Archive for the ‘Skin Stem Cells’ Category

MELBOURNE, Australia--(BUSINESS WIRE)--Propanc Biopharma, Inc. (OTC Pink: PPCB) (Propanc or the Company), a biopharmaceutical company developing novel cancer treatments for patients suffering from recurring and metastatic cancer, today announced that Chief Scientific Officer and Co-Founder, Dr Julian Kenyon, MD, MB, ChB, explains why pancreatic and ovarian cancers are selected as the primary target therapeutic indications for planned PRP human studies. According to Dr Kenyon, target indications were selected based on in vitro and in vivo data, as well as clinical observations from a compassionate use study investigating the effects of two proenzymes, trypsinogen and chymotrypsinogen against a range of malignant tumors. Overall, proenzymes appeared to exert significant effects against more aggressive, less differentiated tumor types, like pancreatic and ovarian tumors. Patients from the compassionate use study suffering from cancers of the GI tract, or endocrine tumors, such as pancreatic and ovarian cancers, benefited most from treatment. The world market for pancreatic and ovarian cancer drugs is projected to grow to $4.2 Billion in 2025 according to Grandview Research and $10.1 Billion by 2027 according to iHealthcareAnalyst, respectively, resulting in a combined global market of $14.3 Billion over the next 5-year period.

Extensive laboratory analysis confirmed that PRP reduced the main characteristics of cancer spread, namely angiogenesis (blood vessel formation), which is a critical step in tumor development, as well as the spreading of tumor metastases. In addition, assays revealed that the migration capacity of ovarian, pancreatic, melanoma and colon cancer cells was suppressed after incubation with PRP. Furthermore, evidence suggests the epithelial to mesenchymal transition (EMT), a biological process associated with wound healing and cell migration, which causes cancer stem cells (CSCs) to become motile and invasive, is associated with metastasis and inducing drug resistance in many cancers, such as pancreatic and ovarian cancers. Studies in pancreatic and cancer cell lines after PRP treatment demonstrated a significant reduction in EMT markers and genes and in fact, a reversal of the EMT process so that CSCs become benign and less resistant to standard treatments.

The in vivo effects of PRP at different doses on tumor weight in implanted pancreatic and ovary tumors was evaluated. In the pancreatic tumor model, there was significant reduction in mean tumor weight in animals treated for 26 days with PRP with more than 85% tumor growth inhibition compared with the control. Furthermore, ovary tumor-bearing mice showed a significant reduction in mean tumor weight in animals treated for 21 days with two different doses of PRP, resulting in a 46 52% tumor growth inhibition compared with the control.

The clinical efficacy of a suppository formulation containing bovine pancreatic proenzymes trypsinogen and chymotrypsinogen was evaluated in the context of a UK Pharmaceuticals Special Scheme and the results were published in Scientific Reports. Clinical effects were studied in 46 patients with advanced metastatic cancers of different origin (prostate, breast, ovarian, pancreatic, colorectal, stomach, non-small cell lung, bowel cancer and melanoma) after treatment with a rectal formulation of both pancreatic proenzymes. No severe or serious adverse events related to the rectal administration were observed. Patients did not experience any hematological side effects as typically seen with classical chemotherapy regimens.

In order to assess the therapeutic activity, overall survival of patients under treatment was compared to the life expectancy assigned to a patient prior to treatment start. Nineteen from 46 patients (41.3%) with advanced malignant diseases, most of them suffering from metastases, had a survival time significantly longer than their expected, in fact, for the whole set of cancer types, mean survival (9.0 months) was significantly higher than mean life expectancy (5.6 months). In the case of pancreatic and ovarian cancers, 2 from 4 pancreatic cancer patients and 4 from 7 ovarian cancer patients significantly exceeded life expectancy.

As a result of the extensive studies undertaken, particularly in pancreatic cancer, the Company applied for and received Orphan Drug Designation (ODD) from the US Food and Drug Administration (USFDA) for the use of its lead product, PRP, for the treatment of pancreatic cancer. The approved indication is one of the most lethal malignancies with a median survival of 6 months and a 5-year survival rate of less than 5%. The lethal nature of this disease stems from its propensity to rapidly disseminate to the lymphatic system and distant organs, and is a major unmet medical issue. Under the Orphan Drug Act (ODA), drugs, vaccines, and diagnostic agents qualify for orphan status if they are intended to treat a disease affecting less than 200,000 American citizens. Under the ODA, orphan drug sponsors qualify for seven-year FDA-administered market Orphan Drug Exclusivity (ODE), tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance and may get clinical trial tax incentives.

Over the past 15 years, our extensive research has uncovered a truly unique and exciting technology that selectively targets and eradicates cancer stem cells, whilst leaving healthy cells alone, making it less toxic compared with standard treatment approaches, said Dr Kenyon. Furthermore, our technology appears to be effective against more aggressive, less differentiated tumor types where few treatment options exist, and prognosis is poor, especially in the case of pancreatic and ovarian cancers. I look forward to advancing PRP to human studies where we can fully assess the clinical efficacy of PRP in a controlled setting.

Propanc plans to undertake a First-In-Human study in 30 to 40 advanced cancer patients suffering from solid tumors to determine a maximum tolerated dose for PRP treatment, followed by two proof of concept studies in pancreatic and ovarian cancers, 60 patients in each study, to confirm the clinical efficacy of PRP in the selected target therapeutic indications.

PRP is a mixture of two proenzymes, trypsinogen and chymotrypsinogen from bovine pancreas administered by intravenous injection. A synergistic ratio of 1:6 inhibits growth of most tumor cells. Examples include kidney, ovarian, breast, brain, prostate, colorectal, lung, liver, uterine and skin cancers.

About Propanc Biopharma, Inc.

Propanc Biopharma, Inc. (the Company) is developing a novel approach to prevent recurrence and metastasis of solid tumors by using pancreatic proenzymes that target and eradicate cancer stem cells in patients suffering from pancreatic, ovarian and colorectal cancers. For more information, please visit http://www.propanc.com.

The Companys novel proenzyme therapy is based on the science that enzymes stimulate biological reactions in the body, especially enzymes secreted by the pancreas. These pancreatic enzymes could represent the bodys primary defense against cancer.

To view the Companys Mechanism of Action video on its anti-cancer lead product candidate, PRP, please click on the following link: http://www.propanc.com/news-media/video

Forward-Looking Statements

All statements other than statements of historical facts contained in this press release are forward-looking statements, which may often, but not always, be identified by the use of such words as may, might, will, will likely result, would, should, estimate, plan, project, forecast, intend, expect, anticipate, believe, seek, continue, target or the negative of such terms or other similar expressions. These statements involve known and unknown risks, uncertainties and other factors, which may cause actual results, performance or achievements to differ materially from those expressed or implied by such statements. These factors include uncertainties as to the Companys ability to continue as a going concern absent new debt or equity financings; the Companys current reliance on substantial debt financing that it is unable to repay in cash; the Companys ability to successfully remediate material weaknesses in its internal controls; the Companys ability to reach research and development milestones as planned and within proposed budgets; the Companys ability to control costs; the Companys ability to obtain adequate new financing on reasonable terms; the Companys ability to successfully initiate and complete clinical trials and its ability to successful develop PRP, its lead product candidate; the Companys ability to obtain and maintain patent protection; the Companys ability to recruit employees and directors with accounting and finance expertise; the Companys dependence on third parties for services; the Companys dependence on key executives; the impact of government regulations, including FDA regulations; the impact of any future litigation; the availability of capital; changes in economic conditions, competition; and other risks, including, but not limited to, those described in the Companys periodic reports that are filed with the Securities and Exchange Commission and available on its website at http://www.sec.gov. These forward-looking statements speak only as of the date hereof and the Company disclaims any obligations to update these statements except as may be required by law.

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Propanc Biopharma Targets Pancreatic & Ovarian Cancers for PRP Clinical Studies with Combined Markets to Reach Over $14.3 Billion by 2027 -...

By Dr Chytra V Anand

The fascination with beauty and skincare in India has grown leaps and bounds in recent times, and understandably so, given that the culture of beauty is deeply rooted in the country. The days when beauty was an aspect of social class and the cosmetic treatments and products you access gave away your economic status are long gone, as are the days when cosmetic treatments were considered a girl thing. With cosmetic treatments becoming more accessible and sought-after, the Indian skincare and derma cosmetics market generated an estimated revenue of a whopping USD 188.2 million in 2021. The same is projected to grow at a CAGR of 10.2% between 2021 and 2030.

Today, with changing lifestyles, demographic growth, cutting-edge technology, and improving economic and social conditions thanks to rising per capita and disposable income, India is quickly heading towards becoming a leader in the global cosmetics industry. But for a bit of self-introspection, what are Indian consumers looking for when it comes to cosmetic treatments? What does their consumption tell industry players?

Body hair removal has become one of the most popular cosmetic procedures done across the world today. But compared to shaving, waxing, or using an epilator or a trimmer, laser hair removal is a more permanent hair removal method that has gained immense traction of late. Especially in urban India, laser hair removal has quickly gained popularity, with mothers even bringing their 16-year-olds for Laser hair removal.

In 2021, the global laser hair removal market was valued atUSD 798.6 million, with an estimated CAGR of 18.4% from 2022 to 2030. Given that laser hair removal is a one-time procedure, although one has to sit through multiple sessions, the results, when done by a reliable cosmetic professional, are impressive. The Asia Pacific is projected to be the fastest-growing segment for laser hair removal, especially in countries like India and China.

A cosmetic procedure where a chemical solution is applied to your skin to remove the top layers, Chemical Peels ensure that the skin becomes smoother and clearer, making it radiant. On the other hand, a Medical Clean-up, in the simplest terms, is the procedure of cleaning your skin, ridding impurities like blackheads and white head spots to clear clogged pores. Besides, Medical Clean-ups are also beneficial for people struggling with acne scars, making it a popular procedure that an increasing number of people are choosing. For Chemical Peels, the market size is expected to touch USD 68.81 million between 2021 to 2025, making their popularity surge.

As we grow older, our skin begins to age too, and wrinkles and fine lines begin to appear on our face. Cosmetic procedures like Hydra Facials and skin maintenance with Laser Photofacials are a weekly must-do for 30-45-year-olds to ensure their skin is supple and glowing. Apart from this, the perception of Indian consumers when it comes to cosmetic treatments like Botox and Fillers has begun to change. These are no longer viewed as taboo as people now realise that they give your skin a lift.

Such treatments are also no longer only available for a certain section of society, like the wealthy. Botox and Fillers are now available to everyone, and consumers are looking at them from a skin maintenance standpoint rather than as a luxury, unnecessary treatment. Annually, the Botox segment is registering 20-25% growth in the country proof of evolving consumer preferences and the rising popularity of such treatments. Besides these, derma cosmetics and medical skin care have also gained a fair amount of traction, with skincare aficionados looking for effective and efficient skin care procedures that are non-surgical.

Alongside our skincare, taking care of our mane is equally important. For people struggling with hair fall, flaky and dry scalp, and other issues that affect your hair, stem cell therapy is the answer. Often done annually, stem cell therapy helps rejuvenate your hair cells to retain hair and repair damage. And with the global hair restoration market standing at over USD 4.2 billion in 2020, we can safely say its here to stay.

With consumerism changing face gradually and Indian consumers gaining access to world-class cosmetic treatments that are non-surgical, which still trump surgical procedures, the future of the Indian cosmetic treatments market shines bright. As long as the procedures are done by qualified and experienced professionals and are reliable and effective, the demand for such cosmetic procedures will continue to grow.

(The author isfounder ofKosmoderma Healthcare Pvt. Ltd.Views expressed are personal and do not reflect the official position or policy of the FinancialExpress.com.)

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A glimpse into Indian consumers expectations for cosmetic treatments and consumption insights - The Financial Express

Figure 1 |. Surface ectoderm and CNCC co-induction leads to hair-bearing skin generation.

a, b

a, b, Overview of (a) study objectives and (b) skin organoid (SkO) protocol. c, Brightfield images of WA25 aggregates on days 12 and 30 in optimized culture. d, Immunostaining for KRT5+KRT15+ basal and KRT15+ peridermal layers at day-55. e, f, Representative HF-induction images (e) in brightfield of days 6585 WA25 SkOs and (f) max-intensity confocal image (endogenous DSP-GFP) of days 6595 DSP-GFP SkO. Dashed-box: magnified-HF; dashed-line: HF; dashed-circles: developing hair germs; asterisks: dermal papilla. g, h, Violin plots showing (g) frequencies of HF-formation in WA25 (average 87.4%, min=68.8%, max=100%, n=212 organoids), DSP-GFP (average 87.2%, min=66.7%, max=100%, n=212 organoids), and WA01 (71%, n=130 organoids) cultures, and (h) average number of HFs formed in WA25 (average 64 HFs/organoid, min=9, max=285, n=80 organoids) and DSP-GFP (average 48 HFs/organoid, min=7, max=128, n=80 organoids) cultures between days 75147. i-k, Immunostained day-75 WA25 SkO with hair placodes. Antibodies highlight epidermal (KRT5+KRT15+CD49f+) and periderm (KRT15+) layers, dermis (PDGFR+P75+), and DC cells (SOX2+PDGFR+P75+). Dashed-boxes: magnified-regions. l, Wholemount of day-85 WA25 SkO with head-tail structures. KRT5 highlights epidermis and HF outer root sheath. SOX2 marks DC, DP, Merkel cells and melanocytes. Dashed-box: area shown to the right. Abbr: frontonasal prominence (FNP); cranial neural crest cells (CNCCs); dermal papilla (DP); matrix (Mtx); periderm (PD); hair root (HR); dermal condensate (DC). Scale: 500 m (c), 250 m (l; left), 100 m (e; first three panels, f; third-panel, i-k; upper-panels), 50 m (d, f; second-panel, i-k; lower-panels, l; right), 25 m (e; last-panel, f; first/last-panels). See Statistics and Reproducibility for plot and experimental information.

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Hair-bearing human skin generated entirely from pluripotent stem cells

FACTORFIVE Skincare The Power of Stem Cells for Skin icon-star icon-bag icon-search icon-close icon-list icon-plus minus icon-loading arrow-left arrow-right chevron-left chevron-right mail linkedin facebook instagram pinterest tumblr youtube stumbleupon google print heart share icon-visa icon-mastercard icon-american-express icon-discover icon-paypal icon-apple-pay icon-stripe

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Dr. Annie BowlesStem Cell Scientist

Backed by years of scientific research, FACTORFIVE is committed to providing you with the most cutting-edge and innovative skincare on the market. Human growth factors are essential to your skins appearance and health, and now their regenerative powers have finally been harnessed. Not only have we developed an exceptional skin serum, we continue to leverage the latest scientific discoveries to shape the future of aesthetics.

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FACTORFIVE Skincare The Power of Stem Cells for Skin

Hematopoietic Stem Cells: In living organisms, a specialized system that consist of blood and its progenitors are referred to as the hematopoietic system.

In particular, this system is made up of cells with specialized functions such as the red blood cells (for carrying oxygen to tissues), white blood cells (for immune defense against pathogens, and foreign agents), platelets (for blood clotting), macrophages and lymphocytes (also for immune defense).

However, many of the said blood cells are temporary and need to be replaced with new ones continuously. But fret not because a single cell can solve the problem!

Every day, almost billions of new blood cells are synthesized within the body with each coming from a specific progenitor cell called the hematopoietic stem cell.

How to pronounce Hematopoietic Stem Cells?

What is Hematopoiesis?

The formation of all kinds of blood cells including creation, development, and differentiation of blood cells is commonly known as Hematopoiesis or Haemopoiesis.

All types of blood cells are generated from primitive cells (stem cells) that are pluripotent (they have the potential to develop into all types of blood cells).

Also referred to as hemocytoblasts, hematopoietic cells are the stem cells that give rise to blood cells in hematopoiesis.

Where Does Hematopoiesis Occur?

In a healthy adult, hematopoiesis occurs in the bone marrow and lymphatic tissues, where 1000+ new blood cells (all types) are generated from the hematopoietic stem cells to main the steady-state levels.

Where Are Hematopoietic Stem Cells Found?

They can also be found in the umbilical cord and in the blood from the placenta.

Who Discovered Hematopoietic Stem Cells?

It was long believed that the majority of hematopoiesis occurs during ontogeny (origination and development of organism) and that the mammalian hematopoietic system originated from the yolk sac per se.

Functions of Hematopoietic Cells

As alluded to earlier, blood cells and blood cell components are formed in a process called hematopoiesis.

Coming from the Greek words hemato and poiesis which mean blood and to make respectively, hematopoiesis occurs in the bone marrow and is responsible not only for the synthesis but also the multiplication, and differentiation of blood cells.

Shown below is a diagrammatic illustration of the different blood cell types that hematopoietic cells can give rise to:

Clinical uses of Hematopoietic Stem Cells

The mammalian blood system showcases the equilibrium between the functions of hematopoietic stem cells. Intensive studies have already shown the structures and molecules that control these stem cells, but the exact picture of the underlying molecular mechanisms is still unclear.

Above everything else, it is important to note that such issues are not just of academic interest but can also be relevant in devising future novel methods of diagnosing and treating various diseases associated with cells.

Key References

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Hematopoietic Stem Cells | Hematopoiesis | Properties & Functions

Cells in the body have specific purposes, but stem cells are cells that do not yet have a specific role and can become almost any cell that is required.

Stem cells are undifferentiated cells that can turn into specific cells, as the body needs them.

Scientists and doctors are interested in stem cells as they help to explain how some functions of the body work, and how they sometimes go wrong.

Stem cells also show promise for treating some diseases that currently have no cure.

Stem cells originate from two main sources: adult body tissues and embryos. Scientists are also working on ways to develop stem cells from other cells, using genetic reprogramming techniques.

A persons body contains stem cells throughout their life. The body can use these stem cells whenever it needs them.

Also called tissue-specific or somatic stem cells, adult stem cells exist throughout the body from the time an embryo develops.

The cells are in a non-specific state, but they are more specialized than embryonic stem cells. They remain in this state until the body needs them for a specific purpose, say, as skin or muscle cells.

Day-to-day living means the body is constantly renewing its tissues. In some parts of the body, such as the gut and bone marrow, stem cells regularly divide to produce new body tissues for maintenance and repair.

Stem cells are present inside different types of tissue. Scientists have found stem cells in tissues, including:

However, stem cells can be difficult to find. They can stay non-dividing and non-specific for years until the body summons them to repair or grow new tissue.

Adult stem cells can divide or self-renew indefinitely. This means they can generate various cell types from the originating organ or even regenerate the original organ, entirely.

This division and regeneration are how a skin wound heals, or how an organ such as the liver, for example, can repair itself after damage.

In the past, scientists believed adult stem cells could only differentiate based on their tissue of origin. However, some evidence now suggests that they can differentiate to become other cell types, as well.

From the very earliest stage of pregnancy, after the sperm fertilizes the egg, an embryo forms.

Around 35 days after a sperm fertilizes an egg, the embryo takes the form of a blastocyst or ball of cells.

The blastocyst contains stem cells and will later implant in the womb. Embryonic stem cells come from a blastocyst that is 45 days old.

When scientists take stem cells from embryos, these are usually extra embryos that result from in vitro fertilization (IVF).

In IVF clinics, the doctors fertilize several eggs in a test tube, to ensure that at least one survives. They will then implant a limited number of eggs to start a pregnancy.

When a sperm fertilizes an egg, these cells combine to form a single cell called a zygote.

This single-celled zygote then starts to divide, forming 2, 4, 8, 16 cells, and so on. Now it is an embryo.

Soon, and before the embryo implants in the uterus, this mass of around 150200 cells is the blastocyst. The blastocyst consists of two parts:

The inner cell mass is where embryonic stem cells are found. Scientists call these totipotent cells. The term totipotent refer to the fact that they have total potential to develop into any cell in the body.

With the right stimulation, the cells can become blood cells, skin cells, and all the other cell types that a body needs.

In early pregnancy, the blastocyst stage continues for about 5 days before the embryo implants in the uterus, or womb. At this stage, stem cells begin to differentiate.

Embryonic stem cells can differentiate into more cell types than adult stem cells.

MSCs come from the connective tissue or stroma that surrounds the bodys organs and other tissues.

Scientists have used MSCs to create new body tissues, such as bone, cartilage, and fat cells. They may one day play a role in solving a wide range of health problems.

Scientists create these in a lab, using skin cells and other tissue-specific cells. These cells behave in a similar way to embryonic stem cells, so they could be useful for developing a range of therapies.

However, more research and development is necessary.

To grow stem cells, scientists first extract samples from adult tissue or an embryo. They then place these cells in a controlled culture where they will divide and reproduce but not specialize further.

Stem cells that are dividing and reproducing in a controlled culture are called a stem-cell line.

Researchers manage and share stem-cell lines for different purposes. They can stimulate the stem cells to specialize in a particular way. This process is known as directed differentiation.

Until now, it has been easier to grow large numbers of embryonic stem cells than adult stem cells. However, scientists are making progress with both cell types.

Researchers categorize stem cells, according to their potential to differentiate into other types of cells.

Embryonic stem cells are the most potent, as their job is to become every type of cell in the body.

The full classification includes:

Totipotent: These stem cells can differentiate into all possible cell types. The first few cells that appear as the zygote starts to divide are totipotent.

Pluripotent: These cells can turn into almost any cell. Cells from the early embryo are pluripotent.

Multipotent: These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets.

Oligopotent: These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this.

Unipotent: These can only produce cells of one kind, which is their own type. However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells.

Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta.

Stem cells themselves do not serve any single purpose but are important for several reasons.

First, with the right stimulation, many stem cells can take on the role of any type of cell, and they can regenerate damaged tissue, under the right conditions.

This potential could save lives or repair wounds and tissue damage in people after an illness or injury. Scientists see many possible uses for stem cells.

Tissue regeneration is probably the most important use of stem cells.

Until now, a person who needed a new kidney, for example, had to wait for a donor and then undergo a transplant.

There is a shortage of donor organs but, by instructing stem cells to differentiate in a certain way, scientists could use them to grow a specific tissue type or organ.

As an example, doctors have already used stem cells from just beneath the skins surface to make new skin tissue. They can then repair a severe burn or another injury by grafting this tissue onto the damaged skin, and new skin will grow back.

In 2013, a team of researchers from Massachusetts General Hospital reported in PNAS Early Edition that they had created blood vessels in laboratory mice, using human stem cells.

Within 2 weeks of implanting the stem cells, networks of blood-perfused vessels had formed. The quality of these new blood vessels was as good as the nearby natural ones.

The authors hoped that this type of technique could eventually help to treat people with cardiovascular and vascular diseases.

Doctors may one day be able to use replacement cells and tissues to treat brain diseases, such as Parkinsons and Alzheimers.

In Parkinsons, for example, damage to brain cells leads to uncontrolled muscle movements. Scientists could use stem cells to replenish the damaged brain tissue. This could bring back the specialized brain cells that stop the uncontrolled muscle movements.

Researchers have already tried differentiating embryonic stem cells into these types of cells, so treatments are promising.

Scientists hope one day to be able to develop healthy heart cells in a laboratory that they can transplant into people with heart disease.

These new cells could repair heart damage by repopulating the heart with healthy tissue.

Similarly, people with type I diabetes could receive pancreatic cells to replace the insulin-producing cells that their own immune systems have lost or destroyed.

The only current therapy is a pancreatic transplant, and very few pancreases are available for transplant.

Doctors now routinely use adult hematopoietic stem cells to treat diseases, such as leukemia, sickle cell anemia, and other immunodeficiency problems.

Hematopoietic stem cells occur in blood and bone marrow and can produce all blood cell types, including red blood cells that carry oxygen and white blood cells that fight disease.

People can donate stem cells to help a loved one, or possibly for their own use in the future.

Donations can come from the following sources:

Bone marrow: These cells are taken under a general anesthetic, usually from the hip or pelvic bone. Technicians then isolate the stem cells from the bone marrow for storage or donation.

Peripheral stem cells: A person receives several injections that cause their bone marrow to release stem cells into the blood. Next, blood is removed from the body, a machine separates out the stem cells, and doctors return the blood to the body.

Umbilical cord blood: Stem cells can be harvested from the umbilical cord after delivery, with no harm to the baby. Some people donate the cord blood, and others store it.

This harvesting of stem cells can be expensive, but the advantages for future needs include:

Stem cells are useful not only as potential therapies but also for research purposes.

For example, scientists have found that switching a particular gene on or off can cause it to differentiate. Knowing this is helping them to investigate which genes and mutations cause which effects.

Armed with this knowledge, they may be able to discover what causes a wide range of illnesses and conditions, some of which do not yet have a cure.

Abnormal cell division and differentiation are responsible for conditions that include cancer and congenital disabilities that stem from birth. Knowing what causes the cells to divide in the wrong way could lead to a cure.

Stem cells can also help in the development of new drugs. Instead of testing drugs on human volunteers, scientists can assess how a drug affects normal, healthy tissue by testing it on tissue grown from stem cells.

Watch the video to find out more about stem cells.

There has been some controversy about stem cell research. This mainly relates to work on embryonic stem cells.

The argument against using embryonic stem cells is that it destroys a human blastocyst, and the fertilized egg cannot develop into a person.

Nowadays, researchers are looking for ways to create or use stem cells that do not involve embryos.

Stem cell research often involves inserting human cells into animals, such as mice or rats. Some people argue that this could create an organism that is part human.

In some countries, it is illegal to produce embryonic stem cell lines. In the United States, scientists can create or work with embryonic stem cell lines, but it is illegal to use federal funds to research stem cell lines that were created after August 2001.

Some people are already offering stem-cells therapies for a range of purposes, such as anti-aging treatments.

However, most of these uses do not have approval from the U.S. Food and Drug Administration (FDA). Some of them may be illegal, and some can be dangerous.

Anyone who is considering stem-cell treatment should check with the provider or with the FDA that the product has approval, and that it was made in a way that meets with FDA standards for safety and effectiveness.

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Stem cells: Sources, types, and uses - Medical News Today

This months top grants in regenerative medicine, sourced from Dimensions, includes projects on: a novel platform to enhance single cell interrogation of nervous system development, human endothelial cell regulation of ossification and the development of a dynamic double network hydrogel for generating pancreatic organoids from induced pluripotent stem cells.

This project aims to investigate a strategy, which utilizes novel spatial transcriptomics approaches, integrated multiplexed RNA/protein detection and visualization and computational algorithms to identify and map molecular markers of the preganglionic neurons in the ventral spinal cord and progenitor cell populations of the sympathetic ganglia. If successful, the approach could provide a foundation for basic research of peripheral nervous system birth defects and repair using stem cell-based therapies, as well as future studies of neuroblastoma initiation.

Funding amount:US$206,000

Funding period: 8 August 2022 31 July 2024

Funder:Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Research organization:Stowers Institute for Medical Research (MO, USA)

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Over one million patients undergo bone repair procedures in the USA annually, with autologous bone grafting remaining the preferred treatment for bone defects. The development of therapies that exploit the osteogenic potential of bone marrow-derived mesenchymal stem cells (bm-MSCs) has been limited due to limited understanding of the regulatory mechanisms of in vivo bm-MSC osteogenesis. Previous research from the group showed that the osteogenic potential of bm-MSCs is dependent on sustained proximity to endothelial cells. The goal of the present study is to elucidate the cellular and molecular mechanisms by which endothelial cells regulate the osteogenic differentiation of bm-MSCs and develop a foundation of knowledge upon which to build therapeutic strategies for bone regeneration utilizing autologous bm-MSCs.

Funding amount:US$442,000

Funding period: 10 August 2022 31 May 2027

Funder:National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Research organization:Boston Childrens Hospital (MA, USA)

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Human induced pluripotent stem cells provide a valuable source of cells for basic research and translational applications. While there have been advances in lineage-specific differentiation of human induced pluripotent stem cells, there remains limited understanding on the impact of matrix stiffness, viscoelasticity and integrin ligand presentation on the multi-stage development of exocrine pancreatic organoids. This research aims to define the influence of matrix properties on the generation of exocrine pancreatic organoids by developing a viscoelastic dynamic double network hydrogel platform with controllable matrix mechanical properties and biochemical motifs. This will advance the application of chemically defined matrices as xeno-free artificial stem cell niches for organoid growth and tissue regeneration applications.

Funding amount:US$468,000

Funding period: 1 August 2022 31 July 2026

Funder:National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Research organization: Indiana University Purdue University Indianapolis (IA, USA)

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Top 3 grants in regenerative medicine: July 2022 - RegMedNet

A Taiwanese AI algorithm maker knows the value of the mind behind a face. The company says its software can perform virtual fashion try-ons and parse a consumers personality with the same selfie.

Perfect Corp. last week pushed a new AI and augmented reality makeup app and a fashion industry tie-in that could seed the market for high-end algorithmic social aspiration. In August, the company went down-market with a beard try-on product.

None of that is to take away from Perfects July decision to start selling the AI Personality Finder. It is a combination of facial-feature mapping and rudimentary psychological data that allegedly tells people not only how emotionally attractive they are, but also, what products to use to increase their visual likability.

At least in the United States, Perfect typically sells to fashion and makeup companies, but it also partners with some firms for their mutual marketing benefit.

For instance, the software firm has created a try-on app for toothpaste maker Colgate that reportedly will show people how much brighter their teeth would be by using a Colgate product.

A selfie and a little measure of insecurity is all that someone needs.

A day later, Perfect said it was working with Nolcha Shows on New York Fashion Week (September 9 to 14), a top appointment on many social calendars. Nolcha, a fashion events promoter, has added try-on features to some segments of the show via its YouCam Makeup app.

Then there is Perfects Personality Finder, a subscription service sold to vendors for use by adults and children. It purports to be a biometric recognition algorithm based on the idea that certain faces belong to certain kinds of minds.

The app could raise eyebrows the way that emotion recognition algorithms have done.

It scans a selfie for as many as 65 facial attributes. Out the other end come scores for neuroticism, agreeableness, openness, conscientiousness and extroversion.

It is not unlike another of Perfects apps, its Skin Analysis tool.

Although Perfect says it will remove from its servers information pertaining to children younger than 16, the primary model it uses to illustrate its software appears to be younger.

It was just in March that Perfect left its parent, CyberLink, to acquire Provident Acquisition in order to register for an IPO this year. Provident is referred to as a blank-check company, which makes it the investing version of stem cells. It has all it needs to be something and is waiting for a nudge.

AI | augmented reality | biometrics | CyberLink | face biometrics | facial analysis | mobile app | Perfect | selfie biometrics | Taiwan

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Beauty maybe be skin deep, but AI finds revenue on the faces surface - Biometric Update

September is observed as Blood Cancer Awareness month all over the world. During this month, activists and stakeholders work to raise awareness about the disease and the efforts being taken to fight blood cancers including leukemia, lymphoma, myeloma and Hodgkins disease.

The term blood cancer is a general description of various hematopoietic cancers. Our blood flows through blood vessels to supply all tissues in the body with nutrients. In the approximately 5 litres of blood circulating in our body there are billions of blood cells that carry out various vital functions. All blood cells originate from hematopoietic stem cells.

Haematopoietic stem cells are known as mother cells and do not yet have a specific function. They are able to renew and differentiate into cells with a specific function, thus replacing cells that die. In bone marrow, blood stem cells divide and develop into progenitor cells. Through further division, the progenitor cells mature and transform into different types of blood cells and then enter the bloodstream, says Dr Nitin Agarwal, HOD, Donor Request Management, DKMS BMST Foundation India.

Blood cancer is an abnormal proliferation (abnormal growth) of cells in the bone marrow especially white blood cells (WBCs). Cancer cells flood the bloodstream and drive out healthy cells. As a result, the blood can no longer perform its basic tasks, such as transporting oxygen and protecting the body from infection.

LeukemiaThis cancer is found in the bone marrow and the bloodstream. It is caused by abnormal rapid production of WBCs and high number of abnormal WBCs which cannot fight against infection, and they impair the bone marrows ability to produce red blood cells and platelets, says Dr Jimmy Mirani, Consultant Onco Surgeon, Wockhardt Hospital, Mumbai Central.

LymphomaA type of blood cancer which affects the lymphatic system, which removes the risk excess fluids from body and generates immune cells. Lymphocytes are blood cells which are used to fight against infections. These abnormal lymphocytes become lymphoma cells which multiply and get collected in the tissues, adds Dr Mirani.

There are two types of lymphoma, namely, Hodgkins lymphoma and non-Hodgkins lymphoma.

Non-Hodgkins lymphoma:It mainly impacts the B-cell or T-cell. This type of lymphoma occurs more commonly than Hodgkins lymphoma. Can vary clinically and diagnostically into slow-growing ones to very aggressive types, notes Dr. Amrita Chakrabarti, Consultant, Haemato-Oncology & Bone Marrow Transplant, Max Hospital, Shalimar Bagh.

Hodgkins lymphoma This type of lymphoma affects the B cells. Broadly divided into classical Hodgkins and nodular lymphocyte predominant types. Occurs in the adolescence or elderly age group.

MyelomaIt is the cancer of plasma cells; WBCs which produce disease and infection fighting anti-bodies. Myeloma cells prevent the functions and productions of these antibodies leaving a week immune system.

Multiple myelomaThis starts in the bone marrow when plasma cells begin to grow uncontrollably. As the cells grow, they compromise the immune system and impair the production and function of white and red blood cells causing bone disease, organ damage and anemia among other conditions, adds Dr Agarwal.

In most cases of blood cancer, the patient feels tired and weak. This happens because the number of red blood cells in the blood starts decreasing due to which there is a lack of blood in the person. Someof the commonsymptoms of blood cancers are fever, severe fatigue, bleeding from gums or skin, back ache, or bone pains, says Dr Pravas Mishra, Head Haematology/ Medical Oncology and BMT, Amrita Hospital, Faridabad.

Patients with myeloma might first present to an orthopaedical with a fracture originating from trivial trauma or to a nephrologist with a kidney dysfunction.Pain in bones and joints can be a symptom of not only arthritis but also blood cancer. Blood cancer is a disease in the bone marrow that is found in large amounts around the bones and joints.

Patientsmight present with nodes in the neck or axilla or groin or swelling in any part of the body. However most often a patientwith blood cancermight present with just a low haemoglobin. It is strongly advised not to ignore any anaemia, warns Dr Mishra.

A person suffering from blood cancer is prone to repeated infections. When leukemia cells develop in the body, then complaints of infection can be seen in the patients mouth, throat, skin, lungs, etc.

People who have cancer tend to have an abnormally low weight. If the body weight is reduced without any obvious cause, then it can be seen as the primary symptom of cancer.

The abnormal formation of leukemia cells in the body prevents the bone marrow from forming healthy blood cells such as platelets. Due to its deficiency, more bleeding problems can be seen from the nose of the patient, during menstruation and gums.

Blood cancer is diagnosed with the help of a wide range of diagnostic methods along clinical evaluation, such as blood tests, bone marrow tests, cytogenetic/karyotyping and molecular analysis, flow cytometry.

Myth: Blood cancer cannot be treated?

Fact: Once a patient is diagnosed with blood cancer, the first concern that comes to ones mind Is blood cancer curable?

Blood cancer is one type of cancer that has a high curability rate especially due to the advancement in the medical field, availability of newer, improved chemotherapy regimens, targeted therapy, and improved infection control measures. Timely diagnosis, especially early diagnosis, increases the chances of cure from blood cancer.Some of the other factors that impact the cure of blood cancer include the age of the patient, physical condition, presence of other comorbidities, stage of the disease, subtype of cancer, molecular factors, whether low grade/high grade, acute or chronic, the body parts that are affected and whether the disease is new onset or has come back after a previous cure.

You must understand that the cure or recovery from cancer is unpredictable, adds Dr. Chakrabarti.

There are cases when the patient has recovered even in the later stages of blood cancer. On the other hand, there are recorded cases where the patient couldnt recover even in the initial stages of blood cancer. So, its important to have realistic expectations and focus on following a healthy lifestyle with the advised treatment and measures. Early diagnosis and treatment play an important role in attaining cure.

Myth: All blood cancer patients need a bone marrow transplant

Fact: No, majority of patients suffering from blood cancers are treated without bone marrow transplant. A combination of chemotherapy, targeted therapy and immunotherapy is the best line of treatment.

Myth: Blood cancer occurs only in children?

Fact: No, blood cancers can occur in all age groups. All have a higher incidence in young children whereas Myeloid Leukaemia (MLL) is more frequently seen in senior citizens.

India is reeling under pressure of many misconceptions that exist amongst people about blood stem cell donation, its process and even its after-effects.

Myth: Once you donate blood stem cells, you will lose them forever.

Fact: Only a fraction of total stem cells is extracted during the process. Also, all the cells are naturally replenished within a few weeks

Myth: Donating stem cells is a really invasive and painful process

Fact: Blood stem cells are collected through peripheral blood stem cell collection (PBSC) which is completely safe and a non-surgical procedure. The process is similar to blood platelet donation that takes approximately three to four hours to complete and the donor can leave the collection center the same day.

Myth: Blood donation and a blood stem cell donation are same

Fact: Unlike blood collection for transfusion, blood stem cells are collected only when there is a match between the donor and patients human leukocyte antigen (HLA) combination (tissue type). So, you could be potentially the only match and life saver for a person with blood cancer in need of a transplant, adds Dr Nitin Agarwal. Blood stem cell donors donate only blood stem cells and the process is similar to a platelet donation.

Myth: Pregnant women cant register

Fact: This is untrue, a woman can register even during her pregnancy.

Myth: Stem cell donation leaves prolonged side-effects

Fact: No, there are no major side effects post blood stem cell donation. A person may only experience minor flu like symptoms because of the GCSF injections given to him/her before the donation, to mobilize blood stem cells in your blood stream.

Myth: Piercing and/or tattoo is a restricting factor

Fact: Piercing or a tattoo doesnt stop you from registering yourself to be a potential donor.

Myth: My blood stem cells can be stored

Fact: Your blood stem cells will not be stored. They last for around 72 hours and are delivered for the recipient straight to the hospital by a special courier. If the recipients body accepts them, the stem cells will start making healthy blood cells.

Myth: Joining a blood stem cell registry is no use. Most patients can find a stem cell donor within their own families

Fact: Per statistics, only 30% of blood disorder patients in need of a stem cell transplant are able to find a sibling match. About 70% of patients need an unrelated donor.

A registry like DKMS BMST Foundation India is a data bank of potential blood stem cell donors that houses details on thousands of committed blood stem cell donors. Any patient can benefit from this registry provided an HLA match.

Some of the blood cancer treatments include the following

Chemotherapy

This is the most important aspect of blood cancer treatment and involves using certain chemicals to kill the cancer-causing cells in the patients body. The prescribed drugs are given in a particular timeframe for the best possible improvement in the patients health. In some patients, a stem cell transplant is provided along with high dose chemotherapy.

Radiation therapyRadiation therapy helps to destroy cancer cells with the help of specific high-energy beams to kill cancer cells in precise areas of the body. This treatment is much beneficial for patients with lymphoma

Bone marrow transplantIn this procedure, healthy stem cells are utilized to replace the cells affected by cancer. This helps the patients recover in the best possible manner. Can be autologous (where stem cells are taken from the patients own body) or allogenic (when a healthy donor gives stem cells to the patient.)

Targeted Therapy

Usually in the form of oral medications or pills. They are given alongside chemotherapy/ or radiotherapy and affect specific cancer cells and help in destroying them.

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September is Blood Cancer Awareness Month: All You Need to Know - News18

Memory seems simple enough. For most people, its the ability to create and retrieve memories or information. In reality, memory is a mysterious rabbit hole. Its still not fully understood, especially in the natural world where strange forms of memory exist in chemical compounds and even rocks. There are anthills where memories outlast the ants, and some plants remember being dropped. These facts, and others, might just prove that memory is more amazing than we ever thought possible.

Related: 10 Weird Things You Did Not Know About Memory

A few years ago, evolutionary ecologist Monica Gagliano set out to prove that plants are more intelligent than we give them credit for. More specifically, she wanted to show that plants can learn and remember even though they have no brains. For her experiment, she chose the species Mimosa pudica, a plant that responds to touch by rapidly closing its leaves.

Gagliano created a custom shelf for the plants, one that would suddenly drop a few feet. At first, the plants reacted in a defensive manner and curled their leaves. But after a few drops, the plants seemed to realize there was no danger and stopped clamming up.

Gagliano halted the experiment for a month to give the plants enough time to forget, but they didnt. When the shelf dropped again, none of the Mimosas closed upa tantalizing sign that the plants remembered the falling shelf and that it was also a safe experience.[1]

For a long time, biologists believed that giant tortoises were about as intelligent as a cabbage. However, this misconception lost traction when two zoos tested Galapagos and Aldabra tortoises and discovered that the large reptiles were quick learners. After dangling food as a reward, the tortoises were given two tests. In one instance, they simply had to bite a ball on a stick to get a snack. In the second test, they were shown two balls, but in order to be fed, they had to bite the right color ball.

One zoo tested the animals one by one and got good results. The second zoo tested them in groups, and incredibly, these tortoises seemed to grasp what was expected of them by watching what their fellow tortoises did. Not only did this prove that these animals are capable of individual and social learning, but some of them even remembered to bite the correct color ball when they were tested again nine years later.[2]

In 2018, scientists tested a substance called vanadium dioxide (VO2). The compound was hiding a mystery. For some reason, VO2s resting state made it an insulator, but when heated to above 154.4F (68C), it turned into a conductor. The study revealed why; VO2 has atoms that are capable of rearranging themselves. When heated, they adopt a pattern that turns the compound into a conductor. As it cools, the atoms relax back into their original positions and turn the material back into an insulator.

Remarkably, when researchers heated the VO2 a second time, the atoms behaved as if they remembered the experience of shifting between the two states. Although the discovery is groundbreakingits the first material to behave in this wayVO2 wont win any memory contests. It only seems to remember the shift for three hours after the fact.[3]

Our skin contains plenty of stem cells. When there is a cut or infection, stem cells rush to repair the skin, and they remember the experience. This inflammation memory is mostly a good thing. It helps stem cells respond faster the next time they sense a wound, which speeds up healing times.

However, when researchers looked more closely at the process, they realized that it could be the smoking gun pointing to a new suspect behind inflammatory skin disorders such as psoriasis. In the past, the blame was squarely placed on immune cells. But new studies revealed that the same memory that makes stem cells more effective can also go haywire. As the theory goes, when this happens, the cells hijack the skins inflammatory process, which might either cause psoriasis or make the condition worse.[4]

When a caterpillar turns into a moth or butterfly, the metamorphosis is one of the most drastic in nature. Can memory survive a process that rearranges a creatures entire body? To find out, researchers knew they had to give the caterpillars an enduring memorylike a bad smell. Even better, a pong accompanied by pain. Soon enough, the caterpillars were exposed to light electric shocks accompanied by the smell of nail polish remover.

The caterpillars soon learned to avoid the odor, and remarkably, after they blossomed into moths, the memory and skittishness around the nail polish remover remained. This proved that moths, and probably butterflies too, can remember things from their caterpillar days even though their brains and nervous systems have undergone extensive reshuffling.[5]

Rocks have a curious ability. They can align their magnetic bits with the Earths magnetic field. The manner in which these bits arrange themselves and settle down can act like a snapshot of the planets field. Aptly called magnetic memory, the effect on a rock is permanent, and it gives geologists a way to see how strong or weak the Earths field was a thousand or even millions of years ago.

But when researchers looked at the Devonian period (420 to 360 million years ago), they discovered that rocks from this era have no magnetic memory. What caused this worldwide blank? Thus far, the entire thing remains a compelling mystery. But a leading theory suggests that Earths magnetic field was so disastrously weak that it had no influence on magnetic particles inside stones.[6]

The human brain and ant colonies have a few things in common. They operate without central control, and both also use chemical signals to alter the behavior of important interacting parts. The latter include neurons in brains and ants in colonies.

Researchers were curious to know if ant colonies could also remember things like a brain. To clarify, not the ants. The colony. In other words, could ants behave in a way that suggests they remain affected by something originally experienced by their long-gone predecessors? Incredibly, it would appear so.

Experiments showed that when some nests suffered a disturbance, the ants changed their behavior. Thats not really unusual. But in some cases, subsequent generations of ants also adopted the new behavior even though they were unaware of the disturbance. In this manner, it would appear that a colony can remember a threat when individual ants no longer do.[7]

A few years ago, scientists fitted mosquitoes with tiny helmets. No, really. The hats monitored the brain activity of each mosquito to discover more about its memory processes. The study, which placed the insects in a flight simulator and exposed them to different human chemicals, revealed something interesting.

First, it proved that an old wives tale was true. Mosquitoes find the blood of some people sweeter, and they remember these hosts, often snacking on the same person more than once. The helmets also revealed that mosquitoes are far from dumb because they also remember people who swat at them. Once they recognize the smell of a defensive food source, some mosquitoes abandon the person even though their blood is of the sweet variety.[8]

Gamma-aminobutyric acid (GABA) is a molecule that can be found in humans and animals. It acts as a messenger of the nervous system, which includes the brain. Plants lack brains, and yet, they also have GABA. It helps them with memory-like processes during times of drought, something that surprised the researchers who stumbled upon the fact in 2021.

With plants, GABA works in a simple yet ingenious way to help them limit their water loss in times of drought. During the day, the molecules accumulate within the plants tissues. The drier the weather, the more GABA molecules cram into the fibers. The total amount of GABA then acts like a memory the next day. For example, a dense cluster will remind the plant that yesterday was dry. As a result, the plant protects its internal moisture reserve by not opening its leaf pores too widely.[9]

Slime molds dont have brains or a nervous system. Despite these missing pieces, their minds are surprisingly sophisticated. Experts already knew that slime molds can learn things about their environment and even share these memories with their fellow slime balls. The question was how.

This riddle was cracked in 2019 when researchers noticed that members of one species, Physarum polycephalum, often fused their venous systems with each other. This suggested that individuals can teach other blobs by sharing information through their fused veins. But how do they learn something in the first place?

A test, which used salt as an obstacle to food, threw some light on the learning process. In essence, the blobs get their information by absorbing the item theyre investigating. In this case, they hoovered a little salt, realized it wasnt dangerous, and vein-mailed their fellow blobs the good news.[10]

Jana earns her beans as a freelance writer and author. She wrote one book on a dare and hundreds of articles. Jana loves hunting down bizarre facts of science, nature and the human mind.

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10 Facts That Prove Memory Is Not What You Think - Listverse

BOTHELL, Wash. & TOKYO & RAHWAY, N.J.--(BUSINESS WIRE)-- Seagen, Inc.(Nasdaq:SGEN), Astellas Pharma US, Inc.(TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., Astellas) and Merck & Co. (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the phase 1b/2 EV-103 clinical trial (also known as KEYNOTE-869) Cohort K investigating PADCEV (enfortumab vedotin-ejfv) in combination with Mercks anti-PD-1 therapy KEYTRUDA (pembrolizumab) and PADCEV alone as first-line treatment in patients with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible to receive cisplatin-based chemotherapy. The findings were presented today at the European Society for Medical Oncology (ESMO) Congress as part of a late-breaking abstract presentation (Abstract #LBA73).

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220912005300/en/

In patients treated with enfortumab vedotin and pembrolizumab (n=76), results demonstrated a 64.5% confirmed objective response rate (ORR) (95% CI: 52.7 to 75.1) per RECIST v1.1 by blinded independent central review (BICR), the primary endpoint of Cohort K, with 10.5% of patients experiencing a complete response and 53.9% of patients experiencing a partial response. The median duration of response (DOR) per BICR was not reached (95% CI: 10.25 months to NR). All-grade treatment-related adverse events (TRAEs) of special interest for enfortumab vedotin in combination with pembrolizumab were skin reactions (67.1%), peripheral neuropathy (60.5%), ocular disorders (dry eye, blurred vision, and corneal disorders) (26.3%), hyperglycemia (14.5%), and infusion-related reactions (3.9%). Pembrolizumab adverse events of special interest were consistent with previously observed safety data from monotherapy with the exception of severe skin reactions. Overall, the results were generally consistent with previously reported efficacy and safety results of the EV-103/KEYNOTE-869 dose-escalation cohort and expansion Cohort A.1

Please see Important Safety Information at the end of this press release for both drugs, including BOXED WARNING for enfortumab vedotin and immune-mediated adverse reactions for pembrolizumab.

Cohort K also included a monotherapy arm in which patients were treated with enfortumab vedotin alone (n=73), though this study was not designed to support a formal comparison between the two arms. Results showed a 45.2% confirmed ORR (95% CI: 33.5 to 57.3) per RECIST v1.1 by BICR, with 4.1% of patients experiencing a complete response and 41.1% of patients experiencing a partial response. The median DOR was 13.2 months (95% CI: 6.14 to 15.97) per RECIST v1.1 by BICR. All-grade TRAEs of special interest for enfortumab vedotin were peripheral neuropathy (54.8%), skin reactions (45.2%), ocular disorders (dry eye, blurred vision, and corneal disorders) (28.8%), hyperglycemia (11.0%), and infusion-related reactions (5.5%).

Additional secondary endpoints in the EV-103 Cohort K trial included progression-free survival (PFS) and overall survival (OS). Among patients treated with enfortumab vedotin and pembrolizumab, median PFS was not reached (95% CI: 8.31 months to NR). Median OS was 22.3 months (95% CI: 19.09 to NR). Among patients treated with enfortumab vedotin, median PFS was 8.0 months (95% CI: 6.05 to 10.35) and median OS was 21.7 months (95% CI: 15.21 to NR).

TRAEs of any grade that occurred in more than 20% of patients treated with enfortumab vedotin alone or in combination with pembrolizumab were fatigue, peripheral sensory neuropathy, alopecia, rash maculo-papular, pruritus, dysgeusia, weight decreased, diarrhea, decreased appetite, nausea, and dry eye.

Results from EV-103/KEYNOTE-869 Cohort K support the ongoing investigation of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who are in need of treatment options, and this combination may be an important therapeutic option for these patients, said Jonathan E. Rosenberg, M.D., Chief, Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center and EV-103/KEYNOTE-869 Cohort K primary investigator. Dr. Rosenberg has consulting relationships with Seagen, Astellas and Merck.

Nearly sixty-five percent of patients who were treated with enfortumab vedotin and pembrolizumab responded to the combination, with almost eleven percent showing no detectable cancer following treatment. These study results represent an encouraging finding for people with advanced urothelial cancer who are not eligible for cisplatin treatment, said Marjorie Green, Senior Vice President and Head of Late-Stage Development, Seagen.

We're encouraged by these positive findings from the combination of enfortumab vedotin and pembrolizumab in people with advanced urothelial cancer who historically have had limited treatment options in the first-line setting, and we intend to discuss these results with regulatory authorities, said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas.

Were pleased that this combination provided a meaningful benefit to this group of advanced bladder cancer patients in this study, and we will continue to investigate enfortumab vedotin plus pembrolizumab through our collaboration, said Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, Merck Research Laboratories.

In February 2020, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab for patients with unresectable la/mUC who are ineligible to receive cisplatin-based chemotherapy in the first-line setting. The designation is based on results from the dose-escalation cohort and expansion Cohort A of the phase 1b/2 trial, EV-103/KEYNOTE-869 (NCT03288545), evaluating patients with la/mUC who are ineligible to receive cisplatin-based chemotherapy treated in the first-line setting with enfortumab vedotin in combination with pembrolizumab.

Seagen, Astellas and Merck are further investigating enfortumab vedotin plus pembrolizumab in Phase 3 studies, including EV-302/KEYNOTE-A39 (NCT04223856), which is intended to confirm these results for the investigational treatment combination in previously untreated la/mUC and in muscle-invasive bladder cancer in EV-304/KEYNOTE-B15 (NCT04700124) and EV-303/KEYNOTE-905 (NCT03924895).

About Bladder and Urothelial Cancer

It is estimated that approximately 83,730 people in the U.S. were diagnosed with bladder cancer in 2021.2 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.3 Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.4

About the EV-103/KEYNOTE-869 Trial (Cohort K)

The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with locally advanced or metastatic urothelial cancer (la/mUC) and in patients with muscle-invasive bladder cancer.

Cohort K of the EV-103/KEYNOTE-869 trial is a randomized 1:1 cohort investigating enfortumab vedotin alone (n=73) or in combination with pembrolizumab (n=76) in adult patients with unresectable la/mUC who are ineligible for cisplatin-based chemotherapy and have received no prior treatment for la/mUC. The enfortumab vedotin monotherapy study arm is intended to characterize the activity of enfortumab vedotin alone in this patient population. The key outcome measure of EV-103/KEYNOTE-869 Cohort K is objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1. Secondary endpoints include ORR per investigator assessment; duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per BICR and investigator assessment; overall survival (OS); and assessment of safety.

About PADCEV

PADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).6

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

Indication

PADCEV is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

Important Safety Information

Warnings and Precautions

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS or TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C 8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Pneumonitis Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6). Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.

Peripheral neuropathy (PN) occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without pre-existing PN. The median time to onset of Grade 2 PN was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade 3 PN.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Adverse Reactions

Most Common Adverse Reactions, Including Laboratory Abnormalities (20%)

Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).

Drug Interactions

Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)

Concomitant use with a dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

Specific Populations

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

For more information, please see the full Prescribing Information including BOXED WARNING for PADCEV here.

About KEYTRUDA (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

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Seagen, Astellas and Merck Announce Results of Clinical Trial Investigating PADCEV (enfortumab vedotin-ejfv) with KEYTRUDA (pembrolizumab) and PADCEV...

Dr. Julie Russak, Board-Certified Dermatologist

NEW YORK (PRWEB) September 12, 2022

Julie E. Russak, M.D., FAAD., is a Board Certified Dermatologist, Founder of Russak Dermatology Clinic in Manhattan and specializes in general and cosmetic dermatology, regenerative aesthetic medicine, skin cancer and dermatologic surgery. Dr. Russak has received numerous honors and recognition of her clinical excellence, including being selected as a New York Super Doctor by New York Times Magazine.

An Integrative Approach to Aesthetic Medicine and Metabolic Aging on the Cellular LevelThe new physician and nutritionist-led program utilizes a 360 approach to aesthetics and longevity, designed to empower patients with the clinical data, tools and treatments to reverse the signs of aging and feel their best. The program was designed for patients who want to receive a custom plan on how to approach anti-aging and wellness together.- Dr. Julie Russak

In-house Board Certified Holistic Nutritionist & Celebrity Health Coach, Jennifer Hanway, alongside Dr. Russak, leads all patients through their highly-personalized testing analysis and develops customized nutrition, supplement, lifestyle and aesthetic treatment plans. Jennifers deep knowledge of hormonal imbalances, gut health and body composition informs her holistic approach.

Aging well is the mission of the program, and that requires more than skin deep procedures. We have the ability to reprogram gene expression to increase our healthspan, while resetting our cells to a more youthful state. Benefits of the program include slowing premature aging internally and externally, healthy skin and hair, hormone and metabolism optimization, weight loss, increased lean muscle mass, increased energy levels and mental clarity. - Jennifer Hanway.

Russak Dermatology Clinic works with leading integrative laboratories, specializing in epigenetic and functional testing including biological age, food intolerance, gut health, micronutrient and hormone panels. Hormones tell your tissues and organs what to do. A slight imbalance can cause fatigue, anxiety, acne, hair loss, weight change and more. Hormone health is a critical pillar of the program. -Jennifer Hanway.

A Regenerative ResetDr. Russaks Regenerative Aesthetics menu was designed to go hand-in-hand with the program. It includes therapies such as exosomes, stem cell facelift technology, platelet rich plasma (PRP), IV drips and bio-stimulatory injectables. The clinic carries clinical-grade skincare and nutraceuticals that boost the body's natural regenerative responses and have secured brand partnerships available to their patients, including health-expert designed, organic meal delivery service, Daily Dose and integrative supplement brand, Nutrafol.

Russak Dermatology Clinic ExpansionThe newly expanded aesthetic center will house the Anti-Aging Wellness Program and regenerative aesthetics offerings. The mission of the newly expanded space is to guide patients on how to harness the regenerative power of their own body. Think of your skins health, but elevated and enhanced through integrative and cutting-edge aesthetic treatments that address your bodys total wellness, inside and out.

About Dr. Julie RussakJulie E. Russak, M.D., FAAD., is a Board Certified Dermatologist and Founder of Russak Dermatology Clinic. Dr. Russak serves as Faculty at Mount Sinai Hospital, where she teaches dermatology residents and medical students. Dr. Russak has distinguished herself in the medical community through her clinical research, scientific presentations, publications and aesthetic approach. She attends anti-aging, aesthetic and regenerative medical conferences around the world to incorporate advancements in these fields into her practice. Some notable conferences include the Aesthetic & Anti-Aging Medicine World Congress and the Annual Mount Sinai Winter Symposium Advances in Medical and Surgical Dermatology".

Dr. Russak is frequently sought out by beauty editors and industry outlets as an expert contributor, including Good Morning America, NewBeauty, Cosmopolitan, Forbes, and Marie Claire. Dr. Russak serves as a consulting Dermatologist and formulator to clean skincare brand, Covey.

For all marketing and media inquiries, please contact Gabrielle@RussakDermatology.com. Learn more at http://www.russakplus.com and IG: @russakderm

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NYC Dermatologist, Dr. Julie Russak, launches first Anti-Aging Wellness Program of its kind in the U.S. - PR Web

Dr. Julie Russak is a board-certified dermatologist and founder of Russak Dermatology Clinic and Russak+ Aesthetic Center.

NEW YORK (PRWEB) August 10, 2022

About three months after a person recovers from COVID-19, excess clumps of hair come out in ones hand, stick to the back or clog the shower drain. A brush contains much more hair than normal, or hair litters the bathroom floor or a bed pillow in disturbing amounts.

Some hair loss about 100 hairs per day is natural and normal. When that increases to 300 or more hairs per day, something is not right. Post-COVID, if hair thins perceptibly, the condition is called telogen effluvium.

Telogen effluvium is not specific to COVID. It can happen several months after any time the body undergoes stress, such as after a high fever, the flu or another serious illness, so its no surprise that it happens to COVID patients. Its also common during pregnancy and after giving birth, and certain medications can trigger it. However, since the beginning of the pandemic, the incidence of telogen effluvium has increased 400 percent. The hair loss associated with telogen effluvium occurs primarily on the head and excessive shedding can continue for many months.

Scientists have yet to link hair-loss directly to the COVID virus. Most experts agree that the stress related to contracting COVID, anxiety over the disease, job loss, feelings of isolation and depression, and changes in lifestyle due to the pandemic are the real culprits. The good news is that in most cases of telogen effluvium, hair growth and loss return to normal, but it takes a long time, up to a year.

Dr. Julie Russaks signature Hair Restoration Therapy is a safe, nonsurgical way to stimulate hair growth. The treatment combines Platelet-Rich Plasma (PRP) Therapy, Exosome Stem Cell injections, diffused microneedling and topical and oral supplements. Its a unique, clinically-proven approach that is more proactive because it delivers these regenerative ingredients into the scalp, awakening hair follicles and stimulating hair growth.

PRP TherapyBlood platelets contain hundreds of healing proteins called growth factors, which are known for their regenerative qualities. Normally, platelets make up about 10 percent of the bloods cellular components. In PRP Therapy, that percentage is flipped to 90 percent. When platelet-rich plasma is infused into the scalp, it encourages hair growth at an accelerated rate.

During a Hair Restoration Therapy treatment, first a phlebotomist draws a small sample of the patients blood, which is spun in a centrifuge designed to concentrate platelets. In essence, the red and white blood cells are separated from the platelets and plasma (clear-gold fluid), creating PRP. The concentration of platelets in PRP, and thus the concentration of growth factors, can be up to ten times greater than in normal blood.

Once the PRP is isolated, the clinician injects and microneedles the PRP into the scalp. Microneedling ensures the valuable growth factors in the PRP penetrate directly into the hair follicles, and injections allow the PRP to get even deeper into the skin. The growth factors in the PRP then stimulate stem cells around the hair follicles into an active growth phase.

In addition, non-platelet components of the blood plasma are present in lower amounts, and contains nutrients, vitamins, hormones, electrolytes and proteins that are essential to hair health. As a result, hair grows back and at a faster rate than if left only to Mother Nature.

Exosome BoosterExosomes are a new breakthrough in regenerative hair therapy that triggers healing, cell stimulation and regeneration. Exosomes are extracellular vesicles, or small bubbles, released from stem cells. They contain genetic signals that stimulate cells, in this case healthy hair follicles.

The exosomes released by regenerative cells such as stem cells are potent drivers of repair, regeneration and healing. When hair loss occurs, exosomes signal the follicles to heal themselves which stimulates new hair growth. Exosomes contain bioactive molecules that play a crucial role in cell-to-cell communications and are vital in all cellular regenerative processes. When they are infused directly into the scalp, the result is intensive hair rejuvenation, especially when combined with PRP Therapy.

Reversing Other Types of Hair LossThinning hair can result from many different factors in addition to COVID and stress, including family history, hormonal changes, certain disease and medications, scalp imbalance and more. PRP Therapy enhanced with an Exosome Booster delivers a comprehensive approach to treating hair loss in many situations. Any person who has experienced miniaturization, or hair thinning, is an ideal candidate for this proven hair restoration therapy. Its customized for each patient with the goal of reactivating the hair follicles.

The protocol consists of four sessions spaced one month apart, with maintenance treatments every four to six months after that to keep hair follicles stimulated and to maintain hair growth. These in-clinic treatments are augmented by oral supplements and Russak Dermatologys proprietary topical spray, called Hair Fortifying RX.

Hair Fortifying RX is a concentrated blend of vitamins and hair regrowth stimulants, including 10% minoxidil, which reduces inflammation around the follicle and stimulates hair regrowth on its own. When combined with Hair Restoration Therapy, the result is fuller, denser hair!

Selected by the New York Times as a New York Super Doctor, Dr. Julie Russak, M.D., FAAD, is a board-certified dermatologist, Fellow of the American Academy of Dermatology and the founder/CEO of Russak Dermatology Clinic in New York City. In addition to providing comprehensive care in cosmetic and medical dermatology through the clinic, she serves on the faculty of Mount Sinai Hospital and was awarded Teacher of the Year in 2022. Her expertise includes general, cosmetic and pediatric dermatology, skin cancer and dermatologic surgery. For more information, go to http://www.russakdermatology.com.

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Curbing COVID-Related Hair Loss: Russak Dermatology's Hair Restoration Therapy - PR Web

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One of the many perks of being a Hollywood celebrityother than making millions of dollars to play pretend on a movie or TV setis access to products that can help them look their very best. Thats especially the case when it comes to skincare. And there is one product on the market that countless A-listers swear byAugustinus Bader The Rich Cream.

Of course, celebrity status doesnt make you an expert. But regular shoppers do agree that this luxury moisturizer has completely changed their skin for the better. Yes, its pricey. But, many are certain that this high-dollar skin cream is absolutely worth it.

Augustinus Bader The Rich Cream has been popping up all over social media in recent months. Everyone from Jennifer Aniston to Lily Aldridge to Victoria Beckham to Sandra Oh is swearing by this essential high-end moisturizer.

Supermodel Karen Elsona self-proclaimed high-end beauty addicthas called Augustinus Bader The Rich Cream the secret elixir for her skin that tends to be her go-to for all things.

RELATED: Elizabeth Olsen Swears By This Jennifer Aniston-Approved Device To Tighten And Brighten Skin

The brand credits TFC-8 technology as the reason this moisturizer is so effective. They say it sends your stem cells into repair mode with a mix of ceramides, peptides, amino acids, vitamins C and E, and cholesterol. Also helping to achieve that plump and silky skin is hyaluronic acid, squalane, and shea butter.

According to a 55-year-old cellular biologist on the Nordstrom website, this mix of ingredients has created permanent changes in her skin that has left it unbelievably even-toned and hydrated.

Other reviews indicate that it takes just a tiny amount to see visibly smoother wrinkles and way less prominent dry patches.

I thought it might be too heavy and thick for my skin. I was wrong. It is a thick, rich cream but it does go into the skin easily, and honestly, the first time I used it I could instantly see my skin had plumped, one reviewer shared.

Another added, Hands down the best cream I have ever tried and Ive tried them all. Yes it is expensive but worth every penny. Your skin is smooth, hydrated, and glowing. It just works and you dont need much.

Augustinus Bader The Rich Cream is available in multiple sizes, from a 0.5 ounce bottle, the standard 1 ounce bottle, or a larger 1.7 ounce bottle. Buying the larger size will definitely help you save a few bucks, and it will be an investment that pays off immediately.

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Jennifer Aniston And Sandra Oh Swear By This Moisturizer That Shoppers Say Created Permanent Changes To Their Skin - Suggest

Professor Augustinus Baders skincare products contain the patented TFC8 technology, backed by 30 years of science and research - and results have shown an increase by 110% of more elasticity in the skin as well!

Image: Augustinus Bader)

When we hear on the grapevine that celebrities are obsessing over skincare products or with a beauty brand - we too are equally eager to hear the secret behind their gorgeous, glowing skin.

Augustinus Bader, whos earned a cult-beauty status thanks to his rejuvenating skin care products, is the man whom Jennifer Aniston, Kim Kardashian and Victoria Beckham all love too. And its not just celebrities who hail his namesake products as the secret weapon behind nourished and renewed skin, but beauty editors and dermatologists too. Not to mention contain the patented TFC8 technology, which is backed by 30 years of science and research.

And we have a way to you can get 20% off your next order, thanks to the auto-replenish programme! Customers are able to save 20% on each order when they subscribe to regular, customisable, delivery cycles. How cool is that?

Augustinus Bader

Augustinus Bader

Augustinus Bader

And its so simple too!

The skincare formulas are hand crafted by Professor Augustinus Bader in his own laboratory. Hes a globally recognised biomedical scientist, physician and one of the foremost experts in the field of stem cell biology and regenerative medicine. So its no wonder why celebs are quick to reach for his products before hitting the red carpet.

Not to mention his products have received 90 industry awards in just four years - and products have been voted The Greatest Skincare Of All Time.

Best of all? The results of Augustinus Bader products are proven through extensive clinical trials - and who wouldnt want younger looking skin in as little as four weeks?

Based on a 4-week clinical trial, with participants using hero product The Rich Cream: Forehead wrinkles visibly reduced by 37%, crow's feet wrinkles visibly reduced by 54%, crow's feet fine lines visibly reduced by 46% and of those testers, skin felt 92% firmer and 110% more elasticity in the skin - in just 4 weeks!

So what are you waiting for? Give Augustinus Bader products a go and see how your skin can change in four weeks too!

Have you used any of the Augustinus Bader skincare products before? Or are you keen to give them a try and see what they could do for you? Let us know your thoughts in the comments section below.

Originally posted here:
Victoria Beckham and Kim Kardashian are fans of Augustinus Baders skincare range - and you can get 20% off - The Mirror

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New research clarifies how stem cells repair the intestines.

To act as a robust barrier against pathogens while also absorbing needed nutrients, the lining of the intestines must regenerate on a daily basis to remain equal to the task.

The intestines resident stem cells are responsible for meeting this need for constant repair and replenishment, but each stem cell faces decisions that depend on the overall conditions of the intestine and the needs of the moment.

Bad decisions and poor coordination could result in intestinal diseases or cancer.

A new study suggests that stem cells are able to integrate cues from their surroundings and coordinate their behavior across the tissue through networks of vasculature in their close vicinity.

The researchers found that lymphatic capillariesfine vessels that transport immune cells and drain fluids from tissuesrepresent a signaling hub that communicates with stem cells to regulate their activity. With molecular guidance from the lymphatics, the stem cells produce daughter cells to repopulate the intestinal lining or self-renew to restock the stem cell reserve.

The findings in the journal Cell Stem Cell provide new insights about primary intestinal components whose disrupted communication may contribute to intestinal disorders, such as inflammatory bowel disease.

The key to treating these diseases will be to figure out who talks to whom in this ecosystem and how we can reset the communication networks, says Rachel Niec, a clinical scholar in the laboratory of Elaine Fuchs at Rockefeller University.

The intestinal stem cells reside in so-called crypts, found at the base of densely packed indentations in the intestinal lining. The stem cells may renew and stay in the crypt, or differentiate into specialized cells, which then migrate out of the crypt to replenish the gut lining.

To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches, says Marina Schernthanner, a graduate student in the Fuchs lab.

To zoom in on the crypt, the team used a suite of techniques, including single-cell and spatial transcriptomics, which allowed them to identify cell types at specific locations and study their signaling molecules.

The results showed that lymphatic capillaries, which form an intimate connection with the stem cells in the crypt, produce a number of proteins known to be important for stem cell functioning.

One previously underappreciated protein, REELIN, emerged as a top candidate for mediating communications between lymphatics and stem cells. By manipulating the amount of REELIN in lab-grown intestinal organoid cultures in some experiments and genetically suppressing it in mice in others, the researchers found that REELIN directly governs the regenerative behavior of intestinal stem cells.

The involvement of the lymphatic system in stem cell functioning is a relatively new concept. A previous study by the Fuchs team revealed that lymphatics are also closely involved with stem cells of the skin and play a key role in hair regeneration. There, however, it is the hair follicle stem cells that signal to lymphatic capillaries. By controlling their interactions with lymphatics, the stem cells synchronize hair regeneration across the tissue.

This suggests that lymphatics may be a conserved feature of stem cell niches, but their relationship to stem cells are likely tailored around the needs of each tissue, Niec says.

Source: Rockefeller University

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How your intestines repair and renew themselves - Futurity: Research News

Cells with the highest Hlf-tdTomato expression levels have bone marrow reconstitution capacity

We previously reported that HSCs have higher levels of tdTomato than other hematopoietic progenitors in the fetal livers of Hlf-tdTomato KI mice25. Transplantation experiments were performed to confirm the stem cell potential of bone marrow cells with higher levels of Hlf-tdTomato in the bone marrow of the tibia. Flow cytometry analysis showed that 47.04.4% of whole bone marrow cells from adult long bones of Hlf-tdTomato KI mice were positive for CD45, which is a panhematopoietic marker (Fig.1a, left panel, n=4). Cells with the top 0.011% tdTomato intensity within the CD45-positive cells (0.0049% of the whole bone marrow cells) were defined as Hlf-tdTomatohi cells (Fig.1b). All the Hlf-tdTomatohi cells were located within the Sca-1+c-Kit+ fraction, including phenotypic HSCs (CD150+CD48) and short-term HSCs (CD150CD48) (Fig.1a, right panel and Supplementary Fig.1). To determine whether Hlf-tdTomatohi cells show a high frequency of functional HSCs within the bone marrow of the tibia, we compared engraftment capacity between the Hlf-tdTomatohi and Hlf-tdTomato cells (44.3% of the whole bone marrow cells) by the transplantation assay (Fig.1b). A total of 100 Hlf-tdTomatohi cells were capable of engraftment after primary and secondary transplantation, whereas 5000 Hlf-tdTomato cells were not capable (Fig.1c, d). These results indicate that functional HSCs were enriched within the Hlf-tdTomatohi fraction in the bone marrow of the long bones.

a Hlf-tdTomato expression in the bone marrow blood cells obtained from long bones. The black box indicates the Hlf-tdTomatohi population. b Flow cytometry sorting of Hlf-tdTomato cells. The Hlf-tdTomatohi box population was used for transplantation experiments. The tdTomato box population was used as a negative control. c Bone marrow transplantation (BMT) experiments. Irradiated mice were transplanted with 100 tdTomatohi/CD45+ cells or 5000 tdTomato/CD45+ cells. d Second BMT experiments.

Next, we developed a method to observe the dynamics of Hlf-tdTomatohi HSCs in the tibial bone marrow in vivo (Fig.2). Previous studies have used drilled tibia for intravital imaging of HSCs in the long bones14,15,16,17. However, drilling of the long bones precluded the comparison of the HSC dynamics between adults and neonates for two reasons. First, drilling could disturb the microenvironment of the bone marrow, and second, the long bone of neonates is too fragile to be drilled, and it is not possible to avoid bleeding from the blood vessels penetrating the neonatal tibia (Supplementary Fig.2a and Supplementary Movie1). A multiphoton imaging system equipped with a bone-penetrating fiber laser (average power, >2W; pulse width, 55> fs; wavelength, 1070nm) was established to overcome the limitations of the conventional methods (Fig.2a). In our system, tdTomato-positive cells were observed under the intact tibial bone tissue, which was visualized with second harmonic generation (SHG) signals in adult mice (3 months old) in vivo (Fig.2b; Supplementary Movie2). Blood capillaries in the bone marrow were visualized by intravenous injection of an infrared fluorescent dye Qtracker 655 to confirm the location of the tdTomato-positive cells within the tibial bone marrow. Intravital imaging showed that tdTomato-positive cells were located around the blood capillary network (Fig.2c, d), which are typical blood vessel patterns in the bone marrow of long bones28. These results suggest that Hlf-tdTomato-positive cells in the intact tibial bone marrow can be observed by the method developed in the present study.

a Experimental schema of intravital imaging of the tibial bone. The tibial bone was exposed, and the bone marrow was imaged without bone drilling using a high-powered infrared laser. b Z-stack images obtained via in vivo imaging of the bone marrow in the undrilled tibia of Hlf-tdTomato KI mice. Hlf-tdTomato-positive cells were observed in the bone marrow cavity. Bone surface, bone, and bone marrow cavities. The depth is indicated in the upper right corner of each panel. SHG, second harmonic generation. c Orthogonal view of 3D images confirmed that Hlf-tdTomato-positive cells were in the bone marrow under the tibial bone. Blood capillaries in the tibial bone marrow were visualized by intravenous injection of Qtracker 655. Cells indicated with arrows 1 and 2 are shown in higher magnification in (d). See also Supplementary Movie2. d Higher magnification images of Hlf-tdTomato-positive cells located around the bone marrow capillary. e Intravital imaging of a Runx1-GFP mouse before drilling. Depth is 155m from the bone surface. f Intravital imaging of the Runx1-GFP mouse after drilling. The same region in (d) was reimaged after drilling. Background signals were imaged in the red channel, suggesting that most signals in the green channel were artificial backgrounds. Arrows indicate Runx1-GFP cells that had no background signals in the red channel.

The technical advances of our method were evaluated by comparing it with the conventional method. For the conventional method, intravital imaging of Runx1-GFP transgenic mice, in which HSCs and progenitor cells strongly express GFP29, was conducted using a short wavelength (920nm) laser which does not easily penetrate bone. Intravital imaging showed that Runx1-GFP labeled cells in the bone marrow were blurred without drilling (Fig.2e), and GFP signals were only clearly observed after drilling (Fig.2f), indicating that drilling is essential for the conventional method. As previously reported11, artificial background signals were observed in the green channel (Fig.2f), whereas these were rarely seen using our imaging method (Fig.2b). These results highlight the advances of the intravital imaging developed in the present study.

There were 18.21.0 tdTomato-positive cells in the volume of the intravital images (around 600m600m100m=3.6107m3; n=5 volumes from five mice). Immunohistochemical staining of the tibial bone sections obtained from Hlf-tdTomato KI mice was conducted (Fig.3a) to determine which tdTomato-positive cells in the intravital images corresponded to the Hlf-tdTomatohi HSCs that were identified in the flow cytometry analysis (Fig.1). In the histological sections of the tibial bone, there were 18,201933 CD45-positive cells and 1,630269 tdTomato-positive cells within the same volume as the in vivo-imaged volume (n=3 sections from three mice; Fig.3b, c). Since the cells with the top 0.011% tdTomato intensity in CD45-positive cells were defined as Hlf-tdTomatohi cells (Fig.1), those with the top two tdTomato fluorescent intensities in the in vivo images corresponded to Hlf-tdTomatohi cells (18,201 cells0.011%=2 cells; Fig.3c). We defined the remaining Hlf-tdTomato-positive cells with lower intensity in the intravital images that include differentiated progenitor cells25 as Hlf-tdTomatolow cells (16 cells in Fig.3c), which had lower stem cell potential (Supplementary Fig.3). Most of the tdTomato-positive cells in the histological sections were not visible using intravital imaging due to the very low intensity (1612 cells in Fig.3c). These results suggested that the cells with top two tdTomato fluorescent intensities in the in vivo image were HSCs.

a Immunohistochemical staining of tibial bone sections was obtained from an adult Hlf-tdTomato KI mouse. Ter-119, red blood cell marker; CD45, blood cell marker except for mature red blood cells and platelets; DAPI, nuclear marker. b Fluorescence distribution of tdTomato signals in CD45-positive cells in the histological sections of the tibial bone. The number of CD45-positive cells within the same volume as the in vivo-imaged volume was 18,201933 cells. Error bars indicate standard error. c The number of CD45 and tdTomato-double-positive cells within the same volume as the in vivo-imaged volume was 1630269 cells. The number of tdTomato-positive cells was 18.21.0 cells, suggesting that the remaining 1612 cells were not visible in the intravital images due to the very low fluorescent intensity. The cells with the top 0.011% tdTomato intensity in CD45-positive cells were defined as Hlf-tdTomatohi cells (Fig.1); therefore, the cells with the top two tdTomato fluorescent intensities in the in vivo images correspond to the Hlf-tdTomatohi cells (18,201 cells0.011%=2 cells). We defined the remaining Hlf-tdTomato-positive cells with lower fluorescent intensity (16 cells in average) as Hlf-tdTomatolow cells for quantitative analysis of Hlf-tdTomato-positive cell dynamics in Figs.4 and 5.

Three-dimensional time-lapse imaging of undrilled tibial bone marrow was performed to observe the in vivo dynamics of Hlf-tdTomatohi HSCs (Fig.4a and Supplementary Movie3). Artifactual movement of the image area, mainly caused by the heartbeat, was corrected using image registration. Hlf-tdTomatohi HSCs were stationary (Fig.4b), although they showed oscillatory movements in the restricted area. In contrast, Hlf-tdTomatolow cells migrated (Fig.4c). Quantitative analysis of the HSC migration using TrackMate30 revealed that the velocity of the Hlf-tdTomatohi HSCs (0.0960.019m/min, 10 cells from five mice) was significantly lower than that of Hlf-tdTomatolow cells (0.1690.017m/min, 81 cells from five mice; p=0.008; t=2.886; g=0.505; Fig.4d). We also showed long-term engraftment of Hlf-tdTomatohi cells (Fig.1c, d and Supplementary Fig.1), indicating that HSCs were stationary but oscillatory. However, differentiated cells were motile in the bone marrow of adult long bones. Therefore, our findings demonstrate that Hlf-tdTomato KI mice, the inside-bone intravital imaging system and quantitative bioimaging analysis facilitate the evaluation of the migration dynamics of endogenous HSCs in the native microenvironment of long bones.

a Hlf-tdTomato-positive cells in the tibial bone marrow were imaged for 2h in vivo. Arrows indicate Hlf-tdTomatohi HSCs and arrowheads indicate Hlf-tdTomatolow cells. See also Supplementary Movie3. b Higher magnification time-lapse images of Hlf-tdTomatohi HSCs. c Higher magnification time-lapse images of Hlf-tdTomatolow cells. d Quantitative comparison of the migration dynamics between Hlf-tdTomatohi cells (ten cells from five mice) and Hlf-tdTomatolow cells (81 cells from five mice).

Neonatal HSCs are characterized by fast cell cycling and higher mitochondrial membrane potential4, indicating changes in the cellular properties between adult and neonatal HSCs. Gene expression patterns were compared between developing HSCs and matured HSCs using RNA-seq to evaluate changes in the properties of neonatal HSCs.

Gene set enrichment analysis (GSEA) showed significant enrichment in cell migration-related genes in neonatal HSCs (Supplementary Fig.4a, b). Consistently, changes in the expression of genes related to the cytoskeleton and cell adhesion were observed in neonatal HSCs (Supplementary Fig.4cf). Differences in the cell migration-related genes indicated differences in the migration dynamics of neonatal and adult HSCs in the tibial bone marrow. From these results, we focused on the migration dynamics in subsequent experiments for intravital imaging of neonatal mice.

Migration of HSCs into the bone marrow from other hematopoietic organs has been hypothesized since adult-type definitive HSCs are generated from the aortagonadmesonephros region8,25. However, the migration dynamics of HSCs during development is unclear. Therefore, three-dimensional time-lapse imaging of the bone marrow was performed in the undrilled tibia in neonates (postnatal day 2; Fig.5a, left). The orthogonal view confirmed that the intravital imaging of the intact tibial bone marrow enabled the observation of endogenous tdTomato-positive cells in neonatal Hlf-tdTomato KI mice (Fig.5a, right; Supplementary Movie4). Quantitative analyses showed that the velocity of Hlf-tdTomatohi cells (1.5161.010m/min, six cells from three mice; top two fluorescent intensities) was much higher than that of Hlf-tdTomatolow cells (0.0780.010m/min, 24 cells from three mice; p=0.002; Z=3.059; r=0.558) in neonates (Fig.5b). Furthermore, the velocity of Hlf-tdTomatohi cells in neonates was much higher than that in adults (p=0.017; Z=2.386; r=0.597, Supplementary Fig.2b). These results suggest that HSCs are motile in the tibial bone marrow of neonates.

a Tibial bone was exposed on postnatal day 2 (left). Orthogonal view image of the tibial bone marrow (right). See also Supplementary Movie4. b Quantitative comparison of the migration dynamics between Hlf-tdTomatohi cells (six cells from three mice) and Hlf-tdTomatolow cells (24 cells from three mice) in neonates. c Time-lapse images of developing (P2) bone marrow showing migration of an Hlf-tdTomatohi cell in the blood vessels. White arrows indicate migrating cells in the blood vessel and yellow arrows indicate stable cells outside the blood vessels. See also Supplementary Movie5. d Another example of an Hlf-tdTomatohi cell migrating in the bone marrow blood vessels in a neonatal mouse (P1).

Intravital imaging was conducted after visualizing blood vessels by injecting Qtracker 655 via the superficial temporal vein31 to check whether the motile Hlf-tdTomatohi cells were extravascular or intravascular. Some of the Hlf-tdTomatohi cells rapidly migrated in the blood vessels (Fig.5c, d, white arrows). Moreover, Hlf-tdTomatohi cell attached to the vessels during the imaging session, indicating extravasation and homing to the bone marrow (Fig.5c, 63 and 100min; Supplementary Movie5). In contrast, Hlf-tdTomatohi cells located outside the capillaries, which appeared to be extravasated prior to the imaging session, were stationary (Fig.5c, yellow arrows). These results suggest that motile Hlf-tdTomatohi cells migrate in the blood vessels of the neonatal tibia.

Finally, migration of HSCs from outside the bone marrow was observed using time-lapse imaging of the tibial bone cavity, where the blood vessels that penetrate the bone are located (Fig.6a). An Hlf-tdTomatohi cell was observed to rapidly migrate within the bone cavities (Fig.6b and Supplementary Movie6). Interestingly, the distance between the observed cell and the inner bone surface appeared to be increased (Supplementary Fig.5a, b), suggesting migration of the cell to the deeper part of the bone. Taken together, these results indicate that HSCs migrate in the bone cavities and bone marrow during tibial bone marrow formation.

a Two-photon images showing the blood vessels penetrating the bone cavity in the tibial bone in a neonatal mouse (P3). Yellow arrows indicate bone cavities. b Time-lapse images of Hlf-tdTomatohi cells migrating from the bone surface to the bone marrow cavity. White arrows indicate a migrating cell in the bone cavity. See also Supplementary Movie6. c Transient vessel penetration model for HSC homing during bone marrow formation. HSCs migrate from outside the tibia to inside via transient blood vessels penetrating the bone during bone marrow formation.

Read more:
Bone marrow imaging reveals the migration dynamics of neonatal hematopoietic stem cells | Communications Biology - Nature.com

LAS VEGAS, NV, Aug. 01, 2022 (GLOBE NEWSWIRE) -- via NewMediaWire Meso Numismatics, Inc. (Meso Numismatics or the Company) (MSSV), a technology company specializing in Biotech and Numismatics, is pleased to announce additional global expansion by opening stem cell therapy and regenerative medicine facilities in Indonesia. The new facilities emphasize Global Stem Cells Group's objective of introducing its therapies and technology to meet market demands in populous parts of the world.

In partnership with the Dr. Yanti Aesthetic Clinics, which currently has 6 branches across Indonesia, this latest GSCG expansion will promote high standards of service in regenerative medicine across the country. As part of this effort, through GSCG the International Society for Stem Cells Applications (ISSCA) has granted Dr. Yanti Aesthetic Clinics membership and use of its brand, products, therapies, and training on how to apply stem cell therapies.

This new partnership seeks to expand the Global Stem Cells Group (GSCG) brand and create centers of excellence in cell therapy to meet the high demand within the vast Asian markets, said David Christensen, CEO of MSSV. GSCG is rapidly expanding its global operations as it seeks to become a significant player in the lucrative regenerative medicine industry. To achieve our expansion plans, our organization is partnering with healthcare providers specializing in regenerative medicine with at least five years of experience in the healthcare sector.

Video: https://youtu.be/T2CFjsps9qk

The vision behind the effort.

The Indonesia addition is the latest part of an expanding medical network of partners, and it will formalize and strengthen ties, establishing a global center of excellence to guarantee that we effectively use the underlying basic stem cell technology for medical conditions, where traditional therapeutic approaches seem to have failed. This is consistent with GSCG's overall strategy for developing regenerative medicine through data-driven studies, disease modeling, and cell-based therapeutics.

The Dr. Yanti Aesthetic Clinic is a key partnership because it provides the organizational and physical infrastructure needed to disseminate need-based stem cell locally. And Global Stem Cells Group's outstanding cell and stem cell biology and disease pathophysiology give an edge to patients for which they are prescribed.

The opening in Indonesia also presents the perfect opportunity to translate breakthrough therapies from basic discoveries to useful products by drawing upon the skills and local knowledge promoted within Dr. Yanti Aesthetic Clinics.

GSCG group managing director, Benito Novas, provided a clear description of the new strategic direction and objectives. "Our goal is to make regenerative medicine benefits a reality for both doctors and patients all around the world. We recently launched a very similar effort in Pakistan. Additional announcements are planned in the near future as we attempt to expand our presence." Meso Numismatics and Global Stem Cells Group Expand its Global Footprint

The current market outlook.

Stem cell therapy is striving to become an increasingly effective clinical solution to treat conditions that traditional or mainstream medicine offers only within palliative care and pain management. Patients all over the world are searching for a natural regenerative alternative without the potential risks and side effects sometimes associated with mainstream pharmaceuticals. With the opening of each new treatment center in populous regions such as Indonesia, GSCG is working to help stem cell therapy and regenerative medicine to eventually move from alternative and elective procedures to mainstream protocols.

This new clinic effort will play a significant role in the development of regenerative medicine in Indonesia and indeed the rest of the world by adding yet another opportunity for continuous improvement through research and development, Christensen continued. By adding busy clinics in population centers, we plan to consistently generate high volumes of reliable clinical data to assist us with the development and refinement of even more medicines and treatments.

About Dr. Yanti Aesthetic Clinics

Dr. Yanti Aesthetic Clinics is a premier cosmetic and aesthetics clinic based in Kelapa Gading, Jakarta Utara. Since its inception in 2004 in Surabaya by Dr. Khoe Yanti Khusmiran, the clinic has expanded to over 6 branches throughout Indonesia. Dr. Yanti clinics provide a range of skin and body enhancement treatments through minimally invasive and non-invasive procedures the expertise of which are a natural fit for the addition of a variety of stem cell therapies.

"Indonesians have a growing need for the latest medical technology that is reliable, potent, has reduced side effects, and leverages the bodys own healing biochemistry to resolve injury and aging, said Dr. Yanti. We are honored to be a part of GSCG, which has a proven 10-year track record in the market with a strong and growing international reputation. This new partnership is expected to create a wide variety of custom treatment options we can offer our patients and treat injury and illness in ways we could not before.

The newly formed partnership will deliver revolutionary medicines through Dr. Yanti clinics to assist patients in avoiding permanent harm and live a healthier life, while changing the paradigm from asymptomatic treatments to cures that may improve and restore quality of life.

More about Global Stem Cells Group

GSCG delivers leadership in regenerative medicine research, patient applications, and training through our strategic global networks. We endeavor to enable physicians to treat otherwise incurable diseases using stem cell therapy and to improve the quality of life and care across the world.

For this reason, GSCG works with innovative, next-generation therapy providers like Dr. Yanti Aesthetic Clinics to give access to one-of-a-kind holistic and safe treatment options.

More information regarding this transaction and the Global Stem Cells Group may be found at GSCG.

This press release should be read in conjunction with all other filings on http://www.sec.gov

For more information on Global Stem Cells Group please visit: http://www.stemcellsgroup.com

About Meso Numismatics: Meso Numismatics, Corp is an emerging Biotechnology and numismatic technology company. The Company has quickly become the central hub for rare, exquisite, and valuable inventory for not only the Meso region, but for exceptional items from around the world.

Meso has now added Biotechnology to its portfolio and will continue to grow the company in this new direction. With the Company's breadth of business experience and technology team, the Company will continue to help companies grow.

Forward-Looking Statements

Some information in this document constitutes forward-looking statements or statements which may be deemed or construed to be forward-looking statements, such as the closing of the share exchange agreement. The words plan, "forecast", "anticipates", "estimate", "project", "intend", "expect", "should", "believe", and similar expressions are intended to identify forward-looking statements. These forward-looking statements involve, and are subject to known and unknown risks, uncertainties and other factors which could cause the Company's actual results, performance (financial or operating) or achievements to differ from the future results, performance (financial or operating) or achievements expressed or implied by such forward-looking statements. The risks, uncertainties and other factors are more fully discussed in the Company's filings with the U.S. Securities and Exchange Commission. All forward-looking statements attributable to Meso Numismatics, Inc., herein are expressly qualified in their entirety by the above-mentioned cautionary statement. Meso Numismatics, Inc. disclaims any obligation to update forward-looking statements contained in this estimate, except as may be required by law.

For further information, please contact:investor.relations@mssvinc.com Telephone: (800) 956-3935

Continued here:
Global Stem Cells Group Expands Its Stem Cell Therapy and Regenerative Medicine Centers to Indonesia - GlobeNewswire

ICYMI: Amazon Prime Day is coming to an end tonight and truth be told, the sales appear to be gifts that keep on giving. One of our favorite skin-care tools is having a major discount across all of its devices and treatments. Yep, you guessed it, it's NuFace.

If you're unfamiliar with the brand and the magic it can do, let us school you quickly. NuFace devices use microcurrent technology that the brand calls "fitness for your face." In the same way that consistently hitting weights and cardio whips our body's muscles into shape, the metal nodes on the head of the tools send electrical currents through the various layers of facial skin, down to the muscles, to basically give them a workout.

Into it? Well, lucky for you NuFace products will be available at a discount throughout this two-day epic sale. Starting right now through July 13, you can snag devices, boosters, and activators for up to 36 percent off. The sale includes top-selling products like the Trinity, NuBody, Fix, and more.

So what are you waiting for? This luxury tool rarely goes on sale so get to shopping because these discounts end later on when Prime Day closes its virtual doors.

NuFace Trinity Starter Kit

NuFace Trinity Complete Kit

Both the Trinity Starter Kit and Complete Kit are essentially the same thing, but the complete kit comes with some additional attachments. Both kits feature a NuFace device and a gel primer to apply prior in order to activate the current. However, the Complete Kit holds a dual wand that targets specific areas like around the lips and eyes and a LED light attachment that helps reduce the appearance of fine lines and wrinkles.

If you're not into breaking the $200 mark, consider the Mini Starter Kit it holds the same device and gel primer, just in a smaller (more portable!) version that achieves the same results.

The NuBody features those same nodes on the head as the Trinity but in a handheld body version that utilizes four nodes. With four electrical currents, this device sends waves through the skin down to the muscles to help sculpt and tone the body. Plus, you get a 10-ounce gel primer to ensure the device glides smoothly and evenly.

See the rest here:
NuFace Is Having a Major Sale During Amazon Prime Day 2022 See Deals on Trinity, NuBody, and More - Allure

Global Stem Cell ManufacturingMarket Is Expected To Reach USD 21.71 Billion By 2029 At A CAGR Of 9.1 percent.

Maximize Market Research has published a report on theGlobal Stem Cell Manufacturing Marketthat provides a detailed analysis for the forecast period of 2022 to 2029.

Global Stem Cell ManufacturingMarket Scope:

The report provides comprehensive market insights for industry stakeholders, including an explanation of complicated market data in simple language, the industrys history and present situation, as well as expected market size and trends. The research investigates all industry categories, with an emphasis on key companies such as market leaders, followers, and new entrants. The paper includes a full PESTLE analysis for each country. A thorough picture of the competitive landscape of major competitors in theGlobal Stem Cell Manufacturingmarket by goods and services, revenue, financial situation, portfolio, growth plans, and geographical presence makes the study an investors guide.

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Global Stem Cell Manufacturing Market Overview:

Observing stem cells evolve into cells in bones, the circulatory system, nerve cells, and other organs of the body may help scientists understand how illnesses and disorders occur. Stem cells can be programmed to generate particular cells that can be utilized in humans to grow and mend tissues that have been damaged or harmed by sickness. Stem cell therapy may assist people with spinal cord injuries, metabolic disorders, Parkinsons disease, amyotrophic lateral sclerosis, Alzheimers disease, cardiovascular disorders, brain hemorrhage, burns, malignancy, and rheumatoid arthritis. Stem cells can be used to create new tissue for transplant and genetic engineering. Doctors are always learning more about stem cells and how they might be used in transplant and cellular therapies.

Global Stem Cell ManufacturingMarketDynamics:

Stem cells are crucial in illness treatment and specialized research initiatives such as customized therapy and genetic testing. As public and commercial stakeholders throughout the world become more aware of stem cells therapeutic potential and the scarcity of therapeutic approaches for rare illnesses, they are increasingly focusing on the development of stem cell-based technology.

Specialized procedures are required for stem cell separation, refinement, and storage (such as expansion, differentiation, cell culture media preparation, and cryopreservation). Additionally, the production scale-up of stem cell lines and associated items is frequently accompanied by major technological challenges that impede the whole production process and result in large operational expenses. As a result, stem cell products are frequently more expensive than pharmaceutical medications and biopharmaceuticals.

Additionally, the growing popularity of tailored medications is driving the market growth. Scientists are researching novel procurement strategies that can be used to manufacture tailored medications. For example, iPSC treatments are created by taking a little amount of a patients plasma or skin cells and reprogramming them to make new cells and tissue for transplant. As a result, future tailored treatments can be produced using these cells.

Global Stem Cell ManufacturingMarketRegional Insights:

North America (particularly the United States) held the largest market share in 2021, owing to factors such as the availability of significant contenders active in creating stem cell treatments, enhanced medical facilities, significant R&D financial backing available, and favorable initiatives from healthcare organizations, as well as robust reimbursement. Because of government initiatives and serious scientific activity in the country, the United States leads the continentsGlobal Stem Cell Manufacturingmarket.

Healthcare organizations are promoting cellular therapies for rising ailments. Due to higher advancement of stem cell-based treatments, federal actions for creating regenerative medications, the creation of multiple stem cell banks, and the continents increasing clinical studies for genetic manipulation and medical technology, the APACGlobal Stem Cell Manufacturingmarket is expected to grow at the fastest rate during the forecast period.

Global Stem Cell ManufacturingMarketSegmentation:

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Global Stem Cell ManufacturingMarket Key Competitors:

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Global Stem Cell Manufacturing Market Value Projected To Reach USD 21.71 Billion By 2029, Registering A CAGR Of 9.1% - Digital Journal

In molecular biologist David Sinclair's lab at Harvard Medical School, old mice are growing young again.

Using proteins that can turn an adult cell into a stem cell, Sinclair and his team have reset aging cells in mice to earlier versions of themselves. In his team's first breakthrough, published in late 2020, old mice with poor eyesight and damaged retinas could suddenly see again, with vision that at times rivaled their offspring's.

"It's a permanent reset, as far as we can tell, and we think it may be a universal process that could be applied across the body to reset our age," said Sinclair, who has spent the last 20 years studying ways to reverse the ravages of time.

"If we reverse aging, these diseases should not happen. We have the technology today to be able to go into your hundreds without worrying about getting cancer in your 70s, heart disease in your 80s and Alzheimer's in your 90s." Sinclair told an audience at Life Itself, a health and wellness event presented in partnership with CNN.

"This is the world that is coming. It's literally a question of when and for most of us, it's going to happen in our lifetimes," Sinclair told the audience.

"His research shows you can change aging to make lives younger for longer. Now he wants to change the world and make aging a disease," said Whitney Casey, an investor who is partnering with Sinclair to create a do-it-yourself biological age test.

While modern medicine addresses sickness, it doesn't address the underlying cause, "which for most diseases, is aging itself," Sinclair said. "We know that when we reverse the age of an organ like the brain in a mouse, the diseases of aging then go away. Memory comes back; there is no more dementia.

"I believe that in the future, delaying and reversing aging will be the best way to treat the diseases that plague most of us."

A reset button

In Sinclair's lab, two mice sit side by side. One is the picture of youth, the other gray and feeble. Yet they are brother and sister, born from the same litter -- only one has been genetically altered to age faster.

If that could be done, Sinclair asked his team, could the reverse be accomplished as well? Japanese biomedical researcher Dr. Shinya Yamanaka had already reprogrammed human adult skin cells to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body. The 2007 discovery won the scientist a Nobel Prize, and his "induced pluripotent stem cells," soon became known as "Yamanaka factors."

However, adult cells fully switched back to stem cells via Yamanaka factors lose their identity. They forget they are blood, heart and skin cells, making them perfect for rebirth as "cell du jour," but lousy at rejuvenation. You don't want Brad Pitt in "The Curious Case of Benjamin Button" to become a baby all at once; you want him to age backward while still remembering who he is.

Labs around the world jumped on the problem. A study published in 2016 by researchers at the Salk Institute for Biological Studies in La Jolla, California, showed signs of aging could be expunged in genetically aged mice, exposed for a short time to four main Yamanaka factors, without erasing the cells' identity.

But there was a downside in all this research: In certain situations, the altered mice developed cancerous tumors.

Looking for a safer alternative, Sinclair lab geneticist Yuancheng Lu chose three of the four factors and genetically added them to a harmless virus. The virus was designed to deliver the rejuvenating Yamanaka factors to damaged retinal ganglion cells at the back of an aged mouse's eye. After injecting the virus into the eye, the pluripotent genes were then switched on by feeding the mouse an antibiotic.

"The antibiotic is just a tool. It could be any chemical really, just a way to be sure the three genes are switched on," Sinclair said. "Normally they are only on in very young developing embryos and then turn off as we age."

Amazingly, damaged neurons in the eyes of mice injected with the three cells rejuvenated, even growing new axons, or projections from the eye into the brain. Since that original study, Sinclair said his lab has reversed aging in the muscles and brains of mice and is now working on rejuvenating a mouse's entire body.

"Somehow the cells know the body can reset itself, and they still know which genes should be on when they were young," Sinclair said. "We think we're tapping into an ancient regeneration system that some animals use -- when you cut the limb off a salamander, it regrows the limb. The tail of a fish will grow back; a finger of a mouse will grow back."

That discovery indicates there is a "backup copy" of youthfulness information stored in the body, he added.

"I call it the information theory of aging," he said. "It's a loss of information that drives aging cells to forget how to function, to forget what type of cell they are. And now we can tap into a reset switch that restores the cell's ability to read the genome correctly again, as if it was young."

While the changes have lasted for months in mice, renewed cells don't freeze in time and never age (like, say, vampires or superheroes), Sinclair said. "It's as permanent as aging is. It's a reset, and then we see the mice age out again, so then we just repeat the process.

"We believe we have found the master control switch, a way to rewind the clock," he added. "The body will then wake up, remember how to behave, remember how to regenerate and will be young again, even if you're already old and have an illness."

Science already knows how to slow human aging

Studies on whether the genetic intervention that revitalized mice will do the same for people are in early stages, Sinclair said. It will be years before human trials are finished, analyzed and, if safe and successful, scaled to the mass needed for a federal stamp of approval.

While we wait for science to determine if we too can reset our genes, there are many other ways to slow the aging process and reset our biological clocks, Sinclair said.

"The top tips are simply: Focus on plants for food, eat less often, get sufficient sleep, lose your breath for 10 minutes three times a week by exercising to maintain your muscle mass, don't sweat the small stuff and have a good social group," Sinclair said.

What controls the epigenome? Human behavior and one's environment play a key role. Let's say you were born with a genetic predisposition for heart disease and diabetes. But because you exercised, ate a plant-focused diet, slept well and managed your stress during most of your life, it's possible those genes would never be activated. That, experts say, is how we can take some of our genetic fate into our own hands.

Cutting back on food -- without inducing malnutrition -- has been a scientifically known way to lengthen life for nearly a century. Studies on worms, crabs, snails, fruit flies and rodents have found restricting calories "delay the onset of age-related disorders" such as cancer, heart disease and diabetes, according to the National Institute on Aging. Some studies have also found extensions in life span: In a 1986 study, mice fed only a third of a typical day's calories lived to 53 months -- a mouse kept as a pet may live to about 24 months.

Studies in people, however, have been less enlightening, partly because many have focused on weight loss instead of longevity. For Sinclair, however, cutting back on meals was a significant factor in resetting his personal clock: Recent tests show he has a biological age of 42 in a body born 53 years ago.

"I've been doing a biological test for 10 years now, and I've been getting steadily younger for the last decade," Sinclair said. "The biggest change in my biological clock occurred when I ate less often -- I only eat one meal a day now. That made the biggest difference to my biochemistry."

Additional ways to turn back the clock

Sinclair incorporates other tools into his life, based on research from his lab and others. In his book "Lifespan: Why We Age and Why We Don't Have To," he writes that little of what he does has undergone the sort of "rigorous long-term clinical testing" needed to have a "complete understanding of the wide range of potential outcomes." In fact, he added, "I have no idea if this is even the right thing for me to be doing."

With that caveat, Sinclair is willing to share his tips: He keeps his starches and sugars to a minimum and gave up desserts at age 40 (although he does admit to stealing a taste on occasion). He eats a good amount of plants, avoids eating other mammals and keeps his body weight at the low end of optimal.

He exercises by taking a lot of steps each day, walks upstairs instead of taking an elevator and visits the gym with his son to lift weights and jog before taking a sauna and a dip in an ice-cold pool. "I've got my 20-year-old body back," he said with a smile.

Speaking of cold, science has long thought lower temperatures increased longevity in many species, but whether it is true or not may come down to one's genome, according to a 2018 study. Regardless, it appears cold can increase brown fat in humans, which is the type of fat bears use to stay warm during hibernation. Brown fat has been shown to improve metabolism and combat obesity.

Sinclair takes vitamins D and K2 and baby aspirin daily, along with supplements that have shown promise in extending longevity in yeast, mice and human cells in test tubes.

One supplement he takes after discovering its benefits is 1 gram of resveratrol, the antioxidant-like substance found in the skin of grapes, blueberries, raspberries, mulberries and peanuts.

He also takes 1 gram of metformin, a staple in the arsenal of drugs used to lower blood sugars in people with diabetes. He added it after studies showed it might reduce inflammation, oxidative damage and cellular senescence, in which cells are damaged but refuse to die, remaining in the body as a type of malfunctioning "zombie cell."

However, some scientists quibble about the use of metformin, pointing to rare cases of lactic acid buildup and a lack of knowledge on how it functions in the body.

Sinclair also takes 1 gram of NMN, or nicotinamide mononucleotide, which in the body turns into NAD+, or nicotinamide adenine dinucleotide. A coenzyme that exists in all living cells, NAD+ plays a central role in the body's biological processes, such as regulating cellular energy, increasing insulin sensitivity and reversing mitochondrial dysfunction.

When the body ages, NAD+ levels significantly decrease, dropping by middle age to about half the levels of youth, contributing to age-related metabolic diseases and neurodegenerative disorders. Numerous studies have shown restoring NAD+ levels safely improves overall health and increases life span in yeast, mice and dogs. Clinical trials testing the molecule in humans have been underway for three years, Sinclair said.

"These supplements, and the lifestyle that I am doing, is designed to turn on our defenses against aging," he said. "Now, if you do that, you don't necessarily turn back the clock. These are just things that slow down epigenetic damage and these other horrible hallmarks of aging.

"But the real advance, in my view, was the ability to just tell the body, 'Forget all that. Just be young again,' by just flipping a switch. Now I'm not saying that we're going to all be 20 years old again," Sinclair said.

"But I'm optimistic that we can duplicate this very fundamental process that exists in everything from a bat to a sheep to a whale to a human. We've done it in a mouse. There's no reason I can think of why it shouldn't work in a person, too."

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The 'Benjamin Button' effect: Scientists can reverse aging in mice. The goal is to do the same for humans - KITV Honolulu

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Like many moms, UC Santa Cruz stem cell biologist Lindsay Hinck struggled to make enough milk to feed her infant daughter.

Frustrated by her low supply, she went to a lactation consultant, who advised her to wake up every night at 3 a.m. an optimal time in the hormone cycle to pump precious drops of liquid gold for her baby.

Hinck did it, but she also wondered, why was she having so much trouble and losing so much sleep while other moms had no problem feeding their newborns?

After many exhausting early hours with the pump, Hinck did what she does best: research. She found something remarkable: More than 25% of women worldwide struggle to produce enough milk to feed their infant children.

But when she looked to scientific literature for an explanation, it came up empty.

Hinck, who got a masters degree in biochemistry from UC Davis and her Ph.D. in cancer biology from Stanford University, was shocked to realize scientists have barely studied human lactation. There was almost no information for scientists or moms about how human breast tissue makes milk.

Hinck decided to change that.

She switched her UCSC labs research focus from breast cancer to lactation, specifically looking into how stem cells in breast tissue create milk and why some womens supply comes out low.

Its a topic some view with skepticism; lactation and breastfeeding are still treated by many as uncomfortable or inappropriate. In fact, in the early days of her research, Hinck had to get funding from an animal health firm interested in increasing milk production in cows.

We sexualize breasts in the most amazing ways, and people dont seem to have a problem talking about that, says Hinck, who has been at UCSC since 1998 and serves as co-director of the universitys Institute for the Biology of Stem Cells. Yet when it gets down to their biological function which is to provide nutrition for infants somehow the world clams up.

With the a nationwide baby formula shortage having affected millions of families, Hincks work funded by the National Institutes of Health takes on even greater importance. Parents whose infants have allergies or metabolic conditions rely on formula, and women particularly those who are already struggling to breastfeed cant suddenly build a milk supply overnight when formula is not available.

Hinck spoke with Lookout from her office at UCSC; this interview has been edited for clarity.

Lookout: What is lactation insufficiency?

Lindsay Hinck: Lactation insufficiency is the inability of a woman to produce the breast milk in daily volumes that meet the nutritional needs of her infant.

The statistics that we have are very broad. Somewhere between 25% and 67% of women will experience this worldwide. And this statistic is so broad because lactation insufficiency is understudied, and its hard to study.

A lot of scientists would agree that breast milk does confer an immunological advantage, and that it is filled with immune cells that the mother is giving to her infant; milk is also filled with microbes. Those are two of the major deliveries to children that come through breast milk, not to mention all the comfort of the breastfeeding cycle, psychological comfort and connectedness through the skin on skin feeling of being fed that way.

Lookout: How do you feel about your research in the context of the baby formula shortage?

Hinck: A lot of women rely on formula because they have trouble building a milk supply. Currently there are no FDA (U.S. Food and Drug Administration)-approved drugs in the United States for lactation insufficiency. My research is identifying therapeutically relevant drug targets, so that maybe we will be able to address this issue. We hope that one day women can take a drug to better build a milk supply.

Were working on a nonhormonal drug. The current drugs work on the hormone prolactin, whereas my lab studies stem cells. None of the drugs targeting prolactin have been approved, because they have terrible side effects.

Hormones have wide-ranging effects. Theyre released and they spread throughout the body. I think maybe we have an opportunity to identify a therapeutic that wont have so many deleterious side effects.

(Mel Melcon / Los Angeles Times)

Lookout: Because of the baby formula shortage, an easy answer might be to tell mothers they should just breastfeed. Why might that not be a compassionate or realistic response?

Hinck: No, thats not a compassionate or realistic response. I mean, especially if you havent built your milk supply, its not a trivial thing. If you didnt build a milk supply from the beginning, and even if you are breastfeeding, if you cant meet the daily needs of your infant, you simply dont have the milk. Its just not there.

Building a milk supply doesnt occur over 24 hours, you cant just latch the child on more often and have more milk in a day. Eventually the milk supply will increase, but its complicated. Its hard for some women to initiate and build a milk supply.

Lookout: In the U.S., lactation and breastfeeding seem to be treated as somewhat taboo or uncomfortable topics. How do you respond to that?

Hinck: We dont want to see women doing it. It seems to make people uncomfortable, so at best we provide women a room somewhere, and at worst there are no accommodations. We certainly dont appear as a society that welcomes breastfeeding in public. I am bemused at this, and find it tragic at the same time.

I myself, when I breastfed, I just breastfed. I just got to the point where tough, you know? I know I made people uncomfortable. My mother-in-law would try to drape a huge blanket over me and my child in the summer in the heat, and it was like 100 degrees underneath that blanket. I would just be like, This is crazy! Its just an infant at my breast eating. Seems fine to me. And I dont think the climate has dramatically changed in many places in the world. My daughter is 22 years old, and in 22 years I have not seen that needle budge. It still seems like breastfeeding makes people uncomfortable, and I dont know why.

Lookout: Have you faced any skepticism about this as a research topic, or faced any particular challenges in studying lactation compared to other topics, like cancer?

Hinck: I would say that I have had a harder time getting my lactation research funded. But recently, I received a NIH grant from the National Institutes for Child Health and Human Development, so thats been terrific. There has been a gaining interest in a number of whats been classified as womens diseases that have been understudied for a long time.

But in the early days, I got money from an animal health firm because they were interested in increasing milk supply in cows. The biology is the same, however. So that worked out for me, and we were able to have a project that involves looking to see if this would work for building milk supply in cows, and then we were able to unravel the basic pathways, and now were applying that.

Lookout: What would you say are the big questions driving your current research?

Hinck: How does the breast tissue know how many progenitor cells to release or recruit to expand and to build the milk supply?

Breast stem/progenitor cells have to last a whole lifetime, and they have limited potential. Theyre stemlike in that they undergo an asymmetric cell division, which is a special type of cell division that recreates the stem/progenitor cells and gives rise to daughter cells that can go on to expand and become the milk producing cells.

So how many of those asymmetric cell divisions occur? How many cells are recruited to undergo those asymmetric cell divisions? All of that is unknown. Remember, the stem cell, the progenitor cell, wants to divide as infrequently as possible. Every time they replicate their DNA, it is opening up the possibility of damage that could lead to cancer.

Lookout: How would understanding these progenitor cell pathways help improve peoples lives, or pursue a solution to lactation insufficiency?

Hinck: Its early days. We dont understand a lot, and of course giving drugs to women who are pregnant is tough. There are drugs on the market for lactation domperidone is the best medicine to build milk supply, but its not approved by the FDA in America. It has side effects, cardiac side effects.

So its not unheard of that there would be drugs that could help build a milk supply. I think that would be the ultimate goal of our research, to understand if there is any pharmacological intervention that could help.

Lookout: What do you think nursing mothers who are struggling with lactation need? What can we do as a society to support them?

Hinck: Well, in the short term, certainly make workplace rules that change the climate. I mean, even if the rules are in place, if women dont feel welcome to take the breaks to pump then it doesnt happen. I mean, we all know how that goes.

Give mothers more time off. Create more welcoming environments when they come back to work to support them and their desire to breastfeed their child.

And in the longer term, we could understand the biology of building milk supply, which is still quite mysterious in humans. What are some of the factors that may impinge on that during pregnancy or after pregnancy?

Lookout: What did you have to do in order to feed your child when you were having trouble making enough milk?

Hinck: I saw the lactation consultant and I was told to pump at 3 a.m. when prolactin levels are the highest. I would set the alarm and get up and pump every night. I was also working full time, pumping every four hours. But I could barely pump the amount of milk for the next day.

Thats a burden, you know? Its just hard to balance. Youve got an infant, and youve got this other role, but youre also providing all the food for them. It doesnt always work seamlessly, thats for sure. I went to work to do my science, and I did the best I could.

It was a lot of work. Its so much to expect of mothers. And we just dont give parents, mothers, the space and time to breastfeed at work. Its also underappreciated that there could be other people who want to breastfeed, and we need to open doors for them for non-birth moms, trans people. Why do we keep lactation in just the realm of women? I think that if we understood lactation physiology better, we could help people breastfeed.

Guanan Gmez-Van Cortright is a 2022 graduate of the UC Santa Cruz Science Communication masters program. She has written for Good Times, KQED radio and the San Jose Mercury News.

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Why do some women struggle to breastfeed? A UCSC researcher on what we know, and don't - Lookout Santa Cruz

When was your complexion at its very best? Perhaps in your late teens, after the curse of spots had finally passed? Or a decade on, when elegance had supplanted callow youth and the wrinkles were yet to appear? So advanced is the aesthetic industry that most of Hollywood is already on this quest, with Brad Pitt, Demi Moore and the like, you name them, looking far more youthful than their near 60 years. But, what if one day we could do more than have facials and tweakments to keep us looking younger? What if we could genetically dial back our skin? That is the ultimate promise raised by British researchers who revealed that they had turned the clock back on ageing human skin cells by 30 years. Just imagine: three decades of sunbathing, stress, late nights and the odd bottle of booze, all wiped from the millimetre.

In ex-vivo rejuvenation, we take diseased or damaged skin cells out of the patient, rejuvenate them and then return them to the damaged area of the patients skin so that it vigorously regrows and heals. Dr Diljeet Gill, one of the authors of the new skin study

A significant cause of hearing problems is the loss of minute cochlear hair cells in the inner ear. These are the sensory cells of the auditory system. Over time they die, and dont regenerate.

The news comes amid a wave of renewed interest in the field of regenerative medicinethe idea that we can rejuvenate ageing cells so that our bodies and brains can start afresh, bouncingly free of disease and full of youths resilient energy. In the latest advance, researchers from the Babraham Institute, a research institution partnered with the University of Cambridge, took skin cells from a 53-year-old woman and rejuvenated them to act as though they were 30 years younger.

When the cells were applied to a simulated wound in a laboratory, their healing response was as sprightly as if they had come from a 23-year-old, the scientists said. The team adapted a Nobel prize-winning technique that uses proteins involved in birth development to get adult human cells to revert back to embryo stem cells. This approach takes the cells age right back to zero. Stem cells hold great medical promise as precursor cells that can be turned into any new kind of human cell to replace damaged or diseased ones. But that potential has mostly remained unrealised for decadesnot least because medically implanted stem cells can be lethal.

Stem cells were discovered in the early 1960s. Then, in the late 1990s, scientists managed to isolate them from human embryos and grow them in the lab. I remember when I was a wrinkle-free young reporter how this news prompted a gush of experts to predict that the novel technology would revolutionise health care within a decade, curing our most serious ills, such as cancer, Alzheimers and heart disease. Then stem cells potential for danger rapidly began to emerge.Little anarchists they are, lab-derived stem cells. With all that potential to become anything, it was discovered that they can do precisely that. And anything includes tumour cells or whatever else they fancy. If you grow stem cells into pancreas cells in the hope that they will produce new insulin in people with type 2 diabetes, they can instead decide to make all the hormones that a pancreas could possibly produce, which isnt helpful, said Dr Diljeet Gill, 27, one of the authors of the new skin study.

The technique that Gills experiment used to rejuvenate human flesh was crucially different. Instead of reprogramming the 53-year-old womans skin cells back to being age-zero stem cells, it stopped the age-reversal process before they got that young. Thus the cells had dual identityyouthful enough to fizz with vitality, but old enough to know their job as skin cells. The altered cells matched the profiles of cells 30 years younger. Once rejuvenated, they produced far more skin-pillowing collagen than the unmodified cells.Professor Wolf Reik, the German molecular biologist and group leader at the Babraham Institute, co-authored the study. He said, It looks like you may be able to select the age to which you turn back the cells, at least by the decade, so you could find the general sweet spot.

The approach marks a potential breakthrough for the field of regenerative medicine. Investors are salivating at the prospect, which helps to explain why analysts are predicting that the scientific industry will be worth $50 billion in five years time.Scientific institutions are already developing stem cell-based technologies to regenerate our most frequently worn-out organs. In the UK more than 40 per cent of people over 50 have hearing loss. Now investigators at Frequency Therapeutics, a spin-off company of Massachusetts Institute of Technology, are pioneering a new type of regenerative therapy to reverse it.

A significant cause of hearing problems is the loss of minute cochlear hair cells in the inner ear. These are the sensory cells of the auditory system. Over time they die, and dont regenerate. In March researchers at Frequency Therapeutics explained how they are developing a drug that programs the descendants of stem cells in patients inner ears, called progenitor cells, to awaken and recreate cochlear hair cells.

Eyes are another age-old problem. An Indian biotechnology company called Pandorum Technologies is developing a gel that can carry corneal stem cells into the eye to regenerate peoples corneas.

And where old bones are concerned, researchers from Texas A&M University reported how they had developed new ways of delivering rejuvenating stem cells into damaged and worn limbs using nanotechnology, strengthening hopes that we can keep our skeletons straight and sturdy well into old age.As for being able to completely refresh our midlife flesh, sadly we will have to wait a while. As Gill said, We think the prime opportunity here is for ex-vivo rejuvenation, in which we take diseased or damaged skin cells out of the patient, rejuvenate them and then return them to the damaged area of the patients skin so that it vigorously regrows and heals.

Because the scientists would effectively be giving patients a transplant of their own skin, only decades younger, there is no danger of their bodies rejecting the tissue as foreign. With this we could treat severe flesh wounds such as cuts, burns, lacerations and ulcerssituations where aged cells have real difficulty healing, said Gill.

His next priority involves testing skin-cell rejuvenation further, to be sure that it wont cause cancer, before trialling it in humans. From there, the research is set to swerve into another age-related disease: dementia. Reik believes the technique may reverse age-related decline in our immune systems, too.

The pandemic highlighted how, as we get older, our defences steadily weaken. Im hopeful that the technique can make a vital difference here, he said.Ilaria Bellantuono, a professor of musculoskeletal ageing and co-director of the Healthy Lifespan Institute at the University of Sheffield, is erring on the side of caution, It is very early days. The new experiment is only in a laboratory petri dish. We dont know whether the cells will perform their jobs properly in a living human. We dont know yet how the changes made will affect the skin cells most important functions in humans, such as making collagen and dividing.

Nevertheless, Bellantuono remains optimistic that in decades to come the new Cambridge technology could put scientifically effective age-reversing therapies on our chemists shelves. I think where the new research goes many years from now is the development of drugs that reverse ageing with cells in the organism directly, she said. You may be able to take a pill that partially reverses your age so that it may properly rejuvenate your skin and other organs. If you want to do something about your cellular clocks right now, you need to work on your fitness and general health. Looking after ourselves is the best thing we can currently do to slow the ageing process and protect our skin and other vital tissues. Oh well, back to the treadmill.

Excerpt from:
What if we could genetically dial back our skin? - The Week

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The more scientific our skincare, the better. The second we see an ingredient like stem cell extract in a serum or cream, were instantly intrigued. The creative innovations of the beauty industry are just incredible. Can you believe a product like this is available for an actually affordable price?

While wed expect something scientific with hundreds of stellar reviews to potentially cost $100 or more, Three Ships is proving that modern, effective skincare doesnt have to be out of budget. Ready to meet what might be your new holy grail? Say hello to Radiance!

Get the Radiance Grape Stem Cell + Squalene Day Cream for just $35 at Three Ships! Free shipping!

This cream is for all skin types, but if your skin if feeling dry or tight and/or looking dull, youll especially want to check it out. Its made with grape stem cells and natural squalene, aiming to help your skin retain moisture, look radiant and feel comfortable and nourished. This could also lead to less redness and fewer breakouts!

This cream has a lightweight, fast-absorbing formula. Its also vegan and certified cruelty-free. Its EWG Verified as well, meaning its free of EWGs chemicals of concern. This makes it a safe, reliable clean beauty choice wed feel comfortable recommending to just about anyone!

Another cool thing about this cream is the opaque pump jar. Its designed to minimize the creams exposure to air and fingertips, therefore shielding it from extra bacteria growth or exposure to sunlight that could make it less effective over time. Wed also just like to say that this style of pump jar is our favorite. Its fun to use and keeps Us from accidentally using too much as a time!

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Introduction

Ultraviolet radiation (UVR) is known to be the main extrinsic factor that induces skin pigmentation, which is a vital physiological process to protect nuclear DNA of epidermal cells from UV damage.1 Melanocytes stimulated by UVR synthesize melanin within melanosomes, which are subsequently transferred to adjacent keratinocytes, thus resulting in visually observable skin pigmentation.1 Proposed mechanisms of melanosome transfer include the following models: cytophagocytosis,2 direct membrane fusion,3 shed vesicles,4,5 and coupled exo/phagocytosis.6,7 Recent observations favor the coupled exo/phagocytosis model, which proposed that the melanosome core was released from melanocytes and then phagocytosed by neighboring keratinocytes.8 In this process, keratinocyte phagocytosis serves an important part, however, the detailed mechanism of which has not been fully elucidated.

Transient receptor potential ankyrin 1 (TRPA1), a calcium (Ca2+)-permeable non-selective cationic channel, is a unique member of the mammalian TRP ankyrin subfamily which plays key functions in chemo-, thermo-, and mechano-sensing.9,10 Previous studies indicated that TRPA1 was mainly expressed in sensory neurons, while recent researches confirmed its non-neuronal expressions in lung, brain and vascular endothelial tissues.9 Moreover, TRPA1 was detected to be expressed in human cutaneous cells, including melanocytes and keratinocytes.11 With regard to the biological function of TRPA1 in epidermal cells, it is demonstrated that TRPA1 activated by UVR caused a retinal-dependent current and a rapid calcium influx and was required for the UVR-induced early increase of cellular melanin in melanocytes.12 In mammalian phototransduction, retinal evoked a UVR-sensitive current in melanocytes, probably due to the conversion of trans-retinal to the cis- conformation catalyzed by the retinoid isomerohydrolase RPE65 (retinal pigment epithelium-specific 65kDa protein), which is also expressed in keratinocytes, as in the rod and cone cells of visual cycle.1315 What is more, TRPA1 was found to be involved in the proliferation and differentiation of keratinocytes.11 However, whether it contributes to keratinocyte phagocytosis for promoting skin pigmentation remains unclear.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine-threonine protein kinase, which plays a crucial role in cell-migration-related cytoskeleton dynamics via auto-phosphorylation mediated mechanism.16 -catenin is a core component of the canonical Wnt signaling pathway, and it facilitates the process of gene transcription and cellcell adhesion.17,18 -catenin binds to the intercellular domain of E-cadherin (Epithelia-cadherin) and links catenin, composing a cadherin-catenin complex, which directly anchors the actin cytoskeleton so that mediates the cellcell adhesion.19 In the process of phagocytosis, actin cytoskeleton dynamics is required for the localized protrusion of the plasma membrane and the formation of the extended pseudopodia.20 Given the relevance of the CaMKII and -catenin to the actin cytoskeleton, their involvement in phagocytosis is of great research potential. However, their effect on keratinocyte phagocytosis has not been investigated yet.

Since UVR could activate TRPA1 channels in melanocytes leading to melanin synthesis, the aim of this study was to evaluate whether TRPA1 channels activated by UVR could promote keratinocyte phagocytosis and skin pigmentation in vitro and in vivo, and investigate the possible mechanisms which may involve the phosphorylation of CaMKII and the increased expression of -catenin in keratinocytes.

TRPA1 (19124-1-AP) was purchased from Proteintech Group (Rosemont, IL 60018, USA). CaMKII (4436), pCaMKII (12716), -catenin (8480) were purchased from Cell Signaling Technology (Danvers, Massachusetts, USA). Retinal (R2500), JT010 (SML1672), HC030031 (H4415) were purchased from Sigma Aldrich (Darmstadt, Germany). Dimethyl sulfoxide (DMSO), RIPA buffer (R0100), BCA protein assay kit (PC0020), poloxamer gel (Polyethylene-polypropylene glycol 407, S7071) and formalin (G2161) were purchased from Solarbio (Beijing, China). Protease inhibitor cocktail (B14011) was purchased from Bimake (Shanghai, China). XAV-939 (S1180) was purchased from Selleck Chemicals (Shanghai, China). Fluo-4 AM (ab142773), DIO Staining Solution (C1038) were purchased from Beyotime (Shanghai, China). Stock solutions were prepared as follows: HC030031, and XAV-939 were dissolved in DMSO, JT010, and retinal in absolute ethanol. Masson-Fontana staining solution (G2032) was purchased from Solarbio (Beijing, China). Opti-MEM medium (31985062), Lipofectamine 2000 (11668030) and chemiluminescence (ECL) were obtained from Thermo Fisher Scientific (Massachusetts, USA). The UVA or UVB source used was a 9W UVA or UVB broadband lamp (Philips, Eindhoven, Netherlands) and radiation energies were measured using a UVX radiometer (UVP, Upland, California, USA).

HaCaT cells (human immortalized keratinocytes) were purchased from the CABRI (European Union). Cells were cultured and grown in Minimum Eagles Medium (MEM, Gibco, USA), supplemented with 10% fetal bovine serum (FBS, Gibco, USA) and 1% penicillin/streptomycin solution (Gibco, USA) at the humidified incubator with 5% CO2 (v/v) at 37. hTRPA1-specific primers were designed based on NM_007332.2: F 5-GGTTTGGCAGTTGGCGACATTGCTGA3 and R 5-CTAAGGCTCAAGATGGTGTGTTTTTG-3. The primers amplified a DNA band that was sequenced and found to be identical to hTRPA1. TRPA1 full-length cDNA was then recombined into pcDNA3.1-HA vector and expressed using a transient transfection system. HaCaT cells (50104 cells/well) were overexpressed TRPA1 plasmid in an Opti-MEM medium containing Lipofectamine 2000 at 37. Cells were harvested 48 hours after transfection.

HaCaT cells (50104 cells/well) were seeded in 6-well plates (Corning Costar, USA) and incubated overnight. Cells were treated with different conditions (Retinal 12 M, JT010 1 M, HC-030031 10 M, XVA-939 10 M, UVA 225 mJ/cm2 or UVB 25 mJ/cm2) for 2 hours, and then loaded with 5 M Fluo-4 AM calcium probes in PBS for 30 minutes and then washed twice with PBS. Cells were incubated with 0.8 mM Ca2+-containing solution (140 mM NaCl, 3 mM KCl, 0.4 mM Na2HPO4, 10 mM HEPES, 5 mM Glucose, and 1 mM MgCl2, and 0.8 mM CaCl2 with pH 7.4) by incubation for 30 min at room temperature in the dark. To remove the Ca2+-containing solution, cells were washed two times with PBS solution, harvested, resuspended, and then the fluorescence intensity was measured by flow cytometry (BD Aria II software, USA) with excitation of 340 nm and emission at 510 nm. At least 30,000 cells were collected per sample. Intracellular calcium concentration ([Ca2+]ic) was assessed by the fluorescence intensity ratio of the calcium probe Fluo-4 AM and expressed as relative fluorescence intensity normalized to control cells.

HaCaT cells (20104 cells/dish) were seeded onto culture glass dishes (Nest, China) and incubated overnight. The following day, cells were treated with JT010 (1 M), HC-030031 (10 M), XVA-939 (10 M), UVA exposure (225 mJ/cm2) or UVB exposure (25 mJ/cm2), and loaded with 5 M Fluo-4 AM calcium probes as described in intracellular calcium concentration measurement. After incubation with the Fluo-4 AM calcium probe, calcium imaging was measured by Confocal fluorescence microscopy (Lacia, TCS SP8), and randomly taken from 5 microscopic fields in each experiment. Three independent experiments were conducted for each experiment and the fluorescence areas were measured by Image J software.

HaCaT cells (30104 cells/well) were seeded onto coverslips in 24-well plates (Corning Costar) and incubated overnight. Cells were serum-starved for 6 hours, then incubated with Fluospheres carboxylate-modified red fluorescent microspheres (0.5 m diameter, Invitrogen) for 16 hours, when cells were treated with JT010 (1 M), HC-030031 (10 M), XVA-939 (10 M), UVA exposure (225 mJ/cm2) or UVB exposure (25 mJ/cm2). Cells were vigorously washed 3 times with cold PBS to remove microspheres that had not been internalized. Cells were directly harvested and measured the fluorescence intensity by flow cytometry. In addition, cells were fixed in cold 4% paraformaldehyde for 30 min, stained with Dio for 15 min, and observed by confocal fluorescence microscopy. Quantitative analysis was performed by counting the number of internalized microspheres in 100 cells per condition, which were randomly taken from 6 microscopic fields in three independent experiments.

Total protein was solubilized from cell lysates using RIPA buffer supplemented with protease inhibitor cocktail. Protein concentration was measured using the BCA protein assay kit. A total of 40 mg proteins were electrophoresed in 8% SDS-PAGE gels and transferred to polyvinylidene difluoride (PVDF) membranes, and then were blocked in 5% bovine serum albumin (BSA) in Tris-buffered saline containing 0.1% Tween-20 (TBST) for 1 h. Subsequently, membranes were incubated with TRPA1, CaMKII, pCaMKII or -catenin antibodies (all diluted to 1:1000 with 5%BSA solution) overnight at 4, followed by horseradish peroxidase-conjugated secondary antibodies (diluted to 1:2000 with 5%BSA solution) for 1 hour at room temperature. Finally, immunopositive bands were analyzed by enhanced chemiluminescence (ECL) and visualized using Tanon 5200 software (China). Band quantification for three experiments was done using Image J software (USA).

Experimental procedures were approved by the Animal Ethics Committee of Dalian Medical University (AEE22013), and animal care followed the National Institute of Health guidelines on the care and use of laboratory animals. The dorsal skin of brown guinea pigs (7 weeks old, weighing approximately 500550 g) was divided into 3 areas, Control, Vehicle (33% poloxamer gel), XAV-939 (10 mM in 33% poloxamer gel). The corresponding areas were treated locally for 30 min every other day, and the UVB lamp was placed 15 cm above the guinea pig. The total energy dose of UVB exposure was 500 mJ/cm2 for 2 weeks. The L value was measured in each application area (automatically averaging 3 times per point) by the colorimeter (Thermo), which was used to evaluate the lightness of skin. Experimental areas of skin were biopsied, processed, and fixed overnight in neutral-buffered 10% formalin, and then embedded in paraffin. They were then applied to Hematoxylin Eosin (H&E) staining and Masson-Fontana (M&F) staining. M&F staining was performed according to the manufacturers instructions. The melanin granules were measured by Image J software. Quantitative analysis was performed by counting the positive stained areas of M&F staining in the epidermis, which were randomly taken from 5 microscopic fields in three independent experiments.

All data are presented as means standard deviation (SD), and the data are the mean values from at least three independent experiments. Statistical analyses were performed using GraphPad Prism 8.0 software (San Diego, CA). Significant differences between the groups were performed using Brown-Forsythes test, Students t-test and one-way ANOVA with Tukeys post hoc test. A P-value <0.05 was considered statistically significant.

To unveil the effect of UVA/UVB on the Ca2+ responses in HaCaT cells, the cells were processed with 225 mJ/cm2 UVA or 25 mJ/cm2 UVB (equivalent to 250 s of full sun exposure).12 In Figure 1A and B, the data from flow cytometry assay showed that the [Ca2+]ic had no change after treatment with retinal (the chromophore required for light activation of opsin G protein-coupled receptors)21 or UVA/UVB compared to the control group, respectively. Furthermore, the [Ca2+]ic was increased 102%/66%, respectively, after UVA/UVB exposure in comparison with the control group, when HaCaT cells were preincubated with retinal (Figure 1A and B, p < 0.001). To investigate the effect of TRPA1 on UVA/UVB-induced Ca2+ responses, HaCaT cells were transfected with plasmids to overexpress TRPA1 or treated with JT010 (1 M, a selective TRPA1 agonist), HC-030031 (10 M, a selective TRPA1 antagonist). As shown in Figure 1C, the [Ca2+]ic was significantly increased 70% after treatment with JT010 (p < 0.001), whereas pretreatment with HC-030031 decreased 35%/36% of the UVA/UVB-induced [Ca2+]ic, respectively (p < 0.01), in HaCaT cells. Besides, UVA/UVB exposure significantly increased 224%/232% [Ca2+]ic in HaCaT cells, which were transfected with plasmids overexpressing TRPA1 (Figure 1C, p < 0.001). Subsequently, HaCaT cells were loaded with Fluo4-AM, which showed fluorescence on binding with free calcium, and the fluorescence-positive areas were observed using a fluorescence confocal microscopy. The results of the fluorescence-positive area showed that exposure to UVA/UVB, treatment with JT010, or overexpressing TRPA1 enhanced the Ca2+ responses, but it was significantly decreased after treatment with HC-030031 in HaCaT cells (Figure 1D). These results indicated that UVR-induced Ca2+ responses were regulated by TRPA1 in HaCaT cells.

Figure 1 TRPA1 channels regulated UVA/UVB-induced Ca2+ responses in HaCaT cells. (A) Fluo-4 AM fluorescence intensity indicating calcium concentration was detected by flow cytometry in HaCaT cells after exposure to UVA (225 mJ/cm2) or UVB (25 mJ/cm2) with or without retinal preincubation (12 M). (B and C) Quantification of the fluorescence intensity at different treatments. Values are mean value of relative fluorescence intensity normalized to control from three independent tests SD. (D) Calcium imaging was observed by fluorescence confocal microscopy after treatment with UVA or UVB exposure, JT010 (1 M, TRPA1 agonist), HC-030031 (10 M, TRPA1 antagonist), or HA-TRPA1. (Fluo-4 AM, green fluorescence). (**p < 0.01; ***p < 0.001).

To further explore the effect of TRPA1 mediated Ca2+ responses on UVR-induced keratinocyte phagocytosis, we detected the expression of phosphorylated CaMKII (pCaMKII) using Western bolt, and measured the fluorescent intensity and the fluorescent microspheres uptake by flow cytometry and confocal fluorescence microscopy. As shown in Figure 2A and B, the results showed that the ratio of pCaMKII/CaMKII was significantly increased 1.41-, 1.82- or 1.93-fold after treatment with JT010 (p < 0.05) or UVA/UVB (p < 0.001), respectively. However, the decline of the ratio of pCaMKII/CaMKII was observed in HaCaT cells after treated with HC-030031, and the fold decreases were 0.5 compared with the control group (p < 0.001) (Figure 2A and B). Furthermore, fluorescent microspheres (0.5 m, red) are often used as pseudo-melanocores to study keratinocyte phagocytosis,22,23 and the results showed that the fluorescence intensity was increased 82%/81% after UVA/UVB exposure compared with the control group, respectively (Figure 2C, p < 0.001). At the same time, the fluorescent intensity was increased 70% after treatment with JT010, but it was decreased 36% after treatment with HC-030031, in comparison with the control group (Figure 2C, p < 0.001). Moreover, the fluorescent microsphere uptake was increased 2.21-/2.00-fold after UVA/UVB exposure, as well as treatment with JT010 (2.92-fold) (Figure 2D and E, p < 0.001). The fluorescent microsphere uptake decreased 0.5-fold after treatment with HC-030031 compared with the control group (Figure 2D and E, p < 0.05). These discoveries above proved that TRPA1 regulated UVR-induced phosphorylation of CaMKII and the fluorescent microsphere uptake in HaCaT cells.

Figure 2 UVR-induced phosphorylation of CaMKII and keratinocyte phagocytosis was regulated by TRPA1 in HaCaT cells. TRPA1 channels promoted phosphorylation of CaMKII (A and B), (A) the protein levels of CaMKII and phosphorylated CaMKII (pCaMKII) were measured by Western blot in HaCaT cells, which were treated with UVA or UVB exposure, JT010 (1 M, TRPA1 agonist), HC-030031 (10 M, TRPA1 antagonist). (B) Relative protein levels of pCaMKII to CaMKII. Values are mean value of the ratio relative to control from three independent tests SD. (C) Quantification of fluorescence intensity indicating the uptake of fluorescent microspheres by HaCaT cells detected by Flow cytometry. Values are expressed as mean SD from three independent tests. (D) Fluorescent microspheres uptake was observed by fluorescence confocal microscopy, with red fluorescence indicating microspheres (0.5 m microspheres), and green fluorescence indicating cell membrane stained with DiO. HaCaT cells were treated with UVA or UVB exposure, or JT010 (1 M), HC-030031 (10 M). Scale bar: 50 m. (E) Quantification of fluorescent microspheres per HaCaT cell. Values are expressed as mean SD from three independent tests. (**p < 0.01; ***p < 0.001).

To determine the effect of -catenin on UVR-induced phagocytosis mediated by TRPA1, we measured the expression of -catenin and observed the fluorescent microsphere uptake in HaCaT cells. The results showed that the expression of TRPA1 increased 1.28-/1.30-fold after UVA/UVB exposure in HaCaT cells, which were transfected with HA-TRPA1 plasmids compared to the control group (Figure 3A and B, p < 0.05). Subsequently, compared with the control group, the expression of -catenin increased 1.64-, 1.72-/1.68-fold after treatment with JT010, UVA/UVB exposure in HaCaT cells (Figure 3A and C, p < 0.05). Interestingly, when HaCaT cells were transfected with HA-TRPA1 plasmids, the protein expression of -catenin significantly increased 2.54-/2.49-fold after UVA/UVB exposure (Figure 3AC, p < 0.001). Moreover, the expression of -catenin significantly decreased 0.48-, 0.61-/0.45-fold in HaCaT cells, which were treated with XAV-939 (10 M, decreasing -catenin expression) alone, or before UVA/UVB exposure (Figure 3D and E, p < 0.001). Meanwhile, the fluorescent intensity was decreased 44%, 37%/31% (Figure 3F, p < 0.001), and the fluorescent microsphere uptake decreased 0.32-, 0.27-/0.39-fold compared with the control group (Figure 3G and H, p < 0.001), when HaCaT cells were treated with XAV-939 alone, or before UVA/UVB exposure. These findings indicated that TRPA1 enhanced the protein expression of -catenin to promote UVR-induced phagocytosis in HaCaT cells.

Figure 3 TRPA1 enhanced the expression of -catenin promoting phagocytosis in HaCaT cells. (A) The protein levels of TRPA1 and -catenin were measured by Western blot in HaCaT cells, which were treated with UVA or UVB exposure, JT010 (1 M, TRPA1 agonist), or overexpressed with HA-TRPA1 respectively. (B and C) Quantification of TRPA1 and -catenin protein expression levels. Values are mean value of protein expression normalized to -actin and relative to control from three independent tests SD. (D) The protein levels of -catenin were measured by Western blot in HaCaT cells, which were treated with XAV-939 (10 M, decreasing -catenin expression) alone or before exposure to UVA/UVB. (E) Quantification of -catenin protein expression levels. Values are mean value of protein expression normalized to -actin and relative to control from three independent tests SD. (F) Quantification of fluorescence intensity indicating the fluorescent microspheres uptake was detected by Flow cytometry in HaCaT cells. Values are expressed as mean SD from three independent tests. (G) Fluorescent microspheres uptake was observed by fluorescence confocal microscopy, with red fluorescence indicating microspheres, and green fluorescence indicating cell membrane stained with DiO. HaCaT cells were treated with XAV-939 (10 M) alone or before exposure to UVA/UVB respectively. Scale bar: 50 m. (H) Quantification of fluorescent microspheres per HaCaT cell. Values are expressed as mean SD from three independent tests. (*p < 0.05; **p < 0.01; ***p < 0.001).

To ascertain the effect of -catenin on pigmentation, we carried out the topical application of XAV-939 in vivo UVB-induced skin pigmentation guinea pig models. In the photograph of dorsal skin, XAV-939 (10 mM) showed depigmenting effects on UVB-induced skin pigmentation after 2 weeks of topical application, compared with the control and vehicle groups (Figure 4A). As for colorimetric measurements, the L value (skin lightness) significantly increased 17% and 16% in XAV-939 areas compared to control and vehicle groups (Figure 4B). The skin biopsy specimens were obtained from treated areas and were processed for light microscopy examination with H&E staining and M&F staining. The results showed no obvious changes of epidermal thickness in the control, vehicle and XAV-939 groups determined by H&E staining (Figure 4A). Furthermore, XAV-939 significantly reduced 69% and 70% the melanin granules revealed by M&F staining, which stains melanin granules as black, comparing with control and vehicle groups (Figure 4A and C). This result indicated that XAV-939 displayed a skin lightening effect on UVB-induced skin pigmentation in guinea pig models.

Figure 4 -catenin regulated the UVB-induced skin pigmentation on Guinea pig models. (A) Effect of -catenin on regulation of UVB-induced skin pigmentation in Guinea pigs. (A) Photographs of the lightening effect of XAV-939 (10 mM) on UVB-induced skin pigmentation. (B-C) H&E staining and M&F (Masson-Fontana) staining of biopsy specimens from the Control, Vehicle (33% poloxamer gel), or XAV-939 (10 mM in 33% poloxamer gel)-treated dorsal skin areas of brown Guinea pigs (200). (B) Quantification of L value was measured by colorimeter at the end of the experiment and values are expressed as mean SD from three independent tests. (C) Quantitative analysis of melanin granules stained by M&F. Values are expressed as mean SD from three independent tests. (***p < 0.001).

Melanocytes in the epidermis of skin synthesize melanosomes and transfer them to the nuclear area of approximately 36 surrounding keratinocytes under the stimulation of UVR in the sunlight, which causes skin pigmentation, severing as a photo-protecting mechanism.1 In the process of melanosome transfer, keratinocyte phagocytosis has recently been considered as a crucial section.24 Notably, a recent study suggested that melanocores (the melanin core devoid of surrounding membrane) were internalized by phagocytosis, whereas melanosomes (melanin core with intact surrounding membrane) were internalized by macropinocytosis in keratinocytes.25 In this study, we confirmed that UVR enhanced the phagocytic ability of keratinocytes, which was regulated by TRPA1.

As a Ca2+-permeable cationic channel, TRPA1 was reported to be activated by UVR and increased the [Ca2+]ic in human melanocytes.12 Our results identified similar findings in keratinocytes. Ca2+ is a key second messenger involved in the regulation of numerous cellular functions including adhesion, vesicular trafficking and cytoskeletal rearrangement.20 Calmodulin (CaM), a Ca2+ sensor protein, plays an important role in signal transduction pathways by binding with Ca2+.26 CaMKII is activated by the binding of Ca2+ saturated CaM (Ca2+/CaM) in an auto-phosphorylation manner.27 It is reported that CaMKII is a multi-subunit holoenzyme, which contains a kinase domain, an autoinhibitory/regulatory domain, an actin binding domain and an association domain.27,28 CaMKII possesses two kinds of functional activities including kinase activity and structural function. At basal status, the autoinhibitory domain masks the kinase domain, which inhibits the kinase activity. Meanwhile, the actin binding domain interacts with more than one filament that is composed of filamentous actin (F-actin), and bundles them together, to stabilize the F-actin of cytoskeleton.27 When Ca2+/CaM binds to the regulatory domain, the kinase domain is unmasked and the catalytic activity of the kinase is disinhibited. Once activated, CaMKII not only phosphorylates various substrates but also autophosphorylates itself at the autoinhibitory domain, turning into pCaMKII.27,29 In the meantime, autophosphorylated CaMKII dissociates from F-actin, which is subsequentially unbundled and remodeled by actin regulators, therefore contributing to the cytoskeleton dynamics.30 In the present study, it was demonstrated that UVR increased the [Ca2+]ic in keratinocytes, which was mediated by TRPA1. Moreover, TRPA1 regulated UVR-induced phosphorylation of CaMKII and keratinocyte phagocytosis. Thus, we assumed that UVR enhanced keratinocyte phagocytosis through TRPA1 mediated calcium signaling pathway. The possible mechanism might be that UVR activated TRPA1 and increased the intercellular Ca2+, which phosphorylated CaMKII by binding with CaM, accompanied with the remodeling of F-actin, facilitating phagocytosis in keratinocytes (Figure 5).

Figure 5 Schematic modulation of UVR-induced phagocytosis by TRPA1 in keratinocytes. TRPA1 is activated by UVR to increase the intracellular calcium, which promotes the phosphorylation of CaMKII, contributing to keratinocyte phagocytosis through the remodeling of F-actin. Moreover, TRPA1 activated by UVR increases the expression of -catenin to enhance keratinocyte phagocytosis through cell-cell adhesion and cytoskeleton dynamics.

Direct cellcell contact between MC and KC is a requirement for optimal melanosome transfer, which is accomplished by the adhesion ability of the cadherin-catenin complex, where -catenin binds to E-cadherin and interacts with -catenin.31,32 And -catenin bridges these components to actin cytoskeleton, which recruits and organizes actin filaments.33 Actin remodeling at the cell membrane for melanosome uptake and phagosome vesicular trafficking are key processes in keratinocyte phagocytosis.1,34 Previous studies on neuronal cells indicated that -catenin played a crucial role in the recruitment, localization and distribution of synaptic vesicles in synapses.35 And researches on skeletal muscle cells suggested that -catenin was involved in regulating glucose transporter 4 containing vesicles recruitment by interacting with cadherin to support cortical actin remodeling at the cell membrane, which provided the physical structure to facilitate the movement of vesicles within the cell.36 Previous work had also identified a role for -catenin and cadherins in actin remodeling to facilitate insulin vesicle trafficking in pancreatic -cells.36 Thus, these findings suggested that -catenin was a regulator of vesicle trafficking and acted as a signaling intermediate controlling actin remodeling in multiple tissues. In keratinocytes, it was demonstrated previously that UVB enhanced the protein expression of -catenin.37 In the present study, our results confirmed the increased accumulation of -catenin by UVR in keratinocytes and illustrated that the UVR-induced enhancement of -catenin was regulated by TRPA1. What is more, the alteration of -catenin regulated by TRPA1 affected UVR-induced keratinocyte phagocytosis. Therefore, we proposed that UVR interacted with TRPA1 increased the expression of -catenin which promoted keratinocyte phagocytosis, most likely by enhanced cellcell adhesion and cytoskeleton dynamics mediated by -catenin (Figure 5). In addition, our observations on UVB-induced guinea pig skin pigmentation suggested that the inhibition of -catenin possessed skin lightening effect in vivo, which indicated the therapeutic potential of -catenin for skin pigmentary diseases (such as melasma).

In conclusion, the data presented herein demonstrated that UVR promoted keratinocyte phagocytosis and skin pigmentation by TRPA1 channels. We speculate that TRPA1 is activated by UVR to promote the increase of intracellular calcium, which causes the activation of CaMKII to affect the remodeling of F-actin, contributing to keratinocyte phagocytosis. Furthermore, TRPA1 activated by UVR upregulates the expression -catenin to enhance skin pigmentation by cellcell adhesion and cytoskeleton dynamics. These findings suggest that TRPA1 may be a potential therapeutic target for UVR-induced skin pigmentary diseases.

This work was supported by the National Natural Science Foundation of China [No. 81773305 and No. 82073416].

The authors report no conflicts of interest in relation to this work.

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UVR Promotes Keratinocyte Phagocytosis and Skin Pigmentation Through T | CCID - Dove Medical Press