Archive for the ‘Bone Marrow Stem Cells’ Category

As an athlete, Courtlynn Havard has always set goals for herself to improve her game whether on the soccer or softball field. She has worked toward those goals through hard work and perseverance.

Now her goals have shifted slightly.

Courtlynn, a sophomore at Franklin Parish High School, currently has two main goals: to beat aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) and to help others.

Helping others for Courtlynn brightens her day, strengthens her and gives her hope for a better tomorrow.

From that desire to help others, the Havard family is sponsoring a bone marrow drive at Life Church in Winnsboro Feb. 20 from 10 a.m. until 2 p.m.

The drive will be administered by DKMS, an international nonprofit organization, whose goal is to find bone marrow donors for people like Havard.

It is simple as a swab in your cheek, said Jaimie Havard, Courtlynns mother. That could save a life. It only takes a few minutes and is so easy for you to give somebody a second chance on life.

Anyone 18-55 with good health can participate in the drive. Participates stay in their car, watch a video on their phone and fill out a short form, said Amy Roseman of DMKS.

They are given a kit with a swab for their cheeks. The whole process takes 7-10 minutes.

In October, Courtlynn went to the doctor with kidney stones. When doctors took her blood, they found her blood count was low.

Her mother and Courtlynn met with an oncologist who gave them disturbing news.

At first the oncologist thought it was leukemia, Jaimie said. You feel like your whole world is collapsing. I didnt know what to say or do. Courtlynn was devastated and crying. I was trying to be strong for her.

The Havards were then sent to LSU Health Shreveport. The medical professionals there performed a bone marrow biopsy and found she had aplastic anemia and PNH.

You never think it can be your child, Jaimie said. It is really an unbelievable, indescribable feeling.

Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells, according to the Mayo Clinic. The condition leaves a person fatigued and more prone to infections and uncontrolled bleeding.

A rare and serious condition, aplastic anemia can develop at any age. It can occur suddenly, or it can come on slowly and worsen over time and can be mild or severe.

Treatment for aplastic anemia might include medications, blood transfusions or a stem cell transplant, also known as a bone marrow transplant.

PNH is a rare acquired, life-threatening disease of the blood. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and impaired bone marrow function (not making enough of the three blood components).

PNH affects 1-1.5 persons per million of the population and is primarily a disease of younger adults. The median age of diagnosis is 35-40 years of age, with occasional cases diagnosed in childhood or adolescence. PNH is closely related to aplastic anemia.

Courtynns world use to evolve around sports, mud riding with her friends and being very social.

Now because of her weak immune system, she has to be careful and stay at home with her English Spaniel, Old Mack, and go to school virtually. Courtlynn talks to her friends via cell phone, computer and occasionally gets a visit from one that sits on her porch while she socially distances.

I missed my friends the most, Courtlynn said. I am one of those people that get up and go. I dont stay still.

She also goes to doctors whether it be locally to get her blood count tested, or Shreveport to receive platelets and blood or Memphis to St. Judes.

Saving people around the world

One thing that drives Courtlynn through this situation is keeping up with other kids situations, Jaimie said. There are so many stories out there of kids looking for bone marrow transplants.

The Feb. 20 bone marrow drive is a way Courtlynn and her family can help others.

DKMS has been finding matching bone marrow donors for 30 years. They are now in the United States, Germany, Poland, India and South Africa.

Sadly, only 2 percent of Americans have signed up as potential donors, Roseman said. We are hoping we will have really nice support for Courtlynn and the other patients looking for donors.

Reasons vary for the low percentage of potential donors, but Roseman attributes not knowing the need and ease of the process.

You fill out contact information, swab your cheeks and you are put in a data base that is only seen by medical teams searching for donors, Roseman said. We call it, youre a hero in waiting.

The biggest misconception is the donation of bone marrow if you are a match.

You are asked to donate stem cells from the blood stream, Roseman said. It is a very easy process. It is very similar to donating plasma or platelets and takes a morning or afternoon.

Blood is taken from one arm, and the blood is put back into the other arm, Roseman, said. Stem cells lost in the process will regenerate.

You have given someone a second chance in life, Roseman said.

A person may be asked to donate actual bone marrow if he or she is matched to a three year old or younger. This procedure is done in a hospital and takes less than an hour. DKMS pays for the hospital visit and time loss from work.

It is amazing to think about giving someone a second chance on life by giving up a just morning of your time, Roseman said.

A community comes together

The Franklin Parish community has come together in support of Courtlynn and the Havard family.

Boutique shops, individuals and restaurants have come together to raise money for her cause.

During the Feb. 20 bone marrow drive at Life Church a BBQ chicken plate lunch will be on sale for $10. T-shirts will also be on sale at the event. Keep up with all drives and Courtlynns journey on her Facebook page: Courtlynns Compass.

We have a really amazing group of friends and family that have come together, Jaimie said. Our local community has stepped up big time. Complete strangers are showing so much love and support for my baby. It speaks volumes for our little town we live in.

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Helping others helps Havard through sickness | Community | hannapub.com - The Franklin Sun

Cynata Therapeutics (ASX: CYP), founded by two clever stem cell researchers and one wise Australian techpreneur, is in the process of developing a treatment for COVID-19.

Using its in-house stem cell technology Cymerus, the ASX-listed biotech hopes to treat one of the deadliest complications of COVID-19 -acute respiratory distress syndrome (ARDS).

In doing so Cynata would achieve what competitor Mesoblast (ASX: MSB) couldn't with FDA approval.

By deploying an industrialised approach to stem cell therapeutics, Cynata CEO Ross Macdonald (pictured) is confident the clinical trial process won't leave the company hamstrung.

In 1981 scientists discovered a way to derive embryonic stem cells from early mouse embryos.

The discovery thrilled scientists, and eventually led to the development of a method to do the same in lab-grown human embryos by 1998.

While there have been plenty of discussions surrounding the ethics of using of embryonic stem cells, these major scientific movements have pushed researchers to discover new and inventive ways of treating a whole raft of diseases and infections.

One such researcher, Dr Ian Dixon, saw potential for the use of mesenschymal stem cells (MSCs) - a type of stem cell that can differentiate into a variety of cell types enabling the treatment of many diseases and infections.

However there was still an obstacle to overcome: how do you mass produce enough cells needed to commercialise a treatment?

Luckily, two researchers at the University of Wisconson, Professor Igor Slukvin and Dr Maksym Vodyanik, had invented a biotechnological breakthrough called Cymerus.

The technology was able to do exactly what Dixon needed: the consistent manufacture of MSCs on an ultra-large scale; basically what Henry Ford did to the industrialisation of the auto industry, but for stem cells.

So in 2003 Dixon partnered with the two researchers to start Cynata - now an ASX-listed biotechnology company trialing a number of different treatments for a wide variety of ailments.

Most recently, Cynata's focus has been on developing a treatment for a complication of COVID-19 called acute respiratory distress syndrome (ARDS).

The complication ravages COVID-19 infected patients, destroying their organs through what is known as a cytokine storm. The complication is estimated to kill up to half of COVID-19 patients that suffer from it.

Melbourne-based Cynata is currently in the very early stages of its investigation into whether its MSCs will be able to treat the coronavirus complication overwhelming hospitals globally.

If this all sounds familiar, you might be thinking of another ASX-listed biotech called Mesoblast (ASX: MSB).

In March last year Mesoblast, also based in Melbourne, saw its shares surge after announcing plans to evaluate its stem cell treatment solutions on COVID-19 patients.

The group commenced the arduous clinical trial process to see if its remestemcel-L therapy could treat ARDS by using bone marrow aspirate from healthy donors - a similar approach the company had already taken to treat a condition many suffer from after receiving bone marrow transplants.

Mesoblast was riding high on the ASX following positive announcements surrounding the clinical traila process, especially back in April 2020 when a trial at New York City's Mt Sinai hospital found its remestemcel-L therpay achieved "remarkable" results.

Serious attention gathered around Mesoblast, with the company even securing $138 in funds from investors to continue its important research.

The company went so far as to sign a commercialisation deal for the COVID-19 treatment with Novartis, and the US Food and Drugs Administration (FDA) fast tracked the approvals process for the potential game-changing treatment.

However, in December 2020, Mesoblast hit a stumbling block.

Mesoblast's COVID-19 treatment flunked the test - its remestemcel-L therapy failed to show a lower mortality rate for patients in the prescribed 30-day timeframe of treatment.

At that point Cynata had commenced research into its own ARDS treatment. But did Mesoblast's failure unnerve Cynata CEO Ross Macdonald? Not a chance.

"I'm more confident that our trial will be successful where theirs was a failure," Macdonald said.

"If you use a process like we have developed - we don't rely on multiple different [stem cell] donations. You start with exactly the same material every time."

To explain, Macdonald used the analogy of a local caf; you normally expect a coffee from one caf to taste more or less exactly the same every time you go there - the same beans are used every time.

Whereas Macdonald said Mesoblast's process is like going to the same caf every day, but each visit they use different beans from a different supplier which leads to inconsistency in taste and flavour.

Cynata's approach with its MSCs is in line with the first example - what you get the first time from them will be replicated in each and every dose of the drug - while MSB's is like the latter.

"Yes, you still got the coffee, but the experience of the taste is totally different than it was yesterday," he said.

"The FDA said to Mesoblast, well you've got a manufacturing problem that is reliant upon multiple donors prepared to donate bone marrow and that is flawed.

"So with that in mind it's perhaps not surprising that they had a pretty disappointing result in the clinical trials."

Additionally, Macdonald said the initial investor reactions to MSB's early COVID-19 trail results were overblown.

"The initial data from their trial that got everybody excited was, in my view, quite flawed, because they said "look at how many patients are dying in intensive care units with COVID compared the patients that we treated," he said.

"But the reality of the situation was quite different. The control group at that time - the death rate was way, way higher than you would typically see for ARDS, whether its COVID or anything else. And it was simply because of the chaos that existed in intensive care units in New York in the first wave.

"So we think that the initial enthusiasm was perhaps a little misguided."

When asked why Mesoblast is receiving so much attention compared to Cynata, especially considering the above, Macdonald said it was simply because MSB is bigger and has been around for longer. For context, MSB has a market capitalisation of $1.46 billion, whereas Cynata's is just $94.56 million.

"I'd love to know why there is less attention, and how we can get our market cap above a billion dollars," joked Macdonald.

"I think the answer though is that they've been around for a lot longer than we have, they have spent a hell of a lot more money than we've spent - their monthly spend is more than we've spent for pretty much our entire existence.

"But I think the fundamental reason why is that data drives value in biotech, so the more clinical data you generate that shows your product works, the more attention you attract from investors."

That's not to say Cynata is being totally ignored in favour of the larger Mesoblast.

The company secured a $15 million placement led by $10 million from healthcare investor BioScience Managers in December.

The funds will be used to expand Cynata's clinical development pipeline and scale their operations in Australia.

As such, the company is preparing to expand its clinical development pipeline to include idiopathic pulmonary fibrosis, renal transplantation, and diabetic foot ulcers.

"So we're starting to garner that attention now that says two things - one, cell therapies are definitely a medical revolution and two, Cynata is part of that new generation of companies," Macdonald said.

As for the company's pipeline, in addition to the COVID treatment trials, Cynata is planning on launching three new clinical candidates that will get under way this year.

There's also Cynata's osteoarthritis trial, which Macdonald describes as significant for the biotech company; with 2 million patients in Australia and 30 million in the United States the company is hoping to tap into an $11 billion plus addressable market.

"It will ultimately show whether MSCs are useful in that particularly devastating condition," he said.

"It doesn't just affect people who want to go and play golf or tennis, it affects, particularly manual labourers who can no longer work.

"So the cost to the economy of osteoarthritis is quite significant, which is of course one of the reasons why the Australian Government is funding this trial."

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Business News Australia

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Why Cynata is hopeful its COVID treatment trial will succeed where others have failed - Business News Australia

The anti-emetic agent metoclopramide blocked CD93 signaling in cell culture and delayed leukemia development in mice, according to data from a preclinical study published in Cell Reports. The results indicate that CD93 signaling, which is an important regulator of self-renewal and proliferation of murine and human leukemia stem cells (LSCs), could be a potential therapeutic target for the elimination of LSCs in chronic myeloid leukemia (CML).

To characterize the function of CD93 in CML, the researchers first demonstrated that all subsets of LSCs expressed CD93 while more differentiated leukemia granulocytes did not. Though CD93 was shown to encourage self-renewal and proliferation of murine and human LSCs, it notably had no such effect on hematopoietic stem cells.

In an experiment, the investigators injected mice with LSCs that were either proficient or deficient in CD93. Mice with CD93-deficient LSCs were found to incorporate bromodeoxyuridine, which is used to detect proliferating cells, at a lower rate than mice with CD93-proficient LSCs. The finding suggests that proliferation of LSCs is impaired when CD93 is absent.

Next, a drug library was used to screen for compounds that could block CD93 signaling. Among the 240 compounds evaluated in vitro, 10 blocked CD93 signaling; one of the compounds was the anti-emetic agent metoclopramide.

Mice were then treated with either vehicle or metoclopramide. Notably, metoclopramide-treated mice had delayed leukemia development and lived longer than vehicle-treated mice. Among the metoclopramide-receiving mice, most genes were downregulated in the LSCs, particularly genes that promote stem cell maintenance and myeloid differentiation, cell proliferation and survival, response to cytokine signaling, and gene expression.

In vitro exposure to metoclopramide was found to disrupt colony formation in human bone marrow CML stem/progenitor cells. A control experiment showed that metoclopramide had no effect on hematopoietic stem/progenitor cells from humans with healthy bone marrow.

The study authors reasoned that because metoclopramide is a very well-tolerated and cheap anti-emetic drug, its LSC-eradicating activity in patients with CML can be directly tested in clinical drug repurposing studies.

Reference

Riether C, Radpour B, Kallen NM, et al. Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells. Cell Rep. 2021;34(4):108663. doi:10.1016/j.celrep.2020.108663

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Anti-Emetic Drug Effectively Blocks CD93 Signaling in Preclinical Evaluations, Suggesting Suitability in CML - Cancer Therapy Advisor

World Cancer Day 2021: It is observed on 4 February every year and this year the theme is "I Am and I Will".The campaign shows that our actions have an impact on everyone around us, within our neighbourhoods, communities, and cities. This year is a reminder of the enduring power of cooperation and collective action i.e. together, all our actions matter.

What are Blood Cancers?

It is a type of cancer that affects blood cells and affects the production and function of blood cells.

This type of cancer starts in the bone marrow which is the main source of blood production.

It occurs when abnormal blood cells start growing out of control and interrupt the function of normal blood cells that fight off infection and produce new blood cells.

World Cancer Day 2021: Current Theme, History and Key Facts

Blood Cancer: Types

Mainly, there are three types of blood cancers namely leukemia, lymphoma, and myeloma.

Leukemia

It is a blood cancer that originates in the blood and bone marrow. It is caused by the rapid production of abnormal white blood cells and interferes with the bone marrow's ability to make red blood cells and platelets. These high numbers of abnormal white blood cells are not able to fight infection.

Lymphoma

This type of blood cancer affects the lymphatic system, which removes excess fluids from the body and produces immune cells. As we know that lymphocytes are a type of white blood cell that fights infection. Therefore, abnormal lymphocytes become lymphoma cells that multiply and collect in the lymph nodes and other tissues. And over time, these cancerous cells impair the immune system of the body.

Myeloma

It is a type of blood cancer that begins in the plasma cells of blood which is a type of white blood cell made in the bone marrow. Plasma cells are white blood cells that produce antibodies to fight against infection and disease in the body. So, myeloma cells prevent the normal production of antibodies which make the immune system weak and susceptible to infection.

Blood Cancer: Symptoms

Loss of appetite, nausea

Fever, chills

Night sweats

Persistent fatigue, weakness

Unexplained weight loss

Bone/joint pain

Shortness of breath

Abdominal discomfort

Frequent infections

Itchy skin or skin rash

Swollen lymph nodes in the neck, underarms or groin

Delirium and confusion

Decreased urination and difficulty while urinating

What is High Grade Metastatic Cancer?

Blood Cancer: Treatment

On the type of cancer, treatment depends and how fast the cancer is progressing, where cancer has spread, and other factors. Some common treatment for blood cancer are:

Chemotherapy: In this anticancer cancer drugs are provided to the patient to interfere with and stop the growth of cancer cells in the body. In blood cancer, in chemotherapy treatment, sometimes several drugs are given together in a set regimen. This treatment may also be given before a stem cell transplant.

Radiation therapy: In this type of cancer treatment high-energy rays are given to kill cancer cells. It may also be given before a stem cell transplant.

Stem cell transplantation: In this type of treatment, healthy stem cells are infused into the patient body to help resume healthy blood production following therapy to destroy malignant blood cells. Stem cells may be collected from the bone marrow, circulating blood, and umbilical cord blood.

Blood Cancer in India

In India, over 20,000 new cases of childhood blood cancer are diagnosed every year of which nearly 15,000 of those cases are leukemia as per Globocan 2020.

The most common type of blood cancer is leukemia that affects children and teens (0-19 years) and one of the leading causes of death.

As per some studies, India ranks 3rd highest in reported cases of Blood Cancer after the US and China. Several factors are responsible like low accessibility of affordable healthcare in rural areas, lack of awareness and education on Blood Cancer, etc.

So, now you may have come to know about the blood cancer, types, symptoms, treatment, etc.

GK Questions and Answers on Types of Cancers

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World Cancer Day 2021: What are Blood Cancers, Types, Symptoms, Treatment and data in India? - Jagran Josh

Dave Asprey  |  Photo Credit: Twitter

A man who is determined to live until he is 180 years old says that his bizarre methods will soon be as popular as mobile phones. American millionaire tech entrepreneur Dave Asprey, 47, believes he will live to the year 2153 'at least' by using techniques such as sitting in a cold cryotherapy chamber and intermittent-fasting.

Dave coined the term 'Biohacking' to describe his methods of turning back the biological clock.

He got parts of his bone marrow removed to have the stem cells injected back into his body for $25,000 (Rs 18 lakh).

He speculated that people who are under 40 years of age will be "happy and highly functional" at 100 after applying his methods.

When This Morning's Holly Willoughby asked him why he wants to live so long, he replied, "I'm curious, I think there's a lot of things we can fix and improve in the world and I don't feel like I'm at all done yet."

Dave believes that he won't be the only one to be live for so long.

"The things I am working to pioneer, some of them are expensive, some of them are free like fasting. This will be like cell phones, everyone has cell phones - everyone will have anti-ageing. Change can happen rapidly in society," he said. "There will be many people who are under 40 right now who [will be] walking around under their own power, perfectly happy, highly functional, who are more than 100 years old."

Dave has spent an estimated $1 million on techniques and hacks to try and improve his body's overall functioning.

He added, "I set myself up to have much less inflammation than most people do, by controlling what I eat and how I sleep and a lot of other anti-ageing treatments."

He explained why he re-introduced his stem cells in his body, saying, "When we're young, we have a ton of stem cells and we heal like young people. As we age our stem cells get exhausted, so I do things like intermittent fasting which give me more stem cells and then I take my own stem cells and move them around the body so I heal and move like a young person."

Dave also believes in the benefits of cryotherapy, also known as cold therapy, which is the use of low temperatures in medical therapy to treat a variety of tissue lesions. He has been having cold showers for over ten years.

Another technique that Dave uses to live a long life is intermittent fasting, which involves restricting times that you eat meals to create periods of fasting over a certain period.

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Man who wants to live for 180 years spends Rs 18 lakh to re-inject his own stem cells - Times Now

India Stem Cell Market to surpass huge revenue of USD 1.27 Billion at CAGR +13% by 2028.

Stem cell therapy in India helps in treating several diseases, including leukaemia, lymphoma, thalassemia, Parkinsons, Alzheimers, stroke, cerebral palsy, spinal cord injury, muscular dystrophy, etc. Stem cell therapy in India has shown promising results in India and as well as all over the world.

In comparison, in India it costs INR 10-20 lakh in private hospitals, while in government hospitals it is much cheaper INR 3-6 lakh depending on the type of procedure, he said

On average, private banking of stem cells derived from cord blood costs INR 50,000-70,000. Banks claim to freeze the cells in liquid nitrogen so that it can be used up to 20 years from the date of preservation.

Researchers hope stem cells will one day be effective in the treatment of many medical conditions and diseases. But unproven stem cell treatments can be unsafe so get all of the facts if youre considering any treatment. Stem cells have been called everything from cure-alls to miracle treatments.

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Key players profiled in the report includes:

Thermofisher Scientific India Pvt. Ltd., Pluristem Technologies Ltd., Becton Dickinson Private Limited, Stem Cell Technologies India Pvt. Ltd., Merck Lifescience Pvt. Ltd., Cordlife India Pvt. Ltd., LifeCell International Pvt. Ltd., StemCyte India Therapeutics Private Limited, Stempeutics Research Private Limited, ReeLabs Private Limited, CryoSave, Indu Stem Cell Bank, Path Care Labs Pvt

The aim of the report is to equip relevant players in deciphering essential cues about the various real-time market based developments, also drawing significant references from historical data, to eventually present a highly effective market forecast and prediction, favoring sustainable stance and impeccable revenue flow despite challenges such as sudden pandemic, interrupted production and disrupted sales channel in the India Stem Cell market.

Market segments on the basis of:

This research report is an amalgamation of all relevant data pertaining to historic and current market specific information that systematically decide the future growth prospects of the India Stem Cell market. This section of the report further aims to enlighten report readers about the decisive developments and catastrophic implications caused by an unprecedented incident such as the pandemic that has visibly rendered unparalleled implications across the market.

This report is well documented to present crucial analytical review affecting the India Stem Cell market amidst COVID-19 outrage. The report is so designed to lend versatile understanding about various market influencers encompassing a thorough barrier analysis as well as an opportunity mapping that together decide the upcoming growth trajectory of the market. In the light of the lingering COVID-19 pandemic, this mindfully drafted research offering is in complete sync with the current ongoing market developments as well as challenges that together render tangible influence upon the holistic growth trajectory of the India Stem Cell market.

Besides presenting a discerning overview of the historical and current market specific developments, inclined to aid a future-ready business decision, this well-compiled research report on the India Stem Cell market also presents vital details on various industry best practices comprising SWOT and PESTEL analysis to adequately locate and maneuver profit scope. Therefore, to enable and influence a flawless market-specific business decision, aligning with the best industry practices, this specific research report on the market also lends a systematic rundown on vital growth triggering elements comprising market opportunities, persistent market obstacles and challenges, also featuring a comprehensive outlook of various drivers and threats that eventually influence the growth trajectory in the India Stem Cell market.

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India Stem Cell Geographical Segmentation Includes:

North America (U.S., Canada, Mexico)

Europe (U.K., France, Germany, Spain, Italy, Central & Eastern Europe, CIS)

Asia Pacific (China, Japan, South Korea, ASEAN, India, Rest of Asia Pacific)

Latin America (Brazil, Rest of L.A.)

Middle East and Africa (Turkey, GCC, Rest of Middle East)

Some Major TOC Points:

Chapter 1. Report Overview

Chapter 2. Growth Trends

Chapter 3. Market Share by Key Players

Chapter 4. Breakdown Data by Type and Application

Chapter 5. Market by End Users/Application

Chapter 6. COVID-19 Outbreak: India Stem Cell Industry Impact

Chapter 7. Opportunity Analysis in Covid-19 Crisis

Chapter 9. Market Driving Force

And More

In this latest research publication a thorough overview of the current market scenario has been portrayed, in a bid to aid market participants, stakeholders, research analysts, industry veterans and the like to borrow insightful cues from this ready-to-use market research report, thus influencing a definitive business discretion. The report in its subsequent sections also portrays a detailed overview of competition spectrum, profiling leading players and their mindful business decisions, influencing growth in the India Stem Cell market.

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India Stem Cell Market speedy growth at US$ 1.27 Bn by 2028 with Thermofisher Scientific India, Pluristem Technologies, Becton Dickinson Private...

Introduction

Osteonecrosis of the femoral head is a progressive disorder that causes pain and often progresses to hip joint collapse, finally resulting in disabling arthritis.1,2 It occurs between 30 to 50 years of age, and prevails at a relatively younger age in Asians compared to their western counterparts.3 It is estimated that approximately 20,00030,000 new cases of osteonecrosis are diagnosed in the United States each year, accounting for 10% of total hip arthroplasties performed.4 The Indian Society of Hip and Knee Surgeons has reported that more than 50% of all hip replacements in India are performed for osteonecrosis.5 Many studies have reported osteonecrosis to be more prevalent in men compared to women (3 or 5:1).3 The underlying pathophysiology of osteonecrosis remains unclear; however, it is multifactorial and several traumatic and nontraumatic etiological factors may contribute to its development. Traumatic events that may cause osteonecrosis include femoral neck/head fracture, hip dislocation, or slipped capital femoral epiphysis. Nontraumatic factors include use of steroids, alcoholism, metabolic disorders such as Cushings syndrome, and inherited disorders such as sickle cell disease.6,7 Besides the known traumatic and nontraumatic causes, some cases of osteonecrosis are idiopathic.1,8

Osteonecrosis of the femoral head may progress to secondary arthritis, and degeneration of articulating surface from advanced osteonecrosis necessitates total hip arthroplasty (THA). A primary treatment target of osteonecrosis of femoral head is to delay/prevent progression to osteoarthritis. Core decompression (CD) is the most widely used procedure in clinical practice; however, it has shown poor clinical outcomes, with up to 40% of patients having to undergo THA despite undergoing core decompression procedure.8 Therefore, a more pathophysiological approach may be required to treat osteonecrosis of femoral head. Osteonecrosis is characterized by a reduction in the osteogenic progenitor cells, an increase in osteoblast death, and altered intramedullary vascular supply due to trauma.1 It was observed that the number and function of mesenchymal cells in hematopoietic tissue and stroma of the bone marrow decreased in osteonecrosis patients.2 This observation indicated potential for using bone marrow stromal cells for the treatment of osteonecrosis, and consequently, several clinical studies have demonstrated encouraging results.2 A meta-analysis also showed that treatment with cell therapy compared to core decompression alone increased Harris hip score, decreased necrotic area of femoral head and collapse of femoral head, and reduced THA conversion rate.9 However, a recent randomized study has shown that bone marrow cell implantation in addition to core decompression did not improve THA conversion rate in patients with grade 3 osteonecrosis.10 The ideal treatment goal for osteonecrosis is to facilitate new bone formation in the place of dead bone that can provide pain relief, cease disease progression, prevent joint collapse, and preserve the joint. The fact thatbone marrow aspirate consists of mesenchymal stem cells raised a possibility if bone marrow cells could be differentiated into bone forming cells or osteoblasts and characterized by bone alkaline phosphatase. In a randomized trial, autologous osteoblast implantation was shown to significantly delay the evolution to subchondral fracture and reduce pain compared to bone marrow aspirate.11

OSSGROW (Regrow Biosciences Pvt Ltd., Mumbai, India) is a commercially available technology that involves implantation of autologous adult live-cultured osteoblasts (AALCO) derived from mesenchymal stem cells sourced from the bone marrow aspirate for osteonecrosis of the hip that received conditional marketing approval in India in March 2017.12 Here, we evaluated the efficacy of OSSGROW implantation technique by assessing retrospective data from patients with osteonecrosis who underwent the procedure. We also evaluated the correlation between Ficat-Arlet stages of osteonecrosis and clinical outcomes of the AALCO implantation procedure.

This retrospective, observational, non-comparative study was conducted at 37 centers in India. We retrospectively reviewed the data of patients with osteonecrosis of the femoral head who had undergone OSSGROW (AALCO) from 2010 to 2015. Key inclusion criteria were patients aged 12 years with a confirmed diagnosis of osteonecrosis in one or both hip joints who had undergone AALCO implantation. Diagnosis, analysis, and classification of osteonecrosis were done according to Ficat-Arlet based on radiography, computed tomography (CT) scans, and magnetic resonance imaging (MRI) findings. Patients whose medical records were not complete or were lost to follow-up were excluded from the study.

The protocol was approved by the Institutional Ethics Committee - Regrow Biosciences Pvt Ltd. and as this study was a retrospective study, informed consent was not required to review medical records. We also sought permission from the head of the institutes/departments before data collection. Patient data confidentiality was maintained in this study.

All the patients had undergone AALCO implantation on the recommendation of their consulting orthopedic surgeon after having received an explanation of the complications of osteonecrosis, the therapeutic options available, and the risks involved with the implantation procedure. Osteoblasts from patients were obtained from bone marrow aspiration from the posterior/superior iliac crest. Mesenchymal stem cells from the bone marrow were isolated and differentiated ex vivo into osteoblasts. Osteoblasts were then cultured for approximately 4 weeks under stringent laboratory conditions and multiplied up to 48 million osteoblasts (Figure 1). The cultured cells were implanted using a gel (Tisseel kit from Baxter) at the site of osteonecrosis through a minimally invasive surgery in a 3-step procedure: core decompression, curettage, and injection of osteoblasts (Figure 2).

Figure 1 Microscopic image of osteoblast in culture used for the final cell product before cell implantation.

Figure 2 Steps of osteoblasts implantation. (A) Step 1 Insertion of guide wire in center of lesion as identified on the MRI. (B) Step 2 Guide wire and 8mm cannulated drill for core decompression. The entry point of the guide wire is near the vastus ridge, to prevent a fracture due to stress-riser, greater width of femur and faster healing due to cancellous bone. (C) Step 3 Curettage: a variety of angulated curettes is used to do forage (curettage to remove necrotic bone). This bone is sent for biopsy.

Patients were operated on under spinal anesthesia. Core decompression tunnels were created into the subchondral necrotic lesion of the femoral head, approximately 23 mm away from the joint cartilage, by using 2.0-mm K-wires under fluoroscopic guidance through the greater trochanter and the femoral neck, and over drilled using trephine was performed by the centrally positioned K-wire. Cultured osteoblasts were injected following the curettage, and necrotic tissues were removed.

The patients had to undergo appropriate rehabilitation therapy after the implantation, which included complete bed-rest for 4 weeks post-implantation. After 4 weeks, passive lower limb exercises were performed for 2 weeks following post-implantation. Accordingly, non-weight bearing, partial weight bearing, and full weight bearing exercises were suggested as per the study protocol. Descriptive demographic and clinical data recorded before and after the procedure were collected from patient records. Past medical history, concomitant medications, and surgical treatments undertaken before and after the AALCO were recorded. Pre-existing risk factors for osteonecrosis such as steroid intake, alcohol consumption, comorbid conditions, or trauma were also noted.

Improvement in functional capacity and pain reduction were evaluated using Harris Hip Score (HHS) and visual analog scale (VAS) respectively at the time of pre- and post-operative consultations. Continued use of steroids or alcohol consumption after undergoing the AALCO implantation was recorded. The main outcome of the study was the need for THA (THA conversion rate). Based on these parameters, the treatment outcome was determined to be either improved (better score after AALCO implantation), stable (same condition as before AALCO implantation), or progressive (worse scores following AALCO implantation).

Continuous and quantitative variables were summarized using descriptive statistics and compared using Students t-test or nonparametric test, as applicable. Categorical data were presented as frequency count (n) and percentages (%) and were compared using the 2 test or Fishers exact test. P-values <0.05 were considered significant. All analyses were performed using the SPSS version 10.0.

Data from 64 patients were collected and analyzed as per the study protocol, and 101 hip joints were assessed. The age of patients ranged from 1270 years and BMI ranged from 20.632 kg/m2. The majority of the patients were men (79.7%). The mean duration since diagnosis of osteonecrosis was 7.4 1.6 years and the mean duration of AALCO treatment was 6.3 1.4 years (Table 1). Unilateral involvement of the hip joint was seen in 42.2% of cases. Bilateral involvement of hip joints was seen in 57.8% of patients. The majority of hips diagnosed were grade III (42.1%) and grade IV osteonecrosis (10.5%). While the exact cause for osteonecrosis was not known (idiopathic) in 25% of patients, 35.9% of cases were linked to steroid use and 26.6% to alcohol abuse. Records of concomitant medications revealed that 91.9% of patients were on analgesics, 8.1% were on ayurvedic treatment, and 1 patient took bisphosphonate.

Table 1 Demographic Characteristics

A total of 98 hip joints were assessed as data of 3 patients were not available for changes in mean VAS scores (improvement in pain), before and after the AALCO implantation. As shown in Figure 3A, the mean VAS score reduced significantly after a mean 6.3 years of AALCO treatment compared to the baseline (32.2 32.1 vs 58.8 13.8; mean difference: 26.5 35.2, p = 0.001) indicating significant improvement in pain. Similarly, HHS also improved post-operatively (47.1 12.3 vs 63.7 27.7; mean difference: 16.7 28.7, p = 0.001) showing functional improvement of patients. We categorized patients based on their HSS score (<70: poor, 7080: fair, 8090: good, 90100: excellent). At baseline, 96 hips (98%) had HSS score of <70, each of the two remaining hips had scores of <80 and <90, respectively. Improvement in HSS scores was seen at follow-up with 42 hips (43.3%) with HSS <70, 11 (11.3%) with 7080, 26 (26.8%) with 8090, and 18 (18.6%) with HSS scores of 90100.

Figure 3 (A) Changes in visual analog scale (VAS) and Harris hip scores. (B) Need for hip replacement surgery in different grades of osteonecrosis. (Osteonecrosis graded according to Association Research Circulation Osseous criteria).

The mean follow-up period since diagnosis of osteonecrosis was 6.3 years (range 49 years). Following AALCO treatment, 29 (28.7%) hips underwent THA, indicating that AALCO treatment could prevent and delay THA for 71.3% of hips. The mean time to THA was 3.2 2.0 years (range: 19 years). A total of 9 (39.1%) grade II, 11 (47.8%) grade III, and 3 (13%) grade IV hip joints required THA surgery (Figure 3B). In other words, AALCO treatment could delay THA for up to 3 years in 80% of hips in early stage osteonecrosis (Grades I and II) and 72% of hips in late stage osteonecrosis (Grades III and IV). Univariate analysis showed that the age of the patient, BMI, gender of patients, the side of osteonecrosis, and duration of disease had no effect on the clinical success of the procedure. Following AALCO treatment, 35.9% of patients continued using steroids and 29.7% continued with alcohol consumption. Of the total 29 hip joints that required surgery at follow-up, 20.7% and 41.4% had an associated etiology of alcohol consumption and steroid intake, respectively (Figure 4A). Overall, a significantly greater number of patients with underlying etiologies of alcohol consumption, smoking, or taking steroids required THA compared to those without these etiologies (14 [37.8%] vs 3 [11.1%], p = 0.017).

Figure 4 (A) Need for hip replacement stratified as per etiology of osteonecrosis. (B) Overall outcome stratified as per the grades of osteonecrosis.

Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematous.

Based on the pre- and post-operative data, the condition of 65.6% of patients improved and 1.6% remained stable following AALCO treatment. Overall, the condition of 65.9% of hips (56/85) in grade I to grade III improved (Figure 4B). For quick reference, the pre- and post-operative radiograph images for a given patient are presented in Figure 5.

Figure 5 Pre- and posttransplantation MRI and X-ray images (A): pre-operative MRI (male patient [35 years]): Ficat and Arlet Stage II B with a subchondral fracture of right hip with a large anterolateral lesion(arrow) involving more than 40% of femoral head and less than 2mm depression at high risk of collapse. Etiology is post steroid AVN. (B) Post-operative MRI at 5 months post-surgery. (C) Post-operative X-ray at 4 years after surgery; anteroposterior (AP) view and lateral view.

We retrospectively studied the clinical outcomes of AALCO treatment. Our results showed that there was a reduction in pain and improvement in joint function following AALCO implantation, as was evident from a statistically significant reduction in the mean VAS score and increase in the HHS score. Of all the hips that underwent the AALCO implantation, 60% improved and 38% worsened with a THA conversion rate of 28%.

AALCO is a minimally invasive, surgical 3-step procedure with each step contributing significantly to the overall effectiveness of the treatment. The first step is core decompression that reduces pressure allowing increased blood flow. In the second step, the necrotic bone is debrided by a curette that promotes new bone formation. The third and most important step is implantation of osteoblasts that form new bone. The THA conversion rate is reported lower with core decompression compared to natural progression of disease, but approximately 40% of patients still required THA.8 Bone marrow cell therapy was shown to improve the THA conversion rate further.9 In a recent randomized trial, implantation of autologous bone marrow aspirate concentrate did not show any improvement in patients with grade 3 osteonecrosis.10 In our study, AALCO implantation avoided THA in 72% of hips in late grade osteonecrosis, suggesting that the technique may even benefit patients in advanced stages of disease; however, our results are limited by the relatively small numbers of patients belonging to each stage.

The differences in the THA conversion may not be directly comparable to those with others may be due to the diversity in the presentation of patients, differences in the follow-up period, or the AALCO technique.13,14 The THA conversion rate certainly remains low with AALCO treatment compared to 75% THA conversion rate reported in patients with natural progression to osteoarthritis resulting from osteonecrosis of the femoral head.15,16 A randomized study found autologous osteoblastic cells implantation to be more efficacious than bone marrow implantation as an adjunct to core decompression. The disease progression rate was found to be 20% in patients who had undergone autologous osteoblasts implantation vs 47% in patients in the bone marrow implantation group.11 Bone alkaline phosphatase-characterized osteoblasts have better regenerative potential compared to heterogeneous bone marrow cells.17,18 Use of these characterized cells could explain the favorable outcomes of AALCO implantation in our study.

Intake of alcohol and/or steroids is known to adversely affect bone renewal by causing an imbalance between the normal progenitor cells and the fat-storing bone marrow progenitor cells.1,19,20 The latter phenotype also leads to fat embolism and arteriosclerosis reducing the blood supply to necrotic tissues.1,19,20 In our study, alcohol and steroid intake were associated with occurrence of osteonecrosis of the femoral head in more than a quarter of patients. These results highlight the adverse impact of alcohol and steroid intake on the progression of osteonecrosis that is already evident in the literature in the pathogenesis of osteonecrosis.2125 As expected, THA conversion rate was also higher among patients who consumed alcohol and/or used steroids compared to those who did not in our study, signifying the adverse impact of alcohol and steroids on the AALCO treatment outcomes. However, a consensus on the specific mechanisms leading to these observations is yet to be reached.

A major limitation of our study was the retrospective data collection, and the lack of assessments of radiographic progression of the affected hips.

The results of this study substantiate the therapeutic potential for AALCO in improving clinical outcomes in terms of pain and functional activity, and reducing the risk of disease progression and the need for THA in patients with osteonecrosis. However, this study was limited by the small sample size and the retrospective data collection limiting the power of study for some subgroup comparisons. Further, clinical studies and long-term trials are warranted to confirm the findings of this study.

Authors acknowledge CBCC Global Research for providing medical writing and submission support funded by Regrow Biosciences Pvt. Ltd.

The authors report no conflicts of interest in this work.

1. Hernigou P, Poignard A, Zilber S, Rouard H. Cell therapy of hip osteonecrosis with autologous bone marrow grafting. Indian J Orthop. 2009;43(1):4045. doi:10.4103/0019-5413.45322

2. Gangji V, Hauzeur J-P, Matos C, De Maertelaer V, Toungouz M, Lambermont M. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells: a pilot study. J Bone Joint Surg Am. 2004;86(6):11531160. doi:10.2106/00004623-200406000-00006

3. Vardhan H, Tripathy SK, Sen RK, Aggarwal S, Goyal T. Epidemiological profile of femoral head osteonecrosis in the North Indian population. Indian J Orthop. 2018;52(2):140146. doi:10.4103/ortho.IJOrtho_292_16

4. Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop. 2015;6(8):590601. doi:10.5312/wjo.v6.i8.590

5. ISHKS registry. Available from: http://www.ishks.com/pdf/ISHKS-registry-2019.pdf. Accessed December 17, 2020. 2019.

6. Xie XH, Wang XL, Yang HL, Zhao DW, Qin L. Steroid-associated osteonecrosis: epidemiology, pathophysiology, animal model, prevention, and potential treatments (an overview). J Orthop Translat. 2015;3(2):5870. doi:10.1016/j.jot.2014.12.002

7. Jaffr C, Rochefort GY. Alcohol-induced Osteonecrosisdose and duration effects. Int J Exp Pathol. 2012;93(1):7879. doi:10.1111/j.1365-2613.2011.00798_1.x

8. Houdek MT, Wyles CC, Martin JR, Sierra RJ. Stem cell treatment for avascular necrosis of the femoral head: current perspectives. Stem Cells Cloning. 2014;7:6570. doi:10.2147/SCCAA.S36584

9. Xu S, Zhang L, Jin H, et al. Autologous stem cells combined core decompression for treatment of avascular necrosis of the femoral head: a systematic meta-analysis. Biomed Res Int. 2017;2017:6136205. doi:10.1155/2017/6136205

10. Hauzeur JP, De Maertelaer V, Baudoux E, Malaise M, Beguin Y, Gangji V. Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial. Int Orthop. 2018;42(7):14291435. doi:10.1007/s00264-017-3650-8

11. Hauzeur JP, Toungouz M, Lechanteur C, et al. Autologous osteoblastic cells (PREOBy) versus concentrated bone marrow implantation in osteonecrosis of the femoral head: a randomized study. Revue de Chirurgie Orthopdique et Traumatologique. 2016;102(7):S73. doi:10.1016/j.rcot.2016.08.002

12. Cuende N, Rasko JEJ, Koh MB, Dominici M, Ikonomou L. Cell, tissue and gene products with marketing authorization in 2018 worldwide. Cytotherapy. 2018;20(11):14011413. doi:10.1016/j.jcyt.2018.09.010

13. Pepke W, Kasten P, Beckmann NA, Janicki P, Egermann M. Core decompression and autologous bone marrow concentrate for treatment of femoral head osteonecrosis: a randomized prospective study. Orthop Rev (Pavia). 2016;8(1):6162. doi:10.4081/or.2016.6162

14. Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. 2012;50(1):325330. doi:10.1016/j.bone.2011.11.002

15. Hernigou P, Habibi A, Bachir D, Galacteros F. The natural history of asymptomatic osteonecrosis of the femoral head in adults with sickle cell disease. J Bone Joint Surg Am. 2006;88(12):25652572. doi:10.2106/00004623-200612000-00002

16. Tomaru Y, Yoshioka T, Sugaya H, et al. Ten-year results of concentrated autologous bone marrow aspirate transplantation for osteonecrosis of the femoral head: a retrospective study. BMC Musculoskelet Disord. 2019;20(1):410. doi:10.1186/s12891-019-2797-4

17. Birmingham E, Niebur G, McHugh PE. Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche. Eur Cell Mater. 2012;23:1327. doi:10.22203/eCM.v023a02

18. Prins H-J, Braat AK, Gawlitta D, et al. In vitro induction of alkaline phosphatase levels predicts in vivo bone forming capacity of human bone marrow stromal cells. Stem Cell Res. 2014;12(2):428440. doi:10.1016/j.scr.2013.12.001

19. Cui Q, Wang GJ, Balian G. Steroid-induced adipogenesis in a pluripotential cell line from bone marrow. J Bone Joint Surg Am. 1997;79(7):10541063. doi:10.2106/00004623-199707000-00012

20. Hernigou P, Beaujean F, Lambotte J. Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis. J Bone Joint Surg Br. 1999;81(2):349355. doi:10.1302/0301-620X.81B2.0810349

21. Sakaguchi M, Tanaka T, Fukushima W, Kubo T, Hirota Y. Impact of oral corticosteroid use for idiopathic osteonecrosis of the femoral head: a nationwide multicenter case-control study in Japan. J Orthop Sci. 2010;15(2):185191. doi:10.1007/s00776-009-1439-3

22. Kubo T, Ueshima K, Saito M, Ishida M, Arai Y, Fujiwara H. Clinical and basic research on steroid-induced osteonecrosis of the femoral head in Japan. J Orthop Sci. 2016;21(4):407413. doi:10.1016/j.jos.2016.03.008

23. Cooper C, Steinbuch M, Stevenson R, Miday R, Watts N. The epidemiology of osteonecrosis: findings from the GPRD and THIN databases in the UK. Osteoporos Int. 2010;21(4):569577. doi:10.1007/s00198-009-1003-1

24. Fukushima W, Fujioka M, Kubo T, Tamakoshi A, Nagai M, Hirota Y. Nationwide epidemiologic survey of idiopathic osteonecrosis of the femoral head. Clin Orthop Relat Res. 2010;468(10):27152724. doi:10.1007/s11999-010-1292-x

25. Kang JS, Park S, Song JH, Jung YY, Cho MR, Rhyu KH. Prevalence of osteonecrosis of the femoral head: a nationwide epidemiologic analysis in Korea. J Arthroplasty. 2009;24(8):11781183. doi:10.1016/j.arth.2009.05.022

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[Full text] Retrospective Study on Implantation of Autologous-Cultured Osteoblasts | ORR - Dove Medical Press

The Report Titled on Orthopedic Regenerative Medicine Market which provides COVID19 Impact analysis on Market Size (Production, Capacity, Value, Values & Consumption), Regional and Country-Level Market Size, Segmentation Market Growth, Market Share, Competitive Landscape, Sales Analysis, Impact of Domestic and Market Players. Orthopedic Regenerative Medicine Market detailed study of historical and present/future market data. Economic growth, GDP (Gross Domestic Product), and inflation are some of the elements included in this report to offer crystal clear picture of the Orthopedic Regenerative Medicine industry at global level.

Orthopedic Regenerative Medicine Market competitive landscapes provides details by topmost manufactures like (Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.), including Capacity, Production, Price, Revenue, Cost, Gross, Gross Margin, Growth Rate, Import, Export, Market Share and Technological Developments.

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Market Segmentation & Coverage:

This research report categorizes the Orthopedic Regenerative Medicine to forecast the revenues and analyze the trends in each of the following sub-markets:

By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Based on Geography, the Orthopedic Regenerative Medicine Market studied across Americas, Asia-Pacific, and Europe, Middle East & Africa. The Americas region surveyed across Argentina, Brazil, Canada, Mexico, and United States. The Asia-Pacific region surveyed across Australia, China, India, Indonesia, Japan, Malaysia, Philippines, South Korea, and Thailand. The Europe, Middle East & Africa region surveyed across France, Germany, Italy, Netherlands, Qatar, Russia, Saudi Arabia, South Africa, Spain, United Arab Emirates, and United Kingdom.

Impact of COVID-19 on this Market:

The pandemic of COVID-19 continues to expand and impact over 175 countries and territories. Although the outbreak appears to have slowed in China, COVID-19 has impacted globally. The pandemic could affect three main aspects of the global economy: production, supply chain, and firms and financial markets. National governments have announced largely uncoordinated, country-specific responses to the virus. As authorities encourage social distancing and consumers stay indoors, several businesses are hit. However, coherent, coordinated, and credible policy responses are expected to offer the best chance at limiting the economic fallout.

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Competitive Strategic Window:

Competitive Strategic Window analyses the competitive landscape in terms of markets, applications, and geographies. 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 acquisition strategies, geography expansion, research & development, and new product introduction strategies to execute further business expansion and growth.

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Orthopedic Regenerative Medicine Market Size to Witness A Lucrative Growth Over 2020-2027 | Curasan, Inc., Carmell Therapeutics Corporation, Anika...

World Cancer Day: Blood cancer can be managed with treatments such as chemotherapy, radiation therapy

World Cancer Day 2021: This day is observed on February 4. Blood cancer originates in the blood forming tissues when abnormal blood cells start growing out of control, thereby interrupting the functioning of the normal blood cells. The normal blood cells help strengthen the immune system by fighting infection and producing new blood cells. Most blood cancers begin in the bone marrow where blood is produced. The three most common blood cancers are lymphoma, leukaemia and multiple myeloma. The common symptoms include weakness, shortness of breath, minimal injury resulting in fractures, excessive or easy bruising, bleeding gums, recurrent infections and frequent vomiting sensations. Blood cancer can be managed with treatments such as chemotherapy, radiation therapy and stem cell transplant.

Multiple myeloma

Multiple Myeloma develops in the bone marrow and affects plasma cells of the body. Plasma cells are responsible for producing antibodies that attack infections and diseases. When these cells become cancerous, they collect in the bone marrow and weaken the bones, causing pain on movement. They also produce antibodies that are useless and make the body weaker. Some common symptoms for multiple myeloma include low blood count, high calcium levels, kidney problems and spinal cord compression due to weakened bones.

Also read:Cervical Cancer During Pregnancy: Here's All You Need To Know

Lymphoma

Lymphoma affects the lymphatic system, which is responsible for getting rid of toxins in the body. When the immune cells, or lymphocytes, grow out of control, they collect in the lymph nodes, spleen and in other tissues, and organs. The main types are Hodgkins and non-Hodgkin lymphoma. Some common symptoms for lymphomas include painful swelling in the neck, groin, and armpits, fever and drenching sweats, fatigue, unexplained weight loss and shortness of breath.

Leukaemia

Leukaemia is cancer in the bone marrow that gradually spreads to the bloodstream. It is the most common cause of death due to cancer in India. In Leukaemia, the bone marrow produces metamorphosed cells, that outgrow the healthy blood cells gradually. There are multiple forms of leukaemia, but the diagnosis is determined based on speed of symptom development and the type of blood cells that accumulate. Some common symptoms for leukaemia include severe and frequent infections, recurrent nosebleeds, tiny red spots on the skin and excessive sweating and pain in the bones and joints.

While lymphomas and leukaemia affect both children and adults, Myeloma is more prevalent among adults.

Also read:What To Do When A Cancer Patient Tests Positive For COVID-19?

There are several therapies that can be used for treating the different kinds of blood cancer such as:

While there have been developments and advancement in therapies and treatments available for cancer, a significant portion of the future cancer burden can be prevented if we take necessary precautionary measures in the early stages. Better control on tobacco sale and consumption, dietary changes, expansion and equitable distribution of medical facilities, awareness about education programs and risks, prevention, and knowing the benefits of bone marrow donation can go a long way in reducing the burden of blood cancer.

Also read:Alarming Cancer Symptoms Men Should Not Ignore

(Dr Nitin Sood, Director, Hemato Oncology and Stem Cell Transplant Medical and Haemato Oncology, Cancer Institute, Medanta)

Disclaimer: The opinions expressed within this article are the personal opinions of the author. NDTV is not responsible for the accuracy, completeness, suitability, or validity of any information on this article. All information is provided on an as-is basis. The information, facts or opinions appearing in the article do not reflect the views of NDTV and NDTV does not assume any responsibility or liability for the same.

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World Cancer Day 2021: Know All About The Different Types Of Blood Cancer From Expert - NDTV Doctor

GlobeNewswire2021-02-01

Acumen Research and Consulting, a global provider of market research studies, in a recently published report titledBone Marrow Transplantation Market Global Industry Analysis, Market Size, Opportunities and Forecast, 2020-2027

LOS ANGELES, Feb. 01, 2021 (GLOBE NEWSWIRE) -- The Global Bone Marrow Transplantation Market size is projected to reach US$ 15 Bn by 2027, with CAGR of 5.7% during 2020-2027

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Disease, cancer, or chemotherapy may damage or kill the bone marrow. A surgical procedure is known as bone marrow transplantation, which replaces compromised or lost bone marrow. Stem cells are collected, processed, frozen and stored in a patient's autologous transplant and then returned to the patient after intensive therapy. Stem cells are obtained from an appropriate donor in an allogeneic transplant and transplanted to the recipient to cure the disease and rebuild the immune system of the recipient.

The growing prevalence of cancer and anemia is the leading catalyst for the growth of global demand for bone marrow transplantation. In turn, global demand for bone marrow transplantation will also expand with advances in technology, enhanced health services, recent evidence of cardiac and neuronal bone marrow transplantation, expanded logistic treatment development and increased per-capita health spending. However, high treatment costs, shortage of bone marrow donors and payment instability in many countries remain a major barrier to the global demand for bone marrow transplantation.

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Cell therapy and tissue engineering products for commercialization

The growing demand for bone marrow transplantation is expected to expand in the industry with several organizations involved in clinical trials for cell therapy and tissue engineering products worldwide. Many of the companies have grown from R&D to full market firms. Over the last five years, some have experienced over 30% growth. Stem cell graft is one of the fastest growing cell therapies on the market, estimated at USD 510 million by the end of 2015.

Small Bone Marrow Repayment and Billing Laps

In developed regions, the inability to pay for organ transplantation techniques in tandem with cost-effective bone marrow transplantation has contributed to the slower implementation of the bone marrow transplantation method, particularly in developing regions. Approximately 30% of the world's people consider their bone transplantation to be financially secure.

The CMS payment scheme, which returns significantly low compared to real bone marrow transplantation prices, underlines the limited scope of drugs. The amount of government interest is 47% higher than the actual cost of the operation. This adds up to nearly US$ 40,000 in transplant costs in US medical transplant hospitals.

The increase in allogeneic demand for bone marrow transplants is driven by a lower incidence of disease recurrence and a strong increase in eligible donors.

Bone marrow transplantation with allogeneic substances is currently leading the bone marrow transplantation type. Demand for allogeneic bone marrow transplantation is driven by large increases in healthy patients and a reduced risk of disease recurrence. The market will soon be dominated by autologous bone marrow transplant due to the increasing number of stem cell banks that store healthy cells in patients and the development of healthy blood cells in patients after treatment with conditioning.

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The lymphoma indicator is behind a significant uptick in new cases of Hodgkin and increased survival levels for post-bone marrow transplantation.

The bone marrow transplantation industry is mainly in the lymphoma group. This consists of 2 types of Hodgkin and Non-Hodgkin lymphoma. 83,180 new cases of lymphoma were registered by the National Cancer Center (NCI) in 2018. Lymphoma progression is driven by a large increase in lymphoma patients and a higher survival rate after bone marrow transplantation. Throughout 2018, 60,300 new cases of leukemia have been reported by the National Cancer Institute, while leukemia is irregular in the development of white blood cells in the bone marrow.

Regional Stance

Europe held significant market share in 2019 in bone marrow transplantation owing to the high number of bone marrow transplants and the expansion of bone marrow registries. With strong potential for treatment, Latin America is expected to see a significant increase in the number of bone marrow transplants.

Key Players & Strategies

Participants include major global Agendia, Sanofi, Diadexus Inc., Abbott, Qiagen N.V., and Others.

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Bone Marrow Transplantation Market to Surpass US$ 15 Bn By 2027: Acumen Research And Consulting - IT News Online

Stem Cell Therapy Market is valued at USD 9.32 Billion in 2018 and expected to reach USD 16.51 Billion by 2025 with the CAGR of 8.5% over the forecast period.

Rising prevalence of chronic diseases, increasing spend on research & development and increasing collaboration between industry and academia driving the growth of stem cell therapy market.

Scope of Stem Cell Therapy Market-

Stem cells therapy also known as regenerative medicine therapy, stem-cell therapy is the use of stem cells to prevent or treat the condition or disease. Stem cell are the special type of cells those differentiated from other type of cell into two defining characteristics including the ability to differentiate into a specialized adult cell type and perpetual self-renewal. Under the appropriate conditions in the body or a laboratory stem cells are capable to build every tissue called daughter cells in the human body; hence these cells have great potential for future therapeutic uses in tissue regeneration and repair. Among stem cell pluripotent are the type of cell that can become any cell in the adult body, and multipotent type of cell are restricted to becoming a more limited population of cells.

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The stem cell therapy has been used to treat people with conditions including leukemia and lymphoma, however this is the only form of stem-cell therapy which is widely practiced. Prochymal are another stem-cell therapy was conditionally approved in Canada in 2012 for the treatment of acute graft-vs-host disease in children those are not responding to steroids. Nevertheless, hematopoietic stem cell transplantation is the only established therapy using stem cells. This therapy involves the bone marrow transplantation.

Stem cell therapy market report is segmented based on type, therapeutic application, cell source and by regional & country level. Based upon type, stem cell therapy market is classified into allogeneic stem cell therapy market and autologous market.

Stem Cell Therapy Companies:

Stem cell therapy market report covers prominent players like,

Based upon therapeutic application, stem cell therapy market is classified into musculoskeletal disorders, wounds and injuries, cardiovascular diseases, surgeries, gastrointestinal diseases and other applications. Based upon cell source, stem cell therapy market is classified into adipose tissue-derived mesenchymal stem cells, bone marrow-derived mesenchymal stem cells, cord blood/embryonic stem cells and other cell sources

The regions covered in this stem cell therapy market report are North America, Europe, Asia-Pacific and Rest of the World. On the basis of country level, market of stem cell therapy is sub divided into U.S., Mexico, Canada, U.K., France, Germany, Italy, China, Japan, India, South East Asia, GCC, Africa, etc.

Stem Cell Therapy Market Segmentation

By Type

Allogeneic Stem Cell Therapy Market, By Application

Autologous Market, By Application

By Therapeutic Application

By Cell Source

Stem Cell Therapy Market Dynamics

Rising spend on research and development activities in the research institutes and biotech industries driving the growth of the stem cell therapy market during the forecast period. For instance, in January 2010, U. S. based Augusta University initiated Phase I clinical trial to evaluate the safety and effectiveness of a single, autologous cord blood stem infusion for treatment of cerebral palsy in children. The study is estimated to complete in July 2020. Additionally, increasing prevalence of chronic diseases creating the demand of stem cell therapy. For instance, as per the international diabetes federation, in 2019, around 463 million population across the world were living with diabetes; by 2045 it is expected to rise around 700 million. Among all 79% of population with diabetes were living in low- and middle-income countries. These all factors are fuelling the growth of market over the forecast period. On the other flip, probabilities of getting success is less in the therapeutics by stem cell may restrain the growth of market. Nevertheless, Advancement of technologies and government initiative to encourage research in stem cell therapy expected to create lucrative opportunity in stem cell therapy market over the forecast period.

Stem Cell Therapy Market Regional Analysis

North America is dominating the stem cell therapy market due increasing adoption rate of novel stem cell therapies fueling the growth of market in the region. Additionally, favorable government initiatives have encouraging the regional market growth. For instance, government of Canada has initiated Strategic Innovation Fund Program, in which gov will invests in research activities carried out for stem cell therapies. In addition, good reimbursing scheme in the region helping patient to spend more on health. Above mentioned factors are expected to drive the North America over the forecast period.

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Stem Cell Therapy Market 2021: Global Key Players, Trends, Share, Industry Size, Segmentation, Forecast To 2027 KSU | The Sentinel Newspaper - KSU |...

The SA Bone Marrow Registry (SABMR) says their ability to recruit new donors has been severely limited by the outbreak of the second Covid-19 wave.

SABMR head of donor recruitment Nadia Chalkley said they typically recruit a few hundred new donors each year from the Eastern Cape.

The shrinking pool of donors has had a material impact on our ability to match patients suffering from life threatening blood diseases with suitable donors, she said.

At any given time, there are more than 200 patients in SA that need a bone marrow transplant. The fewer donors we have, the lesser the chance of finding a match. For patients with leukemia, thalassemia and other blood disorders, a bone marrow transplant is their only hope of survival.

Chalkley said the the current odds of finding a successful match is about one in 100,000 and will only get worse as the donor pool continues to shrink.

Sadly, more than 70% of patients struggle to find a stem cell match within their own families, which means many rely on strangers for a second chance at life.

If local donors are not forthcoming, we have to look overseas for potential matches, which is costly.

She said SABMR was working hard to ensure the safety of donors and patients by allowing online registration.

We also offer at-home sampling kits, which only requires a cheek swab. These kits can be delivered and collected free of charge from anywhere in the country.

Once new donors have completed the online registration form, they will be contacted by one of our consultants to discuss the easiest way of dispatching and collecting the kits.

One of the biggest misconceptions with regards to bone marrow donation, according to Chalkley, is that it involves large needles being pushed into ones spine.

However, the most common form of donation is whats called peripheral blood stem cell collection, since the same blood-forming cells found in bone marrow are also present in circulating blood.

The process is similar to donating plasma and doesnt require surgery.

In order to register as a bone marrow donor, you must be between the ages of 16 and 45 and meet the required standards listed by the SABMR.

A full list of the criteria can be found at https://sabmr.co.za/.

Each of us have a role to play. This new year, put away frivolous resolutions and rather direct your energy into making a difference by signing up as a donor. The simple act could just make someones new years wish come true, Chalkley said.

Visit the SABMR website, call 021-447-8638 or email donors@sabmr.co.za

Related

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Covid-19 leads to shortage of bone marrow donors - GO! and Express

EIMEAR Gooderham (ne Smyth) was just 25 when she died peacefully in hospital with her family at her bedside.

It was just a week after she had married Phillip Gooderham in hospital and she was buried in the wedding dress she never got to wear.

Almost two years on, her family hope a television documentary about Eimear - a make-up artist from the Coolnasilla area of west Belfast - will help create a positive and lasting legacy in her memory.

The programme, due to be broadcast on UTV and presented by journalist Sarah Clarke, features Eimear's own video diaries, which she had hoped would raise awareness of a campaign for stem cell donors that she launched before her death.

Ms Clarke said the documentary had aimed to "follow Eimear's journey, treatment and her recovery".

"She was very open about her battle and while a lot of the programme is distressing, it shows how courageous Eimear was," she said.

Eimear was diagnosed with stage two Hodgkins Lymphoma, a type of blood cancer, in September 2016.

She underwent 12 cycles of intensive chemotherapy and was given the all-clear in spring 2017.

But the disease returned and in December that year, Eimear was treated with an autologous stem cell transplant, intensive chemotherapy and her own stem cells returned afterwards to rescue her bone marrow from the effect of the treatment.

Months later she was given the good news she was in remission, but the Hodgkins Lymphoma returned again and doctors said her best chance of survival was another stem cell transplant - this time from a donor.

With neither of her siblings a match, she desperately needed to find a stem cell donor.

Eimear and her father Sean launched an appeal to raise awareness of the stem cell register, which allows donors of the correct tissue types to be matched with patients.

Their campaign saw the number of people joining the register in Northern Ireland soar.

Determined to use her own experience to help others, Eimear began filming videos on her phone for the UTV documentary.

Her desire to show her cancer battle as well as her upbeat outlook on life are reflected in the diaries, with many filmed as she underwent treatment.

Speaking ahead of the broadcast tonight, Ms Clarke said her own family's cancer battle had also inspired her to tell Eimear's story.

"In 2017, my nephew Jack was diagnosed with leukaemia, aged just 15," she said.

"I remember my brother Simon, who is a doctor, saying they may have to pursue a stem cell transplant. He knew how difficult it would be to find a match and to endure.

"Fortunately Jack didn't need it, but he had to undergo a year of intensive chemo and four years of maintenance chemo.

"It was rough and a very difficult period and thankfully he's now in remission, but it made me relate to Eimear and San's appeal."

On October 31 2018 - a year before Eimear and Phillip had planned to marry - she received her stem cell transplant.

A video extract of the days after the operation shows Eimear describe how "it's been really rough", as the donor's cells began attacking her cells - a condition known as graft versus host disease.

Despite being discharged from hospital, months later she became ill again with complications associated with the transplant - she was losing her brave battle.

Phillip tells the programme: "I wanted to tell her it was going to be ok, but I didn't want to lie to her. I wanted it to be over so she wasn't in pain".

In June 2019, the couple tied the knot and Eimear got "her final wish".

"We had had it planned, we had to cancel our wedding so it was, in the most horrific circumstances, the nicest way to end her life, by her getting her final wish," said Phillip.

Eimear died on June 27 2019.

Since then her family have continued to campaign to raise awareness of stem cell donation.

Her father Sean said they hope the programme will "highlight the need for more people in Northern Ireland to join the stem cell donor register, especially young men aged between 16 and 30".

Sarah also said while the documentary is "not exactly the one we set out to make, its still one of hope and courage".

"It was Eimears dying wish to raise awareness of stem cell donation and to help further research into the treatment to help others," she said.

"She was adamant she wanted people to sign the register and raise awareness. Her family feel the onus is now on them to continue this.

"The programme pays tribute to a courageous young woman and her family's desire to create a positive and lasting legacy in her memory."

Up Close: Eimears Wish is on UTV at 10.45pm.

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UTV documentary tells of young Belfast woman's lasting legacy to promote stem cell donation - The Irish News

Leukemia is the cancer of blood cells, usually white blood cells which fight and clears infections. It is also known as cancer of blood-forming tissues i.e lymphatic system and bone marrow. It is usually characterized by greatly increased numbers of abnormal white blood cells in circulating blood. It is a very serious disorder and the patient needs to change the blood regularly with normal blood from donors.

By Aysha Bibi

How does leukemia develop?

Our blood contains many different types of cells. These include red blood cells, white blood cells, and platelets. These cells are made on daily basis in the bone marrow. Leukemia happens when the body starts making white blood cells beyond its need. Immature white blood cells are released in the blood and these are non-functional. Moreover, as white blood cells increase in number, the number of red blood cells and platelets are not enough to maintain a healthy life and perform their normal functions.

Types of Leukemia

Leukemia has four main types

In the acute form of leukemia, cells multiply quickly in the bone marrow and enter the circulatory system too early but these cells are immature and non-functional. Chronic leukemia occurs when marrow produces mature cells and it progresses more slowly than other forms.

Lymphocytic leukemia is a type with an accumulation of apparently mature dysfunctional lymphocytes. Normally lymphocytes differentiate to form B-cells, T-cells, and natural killer cells which are the backbone of the immune system.

Myelogenous leukemia is a cancer of white blood cells usually granulocytes and monocytes. Either it is lymphocytic or myeloid, leukemia results in a compromised immune system, and the body cannot protect itself from different infections.

Acute lymphocytic leukemia(ALL) It is most common in children. It can spread to the central nervous system.

Acute myelogenous leukemia(AML) It is the second most common type of leukemia in children and also common in adults.

Chronic lymphocytic leukemia It is common in adults. This remains stable for many years but in some types, patients need treatment.

Chronic myelogenous leukemia(CML) Older people may are at higher risk for this type of leukemia.

Risk Factors

Some significant risk factors that can cause leukemia

Symptoms of Leukemia

Various types of leukemia can cause different symptoms. These symptoms usually not appear in the early stages, but they may include;

Diagnosis of Leukemia

CBC: with a blood test doctor looks at several different blood cells and their maturity. Immature cells may appear in the blood.

Bone marrow biopsy is done by taking bone marrow. With help of this doctor check the type and severity of leukemia.

CT scan and MRI are also done for the diagnosis of leukemia.

Treatment of Leukemia

Depending on the type of leukemia and its spreading, a doctor may look for the following options:

In a radiation treatment, high energy X-rays are used to kill leukemic cells. But normal cells are also affected.

In chemotherapy, different drugs are given to kill leukemic cells in blood and bone marrow. This may include a pill or injection in muscle or vein.

Targeted therapy is done to block the expression of some genes or proteins that are involved in the production of cancerous cells.

A Stem cell transplant involves a bone marrow transplant from a healthy donor. In this method, high-dose chemotherapy is done to destroy the leukemic cells of a patient. The healthy stems cells of donor are then injected to body.

Splenectomy is the removal of spleen and doctor may look for this option if spleen becomes fills with cancer cell and start affecting other body organs.

Preventing or reducing the risk of leukemia

Unfortunately, there is currently no cure for leukemia. Minimum exposure to pesticides and radiations may help to reduce the risk of leukemia. Leukemia can also be prevented by avoiding tobacco.

One can lower the risk of developing leukemia by following:

It is the best way to lower the risk of leukemia.

Studies have shown that overweight and obesity are also contributing factors to increasing the risk of developing leukemia.

Pollution, gasoline, car exhaust contains low levels of benzene. It is also found in offices and homes and found in paint, glue, etc. wearing a mask while using these may help you lower the risk of exposure.

Medical radiations like x-rays increase the risk of leukemia. Try to avoid unnecessary radiation exposure.

Your body and mind function at their best with a healthy diet. Proper nutrition provides energy fuel for body functioning, it also strengthens the immune system.

References:

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What Is Leukemia: And How To Prevent It? - Technology Times Pakistan

Full TitleA Phase 1 Multi-Dose Study of Human Placental Hematopoeitic Stem Cell Derived Natural Killer Cells (CYNK-001) in Adults with Primary or Secondary Acute Myeloid Leukemia (AML) in Morphologic Complete Remission with Minimal Residual Disease (MRD)Purpose

The purpose of this study is to find the highest dose of the investigational immunotherapy CYNK-001 that can be given safely in patients with acute myeloid leukemia (AML) that is in morphologic complete remission with minimal residual disease (MRD). Morphologic complete remission occurs when white blood cell and platelet counts are within the normal range and the amount of leukemia cells is below 5 percent in a bone marrow sample. MRD means there is still a small number of leukemia cells remaining in the bloodstream.

AML with MRD is often resistant to treatment and has a high chance of coming back. CYNK-001 is a cellular therapy made of healthy donated cells called natural killer (NK) cells. The NK cells are taken from human placenta and grown in a laboratory. There are proteins in NK cells that can kill cancer cells. CYNK-001 is given intravenously (by vein).

To be eligible for this study, patients must meet several criteria, including but not limited to the following:

For more information about this study and to inquire about eligibility, please contact Dr. Aaron Goldberg at 646-608-3752.

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A Phase I Study of CYNK-001 Immunotherapy in Adults with Acute Myeloid Leukemia in Remission with Small Amounts Remaining in the Blood - On Cancer -...

National Institute for Health and Care Excellence (NICE) recommends lenalidomide as a maintenance therapy for people with newly diagnosed multiple myeloma who have undergone a stem cell transplant

Uxbridge, UK, 27th January 2021: Celgene, a Bristol Myers Squibb (BMS) company, today announces that NICE has issued a Final Appraisal Document (FAD) recommending REVLIMID (lenalidomide) as maintenance treatment after an ASCT for newly diagnosed multiple myeloma in adults.[iv] From today, approximately 1150 eligible patients in England will have immediate access to lenalidomide as a treatment option, with interim funding provided via the Cancer Drugs Fund (CDF) before transferring to baseline commissioning. Lenalidomide is the first treatment to be made available on the NHS in this setting and provides an alternative to the standard watch-and-wait approach, allowing patients to receive active treatment to keep their cancer in remission.

Graham Jackson, Professor of Clinical Haematology at Newcastle Upon Tyne NHS Foundation Trust said: Multiple myeloma is a relapsing remitting disease where the goal of treatment is to ensure long periods of remission and a good quality of life. Maintenance therapy is integral to achieving this, particularly for newly diagnosed patients who have received a stem cell transplant. Having lenalidomide within our treatment armoury on the NHS will transform the way we manage the early stages of multiple myeloma. In clinical studies maintenance therapy has been shown to almost double the initial period of remission for this group of patients, so it is fantastic to be able to offer active treatment which can help to keep the cancer at bay.

Multiple myeloma is a cancer that affects the production of plasma cells in the bone marrow and in turn impacts the bodys immune system.[v] It is characterised by a relapsing-remitting pattern, which means that the disease goes through periods where the cancer is active and needs treatment, followed by periods where it is under control.[vi] Each time the cancer relapses, the length of time spent in remission shortens.[vii] The objective of maintenance therapy is to control the cancer during the period of remission and delay relapse of the disease.[viii]

Laura Kerby, Chief Executive of Myeloma UK said: We are delighted with this outcome. Patients who receive lenalidomide maintenance after high-dose therapy and stem cell transplant have a significant increase in overall survival, so the decision to make this available through the NHS is fantastic news.

Across the UK, around 1,500 newly diagnosed multiple myeloma patients undergo an ASCT each year,1,2 and most of them will eventually relapse.[ix] This first remission is a critical period for people with multiple myeloma, as it can be an indicator of the overall survival of the disease and it has been shown that effective maintenance therapy could be essential to long-term survival.[x]

Lynelle Hoch, General Manager at Bristol Myers Squibb UK & Ireland commented: Todays announcement marks an important milestone for those living with multiple myeloma, with lenalidomide being the first maintenance treatment option to be made accessible to eligible patients in England. We are grateful for the continued collaboration with NICE, healthcare professionals and Myeloma UK to ensure patients can benefit from lenalidomide in this setting.

Following the publication of this guidance, the NHS in Wales is expected to provide funding and resources for lenalidomide in this setting within two months. The treatment is already available on the NHS in Scotland and in Northern Ireland.[xi],[xii]

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National Institute for Health and Care Excellence (NICE) recommends lenalidomide as a maintenance therapy for people with newly diagnosed multiple mye...

As public demand grows for limited supplies of covid-19 vaccines, questions remain about the vaccines appropriateness for older adults with various illnesses. Among them are cancer patients receiving active treatment, dementia patients near the end of their lives and people with autoimmune conditions.

Recently, a number of readers have asked me whether older relatives with these conditions should be immunized. This is a matter for medical experts, and I solicited advice from several. All strongly suggested that people with questions contact their doctors and discuss their individual medical circumstances.

Experts advice may be helpful since states are beginning to offer vaccines to adults over age 65, 70 or 75, including those with serious underlying medical conditions. Twenty-eight states are doing so, according to the latest survey by The New York Times.

Q: My 80-year-old mother has chronic lymphocytic leukemia. For weeks, her oncologist would not tell her yes or no about the vaccine. After much pressure, he finally responded: It wont work for you, your immune system is too compromised to make antibodies. She asked if she can take the vaccine anyway, just in case it might offer a little protection, and he told her he was done discussing it with her.

First, some basics. Older adults, in general, responded extremely well to the two covid-19 vaccines that have received special authorization from the Food and Drug Administration. In large clinical trials sponsored by drugmakers Pfizer and Moderna, the vaccines achieved substantial protection against significant illness, with efficacy for older adults ranging from 87% to 94%.

But people 65 and older undergoing cancer treatment were not included in these studies. As a result, its not known what degree of protection they might derive.

Dr. Tobias Hohl, chief of the infectious diseases service at Memorial Sloan Kettering Cancer Center in New York City, suggested that three factors should influence patients decisions: Are vaccines safe, will they be effective, and what is my risk of becoming severely ill from covid-19? Regarding risk, he noted that older adults are the people most likely to become severely ill and perish from covid, accounting for about 80% of deaths to date a compelling argument for vaccination.

Regarding safety, there is no evidence at this time that cancer patients are more likely to experience side effects from the Pfizer-BioNTech and Moderna vaccines than other people. Generally, we are confident that these vaccines are safe for [cancer] patients, including older patients, said Dr. Armin Shahrokni, a Memorial Sloan Kettering geriatrician and oncologist.

The exception, which applies to everyone, not just cancer patients: people who are allergic to covid-19 vaccine components or who experience severe allergic responses after getting a first shot shouldnt get covid-19 vaccines.

Efficacy is a consideration for patients whose underlying cancer or treatment suppresses their immune systems. Notably, patients with blood and lymph node cancers may experience a blunted response to vaccines, along with patients undergoing chemotherapy or radiation therapy.

Even in this case, we have every reason to believe that if their immune system is functioning at all, they will respond to the vaccine to some extent, and thats likely to be beneficial, said Dr. William Dale, chair of supportive care medicine and director of the Center for Cancer Aging Research at City of Hope, a comprehensive cancer center in Los Angeles County.

Balancing the timing of cancer treatment and immunization may be a consideration in some cases. For those with serious disease who need therapy as quickly as possible, we should not delay [cancer] treatment because we want to preserve immune function and vaccinate them against covid, said Hohl of Memorial Sloan Kettering.

One approach might be trying to time covid vaccination in between cycles of chemotherapy, if possible, said Dr. Catherine Liu, a professor in the vaccine and infectious disease division at Fred Hutchinson Cancer Research Center in Seattle.

In new guidelines published late last week, the National Comprehensive Cancer Network, an alliance of cancer centers, urged that patients undergoing active treatment be prioritized for vaccines as soon as possible. A notable exception: Patients whove received stem cell transplants or bone marrow transplants should wait at least three months before getting vaccines, the group recommended.

The American Cancer Societys chief medical and scientific officer, Dr. William Cance, said his organization is strongly in favor of cancer patients and cancer survivors getting vaccinated, particularly older adults. Given vaccine shortages, he also recommended that cancer patients who contract covid-19 get antibody therapies as soon as possible, if their oncologists believe theyre good candidates. These infusion therapies, from Eli Lilly and Co. and Regeneron Pharmaceuticals, rely on synthetic immune cells to help fight infections.

Q: Should my 97-year-old mom, in a nursing home with dementia, even get the covid vaccine?

The federal government and all 50 states recommend covid vaccines for long-term care residents, most of whom have Alzheimers disease or other types of cognitive impairment. This is an effort to stem the tide of covid-related illness and death that has swept through nursing homes and assisted living facilities 37% of all covid deaths as of mid-January.

The Alzheimers Association also strongly encourages immunization against covid-19, both for people [with dementia] living in long-term care and those living in the community, said Beth Kallmyer, vice president of care and support.

What I think this question is trying to ask is Will my loved one live long enough to see the benefit of being vaccinated? said Dr. Joshua Uy, medical director at a Philadelphia nursing home and geriatric fellowship director at the University of Pennsylvanias Perelman School of Medicine.

Potential benefits include not becoming ill or dying from covid-19, having visits from family or friends, engaging with other residents and taking part in activities, Uy suggested. (This is a partial list.) Since these benefits could start accruing a few weeks after residents in a facility are fully immunized, I would recommend the vaccine for a 97-year-old with significant dementia, Uy said.

Minimizing suffering is a key consideration, said Dr. Michael Rafii, associate professor of clinical neurology at the University of Southern Californias Keck School of Medicine. Even if a person has end-stage dementia, you want to do anything you can to reduce the risk of suffering. And this vaccine provides individuals with a good deal of protection from suffering severe covid, he said.

My advice is that everyone should get vaccinated, regardless of what stage of dementia theyre in, Rafii said. That includes dementia patients at the end of their lives in hospice care, he noted.

If possible, a loved one should be at hand for reassurance since being approached by someone wearing a mask and carrying a needle can evoke anxiety in dementia patients. Have the person administering the vaccine explain who they are, what theyre doing and why theyre wearing a mask in clear, simple language, Rafii suggested.

Q: Im 80 and I have Type 2 diabetes and an autoimmune disease. Should I get the vaccine?

There are two parts to this question. The first has to do with comorbidities having more than one medical condition. Should older adults with comorbidities get covid vaccines?

Absolutely, because theyre at higher risk of becoming seriously ill from covid, said Dr. Abinash Virk, an infectious diseases specialist and co-chair of the Mayo Clinics covid-19 vaccine rollout.

Pfizers and Modernas studies specifically looked at people who were older and had comorbidities, and they showed that vaccine response was similar to [that of] people who were younger, she noted.

The second part has to do with autoimmune illnesses such as lupus or rheumatoid arthritis, which also put people at higher risk. The concern here is that a vaccine might trigger inflammatory responses that could exacerbate these conditions.

Philippa Marrack, chair of the department of immunology and genomic medicine at National Jewish Health in Denver, said theres no scientifically rigorous data on how patients with autoimmune conditions respond to the Pfizer and Moderna vaccines.

So far, reasons for concern havent surfaced. More than 100,000 people have gotten these vaccines now, including some who probably had autoimmune disease, and theres been no systematic reporting of problems, Marrack said. If patients with autoimmune disorders are really worried, they should talk with their physicians about delaying immunization until other covid vaccines with different formulations become available, she suggested.

Last week, the National Multiple Sclerosis Society recommended that most patients with multiple sclerosis another serious autoimmune condition get the Pfizer or Moderna covid vaccines.

The vaccines are not likely to trigger an MS relapse or to worsen your chronic MS symptoms. The risk of getting COVID-19 far outweighs any risk of having an MS relapse from the vaccine, it said in a statement.

Were eager to hear from readers about questions youd like answered, problems youve been having with your care and advice you need in dealing with the health care system. Visitkhn.org/columniststo submit your requests or tips.

Judith Graham: khn.navigatingaging@gmail.com,@judith_graham

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If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? - Kaiser Health News

Global Adipose Derived Stem Cell Therapy Market 2020 by Company, Regions, Type and Application, Forecast to 2026

Adipose derived stem cells (ADSCs) are stem cells derived from adipocytes, and can differentiate into variety of cell types. ADSCs have multipotency similar to bone marrow mesenchymal stem cells, thus ADSCs substitute for bone marrow as a source of stem cells. Numerous manual and automatic stem cell separation procedures are adopted in order to separate adipose stem cells (ASCs) from adipose tissue. Flow cytometry can also be used to isolate ADSCs from other stem cells within a cell solution.

This report is an essential reference for those who look for detailed information on the Global Adipose Derived Stem Cell Therapy Market. The report covers data on global markets including historical and future trends for supply, market size, prices, trading, competition and value chain as well as Global major vendor information. In addition to the data part, the report also provides an overview of Adipose Derived Stem Cell Therapy market, including classification, application, manufacturing technology, industry chain analysis and the latest market dynamics.

Global Adipose Derived Stem Cell Therapy Market Research Reports provides information regarding market trends, competitive landscape, market analysis, cost structure, capacity, revenue, gross profit, business distribution and forecast 2024.

Adipose Derived Stem Cell Therapy Market was valued at xx million US$ in 2020 and will reach xx million US$ by the end of 2025, growing at a CAGR of xx% during 2020-2025.

The Global Adipose Derived Stem Cell Therapy market is highly competitive and consists of a number of major manufacturers like BioRestorative Therapies, Inc., Celltex Therapeutics Corporation, Antria, Inc., Cytori Therapeutics Inc., Intrexon Corporation, Mesoblast Ltd., iXCells Biotechnologies, Pluristem Therapeutics, Inc., Thermo Fisher Scientific, Inc., Tissue Genesis, Inc., Cyagen US Inc., Celprogen, Inc., and Lonza Group, among others.

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Scope of the Report:

The segmentation has been done on the basis of types, applications, technology, and users. Each segment has been further explained with the help of Table of Content, Tables and Figures. This breakdown of the market gives the readers an objective view of the global Adipose Derived Stem Cell Therapy market, which is essential to make sound investments. Both these assess the path the market is likely to take by factoring in strengths, weaknesses, opportunities, and threats.

This report also includes the overall and comprehensive study of the Adipose Derived Stem Cell Therapy market with all its aspects influencing the growth of the market. This report is an exhaustive quantitative analysis of the Adipose Derived Stem Cell Therapy industry and provides data for making strategies to increase the market growth and effectiveness.

The Global Adipose Derived Stem Cell Therapy market 2019 research provides a basic overview of the industry including definitions, classifications, applications and industry chain structure. The Global Adipose Derived Stem Cell Therapy market analysis is provided for the international markets including development trends, competitive landscape analysis, and key regions development status.

Development policies and plans are discussed as well as manufacturing processes and cost structures are also analyzed. This report also states import/export consumption, supply and demand Figures, cost, price, revenue and gross margins.

In addition to this, regional analysis is conducted to identify the leading region and calculate its share in the global Adipose Derived Stem Cell Therapy market. Various factors positively impacting the growth of the Adipose Derived Stem Cell Therapy market in the leading region are also discussed in the report. The global Adipose Derived Stem Cell Therapy market is also segmented on the basis of types, end users, geography and other segments.

On the basis of geography, the market is segmented into North America, Europe, Asia Pacific, Latin America, and the Middle East and Africa.

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The major factors defined in this report are:

The study objectives of this report are:

To study and analyze the global Adipose Derived Stem Cell Therapy consumption (value & volume) by key regions/countries, product type and application, history data from 2014 to 2018, and forecast to 2024.

To understand the structure of Adipose Derived Stem Cell Therapy market by identifying its various subsegments.

Focuses on the key global Adipose Derived Stem Cell Therapy manufacturers, to define, describe and analyze the sales volume, value, market share, market competition landscape, SWOT analysis and development plans in next few years.

To analyze the Adipose Derived Stem Cell Therapy with respect to individual growth trends, future prospects, and their contribution to the total market.

To share detailed information about the key factors influencing the growth of the market (growth potential, opportunities, drivers, industry-specific challenges and risks).

To project the consumption of Adipose Derived Stem Cell Therapy submarkets, with respect to key regions (along with their respective key countries).

To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the market.

To strategically profile the key players and comprehensively analyze their growth strategies.

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Table of Content:

Chapter One: Industry Overview of Adipose Derived Stem Cell Therapy

Chapter Two: Manufacturing Cost Structure Analysis

Chapter Three: Development and Manufacturing Plants Analysis of Adipose Derived Stem Cell Therapy

Chapter Four: Key Figures of Major Manufacturers

Chapter Five: Adipose Derived Stem Cell Therapy Regional Market Analysis

Chapter Six: Adipose Derived Stem Cell Therapy Segment Market Analysis (by Type)

Chapter Seven: Adipose Derived Stem Cell Therapy Segment Market Analysis (by Application)

Chapter Eight: Adipose Derived Stem Cell Therapy Major Manufacturers Analysis

Chapter Nine: Development Trend of Analysis of Adipose Derived Stem Cell Therapy Market

Chapter Ten: Marketing Channel

Chapter Eleven: Conclusion

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Adipose Derived Stem Cell Therapy Market Projected to Witness a Double-Digit CAGR During 2018 to 2026 | Coherent Market Insights - The Courier

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New Jersey, United States,- Stem Cell Therapy Market Report gives a detailed analysis of the market. After a detailed examination of the current trends, the report shares the details around the factors fueling the markets momentum.

Forgiving an in-depth review of the market, the report showcases the factors that are affecting the markets overall growth. From network partners, production methods to revenue generating techniques, every detail is added in the report. In addition, the Stem Cell Therapy report has enclosed the data about the established players of the market.

Stem Cell Therapy report has a dedicated section that highlights the actions that can be appointed for global level expansion. The report is designed to guide through every step from planning till implementation.

The major players covered in the Stem Cell Therapy market are

Osiris Therapeutics Medipost Co. Ltd. Anterogen Co. Ltd. Pharmicell Co. Ltd. HolostemTerapieAvanzateSrl JCR Pharmaceuticals Co. Ltd. Nuvasive RTI Surgical Allosource

It is worth noting that the Stem Cell Therapy market report also gives a complete overview in terms of volume, market value, demand and supply. All these factors add up to become the market dynamics of the Stem Cell Therapy market. For leaping ahead of the competition and to make the most out of the emerging opportunities, it is essential to understand the market dynamics.

As per the Verified Market Reports experts, the Stem Cell Therapy market is going to balloon in terms of revenue and customer base. This conclusion was drawn out from the market indicators that are considered in the Stem Cell Therapy market report to form curated data. The crucial pieces of data are included in the form of tables, charts and graphs to give a visual representation of the complex and huge database.

What key insights does the Stem Cell Therapy market research provide?

Past and current revenue statistics of the Stem Cell Therapy market players analyzed at the regional level. Individual profiling of major stakeholders. Analysis of the Stem Cell Therapy market size on the basis of product type and end-use type. Accurate Stem Cell Therapy market forecast of volume in numbers and percentages. Demand prospect of individual segments covered in the Stem Cell Therapy report.

Segmentation of Stem Cell Therapy Market:

1.Stem Cell Therapy Market, By Cell Source:

Adipose Tissue-Derived Mesenchymal Stem Cells Bone Marrow-Derived Mesenchymal Stem Cells Cord Blood/Embryonic Stem Cells Other Cell Sources

2.Stem Cell Therapy Market, By Therapeutic Application:

Musculoskeletal Disorders Wounds and Injuries Cardiovascular Diseases Surgeries Gastrointestinal Diseases Other Applications

3.Stem Cell Therapy Market, By Type:

Allogeneic Stem Cell Therapy Market, By Application Musculoskeletal Disorders Wounds and Injuries Surgeries Acute Graft-Versus-Host Disease (AGVHD) Other Applications Autologous Stem Cell Therapy Market, By Application Cardiovascular Diseases Wounds and Injuries Gastrointestinal Diseases Other Applications

Stem Cell Therapy Market Report Scope

What queries are resolved by the Stem Cell Therapy market research?

1. What are the restraints slowing down the progress of Stem Cell Therapy market?2. Why are the end consumers getting more inclined towards alternative Stem Cell Therapy market products?3. How the Stem Cell Therapy market expected to shape in the next septennial?4. What strategies are being appointed by the major players of the Stem Cell Therapy market to stay ahead of the competition?5. What innovative technologies are being used by the established players of the Stem Cell Therapy market to stay ahead of the competition?

Why choose Verified Market Reports?

Smart dashboard to provide details about updated industry trends. Data collection from different network partners such as suppliers, vendors, service providers, for giving out a clear perspective of the Stem Cell Therapy market. Strict quality checking standards Data collection, triangulation, and validation. 24/7 at your service.

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Stem Cell Therapy Market Size, Growth Opportunities, Trends, Key Players and Forecast to 2027 - The Courier

The market research report titled Cell Isolation Market by Product (Instruments and Consumables), by Cell Type (Animal and Human), by Cell Source (Adipose Tissue, Embryonic/Cord Blood Stem Cells, and Bone Marrow), by Technique (Surface Marker-Based Cell Isolation, Centrifugation-Based Cell Isolation, and Filtration-Based Cell Isolation), by Application (Cancer Research, Biomolecule Isolation, Tissue Regeneration & Regenerative Medicine, Stem Cell Research, In Vitro Diagnostics, and Others), and By End-User (Hospitals & Diagnostic Laboratories, Research Laboratories & Institutes, Biotechnology & Biopharmaceutical Companies, and Others): Global Industry Perspective, Comprehensive Analysis, and Forecast, 20182025 published by Zion Market Research provides an insightful comprehension about the growth aspects, dynamics, and working of the globalCell IsolationMarket. The report entails details about the market with data collected over the years with its wide-ranging analysis. It also comprises the competitive landscape within the market together with a detailed evaluation of the leading players within the global Cell Isolation Market. In addition, it sheds light on the profiles of the key vendors/manufacturers comprising thorough assessment of the market share, production technology, market entry strategies, revenue forecasts, and so on. Further, the report will encompass the fundamental strategic activities such as product developments, mergers & acquisitions, launches, events, partnerships, collaborations, and so on. Apart from this, it will also present the new entrants contributing their part in the market growth.

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Global Cell Isolation Market: Competitive Players

Becton, Dickinson, and Company, Thermo Fisher Scientific, Inc., Merck KGaA, Beckman Coulter Inc., Terumo BCT, Bio-Rad Laboratories, Inc.

The Cell Isolation Market report also entails exhaustive examination of the key factors likely to propel or restrict the expansion of the global Cell Isolation Market during the forecast period in addition to the most recent and promising future trends in the market. Moreover, the report uses SWOT analysis and other methodologies to analyze the numerous segments [Product, Applications, End-Users, and Major Regions] of the global Cell Isolation Market. Furthermore, it comprises valuable understanding about the segments like their growth potential, market share, and developments. It also evaluates the market on the basis of its major geographical regions [Latin America, North America, Asia Pacific, Middle & East Africa, and Europe]. It entails quantitative and qualitative facets of the market in association to each country and region enlisted in the report.

Promising Regions & Countries Mentioned In The Cell Isolation Market Report:

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The Cell Isolation Market report also stipulates the computed expected CAGR of the market estimated on the basis of the existing and previous records concerning the global Cell Isolation Market. The report analyzes the market with the aim of being capable to get a clear picture of prevailing and anticipated growth patterns of the market. Furthermore, it entails the impact of numerous federal policies and rules on the growth and dynamics of the market during the forecast period. The thorough assessment put forth by our analysts assist to get more profound acquaintance of global markets and related industries. In addition, the report encompasses various tactics to discover the weaknesses, opportunities, risks, and strengths having the potential to impact the global market expansion.

Impact of COVID-19 (Coronavirus):The report will also entail a dedicated section assessing the influence of COVID-19 on the expansion of the global Cell Isolation Market during the coming period.

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Global Cell Isolation Market SWOT Analysis, Key Indicators, Forecast 2027 : Becton, Dickinson, and Company, Thermo Fisher Scientific KSU | The...

DILLON Dylan Pope concurs that 2020 was, by and large, not a great year. But he still found a way to make the most of it.

"It was a pretty tough year but having this to look forward to and reflect on has been something pretty big for me," he said.

Pope, a Montana Western defensive back, made the decision to donate bone marrow in December.

"I was nervous, but I was excited to help somebody," Pope said.

At the encouragement of his sister, Mariah, Pope registered with a non-profit called Be The Match in March, shortly after coronavirus knocked the world off kilter.

According to the organization's website, only one out of every 430 registered members will actually go on to donate bone marrow. Pope's sister has been registered for years without a match.

So, Pope was understandably taken aback when, after a little more than three months, he received a call telling him that he had been deemed a suitable donor for an anonymous recipient to receive his blood stem cells, which are derived from bone marrow.

"At first I thought it was fake," Pope said. "I didn't think there was any way it was going to happen after just three months."

With a donation date set in December -- because of confidentiality policies, Pope can't disclose what state or hospital the procedure took place at -- the next months were what one would expect: a lot of paperwork and a lot of blood tests.

The week before the donation, he began receiving daily injections to increase his stem cell count. He then made the trip with his younger brother, Brayton.

The process took eight hours and required only local anesthesia. A needle in his right arm drew blood, ran it through a machine that extracted stem cells and then a needle in his left arm injected blood back into his body.

"It's really not nearly as scary when you get there as you think it's going to be," Pope said.

It'll be a year before Pope learns the identity of who received his bone marrow. He's certain it'll be a moving, powerful experience.

"I bet it'll be pretty emotional thing for both of us, because it was pretty cool to be able to help them," Pope said.

Ryan Nourse, Montana Western's head football coach, said he wasn't surprised by Pope's willingness to donate bone marrow and said he and the program supported him the entire way.

"I think that's a really brave thing, courageous thing for Dylan to go do," Nourse said. "I think that selflessness will shine through to the other guys knowing that maybe I could help somebody in a similar position someday."

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'I was excited to help somebody': Montana Western's Dylan Pope reflects on donating bone marrow - MontanaSports

Mesoblast, MESO, is an Australian based biopharmaceutical company that has been a market favorite, even though the companys ups and downs have confused many investors.

The MESO share price has been inconsistent lately. This has prompted many investors to ask why. Analyzed carefully, MESO has done better than many stem cell businesses. Most stem cell businesses fail to ever make a profit and fail to even get a product to market. This can cause long-term problems with the stock price of any company.

ByMichael A. Mannen, MS

Mesoblast as a company is committed to offering groundbreaking cellular therapies for the treatment of many severe diseases using Mesenchymal Stem Cells. They are dedicated to cellular medicines and leveraging their stem cell technology. There are not many successful companies in this niche.

Adult stem cells are undifferentiated cells that divide and rebuild the damaged tissue. Mesenchymal Stem Cells are a type of adult stem cells generated from some of the adult tissues present in the body.

Stem cells have been found by scientists to have two properties: self-renewal and the potential to divide into specialized cell types. Multi-potent, mesenchymal stem cells are found to be present in many adult tissues. The bone marrow is considered by many scientists to be the most usable reservoir of adult human stem cells.

For several disorders, such as heart failure, the capacity to rebuild tissue may be groundbreaking for treatment. And this has been the inspiration for many companies exploring stem cell therapies.

However, what differentiates Mesoblast from other stem cell companies is its approach to treating inflammatory diseases. Their products have the potential to make breakthroughs a reality for many diseases.

The company has developed and manufactured its own patented mesenchymal lineage cells to be used for a range of ailments. These have a potential for the regeneration of tissues. These cells, however, secrete a number of biomolecules which can help the body heal more than just tissue damage. They may be important to supporting immune responses needed for recovery in many diseases.

Possible rejection of the patients immune system is the biggest problem with the use of stem cell therapies in heart diseases and other diseases. This can worsen many illnesses.

MESO does appear committed to the quality of its product. For MESO it is a question of the effectiveness and safety of their products. Its a long and winding road to provide adequate scientific proof when presenting breakthrough treatments to regulators. Many less reputable organizations have touted stem cells without doing the necessary scientific investigation or seeking the necessary regulatory approval. Mesoblast is trying to do things the right way. Committing to doing science the right way leads to a lot of inevitable ups and downs. This raises financial speculation and can lead to wild fluctuations in the stock price of any company.

A further significant advantage of some of Mesoblasts products is that they apparently can be administered to patients without needing donor matching. This increases their viability. Moreover, it allows for a wide spectrum of patients to be treated from their products. This gives them an advantage in comparison with other firms and should potentially allow them to increasingly gain a larger market share.

Of great interest to investors include the many clinical trial phase 3 products that Mesoblast has in its pipeline. These include MPC-06-ID, Remestemcel-L, and REVASCOR.

Remestemcel-L is a Mesoblast therapy that may theoretically have properties to help with the treatment of ventilator-dependent patients with COVID-19 patients. However, a clinical trial reported some concerns with the therapy meeting its primary endpoint. And it sent the stock down in December 2020. Obviously, there is a large demand for the treatment of complications linked to Covid-19, so this bad news disappointed investors.

However, another therapy has shown promise in the DREAM-HF Phase 3 for patients with chronic heart failure. Although the Revasacor did not stop heart failure, it did seem to deliver dramatic reductions in heart attacks and other negative cardiovascular events that plague heart failure patients.

Heart failure is a pathology that involves ones heart having trouble pumping. The condition impacts millions of people worldwide. In order to feed and maintain it working, the heart muscle depends on a continuous supply of oxygen rich blood. Having stem cell therapies is highly desirable to treat cardiovascular diseases. Hopefully, many Cardiovascular disorders can be treated with stem cell therapies in the future.

Other conditions such as hypertension and Coronary artery disease can help lead to heart failure. According to the Mayo Clinic, heart failure can cause significant health complications and lead to Liver and Kidney damage in patients.

Some scientists believe that Mesenchymal Stem Cells when used to treat cardiovascular diseases can preserve the myocardium by reducing the intensity of inflammation and supporting angiogenesis. Angiogenesis is a mechanism used by the body to create new blood vessels. Their low immunogenicity once more makes them a perfect treatment. This helps ensure that the immune system of the patient does not produce a negative response to the therapy. This theoretically can give stem cell therapies an advantage over some protein-based treatments that are easily recognized by the patients immune system.

This product could be a major development for Mesoblast moving forward, although further analysis and testing is still needed.

Stem cell therapies are not without experimental and medical challenges. For example, there are concerns with the ability of stem cell migration to tissues that require regeneration. There may also be cases whereby stem cells are divided into unintended cells. There may also be difficulties with the manufacturing and culturing of stem cells. Identification of Mesenchymal stem cells in cell populations can be problematic. From a scientific point of view, bone marrow derived Mesenchymal Stem Cells are known to be the best source for obtaining these cells in the human body.

Mesoblast has a wide range of advanced research programs related to different stem cell therapies. MPC-06-ID could potentially be a viable therapy for treating chronic low back pain attributable to degenerative disc disease.

These are products that consumers should be thrilled about.

The company has solid financials for a stem cell company and has a lot of cash on hand. The stock had a market cap of over 2 billion on 9/30/2020 and a 52-week high of 21.28. Lately the news surrounding the companys clinical trials has been a potpourri of both good and bad, so the share price has settled at around $9. It has a float of 93.7 million shares.

Mesoblast is a really exciting healthcare business. The business has made a commitment for the future. And it should be a stock that investors continue to follow.

Follow this link:
Mesoblast Limited: Is Stemcell Therapy Ready For Prime Time? - Sick Economics

Introduction

Chronic myeloid leukemia (CML) is a hematological malignancy that develops when the 9;22 translocation in a single hematopoietic stem cell (HSC) results in the expression of BCR-ABL1 tyrosine kinase fusion protein. If left untreated, CML progresses over approximately 5 years, from relatively benign chronic phase to accelerated phase, and then to fatal blast crisis. The introduction of tyrosine kinase inhibitors (TKIs) specifically targeting the BCR-ABL1 fusion protein was a breakthrough in the management of CML, leading to a significant reduction in mortality and improved 5-year survival rates. However, despite the high annual acquisition costs of all the TKIs; first-, second-, and-third line TKIs1 induce only transient responses in the 10% to 15% of CML patients diagnosed in advanced phase, suboptimal responses in approximately 30% of CML patients during chronic phase (CP) cases that experience disease progression each year during, and only 1020% chance of successful treatment discontinuation due to disease persistence.2 Among the causes of disease persistence, studies have shown that CML leukemia stem cells (LSC) play a major role in inducing therapeutic resistance and disease progression because they are able to self-renew.3,4 These LSC a rare subset of immature cells residing in the bone marrow niche are protected from the action of TKI5 because these cells are normally quiescent and the TKIs are designed to target malignant blast cells that proliferate. That is why current strategies are not able to effectively eliminate the LSC or the disease.3 In CML, LSC are primitive cells expressing CD34+ CD38- with the 9;22 translocations, or the Philadelphia chromosome (Ph).6 However, these markers cannot distinguish the cancer hematopoietic cells from normal ones. Additionally, the BCR-ABL fusion gene encodes for an intracellular tyrosine kinase protein rather than a surface protein, calling for the need to identify unique surface biomarkers for efficient targeting of this cell population with subsequent eradication of the root of the disease.

In 2010, a single biomarker, Interleukin 1 receptor accessory protein (IL1RAP), was found to be up-regulated on the cell surface of BCR-ABL+ LSC. They were able to distinguish Ph+ from Ph- LSCs using IL1RAP.7 A polyclonal anti-human IL1RAP was generated that not only targeted the LSC population but also killed normal peripheral blood mononuclear cells, indicating that this marker was not specific to the LSC.7 Another characteristic cell surface marker has been investigated; ThomsenFriedenreich antigen (TF, or CD176) a tumor-associated carbohydrate epitope. The CD176 antigen was found to be expressed on the surface of various cancer-initiating cells, such as breast carcinomas,8 colorectal carcinomas,9 several leukemias,10 and other types of cancer, but was absent from almost all normal adult cell types.11 CD176 was also found to be expressed on the surface of CD34+ hematopoietic stem cells of the K562 erythroblastic leukemia cell line; a cell line derived from a CML patient. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a suitable target for cancer biotherapy8 with the development of an anti-CD176 antibody that induced apoptosis of leukemic cells.12

Using monoclonal antibodies (mAb) as a tool for cancer therapy still has its limitations. Patients who receive mAb therapy may develop drug resistance or fail to respond to treatment owing to the multiple signaling pathways involved in the pathogenesis of cancer and other diseases.13 Targeting more than one molecule has proven to circumvent the regulation of parallel pathways and avoid resistance to the treatment.14 Bi-specific antibodies (Bis-Ab) are antibodies that can recognize two different epitopes. They can redirect specific immune cells to the tumor cells to enhance tumor eradication, enable the simultaneous blocking of two different targets that have common signaling pathways, or interact with two different cell-surface antigens instead of one with subsequent boosting of the binding specificity.13 Thus, the identification of two surface markers specific to the cancer stem cells would be useful in characterizing and targeting CML stem cells, without affecting other blood cells.

In this study, we evaluated co-expression of IL1RAP, linked to BCR-ABL+ expression, and the CD176 antigen, carried on the hematopoietic stem cell marker CD34 molecule, in CML patients. We identified PBMCs co-expressing CD34, IL1RAP, and CD176 antigens using flow cytometry, a finding that allowed for subsequent separation and targeting of such cells from normal HSCs. A bi-specific antibody (TF/RAP), was generated in order to target the IL1RAP+ and CD176+ cell population among PBMCs in patients with CML. We used a flow-cytometry assay as a cell-based assay to measure the antibody binding capability of the TF/RAP Bis-Ab to the cell surface antigens. Our TF/RAP Bis-Ab, increased targeting of the IL1RAP+ and CD176+ cell population among CML PBMCs but not corresponding normal cells, using complement-dependent cytotoxicity assay (CDC). This novel TF/RAP Bis-Ab may provide a novel strategy for the eradication of CML stem cells.

Deidentified samples of peripheral blood from healthy volunteers were obtained from Gulf Coast Regional Blood Bank (Houston, TX, USA) after signing informed consent and used as reference samples. Deidentified samples of peripheral blood mononuclear cells (PBMCs) from consented patients with CML were obtained from Oncology Research Gundersen BioBank (https://www.gundersenhealth.org/research/biobank/, La Crosse, WI, USA). While the samples were de-identified, necessary CML patient characteristics were collected (Table 1). The collection and dissemination protocols for the samples are approved by The Gundersen Human Subjects Committee/Institutional Review Board (IRB) and are in full compliance with National Cancer Institute Best Practices for Biospecimen Resources. Because the de-identified samples were received through Biobanks and not through direct intervention/interaction with a research subject, the Tulane University Human Research Protection Office was notified and this study was classified by the IRB as exempt as the study did not meet the definition of human subjects research according to US Federal policy (HHS regulations, 45 CFR part 46, subpart A, also known as the Common Rule). The study was conducted in accordance with the Declaration of Helsinki.

Table 1 CML Patients Characteristics

HEK 293FT cell line (Invitrogen # R70007) was cultured in DMEM (Life Technologies, Carlsbad, CA, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 U/mL penicillin, 100 g/mL streptomycin sulfate, and 4.0 mM L-glutamine (Gibco BRL products, Gaithersburg, MD), at 37C in a humidified 5% CO2 incubator. The KG1 cell line (ATCC #CCL-246) and transduced derivative cells were cultured in Iscoves Modified Dulbeccos Medium (Life technologies) supplemented with 20% FBS at 37C in a humidified 5% CO2 incubator. K562 cell line (ATCC# CCL-243) was maintained in RPMI-1640 (Life technologies) supplemented with 10% FBS, 100 U/mL penicillin, 100 g/mL streptomycin sulfate at 37C in a humidified 5% CO2 incubator.

The IL1RAP cDNA was PCR amplified from an expression plasmid containing Human IL-1RAcP/IL-1R3 Gene ORF cDNA (Sino biological Inc., HG10121-CM) using Clone Amp HiFi PCR Premix (Takara Bio USA, Inc.), and primers that included either a BamHI or an XhoI site (F-IL1RAP: acgggatccccaccaagcttggtaccatgac; R-IL1RAP: acgctcgagttatacatttttcaaagatg). The PCR fragment was gel extracted as above, sub-cloned into BamHI and XhoI sites in the pHRST-MPSV vector according to standard protocols and confirmed by restriction mapping and sequencing.

Transient production of lentiviral particles in adherent HEK293T was modified from previously described.15 Briefly, HEK293T cells were seeded in a T-75 flask, where we used 4.0 g of envelope plasmid pMPSV-VSV-G, 10.0 g packaging plasmid psPAX2, and 26 g transfer plasmid that has the gene of interest. In our case, the transfer plasmid is either the antibody plasmid or the control. The plasmids were mixed into 500 L 0.25 M CaCl2 (Sigma Aldrich, St. Louis, MO) and incubated at room temperature for 5 minutes, and then mixed with 500 L 2xHBS and briefly vortexed. The mixed transfection cocktail was then incubated for 3 minutes at room temperature, and added into the medium of the cells, and mixed gently to make an even distribution. After 16 hours of incubation, the medium was replaced with fresh medium and collected every 24 hours for 3 days. The conditioned medium that contained the vector virus was then pelleted for 10 minutes at 1500 g and passed through a 0.45-m filter to remove the cell debris, and then frozen at 80C for long-term storage, or used for the transduction of target cells.

Lentiviral transduction was done as previously described.1618 In brief, lentiviral supernatant was added to KG1 cells cultured in complete IMEM. After overnight incubation, the lentiviral vector was removed, and fresh media was added. After 48 hours, IL1RAP expression was demonstrated by flow cytometry using anti-Human IL-1 RAcP/IL-1 R3 PE-conjugated antibody (#FAB676P, R&D Systems, Minneapolis, MN).

The CH and CL constant domains in the pLM219 plasmids were amplified with 0.5 nM overlapping mutant primers (Table S1), Deep Vent Polymerase (New England Biolabs), and reaction buffer for forty cycles at 94C for 10 seconds, 60C for 45 seconds, and 72C for 2 minutes. Initial fragments were purified, combined, and used to amplify the entire heavy or light domains (Table S2). The mutated fragments were then gel purified and sub-cloned into their corresponding vectors using restriction enzymes according to standard protocols (Table S2). Sequences were then verified by restriction digestion and sequencing.

For antibody sequences towards CD176 (TF) and IL1RAP, the VH and VL domains from two clones with the most conserved amino acid sequences (TF Clone 1 and Clone 2 called TF1 and TF2 for CD176; Clone 4B6 and Clone 4G9 called RAPa and RAPb for IL1RAP, respectively) were chosen from published sequences.20,21 IL1RAP antibody was designed to target the extracellular membrane anchor-proximal region that comprises an amino acid primary sequence VPAPRYTVELAC within 10 to 15 amino acids of amino acid 361 of human ILR1AP (Gene bank accession Q9NPH3) while the TF antibody was designed to target the same Gal(13)GalNAc disaccharide epitope20 as the Bis-Ab. Variable domains (VD) were codon-optimized and synthesized (Gene Art, Invitrogen) to be compatible with 15 base pairs of homologous sequences on both the 3 and 5 ends of pLM2 recipient plasmid flanking the EcoRI restriction enzyme site.

The pLM2 expression vector was digested with EcoRI to generate a double-stranded break. An In-Fusion HD cloning kit (Clontech, Inc) was used to clone the VD regions of the antibodies between the leader and constant regions of the pLM2 vectors. The correct clones were identified by PCR and restriction mapping and then verified by sequencing.

Adherent HEK cells were transfected as above. A total of 14 g high-quality plasmid-DNA, 10% GFP plasmid for assessment of transfection efficiency, while the rest was heavy and light chain plasmid DNA combined at a ratio of 1:1. Six to 8 hours later, cells were gently washed once with PBS and fresh growth medium added. Sixteen hours post-transfection, the medium was replaced with DMEM supplemented with 5% FCS and incubated at 5% CO2 for 24 hours prior to the initial collection of antibody supernatant. A second collection was made after a further 24 hours.

Flow antibodies used were as follows: anti-TF/CD176 mAb mouse IgM (Glycotope, Berlin, Germany) targeting Gal1-3GalNAc epitope; FITC-conjugated anti-mouse IgM secondary antibody (-chain specific, #F9259; Sigma); PE-conjugated mouse anti-human IL-1 RAcP/IL-1 R3 monoclonal IgG1 antibody, epitope Ser21-Glu359 (#FAB676P, R&D Systems); APC-conjugated mouse anti-human CD34 monoclonal IgG1 antibody (#QBEnd10, FAB7227A-025, R&D Systems); APC-conjugated mouse antihuman IgG monoclonal antibody (Clone G18-145, mouse IgG1 , #550,931, BD Pharmingen).

LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (#L34957, Invitrogen); Vibrio Cholera Neuraminidase (VCN; Sigma Aldrich Inc), an enzyme used to expose the CD176 on the surface of expressing cells. Flow cytometric analyses were performed in a BD LSR Fortessa (BD Biosciences, USA) and flow cytometric cell sorting was done in a FACSAriaII (P0010) cell sorter (BD Biosciences, USA). The amount of bi-specific antibody bound to the receptors was calculated from the frequency of total IgG bound receptors.

Sorted cells were received in RPMI media and then fixed using the standard 3:1 methanol: acetic acid fixative. Standard procedures were used for FISH hybridization and washing.22 The BCR/ABL1 Plus translocation, dual fusion probe set (Cytocell Inc., Tarrytown, NY) was used. Slides were analyzed using Leica Biosystems Cyto Vision. FISH nomenclature was described according to the ISCN 2016.23

CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- cells were sorted from PBMC samples derived from patients with CML. Cells (1 x 103) were plated in Metho Cult Express (#04437, Stem Cell Technologies, Vancouver, Canada) semi-solid media containing recombinant human IL-3, IL-6, G-CSF, GM-CSF, SCF, TPO and cultured for 2 weeks in a humidified atmosphere at 37C with 5% CO2. Fourteen days after plating, the number of colonies was counted by microscopy.24,25

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% v/v) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% (v/v)) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

We measured the production of the Bis-Ab by ELISA. Plates were initially coated with goat anti-Human IgG heavy chain antibody (Axell) and blocked with PBS containing 0.5% Tween 20 (Fisher), 10% FBS (FetalPlex Animal Serum Complex, GeminiBio, Cat#100-602), 4% whey protein (BiPRO, AGROPUR). Undiluted or diluted supernatant was added, including the standard curve samples (human IgG MAb 1.7B, kindly provided by Dr. James Robinson), and negative blocking buffer. After incubating at 37C for 60 min, the plates were washed. Then, goat anti-Human lambda antibody conjugated to HRP (Southern Biotech, Cat# 207005) was added at 1:300 in blocking buffer for 60 min and washed five times. A mixture of 0.1M Na Acetate (pH 6), peroxide, and TMB substrate were added. The reaction was terminated by adding 1M phosphoric acid, and the absorbance of each well was measured at 450 nm using a Synergy H1 microplate reader (BioTek).

For each experiment, more than three independent replicates were conducted, and the results were expressed as average standard deviation. Comparison of multiple groups was conducted using ANOVA-based Test and p< 0.05 (*) represented significances with statistical meaning. Calculation of the Kd was done using the equation % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody and Kd is the equilibrium dissociation constant.

In order to analyze the co-expression of CD176 and IL1RAP antigens on CD34+ cells, peripheral blood mononuclear cells from a normal volunteer (NPBMCs), patients with CML, and K562 cells were isolated and stained with anti-CD34, anti-CD176, and anti-IL1RAP monoclonal antibodies and analyzed by flow cytometry (Figure 1A). It has been previously established that these markers were not expressed on normal PBMCs nor on stem cells7,10 CD34+ cell expression ranged from an average 938% in CML samples versus 83.7% in K562 cells (Figure 1A, upper panel). Within the CD34+ cell population, CD176 and IL1RAP antigens were variably expressed in CML samples, ranging from 1.35% in CML-4 to over 50% in CML-1 (Figure 1A, lower panel), while CD176+ IL1RAP+ was detected in 78% of CD34 cells in K562 cells. Surprisingly, surface co-expression of CD176 and IL1RAP was not only detectable on CD34+ cells in patients with BCR-ABL positive CML but was also demonstrable in cells from a treated patient who was BCR-ABL negative (CML-2) (Figure 1B). In Figure 1C, CD34+ cells revealed higher frequency of CD176+ IL1RAP+ in CML group compared to control sample (17.5% versus 3.4%, p<0.001).

Figure 1 CD176 and IL1RAP antigens are co-expressed on CD34+ Leukemia stem cells. Peripheral blood mononuclear cells from patients with CML and healthy volunteers were isolated and stained for flow-cytometry analysis. (A) FACS Dot Blot showing expression of CD34 (top row) and co-expression of CD176 and IL1RAP antigens on the CD34+ cells (bottom row) in PBMCs from patients with CML compared to NPBMCs. (B) Bar graphs showing the BCR-ABL status relative to the percentage of IL1RAP and CD176 co-expression in the CD34+ subsets from patients with CML as compared to the normal control and the positive control (K562 cells). The BCR-ABL status is indicated below the sample. The error bars represent the variation in two independent experiments. (C) Average percentage of CD34+ and CD34+ CD176+ IL1RAP+ subsets in normal versus CML patients respectively. (D) Bar graphs showing the average count of colony-forming units (CFU) per 1000 CD34+CD176+IL1RAP- cells (open bar) or CD34+CD176+IL1RAP+ cells (solid bar) obtained from CML-2 and CML-4 samples. **p< 0.01, n.s represents that there is no significant difference between groups.

In order to analyze the progenitor activity of the various subpopulations, CML-2 and CML-4 were flow-sorted for CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- then plated in media t support hematopoietic colony formation. The number of colonies, or colony-forming units (CFU), in CD34+CD176+IL1RAP+ pool represented 6% of the sorted cells with a significant difference between both populations, p<0.01 (Figure 1D and Figure S1).

To facilitate correct interaction of the VH and VL domains, site-directed mutagenesis was used to generate knob-in-hole mutations in the heavy and light chains of the constant domains (Figure 2A) via polymerase chain reaction overlap extension (Figures S2 and 3). Two PCR reactions were performed to generate two amplicons with the specific mutations included in the overlapping primers. The two fragments were then combined in a subsequent fusion reaction, in which the overlapping ends anneal, allowing the 3 overlap of each strand to serve as a primer for the 3 extension of the complementary strand. The resulting fusion product served as a template for amplification of the entire constant domain. In order to circumvent the light chain mismatching, an Orthogonal Fab interface was generated. In one Fab, complementary mutation was introduced and verified at the heavy chain constant domain (CH1_H172A_ F174G) and at the light chain constant domain (CL_L135Y_S176W), respectively (Figures S46). For the heavy chain heterodimerization, we used the Knob-in-Hole strategy, where we inserted the CH3 mutations (S354C and T366W) into different heavy chains (Figures S7 and 8). The VH and VL sequences were synthesized and cloned into the new pLM2-CH and -CL plasmids (Figure 2A) where CD176 was represented by TF1 (VH1 and VL1) and TF2 (VH2 and VL2) while IL1RAP was represented by Clone 4B6 (VHa and VLa) and Clone 4G9 (VHb and VLb). Then, we generated the four different bi-specific antibody mixtures (TF1RAPa, TF1RAPb, TF2RAPa, and TF2RAPb) to evaluate the most effective Bis-Ab (Figure 2B). The bispecific antibody was quantified by ELISA at 283 ng/mL. Since ELISA used the human IgG heavy chain antibody as the primary antibody and a goat anti-human lambda antibody conjugated to HRP as the secondary antibody, these data also confirm the correct association of the heavy and light chains and ensure that monomers are excluded.

Figure 2 The bi-specific antibody arms. (A) Schematic diagram of the bi-specific antibody showing the mutant arms and the antigen-binding domains. Thomsen-Freidenrich or CD176 domains (TF); IL1RAP domains (RAP); variable domain-heavy chain (VH); variable domain-light chain (VL); L135Y and S176W mutations (Y-W) in constant domain-light chain; H172A and F174G mutations in CH1 domain (A-G); S354C (C) or T366W (W) mutations in CH3. (B) Antibody mixtures generated by transient transfection of HEK 293T cells. TF1 and TF2 was paired with RAPa and RAPb to generate four Bis-Ab mixtures. The bispecific antibody concentration was 283 ng/mL as measured with ELISA. The correct association of the human IgG heavy chain and the lambda light chain was confirm and monomers were excluded by using anti-IgG primary antibodies and anti-light chain secondary antibodies.

KG1 cell line is an acute myeloid leukemia cell line that is known to be a positive control for CD176. For optimizing the staining protocol of CD176, KG1 cells were pre-treated with VCN to expose CD176 antigens for better staining (Figure S9). In order to test the binding capability and functional potential of our bi-specific antibody, we generated a dual-positive cell line for expressing both IL1RAP and CD176 through lentiviral transduction (Figure S10A and B). IL1RAP expression was increased by 1.5 folds in KG1/RAP cells as verified by flow cytometry (Figure S10C and D).

CD176 antigen is a glycosylated antigen; a protein antigen bound to GAL-NAC moiety which makes the antigen displayed on the cell surface yet not easy to isolate.21 For this reason, a flow-cytometry assay was used to evaluate both the binding capability and toxicity of our Bis-Ab using the gating strategy in Figure S11. KG1 and KG1/RAP cell lines were treated with the various Bis-Ab mixtures. Binding percentage was calculated from the percentage of IgG positive cells, where the secondary IgG antibody is bound to the primary Bis-Ab. The TF1RAPa Bis-Ab showed the highest binding in KG1/RAP cells (Figure 3A) as compared to other mixtures (p<0.001). In contrast, the TF1RAPb antibody revealed slightly reduced binding in KG1/RAP cells. On treating KG1/RAP cells with increasing amounts of TF1RAPa, more binding to the dual-positive KG1/RAP cells was observed (Figure 3B). To demonstrate the specificity of the Bis-Ab, we measured the competition with the CD176 and the IL1RAP monoclonal antibodies. Increasing concentrations of the Bis-Ab specifically inhibited the binding of both the IL1RAP and CD176 mAbs (Figure S12). Then, our KG1/RAP cells were treated with the Bis-Ab TF1RAPa and complement prior to staining with the LIVE/DEAD Fixable Aqua Dead Cell Stain Kit, in order to evaluate whether CDC could be achieved using IL1RAP and CD176 as targets. Flow cytometric analysis revealed a significant increase in dead cells in the Bis-Ab treated CD176/IL1RAP dual-positive KG1/RAP population as antibody binding also increased (Figure 3C), p<0.001.

Figure 3 Validation of TF-RAP Bi-specific antibody in KG1 cell line and CML samples. (A) MFI for binding of different Bis-Ab mixtures in KG1/RAP (p <0.001). (B) Binding (%) of the Bis-Ab in KG1/RAP cell lines. (C) Shows live/dead (LD) staining (%) in KG1/RAP cell lines after treatment with the Bis-Ab and complement. (D) MFI for binding of different Bis-Ab mixtures p <0.001 in CML cells. (E) Binding of the Bis-Ab (%) in PBMCs from patients with CML. The binding affinity (Kd) of our bispecific antibody was 21ng/mL, calculated using the % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody, and Kd is the equilibrium dissociation constant. This Bis-Ab platform used in this study had the correct molecular weight (95 KDa) and assembled properly (93%) as revealed by SDS-PAGE analysis.38 (F) Live/dead (L/D) staining (%) from patients with CML after treatment with the Bis-Ab and complement. The red square were L/D positive cells treated with CyO2; the percent of L/D staining in normal PBMCs is shown in blue. Each point represents the mean increase in L/D staining SEM with three to four replicates. Data from normal samples were low for all doses (data not shown).

Binding of TF1RAPa, TF2RAPa, and TF2RAPb was also tested in PBMCs from patients with CML. Again, TF1RAPa showed the highest binding relative to other mixtures (p<0.001) (Figure 3D) and with increasing doses (Figure 3E). Based on the CML binding curve, the binding affinity (Kd) of our bispecific antibody was 21 ng/mL. Other therapeutic antibodies, such as ofatumumab directed against CD20, have shown significant CDC against peripheral blood cells obtained from CML patients in chronic phases26 and B cells in CLL,29 respectively. Thus, the TF1RAPa cocktail was used to generate the doseresponse curve and to evaluate whether CDC could be achieved using both IL1RAP and CD176 as targets. The ability of the TF1RAPa cocktail was compared to human anti-IL1RAP and anti-CD176 monoclonal antibodies to induce cell death in PBMCs from patients with CML. PBMCs from CML1-4 were tested in CDC assays in parallel to cells from healthy control samples. In CML cells, the binding of TF1RAPa mediated CDC at higher levels than in normal peripheral blood mononuclear control cells, correlating with the expression level of IL1RAP and CD176, particularly at lower antibody concentrations (Figure 3F). More strikingly, among peripheral blood cells, TF1RAPa did not induce CDC of normal cells, whereas a clear dose-dependent CDC effect was observed in CML cells (Figure S13A and B). To address the selectivity of IL1RAP/CD176-targeting antibodies, we also validated the bispecific antibody cytotoxicity on the various subpopulations in peripheral blood. The dual-positive CD176+IL1RAP+ cell populations showed the highest CDC activity as compared to CD176+IL1RAP-, CD176-IL1RAP+, and CD176-IL1RAP- populations (Figure 4 and S13CF, S14).

Figure 4 Dose-response curve of TF1RAPa Bis-Ab on CDC in CML samples. A dose-response curve showing the selective killing potential of CD176+IL1RAP+ subpopulation by the TF1RAPa Bis-Ab as compared to other subpopulations in PBMCs from patients with CML. Each point represents the mean SEM of the four samples.

Targeting molecules involved in multiple pathways is proving to be one of the most reliable strategies for eradicating cancer stem cells. In this report, we present a novel bi-specific antibody, TF/RAP, capable of targeting ThomsenFriedenreich (TF, CD176) and IL1RAP antigens on CD34+ HSCs in CML and on cell lines. TF is a glycoprotein that has many domains and motifs (eg, LGALS3, Gal(1,3)GalNAc, LGalS3BP), many related to signaling pathways. It is a known marker for ongoing tumorigenesis and metastasis, as it is expressed on various cancer-initiating cells.8 Interestingly, CD34 and LGALS3 were found to be co-expressed in myeloid cells.30,31 LGALS3 and ABL1 are involved in regulating RUNX1 and the transcription of genes involved in differentiation of hematopoietic stem cells,32 especially myeloid cells33 (Figure S15) IL1RAP, on the other hand, is a member of the Toll-like receptor superfamily and is a well-known co-receptor of IL1R1.34 IL1RAP plays a role in mediating the effect of the pro-inflammatory cytokine IL-1 and is also involved in activating T cells and mast cells after mediating the signal of IL-1 cytokine.35 It has previously been characterized as a tightly related marker for BCR-ABL positive cells.7 Together, both TF and IL1RAP were related to apoptotic pathways; IL1RAP up-regulation was associated with decreased apoptosis in AML,36 and anti-CD176 antibody induced apoptosis of CD176-positive leukemic cells through multiple pathways.12 Although we did not find a direct link between IL1RAP, CD176 and leukemogenesis, previous studies have shown that each of them is separately expressed on CD34+ cells in leukemia cell lines8,10,12 and patients with CML7

Therefore, we conducted this pilot study, in order to assess the co-expression of IL1RAP and ThomsenFriedenreich (CD176) antigens on CD34+ HSCs in peripheral blood of patients with CML, using FACS gene expression analyses. Flow-drop FISH and CFU assays were used for the separation of CD34+CD176 BCR-ABL+ and BCR-ABL CML stem cells, based on IL1RAP expression.7 CFU numbers were significantly lower in CD34+CD176+IL1RAP- cells than in CD34+CD176+IL1RAP+ cells, obtained from CML-2 and CML-4 samples (Figure 1D), particularly CML-2 sample which was obtained from a patient in remission (BCR-ABL-). We found that the frequency of clonogenic hematopoietic progenitor cells was increased in the CD34+ CD176+IL1RAP+ cells in these samples. Testing the stem-cell characteristics of these two cell populations in immune-deficient mice would have been advantageous. Yet, the low numbers of sorted CML cells acquired from the CD34+CD176+ IL1RAP and IL1RAP+ cell subpopulations, alongwith the general low engrafting efficiency of chronic phase CML cells in these mice7 prevented us from successfully performing such experiments. Importantly, as IL1RAP expression was correlated with changes from chronic phase (CP) into accelerated phase (AP) and blast phase (BP)37, we also found that the level of IL1RAP/CD176 co-expressionwas increased, in our patient samples, as the disease progressed, independent of the treatment status(Table S3).

To target both TF and IL1RAP simultaneously, we developed a Bis-Ab specific for both antigens. Because antibodies are normally heterodimers of two heavy and two light chains, we modified the constant domains in the Bis-Ab to maximize the correct interactions of the four immunoglobulin chains within single cells. Here, we used the orthogonal Fab design; CH1_H172A_F174G and CL_L135Y_S176W38 to facilitate selective assembly of the Fab arms for correct dimerization of the antigen-binding domains.39 Therefore, we mutated CH1 and CL binding sites to restrict the assembly of the Fab with the correct VD pairs. The RAP VDs were cloned with the wild type Fab; and the TF VD was linked to the mutant orthogonal Fab design. Published data have shown that the component proteins of this Bis-Ab platform proper assembly were detected at 93% and the complex had a molecular weight of 95 KDa, as revealed by SDS-PAGE analysis.38 Additionally, the CH3 for each Fab was mutated with previously described knob-into-hole mutations40,41 to facilitate hetero-dimerization between the TF and the RAP heavy chains. In our study, we used ELISA to demonstrate that both the VD and Fc were properly paired. Here, because the primary antibody was anti-human VL and the secondary antibody was anti-human IgG, quantifying the Bis-Ab also demonstrated the VD-Fc interactions.

To efficiently validate the specific binding of our Bis-Ab, we generated a dual-positive cell line; KG1/RAP. KG1 cell line expresses CD176+, but IL1RAP is low or absent. Therefore, we induced IL1RAP expression in KG1 cells by lentiviral mediated-gene transfer, as previously usedin both immune42 and leukemic cells.43 In the competitive binding assay, increasing concentrations of the Bis-Ab blocked the binding of CD176 and IL1-RAP monoclonal antibodies to the KG1/RAP and KG1 parental cells, demonstrating the specific binding of the Bis-Ab. The level of CD176 expression in KG1 cell line was detected before and after VCN treatment. Increased staining of the KG1/RAP cells compared to the parental KG1 cells indicated that expression of the IL1RAP facilitates the interaction of the Bis-Ab with the target cell. This increased binding of the Bis-Ab to the KG1/RAP cells also increased their susceptibility to complement-dependent cytotoxicity (CDC). We also observed increased binding and increased CDC in the CD176+ IL1RAP+ population of the peripheralblood from patients with CML. As a pilot study and given that on average, 50% of the cells within the CD34+ subpopulation in the patients tested were dual positive for CD176 and IL1RAP antigens, in addition to the almost undetectable CDC in CD34+ cells in normal controls, our data strongly support the idea that the bi-specific antibody (TF/RAP) indeed induces CDC preferentially in CD176+ IL1RAP+ CML CD34+ cells. In generating a bi-specific antibody that targets CD176 and IL1RAP, we are unique in providing proof of concept that CML CD34+CD176+ IL1RAP+ cells can be targeted while preserving corresponding normal cells. The potential to target multiple antigens is supported by studies that demonstrated increased or synergistic CDC activity by non-cross blocking CD20 antibody combinations.44

Therapeutic antibodies are commonly administered intravenously, yet selectivity and specificity are a major concern for reduced toxicity. CD176/IL1RAP co-expression was not present in monocytes unlike the reported weak but present IL1RAP expression in monocytes.7 Both antigens were low or absent in most types of normal bone-marrow progenitor and mature cell types, suggesting that CD176/IL1RAP dual targeting antibodies are expected to show low toxicity on normal hematopoietic cells. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a potential target for cancer biotherapy with the development of anti-CD176 antibody that induced apoptosis of leukemic cells.8 Added to this, antibodies against IL1RAP were found to be capable of blocking IL-1 signaling as well as inhibiting tumor cells' growth in AML,34 CML,7 breast cancer,45 prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas46 especially in cancer stem cells, or (CSCs) and progenitor cells, which are responsible, directly or indirectly, for the development of a solid tumor.47 Thus, it may be thatour Bis-Ab will not only eradicate the CD176+IL1RAP+ drug-resistantCML stem cells but also may have universal therapeutic potential for preventing relapses in both solid and hematological cancers.Given that the mode of action in CDC is having the antibody direct the complement pathway to target cell killing, we suggest that this therapeutic strategy would be independent of known mechanisms of TKI resistance in CML. Thus, the concept of complement-mediated killing of IL1RAP/CD176 expressing cells may also have the potential to eradicate such cells in patients, either alone or in combination with current regimens, in order to increase their therapeutic effectiveness. And finally, expanded studies need to be performed in order to confirm the co-expression of both markers, especially in resistant and relapsed cancer patients as well as in patient-derived xenografts (PDX).

The experimental research was mostly supported by a fellowship to REE from the Egyptian Ministry of Higher Education, Cultural, and Missions Section (JS 3577). The lentiviral vectorHRST-cmvGFPand the packaging plasmids were akind gift from Richard C.Mulligan in the Harvard Gene Therapy Institute. The human IgG heavy and light chain constant genes were provided by JE Robinson (Tulane University). C Wu and SEB were supported by AI110158 and/or OD01104-51; EUA and SEB were supported by the Applied Stem Cell Laboratory.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors have given approval of the final version of the article; and have agreed to be accountable for all aspects of the work.

The abstract of this paper was presented at the AACR annual Meeting 2019; March 29 April3, 2019; Atlanta, GA, as a poster presentation with interim findings. The posters abstract was published in Poster Abstracts in the AACR meeting proceedings and as a supplement in the AACR Cancer Research Journal [https://cancerres.aacrjournals.org/content/79/13_Supplement/1222A].

Raghda Eldesouki reports grants from Egyptian Ministry of Higher Education. Stephen EBraun reports grants from Egyptian Ministry of Education, Alliance for Cardiovascular Research, NIAID OD01104, and Braun/McGroarty Charitable Fund, during the conduct of the study. In addition, Dr Raghda Eldesouki, Dr Stephen Braun, Dr Fouad Badr and Dr Eman Abdel-Moemen Mohammedhave apatent, PCT/EG2019/000014, pending. The authors report no other conflicts of interest in this work.

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34. gerstam H, Karlsson C, Hansen N, et al. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2015;112(34):1078610791.

35. McEntee CP, Finlay CM, Lavelle EC. Divergent roles for the IL-1 family in gastrointestinal homeostasis and inflammation. Front Immunol. 2019;10:1266.

36. Barreyro L, Will B, Bartholdy B, et al. Over expression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood. 2012;120(6):12901298. doi:10.1182/blood-2012-01-404699

37. Zhao K, Yin LL, Zhao DM, et al. IL1RAP as a surface marker for leukemia stem cells is related to a clinical phase of chronic myeloid leukemia patients. Int J Clin Exp Med. 2014;7(12):47874798.

38. Lewis SM, Wu X, Pustilnik A, et al. Generation of bi-specific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol. 2014;32:191198. doi:10.1038/nbt.2797

39. Spidel JL, Vaessen B, Chan YY, Grasso LJ, Kline B. Rapid high-throughput cloning and stable expression of antibodies in HEK293 cells. J Immunol Methods. 2016;439:5058. doi:10.1016/j.jim.2016.09.007

40. Ridgway JB, Presta LG, Carter P. Knobs-into-holes engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617621. doi:10.1093/protein/9.7.617

41. Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol. 1997;270:2635. doi:10.1006/jmbi.1997.1116

42. Pan H, Mostoslavsky G, Eruslanov E, Kotton DN, Kramnik I. Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. J Immunol Methods. 2007;329(12):3144. doi:10.1016/j.jim.2007.09.009

43. Biagi E, Bambacioni F, Gaipa G, et al. Efficient lentiviral transduction of primary human acute myelogenous and lymphoblastic leukemia cells. Haematologica. 2001;86(1):1316.

44. Melis JP, Strumane K, Ruuls SR, Beurskens FJ, Schuurman J, Parren PW. Complement in therapy and disease: regulating the complement system with antibody-based therapeutics. Mol Immunol. 2015;67:117130. doi:10.1016/j.molimm.2015.01.028

45. Liberg D, nnervik P, Riva M, Larsson L, Forsberg G, Wachenfeldt K. Antibody Blockade of IL1RAP Signaling Reduces Metastasis in a Breast Cancer Model. Annual Meeting of the American Association for Cancer: McCormick Place North/South Chicago, Illinois, USA; 2018.

46. Fioretos T, Jaras M Method of treatment of a solid tumor with interleukin-1 accessory protein antibody. United States patent US 9403906B2. 2016 Aug 02.

47. Fioretos T, Jaras M. Anti - IL1rap antibodies and their use for treating human. European patent EP2665749A1. 2013 Nov 27.

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[Full text] Identification and Targeting of ThomsenFriedenreich and IL1RAP | OTT - Dove Medical Press

NEW YORK, Jan. 20, 2021 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, announced today the peer-reviewed publication of a preclinical study in the journal Stem Cell and Research Therapy. The study, entitled "MSC-NTF (NurOwn) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model," evaluated the use of NurOwn (MSC-NTF cell) derived exosomes in a mouse model of acute respiratory distress syndrome (ARDS).

ARDS is a type of respiratory failure that is frequently associated with COVID-19 and mediated by dysregulated cytokine production. While there are currently no effective therapies to prevent or reverse ARDS, mesenchymal stem cell (MSC)-derived exosomes have been suggested as a potential novel treatment option due to their ability to penetrate deep into tissues and efficiently deliver immunomodulatory molecules.

Results from the recently published study showed that intratracheal administration of NurOwn derived exosomes led to a statistically significant reduction in lung disease severity score (p < 0.05; based on criteria set forth by the American Thoracic Society Documents: Matute-Bello et al., Am J Respir Cell Mol Biol 44;725-738, 2011) and improvements in several additional clinically relevant lipopolysaccharide (LPS)-induced ARDS markers such as lung function, fibrin presence, neutrophil accumulation, cytokine expression, and blood oxygenation levels. Notably, these improvements were significantly superior to those observed following administration of nave MSC-derived exosomes.

"These exciting preclinical data suggest that NurOwn derived exosomes have the potential to treat COVID-19-induced ARDS or other severe respiratory complications, and that they are more effective than exosomes isolated from nave MSCs at combatting the various symptoms of the syndrome," said Dr. Revital Aricha, Vice President of Research & Development at BrainStorm. "This publication in a highly regarded journal provides important validation for the scientific advances and significance of BrainStorm's preclinical research programs, including on our exosome-based technology platform."

Chaim Lebovits, Brainstorm's Chief Executive Officer added, "While our primary focus is on advancing NurOwn towards regulatory approval in ALS, we continue to evaluate the potential of our exosome-based platform to address unmet medical needs. The publication of these proof-of-concept data highlights this potential, and we are now actively assessing next steps to determine how to best generate value. We are also actively discussing with possible partners several development opportunities for the exosome technology."

About NurOwn

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm is in active discussions with the FDA to identify regulatory pathways that may support NurOwn's approval in ALS. BrainStorm is also conducting an FDA-approved phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed dosing inDecember 2020, and topline results are expected by the end of the first quarter 2021.

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

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Introduction

Bone remodelling is a tightly coupled lifelong process, whereby old bone is removed by osteoclasts (bone resorption) and new bone is formed by osteoblasts (bone formation).1,2 Osteocytes, which act as mechanosensors/endocrine cells, and bone lining cells3 are also involved in bone remodelling.4 Myriad pathophysiological factors affecting bone remodelling have been observed in skeletal diseases such as osteoporosis, arthritis and periodontal disease.5 Oxidative stress is one of the pathophysiological factors affecting bone remodelling. Oxidative stress stimulates osteoclast differentiation, thereby enhancing bone resorption.6,7 Reactive oxygen species (ROS) stimulate the apoptosis of osteoblasts and osteocytes, thus affecting bone formation. ROS also activate mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases (ERK1/2), c-Jun-N terminal kinase (JNK) and p38, and enhance osteoclastogenesis and bone resorption.811 These phenomena skew the bone remodelling process in favour of bone loss.

Antioxidants are compounds which reduce free radicals and oxidative stress.12 Antioxidants have been reported to promote differentiation of osteoblasts, bone formation and survival of osteocytes, as well as suppressing osteoclast differentiation and activity.8,1315 Some studies associate the age-related reduction in circulating antioxidants to osteoporosis in rats and women.1618 A decline in antioxidant levels has been reported to promote bone loss by triggering the tumour necrosis factor-alpha (TNF)-dependent signalling pathway,6 while administration of antioxidants, such as vitamin C, E, N-acetylcysteine and lipoic acid, have been reported to exert favourable effects in animal models of osteoporosis1921 and individuals with osteoporosis.2225

Caffeic acid (CA) is a metabolite of hydroxycinnamate and phenylpropanoid commonly synthesized by all plant species. It is a polyphenol present in many food sources like coffee, tea, wine, blueberries, apples, cider, honey and propolis.26 CA and its major derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) are reported to possess potential antibacterial, antidiabetic, antioxidant, anti-inflammatory, antineoplastic and cardioprotective activities (reviewed in2729). As a potent antioxidant, CA has been demonstrated to decrease lipoperoxyl radicals (ROO) by donating a hydrogen atom to its corresponding hydroperoxide, which terminates the lipid peroxidation chain reaction. It also inhibits human low-density lipoprotein (LDL) oxidation induced by cupric ions.30 Furthermore, it interacts with other compounds, such as -tocopherol, chlorogenic and caftaric acids, to exert more potent antioxidant activity in a variety of different systems.3133 Therefore, the antioxidant activities of CA might protect against the negative effects of oxidative stress on bone cells and the skeletal system. This systematic review aims to summarise the effects of CA and its derivatives on bone cells and bone in literature.

A systematic literature search was conducted from July until November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases to identify studies on the effects of caffeic acid on bone and bone cells including osteoblasts, osteoclasts and osteocytes. The search string used was (1) caffeic acid AND (2) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes).

Studies with the following characteristics were included: (1) original research article with the primary objective of determining the effects of caffeic acid on bone and bone cells; (2) studies using cellular or animal models, or humans; (3) studies administering caffeic acid as a single compound but not in a mixture or food. Articles were excluded if they (1) do not contain original data; (2) use food rich in caffeic acid or mixtures containing caffeic acid. The bibliography of relevant review articles was traced for potential articles missed during database search. The search results were organised using EndNoteTM software (Clarivate Analytics, Philadelphia, USA). Duplicates were identified using EndNoteTM and confirmed by manual checking.

Two authors (S.O.E. and K.L.P.) searched the same databases using the search string mentioned and screened the search results. All the articles that did not match the selection criteria were excluded. Next, the articles which used caffeic acid in treating models other than bone-related diseases were removed. Finally, articles which used caffeic acid in combination with other compounds were also excluded. Any disagreement on the inclusion or exclusion of articles was resolved through discussion among the two authors. The corresponding author (K.Y.C.) had the final decision on articles included if a consensus could not be reached between authors responsible for screening. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist.34 Steps in the selection process, from identification, screening, eligibility to the inclusion of articles, are shown in Figure 1.

Figure 1 Flowchart of the article selection process.

From the literature search, 381 articles were identified, of which 87 were obtained from PubMed, 182 were from Scopus, 3 from Cochrane Library and 109 from Web of Science. A total of 155 duplicate articles were identified and removed. Of the 226 articles screened, 202 articles were excluded based on the selection criteria, whereby 51 articles did not contain primary data (3 book chapters, 2 commentary and 46 review articles), 147 articles and 2 conference abstracts presented topics irrelevant to the current review, a conference abstract had been published as a full-length research article and another conference abstract did not contain sufficient experiment details (Supplementary Material). Finally, 24 articles fulfilling all criteria mentioned were included in the review.

The included studies were published between 2006 and 2020. Seven studies were in vitro experiments using mouse bone marrow macrophages (BMMs), RAW264.7, RAW D and MG63 osteoblast cell lines3541 while 19 studies were in vivo studies using Sprague Dawley/Sprague Dawley albino rats, Wistar/Wistar albino rats, Balb/c mice, lipopolysaccharide (LPS)-resistant C3H/HEJ mice, C57BL/6J mice and ICR mice.35,38,4258 No human studies on this topic were reported.

Six in vitro studies focused on the effects of CA on osteoclast differentiation from haematopoietic cells using macrophage colony-stimulating factor (M-CSF), receptor activator of NF-B (RANK) ligand (RANKL) or TNF-,3539,41 while one in vitro study focused on the effect of CA on osteoblasts using MG63 osteoblast cell line.40 Four in vitro studies used CA doses between 0.15 M.35,37,38,40 Ang et al.36 used doses between 00.3 M and Sandra et al.41 and Sandra and Ketherin39 used a dose of 10 g/mL (55.5 M). The treatment period was 57 days for the differentiation of osteoclasts.

For animal studies, Duan et al.,55 Zawawi et al.,58 William et al.,51 Wu et al.,38 Zych et al.49 and Folwarczna et al.48,52 used CA or its derivatives at doses between 0.550 mg/kg via oral or intraperitoneal (i.p.) administration. Ucan et al.,57 Erdem et al.,53 Cicek et al.,54 Yigit et al.,45 Yildiz et al.50 and Tolba et al.56 used doses between 1020 mol/kg/day (2.845.69 mg/kg/day) via i.p. administration. Kizilda et al.4244 and Kazanciolu et al.46,47 used the dose of 10 mmol/kg/day (2.843 g/kg/day) for an i.p. administration, Kazanciolu et al.47 employed 50100 mmol/kg/day (14.2228.43 g/kg/day) for a localised administration, while Ha et al.35 used a collagen sponge soaked with CAPE with the final dose of 250 g/mouse. For oral administration, first-pass effect might affect the enteric absorption of CA or its derivatives.59 For i.p. administration, the injection is commonly performed at the lower left or right quadrant of the abdomen. The peritoneum can absorb the compounds fast and reach systemic circulation with greater bioavailability with fewer handling errors.60

The bone-related disease models used included ovariectomy (OVX)- or glucocorticoids (dexamethasone)-induced osteoporosis, polyethylene particle-induced bone defect and osteolysis, electromagnetic force (EMF)-stimulated bone loss, osteotomy- or anti-collagen antibody-induced arthritis (CAIA) and rapid maxillary expansion (RME) and LPS-induced periodontitis. The endpoints studied included bone microstructure, histomorphometry, bone remodelling and oxidative status. The effects of CA and its derivatives on bone remodelling have been summarized in Table 1.

Melguizo-Rodrguez et al. reported that 24-hour CA (1 M) incubation increased the number of MG63 osteoblast cells compared with control.40 Gene expression studies revealed that CA increased the expression of osteoblast-related genes such as bone morphogenetic protein-2 and -7 (BMP-2 and BMP-7), transforming growth factor-beta 1 (TGF-1), transforming growth factor-beta receptor 1, 2 and 3 (TGF-R1, TGF-R2 and TGF-R3) and osteoblastogenesis genes including Runt-related transcription (RUNX-2), alkaline phosphatase (ALP), collagen type 1 (COL-I), osterix (OSX) and osteocalcin (OSC).40 Additionally, pretreatment of CA (10 g/mL or 55.5 M) on RAW D cells for 2 h also significantly inhibited the RANKL and TNF-induced osteoclastogenesis with the suppression of p38 MAPK phosphorylation and tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells (OCLs) formation.39 Similarly, pretreatment of CA (0.1, 1 and 10 g/mL or 0.555, 5.55 and 55.5 M) on RAW D cells and BMMs for 3 days significantly inhibited the RANKL and TNF-induced osteoclastogenesis and NF-B activity in RAW-D cells and RANKL, TNF and M-CSF-induced osteoclastogenesis in BMMs.41

On the other hand, CAPE treatment (00.3 M; 57 days) suppressed the formation of TRAP-positive OCLs on RANKL-treated RAW264.7 cells and BMMs.36 Apoptosis occurred in CAPE-treated RAW264.7 cells with the disruption of the microtubule network in OCLs.36 Similarly, Kwon et al. reported that CAPE treatment (0.15 M) for 5 days suppressed OCLs formation from RANKL-stimulated RAW264.7 cells.37 Another study by Ha et al. treating M-CSF and RANKL-stimulated BMMs with CAPE (05 M for 57 days) also showed decreased OCLs formation in a concentration-dependent manner.35 The amount of TRAP-positive OCLs was decreased upon 0.1 and 0.5 M CAPE treatment by 30% and 95% respectively.35 No OCL formation was observed upon 1 M CAPE treatment.35 The anti-osteoclastogenic activities of CAPE are mainly contributed by its anti-inflammatory and antioxidant properties. Mechanistically, CAPE reduces superoxide anion generation by downregulating the nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression through the interruption of nuclear factor-kappa B (NF-B) and c-Jun N-terminal kinase (JNK) signalling pathways.37 CAPE suppresses RANKL-mediated activation of the NF-B pathway by downregulating NF-B p65 subunit expression and its nuclear translocation,37 suppressing nuclear factor of activated T cells (NFAT) activities36 and degradation of NF-B inhibitor (IB),36,37 as well as inducing the degradation of IB kinase (IKK).37 CAPE also suppresses the expression and activation of JNK and its downstream transcription factors, such as c-Fos and c-Jun, which subsequently interrupt the protein activator-1 (AP-1) complex formation.37 Additionally, CAPE suppressed RANKL-induced activation of the Nox1 by inhibiting the Nox p47PHOX subunit translocation to the cell membrane and downregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) expression.37

On the other hand, Wu et al. reported that CADPE (0.15 M for 7 days) also concentration-dependently reduced OCL formation in the M-CSF and RANKL-stimulated BMMs and RAW264.7 cells.38 Mechanistic and characterisation examination revealed that CADPE suppressed RANKL-induced tumour necrosis factor receptor-associated factor 6 (TRAF6) activation and protein kinase B (PKB or also known as Akt) and activation of major MAPKs including ERK, JNK and p38.38 Subsequently, CADPE suppressed downstream expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), nuclear translocation of c-Fos protein and expression of osteoclastic markers, such as TRAP and cathepsin K, possibly through the non-receptor tyrosine kinase c-Src signalling.38 Interestingly, CADPE did not significantly affect the NF-kB signalling pathway and M-CSF-induced proliferation and differentiation of BMMs.

Supplementation of CA in animal models of bone loss yielded heterogeneous findings.48,49,52 This observation might be attributable to oral administration. Folwarczna et al. reported that CA (5 and 50 mg/kg, by stomach tube for 4 weeks) improved the bone mechanical properties by increasing the width of the trabecular metaphysis of the femur and decreasing the transverse growth in endosteal of the femur in OVX rats.48 Folwarczna et al. then demonstrated that CA (10 mg/kg/day; oral administration for 4 weeks) could reduce the width of tibial periosteal and endosteal osteoid compared with untreated OVX rats.52 However, CA did not promote or reduce the resorption of compact bone in the tibia of OVX-induced osteoporotic rats as evidenced by negligible changes of bone mass, bone mineral mass, bone mass/body mass ratio and bone mineral mass/body mass ratio.52 On the other hand, Zych et al. reported that CA at a similar dose (10 mg/kg/day; by stomach tube for 4 weeks) worsened the bone mechanical properties of healthy female Wistar Cmd:(WI)WU rats by decreasing the load of fracture at the femoral neck, decreasing the width of periosteal osteoid in the tibia and decreasing the width of the epiphysis and metaphysis trabecular in the femur compared with the negative control group.49

CAPE is the most extensively studied caffeic acid derivative in animal studies. The beneficial effects on new bone formation and healing upon systemic administration of CAPE had been reported.46,47,53,57 Erdem et al. reported that a low dose of CAPE (10 mol/kg; i.p. injection for 22 days) increased new bone formation and bone strength by increasing maximum torsional fracture momentum and degree of rigidity compared with negative control in rats that underwent unilateral femoral lengthening (osteotomy).53 Similarly, a 30-day i.p. injection of CAPE (10 mol/kg/day) also increased bone healing level in Sprague Dawley rats with cranial critical size bone defect.57 A higher dose of CAPE (10 mmol/kg/day, i.p. for 20 days) also further promoted the RME procedure-induced new bone formation in midpalatal suture of male Sprague Dawley rats.47 Similarly, a longer treatment period of CAPE (10 mmol/kg/day; i.p. injection for 28 days) also significantly promoted bone healing by increasing the total new bone areas in surgical-induced calvarial defects of male Wistar rats compared with the negative control.46 However, localised administration of CAPE (28 days) on surgical-induced calvarial defects by pre-mixing 50 and 100 mmol/kg CAPE solutions with gelatin sponges did not significantly improve the new bone formation.46

Localised and systemic administration of CAPE was reported to be beneficial in reducing osteolysis and bone loss.35,4245,50,5456,58 Ha et al. reported that collagen sponge implant impregnated with 250 g CAPE and RANKL could reduce osteoclastogenesis with significantly lesser TRAP-stained area in mouse calvariae compared with implants with RANKL only.35 Subcutaneous injection of CAPE (1 mg/kg/day for 10 days) reduced the polyethylene particle-induced calvarial osteolysis, surface bone resorption and TRAP-positive cells formation with an increase of bone volume (BV) on LPS-resistant C3H/HEJ female mice.58 However, no significant changes were observed in carboxy-terminal cross-linked type 1 collagen (CTX-1) and osteoclast-associated receptor levels among untreated and CAPE-treated rats with calvarial osteolysis.58

Similarly, Duan et al. reported that lower dose and frequency of CAPE injection (0.5 mg/kg twice a week; i.p. injection for 4 weeks) also increased the BV and trabecular number (Tb.N) due to the decrease of bone osteoclast formation (evidenced by decreased osteoclast number/bone perimeter) in OVX mice.55 Tolba et al. also reported that i.p. injection of CAPE (10 and 20 mol/kg) for 3 weeks increased femur weight and length in rats with dexamethasone-induced bone loss.56 The preservation of skeletal health in their study was associated with an improved antioxidant defence, such as higher levels of glutathione (GSH) and superoxide dismutase (SOD), and the reduction of malondialdehyde (MDA, lipid peroxidation product).56 This event led to an increase of osteoblastogenesis indicated by upregulation of RUNX-2 and ALP (osteoblast marker) levels56 On the other hand, decreased RANKL/osteoprotegerin (OPG) ratio was observed with CAPE treatment, indicating the suppression of osteoclastogenesis, which was further confirmed by lower acid phosphatase level and TRAP activity.56 In another study by Yildiz et al., CAPE (10 mol/kg/day; i.p. injection for 22 days) also increased the spine and femur BMD in rats with EMF-induced bone loss.50 Similarly, Cicek et al. reported a longer treatment of CAPE (10 mol/kg/day; i.p. injection for 28 days) also significantly improved the mechanical strength of cortical bone by increasing the breaking force, bending strength and total fracture energy in rats with EMF-induced bone loss compared with negative control.54

Additionally, a study by Wu et al. treated mice with an OVX-induced bone loss with a moderately high dose of CADPE (10 mg/kg; i.p. injection) every 2 days for 3 months.38 Results showed that CADPE could increase the BV fraction (BV/TV) and Tb.N, as well as decreased trabecular spacing (Tb.Sp) compared with the negative control.38 The improvement in the bone structure was contributed by reduced osteoclast number and eroded surface on the bone.38 Assessment of bone remodelling markers also revealed that serum TRAP5b and CTX-1 levels were reduced in CADPE-treated group compared with the negative control.38

On the other hand, CAPE was effective in reducing periodontitis-related bone loss and osteolysis.4245 CAPE (10 mol/kg/day, i.p. for 14 days) significantly reduced the subgingival ligature placement-induced periodontitis-mediated articular bone loss, histopathological features and severity of periodontal inflammation with lesser polymorphonuclear cells (PMNLs) infiltration in the junctional epithelium and connective tissues among Wistar albino rats.45 CAPE also suppressed the periodontitis-upregulated interleukin (IL)-1, IL-6, IL-10, TNF, MDA levels and the percentage of gingival apoptosis with the parallel restoration of periodontitis-downregulated GSH and glutathione peroxidase (GPx).45 Administration of high-dose CAPE (10 mmol/kg/day; i.p. for 15 days) in streptozotocin (STZ)-induced diabetic male Sprague Dawley rats reduced RANKL-positive osteoclast number, IL-1 levels, oxidative stress index (OSI), alveolar bone loss and histological analysis score in LPS-induced periodontitis. The treated rats also suffered lesser inflammatory reactions, ulcers and hyperemia.42 Similar changes of osteoclast number, IL-1 and OSI were observed in male Sprague Dawley rats with chronic stress and LPS-induced periodontitis treated with CAPE (10 mmol/kg/day, i.p. for 14 days).44 In addition, CAPE also increased the mesial and distal periodontal bone supports (MPBS and DPBS) in these rats.44 The effects of CAPE were sustained with a longer treatment period of CAPE (10 mmol/kg/day, i.p. for 28 days) on male Sprague Dawley rats with LPS-induced periodontitis.43

In contrast to the above findings, Williams et al. reported that subcutaneous injection of CAPE (1 mg/kg; at day 3, 7 and 10) did not reduce paw inflammation or bone loss in CAIA mice.51 Cartilage and bone degradation, as well as TRAP-positive cells on the bone surface and soft tissues, were still apparent in the supplemented CAIA group compared with the normal control.51

This systematic review found that although CA and its derivatives is a potential anti-osteoporosis agent by suppressing the formation of osteoclasts and their bone resorption activity, it worsened bone mechanical properties in some cases. The anti-osteoclastogenesis action of CA and its derivatives was mediated by the antioxidant activities, which blocked RANKL-induced TRAF6/Akt and MAPK signalling, as well as M-CSF/c-Src signalling. In animals, CA and its derivatives (mainly CAPE) prevented bone resorption in rodent calvariae when implanted in situ, facilitated the healing of bone defects, preserved bone structure and improved mechanical strength in osteoporosis models induced by OVX, dexamethasone, osteotomy, LPS-mediated periodontitis and EMF. However, CA did not alter bone resorption in OVX-induced osteoporotic rats and worsened the mechanical properties in normal rats. Additionally, CAPE did not suppress bone loss in rats with CAIA-induced bone loss.

Osteoblasts are bone-forming cells derived from bone marrow mesenchymal stem cells and are responsible for the synthesis, secretion and mineralisation of bone matrix.61 The expression of osteoblast markers was increased following CA or CAPE supplementation, an indication that CA and CAPE stimulated osteoblast proliferation, differentiation and maturation.40,56 Osteoblasts and osteocytes regulate the formation of osteoclasts through RANKL/OPG axis. Osteoblasts and osteocytes synthesise RANKL, which binds to RANK to activate the canonical pathway for osteoclastogenesis. They also secrete OPG, which is a decoy receptor for RANKL to suppress osteoclastogenesis. The production of RANKL is stimulated under conditions such as oestrogen deficiency62 and oxidative stress.63 Osteoclastogenesis can also be stimulated via a non-canonical pathway, for instance, through the binding of TNF with TNF receptor I or II.64 Glucocorticoids are potential modulators of RANKL/OPG axis, whereby dexamethasone is shown to downregulate OPG levels in osteoblasts.65 Tolba et al. showed that the RANKL/OPG level reduced in rats induced with dexamethasone with CAPE treatment.56 Other cellular studies showed that CA and its derivatives suppressed RANKL- and TNF-induced formation of OCLs from haematopoietic cells,3539 indicating that CA and its derivatives suppressed both canonical and non-canonical osteoclastogenesis.

The complex formed by the binding of RANKL to RANK causes the recruitment of the adaptor molecules tumour necrosis factor receptor-associated factors (TRAFs), including TRAF6.66 This event leads to the activation of several downstream signalling pathways, including c-Src/Akt/phosphatidylinositol 3-kinase and MAPKs (ERK/p38/JNK). CADPE was shown to suppress RANKL-induced activation of TRAF6 activation and the subsequent signalling pathways in multiple osteoclast progenitors, such as BMMs,38 RAW264.738 and RAW D cells.39 Sandra and Ketherin suggested that the downregulation of p38 is the key step of CA-mediated osteoclastogenesis.39 Upon activation, p38 initiates osteoclastogenesis by inducing NF-B and NFATc1 expression.67,68 Inhibition of p38 MAPK reduces RANKL (canonical) and TNF-induced (non-canonical) osteoclast formation.69

The NF-B pathway is another signalling pathway downstream of TRAFs critical for osteoclast differentiation and bone reabsorption activity. Upon activation, IKK (consisting of IKK, IKK and IKK) phosphorylates and degrades IB, which enables translocation of NF-B p65/p50 heterodimers into the nucleus to allow transcription of osteoclast-related genes.70 Kwon et al. demonstrated that the anti-osteoclastogenesis effects of CAPE were mediated via the degradation of total IKK, thereby preventing the phosphorylation and degradation of IB and subsequently suppresses the nuclear translation of p65.37 On the other hand, Wu et al. reported that CADPE did not affect phosphorylation or degradation of IB, as well as nuclear translocation, and DNA-binding activity of p65.38 This observation suggests that compared with CAPE, CADPE does not influence the NF-B signalling pathway.

ROS are one of the important secondary signals in the early stages of osteoclast differentiation.71,72 These ROS are mainly produced as superoxide anions by Nox1.73 Blocking of Nox1 ameliorates ROS production and the downstream MAPKs (JNK, p38 and ERK) and NF-B activation74 and subsequently suppresses the osteoclast formation.71 The reduction of Nox 1 and Rac1 expression by CAPE is accompanied by RANKL-downstream signalling, denoting that anti-osteoclastogenesis effects of CAPE are dependent on suppression of Nox1-mediated superoxide anion production. Besides, dexamethasone has been reported to increase the expression of oxidative stress-related genes in human osteoblasts.75 Tolba et al. showed that CAPE increased GSH and SOD but reduced MDA in the bone of the rats exposed to dexamethasone, indicating an improvement of redox status in the skeletal environment.56 Additionally, CAPE also reduced the OSI and bone loss with an improvement of bone support in rats with LPS-induced periodontitis.

NFATc1 is the master regulator of osteoclast-related gene expression, and it is activated by c-Fos and NF-B.76 Ha et al. observed that CAPE inhibited the recruitment of NF-B to NFATc1 promoter, and the combined effect of NF-B inhibition on c-Fos and NFATc1 may have caused CAPE to suppress osteoclastogenesis effectively.35 Holland et al. demonstrated a new fluorinated derivative of CAPE possesses potent anti-osteoclastogenic properties on RAW 264.7 cells by downregulating NFATc1 via suppression of c-Fos and NF-B signalling pathways.77 Besides, this new fluorinated CAPE also exhibits improved stability with a 2-fold higher potency than CAPE.77 On the other hand, although CADPE did not alter NF-B signalling, it still could suppress NFATc1 and other osteoclast-related markers, indicating other mechanisms of suppression could be involved, for instance, c-Src and MAPKs signalling pathways.38

Matrix metalloproteinases (MMPs), including gelatinases (MMP-2 and MMP-9) are examples of zinc-dependent extracellular matrix-degrading enzymes, which actively participate in bone resorption.78 MMPs are expressed as inactive proenzymes or zymogens that can be activated by several mediators including AP-1, NF-B, TNF and TGF.78 Currently, there is no study conducted to investigate the inhibitory effects of CA and CAPE on osteoclastic MMPs activity and its subsequent linkage in bone resorption; interestingly, CA and CAPE were reported to inhibit MMP-9 activity in human hepatocellular carcinoma HEP3B cells.79,80 This observation renders an interesting research gap in osteoclastic MMP inhibition upon CA and its derivatives treatment.

Suppression of osteoclastogenesis by CA or its derivatives have significant therapeutic potential against bone disorders induced by excessive bone resorption. Bone loss after osteotomy is a rapid process that affects both fractured and unfractured bone and may be incompletely reversible.81 CAPE was reported to improve bone formation and mechanical strength of bone in osteotomy.53 Exposure to EMF radiation caused by high-voltage transmission lines and transformers could affect bone health through decreased BMD, serum calcium and ALP level leading to the increase of bone resorption.82 CAPE increased the spine and femur BMD levels50 and increased mechanical strength of bones54 in rats exposed to EMF radiation. Total hip arthroplasty without cement often caused osteolysis induced by polyethylene particles.83 CAPE was shown by Zawawi et al. to prevent calvarial bone resorption in a murine polyethylene particle-induced osteolysis model.58 Therefore, biomaterials impregnated with CA or its derivatives could be adopted to prevent osteolysis in the arthroplasty procedure. CA has been incorporated in chitosan/(3-chloropropyl) trimethoxysilane scaffold for hard-tissue engineering applications and this adopted material exhibits antibacterial and anticancer effects.84 Ucan et al. observed that CAPE increased cranial bone healing in rats with critical size bone defect, suggesting that it could be administered systematically or locally to treat bone fracture/defect healing.57

Similarly, CAPE also effectively reduced the articular bone loss, inflammatory cytokines production and oxidative stress in rats with LPS-mediated periodontitis. Additionally, Wu et al.38 and Duan et al.55 demonstrated that CADPE prevented the ovariectomy-induced bone loss by suppressing osteoclast activity in a mouse model, while Folwarczna et al. showed increased width of trabecular metaphysis in the femur of OVX rats.48 Similarly, Tolba et al. showed improved bone formation and skeletal health in rats with dexamethasone-induced bone loss upon receiving CAPE.56 Additionally, CA and its derivatives may be involved in oestrogen production and signalling. Zych et al. reported that an oral administration of CA (10 mg/kg/day for 4 weeks) significantly restored the serum oestradiol levels in OVX rats.85 Interestingly, CA at 10 and 100 M did not cause any alteration in calcium content in the femoral-diaphyseal and metaphyseal ex vivo culture, suggesting its bone-protecting effect may not involve calcium metabolism and regulation.86 Additionally, CAPE was reported as a selective human oestrogen receptor agonist with the EC50 value of 3.72 M in oestrogen-responsive element transcription.87 A recent in silico study by Zhao et al. suggested potential osteoimmunological effects of CAPE, which may explain its biological activities on both immune and skeletal systems.88 However, the findings from this modelling study requires further validation through in vitro and in vivo models. As oestrogen deficiency due to menopause and glucocorticoids present the most significant cause of primary and secondary osteoporosis globally, CA and its derivatives have the potential to be used as an adjuvant therapy to existing osteoporosis management strategies. The mechanisms of action of CA and its derivatives in osteoclastogenesis have been summarized in Figure 2.

Figure 2 Mechanism of action of caffeic acid and its derivatives.

Abbreviations: , decrease or downregulate; ?, unknown mechanism; Akt, protein kinase B; AP-1, activator protein 1; CA, caffeic acid; CADPE; caffeic acid 3,4-dihydroxy-phenethyl ester; CAPE, caffeic acid phenethyl ester; c-Src, cellular sarcoma tyrosine kinase; ERK1/2, extracellular signal-regulated kinases 1/2; GM-CSF, granulocyte-macrophage colony-stimulating factor; Grb2, growth factor receptor-bound protein 2; IFN-, interferon-gamma; IL, interleukin; IL1R, interleukin-1 receptor; IB, NF-B inhibitor protein; IKK, IB kinase; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; M-CSF-R, M-CSF receptor; MAPKs, mitogen-activated protein kinases; NFAT, nuclear factor of activated T cells; NF-B, nuclear factor kappa B; NIK, MAPK kinase kinase 14; Nox1, nicotinamide adenine dinucleotide phosphate oxidase 1; OPG, osteoprotegerin; PI3k, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; ROS, reactive oxygen species; TAK, MAPK kinase kinase 7; TLR4, Toll-like receptor 4; TNF, tumour necrosis factor-alpha; TNFR1/2, TNF receptor 1/2; TRAF2, tumour necrosis factor receptor-associated factor 2; TRAF6; tumour necrosis factor receptor-associated factor 6.

Regardless of the positive effects of CA on bone status, some studies have reported negative effects associated with supplementation of CA and its derivatives. CA supplementation did not affect the bone resorption52 and reduced transverse growth of endosteal in femur48 of rats with OVX-induced osteoporosis. In normal rats, CA supplementation even negatively affected their bone mechanical properties.49 Moreover, CAPE supplementation has been reported to stimulate the synthesis of PGE2,89 which mediates osteoclastogenesis through RANKL stimulation and activation of the NF-B pathway.90 This event will eventually increase TRAP-positive OCLs. Similarly, Williams et al. showed that CAPE did not suppress osteoclastogenesis in rats with CAIA.51

In term of safety, the International Agency for Cancer Research classifies CA as Class 2B (possibly carcinogenic to humans),91 and it was reported to induce renal tubular cell hyperplasia, forestomach hyperplasia, renal cell adenoma and forestomach cancer in rodents.9294 CA has been reported to be non-mutagenic and non-clastogenic.91 Therefore, its carcinogenicity may involve epigenetic modification. Human toxicity and carcinogenicity of CA and its derivatives remain unknown. CA also showed anti-implantation activity in pregnant mice at a median effective dose of 4.26 mg/kg/day.95 Similarly, 5 mg/kg/day and 150 mg/kg of CA in mice demonstrated anti-implantation activity in early pregnancy.96 On the other hand, 0.15 mg/kg/day, 5 mg/kg/day and 150 mg/kg/day of CA for 21 days in mice showed no maternal toxicity, foetal teratogenesis or post-natal effects on pup development and mortality.96 The same experiment stated that the no-observed-adverse-effect level of CA for pregnant female mice was 0.15 mg/kg/day.96 Therefore, high-dose CA should be cautioned in humans, especially pregnant women.

Several common limitations can be identified from the studies reviewed. Most studies did not adopt a positive control to compare against the anti-osteoclastogenesis or anti-osteoporosis effect of CA. Therefore, the therapeutic effects of CA and currently available anti-resorptive therapy cannot be compared. Although osteoblastogenesis and bone formation are also important in bone remodelling, evidence of CA on these processes is limited in the literature. The actions of CA in humans cannot be confirmed due to the lack of human clinical trials. These aspects can be improved in future studies.

The current review also has several limitations. We only considered articles indexed by PubMed, Scopus, Cochrane Library and Web of Science; therefore, non-indexed articles could be overlooked. We only selected articles studying CA or its derivatives as a single compound to understand its mechanism of action properly without other interference, but not a mixture of compounds or natural products rich in CA. CA are present in foods, and interaction with other compounds in the food matrix might alter its absorption, bioavailability and action on the target tissue. Moreover, the heterogeneous findings of CA in bone loss reduction upon oral administration further emphasise these possibilities.

The current preclinical evidence agrees that CA and its derivatives exert promising skeletal protective effects by inhibiting osteoclastogenesis and bone resorption, but literature on bone formation is limited. Notwithstanding that, the skeletal effects of CA and its derivatives in models of normal bone health should be investigated because the limited studies available show undesirable effects. Human clinical trials to validate the skeletal effects of CA are lacking. Therefore, a well-planned clinical trial should be conducted to confirm the potential of CA as an antiresorptive agent. This information is critical for CA and its derivatives to be incorporated as part of the strategies to prevent bone loss.

The researchers are funded by Universiti Kebangsaan Malaysia through Research University Grant (GUP-2020-021). S.O.E. and K.L.P. are post-doctoral researchers funded by Universiti Kebangsaan Malaysia through FPR-1 and RGA-1 grants.

The authors report no conflicts of interest in this work.

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