see. Currently, there are no effective treatments for MLD. In its late infantile form, mortality at 5 years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1 OTL-200 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MLD. OTL-200 was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.

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

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

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

Forward-Looking StatementsThis press release contains certain forward-looking statements which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchards expectations regarding the timing of regulatory submissions for approval of its product candidates, including OTL-200 for the treatment of metachromatic leukodystrophy, the timing of interactions with regulators and regulatory submissions related to ongoing and new clinical trials for its product candidates, the timing of announcement of clinical data for its product candidates, including OTL-200, and the likelihood that such data will be positive and support further clinical development and regulatory approval of its product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchards product candidates, including OTL-200, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchards ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, the delay of any of Orchards regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchards ability to commercialize its product candidates, if approved. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

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

1Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature. Journal of Child Neurology 2010, DOI: http://doi.org/10.1177/0883073809341669

Contacts

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

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

Figure 1

Profiles of VCN in bone marrow CD34+ cells: OTL-200 cryopreserved vs. OTL-200 fresh

Figure 2

ARSA activity profile in peripheral blood: OTL-200 cryopreserved vs. OTL-200 fresh; c = cryopreserved; f = fresh; Sbj. = subject

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Making blood in the lab | Interviews – The Naked Scientists

By daniellenierenberg

The volume of blood needed every day by the NHS, and around the world, is staggering. But what about growing blood in a lab, could we do that? Chris Smith was joined by Cedric Ghevaert from the department of haematology at the University of Cambridge, to find out more about lab grown blood...

Cedric - So platelets are one of the three main blood components. Theyre actually the smallest cell in the body, if you look at a millimetre on a ruler you can line 250 platelets in that millimetre. The interesting thing is that some people argue they're not even a cell, because they don't contain a nucleus, they don't have DNA.

Chris - When I was learning biology at school they said platelets are bits of cells.

Cedric - That's absolutely true. They are fragments of a parent cell that lives in the bone marrow, and called a megakaryocyte, and one megakaryocyte will release about 1000 to 2000 of these little fragments called the platelets.

Chris - Every day?

Cedric - Every day we produce 10 to the 11 platelets

Chris - 100 billion Every day?

Cedric - Thats right.

Chris - And so these cells are just budding off little bits of themselves, which then go circulating around in the bloodstream.

Cedric - That's absolutely right.

Chris - And what are they doing there? What is their role?

Cedric - The main role of the platelets is to monitor your blood vessels, so they contain two things: Their outer layer, which is called the membrane. And on that membrane they have all sorts of little receptors, and these receptors will tell the platelets that the blood vessel has been damaged. When the platelet detects that it does two things, it will attach to the damaged blood vessel, and it will become activated and by that, it will then tell other platelets around, you need to come and help. These platelets will then stick to each other and form a plug to literally block the hole.

Chris - Do they change shape or anything? Do they become, sort of spiky or anything, to become more jagged so they jam in the hole.

Cedric - So they do become spiky, indeed you see that under the microscope when you activate the platelets. They go from a disc to this sort of spider, and that allows them to indeed interact with each other even better. The thing that they also do, is to then pull. They literally pull the wound together to try to stem the blood flow.

Chris - And they're presumably the first responders when you have a wound. They're there first because they're at the scene of the crime already because they're in the blood. And then as more come along, they're recruiting more of their mates from the numbers that come in the blood flow, and what do they provide the initial foundation of a blood thrombus or a clot.

Cedric - That's absolutely right. So once they become activated, inside the platelets there are granules, and those granules contain things that tell the blood, you need to clot. These things are released when the platelets become activated. And that leads to an amplification of the blood clotting that proteins are linked together, they form a polymer, and that polymer is a sort of a mesh that will capture more platelets and really plug the hole.

Chris - So the platelets are pulling more raw materials that are dissolved in the blood into that wound site, and then turning it into this dense mesh work that's gonna be a stable repair.

Cedric - That's absolutely right.

Chris - So they're really critical aren't they?

Cedric - Absolutely.

Chris - We can't do without them. And what's the problem with just growing them in a dish, because we can grow loads of things in dishes these days. We can you know, cells grow in dishes easily. So why can't you just churn out platelets in a dish?

Cedric - The main challenge with producing platelets in a dish is to do it so efficiently that actually we have a product that can be used, for example by the NHS and cost efficient. So if you look at a bag of platelets which we give for a transfusion, it contains three times ten to the eleven.

Chris - So 300 billion platelets.

Cedric - So where the platelets score as it were, is that we only need to produce one megakaryocyte, to produce a thousand platelets. And we can grow the megakaryocyte from stem cells. So the idea is that we can take stem cells, grow them into a megakaryocyte, and then right at the last stage of production, suddenly you have this massive amplification, a thousand times more platelets than you had megakaryocytes.

Chris - But if it's that easy to just grow these things in a dish, why are we not doing it? What is the what's the problem at the moment.

Cedric - The main problem is that particular last step. When the megakaryocyte is in the bone marrow it gets its cue from its environment. And it will detect the blood flow. It will be talked to by the cells that are around it, and that, it's very difficult to reproduce in the dish. If we produce megakaryocytes in liquid, in a culture dish they can produce 1 to 10 platelets, so we are at least a hundred times below what a megakaryocyte can do.

Chris - So you've got to have some way of recreating that very specialised three dimensional relationship in the bone marrow, where all these cells are in contact in a particularly special arrangement which seems to be the cue to them, to churn out platelets with the efficiency that they do when they're inside the body.

Cedric - And that's exactly the challenge that my group and several other groups across the world are trying to answer. And there are two ways to do this. First we need to tell the megakaryocyte theres a flow. They sense the flow, and that makes them release the platelets. So we put them in a bioreactor where they're exposed to shear, which is basically fluid going along them.

Chris - That's kind of mimicking the blood flowing through the bone marrow. So that would normally be bending and distorting the cells a bit, I presume, and that's what makes them churn off or snap off bits.

Cedric - That's right. So they produce these long digits which we call proplatelets, and these long digits elongate in the bloodstream and then snap off these platelets.

Chris - And when you make them, having mimicked this as best you can, do the platelets that you produce in the dish look like, and critically work like, the ones that are made naturally in the bone marrow?

Cedric - That's the critical thing that we are trying to address at the moment. They are bigger when we produce them in the dish, and they don't seem to quite react like normal platelets. However that doesn't mean that it wont work really well. What we need to do is to test them through a range of assays to really make the statement; these platelets are good, they will monitor your blood vessel, they will last in circulation.

Chris - Is your aim to make platelets bespoke for a patient? Or would you make off the shelf platelets, a bit like we'd currently do with transfusion medicine, where we just make a big bag of platelets collected from a range of donors?

Cedric - So at the moment we can produce platelets from either four donations, from four different donors, or we take them off a special machine where we have one pool of platelets coming from one donor, but we've talked the blood group before, one of the challenges with platelets, is that some people are immunised and they need platelets of a very specific blood type.

Chris - When you say immunisation, you mean that they've made an immune reaction to certain types in the past, so you've got to basically restrict what types you give them?

Cedric - Exactly. The beauty of working with stem cells is that we can edit the DNA somewhat, and because we can edit the DNA we can actually make platelets that don't express blood group, that are universal platelets. The one we produce in the dish can go to anyone. And that's one of the beauties of this technology.

Chris - And are you far away?

Cedric - We are not that far away. We are looking at human clinical trials in the next two to three years.

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When Added to Gene Therapy, Plant-Based Compound May Enable Faster, More Effective Treatments – Lab Manager Magazine

By daniellenierenberg

Blood stem cells protect themselves against viruses with structures known as 'interferon-induced transmembrane proteins,' seen here in green. These normally useful proteins are problematic for gene therapy treatments, as they work to keep therapeutic lentiviral vectors from infiltrating cells. Scripps Research scientists found a natural compound that lets down this shield, boosting the success rate of gene delivery.Credit: Image courtesy of the Torbett lab at Scripps ResearchLA JOLLA, CA Gene therapy has broadened the treatment possibilities for those with immune system deficiencies and blood-based conditions, such as sickle cell anemia and leukemia. These diseases, which once would require a bone marrow transplant, can now be successfully treated by modifying patients' own blood stem cells to correct the underlying genetic problem.

But today's standard process for administering gene therapy is expensive and time-consuminga result of the many steps required to deliver the healthy genes into the patients' blood stem cells to correct a genetic problem.

In a discovery that appears in the journalBlood, scientists atScripps Researchbelieve they have found a way to sidestep some of the current difficulties, resulting in a more efficient gene delivery method that would save money and improve treatment outcomes.

"If you can repair blood stem cells with a single gene delivery treatment, rather than multiple treatments over the course of many days, you can reduce the clinical time and expense, which removes some of the limitations of this type of approach," says Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology, who led the research.

The new finding centers on caraphenol A, a small molecule closely related to resveratrol, which is a natural compound produced by grapes and other plants and found in red wine. Resveratrol is widely known as an antioxidant and anti-inflammatory agent. Similar to resveratrol, caraphenol A is anti-inflammatory, but in this study, it served a different role.

Torbett and his team became interested in the unique chemical properties of resveratrol and similar types of molecules and wondered if they could enable viral vectors, used in gene therapy to deliver genes, to enter blood stem cells more easily. This would be momentous because stem cellsand in particular, self-renewing hemopoietic stem cellshave many barriers of protection against viruses, making them challenging for gene therapy to infiltrate.

Related Article:Solution to 50-Year-Old Mystery Could Lead to Gene Therapy for Common Blood Disorders

"This is why gene therapy of hemopoietic stem cells has been hit-or-miss," Torbett says. "We saw a way to potentially make the treatment process significantly more efficient."

The gene therapy treatment process currently requires isolating a very small population of hemopoietic stem cells from the blood of patients; these young cells can self-renew and give rise to all other types of blood cells. Therapeutic genes are then delivered to these cells via specially engineered viruses, called "lentiviral vectors," which leverage viruses' natural knack for inserting new genetic information into living cells.

However, hemopoietic stem cells are highly resilient to viral attacks. They protect themselves with structures known as interferon-induced transmembrane (IFITM) proteins, which intercept lentiviral vectors. Because of this, it can take many attemptsand a large quantity of expensive gene therapy vectorsto successfully delivery genes into hemopoietic stem cells, Torbett says.

Torbett and his team found that by adding the resveratrol-like compound, caraphenol A, to human hemopoietic stem cells, along with the lentiviral vector mix, the cells let down their natural defenses and allowed vectors to enter more easily. Once the treated stem cells were placed into mice, they divided and produced blood cells containing the new genetic information.

Another key benefit of the approach is time: If gene delivery treatment of blood stem cells can be accomplished in less time, the cells can be re-administered to the patient sooner. This not only makes treatment more convenient for the patient, but it helps to ensure the stem cells don't lose their self-renewing properties, Torbett says. The longer stem cells exist outside of the body and are manipulated, the more likely it is they will lose their ability to self-generate and ultimately correct disease.

Torbett and his team are continuing to study the underlying reasons for stem cells' inherent resistance to genetic modification, with the goal of further improving treatment efficiency and reducing cost. Because many of the diseases treatable with gene therapy affect children, Torbett says he feels a special urgency to advance this discovery from the lab into the clinic.

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Can Triliaciclib Improve Chemotherapy Tolerance in Triple-Negative Breast Cancer? – Cancer Network

By daniellenierenberg

The combination of trilaciclib and chemotherapy was generally welltolerated with promising activity in a phase II trial of patients with metastatic triple-negative breast cancer. However, it did not offer improvements in measures of myelosuppression compared with chemotherapy alone.

Chemotherapy-induced myelosuppression commonly leads to dose reductions that can restrict therapeutic dose intensity, wrote study authors led by Antoinette R. Tan, MD, of the Levine Cancer Institute in Charlotte, North Carolina. Introducing therapy that can protect the immune cells and bone marrow from the cytotoxic effects of chemotherapy has the potential to optimize antitumour activity while minimizing myelotoxicity.

Triliciclib is an inhibitor of cyclin-dependent kinases-4/6; it can enhance antitumor immunity and preserve hematopoietic stem and progenitor cells during chemotherapy. The new phase II study included a total of 142 patients with metastatic triple-negative breast cancer randomized to receive either gemcitabine (Gemzar) plus carboplatin alone (group 1) or 1 of 2 regimens with those agents plus trilaciclib. One regimen included intravenous trilaciclib along with the chemotherapy agents on days 1 and 8 of 21-day cycles (group 2), while the other included gemcitabine and carboplatin on days 2 and 9 along with trilaciclib on days 1, 2, 8, and 9 (group 3). The results of the study werepublishedonline ahead of print on September 28 inLancet Oncology.

The median follow-up for the three groups was 8.4 months, 12.7 months, and 12.9 months, respectively. During the first cycle, the mean duration of severe neutropenia was 0.8 days in the chemotherapy alone group, 1.5 days in group 2, and 1.0 days in group 3; these differences were not significant.

A total of 9 of 34 patients (26%) in group 1, compared with 12 of 33 patients (36%) in group 2 and eight of 35 patients (23%) in group 3 (P= 0.70). There were no differences between the groups with regard to all-cause dose reductions, patients requiring G-CSF, or patients requiring red blood cell transfusion, among other outcomes. The most common treatment-emergent adverse events included anemia, neutropenia, and thrombocytopenia in groups 1 and 2, and in group 3 they included neutropenia, thrombocytopenia, and nausea.

Overall survival outcomes in the 2 trilaciclib groups were significantly better than in the chemotherapy alone group. The combined trilaciclib groups had a median OS of 20.1 months, compared with 12.6 months without trilaciclib.

Though the trilaciclib regimens did not show significant improvements with regard to myelosuppression compared with chemotherapy, the authors highlighted the improvement in anti-tumor activity.

Together with the safety profile reported, the clinically meaningful improvements in overall survival support further studies of trilaciclib in patients with metastatic triple-negative breast cancer, they wrote.

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Can Triliaciclib Improve Chemotherapy Tolerance in Triple-Negative Breast Cancer? - Cancer Network

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Patients with ultra-rare bone marrow disease set to benefit from 1.15m grant from LifeArc and The Aplastic Anaemia Trust – PharmiWeb.com

By daniellenierenberg

Grant will support researchers from Kings College London and Kings College Hospital to test a personalised treatment approach for Aplastic Anaemia patients who have not responded to available therapies

21 October 2019 - LifeArc, a UK-based medical research charity, and the Aplastic Anaemia Trust (AAT) have jointly awarded a 1.15m research grant to Kings College London and Kings College Hospital to investigate the potential of a novel type of personalised cellular therapy to reverse the ultra-rare condition aplastic anaemia (AA). The results of this research could give new hope to people living with a severe, life-limiting form of this condition.

The grant will fund a clinical trial to investigate the safety and efficacy of using a patients own T-reg cells to restore the blood-making function of the bone marrow. This follows laboratory-based research from the team of scientists where T-reg cells from a patients own blood were collected, selected for activity and multiplied. In a test tube, these cells prevented the immune system from attacking the patients bone marrow stem cells.[i]

Professor Ghulam Mufti, Department of Haematological Medicine at Kings College London and Kings College Hospital, and lead study investigator said: For patients with this ultra-rare disease, were looking for the first time at a personalised medicine approach where their own immune cells could be used to alter their disease. In AA there is a reduction in the number of T-regs and most of the ones that the AA patients do have are non-functional. Weve seen success in the laboratory by selecting and bolstering the number of functional T-reg cells. Now, with funding from LifeArc and the AAT, we can investigate the potential of this approach in treating AA patients who currently have very limited treatment options. AA is an ultra-rare life-threatening illness caused by the bone marrow failing to make enough of all three types of blood cellsred blood cells, white blood cells and platelets. Only around 100150 people in UK are diagnosed per year, affecting all ages but most commonly people between the ages of 10 to 20 years old and those over the age of 60 years.

People with the illness are at greater risk of infections, bleeding, and can experience extreme fatigue, which leaves them unable to carry out simple daily tasks that most people take for granted. Around one in three patients with severe AA fail to respond to existing drug treatments and the other option a bone marrow transplant is reliant on finding a suitable donor, requires life-long treatment with immunosuppression therapy and is unsuccessful in one in three people. Dr Catriona Crombie, LifeArcs Head of Philanthropic Fund explained why the charity had approved the funding: LifeArc set up the Philanthropic fund to support translational research into rare diseases, where there is less interest from commercial organisations. Patients with AA can have limited treatment options; this opportunity with Kings College London, Kings College Hospital and the AAT has the potential to transform the lives of patients living with a severe form of the disease. The trial at Kings College London and Kings College Hospital will run for a duration of three years and aims to recruit nine patients. A blood sample of the patients T-reg cells will be extracted, purified and grown in the lab before being given back to the patient in a higher concentration. As patients with AA are more susceptible to infection, this personalised treatment approach is more likely to avoid the risk of severe infection and inflammation.

Grazina Berry, CEO of the AAT said: AA can severely impact a persons quality of life. Through AATs close work with Kings College London and Kings College Hospital as a specialist centre of clinical care and research in AA, we identified the project with the most potential to directly benefit patients who are currently at a loss for solutions. We are delighted to have partnered with LifeArc and Kings College London and Kings College Hospital to progress this ground-breaking work, which could potentially enable people living with severe AA to once again lead a normal life.

Link:
Patients with ultra-rare bone marrow disease set to benefit from 1.15m grant from LifeArc and The Aplastic Anaemia Trust - PharmiWeb.com

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Twice-diagnosed leukaemia patient Cameron Patel reveals he has a donor after heartbreaking appeal – Leicestershire Live

By daniellenierenberg

A twice-diagnosed leukaemia patient from Leicester has found a donor after making an emotional plea from his hospital bed.

Cameron Patel was first diagnosed with the illness aged 18 after being rushed to A&E with a dangerously high heart rate.

After months of treatment at Leicester Royal infirmary he was given the all-clear in February and was looking forward to his life getting back to normal.

Despite there being a low chance of Cameron having a relapse in June this year that's exactly what happened.

The leukaemia had returned and this time doctors said he would need a bone marrow transplant.

So the search for the best possible match began.

Due to his dual heritage, the chances of finding a suitable match for him were significantly low so Cameron was told that the search would not be easy.

After celebrating his 20th birthday this month, Cameron from Knighton, Leicester has now revealed that he will be receiving a transplant from his own mother.

"My mum brought me into this world and she's keeping me here," he told LeicestershireLive.

Sarah Patel, Cameron's mum, is only a 50 per cent match for him which is less than a potential match from a stranger would be.

She said: "You support as much as you can but at the end of the day you have to watch him go through it - so to be his donor makes me really happy, even if it is just a half match."

Although every effort was made to find him a match doctors couldn't find a single donor despite looking worldwide.

Now he will have what is called a haploidentical transplant which involves a half-match from a parent.

Sarah said: "Being one of the last resorts made me feel quite worried because even though I'm his mum, a stranger could have been a higher match.

"But he can't keep having chemotherapy forever and we can't wait around too long because he relapsed quite quickly so we know the pattern of his disease now.

"It's been mixed emotions but I'd do anything for him."

In the months leading up to his transplant, which will happen on Thursday 24 October, Cameron and his mother have undergone health checks and and tests to ensure that she is well enough to be his donor.

Any signs of illness or underlying health conditions in Sarah would mean that her stem cells could not be used.

Due to the low percentage match there are risks with the haplo transplant, including graft versus host disease (GvHD) in which the donated bone marrow or stem cells attack the body due to it being foreign.

Cameron will receive conditioning therapy in which chemotherapy will prepare his body for the transplant.

Following the transplant, he will have to remain isolated for 100 days - only his sister and mum will be allowed to see him.

"I've got a few films and games for my recovery period but I can't wait to just get out," he said.

Sarah said that her daughter, Charis has been a "great support for Cameron" and herself.

"They just love each other so much," the 55-year-old said about the siblings.

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The family have coined the day of Cameron's transplant as "day 0" and will count down the days until he can start living a normal life.

"It's been a difficult year or so but I can't really process things - I'm just sort of in this sub-universe where I'm just getting on with it."

"We couldn't do it with out our friends and family and Cameron's friends have been amazing," Sarah said.

Cameron has now moved to Nottingham University Hospital for his transplant, after spending the majority of the last year at Leicester Royal Infirmary.

"To be honest, I've been a bit low about leaving, I miss the nurses and everyone in ward 27 - they're family to me," Cameron said.

"When I relapsed I was in a really bad place and the nurses would come in and watch a film with me or play cards.

"There's doing nurse duties and there's being a friend - I want to thank them for everything."

Throughout his treatment, Cameron has made it his mission to raise awareness of blood disease and how people can help.

"I'm glad that I've been able to get out once in a while to spread the message - it's all good sitting in hospital and doing it from my iPhone but it's nice to go out and see the people you're speaking to," he said.

"Once I'm out of here I want to travel a bit and then carry on spreading awareness to young people," he added.

During his time on the teenage cancer ward Leicester Royal Infirmary, Cameron became friends with Coalville Town's footballer Courtney Wildin, who was also undergoing treatment for leukaemia.

Courtney had a transplant earlier this year and has since stayed in touch with Cameron.

They plan to work together to encourage young people to join the bone marrow donor register.

"He reached out to me while we were both on the ward and we ended up becoming good friends," Courtney said.

"We're going to start off going to colleges and tell people our story."

Without the haploidentical stem cell transplant, Cameron would still be left without a single match.

He wants to help to make sure that there can be a donor for everyone.

He said: "There are a lot of people out there who need a donor - two minutes of your life could save someones entire life."

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Red wine-like molecule when added to gene therapy, may enable faster, more effective… – ScienceBlog.com

By daniellenierenberg

Gene therapy has broadened the treatment possibilities for those with immune system deficiencies and blood-based conditions, such as sickle cell anemia and leukemia. These diseases, which once would require a bone marrow transplant, can now be successfully treated by modifying patients own blood stem cells to correct the underlying genetic problem.

But todays standard process for administering gene therapy is expensive and time-consuminga result of the many steps required to deliver the healthy genes into the patients blood stem cells to correct a genetic problem.

In a discovery that appears in the journal Blood, scientists at Scripps Research believe they have found a way to sidestep some of the current difficulties, resulting in a more efficient gene delivery method that would save money and improve treatment outcomes.

If you can repair blood stem cells with a single gene delivery treatment, rather than multiple treatments over the course of many days, you can reduce the clinical time and expense, which removes some of the limitations of this type of approach, says Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology, who led the research.

The new finding centers on caraphenol A, a small molecule closely related to resveratrol, which is a natural compound produced by grapes and other plants and found in red wine. Resveratrol is widely known as an antioxidant and anti-inflammatory agent. Similar to resveratrol, caraphenol A is anti-inflammatory, but in this study, it served a different role.

Torbett and his team became interested in the unique chemical properties of resveratrol and similar types of molecules and wondered if they could enable viral vectors, used in gene therapy to deliver genes, to enter blood stem cells more easily. This would be momentous because stem cellsand in particular, self-renewing hemopoietic stem cellshave many barriers of protection against viruses, making them challenging for gene therapy to infiltrate.

This is why gene therapy of hemopoietic stem cells has been hit-or-miss, Torbett says. We saw a way to potentially make the treatment process significantly more efficient.

The gene therapy treatment process currently requires isolating a very small population of hemopoietic stem cells from the blood of patients; these young cells can self-renew and give rise to all other types of blood cells. Therapeutic genes are then delivered to these cells via specially engineered viruses, called lentiviral vectors, which leverage viruses natural knack for inserting new genetic information into living cells.

However, hemopoietic stem cells are highly resilient to viral attacks. They protect themselves with structures known as interferon-induced transmembrane (IFITM) proteins, which intercept lentiviral vectors. Because of this, it can take many attemptsand a large quantity of expensive gene therapy vectorsto successfully delivery genes into hemopoietic stem cells, Torbett says.

Torbett and his team found that by adding the resveratrol-like compound, caraphenol A, to human hemopoietic stem cells, along with the lentiviral vector mix, the cells let down their natural defenses and allowed vectors to enter more easily. Once the treated stem cells were placed into mice, they divided and produced blood cells containing the new genetic information.

Another key benefit of the approach is time: If gene delivery treatment of blood stem cells can be accomplished in less time, the cells can be re-administered to the patient sooner. This not only makes treatment more convenient for the patient, but it helps to ensure the stem cells dont lose their self-renewing properties, Torbett says. The longer stem cells exist outside of the body and are manipulated, the more likely it is they will lose their ability to self-generate and ultimately correct disease.

Torbett and his team are continuing to study the underlying reasons for stem cells inherent resistance to genetic modification, with the goal of further improving treatment efficiency and reducing cost. Because many of the diseases treatable with gene therapy affect children, Torbett says he feels a special urgency to advance this discovery from the lab into the clinic.

Authors of Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes, include Stosh Ozog, Nina D. Timberlake, Kip Hermann, Olivia Garijo, Kevin G. Haworth, Guoli Shi, Christopher M. Glinkerman, Lauren E. Schefter, Saritha DSouza, Elizabeth Simpson, Gabriella Sghia-Hughes, Raymond R. Carillo, Dale L. Boger, Hans-Peter Kiem, Igor Slukvin, Byoung Y. Ryu, Brian P. Sorrentino, Jennifer E. Adair, Scott A. Snyder, Alex A. Compton and Bruce E. Torbett.

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Healthcare Terms Are Out of Touch, Says Mom Advocate – Medscape

By daniellenierenberg

This transcript has been edited for clarity.

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief for Medscape. I'm thrilled to speak with Hala Durrah today, who I got to know about through a remarkable essay she wrote for Health Affairs back in March. Hala, welcome to our program.

Hala H. Durrah, MTA: Thank you for having me.

Topol: It's a real pleasure and this an important and critical topic. Your essay was "My Child Is Sick; Don't Call Her a 'Consumer.'"[1] There is so much to learn here for Medscape folks. Can you tell us a little bit about your background and your family?

Durrah: Sure. I am a patient/family engagement consultant by profession, which basically means that I work with healthcare organizations and systems around the concept of patient/family engagement, spanning anywhere from patient-centered measurements to quality improvement, and so on. I came to the work, though, not as part of a plan, but by fate and destiny. My firstborn, whose name is Ayah, was born with a very rare liver disease which we knew would require liver transplantation. She is 16 years old now, but as you can imagine, we've been on quite a journey in the healthcare system. In addition, I have four other children and my husband is an adult medical hospitalist at a major academic center on the East Coast, so healthcare is a big piece of our lives.

I realized a few years into the journey with my daughter that I wanted to become more engaged in improving healthcare and partnering with our care teamthe physicians, nurses, pharmacists, and the larger group of specialists that she was seeing on a regular basis. I had the opportunity to volunteer at a local hospital that was looking for more patient/family involvement in some of their quality improvement work, and I decided that this was definitely something I wanted to pursue further, so I did. But my daughter's healthcare journey continues and I continue to see the good, the not so good, and everything in between.

In addition, I think I have a unique perspective because my husband is a physician and works in the hospital setting. I understand and can empathize with the real challenges facing physicians that are constantly placing pressure on them and demanding their time. I am very cognizant of that, so in my work I really try to balance the voice of the patient or caregiver, and the voice of the physician or nurse, because I can definitely see all of the different perspectives. At the end of the day, I think we all really want these meaningful relationships where we communicate and empathize with one another, and at the same time, we all want the best care for each other. That is my goal and the work I've been doing for the past several years.

Topol: That is terrific. You have a panoramic view of the healthcare landscapethat's for sure.

Topol: You wrote about your daughter; it is a miracle story in so many respects. Her name, Ayah, means "sign of God"is that right?

Durrah: Yes. We named her that before I knew she was going to be born with this illness, and it's pretty remarkable that she fit that name and the meaning of her name since she was born. Her first liver transplant, unfortunately, failed within the first 24 hours. As you all know, a liver does not wait, so we were preparing to say goodbye to her when she was about 5 years old.

Subsequently, by miracle, she got another liver 2 days later. It was from the same hospital where she was at, which was even more amazing because her surgeons were prepared to travel anywhere to get another liver. She was placed number one on the nation live listing after that first transplant failed, and it's remarkable that she got another one.

Topol: After she had these two liver transplants at age 5, she got Burkitt lymphoma.

Durrah: Unfortunately, because of her therapies, and also being Epstein-Barr viruspositive, she developed stage III Burkitt lymphoma 2 years after the liver transplant, which was quite devastating, to say the least.

Topol: It required another type of transplant, a bone marrow transplant.

Durrah: Yes. Unfortunately, she had several months of a pretty intense chemotherapy regimen that ultimately failed, and we had to move to an autologous bone marrow transplant. She was not able to have donor cells because she was already an organ transplant recipient. She sat one day in the hospital with a catheter, and they took her stem cells and then gave them back to her about a month later after some more intense chemotherapy.

In all our experiences, I don't believe that physicians and nurses ever defined my daughter as a consumer.

Obviously, she has been through quite a bit. A lot goes along with being a patient of liver disease or a patient who survived cancer with all of the chemotherapy, so while her health is stable, things are constantly moving in the background that we're watching. I tell people that I sometimes look at it like a radar screen. You kind of see the little red dots bleeping and some of them get brighter and some of them get dimmer. A lot of people are monitoring those lights, but I'm the chief monitor of all of those lights and the coordinator of making sure we stay on top of them.

Topol: You are quite an advocate and it is just an amazing story. I want to get into this message that you have about using the term "consumer," because I have hated that term for years. Why do we use this term when we're talking about patients in the health world? You wrote, "I share our story because I am becoming increasingly troubled by a trend in healthcaretoward thinking of patients as 'consumers' but not actually engaging communities in healthcare improvement and innovation." Tell us a bit about this objection of this term, because I think if anybody has a right to object to the use of that term, it would be you.

Durrah: The term definitely does not resonate with me, and I share your strong feelings against the utilization of this term. Overall, I think it continues to underline and push the business imperative of healthcare versus the humanity imperative in which healthcare was initially built upon. I reject in some ways that this notion of consumerism will improve healthcare because healthcare did not start as a business imperative, nor was the framework built to support such a term.

In all of our experiences, I don't believe that physicians and nurses ever defined my daughter as a consumer. I believe [the term] distances us from one another and does not amplify or support that relationship-based care that we all seek to have and to improve. I also don't think "consumer" empowers us, although I understand why some believe it may, because the framework of healthcare is not set up in such a way where "consumer" denotes choice. A lot of healthcare is dictated to the patient or to the caregivers by their insurance companies or their lack thereof, or the communities in which they live, or by lots of different other parties that are involved in it. I'm not quite sure where the choice comes in, especially because no one chooses to be sick. A consumer has choices, but we don't have that choice.

It does not make sense to use that term. I understand where people come from wanting to empower individuals by changing the terminology [to a less] "passive" role of the patient, but I'm not quite sure that changing the terminology we use makes us equals, gives us any more choices, or improves the care we will receive.

Topol: Words are important. This term is hackneyed, it's pervasive, and I think you made the most eloquent case in the history of the medical literature because your intersection with the healthcare world is extensive.

Durrah: Oh my gosh. I'm humbled by that. I'm not sure if I deserve all that, but I appreciate it.

Topol: You have a master's degree from George Washington and you worked in tourism, and you made some interesting parallels between a consumer of tourism versus a patient. Can you talk to us about that?

Durrah: Sure. My master's is in tourism and administration, with a focus in meeting and event management, and here I am in healthcare advocacy now. But I found that it's been very useful because you do see in healthcare this shift of trying to create a tourism-type experience for healthcare. And generally speaking, tourism is a choice; we all choose to travel or to use a certain hotel or rental car company because we've had experiences. Most of the time, you come back from a vacation with great memories, and when you share those memories with others, they may want to have the same experiences as you.

But I don't believe that we can really equate healthcare to a vacation. I'm not quite sure who would utilize that same experience as a vacation. Things that healthcare has that no other industry has are the trauma, pain, and anguish that go into being either a patient or the caregiver of someone. I think physicians and nurses have a lot of emotions in the healthcare experience that you could never find in tourism. And tourism tries to have a constant feedback loop with their customers or consumers; healthcare does not. Yes, we tout these wonderful surveys that are supposed to increase patient satisfaction, but were any of them co-designed with the communities the health systems serve? The answer is no. Do they allow you to really respond in such a way that will provide meaningful data using stories of your experiences in the system? No. So again, trying to equate the healthcare experience with the lessons learned from tourism is a mismatch.

Topol: Right. Even that term "medical tourism" is about a different concept.

There are many parts of your daughter's story that were really touching and deep, but one of the things that stood out was how her liver doctor would hold your hand, and how that was not about consumerism but, as you say, a choice driven by humanity and compassion. This, I think, speaks to the stark dramatic differences between the terms.

Topol: Another term I'm interested in asking you about is "providers." It's another term I don't care for. Should that term be used?

Durrah: It's interesting, because I believe that in the article I do reference "care providers" at one point. Initially when I started in this work, I always [used the specific terms of] "physicians," "nurses," "pharmacists," and so on. All of a sudden that term "provider" got thrown into the mix, and I adapted it because it seemed that everyone was using it to cover all the members of the care team that might interact or touch a patient. I'm guilty of using that term and I got a lot of response after my article came out, particularly from physicians, about how the term "provider" was not liked. I believe the term came about with this whole business imperative/push in healthcare. Insurance companies use that term and healthcare systems have now adopted that term as well, and it probably is in play because of this whole consumerism push as well.

I did prefer saying "physicians" or "nurses" or "pharmacists" and that we're all part of the "care team." I prefer that terminology, just as I prefer to be called a "partner" in my care versus a "consumer" or a "customer." I think that the term does not fit the role that physicians and nurses play. They are not just a provider. I look at them as part of my team and I'm on their team, so we're all working together. I think "provider" also sounds a little bit like a hierarchy. It does not suggest that notion of that partnership and just reinforces a distance. Consumerism is kind of defined by this transactional relationship, so you would use that term to reinforce that. I see how it has developed and how it's being pushed, and I think it's all related to the business of medicine versus the actual human experience and the humanity of medicine.

We so largely lost the 'care' in 'healthcare.

Topol: These terms got adopted when healthcare was transformed to a business, and now we're relooking at this.

Your work and eloquence and what you continue to do as an advocate in patient care will help us get back on track. It's just one of many things we need to do.

Topol: You also brought up the term "lean principles." It would be interesting for you to just touch on this as well.

Durrah: I've noticed in my work in healthcare thus far that health systems are adopting a lot of frameworks. One of these is becoming "lean" or utilizing "lean principles," which are driven by efficiency and cost savings.

Typically, those who advocate for lean principles within health systems say, "This is going to benefit everyone: physicians, nurses, patients and families, and the communities we serve." But if you really dig down deep, I don't think it has trickled down at all to any cost savings for patients or families. I don't think it's improved quality for communities which the healthcare system serves. And I certainly don't see physicians and nurses not being more burned out or more extended. They get affected by lean principles, where staffing is cut in order for that cost savings to occur. They are being told to do 150 things versus 100 things a day.

When I first learned about "lean" and read about it, I thought it sounded great. But then when I got deeper into this work, I thought, "Wait a minutewho is this benefiting other than the bottom line of healthcare systems?" It's really interesting how healthcare tends to cherry-pick principles or terminology from other industries with the goal of trying to improve healthcare, when it's really not doing that. It's simply putting a Band-Aid on one problem and creating a new one.

Topol: We so largely lost the "care" in "healthcare." You referred to the "care team." You undoubtedly experienced that with your daughter, and we want to bring it back. We should be more precise about language and avoid business terms, and talk about clinicians as doctors, nurses, pharmacists, physical therapists, or whoever. We should be more specific than using this "provider" term which obviously could be a relative or a friend.

Topol: What response did you receive from the essay you wrote in Health Affairs? It clearly resonated, and when I posted it on Twitter, there was quite a bit of response.

Durrah: I got an incredible response from the article, and I appreciate you tweeting and retweeting it because a lot of people saw that and reached out to me and started retweeting as well. A number of people sent me personal emails and messages, and I really was humbled by the response. I was quite nervous to write the article I did because in my work, there is kind of a fine line that you can only push the boundary so far, and then if you push them too far you get a lot of pushback. I sometimes feel like I'm this one little patient advocate voice among all these other voices. The article really resonated with physicians in particular, and they really understood the story which I shared about my daughter's liver doctor.

When we found out that she was diagnosed with cancer, she asked to sit in the meeting with the oncologists. She didn't have to do that, but she wanted to. I said, "Of course you can join us." She sat next to me and held my hand the entire meeting. Every time they said something distressing, she would just squeeze my hand, but she didn't utter a word. I think that encapsulates the relationship that patients and caregivers have with their physician or nurse. It's such a special bond, and the term "consumer" could never define that particular bond; she would never look at this as a transactional relationship. Would "consumer" teach her to do that? No. As you said before, it is the humanity and compassion of medicine, and that is why most everyone who comes into the profession really wants to help humanity and give that empathy and compassion.

We have a lot to learn, and it's going to take many voices to speak up and push back against consumerism because some pretty large organizations and groups are trying to push consumerism and continue this business imperative of healthcare that is motivated by bottom lines. I think we're going to get there. Maybe we're already there. We're at a tipping point. There is so much dissatisfaction, and so many parts of the system are broken. To say that consumerism will give you more choices, shorter wait times, and maybe even price transparency, even though you still have to deal with your insurance provider or lack thereof, makes me giggle because I don't think that is going to be the solution.

The only solution I see is that we have to partner with one another and co-create solutions to improve healthcare as teamsequal voices at the tableand begin this pushback. If we don't, I fear what is ahead because I've already had a glimpse of it. I'm nervous because as my daughter slowly moves into adulthood, and she is almost there, these were the things I hoped we would have conquered before she got to that point. A lot of this is pushing us away from one another and distancing ourselves from one another, and that is not going to change healthcare.

Topol: You said it so well. I've been eager to meet you since I read your work months ago, and I wanted the whole Medscape audience to get to know you and your story. Most of them are not on Twitter and most don't read Health Affairs. Your story is so darn important, and you convey it in a powerful way.

I'm so glad to know that your daughter is okay, having gone through 16 years of rough times, especially in her earlier years. I just want you to carry on. You are an important voice. You may qualify yourself as only one, but it's a powerful one, and very few people have had an experience like yours. You're in a rarified group and can transmit the emotion and the sense of caring. Let's get these words right, and let's zap "consumer" from this story of future healthcare.

Thanks so much for joining us today on Medscape, and we will look forward to following you and learning more from you in the future.

Durrah: Thank you. I look forward to partnering with your audience on improving healthcare.

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Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report 2019: by Trends, Development, Types,…

By daniellenierenberg

Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Market Research 2019 report by Mart Research outlays comprehensive insights of present scenario and growth prospects across the indication. A detailed picture of the Fanconi Anemia (FA) Fanconi Hypoplastic Anemia pipeline landscape is provided which includes the disease overview and Fanconi Anemia (FA) Fanconi Hypoplastic Anemia treatment guidelines. The assessment part of the report embraces, in depth Fanconi Anemia (FA) Fanconi Hypoplastic Anemia commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Fanconi Anemia (FA) Fanconi Hypoplastic Anemia collaborations, licensing, mergers and acquisition, funding, designations and other product related details.

Fanconi Anemia Understanding

According to the Cancer and Blood Disorders Center, Fanconi Anemia (Fanconi hypoplastic anemia, Fanconi pancytopenia, Fanconi panmyelopathy) is a rare inherited disease characterized by multiple physical abnormalities, bone marrow failure, and a higher than normal risk of cancer. Researchers have shown that mutations in one of at least 15 different genes can cause FA. The proteins normally produced by these genes form a kind of cellular machine that helps detect and repair damaged DNA in blood stem cells and other cells in the body, in FA this damaged DNA repair is slowed. Therefore, blood stem cells (in the bone marrow) accumulate damaged DNA and do not survive. FA is usually discovered between birth and age 10-15 years; however, there also have been cases identified in adulthood. FA occurs equally in males and females. It has been identified in all ethnic groups. Researchers continue to clone and characterize the genes responsible for FA, which is bringing considerable progress in the diagnosis and understanding of this disease. It is more common in male as compared to female.

Fanconi Anemia Pipeline Development Activities

The report provides insights into different therapeutic candidates in discovery and preclinical, phase 1, phase 2, and phase 3 stage. Drugs under development as a monotherapy or combination therapy are also included. It also analyses key players involved in FA targeted therapeutics development with respective active and dormant or discontinued projects. FA pipeline report covers 7+ companies. Some of the key players include Rocket pharma (RP-L102), Bellicum Pharmaceuticals (BPX-501), etc.

The report is built using data and information traced from the researchers proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university web sites and industry-specific third party sources, etc.

Browse Full Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report @ https://martresearch.com/market-analysis/fanconi-anemia-(fa)-pipeline-insight/2/42145

Companies Covered in Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Mart Research:Abeona TherapeuticsRocket PharmaceuticalsCIEMATCellenkosPluristem TherapeuticsBioLineRxForesee PharmaceuticalsGamida CellAmgenNovartis

Drugs Covered in Fanconi Anemia (FA) Fanconi Hypoplastic AnemiaPipeline Insight Market Research:Research programme: rare haematological disorder gene therapiesResearch programme: gene therapiesRP L101RP L102CK 0801PLX R18MotixafortideFP 045OmidubicelRomiplostimEltrombopag

Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Analytical Perspective by Mart Research

In-depth Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Commercial Assessment of products

This report provides an in-depth Commercial Assessment of therapeutic drugs have been included which comprises of collaborations, Licensing, Acquisition Deal Value Trends. The sub-segmentation is described in the report which includes Company-Company Collaborations (Licensing / Partnering), Company-Academia Collaborations, and Acquisition analysis in both Graphical and tabulated form.

Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Clinical Assessment of products

The report comprises of comparative clinical assessment of products by development stage, product type, route of administration, molecule type, and MOA type across this indication.

Scope of the report

The Fanconi Anemia (FA) Fanconi Hypoplastic Anemia report provides an overview of therapeutic pipeline activity for Fanconi Anemia (FA) Fanconi Hypoplastic Anemia across the complete product development cycle including all clinical and non-clinical stages

It comprises of detailed profiles of Fanconi Anemia (FA) Fanconi Hypoplastic Anemia therapeutic products with key coverage of developmental activities including technology, collaborations, licensing, mergers and acquisition, funding, designations and other product related details

Detailed Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Research and Development progress and trial details, results wherever available, are also included in the pipeline study

Therapeutic assessment of the active pipeline products by development stage, product type, route of administration, molecule type, and MOA type

Coverage of dormant and discontinued pipeline projects along with the reasons if available across Fanconi Anemia (FA) Fanconi Hypoplastic Anemia.

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Reasons to Buy

Establish a comprehensive understanding of the current pipeline scenario across Fanconi Anemia (FA) Fanconi Hypoplastic Anemia to formulate effective R&D strategies

Assess challenges and opportunities that influence Fanconi Anemia (FA) Fanconi Hypoplastic Anemia R&D

Develop strategic initiatives by understanding the focus areas of leading companies.

Gather impartial perspective of strategies of the emerging competitors having potentially lucrative portfolio in this space and create effective counter strategies to gain competitive advantage

Get in detail information of each product with updated information on each project along with key milestones

Devise Fanconi Anemia (FA) Fanconi Hypoplastic Anemia in licensing and out licensing strategies by identifying prospective partners with progressing projects for Fanconi Anemia (FA) Fanconi Hypoplastic Anemia to enhance and expand business potential and scope

Our extensive domain knowledge on therapy areas support the clients in decision-making process regarding their therapeutic portfolio by identifying the reason behind the inactive or discontinued drugs

Table of Content for Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report:Chapter One: Report IntroductionChapter Two: Fanconi Anemia (Fanconi hypoplastic anemia, Fanconi pancytopenia, Fanconi panmyelopathy)Chapter Three: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Current Treatment PatternsChapter Four: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Mart Researchs Analytical PerspectiveChapter Five: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline TherapeuticsChapter Six: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia -Products AnalysisChapter Seven: Recent TechnologiesChapter Eight: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Key CompaniesChapter Nine: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Key ProductsChapter Ten: Dormant and Discontinued ProductsChapter Eleven: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Unmet NeedsChapter Twelve: Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Future Perspectives

List of Tables for Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report:Table 1. Diagnostic GuidelinesTable 2. Treatment GuidelinesTable 3. Assessment SummaryTable 4. Company-Company Collaborations (Licensing / Partnering) AnalysisTable 5. Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Acquisition AnalysisTable 6. Assessment by Phase of DevelopmentTable 7. Assessment by Product Type (Mono / Combination)Table 8. Assessment by Stage and Product TypeTable 9. Assessment by Route of AdministrationTable 10. Assessment by Stage and Route of AdministrationTable 11. Assessment by Molecule TypeTable 12. Assessment by Stage and Molecule TypeTable 13. Assessment by MOATable 14. Assessment by Stage and MOATable 15. Late Stage Products (Phase-III)Table 16. Mid Stage Products (Phase-II)Table 17. Early Stage Products (Phase-I)Table 18. Pre-clinical and Discovery Stage ProductsTable 19. Inactive ProductsTable 20. Dormant ProductsTable 21. Discontinued Products

To Check Discount on Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report @ https://martresearch.com/contact/discount/2/42145

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Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report 2019: by Trends, Development, Types,...

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categoriaBone Marrow Stem Cells commentoComments Off on Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report 2019: by Trends, Development, Types,… | dataOctober 21st, 2019
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More awareness needed on stem cell donation: expert – The Hindu

By daniellenierenberg

Hematopoietic stem cell transplantation (HSCT), popularly known as bone marrow transplantation (BMT), is a curative modality for a number of benign and malignant blood disorders, said Dr. Murali Krishna Voonna, surgical oncologist and managing director of Mahatma Gandhi Cancer Hospital and Research Institute.

Speaking at an awareness programme on stem cell donation organised here by the hospital, in association with Datri Blood Stem Cell Donor Registry, he said hematopoietic stem cells are immature cells that can develop into all types of blood cellswhite blood cells, red blood cells, and platelets. They are found in the peripheral blood and bone marrow.

A sizeable population are diagnosed to have benign diseases such as thalassemia major, sickle cell anaemia and aplastic anaemia, and the HSCT is among the efficient curative measures. Acute leukaemia and other blood cancers also need this procedure, he said.

Highlighting that stem cell donation and a registry are vital, Dr. Muralikrishna explained for a successful hematopoietic stem cell transplant, the patients genetic typing (HLA typing) needs a close match with that of the donor. Every patient has 25% chance of finding a match within the family, he said.

Dr. Muralikrishna stated that in such cases, finding a donor is a pressing need. There are over 80 donor registries and more than 30 million registered donors across the globe, with a very few Indians being a part of it. This reduces the chances of finding a possible match for patients of Indian origin. Patients are more likely to find a possible match within their ethnicity, which means people sharing the same cultural linguistic and biological traits, he explained.

The problem can be solved if the donors enroll themselves with a registry which will store the stem cell details and the details. Pledging to donate stem cells is easy like swabbing the inner-cheek. The donors are contacted if patients have HLA matching, he said, adding that the stem cell donation was carried out only when a match was found for a patient, not when one pledge to donate.

A blood stem cell collection centre was inaugurated at the hospitals premises on the occasion. Earlier, to avail of such service and for HLA-typing, one has travel to Hyderabad and Chennai, Dr. Muralikrishna said.

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More awareness needed on stem cell donation: expert - The Hindu

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categoriaBone Marrow Stem Cells commentoComments Off on More awareness needed on stem cell donation: expert – The Hindu | dataOctober 20th, 2019
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Students from over 50 universities across the UK help blood cancer charity – FE News

By daniellenierenberg

150,000 POTENTIAL STEM CELL DONORS ARE GIVING BLOOD CANCER PATIENTS HOPE THANKS TO ONE UNIVERSITY SOCIETY -1 in 4 stem cell donors are now recruited by Marrow university societies

Students from over 50 universities across the UK have helped blood cancer charity Anthony Nolan recruit an incredible 150,000 students to the Anthony Nolan stem cell register, since the first Marrow group was created 21 years ago.

Marrow is the name given to blood cancer charity Anthony Nolans network of student volunteer groups.

The first Marrow society was created at the University of Nottingham, with the aim of recruiting students to the Anthony Nolan stem cell register. For many people with blood cancers or blood disorders, receiving stem cells from a stranger is their best chance of survival.

Research has found that younger donors are more likely to save the lives of patients, so the work done by Marrow is invaluable. Over a quarter of all stem cell donations that have occurred in the last two years were from donors recruited by Marrow. University students across the country are continually giving people with blood cancer and blood disorders a second chance of life.

Liam Du Ross, 24, from North Wales is a research chemist and signed up to the Anthony Nolan register in September 2014, while at Bangor University.

Liam said: I was at my university freshers fair and stopped to talk to the volunteers running the Marrow stall. I wanted to help someone in need, and I had already signed up to donate blood at this point, so the Anthony Nolan stem cell register seemed like the next step.

Earlier this year Liam received a call to say that he had been found to be a match for someone in desperate need of a stem cell transplant.

When I found out that I was a match for someone, I felt really lucky. I had absolutely no doubts about going through with the donation at all, the whole experience was a pleasure. The nurses involved in the process were exceptional, and they helped to put me at ease. I donated via PBSC (peripheral blood stem cell collection) so I was able to lie there and catch up on podcasts and TV shows!

I thought about my recipient a lot during my donation and how I would feel if I were in their situation. I would love to meet them one day and I hope they feel the same.

To anyone thinking of signing up to the register, I would say that you should absolutely sign up. If someone you knew was that person who needed a transplant, you'd want to doeverythingin your power to help them.

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Shaswath Ganapathi, 21, is a 4th year medical student at Birmingham University and the secretary of Birmingham Marrow. He decided to volunteer with Marrow after his friend, Rohan, sadly died from leukaemia last year. Shaswath and the other committee members hold events across their university, where they encourage students to sign up to the Anthony Nolan stem cell register, any of whom could go on to donate their stem cells in the future.

Shaswath said: The donors I have spoken to have said that its the most life changing thing they have ever done, and they would never have thought that spending a few minutes signing up at a stand and doing a quick cheek swab could lead to potentially saving someones life.

Aisling Cohn, Youth Programmes Manager at Anthony Nolan, said: Marrow really are the unsung heroes helping Anthony Nolan give hope to patients with blood cancer, by signing up an incredible number of potential donors to the stem cell register. Any one of these people could save the life of someone with blood cancer.

It costs 40 to add each new person to the Anthony Nolan register, any money raised by Marrow will directly help save lives. They really are lifesavers!

If a patient has a condition that affects their bone marrow or blood, then a stem cell transplant may be their best chance of survival. Doctors will give new, healthy stem cells to the patient via their bloodstream, where they begin to grow and create healthy red blood cells, white blood cells and platelets.

Marrow

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Students from over 50 universities across the UK help blood cancer charity - FE News

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categoriaBone Marrow Stem Cells commentoComments Off on Students from over 50 universities across the UK help blood cancer charity – FE News | dataOctober 20th, 2019
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Synthetic presentation of noncanonical Wnt5a motif promotes mechanosensing-dependent differentiation of stem cells and regeneration – Science Advances

By daniellenierenberg

INTRODUCTION

Human mesenchymal stem cells (hMSCs) have become increasingly popular as a cell source for repairing bone and other musculoskeletal tissues due to their availability, accessibility, and multipotency (1). The lineage commitment of hMSCs has been shown to be regulated by various signals, including mechanical stimuli, soluble factors, and cellextracellular matrix (ECM) interactions, in their natural niche microenvironment (2). Meanwhile, the delayed reunion of fractured bone remains a major clinical complication of surgery despite advances in operative techniques. The direct injection of stem cells into bone defects generally leads to limited stem cell grafting and differentiation due to the lack of necessary biochemical cues in the defect sites (3). Developing osteoinductive biomaterial scaffolds by incorporating developmentally relevant signaling cues to support and guide the differentiation of implanted stem cells in situ will enhance the clinical outcomes of stem cell therapies (4). For instance, scaffolds have been decorated with a wide range of bioactive motifs, including growth factors, bioactive peptides, and small molecules, to boost their osteoinductivity (5, 6). In recent years, biomimetic/bioactive peptides have become increasingly popular as inductive motifs for the biofunctionalization of biomaterials due to their major advantages, including their ease of immobilization onto various biomaterials via bioconjugation, better stability than proteins, and low cost (7). We previously demonstrated that the decoration of a hydrogel scaffold with an N-cadherin mimetic peptide promoted the chondrogenesis or the osteogenesis of hMSCs by emulating the enhanced intercellular interactions (8, 9). Therefore, there is an acute demand for previously unidentified osteoinductive ligands, which can potentially be identified by examining developmentally relevant proteinaceous cues (10).

Wnt signaling pathways have been reported to be essential to many developmental events, especially osteogenesis and bone formation (11, 12). The canonical Wnt signaling pathways generally involve the preservation and nuclear translocation of -catenin, which further triggers the activation of downstream genes to initiate osteogenic differentiation (13). On the other hand, the -cateninindependent noncanonical Wnt signaling cascade is activated by noncanonical Wnt ligands, such as Wnt5a (14). Wnt5a activation has been reported to contribute to the regeneration of multiple tissues, including the articular cartilage, the colonic crypt, and the liver, via paracrine or autocrine regulation (1517). During in vitro osteogenesis, embryonic stem cells express Wnt5a early on, rather than canonical Wnt3a, and cells expressing Wnt5a or treated with exogenous Wnt5a show a substantially enhanced osteogenic yield (18). In trabecular bone and bone marrow, Wnt5a is mainly expressed and secreted by osteoblastic niche cells, including precursor cells, osteoblasts, osteoclasts, and osteocytes (19). Wnt5a has been reported to preserve the proliferation and differentiation potential of stem cells in bone marrow and induce osteoblast maturation (20). Wnt5a signaling is a substantial constituent of bone morphogenetic protein 2mediated osteoblastogenesis (21). Collectively, these findings indicate that Wnt5a is an essential cue for the development of bones.

Wnt5a signaling is mediated through the Disheveled (Dvl) segment polarity proteindependent mechanism, which activates the small guanosine triphosphatase (GTPase) RhoA and its effector ROCKs (Rho-associated protein kinases) (22). RhoA-ROCK signaling plays a major regulatory role in the mechanotransduction signaling of cells by promoting focal adhesion formation (16), stress fiber assembly (23), and actomyosin contractility, and all these cellular events have been shown to enhance the osteogenesis of mesenchymal stem cells (MSCs). However, to the best of our knowledge, no prior studies have capitalized on the osteoinductive potential of noncanonical Wnt ligands to functionalize biomaterials or investigated the efficacy of such a developmental biologyinspired strategy to enhance the osteogenesis of MSCs and associated bone formation.

Recently, a Wnt5a mimetic hexapeptide, Foxy5 (formyl-Met-Asp-Gly-Cys-Glu-Leu), was shown to trigger cytosolic calcium signaling by activating -cateninindependent noncanonical Wnt signaling (24), and Foxy5 has recently been tested in a phase 1 clinical trial for treating cancer (www.clinicalTrials.gov; NCT02020291) (25). Here, we hypothesized that the functionalization of biomaterials with Foxy5 peptide can promote the mechanosensing and osteogenesis of hMSCs by activating noncanonical Wnt signaling (Fig. 1A). Our findings showed that this synthetic presentation of Wnt5a mimetic ligand activated noncanonical Wnt signaling, elevated the intracellular calcium, and promoted the mechanotransduction and osteogenesis of hMSCs, resulting in the enhanced bone regeneration in vivo. These findings emphasize the significance of the biofunctionalization of biomaterial scaffolds with developmentally guiding cues to enhance in situ tissue regeneration via grafted stem cells (26, 27).

(A) Porous, Foxy5 + RGD peptideconjugated MeHA hydrogels were developed by conjugating cysteine-containing functional peptides to MeHA molecules. (B) The porous scaffolds were used to copresent the adhesive ligand (RGD) and noncanonical Wnt5aactivating ligand (Foxy5) to synergistically induce the osteogenic lineage commitment of stem cells both in vitro and in vivo. (C) Rat MSC (rMSC)seeded hydrogels were used to fill calvarial defects for regeneration. (D) Micrographs of the 3D porous hydrogels with 200-m pores. The inset shows the microstructure of the MeHA porous hydrogel; scale bar, 50 m. (E) The Young modulus of the DTT-crosslinked MeHA hydrogels was verified using the Mach-1 mechanical tester. (F) The live/dead staining of the hMSCs seeded in the porous MeHA hydrogels showed the uniform distribution of the cells in the hydrogels. (G) Viable cell metabolic activity in the RGD, Foxy5 + RGD, and Scram + RGD hydrogels on day 7 of culture was characterized by alamarBlue assay. Data are shown as the means SD (n = 3).

To determine the effect of the Wnt5a mimetic peptide (Foxy5) on cellular behaviors, we grafted methacrylated hyaluronic acid (MeHA) with Foxy5 peptide (MDGECL, 1 mM) and arginylglycylaspartic acid (RGD) peptide (GCGYGRGDSPG, 1 mM) via Michael addition between the cysteine thiols of the peptide and the methacrylate groups of the MeHA (Fig. 1A and fig. S1). The peptide-functionalized MeHA (degree of methacryloyl substitution or methacrylation degree = 100 or 30%) (fig. S1) was then cross-linked to fabricate a three-dimensional (3D) porous hydrogel scaffold or a 2D hydrogel substrate for subsequent experiments (Foxy5 + RGD) (Fig. 1, B to D). Control hydrogels were fabricated with either RGD peptide alone (RGD) or the combination of scramble-sequenced Foxy5 peptide and RGD (GEMDCL, 1 mM, Scram + RGD). The RGD peptide was included in all groups to promote cell adhesion. The average Young moduli of the hydrogels from the RGD, Foxy5 + RGD, and Scram + RGD groups were determined to be 11.26, 10.82, and 10.96 kPa, respectively, indicating similar hydrogel stiffness in all groups (Fig. 1E). The storage moduli and loss moduli acquired from the frequency sweep analysis were not significantly different among the RGD, Foxy5 + RGD, and Scram + RGD groups (fig. S2A). Similarly, the surface roughness and the stiffness of 2D ultraviolet (UV)cross-linked hydrogels are not significantly different (fig. S2B). Our previous experience shows that the photocrosslinked MeHA hydrogels are typically stiffer than the dithiothreitol (DTT)cross-linked MeHA hydrogels given the same macromer content and methacrylation degree. This can be due to the semirigid nature of hyaluronic acid (HA) backbone, which may hinder the efficient crosslinking of HA-grafted methacryloyl groups by bifunctional crosslinkers (e.g., DTT). Therefore, by using the MeHA with the lower (30%) methacrylation degree to fabricate 2D hydrogels, the average Young moduli of the photocrosslinked hydrogels with 667 s of UV radiation were not significantly different from those of the DTTcross-linked MeHA hydrogels (100% methacrylation degree) (fig. S2, C and D). We believe that the results acquired from the 2D hydrogel substrates are representative and comparable with the data obtained from the 3D macroporous hydrogels. The 3D porous hydrogels used in this work have large pore sizes of around a few hundred micrometers, which are significantly larger than that of cells. The cells seeded in these 3D hydrogels are essentially still residing on top of the curved surfaces of the pores and are interacting with a more 2D-like rather than 3D microenvironment, and this is similar to the lining of osteoblasts on the surface of porous trabecular bone.

To evaluate the cytocompatibility of the peptide-functionalized hydrogels, we seeded hMSCs into the porous hydrogel constructs and allowed them to adhere for 4 hours, followed by further culture in basal growth media for another 7 days. Live/dead staining after 7 days of culture revealed that the majority of the seeded stem cells were viable and uniformly adhered to the RGD, Foxy5 + RGD, and Scram + RGD porous hydrogels (Fig. 1F). The alamarBlue assay showed that the seeded cells in all groups maintained consistent and robust metabolic activity in the porous hydrogel scaffolds for 7 days (Fig. 1G). These results indicate that the conjugated bioactive Foxy5 peptide was noncytotoxic, consistent with previous reports (24).

To further investigate the molecular events mediated by the noncanonical Wnt5a mimetic Foxy5 peptide, we used immunofluorescence staining to examine the expression levels of integrin V, integrin 1, phosphorylated focal adhesion kinase (p-FAK), and ROCK2 (fig. S3), which are essential elements for mediating mechanotransduction and have been reported to promote the osteogenic differentiation of stem cells. The staining intensities of integrin V and integrin 1 in the hMSCs cultured in the Foxy5 + RGD group appeared slightly higher but were not statistically different compared with that in the RGD and Scram + RGD groups (fig. S3, A and B). The staining intensity of p-FAK in the Foxy5 + RGD group was 92 and 33% higher than those in the RGD and Scram + RGD groups, respectively (fig. S3C). Consistent with the elevated expression of focal adhesion complex components, the Foxy5 + RGD group also showed ROCK2 staining intensity 135 and 34% higher than those in the RGD and Scram + RGD groups, respectively, after 7 days of osteogenic culture (fig. S3D). This enhanced expression of p-FAK and ROCK2 supports our speculation that the Foxy5 peptide presented by the biomaterial facilitates the mechanotransduction of the cells by activating noncanonical Wnt signaling to up-regulate the expression of focal adhesion complex molecules (p-FAK) and mechanotransduction signaling molecules (ROCK2).

We next explored the molecular signaling events by which the presentation of Foxy5 peptide via the hydrogel scaffold increased the mechanotransduction and consequent osteogenic lineage commitment of hMSCs (Fig. 2A). Noncanonical Wnt5a signaling has been shown to regulate the signaling of the Rho family of GTPases, such as RhoA, and studies have shown that RhoA is essential for actin cytoskeletal stability and associated actomyosin contractility via its downstream effectors, including ROCKs (22). Therefore, to examine the contribution of RhoA signaling and actomyosin contractility to the osteogenic effect of Foxy5 peptide presentation, we added Y-27632, an inhibitor of ROCKs, and blebbistatin, an inhibitor of nonmuscle myosin II (NMII), to the media in the Foxy5 + RGD group during the 7 days of osteogenic culture. The inhibition of ROCK with Y-27632 completely abolished the up-regulated osteogenic gene expression in the Foxy5 + RGD hydrogels. Blocking NMII activity also led to significantly down-regulated expression of the osteogenic genes alkaline phosphatase (ALP), type I collagen, and osteopontin (OPN) compared with the corresponding levels in the RGD group (fig. S4). Specifically, after 7 days of osteogenic culture, the expression levels of type I collagen, ALP, RUNX2, and OPN in the Y-27632Foxy5 + RGD group were down-regulated by 80.20, 97.96, 71.10, and 97.70%, respectively, compared with those in the Foxy5 + RGD group. The expression levels of type I collagen, ALP, RUNX2, and OPN in the blebbistatinFoxy5 + RGD group were down-regulated by 86.23, 98.54, 24.24, and 87.48%, respectively, compared with those in the Foxy5 + RGD group. These findings suggest that the pro-osteogenic effect of the Foxy5 peptide presentation can be attributed to the activation of RhoA signaling and associated actomyosin contractility.

(A) Schematic illustration of the seeding of hMSCs on the Foxy5/Scram + RGD peptidefunctionalized 2D hydrogel substrate. (B) Gene expression level of the RhoA signaling cascade (Wnt5a coreceptor Dvl2, RhoA, ROCK), downstream mechano-effector (NMII), and major focal adhesion adaptor protein (vinculin) in hMSCs in 3D porous hydrogels conjugated with RGD peptide alone (RGD), Foxy5 and RGD peptide (Foxy5 + RGD), or scrambled Foxy5 peptide and RGD peptide (Scram + RGD), respectively, after 7 days of osteogenic culture (n = 9). (C) Representative micrographs of fluorescence staining for F-actin (red), nuclei (blue), and RhoA (green) in hMSCs cultured on the 2D RGD, Foxy5 + RGD, and Scram + RGD hydrogels. Quantification showed a significantly higher RhoA staining intensity in the Foxy5 + RGD group than in the RGD and Scram + RGD groups (n = 20). a.u., arbitrary units. (D) Western blot bands and quantification of the expression level of mechano-responsive kinases ROCK2 and p-FAK (phosphorylated at the Ser722 sites) in each group (RGD, Foxy5 + RGD, Scram + RGD). (E) Representative merged fluorescence and bright-field micrographs of intracellular calcium in hMSCs cultured on RGD, Foxy5 + RGD, and Scram + RGD 2D hydrogels (stained with Fura-AM). (F) Quantification showed a significantly higher intracellular calcium level in the Foxy5 + RGD group than in the RGD and Scram + RGD groups. Scale bars, 50 m. Data are shown as the means SD (n = 9). Statistical significance: *P < 0.05, **P < 0.01, and ***P < 0.001.

We further investigated the mechanism underlying the enhanced RhoA signaling and actomyosin contractility via Foxy5 peptidemediated noncanonical Wnt signaling. Gene expression analyses revealed the up-regulated expression of Dvl2, RhoA, ROCK2, vinculin, and NMII in the presence of conjugated Foxy5 peptides after 7 days of osteogenic culture (Fig. 2B). Specifically, the Foxy5 + RGD group showed Dvl2, RhoA, ROCK2, vinculin, and NMII expression levels that were increased by 43, 27, 65, 72, and 24%, respectively, compared with those in the RGD group. Meanwhile, the expression of ROCK1, which was speculated to contribute to F-actin instability, was down-regulated by 25% in the Foxy5 + RGD group compared with that in the RGD group. Furthermore, the expression of the canonical Wnt signalingrelated genes (Wnt3a, Frizzled 3, LRP5, LRP6, and -catenin) was significantly up-regulated in the Foxy5 + RGD group compared with that in the control groups (fig. S5), and this is consistent with a previous report showing that the activated noncanonical Wnt signaling up-regulated the expression of canonical Wnt signaling factors during osteoblastogenesis (28). The expression of these mechanotransduction-related genes and canonical Wnt signalingrelated genes in the Scram + RGD group was not significantly different from that in the RGD group (Fig. 2B and fig. S5). We further quantified the expression of RhoA, ROCK2, and p-FAK based on immunofluorescence staining and Western blot analysis. The Foxy5 + RGD hydrogels showed RhoA staining intensity 92 and 134% higher than that in the RGD group and Scram + RGD groups, respectively, after 7 days of osteogenic culture (Fig. 2C). Further analysis showed a significantly increased cytoplasmic distribution of RhoA, consistent with the more prominent F-actin cytoskeleton, in cells cultured on hydrogels conjugated with Foxy5 peptide compared with those cultured on the controls. The Western blotting results showed that the expression levels of ROCK2 and p-FAK, two key mechanotransduction signaling molecules, were significantly up-regulated in the Foxy5 + RGD hydrogels (Fig. 2D) by 83 and 75% compared with those in the RGD hydrogels, respectively, and by 39 and 35% compared with those in the Scram + RGD hydrogels, respectively (Fig. 2E). Together, these data suggest that Foxy5 peptide immobilized on hydrogels is capable of initiating noncanonical Wnt signaling via the up-regulation of Dvl2, which further activates downstream RhoA signaling, leading to enhanced F-actin stability, actomyosin contractility, and cell adhesion structure development. Furthermore, the canonical Wnt signaling has been shown to promote the osteogenesis of hMSCs directly through the up-regulation of -catenin and downstream osteogenic genes including RUNX2, Dlx5, and Osterix (29). The immobilized Foxy5 peptide may indirectly facilitate the canonical Wnt signaling via the up-regulation of Frizzled3, LRP5/6, and -catenin. More thorough examinations on the effect of Wnt5a mimetic ligands on both canonical and noncanonical Wnt signaling are certainly worthy of further investigations in the future.

Our data reveal that the Foxy5 peptidemediated activation of noncanonical Wnt signaling is essential for regulating the expression and localization of critical signaling molecules involved in cell adhesion and mechanotransduction, including YAP, ROCK2, and p-FAK, which are essential for the osteogenesis of MSCs. The subtypes of ROCK, ROCK1, and ROCK2 have been shown to play distinct roles in regulating cytoskeletal tension. ROCK1 is a nonsecreted protein that destabilizes the actin cytoskeleton by regulating myosin light chain phosphorylation and peripheral actomyosin contraction, whereas ROCK2 is required for stabilizing the actin cytoskeleton by regulating cofilin phosphorylation (30). Previous studies have revealed that ROCK2 activity is effectively activated upon Wnt5a ligation to its receptors (22). We observed the up-regulation of ROCK2 expression and the down-regulation of ROCK1 expression, along with a significant increase in the focal adhesion levels in the MSCs presented with hydrogel-conjugated Foxy5 peptide. Therefore, the elevated ROCK2 activity results in enhanced cytoskeletal stability and more robust mechanotransduction signaling, both of which contribute to enhanced osteogenesis. When we inhibited ROCK activity in the Y-27632Foxy5 + RGD group using 10 M Y-27632, the expression of osteogenic genes was greatly reduced, thereby further confirming the important role of ROCK2 in Foxy5 peptideinduced osteogenesis.

Apart from RhoA activation, noncanonical Wnt5a activation has also been reported to lead to the mobilization of free intracellular calcium, which regulates multiple cellular behaviors, including the motility and differentiation of MSCs (31). To test the effect of Foxy5 peptide on the intracellular calcium level, we subjected hMSCs to Furaacetoxymethyl (AM) staining after being seeded on 2D peptide-conjugated MeHA hydrogels and cultured in osteogenic media. After 7 days of osteogenic culture, Fura-AM staining showed that cells on Foxy5 + RGD hydrogels exhibited 122 and 127% higher fluorescence intensity than those on RGD and Scram + RGD hydrogels, respectively (Fig. 2F). This finding suggests that the conjugated Foxy5 peptide is capable of activating noncanonical Wnt signaling to elevate the intracellular calcium level of MSCs, promoting osteogenesis.

Calcium-dependent noncanonical Wnt signaling pathways are known to participate in osteoblast differentiation, maturation, and bone formation (31, 32). Intracellular Ca2+ and calcium-binding/activatable signaling factors (calmodulin, calmodulin kinase II, calcineurin, etc.) are critical to the growth and differentiation of osteoblasts (33). Our biochemistry analysis and histological staining further showed that the amount of bone ECM production by hMSCs was significantly enhanced together with the intracellular calcium concentration in the hydrogels conjugated with the Foxy5 peptide, and this indicates that the elevated intracellular calcium level contributes to the enhanced osteogenesis of MSCs seeded in Foxy5 peptidefunctionalized hydrogels.

The guided lineage commitment of stem cells is a critical prerequisite for successful and efficient tissue regeneration, which is known to be modulated by the concerted actions of multiple microenvironmental signals (34). We next examined whether the hydrogels functionalized with the Wnt5a mimetic peptide could promote the osteogenic differentiation of hMSCs. We cultured hMSCs on 2D hydrogel substrates that were functionalized with RGD alone (RGD) or RGD with either Foxy5 peptide (Foxy5 + RGD) or scrambled Foxy5 peptide (Scram + RGD) in osteogenic induction media. Supplementation of the culture media with nonconjugated soluble Foxy5 peptide was previously reported to affect the chemotaxis of cancer cells (35). To compare the effects of the freely diffusing soluble form and the hydrogel-immobilized form of Foxy5 peptide on hMSCs, we included two control groups in which the osteogenic medium was supplemented with soluble, free, nonconjugated Foxy5 or scrambled Foxy5 peptide (free Foxy5 and free Scram) in the same amounts as those present in the conjugated hydrogels (Foxy5 + RGD and Scram + RGD).

Previous studies have demonstrated the critical role of YAP/TAZ-mediated mechanotransduction signaling in osteogenesis (36). We performed immunofluorescence staining for YAP and RUNX2 after 7 days of osteogenic culture. The hMSCs cultured on Foxy5 + RGD hydrogels consistently exhibited more YAP nuclear localization than those in all other control groups on 2D hydrogels (Fig. 3A). Specifically, quantification of the average nuclear-to-cytoplasmic staining intensity ratio (N/C ratio) of YAP in at least 20 representative cells from each group showed that the YAP nuclear localization in the Foxy5 + RGD group was 134 and 88% higher than that in the RGD and Scram + RGD groups, respectively (Fig. 3, A and D). Moreover, the addition of soluble Foxy5 peptide in the culture media (free Foxy5) failed to significantly increase the YAP nuclear localization as much as the hydrogel-conjugated Foxy5 peptide (only a 53% increase compared with the RGD group), whereas the free, soluble scrambled peptide had no significant effect (Fig. 3, A and C). This finding indicates that the hydrogel-conjugated Foxy5 peptide has significantly higher bioactivity than the unconjugated Wnt5a peptide directly added to the media in terms of promoting mechanosensing and osteogenesis. The immobilization of this ligand on the porous scaffold greatly enhanced the local effective concentration in the microenvironment of hMSCs, thereby facilitating the ligation of Wnt5a ligands to the receptors on the cell membrane. In contrast, the direct supplementation of the ligand resulted in its dilution in the entire volume of the media and therefore reduced the local effective ligand concentration. We also speculated that the immobilized ligands are unlikely to be internalized by cells upon ligation to membranous receptors, whereas the free ligands can be quickly internalized by cells and lose their activation function (37).

(A) Fluorescence micrographs of hMSCs stained for F-actin (red), nuclei (blue), and the mechanosensing marker YAP (green) or the osteogenic marker RUNX2 (green) (B) and ALP (blue in bright-field) (C), cultured on the RGD, Foxy5 + RGD, and Scram + RGD hydrogels. (D) Analysis of the nuclear localization of YAP determined by the nuclear-to-cytoplasmic fluorescence intensity ratio (N/C ratio) (n = 20) and (E) RUNX2 nuclear localization (n = 20) and (F) ALP expression of representative cells cultured on 2D hydrogels in the different experimental groups (n = 9). Scale bars represent 50 m in the fluorescence micrographs and 200 m in the bright-field images. Data are shown as the means SD. Statistical significance: *P < 0.05, **P < 0.01, and ***P < 0.001 significant difference.

To examine the effect of YAP nuclear accumulation on the osteogenesis of hMSCs, we analyzed the early osteogenic lineage commitment by immunofluorescence staining for RUNX2, an essential osteogenic transcription factor, after 7 days of osteoinductive culture. Cells in the Foxy5 + RGD group showed RUNX2 nuclear-to-cytoplasmic ratio 97 and 116% greater than that in the RGD and Scram + RGD groups, consistent with the YAP nuclear localization results (Fig. 3, B and E). In contrast, the expression levels of RUNX2 in the free Foxy5 and free Scram groups were only slightly higher than those in the RGD group. Furthermore, staining for ALP, another key osteogenesis marker, showed that the average percentage of ALP-positive cells in the Foxy5 + RGD group was 55, 52, 94, and 77% higher than that in the RGD, Scram + RGD, free Foxy5, and free Scram groups, respectively (Fig. 3, C and F). These findings indicate that hydrogel-conjugated Foxy5 peptide promotes the mechanosensing-dependent osteogenic differentiation of hMSCs and that the immobilization of Foxy5 peptide on hydrogels is more effective than the continuous supplementation of media with soluble Foxy5 peptide to enhance the osteogenesis of hMSCs. To further examine the effectiveness of the immobilized Foxy5 peptide on the substrates with different stiffness, we analyzed the mechanosensing and the early osteogenic lineage commitment by immunofluorescence staining for YAP and RUNX2 on the 2D MeHA hydrogels with varying stiffness of 2, 5, and 14 kPa (38). Cells in the Foxy5 + RGD group showed significantly higher YAP and RUNX2 nuclear-to-cytoplasmic ratio than that in the RGD and Scram + RGD groups at each of the selected hydrogel stiffness levels (fig. S6). This indicates that the biomaterial-conjugated Foxy5 peptide promotes osteogenesis in a wide range of substrate stiffness, and we found that the pro-osteogenic effect of the conjugated Foxy5 peptide is more significant at low substrate stiffness (2 kPa) (fig. S6).

We next examined the effect of Foxy5 peptide conjugated to 3D porous hydrogels on the osteogenic differentiation of seeded hMSCs from three different donors after 7 days (Fig. 4, A and B, fig. S7A, and tables S1 and S2) and 14 days (fig. S7B) of osteogenic culture. The real-time quantitative polymerase chain reaction (RT-qPCR) data showed that the expression levels of type I collagen, ALP, RUNX2, and OPN in cells seeded in the Foxy5 peptidefunctionalized porous hydrogels (Foxy5 + RGD group) were up-regulated by 33, 57, 35, and 422%, respectively, compared with those in cells seeded in the hydrogels without Foxy5 functionalization (RGD group) (Fig. 4B) after 7 days of osteogenic culture. In contrast, presentation of the nonfunctional scrambled peptide (Scram + RGD group) had no significant influence on the expression levels of these osteogenic genes compared with corresponding levels in the RGD group. The pro-osteogenic effect of the conjugated Foxy5 peptide diminished after 14 days of culture (fig. S7B). The diminishing effect of Foxy5 peptide can be attributed to the decreasing membrane presence of available LRP5/6 in the osteogenically differentiating hMSCs (39, 40). In addition, the increasing extracellular matrix that accumulated around hMSCs over time may have also contributed to the effect of conjugated Foxy5 peptide. It is noteworthy that the declining expression of Wnt receptors and Wnt signaling are essential for the formation of mineralized matrix (39). Therefore, this diminished effect of Foxy5 peptide over time may be beneficial to the osteogenesis of seeded hMSCs and subsequent neobone formation. Consistent with the gene expression data, both Alizarin Red and von Kossa staining revealed more substantial calcification in the Foxy5 + RGD group than in the other control groups. Quantitative analysis showed that the Alizarin Red and von Kossa staining intensities in the Foxy5 + RGD group were 262 and 107% higher than those in the RGD groups after 14 days of culture, respectively (Fig. 4, C and D). Furthermore, we assessed the organic bone matrix synthesis of stem cells by type I collagen staining. The Foxy5 + RGD group exhibited 163 and 179% higher type I collagen staining than the RGD and Scram + RGD groups, respectively (Fig. 4, C and D). These findings suggest that Foxy5 conjugated to the 3D porous hydrogel scaffold significantly promotes the expression of both early- and late-stage osteogenic genes in hMSCs and inorganic/organic bone matrix synthesis.

(A) Schematic illustration of the seeding of hMSCs in the Foxy5/Scram + RGD peptidefunctionalized 3D hydrogel scaffolds. (B) Quantitative gene expression of osteogenic markers (type I collagen, RUNX2, ALP, and OPN) in hMSCs seeded in porous hydrogels conjugated with RGD peptide alone (RGD), Foxy5 and RGD peptides (Foxy5 + RGD), or Scram and RGD peptides (Scram + RGD) in osteogenic culture. (C) von Kossa staining, Alizarin Red S staining, and immunohistochemistry staining of type I collagen and (D) quantification of the staining intensities after 14 days of osteogenic culture. Scale bars, 50 m. Data are shown as the means SD (n = 9). Statistical significance: * P < 0.05, **P < 0.01, and ***P < 0.001.

In mature bone tissues, the unique osteoblastic microenvironment niche provides MSCs with the necessary biological cues, including stromal cellderived factor 1, angiopoietin 1, and OPN, derived from osteoblasts, osteoclasts, osteocytes, and endothelial cells in trabecular bone and bone marrow (19, 41). Many previous studies have reported the regulation of MSC signaling and lineage commitment by systemic hormones or localized growth factors (42). Fu et al. demonstrated that Wnt3a-mediated canonical Wnt signaling activation antagonizes the terminal osteogenic differentiation of MSCs, while Wnt5a-mediated noncanonical Wnt signaling mitigates the inhibitory effect of Wnt3a. In the natural osteoblastic niche, Wnt5a proteins are secreted by the surrounding tissues and bind to the Frizzled/Ror2 surface Wnt receptors of hMSCs via paracrine mechanisms (43). We used porous hydrogels functionalized with Wnt5a mimetic Foxy5 peptide to emulate this pro-osteogenic niche and promote the osteogenesis of hMSCs. In addition to Foxy5 peptide, RGD peptide was also conjugated to all hydrogels to provide adhesive motifs for the hMSCs because Foxy5 peptide alone cannot support effective cell adhesion. The promechanotransduction and pro-osteogenic effects of Foxy5 peptide were therefore not studied in the absence of RGD peptides, which is a limitation of the study. Nevertheless, integrin ligands are important components of the natural osteogenic niche in bones. The potential crosstalk between integrin signaling and Wnt signaling and the associated effects on stem cell differentiation certainly warrant further investigation.

We further evaluated the efficacy of the Foxy5 peptide conjugated to the hydrogel in assisting in vivo bone regeneration in rat calvarial defects. Rat MSCs (rMSCs) with trilineage differentiation potential (4446) were first seeded in porous hydrogels functionalized with RGD, Foxy5 + RGD, or Scram + RGD peptides and cultured in osteogenic media for 7 days prior to transplantation into the defects (Fig. 5A). The RT-qPCR data showed that the expression levels of type I collagen, ALP, RUNX2, OPN, Dvl2, RhoA, and vinculin in rMSCs of the Foxy5 + RGD group were all significantly higher compared with those in the control groups (RGD group, Scram + RGD) after 7 days of osteogenic culture (fig. S8, A and B). Eight weeks after transplantation, both hematoxylin and eosin (H&E) staining and immunohistochemical staining for osteocalcin and type I collagen revealed enhanced osteoblastic marker expression and bone matrix formation in the Foxy5 + RGD group compared with the RGD, Scram + RGD, and blank groups (Fig. 5B). The average staining intensity for osteocalcin was 124, 114, and 240% higher and that of type I collagen was 105, 104, and 144% higher in the Foxy5 + RGD group than in the blank, RGD, and Scram + RGD groups, respectively (Fig. 5D). The average staining intensity for osteocalcin and type I collagen in the Foxy5 + RGD group was still around 30% lower than that in the native calvarial tissue (Fig. 5D). Furthermore, the microcomputed tomography (micro-CT) reconstruction data revealed considerably more new bone formation in the defects treated with hydrogels conjugated with Foxy5 and RGD peptides (Foxy5 + RGD group) than in those treated with the control hydrogels (blank, RGD, and Scram + RGD groups) (Fig. 5C). Quantitative analysis showed that the bone volumetototal tissue volume (BV/TV) ratio in the Foxy5 + RGD group was 107, 57, and 198% higher than that in the RGD, Scram + RGD, and sham blank groups, respectively. Notably, the average BV/TV ratio of healthy calvarial bone was determined to be 35.25% due to other skeletal components, such as fibrous connective tissues. The average BV/TV ratio in the Foxy5 + RGD group was 25.19%, suggesting a substantial recovery of approximately 71.49% of the healthy calvarial bone volume. These findings demonstrate that the functionalization of biomaterial scaffolds with this Wnt5a mimetic peptide can substantially enhance bone regeneration in vivo. No significant abnormalities in tissue structure or morphology were observed around the implantation site. We believe that the restricted bioactivity of the mimetic peptide (compared with that of the parent protein) and the immobilization of this Wnt5a ligand on the biomaterial for local implantation will limit potential undesired nonspecific actions that may arise due to peptide transportation to other off-target sites (47).

(A) Schematic illustration of the implantation of rMSC-seeded and peptide-functionalized porous hydrogels in rat calvarial defects. (B) H&E staining and immunohistochemical staining of the native healthy bone tissue and the calvarial defects treated with the RGD hydrogels, Foxy5 + RGD hydrogels, Scram + RGD hydrogels, and no hydrogels (blank) 8 weeks after implantation (n = 3). High-magnification images showing the defect/native bone boundaries highlighted in yellow and red boxes and defect center areas in blue boxes in the low-magnification images of H&E-stained sections. The dotted lines indicate the boundary between the defect and native bone. The newly formed bone was seamlessly integrated with the neighboring native bone in the Foxy5 + RGD group. Scale bars, 50 m. (C) Top view of 3D micro-CT images showing calvarial bone defects after 8 weeks in all groups (n = 3). (D) Bone volume (normalized to total tissue volume, BV/TV) in the calvarial defects in all groups after 8 weeks (n = 3). The bone volume of healthy rat calvarial bone is shown as the benchmark. Quantification of the immunohistochemical staining intensity of the osteogenic markers, including osteocalcin and type I collagen, showing the higher intensity in the Foxy5 + RGD group compared with those of the RGD and Scram + RGD control groups. Data are shown as the means SD (n = 9). Statistical significance: *P < 0.05, **P < 0.01, and ***P < 0.001 significant difference.

MeHA macromolecules were synthesized from sodium hyaluronate powder (molecular weight, ~74 kDa; Lifecore, Chaska, Minnesota, USA), as previously reported (8). Briefly, 100 ml of 1% (w/v) sodium hyaluronate solution was reacted for 24 hours with 4 or 1.5 ml of methacrylic anhydride at pH 9.5, adjusted with 2 M NaOH solution. After complete dialysis and lyophilization, 100% methacrylation or 30% methacrylation was confirmed using proton nuclear magnetic resonance (1H NMR). The RGD peptide (GCGYGRGDSPG) and Foxy5 peptide (MDGCEL) (GenScript, Nanjing, Jiangsu, China) with a cysteine amino acid at the C-terminal end were conjugated to the MeHA backbone with a Michael addition reaction between the methacrylate groups and the thiol groups of each peptide in basic phosphate buffer (pH 8.0) containing 10 M tris(2-carboxyethyl)phosphine at 37C. The molar ratio of methacrylate to each peptide thiol was 100:3. RGD-functionalized, Foxy5-conjugated porous MeHA hydrogels were fabricated from 50 l of the peptide-conjugated MeHA solution (3% w/v, 100% methacrylation) after 2 hours, with 1.51 mol of DTT as the cross-linker to consume all residual methacrylic groups, in round polyvinyl chloride molds fully packed with a poly(methyl methacrylate) (PMMA) microsphere porogen ( 200 m). The constructs generated were immersed in acetone and shaken at 90 rpm to dissolve the PMMA porogen, sterilized with 75% ethanol for 1 day, and rinsed three times with sterile phosphate-buffered saline (PBS). In the directly Foxy5 peptidesupplemented MeHA (free Foxy5) group and the directly scrambled peptidesupplemented MeHA (free Scram) group, we only used the same Foxy5 + RGDfunctionalized MeHA solution or Scram + RGDfunctionalized MeHA solution (3% w/v, 100% methacrylation) to fabricate the porous hydrogels, respectively.

We used MeHA with 30% methacrylation supplemented with 0.05% (w/v) photoinitiator I2959 (Sigma-Aldrich, MO, USA) to make Foxy5 + RGDfunctionalized MeHA solution, Scram + RGDfunctionalized MeHA solution, or RGD-functionalized MeHA solution (3% w/v, 30% methacrylation) and to fabricate 2D hydrogels with different stiffness in polyvinyl chloride molds under 367, 467, 667, or 1067 seconds of UV exposure. All 2D hydrogels were sterilized before cell culture. The surface roughness and modulus were determined by atomic force microscopy (Bruker, MA, USA).

2D-biofunctionalized substrates were fabricated by polymerizing peptide-conjugated MeHA precursor solutions (3% w/v, 30% methacrylation) under UV light (wavelength, 365 nm; intensity, 7 mW/cm2) on methacrylated glass coverslips. The porous MeHA hydrogel constructs (height, ~1.5 mm; 1 mm) were polymerized in molds filled with 200-m PMMA microbeads to form an interconnected porous structure for in vitro experiments and for in vivo calvarial defect regeneration (Fig. 1, B and C) (9). Homogenous, interconnected spherical structures within the hydrogels were characterized through bright-field images captured using a fluorescence microscope (Nikon, Japan) (Fig. 1D). The Young moduli of the hydrogels were determined using a mechanical tester (Mach-1, Biomomentum Inc., Suite, Canada), and the strain-controlled frequency sweep mechanical tests were performed using a rheometer (Malvern Inc., Malvern, Britain).

Passage-4 hMSCs (Lonza, Walkersville, Maryland, USA) were expanded in basal growth medium [-minimal essential medium (MEM) supplemented with 16.7% (v/v) fetal bovine serum (FBS), penicillin-streptomycin (P/S; 100 U ml1), and 2 mM l-glutamine]. Growth medium (50 l) containing 5 105 hMSCs (108 cells ml1) was injected into one semidry, porous MeHA-RGD hydrogel, which was incubated at 37C for 4 hours to allow cell attachment to the hydrogels. Then, 1 ml of osteogenic medium [-MEM, 16.67% FBS, 1% P/S, 2 mM l-glutamine, 10 mM -glycerophosphate disodium, l-ascorbic acid 2-phosphate (50 mg ml1), and 100 nM dexamethasone] was added to all the hydrogels, and the medium was changed every 2 days. In the control group, Foxy5 peptide or scrambled peptide solution was added directly to the hydrogels at the beginning of osteogenic culture. Samples were collected on days 7 and 14 to evaluate the degree of osteogenesis by traditional qPCR and immunofluorescence staining. Cell viability was determined by alamarBlue assay (Invitrogen, Carlsbad, California, USA) after 7 days in osteogenic culture. Live/dead staining was performed by adding 3 M calcein AM and 3 M propidium iodide (Thermo Fisher Scientific, Waltham, Massachusetts, USA) to the hydrogels. After incubation for 30 min at 37C, the hydrogels were washed three times with PBS, and fluorescence images were captured using a confocal microscope (Nikon C2, Tokyo, Japan). The quantification of immunofluorescence staining results was conducted by using the ImageJ software [National Institutes of Health (NIH), Baltimore, Maryland, USA]. First, we adjusted the color images of the immunofluorescence staining to the 8-bit grayscale images, and then we selected the region of cells that best represent the overall staining intensity of the samples in the immunofluorescence staining results. The average grayscale values of the region of interest taken from at least 20 cells in each group were determined and compared to get the quantification results. The reported data of biochemical assays are the pooled results from three experiments.

All samples were homogenized in 1 ml of TRIzol reagent (Invitrogen), and total RNA was extracted according to the manufacturers protocol. The RNA concentration was measured using a NanoDrop One spectrophotometer (NanoDrop Technologies, Waltham, Massachusetts, USA). Total RNA (1 g) was reverse transcribed into cDNA using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific). qPCR was performed on an Applied Biosystems StepOnePlus Real-Time PCR System with TaqMan primers and probes (Applied Biosciences, Waltham, Massachusetts, USA) specific for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and other osteogenic genes, including those encoding RUNX2, ALP, and type I collagen. The sequences of the TaqMan primers and probes used are listed in table S2. The osteogenic gene expression levels were normalized to that of GAPDH, and the relative expression levels were calculated with the 2Ct method.

Hydrogel samples were fixed overnight in 4% paraformaldehyde at 4C, dehydrated in a graded series of ethanol, crystalized in a graded series of xylene, and embedded in paraffin. Histological sections (7 m) were stained for type I collagen using the VECTASTAIN ABC Kit and the DAB Substrate Kit (Vector Laboratories, Burlingame, California, USA). Briefly, hyaluronidase (0.5 g liter1) was applied to the rehydrated samples to predigest them at 37C for 30 min. The samples were then incubated with 0.5 N acetic acid for 4 hours at 4C to induce swelling, followed by incubation at 4C overnight with a primary antibody directed against type I collagen (antitype I collagen, diluted 1:200; sc-59772, Santa Cruz Biotechnology). Immunofluorescence staining for the osteogenic-related proteins (YAP and RUNX2) and cellular contractionrelated proteins (RhoA) was conducted as previously reported (9). The calcification of phosphates and calcium ions was identified with von Kossa staining and Alizarin Red S staining, respectively. Briefly, von Kossa stain was applied to the rehydrated sections, as previously reported. To stain with Alizarin Red S, 1 ml of 0.5% (w/v) Alizarin Red S solution (Sigma) was applied to each hydrogel sample; the samples were then incubated for 5 min at room temperature before being washed, dehydrated, cleared, and sealed. Images were captured using a bright-field microscope (Nikon). The quantification was conducted by using the ImageJ software (NIH). First, we adjusted the color images of immunohistochemistry (IHC) staining to the 8-bit grayscale images, and then we selected regions of interests of identical size that best represent the overall staining intensity of the samples in the IHC staining results. The average grayscale values of the region of interest taken from three parallel samples in each group were determined and compared to get the quantification results. The reported data of biochemical assays are pooled results from three experiments.

Strictly following the guidelines of the Institutional Animal Care and Use Committee at The Chinese University of Hong Kong, 12-week-old male Sprague-Dawley rats were randomly divided into four groups, shaved, and prepped for aseptic surgery. A midline skin flap was raised over the parietal bones and reflected caudally to expose the midsagittal and transverse sutures. The periosteum was incised along the midsagittal suture and the right or left transverse suture and removed to expose the parietal bone. A 5-mm-diameter defect was created using a trephine with normal saline irrigation during processing, and a section of the bone was removed to expose the dura mater. 3D porous peptidefunctionalized HA hydrogels (n = 3 per group) 5 mm in diameter and 1 mm thick were seeded with 1 million rMSCs with trilineage differentiation potential (46). After 7 days of in vitro osteogenic induction in the incubator, the hydrogels were implanted into the calvarial defects. All experimental animals were maintained until 8 weeks from the day of defect creation. After the rats were euthanized, the parietal bones were harvested and decalcified with 10% EDTA solution. The subsequent H&E staining and histological analysis were performed as described in previous publications (9).

All data are presented as the means SD. Statistica (Statsoft, Tulsa, Oklahoma, USA) was used to perform the statistical analyses using two-way analysis variance (ANOVA) and Tukeys honest significant difference post hoc test of the means; the culture period and experimental groups were used as independent variables.

Acknowledgments: We are grateful for the technical support from J. Lai, S. Wong, and A. Cheung from the School of Biomedical Sciences (The Chinese University of Hong Kong). We thank M. Zhu and K. Zhang for proofreading the manuscript. We sincerely thank M. Wong, N. So, K. Wei, M. Zhu, B. Yang, H. Chen, K. Zou, K. Zhang, Y. Jing, D. Siu Hong Wong, X. Xu, E. Yingrui Deng, X. Chen, and W. Li for the valuable discussions, support, and love. Funding: Project 31570979 is supported by the National Natural Science Foundation of China. The work described in this paper is supported by a General Research Fund grant from the Research Grants Council of Hong Kong (project nos. 14202215 and 14220716). This research is also supported by project BME-p3-15 of the Shun Hing Institute of Advanced Engineering (The Chinese University of Hong Kong). This work is supported by the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (reference no. 04152836). This research is supported by the Chow Yuk Ho Technology Centre for Innovative Medicine (The Chinese University of Hong Kong). The work was partially supported by the Hong Kong Research Grants Council Theme-based Research Scheme (reference no. T13-402/17-N, Functional Bone Regeneration in Challenging Bone Disorders and Defects, 1 November 2017 to 31 October 2022). Author contributions: S.L. contributed to the animal experiments and analysis. M.Z. and J.X. contributed to the peptide synthesis and porous gel fabrication. Y.D. contributed to the cell culture and qPCR assay. X.C. contributed to the polymer synthesis and NMR characterization. K.W. contributed to the macromer synthesis and proofreading of the manuscript. R.L. contributed to the rest of the experiments and the manuscript. G.L. led the in vivo study of the project. L.B. led the project as the supervisor. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Synthetic presentation of noncanonical Wnt5a motif promotes mechanosensing-dependent differentiation of stem cells and regeneration - Science Advances

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Stem Cell Banking Market was valued at $1986 million in 2016 – Markets Gazette

By daniellenierenberg

A fresh report titled Stem Cell Banking Market has been presented by KD market insights. It evaluates the key market trends, advantages, and factors that are pushing the overall growth of the market. The report also analyzes the different segments along with major geographies that have more demand for Stem Cell Banking Market. The competition analysis is also a major part of the report.

The global stem cell banking market was valued at $1,986 million in 2016, and is estimated to reach $6,956 million by 2023, registering a CAGR of 19.5% from 2017 to 2023. Stem cell banking is a process where the stem cell care isolated from different sources such as umbilical cord and bone marrow that is stored and preserved for future use. These cells can be cryo-frozen and stored for decades. Private and public banks are different types of banks available to store stem cells.

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Increase in R&D activities in regards with applications of stem cells and increase in prevalence of fatal chronic diseases majorly drive the growth of the global stem cell banking market. Moreover, the large number of births occurring globally and growth in GDP & disposable income help increase the number of stem cell units stored, which would help fuel the market growth. However, legal and ethical issues related to stem cell collections and high processing & storage cost are projected to hamper the market growth. The initiative taken by organizations and companies to spread awareness in regards with the benefits of stem cells and untapped market in the developing regions help to open new avenues for the growth of stem cell banking market in the near future.

The global stem cell banking market is segmented based on cell type, bank type, service type, utilization, and region. Based on cell type, the market is classified into umbilical cord stem cells, adult stem cells, and embryonic stem cells. Depending on bank type, it is bifurcated into public and private. By service type, it is categorized into collection & transportation, processing, analysis, and storage. By utilization, it is classified into used and unused. Based on region, it is analyzed across North America, Europe, Asia-Pacific, and LAMEA.

KEY MARKET BENEFITS

This report offers a detailed quantitative analysis of the current market trends from 2016 to 2023 to identify the prevailing opportunities.

The market estimations provided in this report are based on comprehensive analysis of the key developments in the industry.

In-depth analysis based on geography facilitates in analyzing the regional market to assist in strategic business planning.

The development strategies adopted by key manufacturers are enlisted in the report to understand the competitive scenario of the market.

KEY MARKET SEGMENTS

By Cell Type

Umbilical Cord Stem Cell

Cord Blood

Cord Tissue

Placenta

Adult Stem Cell

Embryonic Stem Cell

By Bank Type

Public

Private

By Service Type

Collection & Transportation

Processing

Analysis

Storage

By Utilization

Used

Unused

By Region

North America

U.S.

Canada

Mexico

Europe

Germany

UK

France

Spain

Italy

Rest of Europe

Asia-Pacific

Japan

China

Singapore

India

South Korea

Rest of Asia-Pacific

LAMEA

Brazil

Saudi Arabia

South Africa

Rest of LAMEA

KEY PLAYERS PROFILED

Cord Blood Registry

ViaCord

Cryo-Cell

China Cord Blood Corporation

Cryo-Save

New York Cord Blood Program

CordVida

Americord

CryoHoldco

Vita34

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Table of Content

CHAPTER 1: INTRODUCTION

1.1. Report description1.2. Key benefits for stakeholders1.3. Key market segments1.4. Research methodology

1.4.1. Secondary research1.4.2. Primary research1.4.3. Analyst tools and models

CHAPTER 2: EXECUTIVE SUMMARY

2.1. CXO perspective

CHAPTER 3: MARKET OVERVIEW

3.1. Market definition and scope3.2. Key findings

3.2.1. Top investment pockets3.2.2. Top winning strategies

3.3. Porters five forces analysis3.4. Top Player Positioning3.5. Market dynamics

3.5.1. Drivers

3.5.1.1. Large number of newborns3.5.1.2. Increase in R&D activities for application of stem cells3.5.1.3. Increase in prevalence of fatal chronic diseases3.5.1.4. Growth in GDP and disposable income

3.5.2. Restraints

3.5.2.1. Legal and ethical issues during collection of stem cells3.5.2.2. High processing and storage cost3.5.2.3. Lack of acceptance and awareness

3.5.3. Opportunities

3.5.3.1. Initiatives to spread awareness3.5.3.2. Untapped market in developing regions

CHAPTER 4: STEM CELL BANKING MARKET, BY CELL TYPE

4.1. Overview

4.1.1. Market size and forecast

4.2. Umbilical Cord Stem Cells

4.2.1. Key market trends and growth opportunities4.2.2. Market size and forecast4.2.3. Market analysis, by country4.2.4. Cord Blood

4.2.4.1. Market size and forecast

4.2.5. Cord Tissue

4.2.5.1. Market size and forecast

4.2.6. Placenta

4.2.6.1. Market size and forecast

4.3. Adult stem cells

4.3.1. Key market trends and growth opportunities4.3.2. Market size and forecast4.3.3. Market analysis, by country

4.4. Embryonic stem cells

4.4.1. Key market trends and opportunities4.4.2. Market size and forecast4.4.3. Market analysis, by country

Continue

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About KD Market Insights

KD Market Insights offers a comprehensive database of syndicated research studies, customized reports, and consulting services. These reports are created to help in making smart, instant and crucial decisions based on extensive and in-depth quantitative information, supported by extensive analysis and industry insights.

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Stem Cell Banking Market was valued at $1986 million in 2016 - Markets Gazette

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How Young India is fuelling the future of stem cell therapy and signing up to save lives – YourStory

By daniellenierenberg

Eighteen-year-old Aisha Choudhary was just like any other adolescent eyes filled with dreams and a heart brimming with energy. The only difference was she was battling a rare genetic disease, Severe Combined Immune Deficiency (SCID). Diagnosed when she was six months old and undergoing medical treatment for years, she was iron-willed in playing the cards she was dealt.

Since one of the most effective cures for SCID is a stem cell transplant (grafting of the parent cells from which all blood cells develop), Aishas parents, Niren and Aditi, decided to opt for that treatment mode. But their cells were not a complete match with their daughters, and they had to look at external donors. However, due to a low number of voluntary, registered stem cell donors, Aisha could not get a compatible donor whose genetic markers were a close enough match to hers. With no other alternative treatment available, Aisha had a bone marrow transplant. But, it came with a side-effect that cost her life Pulmonary Fibrosis, a disease known to damage the lung tissues.

Aishas Choudhary's role has been played by Zaira Wasim in The Sky is Pink.

Aishas journey has been captured in The Sky is Pink, a recent Bollywood movie starring Priyanka Chopra, Farhan Akhtar, Zaira Wasim, and Rohit Saraf.

The 18-year-olds life story is mirrored in the experiences of many who await stem cell donation as treatment for blood-related illnesses likeleukemia, lymphoma, and sickle cell anemia every year. With very few individuals signing up as donors and the probability of finding a match being a dismal 0.0008 percent in India (against a lean 16 percent abroad), fatalities are mounting year on year.

However, in recent times, there has been one small break in the clouds a number of youngsters, non-governmental organisations, and medical professionals have come forward and are working to spread awareness about stem cell donation and motivate a larger number of people to register as donors.

The stem cells in a human body mainly comprise red blood cells, platelets, and white blood cells. These are found in the umbilical cord of newborns and in the peripheral or circulating blood and bone marrow.

A stem cell donation is as simple and painless as a blood donation.

Certain diseases like blood cancer and leukemia tend to destroy the bone marrow or affect its functioning.For these, treatments like chemotherapy and radiotherapy are tried initially. However, in some cases, they do not prove effective for a cure. The only recourse then is replacing the patients stem cells with those of a healthy person.

One of the main criteria for a successful transplant is a good match between the stem cells of the donor and those of the patient. Therefore, a donor registry will administer a cheek swab test (tissue samples extracted from the cheek) on all potential donors to match cell characteristics. This procedure of pairing generic markers is called Human Leukocyte Antigen (HLA) in medical terms.

A cheek swab test in progress.

Each potential donors tissue is entered in the registry and given an identification number after the test is done. If the registry finds a match at any point in time, the donor is contacted to initiate the transplant.

There are many organisations today that are leading the charge in saving the lives of people suffering from serious blood disorders like cancer, thalassemia, and anaemia.

For instance, Datri, an Ahmedabad-based NGO, is working to create a wide and diverse database of potential stem cell donors by organising donation drives. Founded in 2009 by two doctors and an engineer, the organisation focuses on conducting awareness campaigns and helping individuals sign up on its registry as a committed and voluntary benefactor.

The team of the NGO Datri.

The idea for Datri was initially born in the minds of doctors Nezih Cereb and Soo Young Yang, who run a laboratory, Histogenetics, for determining tissue matches between patients and donors. Since pairing tissue types is imperative for any stem cell transplant, and confronting a severe shortage of donors, the doctor duo would run from pillar to post to meet hospitals requirements. Working with a number of the hospitals in India, they realised just how acute the shortfall was in people willing to donate stem cells. They recognised the immediate need to create a donor registry here.

Soon after, Raghu Rajagopal, an engineer from BITS Pilani and Director of ready-to-eat venture Millets and More, connected with them and they decided to start Datri.

Today, the functioning of the registry, its maintenance, and even the substantial costs involved in conducting the HLA matching are taken care of by the lab. In the last 10 years, Datri has gotten over four lakh people to register as donors and has saved around 600 lives through successful transplantation.

Every day, about 40 people are diagnosed with blood disorders in India. Though these can be cured through a stem cell transplant from a genetically matched donor, there is only a 25 percent chance of finding a match from within the family. Others have no option but to rely on unrelated donors. But the chances of getting a match is anywhere between one in 10,000 and one in two million. There is an urgent need to rope in as many potential donors as possible, which is precisely what Datri is trying to do, Raghu explains.

Another organisation that is dedicated to fighting blood disorders with stem cell treatment is DKMS-BMST. It was formed through a joint venture between two renowned NGOs DKMS, which is one of the largest international blood stem cell donor centres globally, and the Bangalore Medical Services Trust (BMST).

The team of DKMS-BMST.

DKMS was founded in Germany in 1991 by businessman Dr Peter Harf, after he lost his wife to leukemia. BMST was born in 1984 from the vision of Dr Latha Jagannathan, a medical director and managing trustee. Since both organisations had a common goal to find a matching donor for every patient with a blood disorder, they decided to come together to achieve it.

A group of youngsters registering to be stem cell donors.

So far, more than 37,000 people in India have registered as potential donors after attending DKMS-BMSTs donor drives.

In highly populous countries like India, thousands of people are in need of stem cell transplants every year to survive. Though donating stem cells is a painless and non-invasive process, it remains a lesser-known medical concept in India, with only 3.6 lakh people willing to play a part in it. Besides, the chances of stem cells of people of the same ethnicity matching are higher than those of individuals from different ethnic backgrounds. But, it is due to sheer lack of awareness that India lags severely in stem cell donations, say experts.

Students taking a cheek swab test at one of the colleges in Bengaluru.

Dr Govind Eriat, a reputed hematologist and bone marrow transplant specialist, says,

With a major hurdle to stem cell donation in India proving to be the myths surrounding the subject, the youth are coming forward to deconstruct common misconceptions.

For instance, 21-year-old Tejaswini Patel, a student of Information Science at New Horizon College of Engineering, Bengaluru, has been busting the false ideas on stem cell donation, starting among her family and friends. She says,

She adds, with a notable sense of pride, In the last two years alone, around 400 students from my college have registered themselves as donors.

(Edited by Athirupa Geetha Manichandar)

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ARMI summit: With synthetic meat within grasp, why not synthetic liver? – The Union Leader

By daniellenierenberg

MANCHESTER Now that the world has the Impossible Whopper, will the impossible liver be far behind?

Such possibilities are being broached this week as inventor Dean Kamen, founder of the Advanced Regenerative Manufacturing Institute, hosts the fourth semi-annual summit since launching ARMI in July 2017.

The three-day conference started Tuesday with a members-only day for BioFab USA and ARMI. It included a dinner at Kamens Bedford home.

Two public days of speeches and workshops are scheduled through Thursday. A total of 150 have signed up for the event.

Guests listen to a speaker at the Meeting in the Millyard at ARMI in Manchester on Wednesday, Oct. 16, 2019.

The keynote speaker on Wednesday was Jason Kelly, co-founder and chief-executive of Ginkgo Bioworks, a synthetic biology company that programs cells for customers in the chemical, pharmaceutical, food and energy industries.

We program cells because they run on digital code in the form of DNA, Kelly told a crowd of scientists, entrepreneurs and regulators.

Much of ARMIs work has focused on the use of stem cells to generate replacements for human tissue, bones and organs. For example, one of ARMIs biggest accomplishments to date has been the Tissue Foundry; its first production was bone-ligament tissue grown together from bone-marrow stem cells.

But Kamen, who prides himself on introducing new technologies to a field, had Kelly speak about a different kind of cells synthetic cells.

Ginkgo Bioworks has partnered with Bayer to develop self-fertilizing crops, with Roche to develop antibiotics, and with Motif to produce animal-free protein ingredients. Kelly said synthetic cell production played a role in the Impossible Whopper, the plant-based patty that Burger King claims tastes like beef.

(According to the website of Impossible Food, the company that makes the patty, the company extracts DNA from soy plants and inserts it into genetically engineered yeast, which ferments to produce heme, the molecule that gives meat its taste.)

Ginkgo has made CNBCs Disruptor 50 List in the last three years and recently raised more than $430 million in venture capital. In doing so, Ginkgo has achieved what Kamen wants for ARMI to move from theoretical design and laboratory work to mass production.

Theyve learned how to scale it, Kamen said in his introduction. Kamen said he expects ARMI-linked production to start relatively quickly.

(Finding) talent is not the problem. Capital is the problem, Kelly said about tech startups. Many venture capitalists arent experts in the science-heavy world of what he calls tough tech. So they are wary about investing in something they cant grasp.

He advised startups to seek government grants Ginkgo would not have succeeded without them hustle the non-specialist investor and find third-party validation from agencies such as the FDA or the Standards Coordinating Body, a voluntary organization that sets standards for the regenerative medicine industry.

Kelly said the time is now for tough tech. He noted the work of SpaceX and Tesla, and he said Silicon Valley is embracing biotech.

People have run out of things to invent that end up as a square on your phone, he said.

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The Week That Wasn’t: Viagra BMTs, Pregnancy Stress, Breast Cancer Vaccine – Medscape

By daniellenierenberg

Stories of using the little blue pill for bone marrow transplants, how pregnancy stress is related to the baby's sex, and a vaccine for breast cancer proliferated on the Internet this week. Here's why you didn't read about them on Medscape.

Researchers at the University of California, Santa Cruz, seem to think Viagra has more to offer in medicine. In a recent study of mice, they tested whether the vasodilator couldspeed up the migration of hematopoietic stem cells and progenitor stem cells from the bone to the blood, where the cells could be harvested noninvasively.

The standard protocol for preparing bone marrow donors for the harvesting procedure, a 5-day regimen of granulocyte-colony stimulating factor (G-CSF),is "complex, costly, unsuccessful in a significant proportion of donors," the study authors write, and typically results in fatigue, nausea, and bone pain. Using a two-drug strategy, oral Viagra and a single injection of the CXCR4 antagonist AMD3100 (plerixafor), elicited the same mobilization of stem cells in 2 hours.

We didn't cover the study because it's still too early to say whether this strategy might be effective in people. After this mouse study, the next step is testing the approach in larger animals before human clinical trials.

A study of 187 healthy pregnant women age 18 to 45 years suggests that preterm mental and physical stress may be related to the baby's sex and increase the risk for preterm birth. In the study, 16% of women were physically stressed, as measured by higher blood pressure and calorie intake; and 17% were mentally stressed with high levels of depressionand anxiety; 66% of the women were in the healthy (nonstressed) group.

Women who were stressed during pregnancy were more likely to give birth to a girl. Typically, 105 males are born for every 100 females, but the study authors found that the male-to-female ratio decreased to 2:3 in psychologically stressed patients and 4:9 in physically stressed patients. Physically stressed mothers also gave birth an average of 1.5 weeks earlier than mothers in the healthy group, with 22% giving birth preterm compared with 5% in the healthy group.

The study authors say the findings demonstrate the importance of maternal mental health. Medscape has covered the consequences of maternal stress extensively, including preterm birth, neurobehavioral risks, and potential links to hyperactivity during the offspring's teen years. However, the sample size in this study was small: the mentally and physically stressed groups combined only included about 60 women. That's not sufficient to inform clinical practice in counseling women who want to get pregnant about how stress may affect the sex of their baby, so we didn't cover it.

News spread this week that Floridian Lee Mercker became the first woman to "beat" breast cancer with the help of a new vaccine. The vaccine, which stimulates the immune system to fight off early-stage breast cancer, was developed and administered by researchers at the Mayo Clinic in Jacksonville, Florida. The vaccine is currently in an early trial.

Reports of Mercker's success raise hopes, but she's reportedly the first participant in the trial. The news report also says she underwent a double mastectomy after her diagnosis in March, so it's unclear what evidence of the vaccine's efficacy the researchers measured. Before this experimental vaccine is relevant to Medscape readers, we need to see additional detailed data from more patients in the clinical trial published in a peer-reviewed journal.

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Bone marrow recipient comes face-to-face with CT donor for the first time – WTNH.com

By daniellenierenberg

BRIDGEPORT, Conn. (WTNH) The Gift of Life Marrow Registry organized the meeting Thursday between a bone marrow donor from Connecticut and the recipient whose life was saved by the donation.

Jennie Bunce, 25, of Redding donated her marrow. According to a representative for Gift of Life, Bunce was studying physical therapy and joined Gift of Life through a sorority event at North Carolinas High Point University in 2016.

I never win or get picked for anything, but it just felt like the right thing to do, Bunce told Gift of Life. Im just incredibly happy and grateful to be part of something so special. Its similar to holding the door open for someone or helping a friend in a time of need.

Across the country in Mesa, Arizona, father-of-6, Mark Roser, 33, was battling Acute Lymphoblastic Leukemia. He found out about the diagnosis after he broke a hip in 2018 and had continued weakness. Roser was told he needed a bone marrow transplant to survive.

The hardest part was knowing, no matter how hard I worked, that what I did would not be a deciding factor in my ability to receive this gift, said Roser.

The match was made by Gift of Life in about six months, and the transplant took place in Phoenix.

She is a hero to all the people in my life, said Roser.

She gave me life, she gave my children a future with their dad, she gave my wife a chance to hold her husband, to have someone hold her back. She allowed me to go to work, to play, to see things from a different perspective. I am grateful for every moment I have, and its because of her.

According to Gift a Life, medical privacy laws dictate that recipients and donors must remain anonymous and wait at least a year before meeting.

The two came face-to-face for the first time Thursday in Bridgeport at the Boca Oyster Bar.

Since its start in 1991, the Gift of Life Registry 349,000 individuals who have donated blood stem cells or bone marrow to save a life. The program has facilitated 16,800 matches and over 3,500 transplants.

To learn more about the organization and/or how to donate: https://www.giftoflife.org/.

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CAR-T Therapy May Be More Effective When Administered Earlier in the Multiple Myeloma Treatment Continuum – Cancer Therapy Advisor

By daniellenierenberg

Results of an ex vivo study evaluating the phenotypic and growth characteristics of T cells collected by leukapheresis from cohorts of patients with newly diagnosed or relapsed/refractory multiple myeloma support use of chimeric antigen receptor (CAR)-T therapy earlier in course of the disease. The hypothesis-generating findings from this study were published in Blood Advances.

While CAR-T therapy targeted against the B-cellmaturation antigen (BCMA) has been associated with promising results inpatients with multiple myeloma, nearly all of the patients responding to thisapproach eventually develop progressive disease. Hence, strategies to optimizepatient selection for CAR-T therapy in the setting of multiple myeloma arebeing actively pursued.

Theratio of CD4 to CD8 T cells and/or the frequency of the CD81 CD45RO2 CD271 T-cell memory phenotype were usedin this study as surrogates for the clinical effectiveness of CAR-T therapysince previous studies ofCAR-T therapy in patients with chronic lymphocyticleukemia and multiple myeloma showed that of all baseline patient- anddisease-related characteristics considered, clinical response to CAR-T therapywas associated only with this T-cell ratio and/or the frequency of this subsetof memory T cells in the premanufacturing leukapheresis product.

Twocohorts of patients where compared in this study: 38 patients with newly diagnosedmultiple myeloma who had participated in clinical trials of induction therapy andon whom leukapheresis was performed before consolidation therapy and autologousstem cell transplantation (ASCT); and 25 patients with relapsed/refractorymultiple myeloma enrolled in a phase 1 clinical trial of anti-BCMA CAR-Ttherapy and on whom leukapheresis was performed during a washout period shortlyfollowing study enrollment.

Inboth patient cohorts, leukapheresis samples were exposed ex vivo to anti-CD3and anti-CD28 monoclonal antibodies covalently linked to magnetic beads toprovide stimulatory/costimulatory signals for T-cell proliferation and theexpansion of functional T cells.

The 2 patient cohorts were similar with respect to median age (ie, 55 years; 58 years [relapsed/refractory]), although the time from multiple myeloma diagnosis was 222 days for those treated with induction therapy and 4.6 years for those with relapsed/refractory disease.

Inaddition, differences in the median number of prior lines of therapy (1 vs 7),and bone marrow cellularity occupied by myeloma plasma cells (13% vs 65%) wereobserved when the former and latter cohorts were compared at the time thatleukapheresis was performed.

Akey finding from this study was a significantly higher frequency of T cellswith the CD81 CD45RO2CD271 T-cell memory phenotype(43.9% vs 29.0%; P =.001), as well asa significantly higher median CD4/CD8 ratio (2.6 vs 0.87; P <.0001) in the postinduction versus the relapsed/refractorypatient cohort.

Inaddition, the CD4/CD8 ratio was also significantly higher in the postinductioncohort compared with responders to anti-BCMA CAR-T therapy from the relapsed/refractorycohort (2.6 vs 1.3; P= .0009); however,while higher in the postinduction cohort, the difference in the frequency of Tcells with the CD81 CD45RO2CD271 T-cell memory phenotypewas not statistically significant when these 2 groups were compared.

Regardingcapacity for ex vivo proliferation during manufacturing, significantly highernumbers of population doubling by day 9 (PD9) were observed for thepostinduction cohort compared with either the overall relapsed/refractorycohort or the group of responders within the relapsed/refractory cohort.

Ourresults suggest that CAR T cells manufactured from leukapheresis samplesobtained after response to induction therapy would be, on average, moreclinically effective than those obtained from heavily relapsed/refractorymultiple myeloma patients, the study authors concluded.

Reference

Garfall AL, Dancy EK, Cohen AD, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3:2812-2815.

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CAR-T Therapy May Be More Effective When Administered Earlier in the Multiple Myeloma Treatment Continuum - Cancer Therapy Advisor

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