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.

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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

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

Bone Marrow Stem Cells Comments Off on Fanconi Anemia (FA) Fanconi Hypoplastic Anemia Fanconi Hypoplastic Anemia Pipeline Insight Market Research Report 2019: by Trends, Development, Types,… | October 21st, 2019

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

Bone Marrow Stem Cells Comments Off on Healthcare Terms Are Out of Touch, Says Mom Advocate – Medscape | October 21st, 2019

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

Bone Marrow Stem Cells Comments Off on More awareness needed on stem cell donation: expert – The Hindu | October 20th, 2019

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

Bone Marrow Stem Cells Comments Off on Students from over 50 universities across the UK help blood cancer charity – FE News | October 20th, 2019

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

Bone Marrow Stem Cells Comments Off on Synthetic presentation of noncanonical Wnt5a motif promotes mechanosensing-dependent differentiation of stem cells and regeneration – Science Advances | October 19th, 2019

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

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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

Bone Marrow Stem Cells Comments Off on Stem Cell Banking Market was valued at $1986 million in 2016 – Markets Gazette | October 19th, 2019

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

Bone Marrow Stem Cells Comments Off on How Young India is fuelling the future of stem cell therapy and signing up to save lives – YourStory | October 18th, 2019

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

Bone Marrow Stem Cells Comments Off on ARMI summit: With synthetic meat within grasp, why not synthetic liver? – The Union Leader | October 18th, 2019

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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The Week That Wasn't: Viagra BMTs, Pregnancy Stress, Breast Cancer Vaccine - Medscape

Bone Marrow Stem Cells Comments Off on The Week That Wasn’t: Viagra BMTs, Pregnancy Stress, Breast Cancer Vaccine – Medscape | October 18th, 2019

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

Bone Marrow Stem Cells Comments Off on Bone marrow recipient comes face-to-face with CT donor for the first time – WTNH.com | October 18th, 2019

Company Announcement

Copenhagen, Denmark; October 18, 2019 Genmab A/S (Nasdaq:GMAB) announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending broadening the existing marketing authorization for DARZALEX (daratumumab) in the European Union. The recommendation is for the use of DARZALEX in combination with lenalidomide and dexamethasone (Rd) as treatment for newly diagnosed adult patients with multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). The Type II variation application, based on the Phase III MAIA (MMY3008) study, was submitted to the EMA by Janssen Pharmaceutica NV in March 2019. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

We are encouraged that the CHMP are recommending a broadening of the current DARZALEX marketing authorization in the European Union to include DARZALEX in combination with lenalidomide and dexamethasone as a possible treatment for patients newly diagnosed with multiple myeloma. This would give patients another treatment option, in addition to the already approved combination of daratumumab plus bortezomib, melphalan and prednisone in this same setting, said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About the MAIA (MMY3008) studyThe Phase III study (NCT02252172) is a randomized, open-label, multicenter study that includes 737 newly diagnosed patients with multiple myeloma who are not candidates for high dose chemotherapy and ASCT. Patients were randomized to receive either treatment with daratumumab in combination with lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid) or treatment with lenalidomide and dexamethasone alone. In the daratumumab treatment arm, patients received 16 milligrams per kilogram (mg/kg) weekly for first 8 weeks (Cycles 1 and 2), every other week for 16 weeks (Cycles 3 to 6) and then every 4 weeks (Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide is administered at 25 mg orally on days 1 through 21 of each 28-day cycle, and dexamethasone is administered at 40 mg once a week for both treatment arms. Participants in both treatment arms will continue Rd until disease progression or unacceptable toxicity. The primary endpoint of the study is progression free survival.

About multiple myelomaMultiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Approximately 16,830 new patients were expected to be diagnosed with multiple myeloma and approximately 10,480 people were expected to die from the disease in the Western Europe in 2018.2 Globally, it was estimated that 160,000 people were diagnosed and 106,000 died from the disease in 2018.3 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.4

About DARZALEX (daratumumab)DARZALEX (daratumumab) intravenous infusion is indicated for the treatment of adult patients in the United States: in combination with bortezomib, thalidomide and dexamethasone as treatment for patients newly diagnosed with multiple myeloma who are eligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.5 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (U.S. FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy; and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy6. The option to split the first infusion of DARZALEX over two consecutive days has been approved in both Europe and the U.S. In Japan, DARZALEX is approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma and in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. DARZALEX is the first human CD38 monoclonal antibody to reach the market in the United States, Europe and Japan. For more information, visit http://www.DARZALEX.com.

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Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a persons own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).5,6,7,8,9,10

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and refractory and frontline multiple myeloma settings. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases in which CD38 is expressed, such as amyloidosis, NKT-cell lymphoma and B-cell and T-cell ALL. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA for certain indications of multiple myeloma, including as a monotherapy for heavily pretreated multiple myeloma and in combination with certain other therapies for second-line treatment of multiple myeloma.

About Genmab Genmab is a publicly traded, international biotechnology company specializing in the creation and development of differentiated antibody therapeutics for the treatment of cancer. Founded in 1999, the company has two approved antibodies, DARZALEX (daratumumab) for the treatment of certain multiple myeloma indications, and Arzerra (ofatumumab) for the treatment of certain chronic lymphocytic leukemia indications. Daratumumab is in clinical development for additional multiple myeloma indications, other blood cancers and amyloidosis. A subcutaneous formulation of ofatumumab is in development for relapsing multiple sclerosis. Genmab also has a broad clinical and pre-clinical product pipeline. Genmab's technology base consists of validated and proprietary next generation antibody technologies - the DuoBody platform for generation of bispecific antibodies, the HexaBody platform, which creates effector function enhanced antibodies, the HexElect platform, which combines two co-dependently acting HexaBody molecules to introduce selectivity while maximizing therapeutic potency and the DuoHexaBody platform, which enhances the potential potency of bispecific antibodies through hexamerization. The company intends to leverage these technologies to create opportunities for full or co-ownership of future products. Genmab has alliances with top tier pharmaceutical and biotechnology companies. Genmab is headquartered in Copenhagen, Denmark with core sites in Utrecht, the Netherlands and Princeton, New Jersey, U.S.

Contact: Marisol Peron, Corporate Vice President, Communications & Investor Relations T: +1 609 524 0065; E: mmp@genmab.com

For Investor Relations: Andrew Carlsen, Senior Director, Investor RelationsT: +45 3377 9558; E: acn@genmab.com

This Company Announcement contains forward looking statements. The words believe, expect, anticipate, intend and plan and similar expressions identify forward looking statements. Actual results or performance may differ materially from any future results or performance expressed or implied by such statements. The important factors that could cause our actual results or performance to differ materially include, among others, risks associated with pre-clinical and clinical development of products, uncertainties related to the outcome and conduct of clinical trials including unforeseen safety issues, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated entities, changes and developments in technology which may render our products or technologies obsolete, and other factors. For a further discussion of these risks, please refer to the risk management sections in Genmabs most recent financial reports, which are available on http://www.genmab.com and the risk factors included in Genmabs final prospectus for our U.S. public offering and listing and other filings with the U.S. Securities and Exchange Commission (SEC), which are available at http://www.sec.gov. Genmab does not undertake any obligation to update or revise forward looking statements in this Company Announcement nor to confirm such statements to reflect subsequent events or circumstances after the date made or in relation to actual results, unless required by law.

Genmab A/S and/or its subsidiaries own the following trademarks: Genmab; the Y-shaped Genmab logo; Genmab in combination with the Y-shaped Genmab logo; HuMax; DuoBody; DuoBody in combination with the DuoBody logo; HexaBody; HexaBody in combination with the HexaBody logo; DuoHexaBody; HexElect; and UniBody. Arzerra is a trademark of Novartis AG or its affiliates. DARZALEX is a trademark of Janssen Pharmaceutica NV.

1 American Cancer Society. "Multiple Myeloma Overview." Available at http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma.Accessed June 2016.2 Globocan 2018. Western Europe Fact Sheet. Available at http://gco.iarc.fr/today/data/factsheets/populations/926-western-europe-fact-sheets.pdf Accessed March 20183 Globocan 2018. World Fact Sheet. Available at http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed December 2018.4 American Cancer Society. "How is Multiple Myeloma Diagnosed?" http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed June 20165 DARZALEX Prescribing information, September 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761036s024lbl.pdf Last accessed September 20196 DARZALEX Summary of Product Characteristics, available at https://www.ema.europa.eu/en/medicines/human/EPAR/darzalex Last accessed October 20197De Weers, M et al. Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors. The Journal of Immunology. 2011; 186: 1840-1848.8 Overdijk, MB, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015; 7: 311-21.9 Krejcik MD et al. Daratumumab Depletes CD38+ Immune-regulatory Cells, Promotes T-cell Expansion, and Skews T-cell Repertoire in Multiple Myeloma. Blood. 2016; 128: 384-94.10Jansen, JH et al. Daratumumab, a human CD38 antibody induces apoptosis of myeloma tumor cells via Fc receptor-mediated crosslinking.Blood. 2012; 120(21): abstract 2974.

Company Announcement no. 50CVR no. 2102 3884LEI Code 529900MTJPDPE4MHJ122

Genmab A/SKalvebod Brygge 431560 Copenhagen VDenmark

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CHMP Issues Positive Opinion Recommending DARZALEX (Daratumumab) in Combination with Lenalidomide and Dexamethasone in Frontline Multiple Myeloma -...

Bone Marrow Stem Cells Comments Off on CHMP Issues Positive Opinion Recommending DARZALEX (Daratumumab) in Combination with Lenalidomide and Dexamethasone in Frontline Multiple Myeloma -… | October 18th, 2019

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

Bone Marrow Stem Cells Comments Off on CAR-T Therapy May Be More Effective When Administered Earlier in the Multiple Myeloma Treatment Continuum – Cancer Therapy Advisor | October 18th, 2019

BALTIMOREand PHILADELPHIA and IRVINE, Calif., Oct. 15, 2019 (GLOBE NEWSWIRE) -- WindMIL Therapeutics and the University of California, Irvine (UCI) today announced that the first patients have been identified in an investigator-sponsored study for the collection of bone marrow from patients with gliomas. The study will evaluate generating marrow infiltrating lymphocytes (MILs) for these patients through WindMILs proprietary cellular activation and expansion process. The study is being conducted at UCI.

Patients suffering with glioblastoma are in great need of new, promising treatments that might advance the current standard of care, said Daniela A. Bota, MD, PhD, director of theUCI Health Comprehensive Brain Tumor Program,seniorassociate dean for clinical research, UCI School of Medicine and clinical director, UCI Sue & Bill Gross Stem Cell ResearchCenter. The University of California, Irvine is excited toplay a key role in research that may lead to a clinical trial that enlists the immune system in novel ways to fight this terrible disease.

Gliomas are the most common of the malignant brain tumors. Glioblastoma, the most common glioma, has a five-year survival of less than 5 percent. Additional treatment options are urgently needed for these patients. Adoptive immunotherapy is a possible approach for gliomas and the use of MILs, a cell therapy that is naturally tumor-specific, is one such treatment option.

The bone marrow is a unique niche in the immune system to which antigen-experienced memory T cells traffic and are then maintained. WindMIL has developed a proprietary process to select, activate and expand these memory T cells into MILs. Because memory T cells in bone marrow occur as a result of the immune systems recognition of tumor antigens, MILs are specifically suited for adoptive cellular immunotherapy and are able to directly eradicate or facilitate eradication of each patients unique cancer. WindMIL is currently studying MILs in multiple myeloma, non-small cell lung cancer and squamous cell carcinoma of the head and neck, and plans to expand into other solid tumors.

WindMIL is looking forward to working with the University of California, Irvine on this exciting project and is optimistic that MILs may offer the potential to help patients with these hard-to-treat diseases, said Monil Shah, PharmD, MBA, Chief Development Officer at WindMIL.

About WindMIL Therapeutics

WindMIL Therapeutics is a clinical-stage company developing a novel class of autologous cell therapies based on marrow infiltrating lymphocytes (MILs) for cancer immunotherapy. As the leader in cellular therapeutics emanating from bone marrow, WindMIL translates novel insights in bone marrow immunology into potentially life-saving cancer immunotherapeutics for patients. WindMIL believes that Cell Source Matters and the companys proprietary process to extract, activate and expand these cells offers unique immunotherapeutic advantages, including inherent poly-antigen specificity, high cytotoxic potential and long persistence. For more information, please visit: http://www.windmiltx.com.

About UCI Health

UCI Healthcomprises the clinical enterprise of the University of California, Irvine. Patients can access UCI Health at primary and specialty care offices across Orange County and at its main campus, UCI Medical Center in Orange, California. The 417-bed acute care hospital provides tertiary and quaternary care, ambulatory and specialty medical clinics and behavioral health and rehabilitation services. UCI Medical Center features Orange Countys only National Cancer Institute-designated comprehensive cancer center, high-risk perinatal/neonatal program and American College of Surgeons-verified Level I adult and Level II pediatric trauma center and regional burn center. UCI Health serves a region of nearly 4 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us onFacebookandTwitter.

About the University of California, Irvine

Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 222 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visitwww.uci.edu.

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WindMIL Therapeutics and University of California, Irvine Announce Collaboration to Collect Bone Marrow from Patients with Gliomas to Develop Marrow...

Bone Marrow Stem Cells Comments Off on WindMIL Therapeutics and University of California, Irvine Announce Collaboration to Collect Bone Marrow from Patients with Gliomas to Develop Marrow… | October 16th, 2019

A case study published in Leukemia and Lymphoma described a patient with a diagnosis of Waldenstrm Macroglobulinemia (WM) that had subsequently undergone histological transformation to refractory high grade B-cell lymphoma and was successfully treated with CD19-targeted chimeric antigen receptor (CAR)-T cell therapy.1

WMis a type of B-cell non-Hodgkin lymphoma(NHL), typically characterized by overproduction of monoclonal immunoglobulinM, as well as infiltration of malignant lymphoplasmacytic cells into the bonemarrow.

Although considered incurable, WM often follows an indolent course andsome patients can be asymptomatic for long periods. Rarely, the diseasetransforms into a more aggressive form of NHL that has been associated with apoor prognosis.

The patient described in the case studywas a 71-year-old man who was first diagnosed with WM in 1998. The patient wasmonitored without undergoing active treatment for a period of 12 years, atwhich time he developed anemia and splenomegaly. At that time, he underwenttreatment with 6 cycles of fludarabine and rituximab and achieved a partial response totreatment. Following a worsening of symptoms 4 years later, the patient wastreated with 6 cycles of bendamustine and rituximab.

Biopsyof an enlarged cervical lymph node performed at that time revealed high-gradeB-cell lymphoma that was clonally related to the previously seenlymphoplasmacytic infiltrate, consistent with transformation.

Thepatient subsequently achieved a complete response to 6 cycles of rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) plus ibrutinibfollowed by 6 months of ibrutinib maintenance therapy that lasted for 18months.

Salvagetherapy included 2 cycles of rituximab, dexamethasone, cytarabine, cisplatin(R-DHAP) followed by 1 cycle of rituximab plus high-dose cytarabine, followedby autologous stem cell transplantation several months later.

Asthe patients disease was considered to be chemorefractory based on subsequent imagingand pathological analyses, he was treated with axicabtagene ciloleucel, aCD19-targeted CAR-T cell therapy currently approved for the treatment of adultpatients with relapsed or refractory large B-cell lymphoma, including high gradeB-cell lymphoma, after 2 or more lines of systemic therapy.2

Althoughthe patient experienced pancytopenia, grade 1 cytokine release syndrome, andgrade 1 neurotoxicity following CAR-T therapy, he achieved a complete response1 month following treatment.

Notably,there was no evidence of either underlying WM or transformed disease at 6 and 12months follow-up.

Thestudy authors noted that longer term follow up in this patient will beinformative, as late relapses have occurred even in patients who achieve a deepresponse after transplant. CAR-T cell therapy may be an effective treatment forrelapsed or refractory WM that has not yet undergone histologicaltransformation, as CD19 is almost universally expressed on lymphoplasmacyticlymphoma cells. The researchers concluded that further analysis of this iswarranted in the context of clinical trials.

References

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Benefit of CD19-Targeted CAR-T Therapy in Patients With Transformed Waldenstrm Macroglobulinemia - Cancer Therapy Advisor

Bone Marrow Stem Cells Comments Off on Benefit of CD19-Targeted CAR-T Therapy in Patients With Transformed Waldenstrm Macroglobulinemia – Cancer Therapy Advisor | October 16th, 2019

Organizers of this years Light the Night, which is held in support of blood cancer research, hope members of the community can join them Oct. 19 as they take to the Rotary Trail to raise awareness and funds for the eradication of various blood cancers.

Leukemia, lymphoma, Hodgkins lymphoma and myeloma can all be beat, but for every inspirational tale of perseverance and survival, there are even more about those who could not hang on long enough and died as a result of the fast moving diseases that affect blood cells, bone marrow and lymph nodes to name a few.

I lost my niece to leukemia 11 years ago, she was 19, said Westlock organizer Joanne Rimmer, with tears in her eyes as fresh as the day she lost her niece.

I had positive thoughts the whole time, I thought she was going to get over it and everything was going to be back to normal and it didnt work out. I didnt want other families to go through that, so I thought it was a good thing to help raise money.

It has been 11 years and Im still crying. Its one way we can do something to say we really miss her.

Rimmer also has a close friend who was able to survive leukemia after a donation of stem cells from her brother saved her life. She also has another friend in Manitoba who is currently fighting off leukemia, with some success. These are her reasons for lighting up the night, so called because participants often hold lanterns of different colours that denote how thatindividual has been affected.

White lanterns are carried by survivors, gold is in remembrance and red is in support, which together makes for quite a sea of colour moving through the town.

Rimmer, who has been taking part in the event in one form or another for 11 years and helping to organize the Westlock event for the last six years is a proponent of having a bare-bones event with little flash or overhead to make sure as much money as possible is donated to the Leukemia and Lymphoma Society of Canada.

Any sponsors or potential contributors are asked to donate directly to the cause instead of providing other supports, which are appreciated, but ultimately unneeded.

I want every dollar that gets raised to actually go towards what were actually raising money for. I dont want to waste it on silly things.

Rimmer is urging those who want to participate to start collecting sponsors, and to register at http://www.lightthenight.ca. Participants should meet at the Rotary Spirit Centre after 6:30 p.m. Oct. 19 for the walk that will begin at 7 p.m., winding it way east on the Rotary Trail to the healthcare centre, then eventually on to the pool. All are welcome to join, from babies in strollers to their great-great parents, said Rimmer, who also noted the event will take place rain or shine.

Link:
Light the Night Oct. 19 - Westlock News

Bone Marrow Stem Cells Comments Off on Light the Night Oct. 19 – Westlock News | October 16th, 2019

DUBLIN--(BUSINESS WIRE)--The "Cell Harvesting Market" report has been added to ResearchAndMarkets.com's offering.

This report provides a summary of the cell harvesting market, including a market snapshot and profiles of key players in the market. It provides an exhaustive segmentation analysis of the market with in-depth information about each segment. The overview section of the report provides a description of market trends and market dynamics, including drivers, restraints and opportunities. it provides information about market developments and future trends that can be useful for organizations, including wholesalers and exporters. It provides market positionings of key players using yardsticks of revenue, product portfolio, and recent activities. It further includes strategies adopted by emerging market players with strategic recommendations for new market entrants. Readers will also find historical and current market sizes and a discussion of the market's future potential. The report will help market players and new entrants make informed decisions about the production and exports of goods and services.

The report includes:

Key Topics Covered:

Chapter 1 Introduction

Chapter 2 Summary and Highlights

Chapter 3 Market and Technology Background

Chapter 4 Market Breakdown by Type of Harvesting

Chapter 5 Market Breakdown by End User

Chapter 6 Market Breakdown by Application

Chapter 7 Market Breakdown by Component/Equipment

Chapter 8 Market Breakdown by Region

Chapter 9 New Developments and Patent Review

Chapter 10 Analysis of Market Opportunities

Chapter 11 Company Profiles

For more information about this report visit https://www.researchandmarkets.com/r/lahvpd

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Cell Harvesting Market 2019 with Detailed Profiles of Key Companies Including General Electric, Perkinelmer and Thermo Fisher - ResearchAndMarkets.com...

Bone Marrow Stem Cells Comments Off on Cell Harvesting Market 2019 with Detailed Profiles of Key Companies Including General Electric, Perkinelmer and Thermo Fisher – ResearchAndMarkets.com… | October 14th, 2019

Jennifer Adair, a senior scientist at Fred Hutch, speaks at the 2019 GeekWire Summit. (GeekWire Photo / Kevin Lisota)

Genetically editing cells using CRISPR could be the answer to curing genetic disorders such as sickle cell anemia. But in order for the technology to be available for people in countries like Nigeria where around a quarter of the population carries the sickle cell trait the technology will need to become substantially cheaper and less invasive.

Thats where gold nanoparticles come in.

Scientists at the Fred Hutchinson Cancer Research Center are devising an approach that vastly simplifies how CRISPR is applied. Their goal is to create a safe process for gene editing that takes place entirely within the body of a patient.

In order to edit human stem cells using CRISPR today, scientists have to follow a process that involves removing the cells from a patients bone marrow, electrocuting those cells, and modifying them with engineered virus particles.

The process gets even more invasive from there. We actually have to treat these patients with chemotherapy, radiation or other agents in order for these cells that were genetically manipulated to be taken up, Jennifer Adair, a senior scientist at Fred Hutch, said during a talk at the 2019 GeekWire Summit.

The researchers think theyve figured out the first step, which is delivering CRISPR to blood stem cells inside the body. Theyre doing that using gold nanoparticles that are about a billionth the size of a grain of table salt and able to smuggle in RNA, DNA and a protein.

Weve been able to show that not only can we make these, but they passively deliver all of those components to blood stem cells, then we do get genetic editing. And weve been able to go on to show that we can correct the sickle cell defect using this approach, said Adair.

The nanoparticles are big enough to carry the CRISPR payload but small enough to infiltrate cell membranes. Gold is a useful medium since it isnt harmful to humans.

The Fred Hutch team published their work with gold nanoparticles earlier this year in the journal Nature Materials. The system safely edited 10 to 20 percent of the target cells, which the researchers hope will increase as the method is refined.

In an ideal world, clinicians would be able to deliver gene therapy through a syringe, a process that might be accomplished in a single office visit. Adair previously published research on agene therapy in a box concept, a table-top device that could provide gene therapy treatments without the need for expensive medical infrastructure.

We need to develop technologies that make gene editing simpler, more affordable and more accessible to patients around the world, Adair said.

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Fred Hutch scientist on how gold nanoparticles could bring CRISPR to the developing world - GeekWire

Bone Marrow Stem Cells Comments Off on Fred Hutch scientist on how gold nanoparticles could bring CRISPR to the developing world – GeekWire | October 13th, 2019

Gaucher disease can predispose patients to rare types of blood cancer, and doctors should be vigilant for the development of these malignancies, a case report suggests.

The study, A case of bony lytic lesions in a patient with Gaucher disease, was published in the journal Clinical Case Reports.

The most common symptoms of Gaucher disease are reduced platelet count, enlarged liver and spleen, and lesions in the bones. This disease also has been associated with an increased risk ofblood disorders.

Researchers in Canada reported the case of a 57-year-old man who developed a rare type of blood cancer cell probably related to Gaucher disease, as he had Gaucher cells cells that accumulate abnormal amounts of a fat molecule (glucocerebroside) characteristic of the condition in his bone marrow.

The man had a scalp lesion that did not heal and progressively increased in size. Doctors performed a biopsy and discovered it was caused by a plasmacytoma, a rare form of blood cancer in which myeloma cells form a tumor in the bones or soft tissues.

At the time of biopsy, the patient had mild anemia, low levels of platelets, and a family of blood proteins called gamma globulins characteristic of myeloma. His kidney function and calcium levels were normal.

Further tests showed that the man had several bony lytic lesions spots of bone damage caused by cancerous myeloma cells and abone marrow biopsy showed infiltration of both plasma cells and Gaucher cells. That led to a diagnosis of plasma cell myeloma probably associated with Gaucher disease.

Gaucher cells infiltrating the bone marrow may mask the extent of abnormal plasma cell infiltrates, and immunohistochemical staining [a method that identifies abnormal cells in biopsies] can be invaluable in identifying the true burden of plasma cells for appropriate classification of suspected plasma cell neoplasia, the researchers said.

The investigators also noted that the man had a history of abnormal spleen size and reduced blood cell count. A bone marrow biopsy performed years earlier showed the presence of possible Gaucher cells.

Gaucher disease should be considered in the differential diagnosis of unexplained hepatomegaly [abnormal liver size], splenomegaly [abnormal spleen size], or cytopenias [reduced blood cell count], the investigators said. They added that further research of the previous symptoms might have allowed diagnosing Gaucher disease before the cancer appeared.

The patient received a combination of chemotherapy, cyclophosphamide, and Velcade (bortezomib), followed by high doses of melphalan and autologous stem cell transplantation. He tolerated the transplant well and was discharged with the recommendation of long-term follow-up.

Alejandra has a PhD in Genetics from So Paulo State University (UNESP) and is currently working as a scientific writer, editor, and translator. As a writer for BioNews, she is fulfilling her passion for making scientific data easily available and understandable to the general public. Aside from her work with BioNews, she also works as a language editor for non-English speaking authors and is an author of science books for kids.

Total Posts: 20

Ins Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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Gaucher Might Be LInked to Rare Types of Blood Cancer, Report Suggests - Gaucher Disease News

Bone Marrow Stem Cells Comments Off on Gaucher Might Be LInked to Rare Types of Blood Cancer, Report Suggests – Gaucher Disease News | October 13th, 2019

Blood, of course, plays a crucial role in keeping our bodies alive and functioning.

Red blood cells carry oxygen from our lungs to our muscles. White blood cells are the first responders of our immune systems, detecting infections and foreign agents and triggering the immune response needed to deal with the problem. Plasma, the liquid part of blood, transports not only the cells but also proteins, such as antibodies, and hormones, such as insulin, to every part of the body. It is a beautifully complex system that is the key to our bodies functioning correctly.

Parasites, viruses and bacteria all use the circulatory system to spread around the body. When cancer metastasises and spreads to other parts of the body, it is through tumour cells circulating within the bloodstream. There are also myriad blood cancers, such as leukaemias and lymphomas, and blood disorders, such as sickle cell anaemia, not to mention autoimmune diseases like diabetes or lupus. Sepsis, also known as blood poisoning, is a deadly overreaction to an infection which also has its roots in blood.

Magnetic blood filtration is a tool which enables the physical removal of specific substances from the bloodstream

Most of these diseases are treated with drugs or chemotherapies, some with great success, others, much less. There are also various methods of physically extracting different components from the blood by circulating a patients blood outside of the body through whats known as an extracorporeal circuit. Dialysis, for example, removes excess toxins from the blood, acting as a substitute for kidneys when they fail. Plasmapheresis and leukapheresis are methods of removing harmful antibodies from the plasma or white blood cells from the blood. Similar techniques are also used to harvest stem cells from the blood, which can then be used in cancer therapies (known as stem cell transplantation), if the donor and patient are a match.?

Magnetic blood filtration

Despite these methods, millions of people still die every year from blood-borne diseases. At MediSieve a small, London-based start-up company we are using nanotechnology to develop a new technology which we think can transform our ability to tackle these conditions. Magnetic blood filtration (MBF) is a tool which enables the physical removal of specific substances from the bloodstream. It is similar to other extracorporeal procedures like dialysis, but instead of removing every component of a particular size or weight, MBF removes highly specific targets to address the specific medical issue, thereby removing only the substance that doctors want to remove. Alongside this high specificity, various targets, both big and small, can be removed simultaneously, raising the prospect of removing for example specific cells and harmful antibodies in a single procedure.

To achieve this, we use magnetic nanoparticles coated with binding moieties, such as antibodies, which bind specifically to the desired targets in the blood. These particles are infused into the blood within the extracorporeal circuit, binding to their targets. The blood then flows through a magnetic filter which captures the magnetic particles and the targets bound to them, while the rest of the blood flows back into the patient. Several different particles can be used in the same procedure in order to capture different components. Using this method, anything for which there is a specific antibody or other binding moiety can theoretically be removed directly from the bloodstream. I think that in the long-term the technology could be used to remove specific cells, antibodies, bacteria, viruses, toxins, drug molecules and inflammatory cytokines, the drivers of immune conditions such as sepsis.

The MediSieve Filter is a disposable, single-use device in which the magnetic particles and their targets are captured. It is inserted into the MediSieve Magnet, a reusable medical device which activates the filter. Both can be incorporated into a variety of existing extracorporeal systems and integrate with standard blood pumps and tubing sets.

We are currently developing treatments for malaria, sepsis and leukaemia. The Filter and Magnet have completed pre-clinical testing and are now ready for clinical trials, which we hope to start shortly. Magnetic particles for various clinical targets are currently being developed and validated in the laboratory, with promising results. Animal trials for these are expected to start in 2020.

Malaria

Our potential treatment for malaria is the closest to market because malaria infected cells, uniquely, have naturally occurring magnetic properties is it therefore possible to remove them from the blood using the MediSieve Filter without the infusion of any magnetic particles. The magnetic properties arise from a core aspect of the malaria parasites lifecycle. After infecting a red blood cell, the parasite consumes the protein part of haemoglobin, leaving behind an iron-based waste-product known as haemozoin, which is stored inside the cell. Haemozoin is paramagnetic, thereby giving infected cells their unique magnetic properties.

MBF could be used in highly severe malaria cases in which the patient is hospitalised and at high risk of death. Currently, these patients receive intravenous drugs such as artesunate which can achieve parasite clearance in 36-48 hours; parasite clearance rate is the key indicator of patient recovery, and it can take up to eight doses of IV drugs to achieve complete clearance. Mortality in these cases can be as high as 20%.?

Using MBF alongside the first dose of IV drugs could drastically accelerate parasite clearance rate. We claim that, depending on the patient size and initial level of infection, this approach can remove over 90% of red blood cells containing haemozoin in just two hours. Because they have higher quantities of haemozoin, MBF is better at removing later stage infected cells, whereas drugs are much more effective against earlier stage cells, so they should be complimentary.

MBF has the additional benefit of removing free circulating haemozoin, also known as the malaria toxin, which should also improve the treatment for the patient since drugs can cause the large-scale release of haemozoin as infected cells die.

According to the WHO, in 2017 there were 219 million cases of malaria and 435,000 deaths, mostly children. While overall malaria cases and deaths have been trending downwards in recent years, the number of hospitalised patients is increasing as healthcare infrastructure improves in malaria endemic countries and more patients gain access to hospitals. In the future, MBF could be adapted for use in mobile clinics to reach harder to access areas.

While ourinitial target is severe malaria patients, I also believe MBF could be a valuable tool in the fight against drug-resistant malaria strains, which have been emerging in SE Asia and are causing great concern if drug resistance spreads to Africa, the effect could be catastrophic. It can also be used to treat patients for whom drugs cannot be used, such as pregnant women.

Sepsis

Sepsis is one of the leading causes of death in the developed world with more than 1.9M cases in Europe and the US and published mortality rates of 29% - 50%. Sepsis is a complex syndrome in which bacteria or other pathogens create a dysregulated immune response which can escalate to organ failure and death. The immune response creates an overproduction of pro-inflammatory cytokines, while cell damage over time creates damage-associated molecular patterns (DAMPs) that sustain the syndrome. ?

Our approach to sepsis, which we call SepSieve, uses a cocktail of different particles to remove a number of targets from a patients bloodstream: specific pro-inflammatory cytokines (IL-1, IL-6 and IL-18), DAMPs (HMGB-1), endotoxins (LPS), and gram-negative bacteria. This multi-modal approach tackles the disease from two key angles: Removing the pathogens and endotoxins that trigger the immune response and reducing magnitude of the immune response and preventing the cascade towards septic shock.

Like in malaria, SepSieve would be used alongside existing frontline treatments, specifically antibiotics. While antibiotics are critical for treatment of sepsis, the bacterial cell death they cause releases LPS which accelerates the dysregulated immune response MBF could remove the LPS to prevent the condition from worsening. The main benefit of MBF in sepsis is therefore not so-much the removal of bacteria itself (which is tackled by antibiotics and in any case is not present exclusively in the bloodstream), but rather the removal of all the other components driving the disease.

Gram-negative bacteria such as E. coli account for approximately 50% of sepsis patients, but thanks to the removal of other substances, particularly HMGB-1 and the inflammatory cytokines, I think the combined approach could benefit all sepsis patients. Since magnetic filtration is a purely physical method, it can also target and remove pathogens which are resistant to antibiotics, which again are a huge concern with increasing occurrences of resistant infections in hospitals.

Like in malaria, wwe plan to apply sepsis treatment to hospitalised patients and specifically those in Intensive Care Units. These are the most severe cases and those who stand to benefit the most from the treatment. The idea is to intervene early to prevent the sepsis cascade, in which the disease escalates eventually causing organ failure and death.

In fact, we managed to secure grants worth a total of 1.56M from Innovate UK, the UKs government grant funding body, and the UK National Institute of Health Research to develop and validate our sepsis particles. Currently being tested in human blood models in the companys laboratories, we plan to start animal trials in 2020 which, if successful, will be followed by clinical trials in 2021.

Leukaemia

One of the advantages of the particles we develop to remove pro-inflammatory cytokines for sepsis is that they can also be used in other diseases. This includes auto-immune diseases and cytokine storms such as cytokine release syndrome (CRS), a common side-effect of newer leukaemia treatments known as CAR T-cell therapies.?

In CAR-T therapies, T-cells, a type of white blood cell, are modified to attack cancer cells in a patients bone marrow. Taken either directly from the patient or from a matching donor, the modified cells are infused into the patient in order to directly attack the cancer. Results of clinical trials have been mixed, but these cell therapies are seen as a huge leap forward for leukaemia treatment.?

The problem is that the infused T-cells trigger massive immune reactions within the patient. Indeed, that is the intention the immune reaction is intended to kill the cancer cells but it can easily escalate into the condition called CRS. The result is similar to sepsis an immune over-reaction which attacks the patient and can be fatal. Immune mediators can be used to calm this reaction, but they then prevent the infused CAR-T cells from having their effect, eliminating the therapeutic benefit of the treatment.

Our proposal is to use MBF in CRS patients to remove cytokines from the bloodstream. This should calm the immune reaction, alleviating patient suffering and eliminating the risk of death. But since MBF only removes cytokines from the bloodstream, it shouldnt affect the immune effect of the CAR-T cells in the bone marrow, so the therapeutic benefit should be maintained. In addition, MBF can be stopped at will, so it can be used to control the immune response by maintaining the correct balance of cytokines this is of course not possible with immune mediators which are infused into the patient.

A further benefit that MBF can provide in leukaemia patients is the removal of leukaemia cells from the bloodstream leukaemia patients commonly have very high white blood cell counts due to circulating leukaemia cells. These cause a number of issues such as a reduction in immune function, making patients more vulnerable to infection. They can also prevent certain chemotherapies from working effectively, since they block the drug from targeting cancer cells in the bone marrow. High white blood cell counts also increase the risk of side-effects during treatment, since the sudden death of such a large numbers of cells causes debris to circulate in the blood, putting strain on the body and causing immune reactions like CRS; this is known as Tumour Lysis Syndrome. ?

We are currently focussing development on their sepsis particles, but plan to trial their cytokine particles in CRS at the same time as they are trialled in sepsis, since the pre-clinical validation for each disease is the same. The particles to remove white blood cells, however, are at an earlier stage and will be developed further down the line.

Our ambitions for MBF are certainly large. In the long-term we want to revolutionise the way in which blood-borne diseases are treated. Going far beyond malaria, sepsis and leukaemia, we want to develop treatments for all blood-borne diseases if its in the blood, and doctors want it out, we want to be able to take it out.

My vision is that hospitals all around the world will have Magnetic Blood Filtration Units which will address a huge variety of patients. Only time will tell if this can be achieved, or even if our technology will work at all after all, there have, as of yet, been no clinical trials.

However, the ability to remove specific substances from blood would clearly be of benefit to huge numbers of patients. It is something that we cannot do today, but we certainly should want to be able to do tomorrow. Whether it is MediSieve who gets us there or not remains to be seen.

Author:

Dr George Frodsham is CEO and founder of MediSieve

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It's in the blood - Lab News

Bone Marrow Stem Cells Comments Off on It’s in the blood – Lab News | October 13th, 2019

This article, written byKatharine Sedivy-Haley, University of British Columbia, originally appeared on The Conversation and is republished here with permission:

When I was applying to graduate school in 2012, it felt like stem cells were about to revolutionize medicine.

Stem cells have the ability to renew themselves, and mature into specialized cells like heart or brain cells. This allows them to multiply and repair damage.

If stem cell genes are edited to fix defects causing diseases like anemia or immune deficiency, healthy cells can theoretically be reintroduced into a patient, thereby eliminating or preventing a disease. If these stem cells are taken or made from the patient themselves, they are a perfect genetic match for that individual, which means their body will not reject the tissue transplant.

Because of this potential, I was excited that my PhD project at the University of British Columbia gave me the opportunity to work with stem cells.

However, stem cell hype has led some to pay thousands of dollars on advertised stem cell treatments that promise to cure ailments from arthritis to Parkinsons disease. These treatments often dont help and may harm patients.

Despite the potential for stem cells to improve medicine, there are many challenges as they move from lab to clinic. In general, stem cell treatment requires we have a good understanding of stem cell types and how they mature. We also need stem cell culturing methods that will reliably produce large quantities of pure cells. And we need to figure out the correct cell dose and deliver it to the right part of the body.

Embryonic, 'induced and pluripotent

Stem cells come in multiple types. Embryonic stem cells come from embryos which makes them controversial to obtain.

A newly discovered stem cell type is the induced pluripotent stem cell. These cells are created by collecting adult cells, such as skin cells, and reprogramming them by inserting control genes which activate or induce a state similar to embryonic stem cells. This embryo-like state of having the versatile potential to turn into any adult cell type, is called being pluripotent.

However, induced pluripotent and embryonic stem cells can form tumours. Induced pluripotent stem cells carry a particularly high risk of harmful mutation and cancer because of their genetic instability and changes introduced during reprogramming.

Genetic damage could be avoided by using younger tissues such as umbilical cord blood, avoiding tissues that might contain pre-existing mutations (like sun-damaged skin cells), and using better methods for reprogramming.

Stem cells used to test drugs

For now, safety concerns mean pluripotent cells have barely made it to the clinic, but they have been used to test drugs.

For drug research, it is valuable yet often difficult to get research samples with specific disease-causing mutations; for example, brain cells from people with amyotrophic lateral sclerosis (ALS).

Researchers can, however, take a skin cell sample from a patient, create an induced pluripotent stem-cell line with their mutation and then make neurons out of those stem cells. This provides a renewable source of cells affected by the disease.

This approach could also be used for personalized medicine, testing how a particular patient will respond to different drugs for conditions like heart disease.

Vision loss from fat stem cells

Stem cells can also be found in adults. While embryonic stem cells can turn into any cell in the body, aside from rare newly discovered exceptions, adult stem cells mostly turn into a subset of mature adult cells.

For example, hematopoietic stem cells in blood and bone marrow can turn into any blood cell and are widely used in treating certain cancers and blood disorders.

A major challenge with adult stem cells is getting the right kind of stem cell in useful quantities. This is particularly difficult with eye and nerve cells. Most research is done with accessible stem cell types, like stem cells from fat.

Fat stem cells are also used in stem cell clinics without proper oversight or safety testing. Three patients experienced severe vision loss after having these cells injected into their eyes. There is little evidence that fat stem cells can turn into retinal cells.

Clinical complications

Currently, stem cell based treatments are still mostly experimental, and while some results are encouraging, several clinical trials have failed.

In the brain, despite progress in developing treatment for genetic disorders and spinal cord injury, treatments for stroke have been unsuccessful. Results might depend on method of stem cell delivery, timing of treatment and age and health of the patient. Frustratingly, older and sicker tissues may be more resistant to treatment.

For eye conditions, a treatment using adult stem cells to treat corneal injuries has recently been approved. A treatment for macular degeneration using cells derived from induced pluripotent stem cells is in progress, though it had to be redesigned due to concerns about cancer-causing mutations.

A path of cautious optimism

While scientists have good reason to be interested in stem cells, miracle cures are not right around the corner. There are many questions about how to implement treatments to provide benefit safely.

In some cases, advertised stem cell treatments may not actually use stem cells. Recent research suggests mesenchymal stem cells, which are commonly isolated from fat, are really a mixture of cells. These cells have regenerative properties, but may or may not include actual stem cells. Calling something a stem cell treatment is great marketing, but without regulation patients dont know what theyre getting.

Members of the public (and grad students) are advised to moderate their excitement in favour of cautious optimism.

Katharine Sedivy-Haley, PhD Candidate in Microbiology and Immunology, University of British Columbia

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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BEYOND LOCAL: Expert recommends 'path of cautious optimism' about the future of stem cell treatment - CollingwoodToday

Bone Marrow Stem Cells Comments Off on BEYOND LOCAL: Expert recommends ‘path of cautious optimism’ about the future of stem cell treatment – CollingwoodToday | October 12th, 2019