VIVA! Communications

Australians living with an incurable blood cancer set to receive new reimbursed treatment option

Australians living with the incurable blood cancer, multiple myeloma1 are set to gain access to a new treatment option, with the listing of REVLIMID(lenalidomide) for maintenance treatment on the Pharmaceutical Benefits Scheme (PBS) from Wednesday April 1, 2020.2

REVLIMID(lenalidomide) represents Australias first and only maintenance treatment specifically indicated and reimbursed for those newly diagnosed with multiple myeloma (NDMM) who have undergone an autologous stem cell transplant (ASCT). 2, 3

This announcement coincides with an article just published in Medical Journal of Australias MJA Insight, calling for timely access to effective treatments for those living with multiple myeloma.4

According to article author, Professor Miles Prince, Clinical Haematologist and Director of Cancer Immunology and Molecular Oncology (Epworth Healthcare, Melbourne), continuing to broaden access to multiple myeloma treatments is critical to improving patient quality of life.4

Currently, people living with myeloma have a median survival rate of more than seven years which is significant in comparison to the median survival rate of just three years in the early 2000s.4

For survival rates to continue to improve however, patients must receive timely access to the most effective treatments, said Prof. Prince.

The PBS listing of maintenance for multiple myeloma will provide newly diagnosed patients with an additional treatment option for their disease.

Not to be confused with the skin cancer, melanoma, multiple myeloma is an incurable blood cancer that develops from plasma cells, a type of white blood cell found in the bone marrow.5, 6

Representing Australias third most common blood cancer (after lymphoma and leukaemia),7, 8 approximately 18,000 Australians are living with multiple myeloma at any given time,1 only half of whom will survive five years post- diagnosis.9

Myeloma Australia CEO, Steve Roach, today welcomed the availability of a new treatment option for the incurable disease.

The multiple myeloma patient journey involves a pattern of Response, Remission and Relapse, with individuals responding differently to certain treatments due to the complex nature of the devastating disease.

Additional treatment options are required throughout the patient journey, for both the newly diagnosed, and those who have already commenced therapy. Although incurable, we hope that multiple myeloma will one day be treated as a chronic, rather than a terminal disease, Mr Roach said.

The incurable nature of the disease and the likelihood of relapse, may have a psychological impact on patients, who can continue to live in fear even during periods of remission.10, 11

With studies revealing more than half (52%) of those living with multiple myeloma experience symptoms of anxiety or depression,12 improving access to treatment, and extending time spent in remission, may help to improve psychological wellbeing.

Wife and mother-to-two, Maria (53) was diagnosed with multiple myeloma in December 2018 and found her initial diagnosis very overwhelming.

When my husband Danny and I first heard the diagnosis, we were completely overwhelmed. We didnt know what Myeloma was and we didnt know what this meant short or long term. I didnt know if I was going to die in a month, a year or 10 years. How on earth was I going to tell everyone I had cancer, said Maria.

During my journey I blogged about my experience with multiple myeloma and posted to my Facebook daily to keep the calls and fears of my family and friends at bay. I have since accepted that myeloma is now a part of my life. I have no anger or fear and instead just live in the moment and take one day at a time.

Its very exciting to see new treatment options for multiple myeloma being funded by the government, and I hope to keep raising awareness, to ensure the myeloma community continues to receive access to the best treatment options available, Maria said.

About multiple myeloma

Multiple myeloma is a cancer that develops from abnormal plasma cells. A plasma cell is a type of white blood cell found in the bone marrow, that forms part of the immune system and helps to protect against infection.4, 7 The abnormal plasma cells crowd the bone marrow and make it difficult to produce enough normal blood cells.7

Multiple myeloma can be challenging to diagnose due to its wide range of symptoms, including high blood calcium levels, anaemia, fatigue, kidney failure, recurrent infections and bone pain.6

Current treatment for multiple myeloma includes a continuous approach, often comprising initial therapy, consolidation maintenance, and salvage therapy.13 Treatment options for multiple myeloma include chemotherapy, corticosteroids, autologous stem cell transplant (ASCT), immunomodulating drugs (IMiDs) monoclonal antibodies therapy, and proteasome inhibitors.14, 15

About REVLIMID (lenalidomide)

Representing an oral medication approved for the treatment of relapsed myeloma over 10 years ago,16 REVLIMID is an immunomodulating agent (IMiD) that slows the growth of multiple myeloma plasma tumour cells and proteins know to play a key role multiple myeloma, delays the development of new blood vessels, and enhances immune function.3

The most commonly reported side-effects of REVLIMID include diarrhoea, constipation, nausea, vomiting, stomach pain, indigestion, dehydration, dry mouth, mouth ulcer, sore mouth, increase or decrease in weight, increase or decrease in appetite, loss of taste, itchiness, rash, redness of the skin, dry skin, bruising, excessive sweating, dizziness, fainting, headache, shaking or tremors, unusual weakness, night sweats, reduced sense of touch, difficulty sleeping, depression, anxiety, feeling of confusion, back pain, muscle spasms, muscle and/or joint pain, swollen joints, bone pain, muscular weakness, pain in the extremities, feeling tired, falling, swelling of hands, ankles or feet.17

Other possible side effects of REVLIMID include heart palpitations or fast heartbeat, chest pains, dizziness or fainting, shortness of breath, weakness or reduced ability to exercise, bleeding (including nose-bleeds), bruising more than usual, numbness, tingling, blurred vision or difficulty seeing, passing large amounts of urine, excessive thirst, and having a dry mouth and skin, abnormal eye movements, convulsions, mood changes, irregular heart rhythms or tender swollen lymph nodes. 17

All patients receiving REVLIMID must be registered on, and abide by the requirements of, i-access risk management program to avoid exposure to unborn babies, due to the potential for birth defects. It is important to note that a small number of patients with multiple myeloma may develop additional types of cancer, regardless of their type of therapy. At this stage, it cannot be excluded that this risk may be slightly increased with REVLIMID maintenance treatment.17

Disclosure

Celgene supports disclosure and transparency on interactions between the healthcare industry and healthcare professionals to ensure public trust and confidence. No expert spokespeople have been offered compensation for their involvement in this media campaign. All expert spokespeople have been briefed on the approved use of these products and their obligations with regard to promotion to the general public. Prof Miles Prince and Myeloma Australia have received funding from Celgene for projects unrelated to this announcement. All opinions expressed are their own.

About Celgene

Celgene, a Bristol-Myers Squibb Company, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialisation of innovative therapies for the treatment of cancer and inflammatory diseases, through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation.

/Public Release.

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Australians living with an incurable blood cancer set to receive new reimbursed treatment option - Mirage News

Bone Marrow Stem Cells Comments Off on Australians living with an incurable blood cancer set to receive new reimbursed treatment option – Mirage News | April 1st, 2020

VANCOUVER, Washington, March 30, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that an additional three critically ill COVID-19 patients have been treated with leronlimab. These additional patients increase the total to 10 patients receiving leronlimab treatment under an Emergency Investigational New Drug (EIND) granted by the U.S. Food and Drug Administration (FDA).

The treatment with leronlimab is targeted as a therapy for patients who experience respiratory complications as a result of contracting SARS-CoV-2 causing the Coronavirus Disease 2019 (COVID-19). Leronlimab is believed to provide therapeutic benefit by enhancing the immune response while mitigating the cytokine storm that leads to morbidity and mortality in these patients. The laboratory evaluation of the first four patients treated with leronlimab revealed that the immune profile in these patients approached normal levels and the levels of cytokines involved in the cytokine storm (including IL-6 and TNF alpha) were much improved. The results of the three additional patients are expected this week.

Jacob Lalezari, M.D., Interim Chief Medical Officer of CytoDyn, commented, The preliminary results observed in patients who were severely ill with COVID-19 and treated with leronlimab are encouraging. Although the data set is still small, we saw fairly rapid and positive laboratory responses in all 4 patients treated, and in three of the 4 patients these laboratory results were associated with a favorable clinical outcome. We eagerly await the results of additional patients treated under the FDAs emergency IND program, as well as the results of several randomized clinical trials about to start.

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, added, We remain encouraged and hopeful that leronlimab will help patients from this devastating and relentless disease. We will aggressively pursue treatment for COVID-19 patients, and to explore leronlimabs role in helping to alleviate the impending burden of supply chain and institutional capacity issues.

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH. Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

About CytoDyn CytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in April of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as believes, hopes, intends, estimates, expects, projects, plans, anticipates and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Companys forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Companys cash position, (ii) the Companys ability to raise additional capital to fund its operations, (iii) the Companys ability to meet its debt obligations, if any, (iv) the Companys ability to enter into partnership or licensing arrangements with third parties, (v) the Companys ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Companys ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Companys clinical trials, (viii) the results of the Companys clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Companys products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Companys control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEO RedChip Companies Office: 1.800.RED.CHIP (733.2447) Cell: 407.491.4498 dave@redchip.com

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Three Additional Patients with Severe COVID-19 Treated with Leronlimab in New York Medical Center Bringing the Total to 10 Patients - Associated Press

Bone Marrow Stem Cells Comments Off on Three Additional Patients with Severe COVID-19 Treated with Leronlimab in New York Medical Center Bringing the Total to 10 Patients – Associated Press | March 31st, 2020

Dailymail.co.uk

Adam Castillejo (pictured), 40, was known only as the London Patient when doctors revealed his success story last March after a stem cell transplant to treat his cancer.

The second person to be cured of HIV has revealed how he was more fearful of dying from cancer than Aids and considered ending his life at Dignitas.Adam Castillejo, 40, was known only as the London Patient when doctors revealed his success story last March after a stem cell transplant to treat his cancer.He remained anonymous until he decided he wanted to be seen as an ambassador of hope after struggling with his health for almost two decades.Mr Castillejo, who was born in Venezuela and moved to London in 2002, was diagnosed with blood cancer in 2012, having already lived with HIV since 2003.His last hope of cancer survival was a bone marrow transplant from a donor with HIV-resistant genes that could wipe out his cancer and virus in one fell swoop.But in a powerful interview with The Sunday Times,Mr Castillejo admitted that he was more fearful of dying from stage 4 Hodgkins lymphoma than Aids.Calling the second diagnosis another death sentence, the sou-chef revealed that he panicked because cancer can kill you faster than HIV.Adam Castillejo, 40, was known only as the London Patient when doctors revealed his success story last March after a stem cell transplant to treat his cancerMr Castillejo embarked upon a gruelling treatment regime that left him physically emaciated and pushed the Venezuelan to the mental edge.Both illnesses became one because you had to deal with the anti-retroviral medications not interfering with thechemotherapy regime and vice versa, he said.By the end of 2014, he said that he had given up on battling the two illnesses, and had made up his mind to end it all at Dignitas in Switzerland.Around this time,Mr Castillejo disappeared, and was found four days later outside London psychologically broken. He does not remember this period.Doctors gave him six months to live, before a switch flicked.At that time I accepted straight away, because what choice have I got? I would rather die fighting, he explained.Within days, he met with Dr Ian Gabriel at the Chelsea and Westminster Hospital, who advised that he could attempt a bone marrow transplant.The procedure in May 2016 meantMr Castillejo was cleared of both cancer and HIV.But he lost five stone and took 60 pills a day, revealing: I told my doctors there werent enough hours in the day to take all the medication I needed.Mr Castillejo, who was born in Venezuela and moved to London in 2002, was diagnosed with blood cancer in 2012, having already lived with HIV since 2003An American man treated in Germany 12 years ago called Timothy Ray Brown (pictured) the so-called Berlin Patient also survived the transplantHe also developed mouth ulcers which inhibited his ability to eat, and his anti-retroviral medication had to be crushed and washed down.Mr Castillejo also claimed that he felt victimised and guilty when he told people that he was suffering from HIV, saying: This is a punishment for you.The Venezuelan chef is the second person to have survived the life-threatening technique and come out the other side HIV-free.An American man treated in Germany 12 years ago called Timothy Ray Brown the so-called Berlin Patient also survived the transplant.He was put into an induced coma for six months, however.Experts have hailed the treatment as a milestone in the fight against HIV, but are urging caution when calling it a cure so early on.In the context of HIV infection, the term cure means there are no virus-carrying cells left.Anti-retroviral therapy is very effective at reducing the viral load in the blood of infected individuals so that it cannot be transmitted to others.Unfortunately, the Berlin and London Patients cases do not change the reality much for 37 million HIV patients.The treatment is unlikely to have potential on a wider scale because both Mr Castillejo and Mr Ray Brown were given stem cells to treat cancer, not HIV.Stem cell and bone marrow transplants are life-threatening operations with huge risks. Patients can suffer a fatal reaction if substitute immune cells dont take.In his private life, Mr Castillejo likes to walk the streets of Shoreditch and travel.Kat Smithson, director of policy at National AIDS Trust, said: We applaud the London Patient Adam Castillejo for sharing his unique experience of having his HIV cured following a bone-marrow transplant to treat cancer. Mr Castillejo has been through a long and extremely challenging journey with his health, within which HIV is just one part.His decision to speak about his experience without anonymity can only enrich our understanding of his experience on a human level, and we thank him for this.Theres still a great deal of stigma around HIV which can make it harder for people to access the services and support they need and for people to talk openly about HIV.His story helps raise much-needed awareness of HIV, but broader than that its a story about incredible resilience, determination and hope.How a stem cell transplant cured the Berlin and London Patients and how it can go badly wrongUsually, HIV patients expect to stay on daily pills for life to suppress the virus. When drugs are stopped, the virus roars back, usually in two to three weeksThe vast majority of humans carry the gene CCR5.In many ways, it is incredibly unhelpful. It affects our odds of surviving and recovering from a stroke, according to recent research.And it is the main access point for HIV to overtake our immune systems.But some people carry a mutations that prevents CCR5 from expressing itself, effectively blocking or eliminating the gene.Those few people in the world are called elite controllers by HIV experts. They are naturally resistant to HIV.If the virus ever entered their body, they would naturally control the virus as if they were taking the virus-suppressing drugs that HIV patients require.Both the Berlin patient and the London patient received stem cells donated from people with that crucial mutation.WHY HAS IT NEVER WORKED BEFORE?There are many reasons this hasnt worked, Dr Janet Siliciano, at the Johns Hopkins University School of Medicine, told DailyMail.com.1. FINDING DONORSIts incredibly difficult to find HLA-matched bone marrow [i.e. someone with the same proteins in their blood as you], Dr Siliciano said.Its even more difficult to find the CCR5 mutation.2. INEFFECTIVE TRANSPLANT LEADS TO CANCER RELAPSESecond, there is a risk that the bone marrow wont take.Sometimes you dont become fully chimeric, meaning you still have a lot of your own cells.This means they will not defeat the cancer if it returns again.3. THE OLD IMMUNE SYSTEM ATTACKS THE NEW ONEThe other most common reason this approach has failed is graft-versus-host disease: whenthe patients immune system tries to attack the incoming, replacement immune system, causing a fatal reaction in most.4. UNKNOWN QUANTITIESInterestingly, both the Berlin patient and the London patient experienced complications that are normally lethal in most other cases.And experts believe that those complications helped their cases.Timothy Ray Brown, the Berlin patient, had both his cancer returned and he developed graft-versus-host disease, putting him in a coma and requiring a second bone marrow transplant.The London patient had one: he suffered graft-versus-host disease.Against the odds, they both survived, HIV-free.Some believe that, ironically, graft-versus-host disease might have helped both of them to further obliterate their HIV.But there is no way to control or replicate that safely.

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Adam Castillejo 'feared dying of cancer more than Aids and considered ending it all at Dignitas' Daily Mail - westofthepond.com

Bone Marrow Stem Cells Comments Off on Adam Castillejo ‘feared dying of cancer more than Aids and considered ending it all at Dignitas’ Daily Mail – westofthepond.com | March 31st, 2020

Researchers at UCL have developed a new way to make blood stem cells present in the umbilical cord 'more transplantable', a finding in mice which could improve the treatment of a wide range of blood diseases in children and adults.

Blood stem cells, also known as haematopoietic stem cells (HSCs), generate every type of cell in the blood (red cells, white cells and platelets), and are responsible for maintaining blood production throughout life.

When treating certain cancers and inherited blood disorders, it is sometimes necessary to replace the bone marrow by allogeneic stem cell transplantation - which involves using stem cells from a healthy donor.

The umbilical cord is a useful source of blood stem cells, and cord blood transplants lead to fewer long-term immune complications than bone marrow transplants. Although umbilical cord transplants have been used in young children for the last 30 years, most cord blood units* contain insufficient HSCs to be suitable for older children and adults and 30% of all units contain too few even for the youngest children, and go to waste.

The study, published in the journal Cell Stem Cell, highlights how a protein called NOV/CCN3, which is normally found at low levels in the blood, can be used to rapidly increase the number HSCs in single umbilical cord blood units that are capable of transplantation. This finding potentially opens the door to units that would otherwise be discarded being made available for patients of all ages.

"Trying to increase the actual number of hematopoietic stem cells in umbilical cord blood is both expensive and challenging. It is known that not all HSCs present in a cord blood unit can or will transplant, indicating that cord blood units have untapped transplantation potential," explained Dr Rajeev Gupta, Clinical Associate Professor at UCL Cancer Institute and first author of the study.

"We explored an alternative approach to harness this potential by increasing the functionality - rather than the number - of HSCs, and so enhance the ability of umbilical cord blood units to transplant.

"We'd previously discovered that a regulatory protein known as NOV is essential for the normal function of human HSCs, and so we asked whether highly purified NOV might be used to manipulate cord blood HSCs to make them more transplantable."

Using cell cultures and mouse models in the lab, the research team at UCL Cancer Institute found that umbilical cord blood units exposed to NOV showed significantly more transplantation potential than regular samples. In fact, the frequency of functional HSCs in the sample increased six-fold. Strikingly, these effects were achieved with only an eight-hour exposure.

"Using NOV, we've shown that we can rapidly manipulate blood stem cells to alter their state - changing non-functioning HSCs to functioning HSCs - which enhances cord blood engraftment potential. This finding offers a new strategy for improving blood transplants. The next stage will be to take our research into a clinical setting to explore how this can benefit patients with blood cancers and other blood disorders," said Dr Gupta.

Commenting on the study, Professor Alejandro Madrigal, Scientific Director of the Anthony Nolan Institute, and a world-leading scientist in the field of stem cell transplantation, said: "Cord blood transplantation has been shown to improve engraftment and provide a better outcome for many people. However, unfortunately, stem cells numbers in many cord blood units might be inadequate for optimal transplantation.

"This research is extremely encouraging, since with the simple addition of NOV/CCN3, there is an increase in the functionality of existing stem cells.

"This practical solution could enable many more cord blood units, which have a limited number of stem cells, to be made available for transplantation and could make a huge difference to the many patients."

Reference:Gupta, R., Turati, V., Brian, D., Thrussel, C., Wilbourn, B., May, G., & Enver, T. (2020). Nov/CCN3 Enhances Cord Blood Engraftment by Rapidly Recruiting Latent Human Stem Cell Activity. Cell Stem Cell. https://doi.org/10.1016/j.stem.2020.02.012

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

*A 'cord blood unit' is one sample of blood retrieved from one umbilical cord.

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More Effective Stem Cell Transplant Method Could Aid Blood Cancer Patients - Technology Networks

Bone Marrow Stem Cells Comments Off on More Effective Stem Cell Transplant Method Could Aid Blood Cancer Patients – Technology Networks | March 28th, 2020

Mar. 27 /CSRwire/ - As an international non-profit organization, every day DKMS provides 20 lifesaving blood stem cell transplants for blood cancer and blood disorder patients all around the world. Even in the current situation that we are facing with COVID-19, these patients still urgently need our help. It is for this reason that we keep fighting and continue to work together and collaborate with the international blood stem cell community to be able to overcome all barriers, to give as many patients as possible, who are in urgent need of a life-saving blood stem cell transplant, with a second chance at life.

IMPORTANCE OF REGISTRATION

Due to the advice and directions from the health authorities regarding the COVID-19 virus and to play our part to flatten the curve, we have postponed all of our planned donor drives/registration events in all of our six countries. We want to make sure that we look after and protect all of our donors and volunteers. For the thousands of patients around the world who are not able to find a perfect match, we still urgently need to add more donors to the database. We are thankful for every registration and you can still order your registration kit online atwww.dkms.org. Registering is simple and straightforward and you can become a potential lifesaver!

PROTECTING OUR DONORS

Patients around the world still urgently need blood stem cell transplants to survive. This is why we ask all of our donors to make themselves available if they are a match for a patient. The health and well-being of our donors is our number one priority and we consider every case on an individual basis. We will always do everything possible to ensure the safety of our donors.

We have implemented screening for the COVID-19 virus risks before entry to collection centers and before the start of a donation.

These measures serve to protect the donor as well as the recipient and the employees in the collection centers. Health experts have confirmed that there is currently no evidence that the COVID-19 virus can be transmitted via blood, bone marrow, or stem cell products.

We are grateful for every one of our incredible donors and for their commitment to providing patients with a second chance at life.

TRANSPORT OF BLOOD STEM CELL PRODUCTS

75% of all of our life-saving blood stem cell collections from DKMS donors travel across borders to patients in other countries. Due to the travel restrictions imposed by many countries because of the COVID-19 virus, we are faced with additional challenges in ensuring patients receive their transplant.

When it comes to transplants, time is crucial and we are determined to find solutions to be able to provide patients in need with their transplant. We are joining forces with other members of the international transplant community and national and international authorities in order to overcome these challenges. Despite the added difficulties that we are facing at the moment, as always, we are determined to overcome all barriers in order to provide as many patients as possible with a second chance at life.

FAQ's

1. WHY HAVE DONOR DRIVES BEEN CANCELLED OR POSTPONED AND WHAT IS THE ALTERNATIVE?

In light of the increasing spread of the COVID-19 virus, DKMS is postponing all planned events and registration drives for new potential blood stem cell donors until further notice. DKMS sees itself with a special duty of care and with these measures specifically follows the recommendations of the Centers for Disease Control to protect of the population.

Blood cancer patients around the world are still in urgent need of bone marrow and blood stem cell transplants and many are still not able to find a matching donor. This is why DKMS continues to encourage everyone that is able to, to register as a blood stem cell donor and if required, to also make themselves available for a donation."We must not abandon any patient who is currently searching for a blood stem cell donor or waiting for a life-saving blood stem cell transplant. In this difficult situation, I urgently ask that everyone continues to make themselves available as donors. We are taking all precautions necessary to protect each and every one of our donors in the best possible way," said Dr. Elke Neujahr, Global CEO DKMS.

We are grateful for every registration and to enable everyone that is interested to be able to register, DKMS offers the possibility of virtual donor drives that gives initiators, families and friends the opportunity to host a virtual drive to add more potential lifesavers to the donor pool via our online platform which can be found by clicking herehttps://dkmsgetinvolved.org/virtual-donor-drive. With this capability, any planned on ground registration drives can take place digitally instead and potential donors, which are urgently needed, can still register. The links to the online registration drives can be shared via all channels.

As always, registering as a blood stem cell donor via our homepage atwww.dkms.orgis also possible. Anyone who is interested can easily order a registration kit to be sent to their home. With the help of three cotton swabs and clear instructions, as well as a consent form, every potential new donor can take a cheek swab themselves and send it via post back to DKMS. In the DKMS Life Science Lab the individual HLA characteristics (also: tissue characteristics) of the donor are then analyzed, allowing the potential donor to be registered in the DKMS database.

The difference between the online registration drives and the general online registration is that the online registration drives are linked to particular patient appeals and the number of donors can be tracked accordingly. However, in general, it doesnt matter how you register, you will always be available as a potential lifesaver for blood cancer and blood disorder patients searching for a matching donor all over the world!

2. AM I STILL ABLE TO REGISTER ONLINE IF I SUSPECT THAT I MAY HAVE OR DO HAVE COVID- 19?

If it has been confirmed that you have been infected with the COVID-19 virus or you are awaiting test results, you unfortunately will not be able to register until 3 months after the infection has passed.

3. I REGISTERED ONLINE AND HAVENT RECEIVED A CONFIRMATION, IS THERE A DELAY?

We ask anyone registering as a potential donor online for their understanding. Normally we send all registration kits that we receive to our lab within 24 hours, however we are currently waiting 7 days until we do this to ensure the protection of our staff handling the returned registration kits. Please be assured that the analysis of your sample and HLA characteristics that is required for us to add you to the register, will take place as soon as possible.

4. HOW WILL DKMS MAINTAIN THE SAFETY OF DONORS?

The health and safety of our donors is our highest priority. We will consider the circumstances of all of our donors who are asked to donate their bone marrow and blood stem cells, on an individual basis, especially regarding their travel to a collection center. Please be reassured that we provide the best and safest solution possible for our donors.

Unfortunately, donors who live in high risk areas have to be blocked for search requests, as they are currently not eligible to proceed with a donation. We also have implemented screening for the COVID-19 virus risks before entry to any collection center and before the start of a donation. These measures serve to protect the donor as well as the recipient and the employees in the collection centers. Health experts have confirmed that there is currently no evidence that the novel Coronavirus can be transmitted via blood, bone marrow, or stem cell products.

Please also understand that any planned collection may be postponed or cancelled due to the current situation. We will keep you informed about all developments. Regarding the transport of blood stem cell products to the respective transplant clinics, we are in regular and close contact with all parties involved as well as with all relevant national and international authorities and organizations, to ensure that all blood stem cell collections can reach the patients.

5. IS THERE AN INCREASED CHANCE OF DONORS CONTRACTING THE COVID-19 VIRUS DURING THE DONATION PROCEDURE OR PREPARATION FOR THE PR

There is no risk of contracting the COVID-19 virus as a result of a blood stem cell collection. The health and safety of our donors is our number one priority and we will always ensure all procedures are in place to protect their safety.

6. CAN DONORS POSTPONE THEIR DONATION AT THIS TIME?

The final decision to donate is always made by the actual donor. If you have been asked to donate and have any concerns, please contact your DKMS coordinator. We evaluate each case on an individual basis to find the best solution for all parties involved.

7. IS IT STILL SAFE FOR PATIENTS TO RECEIVE A TRANSPLANT?

Health experts have confirmed that there is currently no evidence that the novel Coronavirus can be transmitted via blood, bone marrow, or stem cell products.

8. HOW IS THE TRANSPORT OF COLLECTIONS FROM DONORS IMPACTED BY THE CURRENT TRAVEL RESTRICTIONS?

The majority of blood stem cell collections from DKMS donors travel across borders to patients in other countries. Due to the travel restrictions imposed by many countries we are in regular and close contact with all parties involved in the transport, as well as with the relevant national and international authorities and organizations. Despite the added difficulties that we are facing at the moment, we are, as always, determined to overcome all barriers in order to provide as many patients as possible with a second chance at life.

9. HOW IS DKMS RESPONDING TO THE CURRENT TRAVEL RESTRICTIONS IN THE US?

Due to the restrictions on entry into the USA, DKMS has been in contact with the World Marrow Donor Association (WMDA) and the National Marrow Donor Program (NMDP). Together, we obtained special permits for stem cell couriers from Germany and Europe to enter the USA.

10. HOW WILL THE SPREAD OF THE COVID-19 VIRUS AFFECT DKMS AND ITS OPERATIONS?

As with every organization across the world, DKMS faces challenges caused by COVID-19 and some of the potential impacts are still not yet known. The goal of DKMS remains the same as it always has been and that is, together with our outstanding team of donors and employees, to give as many patients as possible around the world a second chance at life, through a life-saving bone marrow and blood stem cell transplant. The management team of DKMS is working around the clock together with all DKMS employees and relevant stakeholders to achieve this goal.

11. HOW WILL DKMS RESPOND AS THE SITUATION EVOLVES?

A dedicated team made up of experts from relevant departments at DKMS is constantly monitoring and evaluating the ongoing situation and will act accordingly. We will continue to keep our donors and all stakeholders updated.

12. IS DKMS TESTING POTENTIAL DONORS DURING THE REGISTRATION PROCESS?

DKMS does not test potential donors who register with us for the COVID-19 virus. If you are confirmed to have the virus, we ask that you do not register with us for the next 3 months. For donors who are asked to donate we have implemented screening for the COVID-19 virus risks before entering any collection center and before the start of a donation. These measures serve to protect the donor as well as the recipient and the employees in the collection center.

13. IF I AM A POTENTIAL DONOR AND I HAVE QUESTIONS, WHO SHOULD I CONTACT?

If you have been contacted by DKMS as a potential donor and if you have any questions or concerns, you are encourage to contact your DKMS coordinator. As always, DKMS staff is there to help you through the process and answer any questions that you may have.

14. IS THERE A NEED FOR QUARANTINE OR TESTING OF STEM CELL PRODUCTS BEFORE TRANSPLANTATION?

Although SARS-CoV and MERS-CoV have been detected in blood, there have not been any reports of transmission from donor to recipient either in transfusion of blood products or cellular therapies. As there is no evidence of transmission via blood, bone marrow, or stem cell products DKMS endorses the recommendations of the regulatory agencies such as the FDA and AABB which currently do not recommend or require product testing or to quarantine the stem cell product. For more information, please visit:share.wmda.info.

If a patient is in need of a transplant, there is no need to wait or prolong the process by testing or quarantining the stem cell product. Planned transplantations can go ahead.

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Now More Than Ever, the Importance of Second Chances at Life - CSRwire.com

Bone Marrow Stem Cells Comments Off on Now More Than Ever, the Importance of Second Chances at Life – CSRwire.com | March 28th, 2020

LONDON--(BUSINESS WIRE)--The global hematopoietic stem cells transplantation (HSCT) market is poised to grow by USD 4.64 billion during 2020-2024, progressing at a CAGR of about 6% during the forecast period. Request free sample pages

Read the 120-page report with TOC on "Hematopoietic Stem Cells Transplantation (HSCT) Market Analysis Report by Type (Autologous HSCT and Allogeneic HSCT), Geographic segmentation (Asia, Europe, North America, and ROW), and the Segment Forecasts, 2020-2024".

https://www.technavio.com/report/hematopoietic-stem-cells-transplantation-market-industry-analysis

The market is driven by the availability of technologically advanced equipment. In addition, the growing demand for personalized medicine is anticipated to boost the growth of the hematopoietic stem cells transplantation (HSCT) market.

The increasing efforts on improving the success rates of HSCT procedure is encouraging the adoption of advanced technologies and sophisticated instruments. For instance, Marrow Cellution, a patented technology, was developed by Ranfac. This technology is gaining traction in the market as it addresses the issues associated with conventional transplant syringe. It prevents contamination of peripheral blood during transplantation. In addition, this technology allows high-quality stem and progenitor cells to harvest within a narrow space. Thus, the availability of technologically advanced equipment is expected to drive market growth during the forecast period.

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Major Five Hematopoietic Stem Cells Transplantation (HSCT) Market Companies:

AllCells Corp.

AllCells Corp. provides mobilized leukopak, bone marrow and cord blood, whole blood, and leukopak. They also offer Cord Blood, which are collected from a single umbilical cord. They are cryopreserved and offered in the format of isolated cells. Cord Blood products include progenitor cells and CD34 HSCs.

bluebird bio Inc.

bluebird bio Inc. focuses on research, development, and commercialization of potentially transformative gene therapies. The company provides Zynteglo, which is a medicine used to treat patients of 12 years and older who are affected by a blood disorder known as beta thalassaemia.

FUJIFILM Holdings Corp.

FUJIFILM Holdings Corp. operates under various business segments, namely Imaging solutions, Healthcare and material solutions, and Document solutions. The company offers iCell Hematopoietic Progenitor Cells 2.0.

Lineage Cell Therapeutics Inc.

Lineage Cell Therapeutics Inc. focuses on research and development of therapeutic products for blood plasma volume expansion, orthopedics, oncology, diagnostic products for the early detection of cancer, neurological diseases and disorders, and more. The company provides OpRegen, which is in Phase I/IIa clinical trial.

Lonza Group Ltd.

Lonza Group Ltd. offers products through the following business segments: Pharma Biotech and Nutrition and Specialty ingredients. The company offers a wide range of stem cells such as bone marrow stromal cells, human peripheral blood CD14+ monocytes, cryopreseverd human CD34+ cells isolated from single donor, osteoclast precusor, and more.

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Hematopoietic Stem Cells Transplantation (HSCT) Market Type Outlook (Revenue, USD Billion, 2020-2024)

Hematopoietic Stem Cells Transplantation (HSCT) Market Geographic Outlook (Revenue, USD Billion, 2020-2024)

Technavios sample reports are free of charge and contain multiple sections of the report, such as the market size and forecast, drivers, challenges, trends, and more. Request a free sample report

Related Reports on Health Care Include:

Allogeneic Stem Cells Market Global Allogeneic Stem Cells Market by geography (Asia, Europe, North America, and ROW) and application (regenerative therapy and drug discovery and development).

Cancer Stem Cell Therapeutics Market Global Cancer Stem Cell Therapeutics Market by type (allogeneic stem cell transplant and autologous stem cell transplant) and geography (Asia, Europe, North America, and ROW).

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Global Hematopoietic Stem Cells Transplantation (HSCT) Market 2020-2024 | Evolving Opportunities with AllCells Corp. and bluebird bio Inc. | Technavio...

Bone Marrow Stem Cells Comments Off on Global Hematopoietic Stem Cells Transplantation (HSCT) Market 2020-2024 | Evolving Opportunities with AllCells Corp. and bluebird bio Inc. | Technavio… | March 28th, 2020

Global Hematopoietic Stem Cell Transplantation (HSCT) Market Viewpoint

Decorated with a team of 300+ analysts, Hematopoietic Stem Cell Transplantation (HSCT) Market Report serves each and every requirement of the clients while preparing market reports. With digital intelligence solutions, we offer actionable insights to our customers that help them in overcoming market challenges. Our dedicated team of professionals perform an extensive survey for gathering accurate information associated with the market.

Hematopoietic Stem Cell Transplantation (HSCT) Market Research, in its latest business report elaborates the current situation of the global Hematopoietic Stem Cell Transplantation (HSCT) market in terms of volume (x units), value (Mn/Bn USD), production, and consumption. The report scrutinizes the market into various segments, end uses, regions and players on the basis of demand pattern, and future prospect.

In this Hematopoietic Stem Cell Transplantation (HSCT) market study, the following years are considered to project the market footprint:

Request Sample Report @ https://www.marketresearchhub.com/enquiry.php?type=S&repid=2542619&source=atm

The following manufacturers are covered:Escape Therapeutics Inc.Cryo-Save AGRegen Biopharma Inc.CBR Systems Inc.ViaCord Inc.Lonza Group Ltd.Pluristem Therapeutics Inc.China Cord Blood Corp.

Segment by RegionsNorth AmericaEuropeChinaJapanSoutheast AsiaIndia

Segment by TypeAllogeneicAutologous

Segment by ApplicationPeripheral Blood Stem Cells Transplant (PBSCT)Bone Marrow Transplant (BMT)Cord Blood Transplant (CBT)

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The Hematopoietic Stem Cell Transplantation (HSCT) market research addresses the following queries:

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The market study depicts an extensive analysis of all the players running in the Hematopoietic Stem Cell Transplantation (HSCT) market report based on distribution channels, local network, innovative launches, industrial penetration, production methods, and revenue generation. Further, the market strategies, and mergers & acquisitions associated with the players are enclosed in the Hematopoietic Stem Cell Transplantation (HSCT) market report.

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Hematopoietic Stem Cell Transplantation (HSCT) Market Projected to Experience Major Revenue Boost During the Period Between 2019-2048 - Daily Science

Bone Marrow Stem Cells Comments Off on Hematopoietic Stem Cell Transplantation (HSCT) Market Projected to Experience Major Revenue Boost During the Period Between 2019-2048 – Daily Science | March 28th, 2020

The Global Stem Cells Market is expected to grow from USD 115.46 Million in 2018 to USD 325.84 Million by the end of 2025 at a Compound Annual Growth Rate (CAGR) of 15.97%.

The global Stem Cells market research report is a professional research report and in-depth study on the current state on the Stem Cells practices market industry.

The research report presents global drivers, restraints, opportunities trends and forecasts up to 2025. The report further indicates the positive aspects of the industry that influence market growth and trends.

Some of the prominent players operating in this market include: The report deeply explores the recent significant developments by the leading vendors and innovation profiles in the Global Stem Cells Market including are Anterogen Co., Ltd., Holostem Terapie Avanzate Srl, Medipost Co., Ltd., Osiris Therapeutics, Inc., Pharmicell Co., Ltd., Allosource, JCR Pharmaceuticals Co., Ltd., Nuvasive, Inc., and RTI Surgical, Inc.. On the basis of Cell Source, the Global Stem Cells Market is studied across Adipose Tissue-Derived Mesenchymal Stem Cells, Bone Marrow-Derived Mesenchymal Stem Cells, and Cord Blood/Embryonic Stem Cells.On the basis of Type, the Global Stem Cells Market is studied across Allogeneic Stem Cell Therapy and Autologous.On the basis of Therapeutic Application , the Global Stem Cells Market is studied across Cardiovascular Diseases, Gastrointestinal Diseases, Musculoskeletal Disorders, Surgeries, and Wounds and Injuries.

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Request a sample of this market study: https://www.regalintelligence.com/request-sample/23796

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The report overviews the industry including definitions and classifications. The Stem Cells Market report provides international markets including development trends, competitive landscape analysis and key development regions. Market strategies and development policies are briefly discussed. Furthermore, manufacturing process, cost, price and revenue are deeply analysed with a reflection to import/export consumption, supply and demand, and national & international gross-margins.

The objective of Studies:

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The Stem Cells industry is lucrative due to the presence of several small and large market players. Market strategies adopted by manufactures for increasing the sales in the market have been presented. The data and manufacturers are evaluated on the basis of basic information, manufacturing information, and competitors. The recent developments that took place in the global Stem Cells market and their impact on the future growth of the market have also been presented in the industry.

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Players Expected to Witness Maximum Growth | Stem Cells Market - Monroe Scoop

Bone Marrow Stem Cells Comments Off on Players Expected to Witness Maximum Growth | Stem Cells Market – Monroe Scoop | March 28th, 2020

In the past, an injury to the stifle joint of a horse may have certainly ended his or her career or usefulness. Now, with the ever-evolving science of veterinary medicine, afflictions to the joint have a much higher chance of being treated or even healed.

One of the reasons a stifle injury gives apprehension to horse owners is the complicated nature of the joint said Scott Cammack, D.V.M. He practices at Northern Hills Veterinary Clinic in Sturgis, South Dakota, with several other specialists.

Cammack explains that its treatment is much more involved than similar injuries. For example, an injury to the hock can often be resolved by fusing the bottom two joints (the hock consists of four total). Because it is a low-motion joint, the horse will still be sound and function after fusion.

The stifle, on the other hand, is a high-motion joint. Its got a lot of things going on in there. It doesnt have the capacity to be fused and still be sound. I would consider that they are more serious. They are more prone to long-term issues than a hock is, in my mind, he said.

According to Dr. Cammack, the stifle is anatomically similar to a human knee. All the parts are similar to your knee. Just as athletes injure their knees, they injure themselves. They have a patella, theyve got meniscuses, theyve got anterior and posterior cruciate ligaments, theyve got collateral ligaments. One major difference is that humans have one patellar ligament coming off the kneecap, while horses have three. Therefore, horses can have very unique issues.

One condition, often found in younger horses (aged 2-6) is the intermittent upward fixation of the patella or simply a catchy stifle. Dr. Cammack describes this condition: The locking mechanism of the stifle is inappropriately keeping the leg in the locked, extended position. They cant bend their leg and it only bends at the fetlock. That one is one that we treat in different ways. Sometimes, well do a procedure where we put a needle in the medial patellar ligament and we split it a little bit and cause it to thicken up and tighten up a little bit to help correct that. So thats a pretty simple procedure.

Another condition found in younger horses is OCD (osteochondrosis) lesions, a developmental issue. According to Dr. Cammack, they are cyst-like lesions on the bone. Some of them fill in and some require surgery. We saw one just the other day. A four year old had large cysts up in the bone. All they did was turn the horse out and waited. That one filled in on its own, but thats not common. Usually youre injecting the cyst or putting a screw across it or various treatments for something like that.

On the other hand, older horses may have very different afflictions in the joint. He said, In my mind, youre going to see more of the soft tissue injuries in your younger horses and more of the osteoarthritis in the older horses.

Older horses are going to be more prone to seeing arthritis in their stifle, which might be secondary to an injury it had had way back when. They injured a collateral ligament and it wasnt diagnosed, or they have some instability from ligament damage and then it healed some and they got by with it. Years down the road, youre seeing the arthritis, the osteoarthritis in there.

Stifle injuries are often seen in performance horses in various disciplines. When you start getting into any disciplines where theyre having to run hard, turn hard, stop hard, spin. We see it more in the reined cow horses and the reiners and the barrel horses, Dr. Cammack said. However, injuries can occur on the ranch or in other disciplines, as well. Certainly any horse can catch some bad ground or find a hole in the ground or something that can cause them injury.

Interestingly, younger horses may be more prone to injuries that occur in the arena. We are doing our futurities and so much heavy training on them when theyre young and they dont have the muscle memory and the skillset to have their leg in the right place at the right time with that amount of force on it.

Dr. Cammacks procedure for examining horses includes a flex test, where the joint is stressed momentarily to determine the location of any potential weaknesses in the joints. The end goal is to determine how to optimize the horses performance without masking any problems. If the horse deals with chronic issues, the typical injection of HA (hyaluronic acid), a type of steroid, may be administered, costing around $175.

For other injuries, different types of injections may do the trick. Theres certainly a lot more going on with regenerative medicine than there used to be, Dr. Cammack said. Using PRP (platelet-rich plasma) can help the joint heal itself. Youre taking the blood and processing it and pulling out platelet-rich plasma. Its going to have healing factors and certain proteins that can help the joint get better. This may cost around $250.

Theres another one called pro-stride, which is another form of PRP, but its a more concentrated form of PRP. Its more like $450. If youre getting into stem cells, that goes right up. We just pull the bone marrow or the fat, depending on which form were doing and we send it in. With that sample that we send in, we have to send $2,300 to the laboratory. That one can be in excess of $2,500 to do stem cells, Dr. Cammack said. Its an exciting area.

Cammack has devoted his professional career to the study of equines and particularly their joints and movement.

When I was in college, I started working at this clinic with Dr. Margie Jones. I developed a strong affinity for equine work and did a year internship with an equine surgeon in California, but he did a sports medicine practice and then I got in the deep pool of sports medicine and developed a deep love for it, he said.

More severe injuries to the stifle may involve surgeries, which range vastly in involvement and price.

This article serves as a brief overview of a very large field of veterinary study. Dr. Cammack devotes much of his practice and time to learning more about the equine, attending the yearly American Association of Equine Practitioners conferences, and expanding into regenerative medicine.

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Stifle injuries and treatments - Tri-State Livestock News

Bone Marrow Stem Cells Comments Off on Stifle injuries and treatments – Tri-State Livestock News | March 28th, 2020

GOLDEN, CO / ACCESSWIRE / March 26, 2020 / Vitro Diagnostics, Inc. (OTC:VODG), dba Vitro Biopharma, announced its 1st quarter ended January 31st, 2020 financial results of operations.

Vitro Diagnostics Inc. ("Vitro Biopharma") is pleased to announce a record 1st comparative quarter in Total Revenues. Vitro Biopharma recorded 1st quarter revenues of $225,921 vs $192,895 an increase of 17% over the same comparative quarter last year. In addition, Stem Cell treatments accounted for 74% of the revenues up from 71% of the revenues in the prior comparative quarter last year. Current quarter stem cell revenues were $167,750 for the 1st quarter ended January 31, 2020 vs $137,123 for the first quarter ended January 31, 2019.

The company's gross profit margins improved to 75% up from 73% in the comparative prior year's quarter. Gross margin improvement is in line with the strategic direction of the company to expand the market of its flagship product AlloRx Stem Cells. The company's clean-room lab expansion last year and expanded Stem Cell manufacturing using its patent-pending cell line, has increased efficiencies and lowered production costs.

Overall operating expenses increased in the quarter to $193,385 from $147,398 in the prior year's comparative quarter. The increase in expenses reflects additional investment as the Company expands its capability to service its strategic direction of offshore Stem Cell treatments while also expanding into US markets. The company expended additional resources on external consultants supporting our regulatory status in maintaining ISO9001 & ISO13485 certifications, expanding our efforts to approach US markets through FDA filings and advancement of existing patent filings.

The company's first quarter is its most seasonal quarter as the period between Thanksgiving and the New Year is slow for all the company's revenue lines of Nutra Vivo/STEMulize, AlloRx Stem Cells, private labeled InfiniVive-MD Stem Cell Serum and our core research products.

During the quarter the company achieved and pursed the following company objectives

During the quarter the company commenced a Series A Convertible Preferred Stock offering to accredited investors under the SEC Regulation D exemption. The preferred Stock is priced at $25 per share which is convertible at $0.25 cents per share for a total of 100 shares. The minimum investment is $50,000 per unit. The company sold $450,000 of the Series A Convertible Preferred Stock during the quarter. The company has additional interest in the offering and subsequent to the quarter has sold an additional $50,000 unit for a total to date of $500,000. The company has additional interested parties for approximately $200,000. The offering is for a total of $1,000,000.

Our partnership with DVC. Stem in the Cayman Islands continued to advance through treatment of new & previous patients. This IRB-approved protocol targets patients with inflammatory conditions including multiple sclerosis, systemic inflammation and new indications including Chrohn's disease, Alzheimer's disease and COPD. To date we have treated 60 patients including repeat treatments. There have been no serious adverse events and we continue to gain evidence of efficacy. One of the initial MS patients has now received a second transplant of our AlloRx Stem Cells and he has reported significant therapeutic benefits of both the initial and subsequent therapy. He had received an earlier transplant of adipose-derived MSCs that was effective, but the improvement lasted 3 months while AlloRx Stem Cell therapy lasted 18 months. We had predicted such a clinical outcome based on significantly higher potency of umbilical cord MSCS compared to those derived from adipose tissue or bone marrow. The Chrohn's disease patient showed significant improvement as did both the AD & COPD patients.

The strategic development of our stem cell therapies involves pursuit of both offshore and domestic markets. The partnership with DVC Stem, our IRB-approved trial in the Bahamas together with other strategic opportunities represent offshore operations & prospects. During Q1 2020, we initiated expansion into US therapeutic markets through development of an Investigational New Drug (IND) application for submission to FDA. Once approved, an IND allows the conduct of clinical trials for specific medical conditions in the US.

Given the current COVID-19 pandemic, our initial IND application is for use of AlloRx Stem Cells in treatment of Coronavirus infections. This is supported by clinical studies showing that 17 critically ill patients responded favorably to IV infusion of umbilical cord-derived MSCs. All patients were receiving assisted ventilation but 3 days following stem cell therapy, were removed from ventilators and subsequently discharged from the hospital. We are pursuing discussions with FDA to establish the appropriate regulatory pathway and expedited review options given the current emergency circumstances. (See Subsequent Events, below, for additional discussion of our COVID-19 response.) Once our initial IND is in place, we have plans for additional INDs for stem cell therapy of musculoskeletal conditions and Alzheimer's disease.

We have received an initial order of AlloRx Stem Cells for testing purposes by PR Medica located in Cabo San Lucas. Given successful test results, we anticipate subsequent new revenue generation from this customer.

Vitro Biopharma's cosmetic topical stem cell serum is being distributed by InfiniVive MD into cosmetic clinics that are providing the topical treatment as a beautification product. To date the company's product is being offered in 10 cosmetic clinics.

Our partner, Dr Jack Zamora, MD was a keynote speaker at a master session at the American Academy of Cosmetic Surgery annual meeting in late February. The topic of his presentation was "Topical Stem Cells, Exosomes and Conditioned Media Serums in Aesthetics." This was the official launch of the InfiniVive-MD platform including: Dailey Serum, Stem Cell Serum 2.0 & Exosomes within the product line. Vitro Biopharma will manufacture & private label these new products for distribution in the US. We anticipate InfiniVive MD growth, development and revenues to mirror the development of Apyx subdermal plasma skin tightening as a cosmetic treatment and technique that has gone global.

http://www.jackzamoramd.com http://www.infinivivemd.com

Our core research product sales continued to expand in Q1 2020. Our facility expansion continued with addition of manufacturing capacity and development of plans to add operational facility to increase outputs further by 100% or more. We were also in discussions with the USPTO regarding our pending patents for our novel stem cell therapy and stem cell activation technology. We continue to work closely with our examiner and have established communication channels to facilitate awards of these patents.

The COVD-19 pandemic is a significant obstacle for all business. However, Vitro Biopharma is uniquely positioned since we have a potential effective therapy. This is based on 3 independent reports showing efficacy of stem cell therapy in 17 COVID-19 patients. All were treated with IV umbilical cord MSCs comparable to AlloRx Stem Cells and all 17 required respiratory assistance but within 3-4 days of treatment, were able to breath without ventilators and were discharged within 14 days. https://www.scmp.com/news/china/society/article/3053080/coronavirus-critically-ill-chinese-patient-saved-stem-cell On the contrary, untreated patients on ventilators have death rates of 50% or more. We have received a formal request to supply AlloRx Stem Cells for compassionate use from a major university medical center and several other potential clinical partners have also expressed interest in using our cells to treat COVID-19 patients. We are presently working with the FDA to gain authority to begin clinical testing in the US. We are currently assessing the overall financial impact of the COVID-19 pandemic on our business, but this depends on overall control of the pandemic. There have been no staff layoffs and our workers are considered essential since we conduct essential research to the COVID-19 response.

Dr. Jim Musick, CEO of Vitro Biopharma, said, "We are very pleased with the increased revenue growth during our first quarter 2020 compared to the prior year However all our resources are currently focused on the emergency response to the COVID-19 pandemic and increasing our inventory of AlloRx to satisfy anticipated emergency demand to treat critically ill COVID-19 patients." The Company is working to get expedited clinical trial approvals to sell our AlloRx Stem Cells to hospitals coping with the pandemic. Vitro is pleased to have recently been recognized by Bioinformant as "a Company Tracking the Coronavirus". https://bioinformant.com/product/coronavirus-covid-19-report/ We anticipate clinical progress in the effectiveness of our stem cell therapies while expecting to see a reduction in our offshore and cosmetic revenues for the next quarter or two. The company is in a good cash position to weather this storm and simultaneously advance its AlloRx stem cell therapies into clinical trials.

In summary, Vitro Biopharma is advancing as a key player in regenerative medicine with 10- years' experience in the development and commercialization of stem cell products for research, recognized by a Best in Practice Technology Innovation Leadership award for Stem Cell Tools and Technology and a growing track record of successful translation to therapy. We are leveraging our proprietary technology platform to the establishment of international Stem Cell Centers of Excellence and regulatory approvals in the US and worldwide.

Sincerely yours,

James R. Musick, PhD.President, CEO & Chairman of the Boardwww.vitrobiopharma.com

Forward-Looking Statements

Statements herein regarding financial performance have not yet been reported to the SEC nor reviewed by the Company's auditors. Certain statements contained herein and subsequent statements made by and on behalf of the Company, whether oral or written may contain "forward-looking statements". Such forward looking statements are identified by words such as "intends," "anticipates," "believes," "expects" and "hopes" and include, without limitation, statements regarding the Company's plan of business operations, product research and development activities, potential contractual arrangements, receipt of working capital, anticipated revenues and related expenditures. Factors that could cause actual results to differ materially include, among others, acceptability of the Company's products in the market place, general economic conditions, receipt of additional working capital, the overall state of the biotechnology industry and other factors set forth in the Company's filings with the Securities and Exchange Commission. Most of these factors are outside the control of the Company. Investors are cautioned not to put undue reliance on forward-looking statements. Except as otherwise required by applicable securities statutes or regulations, the Company disclaims any intent or obligation to update publicly these forward-looking statements, whether as a result of new information, future events or otherwise.

CONTACT:

Dr. James MusickChief Executive OfficerVitro BioPharma(303) 999-2130 Ext. 3E-mail: jim@vitrobiopharma.comwww.vitrobiopharma.com

The company provides its financial information for investor purposes only, the results published are not audited or necessarily SEC or GAAP compliant

The company provides its financial information for investor purposes only, the results published are not audited or necessarily SEC or GAAP compliant

The company provides its financial information for investor purposes only, the results published are not audited or necessarily SEC or GAAP compliant.

The company provides its financial information for investor purposes only, the results published are not audited or necessarily SEC or GAAP compliant.

SOURCE: Vitro Diagnostics, Inc.

View source version on accesswire.com: https://www.accesswire.com/582759/Vitro-Biopharma-First-Quarter-ended-January-31-2020-Financial-Results-of-Operations

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Vitro Biopharma First Quarter ended January 31, 2020 Financial Results of Operations - Benzinga

Bone Marrow Stem Cells Comments Off on Vitro Biopharma First Quarter ended January 31, 2020 Financial Results of Operations – Benzinga | March 26th, 2020

The positioning of the Global Cell Isolation/Cell Separation Market vendors in FPNV Positioning Matrix are determined by Business Strategy (Business Growth, Industry Coverage, Financial Viability, and Channel Support) and Product Satisfaction (Value for Money, Ease of Use, Product Features, and Customer Support) and placed into four quadrants (F: Forefront, P: Pathfinders, N: Niche, and V: Vital).

New York, March 25, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Cell Isolation/Cell Separation Market - Premium Insight, Competitive News Feed Analysis, Company Usability Profiles, Market Sizing & Forecasts to 2025" - https://www.reportlinker.com/p05872137/?utm_source=GNW

The report deeply explores the recent significant developments by the leading vendors and innovation profiles in the Global Cell Isolation/Cell Separation Market including are Beckman Coulter Inc. (Subsidiary of Danaher Corporation), Becton, Dickinson and Company, Merck KGaA, Terumo Bct, Thermo Fisher Scientific, Inc., Bio-Rad Laboratories, Inc., GE Healthcare, Miltenyi Biotec, Pluriselect Life Science Ug (Haftungsbeschrnkt) & Co. Kg, and Stemcell Technologies, Inc..

On the basis of Product, the Global Cell Isolation/Cell Separation Market is studied across Consumables and Instruments.

On the basis of Cell Type, the Global Cell Isolation/Cell Separation Market is studied across Animal Cells and Human Cells.

On the basis of Cell Source, the Global Cell Isolation/Cell Separation Market is studied across Adipose Tissue, Bone Marrow, and Cord Blood/Embryonic Stem Cells.

On the basis of Technique, the Global Cell Isolation/Cell Separation Market is studied across Centrifugation-Based Cell Isolation, Filtration-Based Cell Isolation, and Surface Marker-Based Cell Isolation.

On the basis of Application, the Global Cell Isolation/Cell Separation Market is studied across Biomolecule Isolation, Cancer Research, In Vitro Diagnostics, Stem Cell Research, and Tissue Regeneration & Regenerative Medicine.

On the basis of End User, the Global Cell Isolation/Cell Separation Market is studied across Biotechnology & Biopharmaceutical Companies, Hospitals & Diagnostic Laboratories, and Research Laboratories & Institutes.

For the detailed coverage of the study, the market has been geographically divided into the Americas, Asia-Pacific, and Europe, Middle East & Africa. The report provides details of qualitative and quantitative insights about the major countries in the region and taps the major regional developments in detail.

In the report, we have covered two proprietary models, the FPNV Positioning Matrix and Competitive Strategic Window. The FPNV Positioning Matrix analyses the competitive market place for the players in terms of product satisfaction and business strategy they adopt to sustain in the market. The Competitive Strategic Window analyses the competitive landscape in terms of markets, applications, and geographies. The Competitive Strategic Window helps the vendor define an alignment or fit between their capabilities and opportunities for future growth prospects. During a forecast period, it defines the optimal or favorable fit for the vendors to adopt successive merger and acquisitions strategies, geography expansion, research & development, new product introduction strategies to execute further business expansion and growth.

Research Methodology:Our market forecasting is based on a market model derived from market connectivity, dynamics, and identified influential factors around which assumptions about the market are made. These assumptions are enlightened by fact-bases, put by primary and secondary research instruments, regressive analysis and an extensive connect with industry people. Market forecasting derived from in-depth understanding attained from future market spending patterns provides quantified insight to support your decision-making process. The interview is recorded, and the information gathered in put on the drawing board with the information collected through secondary research.

The report provides insights on the following pointers:1. Market Penetration: Provides comprehensive information on sulfuric acid offered by the key players in the Global Cell Isolation/Cell Separation Market 2. Product Development & Innovation: Provides intelligent insights on future technologies, R&D activities, and new product developments in the Global Cell Isolation/Cell Separation Market 3. Market Development: Provides in-depth information about lucrative emerging markets and analyzes the markets for the Global Cell Isolation/Cell Separation Market 4. Market Diversification: Provides detailed information about new products launches, untapped geographies, recent developments, and investments in the Global Cell Isolation/Cell Separation Market 5. Competitive Assessment & Intelligence: Provides an exhaustive assessment of market shares, strategies, products, and manufacturing capabilities of the leading players in the Global Cell Isolation/Cell Separation Market

The report answers questions such as:1. What is the market size of Cell Isolation/Cell Separation market in the Global?2. What are the factors that affect the growth in the Global Cell Isolation/Cell Separation Market over the forecast period?3. What is the competitive position in the Global Cell Isolation/Cell Separation Market?4. Which are the best product areas to be invested in over the forecast period in the Global Cell Isolation/Cell Separation Market?5. What are the opportunities in the Global Cell Isolation/Cell Separation Market?6. What are the modes of entering the Global Cell Isolation/Cell Separation Market?Read the full report: https://www.reportlinker.com/p05872137/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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The Global Cell Isolation/Cell Separation Market is expected to grow from USD 5,721.23 Million in 2018 to USD 15,089.25 Million by the end of 2025 at...

Bone Marrow Stem Cells Comments Off on The Global Cell Isolation/Cell Separation Market is expected to grow from USD 5,721.23 Million in 2018 to USD 15,089.25 Million by the end of 2025 at… | March 25th, 2020

Veterans in Pain (VIP) is a national program for veterans who have been hurt severely in combat. Their mission is facilitating regenerative medical solutions for veterans suffering from chronic pain by connecting civilian physicians with our countrys heroes, nationwide.

Dr. Joseph Kanan and his medical staff at Tullahoma Chiropractic Center recently joined the program and performed their first pro bono procedure for a veteran named Ryan in February.

Ryan had severe right hip pain when he came in. My medical team and I gave him a $6,500 procedure, injecting stem cells into his hip, Kanan said. There is no insurance company that covers this procedure so either he would have had to pay for it himself or the VIP organization would have had to do it. We decided to do it for free.

Veteran Ryan, 36, thanks Dr. Kanan after his procedure at Tullahoma Chiropractic Center.

Stem cells are part of the bodys natural repair process. Humans have them in their bone marrow and fat cells. When they are placed at the site of damaged tissue, these stem cells can activate to become the healthy new cells the body needs for pain relief.

No-surgery stem cell therapy helps the body heal damage and relieve pain from arthritis, aging and injuries to joints, tendons, ligaments and muscles.

I think veterans do a lot for our country and there are very few doctors that are performing medical procedures like this, Kanan said. We were very glad to be able to do this for him.

Ryan, 36, lives three hours away. He drove to Tullahoma himself for the procedure. Veterans in Pain provided the funds for his hotel stay while he was in town.

The procedure was done on Feb. 13. He did feel better right after, but this is a procedure where the results take time. You experience 10 percent of improvement every month for 10 months, Kanan said. I own the clinic and I am a chiropractor, so I did not actually perform this procedure. My medical team Jana Wood and Dr. Frank Perry performed the procedure, which was giving injections into Ryans hip.

Tullahoma Chiropractic Center performs these scheduled procedures twice a month. The medical team has seen positive results from the injections, according to Kanan.

I just talked to a patient this morning that had the procedure done one year ago. He had doctors recommending a knee replacement on his left knee. My medical team conducted the stem cell procedure on his knee, Kanan said.

The experience was great. I came in and got the injection and now my knee is fluid. About three months after the injection, I felt a lot better, the patient said. It was much better than having a knee replacement. I am very passionate about golf and my knee was preventing me from doing what I loved. After a year, it is magnitudes better than it was one year ago.

Tullahoma Chiropractic Center is located at 1490 N. Jackson St.

More here:
Veterans in Pain helps ease the pain for veterans - Tullahoma News and Guardian

Bone Marrow Stem Cells Comments Off on Veterans in Pain helps ease the pain for veterans – Tullahoma News and Guardian | March 24th, 2020

VANCOUVER, Washington, March 23, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that the third and fourth coronavirus patients were treated with the Companys investigational new drug, leronlimab. The treatment of the third patient occurred on Friday and the fourth coronavirus patient was treated on Saturday. These patients are under the care of the same leading medical center in the New York City area that treated the first and second patients.

The treatment with leronlimab is being administered under an emergency IND recently granted by the U.S. Food and Drug Administration (FDA). The treatment with leronlimab is intended to serve as a therapy for patients who experience respiratory complications as a result of contracting SARS-CoV-2 causing the Coronavirus Disease 2019 (COVID-19).

Bruce Patterson, M.D., CEO of IncellDx, a diagnostic partner and advisor to CytoDyn, said, IncellDx has developed specific companion diagnostic tests to determine the efficacy and dosing of leronlimab in these severe cases of COVID-19. We believe that leronlimab acts by enhancing the immune response while mitigating the cytokine storm that leads to morbidity and mortality in these patients.

Nader Pourhassan, Ph.D., president and chief executive officer of CytoDyn said, We are encouraged that the onsite medical team is reporting no safety issues and our team continues to be responsive and supportive in any way we can.

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain and it is unclear how easily the virus spreads. COVID-19 is thought to be transmitted person to person through respiratory droplets, commonly resulting from coughing, sneezing and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough and shortness of breath. It is believed that symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure, and that symptoms in patients have ranged from non-existent to severe and fatal. At this time, there are very limited treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients, and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases including NASH. Leronlimab has successfully completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab can significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 plays an important role in tumor invasion and metastasis. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019. Additional research is being conducted with leronlimab in the setting of cancer and NASH with plans to conduct additional clinical studies when appropriate.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation and may be important in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to further support the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD and that blocking this receptor from recognizing certain immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

About CytoDyn CytoDyn is a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a key role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and in immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in the first quarter of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients and plans to initiate a registration-directed study of leronlimab monotherapy indication, which if successful, could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, results from a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients, with some patients on leronlimab monotherapy remaining virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as believes, hopes, intends, estimates, expects, projects, plans, anticipates and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Companys forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Companys cash position, (ii) the Companys ability to raise additional capital to fund its operations, (iii) the Companys ability to meet its debt obligations, if any, (iv) the Companys ability to enter into partnership or licensing arrangements with third parties, (v) the Companys ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Companys ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Companys clinical trials, (viii) the results of the Companys clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Companys products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Companys control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEO RedChip Companies Office: 1.800.RED.CHIP (733.2447) Cell: 407.491.4498 dave@redchip.com

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Two Additional Coronavirus Patients Treated at Leading New York Hospital with CytoDyn's Leronlimab, Bringing the Total to Four Patients - Associated...

Bone Marrow Stem Cells Comments Off on Two Additional Coronavirus Patients Treated at Leading New York Hospital with CytoDyn’s Leronlimab, Bringing the Total to Four Patients – Associated… | March 24th, 2020

LEXINGTON, Mass., March 24, 2020 /PRNewswire/ --Partner Therapeutics, Inc. (PTx) announced that Leukine (sargramostim, rhu-GM-CSF)is being assessed in the SARPAC trial (sargramostim inpatients withacute hypoxic respiratory failure due toCOVID-19 EudraCT #2020-001254-22) at University Hospital Ghent to treat patients with respiratory illness associated with COVID-19. Major medical centers in Germany, Italy and Spain are considering joining the study. The study will evaluate the effect of Leukine on lung function and patient outcomes.

"Patients with COVID-19 who progress to acute hypoxic respiratory failure due to COVID-19 have very limited treatment options and a high mortality rate," said Prof. Bart Lambrecht, Principal Investigator for the trial at University Hospital Ghent and the Flanders Institute of Biotechnology (VIB). "We rapidly initiated this study with Leukine, because GM-CSF has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung, and can promote lung repair mechanisms."

Granulocyte macrophage colony stimulating factor (GM-CSF) is essential for the health of the lungs. Alveolar macrophages, a cell type found in the lungs, are dependent on GM-CSF for differentiation and normal functioning. GM-CSF is an immunomodulator that plays a critical role in host defense against pathogens and maintaining proper functioning of the immune system.1 GM-CSF confers resistance to influenza by enhancing innate immune mechanisms.2 In animal studies, GM-CSF reduced morbidity and mortality due to acute respiratory distress syndrome (ARDS) from viral pneumonia.3 In clinical studies, use of Leukine showed beneficial effects in patients with viral pneumonia.4,5 Recent data highlight the importance of understanding the immune status of patients and role of immunomodulating agents like GM-CSF to activate the immune system to help clear virus and reduce the risk of secondary infections.6

"Partner Therapeutics is committed to investigating Leukine in patients with COVID-19 and we are working with academic and government agencies here in the US and in Europe in this effort," said Dr. Debasish Roychowdhury, Chief Medical Officer at Partner Therapeutics. "We believe, like many investigators and scientists, that GM-CSF has multiple ways by which it may help these patients, including playing a role in clearing the infection, boosting the immune system and repairing damaged tissues."

"In pre-clinical studies, GM-CSF protects the lungs from viral pneumonia and the influenza A virus", stated E. Scott Halstead, MD, PhD, Associate Professor, Penn State University College of Medicine, Department of Pediatrics, Division of Pediatric Critical Care Medicine. "Preliminary data indicate an apparent benefit of inhaled Leukine therapy for autoimmune pulmonary alveolar proteinosis ("aPAP") and suggest it has reduced the need for whole lung lavage therapy for patients receiving treatment. Collectively, the data suggest that aerosolized Leukine may prove to be a meaningful therapy to decrease mortality and increase ventilator-free days in patients with respiratory disorders associated with viruses such as COVID-19 and Influenza A."

For the treatment of COVID-19 associated acute hypoxic respiratory failure and ARDS, Leukine will be used in nebulized form for direct inhalation or through intravenous administration for patients already on a respirator. Nebulized Leukine has been studied in phase 2 and phase 3 randomizedtrials in pulmonary conditions that affect alveolar macrophages, such as aPAP. IV administration of Leukine has been studied extensively in other conditions and in phase 2 randomized trials in ARDS.

Leukine was initially approved in the United States in 1991 and has been approved for use in five clinical indications. Its safety and tolerability profile are well understood. In 2018, Leukine was approved for use as a medical countermeasure to treat Acute Radiation Syndrome (ARS) and has been procured for use by the U.S. Strategic National Stockpile. Leukine is distributed outside the U.S. on a named-patient basis through PTx's designated program manager, Tanner Pharma Group. The use of Leukine to treat respiratory disorders associated with COVID-19 is investigational and has not been fully evaluated by any regulatory authority.

Please see full Prescribing Information for LEUKINE at http://www.leukine.com

About Leukine(sargramostim)Leukine is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF) and the only FDA approved GM-CSF. GM-CSF is an important leukocyte growth factor known to play a key role in hematopoiesis, epithelial repair, and augmentation of innate host defense by effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity.

Important Safety Information for LEUKINE (sargramostim)

Contraindications

Warnings and Precautions

Adverse Reactions

Adverse events occurring in >10% of patients receiving LEUKINE in controlled clinical trials and reported in a higher frequency than placebo are:

Please see full Prescribing Information for LEUKINE at http://www.leukine.com

Indications and Usage

LEUKINE (sargramostim) is a leukocyte growth factor indicated for the following uses:

About Partner Therapeutics, Inc.: PTx is an U.S.-based commercial-stage biotech company focused on the development and commercialization of therapeutics that improve health outcomes in the treatment of cancer. PTx's development focus spans the entire range of cancer therapy from primary treatments to supportive care. The company believes in delivering great products with the purpose of creating the best possible outcomes for patients and their families.

References

Cited References

Other RelevantReferences

SOURCE Partner Therapeutics, Inc.

http://www.partnertx.com

Original post:
Partner Therapeutics Announces Initiation of Clinical Trial to Evaluate Leukine in Patients with COVID-19 Associated Respiratory Illness - PRNewswire

Bone Marrow Stem Cells Comments Off on Partner Therapeutics Announces Initiation of Clinical Trial to Evaluate Leukine in Patients with COVID-19 Associated Respiratory Illness – PRNewswire | March 24th, 2020

Since 1998, advances incord bloodtechnology havemade cord blood transplantsa viable alternativeto traditional bone marrow transplantsin patients requiring astem cell transplant. While bone marrow transplants continue be a more commonprocedure, evidencesuggests this trendmay be changing. But is a cord blood transplant really a more effective procedure? The truth is, it depends on the circumstance.

Both bone marrow and cord bloodstem celltransplants are designed to replace unhealthy cells with healthy ones.

A bone marrow transplant involves the use of bone marrow that is transplanted from a donor into a recipient to cultivate new stem cells. Bonemarrow is a spongy tissue located inside the bones. Most commonly, bonemarrow is extracted fromthe breastbone, skull, hips, ribs or spine, as these contain stem cells that producewhite blood cells (leukocytes), which fight against infection; red blood cells (erythrocytes), which carry oxygen in order to eliminate waste from the organs and tissue; and platelets, which are responsible for making the blood clot. Bone barrow is removed from the donor under a general anesthetic. It isfiltered, treated, and either transplanted immediately into the recipient, or tested, frozen, and stored for later use.

Cord bloodis collected from a newbornsumbilical cord after delivery, so that it may be tested, frozen, and subsequently stored in acord blood bankfor future use.

There are many different criteria used to evaluate whether or not a cord blood transplant is right for you. When making your decision, it is important that both you and your doctor keep the following in mind:

In addition, cord blood transplants are generally better-suited for those younger than 30 years and, depending upon the quantity of available stem cells, may not be suited for patients over a certain weight. Bone marrow transplants, on the other hand, are not recommended for individuals with kidney, lung, liver, or heart conditions.

Sources

Cord Blood vs. Bone Marrow Transplants.Stem Cell Transplants: Bone Marrow vs Cord Blood. N.p., n.d. Web. 06 Feb. 2017.

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Bone Marrow vs. Cord Blood Stem Cell Transplant | Americord

Bone Marrow Stem Cells Comments Off on Bone Marrow vs. Cord Blood Stem Cell Transplant | Americord | March 23rd, 2020

DetailsCategory: DNA RNA and CellsPublished on Monday, 23 March 2020 16:33Hits: 250

GOSSELIES, Belgium I March 23, 2020 I BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the bone cell therapy company addressing high unmet medical needs in orthopaedics and bone diseases, today announces it has received regulatory approvals for its Clinical Trial Applications for the next studies of both of its lead candidates. These two studies are the pivotal JTA-004 PhaseIII clinical study targeting osteoarthritic knee pain and the PhaseIIb study of its allogeneic cell therapy product, ALLOB, in patients with difficult tibial fractures. The JTA-004 trial has been approved by regulatory authorities in Denmark, and the ALLOB by Belgian regulatory authorities.

Bone Therapeutics now has completed preparations for these trials. It is ready to initiate recruitment in both of these studies as soon as the current situation regarding COVID-19 allows, in those two countries. Bone Therapeutics has taken this decision to support healthcare systems in the respective trial countries, enabling them to concentrate on treating COVID-19 patients whilst necessary.

Bone Therapeutics is now ready to commence clinical trials on both its lead products. Receiving regulatory approvals for both Clinical Trial Applications completes the preparative activity for both studies, said Miguel Forte, CEO, Bone Therapeutics. This means that as soon as the current situation allows, we will be able to start recruiting patients for both clinical studies and continue to develop options for patients suffering knee osteoarthritic pain and difficult tibial fractures, both of which are conditions with a high unmet medical need.

The JTA-004 phase III study is a controlled, randomized, double-blind study. It will evaluate the potential of a single, intra-articular injection of JTA-004 to reduce osteoarthritic pain in the knee compared to placebo or Hylan G-F 20, the leading osteoarthritis treatment on the market. The study expects to enrol 676patients with mild to moderate symptomatic knee osteoarthritis in approximately 20centres in 7European countries and Hong Kong SAR.

The ALLOB Tibial Fracture PhaseIIb study is a randomized, double-blind, controlled study in which the fracture healing potential of ALLOB in patients with difficult fractures in the shinbone (tibia) will be evaluated and compared to standard of care alone after a follow-up period of 6 months. ALLOB will be applied by single percutaneous injection 24-72hours post reduction surgery in patients with fresh tibial fractures at risk for delayed or non-union. The study is expected to enrol approximately 178patients in approximately 40sites in up to 7European countries.

About JTA-004

JTA-004 is companys next generation of intra-articular injectable for the treatment of osteoarthritic pain in the knee. Consisting of a unique mix of plasma proteins, hyaluronic acid, a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain. In a phaseII study involving 164 patients, JTA-004 showed an improved pain relief at 3 and 6 months compared to Hylan G-F20, the global market leader in osteoarthritis treatment.

About Knee Osteoarthritis

Osteoarthritis (OA), also known as degenerative joint disease, is the most common chronic joint condition in which the protective cartilage in the joints progressively break down resulting in joint pain, swelling, stiffness and limited range of motion. The knee is one of the joints that are mostly affected by osteoarthritis, with an estimated 250M cases worldwide.

The prevalence of knee osteoarthritis (KOA) is expected to increase in the coming years due to increasingly aging and obese population. Currently, there is no cure for KOA and treatments focus on relieving and controlling pain and symptoms, preventing disease progression, minimizing disability, and improving quality of life. Most drugs prescribed to KOA patients are topical or oral analgesics and anti-inflammatory drugs. Ultimately, severe KOA lead to highly invasive surgical interventions such as total knee replacement.

About ALLOB and Bone Therapeutics proprietary, scalable cell therapy manufacturing process

ALLOB is the companys off-the-shelf allogeneic cell therapy platform consisting of human allogeneic bone-forming cells. These cells are derived from cultured bone marrow mesenchymal stem cells (MSC) from healthy adult donors. To address critical factors for the development and commercialization of cell therapy products, Bone Therapeutics has established a proprietary, optimized production process that improves the consistency, scalability, cost effectiveness and ease of use of the ALLOB platform. This optimized production process significantly increases the production yield, generating 100,000 of doses per bone marrow donation. Additionally, the final ALLOB product is cryopreserved, enabling easy shipment and the capability to be stored in a frozen form at the healthcare site. The process does therefore substantially improve product quality, reduce overall production costs, simplify supply chain logistics, increase patient accessibility and facilitate global commercialization compared to an autologous approach. Bone Therapeutics has implemented the optimized production process to produce clinical batches for the upcoming Phase IIb clinical trial in patients with tibial difficult-to-heal fractures.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and bone diseases. The Company has a broad, diversified portfolio of bone cell therapies and an innovative biological product in later-stage clinical development, which target markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf protein solution, JTA-004, which is entering PhaseIII development for the treatment of pain in knee osteoarthritis. Positive PhaseIIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement. The clinical trial application (CTA) for the pivotal PhaseIII program has been approved by the Danish relevant authorities allowing the start of the study.

Bone Therapeutics other core technology is based on its cutting-edge allogeneic cell therapy platform (ALLOB) which can be stored at the point of use in the hospital, and uses a unique, proprietary approach to bone regeneration, which turns undifferentiated stem cells from healthy donors into bone-forming cells. These cells can be administered via a minimally invasive procedure, avoiding the need for invasive surgery, and are produced via a proprietary, scalable cutting-edge manufacturing process. Following the CTA approval by the Belgian regulatory authority, the Company is ready to start the PhaseIIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process.

The ALLOB platform technology has multiple applications and will continue to be evaluated in other indications including spinal fusion, osteotomy and maxillofacial and dental applications.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

SOURCE: Bone Therapeutics

Excerpt from:
Regulatory authorities approve JTA Phase III study in osteoarthritic knee pain and ALLOB Phase IIb study in difficult fractures | DNA RNA and Cells |...

Bone Marrow Stem Cells Comments Off on Regulatory authorities approve JTA Phase III study in osteoarthritic knee pain and ALLOB Phase IIb study in difficult fractures | DNA RNA and Cells |… | March 23rd, 2020

VANCOUVER, Washington, March 23, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), ("CytoDyn" or the "Company"), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that the third and fourth coronavirus patients were treated with the Company's investigational new drug, leronlimab. The treatment of the third patient occurred on Friday and the fourth coronavirus patient was treated on Saturday. These patients are under the care of the same leading medical center in the New York City area that treated the first and second patients.

The treatment with leronlimab is being administered under an emergency IND recently granted by the U.S. Food and Drug Administration (FDA). The treatment with leronlimab is intended to serve as a therapy for patients who experience respiratory complications as a result of contracting SARS-CoV-2 causing the Coronavirus Disease 2019 (COVID-19).

Bruce Patterson, M.D., CEO of IncellDx, a diagnostic partner and advisor to CytoDyn, said, "IncellDx has developed specific companion diagnostic tests to determine the efficacy and dosing of leronlimab in these severe cases of COVID-19. We believe that leronlimab acts by enhancing the immune response while mitigating the cytokine storm'that leads to morbidity and mortality in these patients."

Nader Pourhassan, Ph.D., president and chief executive officer of CytoDyn said, "We are encouraged that the onsite medical team is reporting no safety issues and our team continues to be responsive and supportive in any way we can."

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain and it is unclear how easily the virus spreads. COVID-19 is thought to be transmitted person to person through respiratory droplets, commonly resulting from coughing, sneezing and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough and shortness of breath. It is believed that symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure, and that symptoms in patients have ranged from non-existent to severe and fatal. At this time, there are very limited treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a "Fast Track" designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients, and the second is for metastatic triple-negative breast cancer.Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases including NASH.Leronlimab has successfully completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab can significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 plays an important role in tumor invasion and metastasis.Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting aPhase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019. Additional research is being conducted with leronlimab in the setting of cancer and NASH with plans to conduct additionalclinical studies when appropriate.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation and may be important in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to further support the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD and that blocking this receptor from recognizing certain immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted "orphan drug" designation to leronlimab for the prevention of GvHD.

About CytoDynCytoDyn is a biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a key role in the ability of HIV to enter and infect healthy T-cells.The CCR5 receptor also appears to be implicated in tumor metastasis and in immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in the first quarter of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients and plans to initiate a registration-directed study of leronlimab monotherapy indication, which if successful, could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, results from a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients, with some patients on leronlimab monotherapy remaining virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is atwww.cytodyn.com.

Forward-Looking StatementsThis press releasecontains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i)the sufficiency of the Company's cash position, (ii)the Company's ability to raise additional capital to fund its operations, (iii) the Company's ability to meet its debt obligations, if any, (iv)the Company's ability to enter into partnership or licensing arrangements with third parties, (v)the Company's ability to identify patients to enroll in its clinical trials in a timely fashion, (vi)the Company's ability to achieve approval of a marketable product, (vii)the design, implementation and conduct of the Company's clinical trials, (viii)the results of the Company's clinical trials, including the possibility of unfavorable clinical trial results, (ix)the market for, and marketability of, any product that is approved, (x)the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company's products, (xi)regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii)general economic and business conditions, (xiii)changes in foreign, political, and social conditions, and (xiv)various other matters, many of which are beyond the Company's control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form10-K, and any risk factors or cautionary statements included in any subsequent Form10-Q or Form8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEORedChip CompaniesOffice: 1.800.RED.CHIP (733.2447)Cell: 407.491.4498dave@redchip.com

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Two Additional Coronavirus Patients Treated at Leading New York Hospital with CytoDyn's Leronlimab, Bringing the Total to Four Patients - Benzinga

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Study in mouse, human cells suggests unique anti-cancer properties of such a therapy

Pictured is a natural killer (NK) cell that researchers developed in the lab from human pluripotent stem cells. These NK cells mimic the properties of those found in the yolk sac during the earliest stages of development. Such NK cells may be more effective as immunotherapy for cancer treatment than adult NK cells that come from bone marrow, according to a new study from Washington University School of Medicine in St. Louis. White arrows point out granules that contain potent anti-cancer enzymes. Adult NK cells have very few of these granules.

Immunotherapy that involves treating cancer with the bodys own immune cells, or those of a matched donor, shows promise in clinical trials for some patients, but not all.

A new study from Washington University School of Medicine in St. Louis suggests that the age of certain immune cells used in such therapy plays a role in how effective the immunotherapy is. These cells natural killer (NK) cells appear to be more effective the earlier they are in development, opening the door to the possibility of an immunotherapy that would not utilize cells from the patient or a matched donor. Instead, they could be developed from existing supplies of what are called human pluripotent stem cells.

We are trying to improve the effectiveness of immunotherapy for more patients, said senior author Christopher M. Sturgeon, PhD, an assistant professor of medicine. This special source of natural killer cells has the potential to fill some of the gaps remaining with adult NK cell therapy. There is early evidence that they are more consistent in their effectiveness, and we would not need to process cells from a donor or the patient. They could be manufactured from existing cell supplies following the strict federal guidelines for good manufacturing practices. The characteristics of these cells let us envision a supply of them ready to pull off the shelf whenever a patient needs them.

Unlike the adult versions of NK cells used in most investigational therapies, earlier versions of such cells do not originate from bone marrow. Rather, these NK cells are a special type of short-lived immune cell that forms in the yolk sac of the early mammalian embryo. But for therapeutic purposes, such cells do not need to originate from embryos they can be developed from human pluripotent stem cells, which have the ability to give rise to many different cell types, including these specialized natural killer cells. Manufacturing such cells which many academic medical centers already have the ability to do would make them available quickly, eliminating the time needed to process the patients or donors cells, which can take weeks.

The study appears March 19 in the journal Developmental Cell.

Before a certain time point in early development, there is no such thing as bone marrow, but there is still blood being made in the embryo, Sturgeon said. Its a transient wave of blood that the yolk sac makes to keep the embryo going until bone marrow starts to form. And thats the blood cell generation thats making these unique natural killer cells. This early blood appears to be capable of things that adult blood simply cant do.

Studying mouse and human induced pluripotent stem cells that have been coaxed into forming these unique NK cells, the researchers showed that the NK cells are better at releasing specific anti-tumor chemicals a process called degranulation than their adult counterparts. Even NK cells derived from umbilical cord blood do not respond as robustly. NK cells of adult origin also release different chemicals that trigger harmful inflammation, but this response is not necessarily effective against cancer.

Past work by other groups suggested NK cells from earlier development might be more effective, but how and why this was the case remained unknown. The specific origin of these cells was also a mystery.

Now we know where these special natural killer cells come from and that we can never get them from an adult donor, only a pluripotent stem cell, Sturgeon said. Based on their unique behavior alone, there is one small clinical trial of these cells that is ongoing. Now that we know how to manufacture them and how they work, it opens the door for more trials and for improving upon their function.

According to Sturgeon, such cells could be produced from existing lines of pluripotent stem cells that would not need to come from a matched donor because, in general, NK cells do not heavily attack the bodys healthy tissues, as many T cell therapies can. T cells are another type of immune cell often used to treat blood cancer as part of a stem cell transplant, commonly called a bone marrow transplant. Even when NK cells do cause harm, they do not stay in the body for long periods of time.

From a basic science standpoint, Sturgeon also is interested in understanding why these cells are present in the early embryo in the first place and where they go in later development and after birth.

We can only speculate at this point, but its possible that during early embryonic development, when there is so much rapid cell division, these cells are there as a surveillance mechanism to protect against pediatric cancers or infection, he said.

This work was supported by the National Institutes of Health (NIH), grant numbers HL007088-41, R01DK09361, R01CA205239, P50CA171963, 5K12CA167540, and UL1TR002345; an American Society of Hematology Scholar Award; the University of Rochester; the American Cancer Society, grant number IRG-58-010-59-2; the Washington University Center of Regenerative Medicine; the technical expertise of Leah Vit; and the M. Napoleon Memorial Foundation. Electron microscopy was performed at the Washington University Center for Cellular Imaging (WUCCI). Transcriptome analyses were performed at the Genome Technology Access Center (GTAC).

Dege C, Fegan KH, Creamer JP, Berrien-Elliott MM, Luff SA, Kim D, Wagner JA, Kingsley PD, McGrath KE, Fehniger TA, Palis J, Sturgeon CM. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Developmental Cell. March 19, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Immunotherapy using 'young cells' offers promising option against cancer - Washington University School of Medicine in St. Louis

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Abstract

Biomaterials composed of extracellular matrix (ECM) provide both mechanical support and a reservoir of constructive signaling molecules that promote functional tissue repair. Recently, matrix-bound nanovesicles (MBVs) have been reported as an integral component of ECM bioscaffolds. Although liquid-phase extracellular vesicles (EVs) have been the subject of intense investigation, their similarity to MBV is limited to size and shape. Liquid chromatographymass spectrometry (LC-MS)based lipidomics and redox lipidomics were used to conduct a detailed comparison of liquid-phase EV and MBV phospholipids. Combined with comprehensive RNA sequencing and bioinformatic analysis of the intravesicular cargo, we show that MBVs are a distinct and unique subpopulation of EV and a distinguishing feature of ECM-based biomaterials. The results begin to identify the differential biologic activities mediated by EV that are secreted by tissue-resident cells and deposited within the ECM.

The development of extracellular matrix (ECM)based biomaterials as surgical meshes, topical powders, and injectable hydrogels is a relatively recent pursuit compared to similar efforts with synthetic biomaterials (1). The evolutionarily conserved composition of the ECM, and its critical role in development, cell, tissue, and organ homeostasis, and the response to tissue injury provide a compelling rationale for its use as an inductive biomaterial to promote the repair of damaged tissues and organs (2). However, gaps in our understanding of the dynamic biophysical properties and composition of ECM limit our ability to design and fabricate ECM-based biomaterials that fully capitalize upon their therapeutic potential. Although advanced proteomic techniques have begun to provide an accurate profile of ECM fibrillar and soluble protein components (2), the effects of constitutive (phospho)lipids and incorporated (extracellular) RNA on matrix biology and the host tissue response following injury are largely unknown.

Extracellular vesicles (EVs) are nanometer-sized vesicles encapsulated by a membrane, which transport cell signaling molecules including microRNA (miRNA), (phospho)lipids, and proteins (3). As a potent mediator of cell signaling, EVs have been the subject of intense investigation and thought to be secreted exclusively into a liquid phase where they can be relocated freely between cells and to distant sites using biologic fluids as a mobile medium. Recently, the presence of EV firmly embedded within the ECM, termed matrix-bound nanovesicles (MBVs), was described (4). In contrast to liquid-phase EV, MBVs are secreted by tissue-resident cells and integrated into the fibrillar matrix, a feature that may define their biological purpose and mechanism of action. The nature and biologic significance of the MBV cargo and lipid membrane has not been characterized. Given that MBVs are integrated within the matrix, it is plausible that the molecular speciation of their constituent phospholipids may facilitate this interaction.

The objective of the present study is to identify similarities and differences between liquid-phase (i.e., exosomes) and matrix-bound forms (i.e., MBV) of EV. However, given that EV present in biological fluids, MBV present in native tissue ECM, and ECM-based biomaterials represent heterologous populations secreted from multiple cell sources, a direct comparative in vivo analysis between these putative EV populations is problematic. As an alternative to using body fluid or tissue-derived vesicles, ECM and conditioned medium produced in vitro by cultured cells can be isolated (5). This approach offers several advantages such as the use of a single cell type source, thereby obviating any doubts regarding vesicle origin, the ability to selectively harvest vesicles from either liquid- or solid-phase compartments, and the ability to control the cell culture environment and thus also control vesicle composition and cargo.

Here, we use a fibroblast cell culture model that allows selective harvesting of liquid-phase EV and MBV integrated into the matrix. We conduct RNA sequencing and bioinformatic analysis to characterize the differential miRNA signature and use liquid chromatographymass spectrometry (LC-MS)based lipidomics and redox lipidomics protocols to perform detailed analysis of molecular speciation of liquid-phase EV and MBV phospholipids. Results from these comparative material analyses show that MBVs represent a subpopulation of nanovesicle distinct from EV found in a liquid phase and significantly expand our understanding of EV and matrix biology. Separately, the use of ECM-based therapies can now be examined by new perspectives, and MBV can assist in the design of next-generation ECM-based materials. For example, given their nanometer size, MBV can be used in minimally invasive applications that are otherwise untenable for decellularized ECM scaffolds from which MBVs are derived, such as intravitreal injections to prevent ischemia-induced retinal ganglion cell axon degeneration (6), or incorporated into existing ECM-based devices for sustainable release of vesicles (7, 8). Furthermore, results of the present study may aid in the future development of EV-based theranostic biomaterials such as artificial EV for clinical use (9).

We used scanning electron microscopy (SEM) to provide high-resolution, high-magnification imaging of MBV embedded within an ECM bioscaffold derived from porcine urinary bladder matrix (UBM). SEM images revealed discrete spheres approximately 100 nm in diameter dispersed throughout the collagen fibers (Fig. 1A). Given their compartmentalization within ECM scaffolds, we hypothesized that MBVs deposited into a solid ECM substrate are a unique class of EV separate from EV secreted into a liquid phase. To test this hypothesis, we used an in vitro 3T3 fibroblast cell culture model that allows selective harvesting of vesicles from a liquid-phase or solid-phase extracellular compartment (Fig. 1B). Representative images from phase-contrast microscopy, and hematoxylin and eosin (H&E) and 4,6-diamidino-2-phenylindolestained sections showed that no residual cells or intact nuclei were visible after decellularization of the cell culture plate (Fig. 1C). Transmission electron microscopy (TEM) imaging of liquid-phase EV harvested from the cell culture supernatant (Fig. 1D) and MBV isolated from decellularized ECM (Fig. 1E) showed that these two populations of vesicles shared a similar morphology. Moreover, nanoparticle tracking analysis (NTA) distribution plots showed similar vesicle size of both liquid-phase EV and MBV, with the majority of vesicles having a diameter of <200 nm (Fig. 1F). To determine whether MBV contained markers commonly attributed to exosomes, immunoblot analysis was performed for CD63, CD81, CD9, and Hsp70 (10). Results showed that, in contrast to liquid-phase EV, the MBV showed a marked decrease in CD63, CD81, and CD9 (Fig. 1G). Furthermore, silver staining of electrophoretically separated proteins showed that MBV contained a protein cargo that was distinctly different than the liquid-phase EV (Fig. 1H), suggesting that MBV may be a unique subpopulation of nanovesicle.

(A) SEM images of an ECM scaffold derived from urinary bladder matrix (UBM) showing discrete spherical bodies approximately 100 nm in diameter dispersed throughout the matrix. Scale bars, 1 m. (B) Illustration of the 3T3 fibroblast cell culture model used to selectively harvest vesicles from a liquid-phase or solid-phase extracellular compartment. (C) Phase-contrast microscopy, hematoxylin and eosin (H&E) staining, and 4,6-diamidino-2-phenylindole (DAPI) staining showing the absence of cells and intact cell nuclei after decellularization. (D and E) TEM of liquid-phase EV (D) and MBV (E) isolated from the 3T3 fibroblast cell culture model. Scale bars, 100 nm. (F) Size distribution plots from nanoparticle tracking analysis (NTA) of liquid-phase EV (top) and MBV (bottom) isolates from the 3T3 fibroblast cell culture. (G) Immunoblot analysis of CD9, CD63, CD81, and Hsp70 expression levels in liquid-phase EV and MBV. (H) Silverstain analysis of electrophoretically separated proteins in liquid-phase EV and MBV. M.W., molecular weight.

We used comprehensive next-generation RNA-sequencing (RNA-seq) to catalog differentially expressed miRNA in MBV and liquid-phase EV relative to the 3T3 fibroblast parent cell from which these vesicles were derived. Bioanalyzer analysis revealed the absence of 18S and 28S ribosomal RNA, and an enrichment of small RNA molecules [<200 nucleotides (nt)] in total RNA isolated from liquid-phase EV and MBV. However, the small RNA size distribution from liquid-phase EV was much broader than MBV with a marked enrichment of small RNA molecules between 100 and 200 nt in liquid-phase EV (Fig. 2A). We focused the analysis on differential miRNA signatures by conducting next-generation sequencing of miRNA libraries generated from the parental cellular RNA, the liquid-phase EV, and the MBV isolates (n = 3 per group). Principal components analysis (PCA) showed that within respective groups, the replicate miRNA profiles clustered close to one another (Fig. 2B). However, extensive differences in miRNA content were observed between the parental cell and the liquid-phase EV and MBV isolates. Overall, 28 (50.91%) miRNAs were found to be differentially expressed in MBV compared to liquid-phase EV by at least twofold (Fig. 2C). In addition, respective liquid-phase EV or MBV and the parental cellular miRNA profiles were clearly distinct (Fig. 2, B and C). To validate the results of miRNA sequencing, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to detect three up-regulated miRNAs (miR-163-5p, miR-27a-5p, and miR-92a-1-5p) and three down-regulated miRNAs (miR-451a, miR-93b-5p, miR-99b-5p) in MBV compared to liquid-phase EV isolated from 3T3 fibroblasts (Fig. 2D). As anticipated, the results showed that the level of miR-163-5p, miR-27a-5p, and miR-92a-1-5p was up-regulated, and miR-451a, miR-93b-5p, and miR-99b-5p was down-regulated in MBV compared to liquid-phase EV, thereby corroborating the results from the miRNA sequencing data. Ingenuity Pathway Analysis (IPA) of differentially enriched miRNAs in MBV compared to liquid-phase EV showed a strong association with organ and system development and function. In contrast, miRNAs differentially enriched in liquid-phase EV compared to MBV were associated with pathways involved in cellular growth, development, proliferation, and morphology (Fig. 2E).

(A) Bioanalyzer analysis of total RNA isolated from 3T3 parental cells and their secreted liquid-phase EV and MBV. (B) Principal components analysis (PCA) comparing liquid-phase EV (green), MBV (blue), and cellular (red) RNA-seq datasets. (C) Volcano plot showing the differential expression of miRNAs in liquid-phase EV, MBV, and the parental cells. The inclusion criteria were a twofold difference of log2 (fold change) in either direction with a P value of <0.05. Each dot represents a specific miRNA transcript; green dots to the right of the vertical dashed line correspond to a relative increase in expression level, and red dots to the left correspond to a relative decrease in expression level. Blue dots indicate miRNA with no significant change in expression level. (D) RT-qPCR validation of the results of miRNA sequencing. *P < 0.05, n = 4. (E) IPA functional analysis. Significantly enriched molecular functions identified by IPA functional analysis considering differentially expressed miRNA in MBV (red) and liquid-phase EV (blue).

Results with the 3T3 fibroblast cell model showed selective packaging of miRNA within MBV deposited in the ECM compared to liquid-phase EV secreted into the cell culture supernatant. We next sought to determine whether MBV miRNA cargo is unique to the cellular origin. We characterized and compared the miRNA composition of MBV isolated from ECM produced in vitro by bone marrowderived stem cells (BMSCs), adipose stem cells (ASCs), and umbilical cord stem cells (UCSCs) isolated from different human donors using next-generation sequencing methods. A representative phase-contrast microscopy image of a decellularized BMSC cell culture plate showed the absence of cells and the presence of branched fibrillar structures (Fig. 3A). TEM imaging of isolated MBV from a decellularized BMSC cell culture plate showed the characteristic morphology attributed to EV (Fig. 3B). Furthermore, NTA showed similar distribution plots between BMSC-, ASC-, and UCSC-derived MBV, with the majority of vesicles having a diameter of <200 nm (Fig. 3, C to E). After isolation of total RNA from these samples, bioanalyzer analysis showed the absence of ribosomal RNA and an enrichment of small RNA molecules (<200 nt) (Fig. 3F). miRNA libraries were generated from the samples (BMSC, n = 3 human donors; ASC, n = 3 human donors; UCSC, n = 3 human donors) and subjected to miRNA sequencing. A PCA showed that samples clustered primarily by the cell type from which they were derived (Fig. 3G). Of note, despite the use of three separate human donors for each cell type used to generate the MBV samples, the PCA showed a high degree of homogeneity in the miRNA profile within the respective groups (Fig. 3G). In addition, volcano plots showed that fewer miRNAs were found differentially expressed between BMSC- and UCSC-derived MBV than between BMSC-ASC and UCSC-ASC.

(A) Phase-contrast microscopy image of a decellularized BMSC cell culture plate showing the absence of cells. (B) TEM of MBV isolated from the decellularized BMSC culture plate. Scale bars, 100 nm. (C to E) Size distribution plots from NTA of MBV isolated from BMSC (C), ASC (D), and UCSC (D) decellularized culture plates. (F) Bioanalyzer analysis of total RNA isolated from BMSC-, ASC-, and UCSC-derived MBV. (G) PCA comparing BMSC MBV (green), UCSC MBV (blue), and ASC MBV (red) RNA-seq datasets. (H) Volcano plot showing the differential expression of miRNAs in BMSC-, ASC-, and UCSC-derived MBV. The inclusion criterion was a twofold difference of log2 (fold change) in either direction with a P value of <0.05. Each dot represents a specific miRNA transcript; green dots to the right of the vertical dashed line correspond to a relative increase in expression level, and red dots to the left correspond to a relative decrease in expression level. Blue dots indicate miRNA with no significant change in expression level.

Several studies have characterized the lipid composition of EV (11). However, there are no data on phospholipid composition of MBV. Therefore, we performed LC-MSbased global lipidomics and redox lipidomics analyses to comparatively evaluate the phospholipid composition of MBV and liquid-phase EV compared to their 3T3 fibroblast parent cells (Fig. 4, A and D). Nine major phospholipid classes were detected in all three types of samples, with the total number of detected molecular species of 536 distributed between the following major classes: bis-monoacylglycerophosphate (BMP), 59 species; phosphatidylglycerol (PG), 37 species; cardiolipin (CL), 117 species; phosphatidylinositol (PI), 33 species; phosphatidylethanolamine (PE), 102 species; phosphatidylserine (PS), 45 species; phosphatidic acid (PA), 26 species; phosphatidylcholine (PC), 107 species; and sphingomyelin (SM), 10 species (Fig. 4D). In terms of their content of polyunsaturated fatty acid (PUFA) residues, PE, PI, PC, and PS represented the major reservoir of these polyunsaturated phospholipid species containing four to seven double bonds (Fig. 4B). These PUFA phospholipids represent the likely precursors of the signaling lipid mediators. The formation of the mediators occurs via the catalytic oxygenation of PUFA phospholipids by 5-lipoxygenase or 15-lipoxygenase to yield oxygenated phospholipids that are subsequently hydrolyzed by one of specialized phospholipases A2 to release oxygenated fatty acids, i.e., lipid mediators (12, 13). In addition, oxidized PUFA phospholipids act as signaling molecules coordinating many intracellular processes and cell responses, including apoptosis, ferroptosis, and inflammation (14). We found significant differences in molecular speciation of these phospholipids and their relative contents between liquid-phase EV and MBV (Fig. 4E). With a notable exception of SM, arachidonic acid (AA) and docosahexaenoic acid (DHA) residues were detected in all phospholipids (Fig. 4E). For many of the phospholipids, the amounts were significantly higher in MBV versus liquid-phase EV and parent cells (Fig. 4E), which identify MBV as a rich reservoir of PUFA phospholipids. PUFA phospholipids can be hydrolyzed by phospholipase A2 (PLA2), resulting in the release of free PUFA and lysophospholipids (LPLs) (15). The former can be further used by two major oxygenases, cyclooxygenase (COX) and lipoxygenase (LOX), to produce lipid mediators with pro- or anti-inflammatory capacities (13, 16, 17). This finding qualifies MBV as potential precursors for synthesis of these lipid mediators dependently on the cell/tissue context (13). Quantitatively, MBVs were enriched in PI, PS, PG, and BMP (Fig. 4C and table S1). In contrast, the content of PE, PA, and SM was higher in liquid-phase EV. PC was a predominant phospholipid in cells and liquid-phase EV. The content of a unique mitochondrial phospholipid, CL, was significantly lower in liquid-phase EV compared to MBV and parent cells (Fig. 4F). Because CL is a unique mitochondria-specific phospholipid localized predominantly in the inner mitochondrial membrane (18), this finding represents a possible link of the MBV biogenesis with the mitochondrial compartment of cells. Plasmalogen phospholipids (or ether phospholipids) are structurally different from diacyl phospholipids (or ester phospholipids) (19). In plasmalogens, vinyl ether bond is linking the sn-1 saturated or monounsaturated chain to the glycerol backbone of phospholipids (19). It has been shown that ether lipids, PE, and PC plasmalogens can facilitate membrane fusion (20) and increase membrane thickness of EV (21, 22) and therefore may play a role in nanovesicle uptake by cells. Detailed MS/MS analysis showed a high level of ether PE and PC species (plasmalogens) in both liquid-phase EV and MBV. These species were identified as PE-16:0p/20:4, PE-16:1p/20:4, PE-18:1p/20:4, PE-18:1p/22:6 and PC-16:0p/20:4, PC-18:0p/20:4, PC-20:0p/20:4, PC-18:0p/22:6, respectively (Fig. 4E).

(A) Typical total ion chromatogram of phospholipids obtained from MBV. (B) Mass spectra of the major phospholipid classes in MBV. Quantitative assessment of saturated (double bond number = 0), monounsaturated (double bond number = 1), and polyunsaturated (double bond number = 2 to 10) species of phospholipids. (C) Pie plots showing the total content of major phospholipids. Data are presented as percentage of total phospholipids. (D to F) Contents of different phospholipid molecular species. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). EV, exosomal vesicles; MBV, matrix-bound vesicles; PC, phosphatidylcholine; PCd, PC diacyl species; PCp, PC plasmalogens; PE, phosphatidylethanolamine; PEd, PE diacyl species; PEp, PE plasmalogens; PI, phosphatidylinositol; PS, phosphatidylserine; BMP, bis-monoacylglycerophosphate; PA, phosphatidic acid; PG, phosphatidylglycerol; SM, sphingomyelin.

LPLs, hydrolytic metabolites of phospholipids created by phospholipases A, are bioactive signaling molecules that modulate a variety of physiological responses, including macrophage activation (23), inflammation and fibrosis (24), tissue repair and remodeling (25), and wound healing (26). LC-MS analysis showed that LPLs were present in all three types of samples, albeit with their total content in MBV and liquid-phase EV being 1.7 to 1.8 times greater compared to the parent cells. More specifically, seven classes of LPL have been identified: lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), lysophosphoinositol (LPI), lysophosphatidic acid (LPA), lysophosphatidylglycerol (LPG), and monolysocardiolipin (mCL) (Fig. 5A). MBVs were enriched in LPE, LPA, and LPG compared to parent cells (Fig. 5B). The content of LPI and mCL was significantly lower in MBV and liquid-phase EV versus cells. We found that the contents of LPA and LPG were significantly higher in MBV compared to EV. The levels of mCL and LPI in MBV were 3 and 6.3 times higher than in EV but 3.3 and 1.9 times lower compared to cells (Fig. 5, C and D). No significant changes in the contents of LPE, LPC, and LPS between MBV and EV were found. The non-oxidizable molecular species containing 16:0, 16:1, 18:0, and 18:1 were the major types found in all LPL species detected (Fig. 5C). As LPL may act as fusogenic lipids facilitating the transfer of the vesicular contents into cellular targets, this important role of LPL found in MBV should be further explored.

(A) Typical mass spectra of major LPL obtained from MBV. (B) Pie plots showing the total content of major LPL. Data are presented as percentage of total LPL. (C and D) Contents of LPL molecular species. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). N = 3. LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; LPA, lysophosphatidic acid; LPG, lysophosphatidylglycerol; mCL, monolysocardiolipin.

Given that exposure of murine bone marrowderived macrophages to MBV results in expression of M2-like markers, Fizz1 and Arg1, which are associated with a constructive macrophage phenotype (4), we performed LC-MS analysis of PUFA and their oxygenated products in MBV versus liquid-phase EV and parent cells. MBVs were strongly enriched in AA (20:4), DHA (22:6), and docosapentaenoic fatty acids (DPA; 22:5) (Fig. 6A). In other words, MBVs represent a reservoir of substrates for the biosynthesis of signaling lipid mediators by the respective enzymatic mechanisms, COXs and LOXs. In liquid-phase EV, the major PUFAs were linoleic (18:2) and linolenic (18:3) acids (Fig. 6A).

(A and B) Content of free PUFA (A) and their oxygenated metabolites (B) in parent cell, liquid-phase EV, and MBV. Data are means SD. *P < 0.05 versus cells or MBV. N = 3. (C) Contents of singly, doubly, and triply oxygenated phospholipid species in parent cells, liquid-phase EV, and MBV. Data are presented as heat maps, autoscaled to z scores, and coded blue (low values) to red (high values). PL, phospholipids; CL, cardiolipin.

As EVs contain enzymatic machinery for biosynthesis of AA-derived lipid mediators (27), redox lipidomics analysis of oxygenated fatty acids was performed. Higher levels of AA metabolites such as 12-HETE (12-hydroxy-eicosatetraenoic acid), 15-HETE (15-hydroxy-eicosatetraenoic acid), and lipoxin A4 (LXA4) were found in liquid-phase EV versus MBV (Fig. 6B). In the context of tissue repair, LXA4 and D-series resolvin D1 (RvD1), produced by 12/15-LOX from AA (20:4) and DHA (22:6), stimulate macrophage activation to the M2-like phenotype (28). Last, we characterized oxidized phospholipids containing oxygenated AA and DHA in MBV and liquid-phase EV. The levels of oxygenated species were higher in MBV than in liquid-phase EV, where PS, PI, and PC were represented by mono-oxygenated species. BMP, PG, and CL contained singly and doubly oxygenated AA and DHA residues; triply oxygenated PUFAs were found only in PE (Fig. 6C). Overall, lipidomics and oxidative lipidomics results show that the levels of free AA, DHA, and DPA and PUFA-containing phospholipids as well as their oxidatively modified molecular species are higher in MBV than those in liquid-phase EV.

To date, research regarding EV has been largely focused on their presence in biological fluids and their potential as biomarkers of disease, with lesser emphasis upon their therapeutic potential. These liquid-phase EVs are broadly categorized based on their biogenesis, morphology, density, or cargo (29). Although it has been shown that liquid-phase EVs contain surface proteins that can mediate binding with cells and ECM molecules (30), the integration of MBV within the fibrillar network of the ECM and trafficking of MBV across all cell membranes is largely unexplored. Traditional in vitro cell culture models neglect to differentiate the liquid-phase EV secreted into the cell culture supernatant from the MBV embedded within the ECM. Here, we fractionated vesicle populations based on their compartmentalization into either the liquid-phase cell culture medium or the solid-phase ECM substrate. In terms of composition, we found that MBV isolated from the ECM of 3T3 fibroblasts contained a differential miRNA and lipid signature compared with liquid-phase EV and with the parent cell. These data are suggestive of a scenario in which molecular sorting occurs during vesicle biogenesis to specifically distribute miRNA and lipids to vesicles destined for different extracellular locations. Moreover, the cells capacity to differentiate between a liquid interface and a solid substrate and to selectively deposit tailored subpopulations of vesicles with distinct lipid signatures into these disparate compartments provides evidence for a different and independent membrane biogenesis of MBV from the biogenesis of EV secreted into a liquid phase. Considering that MBVs were shown to be integrated within the dense fibrillar network of the ECM, it is plausible that MBVs are secreted by cells in concert with ECM components during matrix deposition, tissue development and homeostasis, and dynamic matrix remodeling following injury. Furthermore, given that the ECM is a complex mixture of proteins, proteoglycans, and glycosaminoglycans arranged in a tissue-specific three-dimensional architecture (2), it is logical that MBV cargo and lipid content are also unique to the tissue and cellular origin. We have previously shown that MBVs isolated from ECM bioscaffolds derived from anatomically distinct source tissue have differential miRNA signatures (4). Results from the present study further support this hypothesis in that MBV isolated from ECM produced in vitro by BMSC, ASC, and UCSC derived from different human donors contained a distinctive miRNA signature specific to the cell source. In addition, fewer miRNAs were found differentially expressed between BMSC- and UCSC-derived MBV than between BMSC-ASC and UCSC-ASC, a finding that may be attributed to tissue-specific differentiation potentials of ASC (31). These findings further underline the cell-specific features of MBV miRNA profiles, which were not significantly affected by the intrinsic variability of donors. However, given that the three human donors were all male, further studies to determine sex-related variations in the miRNA cargo of MBV from the stem cell samples are warranted. Gender-specific differential expression of exosomal miRNA has been observed in human subjects (32). Gender variation is just one aspect for further investigation since other variables including age (33) and disease state (34) have been shown to affect EV miRNA cargo. PCA showed a high degree of batch-to-batch consistency of the miRNA cargo from MBV deposited by specific cell types isolated from different human donors, a finding that has important implications for MBV and ECM biomaterial manufacturing for use as research tools or clinical therapeutics. For example, a major challenge in the production of EV or ECM biomaterials for preclinical or clinical use is the standardization of product characterization to meet regulatory requirements for batch consistency and for reproducibility of the manufacturing process (35, 36). Stated differently, the observed batch-to-batch consistency in miRNA cargo from MBV deposited by specific cell types may lend itself to the development of markers to verify identity and purity of MBV intended for clinical testing. Although the present study establishes that MBV integrated into the matrix are a unique subpopulation of EV, we cannot rule out the possibility of heterogeneity within the MBV subset. A similar heterogeneity has recently been described for EV secreted into cell culture medium by mesenchymal stem cells, which were shown to secrete at least three types of liquid-phase EV that could be differentially isolated based on their affinities for membrane lipidbinding ligands (37). In addition, although MBV showed a marked decrease in proteins commonly attributed to exosomes (e.g., CD63, CD81, and CD9), future proteomics studies will be required to identify the differential expression of surface and luminal proteins associated with liquid-phase EV compared to MBV.

As the composition and compartmentalization are different for liquid-phase EV and MBV integrated into the matrix, these subpopulations of vesicles are likely to have different biological functions. IPA network analysis of differentially enriched miRNAs in MBV compared to liquid-phase EV isolated from the 3T3 fibroblast model showed that miRNAs in MBV are associated with significant network-associated functions in organ and system development compared to miRNA enriched from liquid-phase EV. MBVs have previously been shown to recapitulate functional and phenotypical properties attributed to the ECM bioscaffolds from which they are derived, including stem cell differentiation and activation of an anti-inflammatory and pro-resolving macrophage phenotype, both of which are hallmarks of constructive tissue remodeling (2).

In contrast to EV that are secreted into body fluids and readily available for cell-cell communication, MBVs embedded within tissue ECM are stably associated with the matrix and can only be isolated following degradation of the ECM material (4). The requirement for matrix degradation to release MBV may partially define their mechanism of action, including those related to their capacity to generate pro-resolving lipid mediators. Because MBVs remain intact and attached to ECM even after decellularization, the molecular speciation of their constituent phospholipids likely plays a role in facilitating such MBV-ECM interactions. Using LC-MSbased lipidomics and redox lipidomics approaches, we performed detailed characterization of the molecular speciation of MBV phospholipids, LPL, and the oxygenated and non-oxygenated PUFA and can speculate upon the relationship of these various molecular species with their utilization as metabolic lipid signaling platforms. We report that high levels of LPL, bioactive molecules that are important for macrophage differentiation, tissue repair, remodeling, and wound healing, are a characteristic feature of MBV. In addition, as fusogenic lipids, LPL can facilitate the transfer of the vesicular contents to intracellular targets. MBVs, but not liquid-phase EVs, were enriched in PUFA non-oxygenated and oxygenated phospholipids and therefore represent a potential reservoir of oxidized and oxidizable esterified phospholipid species, the role of which has not yet been elucidated. Notably, PUFA-enriched MBV can be viewed as an important source of lipid mediators activated by different phospholipases dependent on the pro-/anti-inflammatory context of the extracellular environment.

A limitation of the present study is the use of a single cell line to evaluate differences in liquid-phase EV and MBV cargo. The 3T3 fibroblast cell line used in this study was chosen because it is a well-characterized and widely used cell line in biologic research. Furthermore, results from the RNA-seq and lipidomic analyses showed that multiple replicates of MBV derived from the 3T3 fibroblast model showed a high level of consistency in terms of miRNA and lipid cargo and that this cargo is significantly different from the cargo of the corresponding liquid-phase EV, which supports the fidelity of our results. However, further studies are required with other cell types, including primary cells, before one can derive a more definitive understanding of the biologic purpose of MBV versus liquid-phase EV. In addition, additional studies are warranted to identify and determine the biologic relevance of MBV in native (nondecellularized) tissues.

The findings of the present study may have significant clinical implications. EVs harvested from biological fluids have been used for diagnostic purposes (38), and EVs isolated from cell culture supernatant are being explored as therapeutic agents in early-phase clinical trials (39, 40). However, delineation of the MBV subpopulation may now allow new perspectives on EV-based therapeutics, especially in the design and manufacture of novel biomaterials and artificial EV for clinical use. Given the selective loading of specific miRNA and lipid cargo within MBV, further studies on MBV biogenesis may prove to be instrumental in guiding new strategies for cargo loading of EV (9) or for the incorporation of EV into ECM-based biomaterials to be used as an inductive substrate for tissue repair (7, 8).

The objective of the present study was to conduct a comparative material analysis of EV secreted into a liquid medium versus MBV integrated into the ECM using an in vitro 3T3 fibroblast cell culture model that allows selective harvesting of vesicles from liquid-phase or solid-phase extracellular compartments. 3T3 fibroblasts were seeded on polystyrene plates in the presence of ascorbic acid to induce deposition of ECM (41, 42). After 7 days, the cell culture medium containing liquid-phase EV was harvested, and the culture plates were decellularized to remove cells while maintaining the molecular composition and ultrastructure of the ECM. Following decellularization, MBVs were isolated from decellularized ECM by enzymatic digestion. We used LC-MSbased lipidomics and redox lipidomics to perform detailed analysis of liquid-phase EV and MBV phospholipids and conducted comprehensive RNA-seq and bioinformatic analysis of the intravesicular miRNA cargo.

Human BMSC, human ASC, and human UCSC ECM plates were provided by StemBioSys (San Antonio, TX) and prepared according to a published protocol (43). Briefly, human BMSCs, human ASCs, or human UCSCs were seeded onto a 75-cm2 cell culture flask coated with human fibronectin (1 hour at 37C) at a cell density of 3500 cells/cm2 and cultured in -minimum essential medium (-MEM) supplemented with 20% fetal bovine serum (FBS) and 1% penicillin-streptomycin for 14 days. The medium was refreshed the day after initial seeding and then every 3 days. At day 7, ascorbic acid 2-phosphate (Sigma-Aldrich) was added to the medium at a final concentration of 50 M. At day 14, plates were decellularized using 0.5% Triton in 20 mM ammonium hydroxide for 5 min and rinsed two times with Hanks balanced salt solution containing both calcium and magnesium (HBSS +/+) and once with ultrapure H2O. Murine NIH 3T3 fibroblast cells were seeded onto a 75-cm2 cell culture flask at a cell density of 3500 cells/cm2 and cultured in Dulbeccos modified Eagles medium (DMEM) supplemented with exosome-depleted FBS (44), 1% penicillin-streptomycin, and ascorbic acid 2-phosphate (Sigma-Aldrich) at a final concentration of 50 M for 7 days. At day 7, the supernatant from cultured 3T3 fibroblast cells was collected, and the culture plates were washed three times with phosphate-buffered saline (PBS), decellularized using 0.5% Triton in 20 mM ammonium hydroxide for 5 min, and then rinsed three times with ultrapure H2O.

MBVs were isolated as previously described with minor modifications (4) . Briefly, the decellularized ECM was enzymatically digested with Liberase DL (100 ng/ml; Roche) in buffer [50 mM tris (pH 7.5), 5 mM CaCl2, and 150 mM NaCl] for 1 hour at 37C. The cell culture supernatant containing the liquid-phase EV and the digested ECM containing the MBV were subjected to differential centrifugation at 500g (10 min), 2500g (20 min), and 10,000g (30 min), and the supernatant was passed through a 0.22-m filter (Millipore). The clarified supernatant containing the liberated MBV or liquid-phase EV was then centrifuged at 100,000g (Beckman Coulter Optima L-90K Ultracentrifuge) at 4C for 70 min to pellet the vesicles. The vesicle pellets were then washed and resuspended in 1 PBS and stored at 20C until further use.

UBM was prepared from market-weight pigs (Tissue Source LLC, Lafayette, IN) as previously described (4). Briefly, the tunica serosa, muscularis externa, submucosa, and muscularis mucosa were removed by mechanical delamination, and the urothelial cells of the tunica mucosa were dissociated from the basement membrane by washing with deionized water. The remaining basement membrane and the lamina propria (collectively referred to as UBM) were decellularized by agitation in 0.1% peracetic acid with 4% ethanol for 2 hours at 300 rpm followed by PBS and type 1 water washes. UBM was then lyophilized and milled using a Wiley Mill with a #60 mesh screen.

UBM was fixed in cold 2.5% glutaraldehyde for 24 hours followed by three 30-min washes in 1 PBS. Samples were then dehydrated in a graded series of alcohol (30, 50, 70, 90, and 100% ethanol) for 30 min per wash and then placed in 100% ethanol overnight at 4C. Samples were washed three additional times in 100% ethanol for 30 min each and critical pointdried using a Leica EM CPD030 critical point dryer (Leica Microsystems, Buffalo Grove, IL, USA) with carbon dioxide as the transitional medium. Samples were then sputter-coated with a 4.5-nm-thick gold/palladium alloy coating using a 108 Auto sputter coater (Cressington Scientific Instruments, UK) and imaged with a JEOL JSM6330F scanning electron microscope (JEOL, Peabody, MA, USA).

TEM imaging was conducted on MBV or liquid-phase EV loaded on carbon-coated grids and fixed in 4% paraformaldehyde as previously described (4). Grids were imaged at 80 kV with a JEOL 1210 TEM with a high-resolution Advanced Microscopy Techniques digital camera. The size of MBV was determined from representative images using JEOL TEM software.

Particle size and concentration of the liquid-phase EV and the MBV were calculated using a NanoSight (NS300) instrument equipped with fast video capture and particle-tracking software. Samples were diluted 1:500 to a final volume of 1000 l using particle-free water. A syringe pump was used to dispense the sample into the system. Measurements were performed from three captures of 45 s each sample. For the video processing and particle calculation, the detection threshold was adjusted to 4. Data are presented as concentration versus particle size for each of the evaluated samples.

Total RNA was isolated from 3T3 cells, liquid-phase EV, and MBV using the RNeasy Mini Kit (Qiagen) according to the manufacturers instructions. Before RNA isolation, liquid-phase EV and MBV samples were treated with ribonuclease A (10 g/ml) at 37C for 30 min to degrade any contaminating RNA. RNA quantity was determined using a NanoDrop spectrophotometer, and its quality was determined by Agilent Bioanalyzer 2100 (Agilent Technologies).

The miRNA library preparation was initiated with 100 ng of each sample and the QIAseq miRNA Library Kit (Qiagen) following the manufacturers instructions. Briefly, mature miRNAs were ligated to adapters on their 3 and 5 ends. The ligated miRNAs were then reverse-transcribed to complementary DNA (cDNA) using a RT primer with unique molecular indices. The cDNA was then cleaned up to remove adapter primers, followed by amplification of the library with a universal forward primer and one of 48 reverse primers that assign a sample index. A presequencing quality control was performed using the Agilent RNA ScreenTape System. Next-generation sequencing was performed on a NextSeq 500 instrument with a loading concentration of 2.5 pM. Bioinformatic analysis was conducted by Genevia Technologies (Tampere, Finland). The quality of the sequencing reads was inspected using FastQC software. TrimGalore! (version 0.4.5) was used to remove the adapter sequences, with default settings, on all the samples. All reads were shortened to 21 bases, the typical size of miRNAs, using the fastx_trimmer software (FASTX-Toolkit by Hannon Lab, version 0.0.14). The reads of each sample were then aligned against the corresponding reference genome (hg38, GRCm38). Tables of miRNA counts across samples were created using the softwares bowtie (version 1.2.2) and miRDeep2 (version 0.0.8). In this process, precursor miRNA and mature miRNA sequences for each species involved in the study were taken from miRbase. Counts of mature miRNAs were obtained by taking the median of all precursor miRNAs associated with them. The counts of mature miRNAs of all samples were normalized using DESeq2. To ensure data quality before further analyses, PCA was performed and the results were visualized using ggplot2, separately for murine and human samples. Normalization of mature miRNA data and statistical testing between sample groups were performed with DESeq2. P values were corrected for multiple testing using the Benjamini-Hochberg method. miRNAs with adjusted P value of <0.05 and absolute log2 fold change >1 were considered as significantly differentially expressed. Tables of differentially expressed miRNAs were annotated with their targets and their confidences using the mirTARbase database of experimentally tested miRNA target interactions. Differentially expressed miRNAs were also annotated with predicted targets using the R package miRNAtap. miRNAtap aggregates the miRNA target predictions from five different databases (PicTar, DIANA, TargetScan, miRanda, and miRDB) and calculates an overall miRNA target score. The minimum amount of database sources required for a potential miRNAtarget interaction to be included into the annotations was 3.

IPA software (version 01-14) was used for functional analysis of differentially expressed miRNAs. miRNA targets were identified using the IPA Core Analysis. The filter was set to Experimentally Observed findings to obtain information about significantly enriched molecular and cellular functions and physiological system development functions that were affected by the miRNAs.

RT and qPCR were performed using the TaqMan Advanced miRNA Assays Protocol (Applied Biosystems). Briefly, 10 ng of total RNA was used with the TaqMan Advanced miRNA cDNA Synthesis Kit (Applied Biosystems, catalog no. A28007) to synthesize and adapt a 3-poly(A) tail to the miRNAs. Universal RT primers recognizing the poly(A) tail were used to synthesize the cDNA in the RT reaction, followed by a miR-AMP step, using miR-AMP forward and reverse universal primers, to increase the number of cDNA molecules. The qPCR was made on a QuantStudio system machine using the TaqMan Fast Advanced Master Mix (Applied Biosystems, catalog no. 4444556) and specific TaqMan Advanced miRNA Assays (Applied Biosystems, catalog no. A25576) recognizing mmu-miR-163-5p, mmu-miR-27a-5p, mmu-miR-92a-1-5p, mmu-miR-451a, mmu-miR-93-5p, and mmu-miR-99b-5p. Fold change expression on the MBV sample was calculated for each of the specific targets using liquid-phase EV as a reference.

Liquid-phase EV and MBV, derived from three separate cultures of 3T3 fibroblasts, were respectively pooled and quantified by nanotracking particle analysis. For both immunoblot and silverstain analysis, an equal number of vesicles for both the liquid-phase EV and MBV samples were loaded onto the gel. MBV or liquid-phase EV (21 1011) was mixed with 2 Laemmli buffer (R&D Systems) containing 5% mercaptoethanol (Sigma-Aldrich), resolved on a 4 to 20% gradient SDSpolyacrylamide gel electrophoresis (Bio-Rad), and then transferred onto a polyvinylidene difluoride membrane. Membranes were incubated overnight with the following primary antibodies: rabbit anti-CD63, rabbit anti-CD81, rabbit anti-CD9, and rabbit anti-Hsp70, at 1:1000 dilution (System Biosciences). Membranes were washed three times for 15 min each before and after they were incubated with goat anti-rabbit secondary antibody, at 1:5000 dilution (System Biosciences). The washed membranes were exposed to chemiluminescent substrate (Bio-Rad) and then visualized using a ChemiDoc Touch instrument (Bio-Rad). Silver staining of gels was performed using the Silver Stain Plus Kit (Bio-Rad) according to the manufacturers instruction and visualized using a ChemiDoc Touch instrument (Bio-Rad).

Lipids were extracted from 3T3 cells, exosomes, and MBV by Folch procedure (45). MS analysis of phospholipids and their oxygenated products was performed on an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific), as previously described (46). Briefly, phospholipids were separated on a normal-phase column [Luna 3 m Silica (2) 100 , 150 2.0 mm (Phenomenex)] at a flow rate of 0.2 ml/min on a Dionex Ultimate 3000 HPLC system. The column was maintained at 35C. The analysis was performed using gradient solvents (A and B) containing 10 mM ammonium acetate. Solvent A contained propanol:hexane:water (285:215:5, v/v/v), and solvent B contained propanol:hexane:water (285:215:40, v/v/v). All solvents were LC-MS grade. The column was eluted for 0 to 23 min with a linear gradient from 10 to 32% B, 23 to 32 min using a linear gradient of 32 to 65% B, 32 to 35 min with a linear gradient of 65 to 100% B, 35 to 62 min held at 100% B, and 62 to 64 min with a linear gradient from 100 to 10% B followed by an equilibration from 64 to 80 min at 10% B. Spectra were acquired in negative ion mode. Deuterated phospholipids were used as internal standards (Avanti Polar Lipids). Three technical replicates for each sample were run to evaluate reproducibility. Analysis of LC-MS data was performed using the software package Compound Discoverer (Thermo Fisher Scientific) with an in-house generated analysis workflow and nonoxidized/oxidized phospholipid database. Lipids were further filtered by retention time and confirmed by fragmentation mass spectrum.

Free fatty acids were analyzed by LC-MS using a Dionex Ultimate 3000 HPLC system coupled online to a Q Exactive hybrid quadrupole-orbitrap mass spectrometer (Thermo Fisher Scientific, San Jose, CA), as previously described (47). Briefly, fatty acids and their oxidative derivatives were separated by a C18 column (Acclaim PepMap RSLC, 300 m 15 cm, Thermo Fisher Scientific) using gradient solvents A [methanol (20%)/water (80%) (v/v)] and B [methanol (90%)/water (10%) (v/v)], both containing 5 mM ammonium acetate. The column was eluted at a flow rate of 12 l/min using a linear gradient from 30% solvent B to 95% solvent B over 70 min, held at 95% B from 70 to 80 min, followed by a return to initial conditions by 83 min and re-equilibration for an additional 7 min. Spectra were acquired in negative ion mode. Analytical data were acquired and analyzed using Xcalibur software. A minimum of three technical replicates for each sample was run to increase the reproducibility.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: We gratefully acknowledge T. Block and S. Griffey from StemBioSys for providing the ECM plates and K.-L. Aho from Genevia for the bioinformatic analysis. This project used the University of Pittsburgh HSCRF Genomics Research Core. We thank H. Deborah for conducting the small RNA-seq assay. Funding: This work was supported by NIH (HL114453-06, U19AI068021) and by Russian academic excellence program 5-100. S.F.B. and G.S.H. were supported, in part, by NIH R01AR073527, Mechanisms of functional skeletal muscle repair: Critical role of matrix associated IL-33. Author contributions: G.S.H., V.E.K., and S.F.B. conceptualized and designed the research. G.S.H., C.P.M., M.C.C., Y.Y.T., V.A.T., Y.C.L., S.O.E.-M., M.H.M., and P.S.T. performed the experiments. G.S.H., C.P.M., Y.Y.T., V.A.T., Y.C.L., P.S.T., V.E.K., and S.F.B. analyzed the data and interpreted the results of experiments. G.S.H., C.P.M., Y.Y.T., and V.E.K. prepared the figures. G.S.H., V.E.K., and S.F.B. drafted the manuscript. Competing interests: S.F.B. is the chief scientific officer and equity holder in ECM Therapeutics Inc., which has license rights to MBV technology from the University of Pittsburgh. S.F.B. and G.S.H. are inventors on several patents related to this work filed by the University of Pittsburgh. The authors declare that they have no other 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 are available from the authors upon request.

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Lipidomics and RNA sequencing reveal a novel subpopulation of nanovesicle within extracellular matrix biomaterials - Science Advances

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With coronavirus dominating the headlines, its easy to forget what else is going on in the world.

And it can be even harder to see any good news as most of the globe tackles the pandemic.

But in recent weeks there has been plenty of positive news to help with the coronavirus worries.

These are eight good news stories from across the world since the coronavirus outbreak began:

A million seagrass seeds were planted off the Welsh coast to help tackle climate change.

The seagrass seeds are being planted in a new 20,000sqm meadow off Pembrokeshire.

Seagrass can absorb carbon dioxide faster than trees, and scientists hope it can boost fish numbers and life in the sea.

In the summer of 2019, one million seeds were collected from areas like Porthdinllaen in the Lln Peninsula by a group of volunteers.

The seagrass, which is found in shallow, sheltered areas along the coast, was reached by snorkelling, diving and wading.

After being taken to Swansea University, the seeds were placed in hessian bags ready to be planted again at Dale Bay.

In more good news for the planet, carbon emissions from the power sector across the world have seen their biggest drop since 1990.

Research from environmental think tank Ember, emissions dropped 2% in 2019.

They said the historic decline was largely caused by the US and Europe moving away from coal power which saw a global drop of 3% - the largest decrease in three decades.

The budget doesnt normally bring much good news. But this year it was announced VAT on all sanitary products will be abolished from 2021.

Although small, it could mean women could save around 40 in a lifetime.

Scientists said a former chef living in the UK has become the second person in the world to be 'cured' of HIV.

Adam Castillejo has remained free of HIV for two-and-a-half years since he was given ground-breaking therapy at Hammersmith Hospital in west London.

The 40-year-old, who was born in Venezuela but lives in England, received a transplant of bone marrow stem cells that rid him of the AIDS-causing virus, the Mirror reported.

Amid the sombre news being reported on the TV was the annual Crufts show.

Viewers saw Maisie the wire-haired Dachshund beat tough competition and be crowned best in show.

The lovable pup even then did her business on the floor during her victory lap in front of a giggling crowd.

Around 28,000 pooches were put through their paces at the biggest dog show in the world at Birmingham's NEC.

In more animal related good news, a seal pup that spent two months in RSPCA care was released back into the wild.

Underweight Graham was looked after for around eight weeks after being rescued in Pembrokeshire.

RSPCA animal collection officer and wildlife officer Ellie West, who released Graham back into the sea at Port Eynon, said: This seal pup who when found was very underweight initially spent a few days coughing up sea shells!

He came into the centre weighing just 16.6kg and needed fluids and antibiotics for a chest infection and was treated for lungworm. He put on weight pretty steadily after starting to eat by himself on day six and then didnt look back.

Ellie released Graham back into the sea on March 7.

The fast-food chain has announced the bargain offer will last for five weeks, meaning customers have until April 19 to grab the discount.

Those wanting a meal for less will get a mini burger, regular fries and two hot wings for just 1.99 instead of the usual 3.99.

The offer was spotted by eagle-eyed deal hunters and posted on the money-saving website LatestDeals.co.uk.

A cleaver Australian teen has come up with a clever way to get rid of plastic waste - by using prawn shells.

17-year-old Angelina Arora has used prawn shells to create a plastic that will decompose in landfill in an average of 33 days.

The teen said she is now in talks with supermarkets to use her products, News.Au reported.

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Eight feel good stories you may have missed during the coronavirus outbreak - Wales Online

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