Alopecia is an autoimmune disorder where immune cells attack and destroy hair follicles, causing hair loss. Uncovering a molecular target of a common treatment for alopecia in a new study, scientists at the Salk Institute claim regulatory T cells (Tregs) and glucocorticoids do not just suppress the immune system, they also make hair grow.

Originally discovered as a specialized subset of T lymphocytes that suppress excessive immune response and maintain balance in immune functions, recent studies have shown Tregs also play a role in tissue repair and regeneration.

First author of the study, Zhi Liu PhD, a research associate at Salk Institute said, We were fascinated by Tregs non-traditional function in tissue repair and the way they communicate with tissue stem cells to facilitate tissue regeneration.

Balance in tissue niches depends on communications between stem cells and supporting cells. That Tregs communicate with stem cells and play a critical role in balancing self-renewal and differentiation in stem cell niches has been reported in earlier studies. Yet, how Tregs sense signals in tissue microenvironments and communicate with stem cells has been unclear until now.

Liu said, Our study identified the glucocorticoid hormone as the upstream signal that alerts Tregs, and the growth factor TGF-beta3 as the downstream signal that promotes stem cell activation and hair regeneration. These signals could be potentially conserved in other tissue injury and repair processes.

The study, led by Ye Zheng, PhD, an associate professor at Salk Institute for Biological Studies in La Jolla, California, was published on June 23, 2022, in an article in the journal Nature Immunology titled Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche. The findings explain how Tregs interact with stem cells in the skin using the steroid hormone glucocorticoid as a messenger to generate new hair follicles and promote hair growth. This regenerative role of Treg cells is independent of its immunosuppressive functions.

Zhengs team was initially interested in uncovering the role of Tregs and glucocorticoids in autoimmune dysfunctions such as multiple sclerosis, Crohns disease, and asthma. However, they detected no functional significance of glucocorticoids or Tregs in these diseases. They then focused on the skin because here Tregs express high levels of glucocorticoid receptors.

The researchers shaved hair off the back of adult mice that lacked the gene encoding the glucocorticoid receptor in their Tregs or had a normal set of genes. After two weeks, the normal mice grew back their hair, but the mice without glucocorticoid receptors barely could, said Liu. It was very striking, and it showed us the right direction for moving forward.

The findings indicated a glucocorticoid-mediated communication between Tregs and stem cells in hair follicles that need to be activated for hair regeneration. Moreover, the authors showed lack of the glucocorticoid receptor in Tregs blocked hair regeneration without affecting immune balance.

After hair loss, skin cells stained blue, from a normal mouse can activate hair follicle stem cells, stained red [left], whereas skin cells in mice without glucocorticoid receptors in their regulatory T cells cannot activate hair follicle stem cells [right] (Salk Institute).The authors found glucocorticoids instruct Tregs to activate hair follicle stem cells (HFSCs), which leads to hair growth. This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors cooperate with a regulatory protein in Tregs called Foxp3, to induce a growth factor called transforming growth factor beta3 (TGF-beta3), which then activates the signaling molecules Smad2/3 in HFSCs to stimulate stem cell proliferation and differentiation into new hair follicles, promoting hair growth. The authors uncovered Tregs dont usually produce TGF-beta3, as they do in the skin. Databases analysis revealed this phenomenon occurs in injured muscle and heart tissue, similar to how hair removal simulated a skin tissue injury in this study.

In acute cases of alopecia, immune cells attack the skin tissue, causing hair loss. The usual remedy is to use glucocorticoids to inhibit the immune reaction in the skin, so they dont keep attacking the hair follicles, said Zheng. Applying glucocorticoids has the double benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, stimulating the activation of the hair follicle stem cells.

In future studies, Zheng and his team would like to explore whether compromised glucocorticoid signaling in Tregs of the skin can cause alopecia. Zheng said, It will be interesting to see if skin Treg cells can be targeted for the treatment of alopecia patients.

Beyond the regeneration of hair follicles, Zheng would like to build upon studies that have shown Tregs help repair and regenerate multiple tissue types. They will study other injury models and isolate Tregs from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.Wed like to explore whether glucocorticoids function as a universal signal to trigger Tregs non-traditional function to promote tissue regeneration.

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Hair Regeneration Requires Regulatory T Cells Signal Skin Stem Cells - Genetic Engineering & Biotechnology News

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Research into the retina and optic nerve using stem-cell models has unveiled specific genetic markers of glaucomathe worlds leading cause of permanent blindness possibly opening up new treatments for the condition.

Glaucoma is a blanket term describing a group of eye conditions that do damage to the retinal ganglion cellsneurons near the inner eye that make up the optic nerve. The optic nerve is the part of the eye that receives light and transmits it to the brain; thus, the damage that glaucoma does leads to permanent blindness. Thecondition is predicted to affect around 80 million people by 2040, yet treatments are extremely limited.

This study linked 97 genetic clusters to the damage done by the most common form of glaucoma, primary open-angle glaucoma or POAG, revealing important genetic components that control the way the condition attacks. POAG is a genetically complicated condition that is likely hereditary and, at the moment, cannot be stopped or reversed. The only treatment of POAG available involves releasing pressure on the eye, and this will only slow down the condition.

The research project was led jointly by the Garvan Institute of Medical Research, the University of Melbourne, and the Centre for Eye Research Glaucoma.

We saw how the genetic causes of glaucoma act in single cells, and how they vary in different people, said joint lead author of the study and Melbourne University academic, Prof. Joseph Powell, in a Garvan Institutemedia release.

Current treatments can only slow the loss of vision, but this understanding is the first step towards drugs that target individual cell types, Powell said.

The research behind the discoverywas published in the journalCell Genomicsand wasthe result of a lengthy collaboration between Australian medical research centres involving the investigation of complicated diseases and their underlying genetic causes, using stem-cell modelling; which the researchers said demonstrated the success of this study and the power of this approach.

Previously, glaucoma research was limited because samples of the optic nerve could not be obtained from participants in a non-invasive fashion. However, stem-cell modelling addressed this issue as it allowed researchers to develop optic nerve samples from skin, a much easier part of the body to extract.

The team administered skin biopsies on183 participants, 91 of whom had advanced primary open-angle glaucoma, to gather skin cells that they could reprogram to revert into stem cells and then guide into becoming retinal cells. Of the 183 samples collected, 110 samples, 54 from participants with POAG, were successfully converted from skin cells into retinal, and over 200,000 of these converted cells were sequenced to generate molecular signatures.

The researchers of this study employedsingle-cell RNA genetic sequencing in order to study individual cells. This form of sequencing creates an incredibly detailed genetic map, which looks for genetic variations that affect the expressionthe process of turning instructions from DNA into functional products like proteins of one or more genes. Through identifying these key genes, further deductions on the influence that genetic variations have on glaucoma can be made.

The signatures of those with and without glaucoma were compared to establish key genetic components that control the way that glaucoma attacks the retina.

The researchers first identified, using the signatures of both those with and without glaucoma,312 genetic variants associated with the ganglion cells that eventually degenerate in a person living with POAG. Further analysis of the genes associated with POAG linked the 97 clusters mentioned above to the damage done by glaucoma.

Another joint-lead author of the paper and Melbourne University professor, Alice Pebay, said that by studying glaucoma in retinal cells, a context-specific profile of the disease was created.

We wanted to see how glaucoma acts in retinal cells specificallyrather than in a blood sample, for instanceso we can identify the key genetic mechanisms to target, Pebay said.

Equally, we need to know which genetic variations are healthy and normal, so we can exclude them from a treatment.

To improve the understanding of complex conditions such as glaucoma, researchers noted it was important to establish a profile of the disease which promotesthe understanding of causes, risks and fundamental mechanisms of diseases. Furthermore, genetic investigations are critical to drug development and pre-clinical trials because they assist in constructing complete human models of diseases.

University of Tasmania professor and a third joint-lead author of the paper,Alex Hewitt said that the findings of this study set up future research into novel glaucoma treatments.

Not only can scientists develop more tailored drugs, but we could potentially use the stem-cell models to test hundreds of drugs in pre-clinical assays, said Hewitt.

This method could also be used to assess drug efficacy in a personalised manner to assess whether a glaucoma treatment would be effective for a specific patient.

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Secrets of Permanent Blindness Revealed by Stem-cell Research - The Epoch Times

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This is the season to soak up the warm, wonderful sun and show off our glowing skin in shorts, tanks and bathing suits.

But this time of year can be most treacherous for skin we can get blasted by everything from poison ivy and mosquitoes to sunburns if were not careful. And even just a little bit of extra sun means we should be doubling down on our hydration and moisturizing, and pulling out the big-gun products to help keep our skin safe.

One of my new favorite products is Lancme Rnergie H.C.F. Triple Serum ($135 on Lancome-usa.com) Its a triple-dose serum that targets volume loss, wrinkles and dark spots, and helps prevent damage with hyaluronic acid, vitamin C+, niacinamide and ferulic acid. That means its a gel, a cream and an emulsion a combo that results in both hydration and moisturizing (the first adds water; the second softens dry skin, so theyre not the same things, and we do indeed need both).

And if the aforementioned glowing is on your summer skin to-do list, then reach for Pat McGrath Labs Divine Skin: Rose 001 The Essence ($86 on Patmcgrath.com). It boosts moisture big-time, illuminates, softens and smooths with natural floral ingredients. Apply it to your face in between cleansing and moisturizing every morning to nourish and replenish the skin barrier, There are zero silicone, parabens, sulfates, gluten, mineral oil and phthalates.

Onto sunscreens. For starters, make SPF a year-round thing, if you havent already. Its your safeguard against hyperpigmentation, inflammation, fine lines and, yes, skin cancer. Use it on your face all year, and then on your body too, especially this time of year. Get one with broad-spectrum coverage (to shield you from both UVB rays that cause burning and UVA rays that cause lasting damage) and with an SPF of 30 or higher. And choose one that smells good, if you have the option. On that front, Chanels UV Essentiel ($55 on chanel.com) is as light in texture as it is in its fragrance a delicate floral that smells fresh as can be.

For anyone with acne-prone skin, non-oily formulas are imperative. Look for liquid sunscreens instead of thick creams that clog pores. A great choice is TIZO 2 Non-Tinted Facial Mineral Sunscreen SPF 40 ($43 on amazon.com).

And if youre in the opposite situation and concerned about dry skin instead go in big for moisturizing and hydration, with EleVen by Venus Williams: Natural Unrivaled Sun Serum ($50 on elevenbyvenuswilliams.com). Its a lightweight mineral protection, SPF 35 and is safe for reefs (so wear it on any beach you like before swimming), cruelty-free, and vegan. It also blends in incredibly well, has a velvety finish, and contains prickly pear extract, to hydrate and soothe inflamed skin in case youve gotten a sunburn.

For sunburns, an RX treatment may be in order. At my day spa, GSpa at Foxwoods, we offer a Soothing Facial ($175 for 50 minutes at foxwoods.com) that uses antioxidants, peptides and botanical stem cells. Each of those ingredients protects the skin from free radical damage and restores hydration soothing and refreshing dry and sensitive skin.

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Youve got skin in the game protect it from summer sun damage - Boston Herald

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BENGALURU: Vitiligo, a skin de-pigmentation disorder which affects 0.1 to 8% of population, is a cause of worry especially for women as it mainly affects face, neck and hands. It relapses in 40% of patients, within a year after stopping treatment. But Mesenchymal stem cell-based therapy can be a hope, experts say.

On World Vitiligo Day on Saturday, dermatologist, Aster R V Hospital, Dr Sunil Prabhu said the disorder is affecting at least 2.16% of children/adolescents. Vitiligo is a long-term condition, where pale white patches develop on the skin due to lack of melanin pigment. According to Dr Praveen Bharadwaj, dermatology consultant, Manipal Hospital, Whitefield, vitiligo is a condition in which the patients immune system weakens which affects the normal functioning of melanin producing cells.

Dr Bharadwaj explained, Mesenchymal stem cells, which are multi-potent adult stem cells, are found in bone marrow, fat tissues, umbilical cord and human foreskin. They are promising agents for therapy for the re-pigmentation of skin in vitiligo. This therapy reduces the main trigger of vitiligo that is immune-mediated melanocyte degeneration (stopping the immune destruction of melanocytes which produces melanin), promotes melanocytes and prevents relapse of the condition, he said.

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Experts offer hope to vitiligo patients - The New Indian Express

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Collagenits the fountain-of-youth protein that makes skin smooth and plump by stimulating tissue growth. But as the body ages and slows down its own collagen production, many turn to supplements for a fix. The downside? Theyre usually made using animal bones, skin, and cartilage. Gross. Thankfully, vegan alternatives that boost our bodys natural collagen production or actually replicate the amino acids in animal-derived collagen are totally in fashion.

Collagen is a protein the body makes naturally that can be found in hair, skin, nails, and bones. The protein is vital for keeping bones strong and skin looking wrinkle-free, and as you age, your body naturally slows down the production of collagen. The much-buzzed-about beauty trend usually refers to the intake of animal-sourced collagen that typically comes animal bones, skin, and cartilage.

There are many ways to boost your bodys collagen by eating foods high in vitamin C, zinc, and copper. These nutrients can be found in foods such as beans, oranges, broccoli, and tomatoes. As demand for plant-based collagen grows, brands are stepping up to create completely vegan collagen using genetically modified yeast and bacteria. Other innovative brands like Geltor are also utilizing high-tech methods to create vegan collagen that will be more widely available in the future. Geltors Type 21 collagen begins with a set of microbes that naturally produce proteins, which are programmed to make collagen without sourcing it cruelly from animals. Its first protein product, Collume, launched in 2018 for use in skincare formulations.

In the meantime, weve rounded up six products thatll give you the best beauty bang for your buck.

Andalou Naturals

Using a first-of-its-kind, bio-designed vegan collagen from tech company Geltor, this nourishing eye cream boasts unparalleled improvement in skin moisture. Apply day and night to let the collagen, hyaluronic acid, and fruit stem cells work their magic to revitalize tired under-eyes.Learn more here

Pacifica Beauty

A mascara that keeps lashes looking thicker and healthier after taking it off may seem too good to be true, but not when vegan beauty brand Pacifica is on the case. Formulated with vegan collagen and plant-based fibers, this glossy, black formula is a must-have for your beauty bag.Learn more here

Moon Juice

For those looking to preserve their natural collagen, why not drink it with your morning cup o joe? With this three-ingredient coffee creamer, supple skin and minimized fine lines are just a sip away thanks to a powerful combination of rice bran, silver ear mushroom, and salt of hyaluronic acid.Learn more here

Follain

A concentrated blend of niacinamide, bakuchiol (a plant-derived retinol alternative), and a peptide complex work together to bring out smoother, firmer skin and tackle signs of aging in this velvety-soft serum. Layer under moisturizer every morning and night to reap the benefits.Learn more here

Carrot & Stick

With a powerful formulation of plant proteins, vitamins, amino-collagen, and alpine rose stem cell extract, this lightweight antioxidant moisturizer nourishes skin to help smooth lines and wrinkles without any unwanted sulfates, parabens, or phthalates.Learn more here

Sourse

Chocolate and beautycould there be a better combo? An infusion of skin-boosting collagen powder and detoxifying spirulina in this low-sugar, functional dark chocolate means were just two heavenly bites away from improved skin texture and elasticity.Learn more here

For more on vegan beauty, read:The VegNews Vegan Beauty AwardsThe 8 Best Vegan Hydrating Skincare ProductsThe 10 Colorful, Vegan Makeup Products for Summer

Aruka Sanchir(@ruukes) is the Beauty & Style Editor at VegNews who is always looking for exciting new vegan products to test out.

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What Is Vegan Collagen? And the 6 Best Products to Try - VegNews

Skin Stem Cells Comments Off on What Is Vegan Collagen? And the 6 Best Products to Try – VegNews | June 30th, 2022

Acute chest syndrome (ACS) is a potential complication of sickle cell disease (SCD). It involves the sudden onset of respiratory symptoms, which may lead to lung injury.

SCD is an inherited disorder that affects red blood cells. In people with SCD, red blood cells are crescent- or sickle-shaped instead of disc-shaped. This impairs their ability to carry oxygen and causes them to stick together.

A person with SCD may develop ACS if sickle cells stick together to form a blood clot in the small blood vessels within the lungs. Other possible causes include viral and bacterial lung infections and postsurgical complications.

The article below takes an in-depth look at ACS, including its causes, treatment, and prevention.

ACS is a serious and potentially life threatening condition involving sudden, severe respiratory symptoms and reduced blood oxygen levels. The condition is a potential complication of SCD.

According to the Centers for Disease Control and Prevention (CDC), the most common symptoms of ACS include:

Red blood cells contain a protein called hemoglobin, which binds to oxygen. Healthy red blood cells are disc-shaped, allowing them to move freely through blood vessels to deliver oxygen to the bodys tissues and organs.

In those with SCD, the hemoglobin inside red blood cells is abnormal and causes the cells to take on a characteristic sickle shape. These cells do not move through the blood vessels in the typical way and have a tendency to clump together.

A person with SCD may develop ACS as a result of sickle cells blocking a pulmonary blood vessel within the lungs. The Sickle Cell Disease Association of America notes that oxygen deprivation within the lungs can result in permanent lung damage. In some cases, ACS is life threatening.

Various factors can cause or contribute to ACS in SCD. Examples include:

In children, doctors are able to identify the cause of ACS in about 40% of cases. In the other cases, the triggering event is unclear.

According to the National Heart, Lung, and Blood Institute, more than 100,000 people in the United States have SCD. There are several types of SCD, each of which involves different gene mutations. According to a 2022 literature review, people with certain genotypes hemoglobin SS (Hb SS) and Hb S-beta0-thalassemia have an increased risk of developing ACS.

Some additional factors that may increase a persons risk of developing ACS include:

A diagnosis of ACS relies on both clinical symptoms and imaging tests.

Clinical symptoms that may indicate a diagnosis of ACS include:

Doctors may perform several tests to help rule out other illnesses and confirm a diagnosis of ACS. Examples include:

Without treatment, ACS may progress rapidly. Early treatment reduces the risk of complications and death.

Most people with ACS require hospitalization for careful respiratory monitoring and treatment. According to a 2017 review, treatment may include the following:

An individual cannot eliminate all risk factors for ACS. For example, people with certain genotypes of SCD have an increased risk of developing ACS. This is a nonpreventable risk factor.

However, people can take steps to reduce their risk of developing ACS. These include:

A 2017 study notes that almost half of all ACS cases develop during hospitalization. In this study, the frequency of an ACS diagnosis decreased from 22% to 12% after implementing a protocol for using incentive spirometry during hospital stays.

Among people with SCD, ACS is the second most common cause of hospitalization and one of the most common causes of death. The condition has a mortality rate of 4.3% in adults and 1.1% in children.

The outlook for people with ACS varies according to the nature and extent of any complications. Possible complications include:

The condition can also be fatal.

According to the British Society for Haematology (BSH), a person who develops ACS will require follow-up treatment, which may include blood transfusions or the chemotherapy agent hydroxycarbamide, which is also known as hydroxyurea.

Acute chest syndrome is a complication of sickle cell disease. People with ACS develop sudden respiratory symptoms, including chest pain and breathing difficulties, along with coughing, wheezing, or rales.

A person with SCD may develop ACS as a result of sickle cells sticking together and forming a blood clot within a pulmonary blood vessel. The condition can also occur due to a viral or bacterial infection, asthma, or complications following surgery.

ACS is a severe and potentially life threatening condition. However, people who receive prompt treatment tend to have a much more favorable outlook. As such, it is important that people with SCD familiarize themselves with the symptoms of ACS so that they can recognize and act on the warning signs, should they occur.

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Acute chest syndrome and sickle cell disease: What is the link? - Medical News Today

Skin Stem Cells Comments Off on Acute chest syndrome and sickle cell disease: What is the link? – Medical News Today | June 30th, 2022

The biotechs all new neurorestorative approach aims to rebuild and replace lost brain cells in Alzheimers that underlies clinical symptoms.

On the back of the trial, the company plans to launch a world-first human trial in 2024.

The veterinary trial, led by Skin2Neuron and published this month in Stem Cell Research and Therapy, reversed the dementia-like syndrome that strikes down many older pet dogs with Alzheimers.

Dementia was reversed in more than half of the canine patients, with a clinically meaningful improvement in 80%. Typically, improvement lasted around two years.

Skin2Neuron champions its new approach as a ray of hope for Alzheimers disease: championing a completely different approach to the amyloid hypothesis of Alzheimers disease.

Our target is the ultimate cause of dementia: lost neurons and synapses. We do this by microinjecting a patients own HFN cells directly into the hippocampus, the brains memory center and first area to be devastated by Alzheimers, explains the company.

While its lead therapeutic target is Alzheimers, it says its technology also has potential to treat neurodegenerative conditions such as Parkinsons disease, Amyotrophic Lateral Sclerosis and more.

A dogs thinking neocortex and hippocampus is similar to the human brain, says the company. Meanwhile, older dogs often develop a dementia syndrome similar to human dementia: becoming forgetful, irritable, lost, wandering around aimlessly, failing to recognize owners and experiencing disrupted sleep.

"Because of deep parallels between the canine brain and human brain, and canine Alzheimer's and human Alzheimer's, I started this trial 10 years ago with the assumption that if it's going to work in humans, then it needs to work in dogs first. And the results exceeded my wildest expectations, said co-founder Professor Michael Valenzuela.

"The hippocampus, the memory center of the brain, was packed with baby neurons and new synapses, precisely where we delivered the cells. Compared to untreated dogs, it was like night and day".

Microscopic analysis confirmed the dogs had classic Alzheimer pathology: meaning the cell therapy worked in the setting of natural disease, a first of its kind, according to the company.

"Given our doggie patients also had many of the same health issues that older people face, it gives me even greater confidence," said Valenzuela.

Study:Valenzuela, M., Duncan, T., Abey, A.et al.Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.Stem Cell Res Ther13,261 (2022). https://doi.org/10.1186/s13287-022-02933-w

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'A new Alzheimer's treatment is on the horizon': Cell therapy reverses dementia-like syndrome in dogs - BioPharma-Reporter.com

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In his February 2, 2022 column in the Palestinian daily Al-Ayyam, journalist 'Abd Al-Ghani Salameh contrasted the scientific breakthroughs taking place in the world today with the situation of the Arab and Muslim world, which he said is mired in backwardness, chaos and internal strife, stemming from an obsolete thinking and hostility towards the West. If this situation persists, he said, the Arab peoples may find themselves in danger of extinction.

'Abd Al-Ghani Salameh (Source: Hadfnews.ps)

The following are translated excerpts from his article:[1]

"Over the last two decades, scientists have made great strides in all areas. Some [of the developments] changed our lives completely, while others brought about a smaller change, but all of them had a significant impact on the future of humanity, laying the foundations for a completely new era and a historic turning point. Just as the steam engine launched the Industrial Revolution and the discovery of electricity led to the invention of countless apparatuses, the internet launched the era of the information and media revolution.

"The achievements of this [20-year] period, a very short time in the life of humanity, are even more important than the achievements of the previous eras. Their significance lies in their potential to bring change, just like the earlier inventions and discoveries

"The following is a summary of the most important achievements [of the last two decades]. The most significant, and also the most expensive, was the establishment of the European Organization for Nuclear Research, CERN, on the border between Switzerland and France, built through the most extensive international scientific cooperation since [the construction of] the international space station. [Housing] the world's largest particle accelerator, 27 km long, it is meant to provide a better understanding of the emergence of the cosmos by simulating the Big Bang

"In the realm of space [exploration], the giant James Webb Telescope was recently launched into orbit and will replace the Hubble Telescope. It is the fruit of 25 years of labor by scientists from NASA and the Canadian and European space agencies, and it is hoped to provide answers to many questions that have preoccupied humanity Scientists have also discovered the closest planet to earth that may be hospitable to life, although it is very far away, and a black hole has been photographed for the first time, in the center of a faraway galaxy. The Phoenix space probe landed on the surface of Mars and took detailed photos of the Red Planet while the Voyager I Space probe continues its journey to the edges of the cosmos

"The most important medical development, which will take biology to another level, is the complete mapping of the human genome, and the discovery of the molecular structure of human [DNA]. This breakthrough allowed the development of synthetic biology, and scientists have managed to create the first living organism using synthetic DNA Also in the field of medicine, American and Japanese scientists managed to clone human stem cells from skin cells, in a way that does not violate any ethical principles and ensures that the body will not reject them. Using these stem cells, they developed the first complete cure for diabetes. The first artificial heart was developed as well as well as a smart prosthetic hand that can be controlled by the mind.

"In the realm of technology, there were incredible breakthroughs in the area of carbon nanofibers, artificial intelligence and robotics; the 3D printer and Bluetooth technology were developed as well as smart surfaces, virtual keyboards, touch screens, smartphones, social media and audiovisual media. Ecommerce is thriving, and distributers like Amazon and Alibaba have emerged. Electric and hybrid cars, as well as self-driving cars, are being made, Google has mapped every part of the [planet] and all its road systems using GPS, and the G5 internet has arrived

"If we go into detail, we will find dozens of additional important inventions and discoveries. But more important is that we [Arabs] understand our situation compared to the world. Where do we stand, and where are we headed? How far can we go?... It is important to give some profound thought to our local reality and remember our [own] achievements in the last [20] years, [namely] the growing corruption of the Arab regimes, which triggered the Arab Spring revolutions that produced a reality no less corrupt. Throughout these years and before them, we have been mired in backwardness, chaos, civil war, bombings, terror, tribal and sectarian conflict and the reduplication of totalitarian regimes. This is due to the fact that we refuse to even acknowledge the problem and are unable to understand its essence, for we are trapped in an obsolete Salafi mentality and are hostile to the entire world, refusing to integrate in the [global] human culture. The truth, gentlemen, is that we Arabs and Muslims are isolated from the world and from reality, light years removed from the train of progress. True, many recent inventions and discoveries were produced by Arab scientists, but they were made in laboratories and research centers located in the 'infidel' West. If we stay on this course, we will be among the peoples in danger of extinction."

[1] Al-Ayyam (Palestinian Authority), February 2, 2022.

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Palestinian Journalist: The Arab And Muslim World Is Mired In Backwardness, Light Years Behind The World's Rapid Development - Middle East Media...

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Retinol has been shown to increase collagen production, eradicating fine lines and wrinkles. Cop these top retinol eye creams right now.

This goes without saying dermatologists adore retinol.

The vitamin A derivative has been shown to increase collagen production, eradicating fine lines and wrinkles. When it comes to your eyes, however, a product created particularly for the delicate skin around the eyes is preferable to your normal retinol cream. So weve compiled a list of the top retinol eye creams you should be using right now.

Because it has the thinnest skin on the body, the under-eye region is extremely sensitive. According to experts, retinol in this region may be overly irritating and, if not used correctly, might potentially induce inflammation. If youre concerned about irritation, only apply the product in the evening. Retinols have traditionally been used at night because UV exposure can inactivate vitamin A derivatives, and retinols can make the skin more UV sensitive, according to dermatologists.

When used on a daily basis, retinol will tighten and smooth the skin beneath and around your eyes. The best part is that there are so many eye cream compositions available that there is no need to use a one-size-fits-all strategy. Instead, we discovered 8 retinol eye products, each of which addresses a distinct issue while leaving all skin types smooth, moisturised, and irritation-free.

Charlottes Magic Eye Rescue dramatically enhances elasticity and firmness with a cocktail of cell-energising winter daphne stem cell extract, rice and soy peptides, saccharide isomerate and free radical-fighting vitamins A, C and E all alongside a proprietary botanical eye contour complex that works to increase stretch, resilience and density for younger-looking eyes. Reparative and protective, this replenishing cream has an instant skin-smoothing and lifting effect ideal for disguising signs of a too-late night while the inclusion of moisturising coconut oil and shea butter helps to lock in precious moisture to restore skins bounce and softness.

Intensely nourishing, this luxurious Avocado Melt Retinol Eye Sleeping Mask is crammed with moisturising, age-defying and brightening ingredients to leave you looking bright eyed and bushy tailed in the morning. Rich in antioxidants including conditioning vitamins E and C, avocado oil and extract soothe and nourishe the delicate under-eye area while protecting it against harmful environmental aggressors like free radicals.

Other hard-working ingredients include niacinamide, which helps to strengthen the skins barrier while visibly improving the appearance of dullness, fine lines and wrinkles, along with caffeine-laced coffeeberry to reduce puffiness and dark circles. The star of the show? Encapsulated retinol, which helps to firm, smooth and plump fine lines and wrinkles without the harsher side effects often associated with retinol.

Vitamin A derivatives have been proven to work at the cellular level to brighten skin and stimulate collagen production. The INKEY List Retinol Eye Cream offers an alternative to traditionally irritating retinoids: a ground-breaking slow-release formula plus rich but lightweight oils so its gentle enough to use around the eyes. This night-time eye cream is formulated with Shea Butter to moisturise and soothe while also reducing the appearance of fine lines and wrinkles. Its an eye cream that actually works.

This quick-absorbing serum features the brands signature Phyto-Retinol Blend that targets signs of ageing around the eyes through three methods of firming skin, boosting hydration, and reducing the look of fine lines. Besides retinol, bakuchiol, rambutan, and ferulic acid also work their magic to smoothen out visible wrinkles.

A supercharged treatment for skin that shows signs of a cellular slow-down, this revitalising serum is jam-packed with instant and time-released retinol to rev your cells engines and rapidly minimise lines while recovering radiance. From firmness to furrows and texture to tone this breakthrough formula has a rapid impact; smoothing and softening wrinkles and boosting resilience, leaving your face looking less lined and youthfully dewy. Created to deliver results without retinols side-effects, this non-irritating elixir is great for all skin types

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This silky, weightless eye cream improves the appearance of skin firmness, texture and elasticity and reduces the appearance of lines and wrinkles around the eye area. It firms with retinol and bioretinols, natural ingredients that mimic the effort of retinol but with less sensitivity. Hyaluronic acid increases hydration and helps smooth the appearance of skin.

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Introduction

Spiradenoma is a rare type of adnexal tumors originating from the eccrine glands.1,2 The etiology remains unknown. This condition was first introduced by Kersting and Helwig in 1956.1 Its clinical features consist of skin-colored, erythematous, gray, or bluish2 nodules1 accompanied with pain.1,2 The lesions of spiradenoma are generally solitary,1 with the most common predilection being on the ventral part of the body,3 especially on the upper part of the trunk.1 Atypical clinical features of spiradenoma may occur as multiple lesions arranged in a linear or zosteriform arrangement.2,3 Spiradenoma can occur at any age,1 most commonly between 15 and 35 years old.2 There is no difference of incidence among genders.1,2 There are various therapeutic modalities for spiradenoma, including surgical excision, dermabrasion, electrodesiccation, cryosurgery, radiotherapy, and CO2 laser.2,4 However, the efficacy of some of these modalities has not been determined.4 In 2013, Gordon et al5 in the United States reported a case of spiradenoma treated using injection of triamcinolone acetonide (TA) 10 mg/mL with minimal improvement. Gottschalk et al6 administered TA 40 mg/mL in one case of adnexal tumor with a 75% reduction in lesion size. This study aims to report a rare case of giant spiradenoma which was treated by 10 mg/mL TA injection.

A 31-year-old man presented with giant painful skin-colored and erythematous nodules on his left eyelid and left temple (Figure 1A). The lesion first appeared 15 years prior to consultation as a skin-colored papule on the left eyelid which enlarged into a nodule after 5 years. New nodules appeared on his left temple around 5 years ago and grew larger one year prior. There was no other significant past medical or family history. Dermatological examination revealed firm, skin-colored nodules with smooth surface and well-defined boundaries, painful upon palpation, measuring 1.52.8 x 0.3 cm and 1.61.7 x 0.4 cm. We performed a punch biopsy on the left temple. The histopathological result revealed a tumor mass consisting of round to oval cells with hyperplastic, compact, and nodular characteristics. Some cells formed a tubular structure, and some appeared paler and larger. The cells had monomorphous nuclei with few inflammatory cells. There were no signs of malignancy (Figure 2A and B). The patient refused surgical therapy. Therefore, we performed intralesional injection of 10 mg/mL TA, consisting of five injections per visit. After four sessions of TA injections with one month interval, the lesions grew thinner and smaller and the pain disappeared (Figure 1B). There were no side effects reported.

Figure 1 (A) Clinical manifestations of spiradenoma in the form of skin-colored and erythematous nodules on the left eyelid and left temple before triamcinolone acetonide injection. (B) Spiradenoma lesions after triamcinolone acetonide injection.

Figure 2 Histopathological findings. (A) Red arrow shows one tumor mass. (B) Tumor mass consisted of round, oval cells showing hyperplastic, compact, and nodular characteristics. Some formed a tubular structure. Some cells appeared paler and larger.

Adnexal tumors are classified based on their differentiation in forming skin adnexal structures into eccrine, apocrine, follicular, and sebaceous gland tumors. They are further divided into benign and malignant types. Benign tumors of the eccrine glands include cylindroma, hidradenoma, syringoma, poroma, and spiradenoma.3 There was no report on the prevalence of spiradenoma worldwide. It is considered to be a very rare disease.1,2

The exact etiology and pathogenesis of spiradenoma are unknown. It is suspected that a defect in the tumor suppressor gene plays a role in this disease.2 Several recent hypotheses have been proposed regarding spiradenoma, including abnormal multipotent stem cells in the folliculosebaceous unit and trauma as a triggering factor.7

Spiradenoma is characterized by skin-colored, erythematous, gray, or bluish2,3 nodules1 accompanied by pain.1,2 The lesions are generally solitary,1 and are often found on the ventral part of the body,3 especially the trunk.1 Our case of spiradenoma manifested as painful skin-colored and erythematous nodules on the patients face. This is in accordance with the signs, symptoms, and predilection of spiradenoma.

Some tumors of the skin are difficult to diagnose clinically due to the lack of external characteristics that allow recognition through inspection alone. Several painful subcutaneous tumors which can be considered as differential diagnoses are spiradenoma, neuroma, glomus tumor, leiomyoma, angiolipoma, neurilemmoma, and dermatofibroma.8 Histopathological examination is therefore necessary to establish the diagnosis of spiradenoma.9 The histopathological features of spiradenoma include non-capsulated dermal neoplasms with single or multinodular nodules,10 consisting of basaloid cells, arranged in a tubular structure.3 There are two types of cells that can be found: small basaloid cells with hyperchromatic nuclei and little cytoplasm located at the edge of the nodules, and large basaloid cells with vesicular nuclei and pale cytoplasm located in the center of the nodules.3,8,10 Lymphocytes are also scattered throughout the tumor.3 The histopathological examination result in our case supported the diagnosis of spiradenoma.

Surgical excision is the current gold standard for treating spiradenoma with low recurrence rates. Meanwhile, the efficacy of several other therapeutic modalities has yet to be determined.4 Several investigators had studied other less invasive therapies for spiradenoma. In 2013, Gordon et al5 in the United States reported a case of spiradenoma treated using intralesional 10 mg/mL TA injection, but there was minimal improvement. Gottschalk et al6 treated a skin adnexal tumor with intralesional 40 mg/mL TA injection. A total of 1 mL of 40 mg/mL TA aqueous suspension was injected into a single 4 cm lesion. After one injection, the size of the tumor was reduced by 75%.6 Steroid use in this case aimed to reduce inflammation that can be associated with pain.5 Corticosteroids have anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.11 The intralesional skin injection method was chosen to achieve a localized corticosteroid concentration in the lesion with less systemic absorption, thereby avoiding systemic side effects. The mechanism of how intradermal steroid affects the course of the disease remains unknown.12 Our patient was treated with intralesional 10 mg/mL TA injections due to refusal to undergo surgery. Improvement was observed after the fourth injection: the skin lesions became thinner and smaller. The pain also diminished.

Intralesional injection of TA can be a therapeutic option for spiradenoma patients who refuse surgical therapy. TA injection is easy to administer and showed good efficacy in spiradenoma case, although further research with a larger number of patients remains needed.

The publication of case images was included in the patients consent. Institutional approval to publish case details has been obtained.

The authors have obtained all appropriate patient consent forms. The patient signed a consent form for the publication of case details and images.

The authors would like to thank the entire staff of the Dermatology and Venereology Department, Faculty of Medicine, Universitas Padjadjaran Hasan Sadikin General Hospital Bandung, West Java Indonesia.

The authors report no conflicts of interest in this work.

1. Kanwaljeet S, Chatterjee T. Eccrine spiradenoma: a rare adnexal tumor. Indian J Cancer. 2017;54(4):695. doi:10.4103/ijc.IJC_301_17

2. Dhua S, Sekhar DR. A rare case of eccrine spiradenomatreatment and management. Eur J Plast Surg. 2016;39(2):143146. doi:10.1007/s00238-015-1103-4

3. Foreman RK, Duncan LM. Appendage tumors of the skin. In: Kang S, Amagai M, Bruckner AL, Enk AH, Margolis DJ, McMichael AJ, editors. Fitzpatricks Dermatology. 9th ed. New York: McGraw-Hill; 2019:18201853.

4. Nath AK, Kumari R, Thappa DM. Eccrine spiradenoma with chondroid syringoma in Blaschkoid distribution. Indian J Dermatol Venereol Leprol. 2009;75(6):600. doi:10.4103/0378-6323.57723

5. Gordon S, Styron BT, Haggstrom A. Pediatric segmental eccrine spiradenomas: a case report and review of the literature. Pediatr Dermatol. 2013;30(6):e285e286. doi:10.1111/j.1525-1470.2012.01777.x

6. Gottschalk HR. Dermatological clinical conference scientific program for the 102nd annual session California medical association. Arch Dermatol. 1974;110(3):473479. doi:10.1001/archderm.1974.01630090095041

7. Englander L, Emer JJ, McClain D, Amin B, Turner RB. A rare case of multiple segmental eccrine spiradenomas. J Clin Aesthet Dermatol. 2011;4(4):38.

8. Naversen DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: LEND AN EGG. J Am Acad Dermatol. 1993;28(2):290300. doi:10.1016/0190-9622(93)70039-V

9. Sharma A, Paricharak DG, Nigam JS, et al. Histopathological study of skin adnexal tumoursinstitutional study in South India. J Skin Cancer. 2014;2014:14. doi:10.1155/2014/543756

10. Weedon D. Tumors of cutaneous appendages. In: Weedons Skin Pathology. 3rd ed. Brisbane: Elsevier Inc; 2010:758807.

11. Kerscher M, Williams S, Lehmann P. Topical treatment with glucocorticoids. In: Ring J, Przybilla B, Ruzicka T, editors. Handbook of Atopic Eczema. 2nd ed. New YorkSpringer-Verlag Berlin Heidelberg; 2006:477491.

12. Firooz A, Tehranchia-Nia Z, Ahmed AR. Benefits and risks of intralesional corticosteroid injection in the treatment of dermatological diseases. Clin Exp Dermatol. 1995;20(5):363370. doi:10.1111/j.1365-2230.1995.tb01351.x

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For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabrys, hemophilia, cystic fibrosis, muscular dystrophy, Huntingtons, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinsons disease, Alzheimers disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the samemutationcan be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial.

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilizestem cellswith the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viralvectorsmay infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue.Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This gene cassette is engineered into a vector or introduced into thegenomeof a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models.

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patients immune system.

If the new gene is inserted into the patients cellularDNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these insulator sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into safe areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability toself-renew and mature into the appropriate cells. Ideally extra cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to becomepluripotent stem cells(iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials.Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

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Stem cell technology will transform medical practice. While stem cell research has already elucidated many basic disease mechanisms, the promise of stem cellbased therapies remains largely unrealized. In this review, we begin with an overview of different stem cell types. Next, we review the progress in using stem cells for regenerative therapy. Last, we discuss the risks associated with stem cellbased therapies.

There are three major types of stem cells as follows: adult stem cells (also called tissue-specific stem cells), embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells.

A majority of adult stem cells are lineage-restricted cells that often reside within niches of their tissue of origin. Adult stem cells are characterized by their capacity for self-renewal and differentiation into tissue-specific cell types. Many adult tissues contain stem cells including skin, muscle, intestine, and bone marrow (Gan et al, 1997; Artlett et al, 1998; Matsuoka et al, 2001; Coulombel, 2004; Humphries et al, 2011). However, it remains unclear whether all adult organs contain stem cells. Adult stem cells are quiescent but can be induced to replicate and differentiate after tissue injury to replace cells that have died. The process by which this occurs is poorly understood. Importantly, adult stem cells are exquisitely tissue-specific in that they can only differentiate into the mature cell type of the organ within which they reside (Rinkevich et al, 2011).

Thus far, there are few accepted adult stem cellbased therapies. Hematopoietic stem cells (HSCs) can be used after myeloablation to repopulate the bone marrow in patients with hematologic disorders, potentially curing the underlying disorder (Meletis and Terpos, 2009; Terwey et al, 2009; Casper et al, 2010; Hill and Copelan, 2010; Hoff and Bruch-Gerharz, 2010; de Witte et al, 2010). HSCs are found most abundantly in the bone marrow, but can also be harvested at birth from umbilical cord blood (Broxmeyer et al, 1989). Similar to the HSCs harvested from bone marrow, cord blood stem cells are tissue-specific and can only be used to reconstitute the hematopoietic system (Forraz et al, 2002; McGuckin et al, 2003; McGuckin and Forraz, 2008). In addition to HSCs, limbal stem cells have been used for corneal replacement (Rama et al, 2010).

Mesenchymal stem cells (MSCs) are a subset of adult stem cells that may be particularly useful for stem cellbased therapies for three reasons. First, MSCs have been isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available (Deans and Moseley, 2000; Zhang et al, 2009; Lue et al, 2010; Portmann-Lanz et al, 2010). Second, MSCs can differentiate into a wide array of cell types, including osteoblasts, chondrocytes, and adipocytes (Pittenger et al, 1999). This suggests that MSCs may have broader therapeutic applications compared to other adult stem cells. Third, MSCs exert potent paracrine effects enhancing the ability of injured tissue to repair itself. In fact, animal studies suggest that this may be the predominant mechanism by which MSCs promote tissue repair. The paracrine effects of MSC-based therapy have been shown to aid in angiogenic, antiapoptotic, and immunomodulatory processes. For instance, MSCs in culture secrete hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) (Nagaya et al, 2005). In a rat model of myocardial ischemia, injection of human bone marrow-derived stem cells upregulated cardiac expression of VEGF, HGF, bFGF, angiopoietin-1 and angiopoietin-2, and PDGF (Yoon et al, 2005). In swine, injection of bone marrow-derived mononuclear cells into ischemic myocardium was shown to increase the expression of VEGF, enhance angiogenesis, and improve cardiac performance (Tse et al, 2007). Bone marrow-derived stem cells have also been used in a number of small clinical trials with conflicting results. In the largest of these trials (REPAIR-AMI), 204 patients with acute myocardial infarction were randomized to receive bone marrow-derived progenitor cells vs placebo 37 days after reperfusion. After 4 months, the patients that were infused with stem cells showed improvement in left ventricular function compared to control patients. At 1 year, the combined endpoint of recurrent ischemia, revascularization, or death was decreased in the group treated with stem cells (Schachinger et al, 2006).

Embryonic stem cells are derived from the inner cell mass of the developing embryo during the blastocyst stage (Thomson et al, 1998). In contrast to adult stem cells, ES cells are pluripotent and can theoretically give rise to any cell type if exposed to the proper stimuli. Thus, ES cells possess a greater therapeutic potential than adult stem cells. However, four major obstacles exist to implementing ES cells therapeutically. First, directing ES cells to differentiate into a particular cell type has proven to be challenging. Second, ES cells can potentially transform into cancerous tissue. Third, after transplantation, immunological mismatch can occur resulting in host rejection. Fourth, harvesting cells from a potentially viable embryo raises ethical concerns. At the time of this publication, there are only two ongoing clinical trials utilizing human ES-derived cells. One trial is a safety study for the use of human ES-derived oligodendrocyte precursors in patients with paraplegia (Genron based in Menlo Park, California). The other is using human ES-derived retinal pigmented epithelial cells to treat blindness resulting from macular degeneration (Advanced Cell Technology, Santa Monica, CA, USA).

In stem cell research, the most exciting recent advancement has been the development of iPS cell technology. In 2006, the laboratory of Shinya Yamanaka at the Gladstone Institute was the first to reprogram adult mouse fibroblasts into an embryonic-like cell, or iPS cell, by overexpression of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 under ES cell culture conditions (Takahashi and Yamanaka, 2006). Yamakana's pioneering work in cellular reprogramming using adult mouse cells set the foundation for the successful creation of iPS cells from adult human cells by both his team (Takahashi et al, 2007) and a group led by James Thomson at the University of Wisconsin (Yu et al, 2007). These initial proof of concept studies were expanded upon by leading scientists such as George Daley, who created the first library of disease-specific iPS cell lines (Park et al, 2008). These seminal discoveries in the cellular reprogramming of adult cells invigorated the stem cell field and created a niche for a new avenue of stem cell research based on iPS cells and their derivatives. Since the first publication on cellular reprogramming in 2006, there has been an exponential growth in the number of publications on iPS cells.

Similar to ES cells, iPS cells are pluripotent and, thus, have tremendous therapeutic potential. As of yet, there are no clinical trials using iPS cells. However, iPS cells are already powerful tools for modeling disease processes. Prior to iPS cell technology, in vitro cell culture disease models were limited to those cell types that could be harvested from the patient without harm usually dermal fibroblasts from skin biopsies. However, mature dermal fibroblasts alone cannot recapitulate complicated disease processes involving multiple cell types. Using iPS technology, dermal fibroblasts can be de-differentiated into iPS cells. Subsequently, the iPS cells can be directed to differentiate into the cell type most beneficial for modeling a particular disease process. Advances in the production of iPS cells have found that the earliest pluripotent stage of the derivation process can be eliminated under certain circumstances. For instance, dermal fibroblasts have been directly differentiated into dopaminergic neurons by viral co-transduction of forebrain transcriptional regulators (Brn2, Myt1l, Zic1, Olig2, and Ascl1) in the presence of media containing neuronal survival factors [brain-derived neurotrophic factor, neurotrophin-3 (NT3), and glial-conditioned media] (Qiang et al, 2011). Additionally, dermal fibroblasts have been directly differentiated into cardiomyocyte-like cells using the transcription factors Gata4, Mef2c, and Tb5 (Ieda et al, 2010). Regardless of the derivation process, once the cell type of interest is generated, the phenotype central to the disease process can be readily studied. In addition, compounds can be screened for therapeutic benefit and environmental toxins can be screened as potential contributors to the disease. Thus far, iPS cells have generated valuable in vitro models for many neurodegenerative (including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis), hematologic (including Fanconi's anemia and dyskeratosis congenital), and cardiac disorders (most notably the long QT syndrome) (Park et al, 2008). iPS cells from patients with the long QT syndrome are particularly interesting as they may provide an excellent platform for rapidly screening drugs for a common, lethal side effect (Zwi et al, 2009; Malan et al, 2011; Tiscornia et al, 2011). The development of patient-specific iPS cells for in vitro disease modeling will determine the potential for these cells to differentiate into desired cell lineages, serve as models for investigating the mechanisms underlying disease pathophysiology, and serve as tools for future preclinical drug screening and toxicology studies.

Despite substantial improvements in therapy, cardiovascular disease remains the leading cause of death in the industrialized world. Therefore, there is a particular interest in cardiovascular regenerative therapies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes) (Codina et al, 2010). It is unclear whether the heart contains resident stem cells. However, experiments show that bone marrow mononuclear cells (BMCs) can repair myocardial damage, reduce left ventricular remodeling, and improve heart function by myocardial regeneration (Hakuno et al, 2002; Amado et al, 2005; Dai et al, 2005; Schneider et al, 2008). The regenerative capacity of human heart tissue was further supported by the detection of the renewal of human cardiomyocytes (1% annually at the age of 25) by analysis of carbon-14 integration into human cardiomyocyte DNA (Bergmann et al, 2009). It is not clear whether cardiomyocyte renewal is derived from resident adult stem cells, cardiomyocyte duplication, or homing of non-myocardial progenitor cells. Bone marrow cells home to the injured myocardium as shown by Y chromosome-positive BMCs in female recipients (Deb et al, 2003). On the basis of these promising results, clinical trials in patients with ischemic heart disease have been initiated primarily using bone marrow-derived cells. However, these small trials have shown controversial results. This is likely due to a lack of standardization for cell harvesting and delivery procedures. This highlights the need for a better understanding of the basic mechanisms underlying stem cell isolation and homing prior to clinical implementation.

Although stem cells have the capacity to differentiate into neurons, oligodendrocytes, and astrocytes, novel clinical stem cellbased therapies for central and peripheral nervous system diseases have yet to be realized. It is widely hoped that transplantation of stem cells will provide effective therapy for Parkinson's disease, Alzheimer's disease, Huntington's Disease, amyloid lateral sclerosis, spinal cord injury, and stroke. Several encouraging animal studies have shown that stem cells can rescue some degree of neurological function after injury (Daniela et al, 2007; Hu et al, 2010; Shimada and Spees, 2011). Currently, a number of clinical trials have been performed and are ongoing.

Dental stem cells could potentially repair damaged tooth tissues such as dentin, periodontal ligament, and dental pulp (Gronthos et al, 2002; Ohazama et al, 2004; Jo et al, 2007; Ikeda et al, 2009; Balic et al, 2010; Volponi et al, 2010). Moreover, as the behavior of dental stem cells is similar to MSCs, dental stem cells could also be used to facilitate the repair of non-dental tissues such as bone and nerves (Huang et al, 2009; Takahashi et al, 2010). Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, the periodontal ligament that links the tooth root with the bone, the tips of developing roots, and the tissue that surrounds the unerupted tooth (dental follicle) (Bluteau et al, 2008). These cells probably share a common lineage from neural crest cells, and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cells in vitro and in vivo (Bluteau et al, 2008). different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression, and cell differentiation. However, the extent to which these differences can be attributed to tissue of origin, function, or culture conditions remains unclear.

There are several issues determining the long-term outcome of stem cellbased therapies, including improvements in the survival, engraftment, proliferation, and regeneration of transplanted cells. The genomic and epigenetic integrity of cell lines that have been manipulated in vitro prior to transplantation play a pivotal role in the survival and clinical benefit of stem cell therapy. Although stem cells possess extensive replicative capacity, immune rejection of donor cells by the host immune system post-transplantation is a primary concern (Negro et al, 2012). Recent studies have shown that the majority of donor cell death occurs in the first hours to days after transplantation, which limits the efficacy and therapeutic potential of stem cellbased therapies (Robey et al, 2008).

Although mouse and human ES cells have traditionally been classified as being immune privileged, a recent study used in vivo, whole-animal, live cell-tracing techniques to demonstrate that human ES cells are rapidly rejected following transplantation into immunocompetent mice (Swijnenburg et al, 2008). Treatment of ES cell-derived vascular progenitor cells with inter-feron (to upregulate major histocompatibility complex (MHC) class I expression) or in vivo ablation of natural killer (NK) cells led to enhanced progenitor cell survival after transplantation into a syngeneic murine ischemic hindlimb model. This suggests that MHC class I-dependent, NK cell-mediated elimination is a major determinant of graft survivability (Ma et al, 2010). Given the risk of rejection, it is likely that initial therapeutic attempts using either ES or iPS cells will require adjunctive immunosuppressive therapy. Immunosuppressive therapy, however, puts the patient at risk of infection as well as drug-specific adverse reactions. As such, determining the mechanisms regulating donor graft tolerance by the host will be crucial for advancing the clinical application of stem cellbased therapies.

An alternative strategy to avoid immune rejection could employ so-called gene editing. Using this technique, the stem cell genome is manipulated ex vivo to correct the underlying genetic defect prior to transplantation. Additionally, stem cell immunologic markers could be manipulated to evade the host immune response. Two recent papers offer alternative methods for gene editing. Soldner et al (2011) used zinc finger nuclease to correct the genetic defect in iPS cells from patients with Parkinson's disease because of a mutation in the -Synuclein (-SYN) gene. Liu et al (2011) used helper-dependent adenoviral vectors (HDAdV) to correct the mutation in the Lamin A (LMNA) gene in iPS cells derived from patients with HutchinsonGilford Progeria (HGP), a syndrome of premature aging. Cells from patients with HGP have dysmorphic nuclei and increased levels of progerin protein. The cellular phenotype is especially pronounced in mature, differentiated cells. Using highly efficient helper-dependent adenoviral vectors containing wild-type sequences, they were able to use homologous recombination to correct two different Lamin A mutations. After genetic correction, the diseased cellular phenotype was reversed even after differentiation into mature smooth muscle cells. In addition to the potential therapeutic benefit, gene editing could generate appropriate controls for in vitro studies.

Finally, there are multiple safety and toxicity concerns regarding the transplantation, engraftment, and long-term survival of stem cells. Donor stem cells that manage to escape immune rejection may later become oncogenic because of their unlimited capacity to replicate (Amariglio et al, 2009). Thus, ES and iPS cells may need to be directed into a more mature cell type prior to transplantation to minimize this risk. Additionally, generation of ES and iPS cells harboring an inducible kill-switch may prevent uncontrolled growth of these cells and/or their derivatives. In two ongoing human trials with ES cells, both companies have provided evidence from animal studies that these cells will not form teratomas. However, this issue has not been thoroughly examined, and enrolled patients will need to be monitored closely for this potentially lethal side effect.

In addition to the previously mentioned technical issues, the use of ES cells raises social and ethical concerns. In the past, these concerns have limited federal funding and thwarted the progress of this very important research. Because funding limitations may be reinstituted in the future, ES cell technology is being less aggressively pursued and young researchers are shying away from the field.

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The benefits and risks of stem cell technology - PMC

IPS Cell Therapy Comments Off on The benefits and risks of stem cell technology – PMC | June 30th, 2022

The future of therapeutics for Parkinson disease (PD) appears to be bright, with the pipeline of clinical development featuring a vast number of investigational and varied approaches to treating the condition. This is notable because although levodopaa gold standard therapyhas provided many patients with relief from PD symptoms, there are still limitations to its abilities, and there are several needs that remain unaddressed.

In a presentation given by Rajesh Pahwa, MD, FANA, FAAN, on these emerging therapies at the2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congressin Washington, DC, June 17-19, four specific therapies on the horizon were highlighted that might be able to address, at least in part, some of the shortcomings of the available options.1 Pahwa, the Laverne and Joyce Rider Professor of Neurology; chief, Parkinsons Disease and Movement Disorders Division; and director, Parkinsons Foundation Center of Excellence, University of Kansas Medical Center, shared that IPX-203, apomorphine subcutaneous infusion, continuous foslevodopa/foscarbidopa infusion (also known as ABBV-591), and continuous subcutaneous liquid levodopa/carbidopa (also known as ND0612) could all enter the market within the next couple years.

If I were to predict, I would say the next four of them would definitely be in the market in the next 3 to 4 years, Pahwa said. We have had levodopa which is the gold standard for the treatment of Parkinson disease. We have had different extended forms of levodopawe had the sustained release carbidopa-levodopa that came out 30 years ago. We had the extended-release capsules that came out, about 4 to 5 years ago now. The next generation, so to speak, is IPX-203.

He said that likely, the next therapy that will become available will be subcutaneous apomorphine infusion, closely followed by foslevodopa/foscarbidopa, and then IPX-203. The Neuroderm subcutaneous liquid levodopa [ND0612] will be another few years later. The rest of themwe do not know where they'll end up with phase 3 studies, he said.

The thing is, we still don't have that perfect carbidopa-levodopa where we can say OK, we have reached the stage that this is the best one out there. But every extended-release formulation, we have made some degree of improvement over the past. The extended-release capsules were better than the sustained release because we could get immediate action. And the same thing, I think, with IPX-203. We will, hopefully, have a better improvement than we saw with the previous one, he continued.

After running through the available clinical data on these therapies, Pahwa began to look further into the future of treatment. Touching briefly on the gene therapies that have been assessedmostly unsuccessfullyin PD, he then turned to stem cell-based therapies. Speaking to the hope that patients often carry when talking about the potential of stem cell approaches, he shared that this approach can often come with difficulties, and the progress has been slow.

READ MORE: The Importance of Treatment Nuance and Novel Options in Treating Parkinson Disease

We are very early in the journey of stem cell therapies. The challenges with Parkinson are multiple. You have to figure out the source of this stem cell, the quality of stem cell, age of the patient, stage of the patient, surgical techniques used, the need to use immunosuppression therapy or not use immunosuppression therapy, Pahwa explained. We are looking at a lot of challenges that we have not completely eliminated when we talk about stem cells. But like I said, every patient really feels that the stem cell is going to be an answer to their Parkinson's disease. The challenge is, as far as being a clinician is that Parkinson's is a progressive disorder that affects multiple areas in the brain. Using stem cell therapy, can we stop this progression? Can we actually slow down the disease or cure it? Or is it really going to only focus on dopaminergic replacement? And I think those are our challenges.

These challenges as well as the promises, he explained, can also be unique to each source of stem cells that is taken with this approach. For fetal ventral mesencephalic cells or embryonic stem cells, there are a few trials ongoingthe TRANSEURO (NCT01898390), STEM-PD (NCT02452723), and NYSTEM (NCT03119636), specificallyand there have been positives with these cells, including good long-term graft survival and their indefinite expandability. But they do carry ethical concerns and can be both unpredictable and limited in terms of their supply. Additionally, tissue rejection and tumorigenesis are possible risks.

Induced pluripotent stem cells are another approach in an ongoing trial at the Center for iPS Cell Research and Application, in Kyoto, Japan. These cells, similar to the aforementioned ones, also come with the benefit of indefinite expandability, and unlike the prior mentioned, have an easily accessible source and lack the need for immunosuppressive therapy. Although, they have a high operative cost, can be time consuming to develop, and require complex procedures.

The final option, neural progenitor cells, are also being assessed in two clinical trials (NCT03309514 and NCT01329926), and offer an easy expansion and differentiation protocol, as well as a large quantity source and multipotency. But, again, they carry risks such as low graft survivability and limited proliferation, and they require invasive tissue collection.

People are surprised that we are so slow with stem cells, Pahwa said. Seven years ago, I used to say, Oh, it's going to be 5 to 10 years, and everyone was led to believe that it was all the federal governments fault that we were going so slow. But really, it takes a long time, looking at the safety of it, because all you need is one patient who have a significant complication, and this is going to be put on the backburner for a long time.

Pahwa stressed the importance of being honest with patients about the progress being made in this area, given the significant interest from the general population in stem cell approaches. He warned about patients seeking out unapproved, unregulated treatment by either traveling out of the United States, or within.

What I tell my patients is don't spend the money because a lot of people out there [are selling this idea], not only if you're talking about going to a different country, even in the US, he said. I have a patient who was walking and doing well, who had stem cells injected in her spine, and could not walk after that. It is very likely she had, some form of fibrosing meningitis or something that that affected her gait significantly. Not only there is no efficacy data, there is no safety data. So, I strongly try to discourage my patients.

But the challenge is, people who are interested in stem cells, they often don't believe you, they want to go because the person who's doing the stem cells is doing a very good job selling this product for them. I don't know how to say we can stop this from happening, and that's why I always talk about how there are very few studies going on, Pahwa said.

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IPS Cell Therapy Comments Off on The Future of Parkinson Disease Therapies and the Challenges With Stem Cell Therapies – Neurology Live | June 20th, 2022

Since their first successful derivation in 1998, human embryonic stem cells have received almost unprecedented attention. Hailed as the next revolution for medicine, they have been described as the future of molecular biology and the biggest development since recombinant DNA.1 It has been predicted that their successful derivation will have a more profound impact on health than even the advent of anaesthesia and the development of antibiotics.2 They are set to create a whole new genre of medical therapies.3 Their potential availability has also, however, opened a Pandoras box of ethical dilemmas, ranging from ongoing issues surrounding the moral status of the human embryo to the conflicting claims of alternative stem cell sources. Although integral to ethical discourse, these dilemmas demand understanding and assessment on scientific grounds. It is our contention that the ethical debate is being hindered by failure to appreciate the subtleties of the scientific background.

Since the ethical problems accompanying destruction of human embryos are well recognised, the advantages of bypassing these by employing adult stem cells are obvious. For many, the ethical conflicts would be avoided, while all the potential benefits to patients with severe diseases would be retained. Consequently, perceived ethical problems would be resolved if it could be demonstrated that adult stem cells are superior to embryonic stem cells as therapeutic agents.

Unfortunately, resolution is far from clear, for this research field is in its infancy. Scientific uncertainty abounds, and yet societies are demanding definitive scientific answers on stem cell technology. Since the least controversial course of action would be to use adult stem cells, the pressures on scientists to emerge with evidence demonstrating that their potential is equal to, or even greater than, that of embryonic stem cells are formidable. Scientific data and interpretation have become integral to the ethical debate, perhaps in inappropriate ways.

An understanding of the most fundamental aspects of stem cell identity and function is required, from the identification of stem cells to the role of environmental factors at both the microscopic and macroscopic levels. Recognising the role of environmental factors has ramifications both clinically and ethically. Acknowledgement of these factors will provide for greater understanding of the obstacles that have to be overcome if the clinical potential of stem cells is to be realised. It will also help clarify the notions of totipotency and pluripotency, concepts central to delineating the moral value of embryonic stem cells and their parent blastocysts.

Stem cells are unspecialised cells, which have the ability to renew themselves indefinitely, and under appropriate conditions can give rise to a variety of mature cell types in the human body. Some stem cells can give rise to a wide range of mature cell types, whereas others give rise to only a few. Stem cells can be derived from a variety of sources including early embryos, fetal tissue, and some adult tissues, of which bone marrow and blood are the best known examples. Hence, there are two populations of stem cells: embryonic and adult stem cells. Of these, embryonic stem cells are derived from the inner cell mass (ICM) of the blastocyst at five to seven days after fertilisation. At this point the blastocyst has differentiated into two cell types, ICM cells (some of which will give rise to the future individual) and the surrounding trophectoderm cells (which will later form the placenta).

The distinction between embryonic and adult stem cells raises the issue of accurate identification, a prerequisite to testing the claims frequently made for the abilities of both embryonic and adult stem cells to produce a wide array of cell and tissue types. Scientifically, the problem is a fundamental one: defining stem cells solely on the basis of their structurethat is, the specific markers they carry on their outer surfaces, is inaccurate and potentially misleading. Identification mayfor example, be complicated by some stem cells expressing markers from several kinds of lineages and may be further confused by the possibility that marker expression changes throughout development.4,5 The potential for misidentification is of considerable importance for the scientific community, which has called for functional as well as structural testing.

Placing far more reliance on the functional properties of stem cells opens up a wider debate, namely, the role of the environment in an understanding of stem cell function. The ability of the structure of stem cells to change points to the existence of a dynamic relationship between stem cells and their immediate microenvironment, the stem cell niche.

The niche concept was first developed in blood cells, where proliferation, differentiation, and survival of distinct progenitor populations were found to be dependent on factors secreted by other cell types.6 This microenvironment is characterised by numerous external signals, including those derived from chemical factors, cell/cell interactions, and relationships between cells and the surrounding tissue.6 These, in their various ways, all have an impact on stem cells, affecting the precise directions in which they subsequently develop.

This microenvironment is governed by regulatory mechanisms, the molecular nature of which is complicated and elusive. Schuldiner et al,7 in their study of the effects of eight growth factors on the capacity of human embryonic stem cells to form other cell types, found that while these factors altered developmental outcome, they did not produce uniform differentiation of the stem cells. Consequently, although the structural markers and functions of stem cells appear to be dependent upon their environment, defining the nature of this environment will be far from straightforward.

An increasing awareness of the role of the niche on stem cell structure and function has led to an evolving concept of the stem cell. For instance, there is now the suggestion that stem cells should be viewed, not as undifferentiated cells, but as appropriately differentiated cells with the potential to display diverse cell types in alternative niches.8 An excellent illustration of this point is provided in a recent study by Wu et al9 where human neural stem cells were primed in a cocktail of chemical factors and then implanted into various regions of the adult rat brain. Not only did the implanted stem cells give rise to a larger number of neurons than previously reported, but most significantly they gave rise to different neuronal types depending upon the region of the brain into which they were grafted. It is possible that the distinctive nature of the local environment in each brain region instructed the neural stem cells to adopt such different fates.

Furthermore, stem cells taken out of their original niche and exposed to an entirely new environment can potentially differentiate into the cell type(s) typical of that new environment. Human neural stem cellsfor example, produced muscle cells when introduced into skeletal muscle10 and human bone marrow cells differentiated into neural cells when transplanted into a neural environment.11 The above two studies were carried out in rodents, but more recently Mezey et al12 have demonstrated that a similar scenario is possible in humans. Following bone marrow transplants in patients with various forms of cancer, bone marrow stem cells entered the brain and generated neural cell types including neurons. In many of these studies, where stem cells have been transformed into cells from different lineages, there has been some form of injury to the stem cells new environment or niche. In light of this, it is possible that various factors, signals, or chemicals normally present in damaged or disrupted tissue may play a role in governing stem cell fate.

The above findings reflect the increasing influence being attributed to environmental factors, acknowledgement of which has led to the view that stem cells are dynamic rather than static entities. This view underpins the concept of stem cell plasticity, whereby stem cells from adult sources have the ability to dedifferentiate or redifferentiate into cells from other lineages. This may blur the absolute distinction so frequently made between embryonic and adult stem cells (let alone between specific types of adult stem cells), a determinative factor in much ethical debate.

Adult stem cells include stem cells from bone marrow, blood, fat, and both fetal and adult organs. Plasticity is particularly characteristic of bone marrow. Stem cells from this source can differentiate into neural cells,11,1315 (see above for further discussion) while other research has indicated that such cells can be incorporated into skeletal muscle.16

While these reports indicate that interest in the potential of adult stem cells is justified, they should be interpreted cautiously. It would be unwise to jump to the conclusion that these studies render the use of embryonic stem cells (with destruction of human embryos) unnecessary. There are a number of reasons for this.

First, accurate identification is a prerequisite for determining the presence and extent of plasticity. For instance, although Jackson et al17 presented data to suggest that a group of muscle cells could turn into blood cells, they later found they were dealing with a subpopulation of cells that normally reside in muscle tissue.18 What is required are more rigorous standards for determining stem cell plasticity.1921 Iffor example, cardiac cells developed from stem cells are to contribute to heart function, they would have to demonstrate synchronous contraction within the heart itself. Similarly, neural cells derived from neural stem cells would have to generate electrical impulses and release and respond to chemicals normally found within the brain.19,20

A second issue concerns frequency of occurrence. Failure to replicate previous experimental work showing that blood cells are capable of differentiating into neural cells, suggests that, if transformations are occurring, they are very rare.22 Consistent with this conclusion is the work of Jackson et al,23 who demonstrated plasticity in human blood stem cells, although the change to the desired heart and blood vessel cells occurred in only 0.02% of cells. Thus, as Winston24 notes, even in apparently rich sources, the cells capable of change may be very few in number, and this may ultimately diminish their therapeutic value.

A third point of concern with clinical applications in mind, is that transformations may occur via hybrid cells, that is, by the fusion of two distinct cell types. Such spontaneous fusion was observed when embryonic stem cells were grown in the laboratory in the presence of neural cells25 or bone marrow cells.26 Such hybrids, however, show chromosomal abnormalities that may preclude them from being used in therapeutic applications.

The apparent formation of such hybrid cells may have important implications for interpretations of stem cell plasticity. Such a phenomenon presents an alternate explanation for the claims that stem cells from one tissue type are able to produce the progeny of another tissue typethat is, bone marrow into muscle, blood into brain, and vice versa. In other words, adult stem cells may not be as plastic as early reports have suggested. Thus, as pointed out by Ying et al25 future stem cell plasticity studies should ensure that any transformed cells are examined and tested to see if they display properties of both the original and the introduced cell types.

A final note of caution is that it has become clear that there is far more data to show that embryonic stem cells are capable of indefinite growth and pluripotency than adult stem cells. Mouse embryonic stem cellsfor example, have been renewing for 10 years,27 a capacity yet to be demonstrated in cells from adult sources. If adult cells have a restricted renewal potential, this will have negative implications for therapeutic applications, which rely on the ability to expand cells accurately in the laboratory in order to provide enough material for effective transplantation. Furthermore, embryonic stem cells exhibit high levels of the enzyme telomerase which indicates their immortality,28 whereas adult stem cells grown in the laboratory do not exhibit this in the same way. This property renders embryonic stem cells important in the study of cellular ageing and stem cell renewal. Work with neural stem cells from biopsies and autopsies suggests that embryonic stem cells may be easier to coax into specific cell types than adult stem cells.18

Overall, there are few confirmed reports of truly pluripotential adult human stem cells,3,29 while even apparently convincing reports30 may raise serious queries when assessed in a critical manner.3 Nearly a dozen teams have reported adult stem cell plasticity31 and it seems unlikely that random mutation or hybrid fusion can explain all these results. What is required is far more understanding of the fundamental biological issues raised by this research. Even as Winston24 outlines the advantages of embryonic stem cell researchfor example, he recognises the benefits of adult stem cells in regard to safety, possible efficacy, and accessibility. Adult sources have the added advantage of not requiring an intermediate embryo for immunocompatibility. Similarly, while the UK Department of Health32 argues that the therapeutic potential of embryonic stem cells outweighs that of adult stem cells, it acknowledges that in the long term both may be useful. The UK government reiterated this point in 2002 by stating that it wishes to advance research with stem cells from all sources.33

Scientifically, therefore, research with both adult and embryonic sources should continue, although caution should be exercised in evaluating the results. Currently, however, adult stem cells are more problematic than their embryonic counterparts. In light of this evaluation, considerable care should be employed in advocating on allegedly scientific grounds, the advantages of adult over embryonic cells as the source of replacement tissues. The impetus behind such a sentiment stems principally from a desire to protect the status of the human embryo than from any demonstrated superiority of adult stem cell sources.14,34

Confusion at this point will do nothing to advance the cause of ethical analysis, since the current state of the science and its likely future directions are integral to serious ethical assessment. In other words, it is short sighted to attempt to circumvent discussion of the moral status of the blastocyst by concentrating on the potential of adult stem cells alone. Until it is accepted that this latter approach is a cul de sac for ethical discourse, the imperatives of some ethicists will continue to come into conflict with current scientific perspectives.

It is generally asserted that totipotency denotes the ability of a cell or group of cells to give rise to a complete individual, whereas pluripotency refers to the capacity to give rise to all the cell types constituting the individualbut not the individual as a whole. Helpful as this distinction is, it is limited, in that it neither acknowledges nor emphasises the importance of environmental influences in defining these abilities.

As we have seen, embryonic stem cells are derived from the ICM of the blastocyst. These ICM cells have the capacity to form all three embryonic germ layers: endoderm, which will form the lungs, liver, and gut lining; mesoderm, which will form the bone, blood, and muscle, and ectoderm, which will form the skin, eyes, and nervous system. Outwardly, these cells appear to give rise to a complete individual and are considered by some to be totipotent.35

The claim of totipotency requires a number of conditions, however, whether this be for blastocysts or embryonic stem cells. The latter must be undifferentiated and, hence, capable of giving rise to all three germ layers, a condition that is met when embryonic stem cells are derived from the ICM of the blastocyst. In addition, there is a requirement for trophectoderm cells, which will eventually form the layers of the placenta. The extraembryonic tissues are a crucial source of signalling molecules and must function optimally for the differentiation of both embryonic somatic cells and for the establishment of germlines.36 Since both trophectoderm and ICM cells are required for successful development of the fetus, both cell types are required to establish totipotency.37 Thus, totipotency becomes a function of the immediate environment of the embryonic stem cell. If a viable fetus is to result, totipotency also requires successful implantation and development within the uterus of a woman.

In the absence of all these conditions embryonic stem cells are only pluripotent, since they are capable of creating all the cell lines of the fetus, but not the fetus itself. In the laboratory environment they are incapable of totipotency, since they have been removed from the context of the trophectoderm, let alone that of the uterus. It is inaccurate, therefore, to refer to embryonic stem cells as totipotent rather than pluripotent.38

These criteria for establishing totipotency also have ramifications for the ethical evaluation of the human blastocyst. While the blastocyst has intact trophectoderm cells and, therefore, the capacity to produce all three germ layers, plus the extraembryonic material necessary for its survival, totipotency is still dependent on the wider environmentsuccessful implantation in a uterus. Hence, blastocysts within the laboratory are only potentially totipotent, in contrast to their counterparts within the body.

A blastocyst or even a later embryo in the laboratory lacks the capacity to develop into a human individual. Unfortunately, this simple observation is frequently overlooked, and moral discussion focuses on the potential of an embryo to grow into a fully developed human without any reference to its context. Ignoring context in this manner inevitably overlooks the crucial importance of an appropriate environment necessary for the realisation of totipotency, changes to which may also alter the moral debate. Just as stem cell identity and arguably moral value depend upon the microenvironment, so too the human embryo is intimately dependent upon its wider environment.

Much opposition to the use of embryonic stem cells relies upon the argument that adult stem cells could serve as a viable source of tissues for regeneration and therapy. In the light of this, the argument continues that embryonic stem cells, with their debatable ethical credentials, should no longer feature in attempts to produce replacement tissues. This stance uses alleged scientific evidence to bolster an ethical position, and stands or falls on the strength of the scientific case.

Apart from the validity or otherwise of this approach, definitive evidence will not be forthcoming for some time (possibly years), since the scientific issues are complex on-going ones. As outlined above, the potential of adult stem cells remains a matter for debate and further experimentation. Additionally, the dynamic nature of stem cells, both embryonic and adult, points to a close interrelationship between their potential and the environment in which they are located. The possibility of cell lineage change also has to be taken into account when the suitability of different stem cell types is being advocated. From a scientific perspective none of this is surprising, and yet it fits uneasily alongside any stance that is a mixture of scientific, ethical, and political rhetoric.

The necessity of paying attention to the scientific framework of the debate, such as we are doing, has implications for other stances as well. With the advance of scientific understanding and, specifically, the advent of a genetic level of understanding, has come a tendency to view the life of an individual on the basis of DNA alone. This too, however, ignores the dependence of the embryo upon a competent environment. The context within which the embryo develops, like the niche for the stem cell, is integral to all aspects of its functioning. The environment provides nutritional requirements as well as numerous cues to ensure the healthy development of the embryo and subsequent fetus. Consequently, the preservation of DNA cannot be equated with the preservation of an individuals life, as has been suggested by McGee and Caplan.39 Adherence to such a reductionist mode of thinking is only made possible by ignoring completely the contribution of the environment. Essential as DNA is for development, it requires an appropriate context if its potential is to be realised.

From this it follows that a notion such as totipotency is a function of the environment both at the microscopic and macroscopic levels. This suggests that ethical debate cannot be reduced to potential for life, since inherent within the potential of an embryo is an assumption regarding the appropriateness of its environment. This means that the context of blastocysts and later embryos is crucial, ethically as well as scientifically and clinically.

In light of this, it is appropriate to ask whether it is useful to continue thinking of the blastocyst as an independent entity with a moral status stemming entirely from its organisation and perceived potential. We have argued that neither blastocysts nor stem cells are to be viewed in isolation from their context. Given that the claim is frequently made that moral value and status are closely associated with embryonic potential, recognition of the importance of the environment will have major implications for ethical thinking.

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Stem cells, embryos, and the environment: a context for both science ...

Cardiac Stem Cells Comments Off on Stem cells, embryos, and the environment: a context for both science … | June 20th, 2022

As eerily relevant as 1992s Death Becomes Her is in 2022, there is an unexpected difference. Unlike Madeline (Meryl Streep) and Helen (Goldie Hawn), we arent hiding our facelifts. Instead, some of us are live streaming the whole experience. Dermal fillers and Botox are getting as common as getting a facial in your local salon.

"There has been a shift of mindset and increased acceptability of these procedures, says Dr Madhuri Agarwal of Yavana Aesthetics, Mumbai. In the next few years, the trend is going to be more innovations and better delivery mechanisms of these minimally invasive procedures that deliver long term, healthy skin.

What you want to do to look and feel good is not up for discussion. While lasers and acids are wonderful for skin texture and even tightening, a non-surgical facelift involving needles can be more effective for the latter. For example, filler that is more natural looking, because a laser isnt doing anything to make up for the lost volume.

Our bodies are dynamic and need maintenance as we age. Even, and especially, our facial skin. But with so many options of non-surgical face lifts available, it can be overwhelming to make a choice. We spoke to a few dermatologists to help break down the details of the best non-surgical facelift treatments involving needles.

Botox involves injecting a very safe neurotoxin called Botulinum to freeze muscles, and relax them, ironing out wrinkles. Wary but curious first timers can choose to start with very minute unitsthey wont erase all wrinkles but will smoothen them out enough to look a little more natural. I suggest this only when fine lines form, says Dr Kiran Sethi, a dermatologist based in Delhi and author of Skin Sense. It lasts 3-6 months, and there isnt much downtime. Its great when combined with fillers or skin boosters. Theres also been a focus on preventive Botox. If you get it done before the lines set in, you will have fewer lines as you age, explains Dr Geetika Mittal Gupta of ISAAC Luxe Clinic in Mumbai and Delhi. You will need less and less Botox as you age, because those muscles are not contracting as much. And by early I mean, when you see certain lines of ageing.

Fillers are usually injections of hyaluronic acid that add back lost volume to parts of your face. The Indian bone structure is such that our cheekbone is a little flat on the centre part of the face, explains Dr. Chytra V Anand, founder, Kosmoderma located in Chennai and Bengaluru. So most Indians, even teenagers, get dark circles and hollows. Its a loss of volume. So you have to put a filler in there. And people are accepting of that. Its not because they want to look like someone else, or they want to look younger. They just want to maintain their body and skin. The down time for fillers is usually 2-7 days, depending on how easily you bruise. And a good treatment can last anywhere between 1 and 2 years.

The vampire facial might have shocked people a few years ago, but today its one of the most popular treatments in India. Platelet-rich plasma is extracted from your blood, rich in growth hormones that renews blood flow and tissue regeneration wherever it is injected back, including your scalp. Its usually a course of 3-4 sessions, monthly, says Dr Sethi. It treats melasma, dehydration, has a mild filler effect too. And when used on the scalp, new hair growth can show in 6 months.

Theres also stem cell therapy for hair and skin rejuvenation. We take a small biopsy of the skin, splice the cells, and use the extract for regenerative therapy, says Dr Anand. It takes less time and commitment than PRP and is great for scar healing.

Its good to remember that these treatments are addictive too, says Dr Akber Aimer, Director of Aesthetic Medicine, Maya Medi Spa. You need to understand your limit. Always look for a good doctor who is experienced and talk about your problems and ask their opinions. Understand everything clearly. Your decision-making is a multi-step procedure. You need to have done proper research on the materials used and the treatment. Understand the technology. Trust your gut. And dont forget to ask for before and after pictures!

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These are the non-surgical facelift treatments to consider for glowing skin - VOGUE India

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While historically lacking in foreign investments, Japans biotech scene is thriving with global investors showing increasing interest. Here are five of the hottest Japanese private companies innovating in the healthcare space.

Japan boasts one of the highest life expectancies in the world, and, faced with a rapidly aging population, is witnessing a growing burden of chronic conditions including cardiovascular disease and type 2 diabetes. For this reason, the Japanese healthcare authorities are encouraging research into the treatment and prevention of these diseases, in addition to promoting the potential of regenerative medicine.

In addition to having a roster of healthcare giants including Takeda, Astellas Pharma and Eisai, Japan is also an Asian hotspot for biotech companies. Upcoming startups have historically been limited in foreign funding and reliant on local venture capital players such as Nippon Venture Capital, Shinsei Capital Partners, and the University of Tokyo Edge Capital Partners.

In 2021, however, the amount of foreign investment flowing into the Japanese biotech space rose to $98 million, almost triple the haul of previous years. The most prominent global backers included Newton Biocapital, F-Prime Capital, and SoftBank Group. This trend arose as the COVID-19 pandemic triggered a wave of investor enthusiasm in biotechnology around the world.

With the help of local experts, weve listed five of the hottest private biotech companies in Japan. These firms, shown in alphabetical order, have raised large funding rounds in the last two years and are developing innovative treatments for a range of conditions including cancer, cardiovascular disease and inflammatory disorders.

Source: Shutterstock

Founded: 2017

Headquarters: Fujisawa

Chordia Therapeutics derives its name from the English term chord referring to a collection of musical notes normally played in harmony. In a similar way, the company aims to work in harmony with stakeholders and collaborators to develop first-in-class small molecule treatments for cancer.

Chordias lead program is a drug that disrupts the processing of RNA in tumor cells. In a healthy cell, RNA molecules are typically transcribed from a DNA template and spliced together to guide the production of new proteins. Some cancer cells accumulate mutations in the RNA splicing machinery and become vulnerable to Chordias drugs that interfere with this process.

Chordia raised $31 million (4 billion yen) in a Series C round in May 2022. The aim of the round was to push the companys lead drug through phase I testing and fund the preclinical development of the rest of its pipeline.

This month, the company announced interim results from the phase I trial of its lead candidate, with four of the recruited patients so far showing signs of responding to the treatment.

Founded: 2015

Headquarters: Tokyo

Heart failure occurs when the heart muscle is irreparably damaged and is unable to pump blood. While this deadly condition can be treated with a heart transplant, there is a general shortage of donors available, making a pressing need for alternatives.

In June 2021, the stem cell therapy developer Heartseed raised $36.5 million (4 billion yen) in a Series C round. The mission is to provide a regenerative route to saving the heart via stem cell therapy.

In the lab, Heartseed reprograms skin cells from the patient into a type of stem cell called induced pluripotent stem cells and grows these stem cells into heart muscle cells. The company then injects the muscle cells as a small cluster, or seed, into heart tissue to repair the muscle.

The proceedings from its Series C round will allow Heartseed to take its lead candidate into clinical development, including a phase I/II trial scheduled for later this year. Last year, Heartseed also licensed its treatment to Novo Nordisk in Denmark to co-develop the treatment outside of Japan.

Founded: 2018

Headquarters: Tokyo

LUCA Science hit the headlines in the last week for raising an impressive $30.3 million (3.86 billion yen) in a Series B round. The company is developing an unusual approach for treating a wide range of diseases: delivering a therapy based on mitochondria, the energy production plants in human cells.

One example where the technology could work well is in strokes and heart attacks, where blood flow is blocked to critical tissue in the brain and heart respectively. The reperfusion of blood to these tissues after the blockage can kill the tissue by damaging its mitochondria. Delivering healthy mitochondria could keep the tissue working properly and protect it from harm.

LUCA Science plans to use its recent Series B winnings to accelerate the preclinical development of its mitochondrial therapies and establish its manufacturing process. In May 2022, the firm also inked a collaboration deal with compatriot pharmaceutical company Kyowa Kirin Co., Ltd. to co-develop a mitochondrial therapy for rare genetic diseases.

Founded: 2016

Headquarters: Boston, U.S., and Tokyo

Modulus Discovery is a preclinical-stage drug discovery specialist. The company focuses on developing small molecule treatments for conditions such as cancer, inflammatory disorders and rare genetic conditions.

The firm uses a mixture of strategies to speed up the drug discovery process. These include simulating target proteins using a supercomputer; structural protein biology; forming collaborations such as with the peptide drug expert PeptiDream; and tapping into global networks for biological expertise. Modulus most advanced drug program is in late-stage preclinical testing for the treatment of chronic inflammatory diseases.

In March 2022, Modulus bagged $20.4 million (2.34 billion yen) in a Series C round. The cash is earmarked to advance the companys R&D programs by expanding its infrastructure, collaborations and headcount.

Founded: 2015

Headquarters: Tokyo

The name Noile-Immune is derived from blending together the phrases no illness and no immunity, no life. This company is developing CAR-T cell therapies for the treatment of cancer, which traditionally consist of extracting the patients immune T cells, engineering them in the lab to hunt down cancer cells, and reinfusing them into the patient.

Unlike approved CAR-T cell therapies, which are limited to treating forms of blood cancer, Noile-Immune aims its therapies at treating solid tumors. The company does this by engineering immune T cells to produce proteins that cause immune cells to migrate into the tumor site.

Noile-Immune is testing its lead candidate in a phase I in patients with solid tumors. The firm is also co-developing therapies with partners including Takeda and the European cell therapy specialists Adaptimmune and Autolus. Additionally, Noile-Immune has an allogeneic version of its cell therapy in the pipeline where immune T cells are sourced from healthy donors rather than the patient.

To finance the clinical development of its lead candidate, Noile-Immune raised $21.8 million (2.38 billion yen) in a Series C round in early 2021. The company hit a setback in January 2022 when a collaboration deal fell through with the U.S. player Legend Biotech. Nonetheless, other external companies remain interested in Noile-Immunes offering, including Japan-based Daiichi Sankyo Company Ltd., which opted to assess Noile-Immunes technology in late 2021.

Cover image via Elena Resko.

Thanks to feedback from Shiohara Azusa, VC Investor at The University of Tokyo Edge Capital, and Hironoshin Nomura, Chief Financial Officer, Sosei Group Corporation.

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The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy.

Until recent years, cancer treatment revolved around surgery, chemotherapy, and radiation. But the FDA approval of ipilimumab (Yervoy) in 2011 led to a fourth leg of that treatment stool: immunotherapy. This enabled new treatment paradigms, sometimes with shocking levels of success.

The types of immunotherapy treatments available are proliferating, with approved immune checkpoint inhibitors (ICIs) and cellular therapies like chimeric antigen receptor (CAR) T cells as well as other modalities in the research and discovery phases. Some even include more established approaches like vaccines that are being revisited with new information and iterations.

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy. The Bacillus Calmette-Gurin vaccine, used to prevent tuberculosis for a century, has also been used as an immunotherapy to treat nonmuscle invasive bladder cancer since 1990.1 And rituximab (Rituxan), a monoclonal antibody therapy approved in 1997 for B-cell malignancies, is seen by some as an early immunotherapy as well.2

What many clinicians think of in terms of immunotherapy, however, are treatments targeting CTLA-4 and PD-1/PD-L1 pathways, brought from the bench by James P. Allison, PhD, and Tasuku Honjo, PhD, respectively, leading to a Nobel Prize awarded jointly to them in 2018.3

Immune responses are tightly controlled by T cells, and these T cells have on/off switches that help control their responses, according to Padmanee Sharma, MD, PhD, a professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine and the scientific director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center in Houston. Previously, she said, clinicians were not aware of the off switches. Sharma showed that CTLA-4 was an inhibitory pathway and that by blocking it, the T cells could stay longer to eradicate the tumors.

With 8 ICIs approved for immunotherapy in hematological and solid tumors,4 researchers are not only investigating newer forms of therapy, but also combining them to fi nd more effective and durable treatments and introducing them into earlier lines of treatment (TIMELINE). Current research is also attempting to predict who will respond to which therapy based on current and emerging biomarkers.

Ipilimumab, which kicked off the current era of cancer immunotherapy treatment with FDA approval in 2011, targets CTLA-4 for newly diagnosed or previously treated unresectable or metastatic melanoma.5 Ipilimumab blocks CTLA-4, removing its inhibitory signals. This allows the T cells to activate and launch an immune response to the tumors antigens.

CTLA-4 is basically the fi rst inhibitory pathway that comes up on the T cells, Sharma said. CTLA-4 is a member of an immunoglobulin-related receptor family responsible for some immune regulation aspects of T cells.6 It is thought to regulate T-cell proliferation mostly in lymph nodes, early in an immune response, by having an inhibitory role.7

What ipilimumab really did and what the immune checkpoint inhibitors really did is they opened up this whole different way to approach the immune system, Elizabeth Buchbinder, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said. Ipilimumab provided amazing durable responses in patients with melanoma with widely metastatic disease, some of whom were alive 10 years later, she said.

The PD-1 and PD-L1 blockades build on ipilimumabs success. Like CTLA-4, PD-1 is a negative regulator of T-cell immune function, inhibiting the target to increase immune system activation. PD-1 suppresses T cells mostly in the peripheral tissues.7 As of November 2021, 8 ICIs have been approved that target CTLA-4, PD-1, and PD-L1 pathways and treat 18 types of cancer.3

AntiPD-1 inhibitors

The percentage of people who benefi tted from ipilimumab was on the low side, Buchbinder said, with only an 11% response rate and 20% of people doing well long term in clinical trials. With PD-1 inhibition, however, there was approximately a 40% response rate and many more patients doing well long term, as demonstrated in clinical trials. So [PD-1 inhibition is] both far more effective and also less toxic, Buchbinder said.

When choosing an agent in the PD-1 class, we dont need to differentiate them. Theyre all antiPD-1, Sharma explained. There arent any data to indicate that patients will respond any differently to pembrolizumab [Keytruda] vs nivolumab [Opdivo]. The mechanism of action for both drugs [is] exactly the same.

Instead, clinicians should consider the FDA approvals for each drugs indications and combinations. But from a scientific standpoint, theres no distinguishing between [them], Sharma said.

AntiPD-L1 inhibitors

PD-1 and PD-L1 targeting drugs were found to work beyond melanoma and kidney cancer, the early indications for treatments targeting the CTLA-4 pathway, Buchbinder said. That was a huge opening up of this fi eld to all of these other cancers, like lung cancer, head and neck cancer, GI [gastrointestinal] cancer, breast [cancer], and beyond, she said.

Before receiving these immunotherapies, patients may need to show PD-1 or PD-L1 expression, although this may not identify all patients who can benefi t from the treatments. Researchers continue to try to identify additional and better biomarkers to indicate which patients may respond.13

In March, the FDA approved the newest ICI, nivolumab and relatlimab-rmbw (Opdualag), for adult and pediatric patients (12 years and older) with unresectable or metastatic melanoma. 3 Nivolumab is a PD-1 inhibitor, and relatlimab blocks LAG3 proteins on immune cells. It is being tested in a lot of other tumors, Buchbinder noted.

Another target in the discovery phase is T cell immunoglobulin and mucin domain 3, which is a checkpoint receptor expressed by many immune cells and leukemic stem cells.14 It is activated by several ligands and is being tested in different cancer types.

Also in clinical trials are tumor-infiltrating lymphocytes (TIL) that recognize cancer cells as abnormal, entering the tumor to kill the cells. TILs already recognize the targets because they originate from the tumor itself.15 Although they need to be expanded, they are not the same as CAR T cells, which must be engineered to recognize the targets.

In addition, older therapies are experiencing a resurgence, with research underway to make interleukin 2 (IL-2) help cytokines function better. That work is trying to optimize what those cytokines do in the body and the immune system, Buchbinder said. There are so many areas where the goal of the therapy is activation of the immune system.

One of these areas includes a return to vaccines. In earlier vaccine therapy, We had no idea that while we were giving therapy to turn on the cells, we were also rapidly turning off the cells because an on switch will automatically drive an off switch for the immune system, Sharma said. The yin and the yang of the immune response is very important to understand because when the immune response is driven in one direction, it will always try to control itself. With that in mind, newer vaccines might work better if given in combination with an antiCTLA-4, for example, to block the inhibitory pathways, she said.

Vaccines are taking many forms, including the mRNA vaccine used for COVID-19, peptide vaccines that include a tiny bit of protein that is expected to be expressed on the tumor surface, and vaccines constructed from dendritic cells, which stimulate T cells, Buchbinder said.

There are also viral therapies injected directly into tumor vaccines, such as talimogene laherparepvec (Imlygic) approved in 2015 for the treatment of some patients with metastatic melanoma that cannot be surgically removed.16 It is a is a modifi ed herpes virus directly injected into the tumor to bring about a local immune response, Buchbinder said.

According to Sharma, approximately 60 targets are currently being evaluated for immunotherapy development.

The FDA has approved 2 CAR T-cell therapies, both in 2017: tisagenlecleucel (Kymriah) for patients 25 years and younger with relapsed B-cell precursor acute lymphoblastic leukemia17 and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to fi rst-line chemoimmunotherapy or that relapses within 12 months of fi rst-line chemoimmunotherapy.18 These treatments involve collecting T cells from the patient and engineering them to express CARs that recognize the patients cancer cells. The cells are then enlarged and infused back into the patient, where they can target the antigen- expressing cancer cells. CARs have been shown to greatly improve clinical response and disease remission in some patients.19

I think CAR T cells are clearly building on the concept that T cells are the soldiers of immune response. They are basically engineering the cell to have an antibody that recognizes a specifi c antigen, Sharma said, adding that its important to ensure the targeted antigen is part of the cancer.

CAR T cells have had limited effectiveness in treating solid tumors, given the low T-cell infiltration and immunosuppressive environment that challenges the immune system from successfully reaching and killing solid tumor cancer cells.20

Natural killer (NK) cells are another cell type being researched to attempt tumor eradication, and this therapy is in the early stages, according to Sharma. CAR NK cells can be generated from allogenic donors, making them more attractive as off the shelf treatments compared with CAR T cells, which are collected from the patient. As of early 2021, more than 500 CAR T-cell trials and 17 CAR T-cell/NK-cell trials were in the works globally.21

A major consideration when choosing any treatment, including immunotherapies, is the adverse event (AE) profile. Immunotherapy drugs have different AEs than oncology treatments like chemotherapy or radiation. [With immunotherapy,] what we see is infl ammation because youre turning on the immune system in such a powerful way, Sharma said. Inflammatory reactions include a skin rash or dermatitis, infl ammation in the colon (colitis and diarrhea), and/or infl ammation in the lung with pneumonitis. Clinicians are now aware of these AEs and can monitor them closely, stopping therapy if needed to control them before they become severe, Sharma said.

Toxicities with ipilimumab can be severe, and patients requiring hospital admission might need high-dose steroids, Buchbinder noted. Common AEs for the CTLA-4 inhibitor are typically GI related, including diarrhea, colitis, and hepatitis. Some patients may experience fatigue or a small rash, but most generally make it through treatment with minimal AEs.

The stronger AEs with ipilimumab can be seen from a trial comparing ipilimumab plus nivolumab to nivolumab and relatlimab. Almost 60% of patients experienced AEs with the ipilimumab combination vs 20% in the latter group.17

PD-1 and PD-L1 inhibition typically involve AEs that cause lung issues rather than GI. The types of organ systems affected by immunotherapy AEs can vary based upon which checkpoint inhibitor you use but in some ways, the mechanism by which these occur is very similar, Buchbinder said. Its all an overactivation of the immune system leading to infl ammation in an organ, and there are very few organs that we have not seen toxicity from immunotherapy.

Buchbinder noted that cellular therapies can cause more severe AEs, such as cytokine release syndrome (CRS). Patients can get very sick very quickly, she said, because the therapies given with the cellsincluding the chemotherapy given before and the IL-2 given aftercause most of the AEs. With a lot of the injection therapies, the AEs are related to delivery method, like injection-site issues, but there are also potential systemic AEs like fever, chills, and reactions someone would get to a virus. Its really a huge range in terms of the different [adverse] effects, Buchbinder said.

CRS is the most common AE of CAR T-cell therapy, and it is caused by large numbers of T cells activating, which releases inflammatory cytokines. Although this demonstrates that the therapy is working, it can cause worrisome symptoms. The CRS and the related neurotoxicity can be treated with tocilizumab (Actemra).

One question in the immunotherapy world is whether the development of immune-related AEs predicts a positive or negative response to treatment. With melanoma, we think the data have been very tricky, Buchbinder said. Early trials appeared to show a higher response rate for patients who developed severe symptoms, but as trials developed, that signal was not always there. I think the overall impression is that yes, severe AEs are associated with a better response, she said. A cosmetic AE that clinicians who treat melanoma are excited to see, she said, is vitiligo. It suggests that the immune system is attacking normal melanocytes and that it is attacking cancer cells as well. Those patients generally do far better than patients who dont get vitiligo.

A meta-analysis of 30 studies on the topic, including 4971 individuals, showed that patients who developed immune-related AEs experienced an overall survival benefi t and a progression-free survival benefi t using ICI therapy compared with those who did not. The authors stated that more studies are needed and that the results are controversial.22

Melanoma has been the proving ground for ICIs, Buchbinder said, But now the bar is higher in terms of immunotherapy.

ICIs are now being tested in more immuneresistant tumors. Although there are huge hurdles in terms of some cancers where its going to be hard for immune therapy to do muchlike pancreatic cancer or prostate cancerthere are still diseases where theres opportunity and a possibility that the correct approach or combination might get to some great therapy for those diseases, Buchbinder said

Immunotherapies are being combined with conventional therapies to better integrate treatment. We dont see cancer as a death sentence anymore, Sharma said. We really do see a lot of hope, [and patients with cancer] should be encouraged to discuss immunotherapy with their physician either in a clinical trial or an FDA-approved agent. If you do have a response, its a pretty phenomenal response.

REFERENCES:

1. Lobo N, Brooks NA, Zlotta AR, et al. 100 years of Bacillus Calmette- Gurin immunotherapy: from cattle to COVID-19. Nat Rev Urol. 2021;18(10):611-622. doi:10.1038/s41585-021-00481-1

2. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds fi rst oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

3. Kruger S, Ilmer M, Kobold S, et al. Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019;38(1):268. doi:10.1186/s13046-019-1266-0

4. Lee JB, Kim HR, Ha SJ. Immune checkpoint inhibitors in 10 years: contribution of basic research and clinical application in cancer immunotherapy. Immune Netw. 2022;22(1):e2. doi:10.4110/in.2022.22.e2

5. FDA approves Yervoy (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. News release. Bristol Myers Squibb. March 25, 2011. Accessed May 11, 2022. https://bit.ly/3PFp7q2

6. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/ blood-2017-06-741033

7. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

8. Keown A. Keytruda approvals: a timeline. BioSpace. Aug 13, 2019. Accessed May 11, 2022. https://bit.ly/3yHvfrL

9. Stewart J. Opdivo FDA approval history. Drugs.com. Updated March 15, 2022. Accessed May 20, 2022. https://bit.ly/3lnmtar

10. Markham A, Duggan S. Cemiplimab: fi rst global approval. Drugs. 2018;78(17):1841-1846. doi:10.1007/s40265-018-1012-5

11. FDA grants accelerated approval to dostarlimab-gxly for dMMr endometrial cancer. FDA. Updated April 22, 2021. Accessed May 20, 2022. https://bit.ly/38BSJns

12. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds first oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

13. Opdualag becomes fi rst FDA-approved immunotherapy to target LAG-3. National Cancer Institute. April 6, 2022. Accessed May 11, 2022. https://bit.ly/3FZWaAp

14. Acharya N, Sabatos-Peyton C, Anderson AC. TIM-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911

15. Boldt C. TIL Therapy: 6 things to know. MD Anderson Cancer Center. April 15, 2021. Accessed May 11, 2022. https://bit.ly/3wmguJb

16. FDA approves talimogene laherparepvec to treat metastatic melanoma. National Cancer Institute. November 25, 2015. Accessed May 20, 2022. https://bit.ly/3woTDwA

17. OLeary MC, Lu X, Huang Y, et al. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25(4):1142-1146. doi:10.1158/1078-0432.CCR-18-2035

18. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. News release. FDA. Oct. 18, 2017. Accessed May 11, 2022. https://bit.ly/3wpECL1

19. FDA approves fi rst CAR T-cell therapy the evolution of CAR T-cell therapy. Cell Culture Dish. October 24, 2017. Accessed May 10, 2022. https:// bit.ly/3LlDD2B

20. Albinger N, Hartmann J, Ullrich E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Ther. 2021;28:513-527. doi:10.1038/s41434-021-00246-w

21. Ahmad A, Uddin S, Steinhoff M. CAR-T cell therapies: an overview of clinical studies supporting their approved use against acute lymphoblastic leukemia and large B-cell lymphomas. Int J Mol Sci. 2020;21(11):3906. doi:10.3390/ijms21113906

22. Zhou X, Yao Z, Yang H, Liang N, Zhang X, Zhang F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? a systematic review and meta-analysis. BMC Med. 2020;18(1):87. doi:10.1186/s12916-020-01549-2

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10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes - Targeted Oncology

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An estimated 1,240,000 blood cancer cases emerge annually worldwide, accounting for approximately 6 per cent of all the cancer cases. Meanwhile 720,000 people die of blood cancer every year, accounting for 7 per cent of the cancer deaths.

These statistics were shared by Dr Munira Borhany, haematologist and associate professor at the National Institute of Blood Diseases & Bone Marrow Transplant (NIBD) at a public awareness seminar held recently in collaboration with the Neurospinal & Cancer Care Postgraduate Institute.

The event was titled Rising Burden of Blood Cancers in Pakistan.

"Cancers of blood, bone marrow and lymphatic system are collectively referred to as blood cancers ranging from slow-growing to very aggressive. When the body's red blood cells, white blood cells or platelet production is unusual or abnormal, blood cancer develops. It normally begins in the bone marrow, which is responsible for the production of blood. The normal functioning, growth and development of blood cells that fight infection and make healthy blood cells are disrupted by this type of cancer. There are 137 types of blood cancers and related disorders, she explained, adding that blood cancer was among the most common form of cancers to affect children and adolescents.

The haematologist said that the symptoms of blood cancer could be quite variable depending upon its type. The common symptoms included unexplained fatigue, fever, weakness, and tiredness which could be fast develop in conditions such as acute leukaemia. There may be bleeding manifestations, bone pains, occurrence of swellings in the entire body, loss of appetite, weight loss and abdominal pain, she added.

She said that in general, the symptoms could be quite non-specific such as flu-like symptoms to more dramatic ones such as bleeding manifestations and severe infection. Highlighting the efficacy of bone marrow transplant (BMT) for such patients, she said the BMT was a highly effective therapy and often the only hope for a cure or a longer life for patients with blood cancers.

Dr Munira explained BMT was a procedure to replace disordered bone marrow with healthy bone marrow stem cells. Transplant physicians use this procedure to eliminate cancer or defective stem cells and restore a patient's blood and immune systems.

She added that not all patients with blood cancer required BMT. The need for a bone marrow transplant is evaluated case-wise based on the individual patientss underlying diagnosis, treatment response and disease genetic profile. She informed the event that patients' response to treatment in cases of acute leukemia had improved, due to the cutting-edge genetic profiling technologies combined with innovative medication.

Highlighting the benefits of BMT, Dr Munira said the procedure had two major advantages over other forms of transplants firstly, the donors did not lose any vital part of their body for life and secondly, the recipients had to take the immunosuppressive drug only for nine months.

The bone marrow transplant unit at the NIBD has successfully performed 750 BMT, including 690 allogeneic and 60 autologous blood stem cell transplants with the success rate of more than 80 per cent despite the pressure placed on the healthcare system due to Covid-19 pandemic as well as national economic crisis and escalation of the dollar value against the rupee, she said.

The expert said a bone marrow transplant surgery cost more than Rs4 million in Pakistan but the entire procedure was performed at the NIBD free of charge. She requested the industrial sector, philanthropists and NGOs to support the NIBD for this noble cause.

Blood cancer treatment success rates are improving drastically, and patients are living longer than ever before. There are now various effective and targeted therapeutic agents that have been effective such as chemotherapy, radiotherapy, targeted therapy, bone marrow transplantation and immunotherapy in beating cancer. There is a better chance of a complete cure with early diagnosis, she maintained.

Earlier, NIBD Chief Executive Officer Usama Sultan Shamsi told the seminar that there was a need for increasing awareness among the public as well as medical fraternity to help realise that blood cancer and related disorders were just another forms of disease with a potential for high cure rates provided that they were investigated properly and specific treatment instituted.

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Success rate of blood cancer treatment drastically improving, seminar told - The News International

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First prospective controlled trial in the world on treating chronic back pain with stem cells shows 70% of participants helped by the treatment

Dr. Sairam Atluri has successfully treated more than 400 patients at his StemCures clinic in Cincinnati over the past five years

Proper use of bone marrow mesenchymal stem cells, or BM-MSCs, for chronic pain treatment follows FDA protocols

CINCINNATI, June 15, 2022 /PRNewswire/ --Local Cincinnati pain physician Dr. Sairam Atluri led the first prospective controlled clinical trial on using bone marrow mesenchymal stem cells (BM-MSCs) for chronic pain. 70% of study participants gained significant pain relief and improved physical and mental function. The first of its kind in the world, the study was completed last month in Ohio.

"Evaluation of the Effectiveness of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Chronic Low Back Pain Due to Severe Lumbar Spinal Degeneration: A 12-Month, Open-Label, Prospective Controlled Trial"was published in the official publication of the American Society of Interventional Pain Physicians, Pain Physician Journal. It is the only scientifically accepted controlled study in the world. 15 other physicians participated in the study.

"When I saw the results my patients were getting at my StemCures health facility, I and my colleagues decided the only way to get physicians to accept this treatment as a mainstream therapeutic for chronic pain was to get a study published in a respected journal," said Dr. Atluri. "About 90 percent of physicians have little to no knowledge of this treatment. They, and their patients, need to know."

40 patients were in the BM-MSC treatment group for the study, and 40 were in a control group, receiving traditional pain modalities such as injections, physical therapy, nerve ablations, and pain medications. The research group then followed their progress for one year:

Almost 70% of those receiving BM-MSCs had significant pain relief and improved physical and mental function. All had cut down or eliminated their pain medication.

Only 8% in the controlled group (not receiving BM-MSCs) had any improved functioning.

Story continues

BM-MSC treatment is a constructive pain therapeutic, as the patient's own cells, that are proven to be safe and effective, are extracted and then injected back into the area that needs repair and healing. The painless procedure takes about 90 minutes and is typically performed just one time for each area affected by chronic pain.

According to Dr. Atluri, it's important the public knows what BM-MSCs are, and what they aren't.

Mesenchymal stem cells are designed to repair and heal. They are present in every tissue, ready to spring into action if you cut your finger, or suffer an acute muscle injury.

BM-MSC treatment, done properly, follows allowed FDA protocols.

BM-MSCs are not embryonic or fetal stem cells. There are almost no cell therapies currently performed with these cell types.

These are not amniotic stem cells. This is important because there are many "pseudo clinics" advertising stem cell procedures that use "off-the-shelf" amniotic stem cells. Most are not performed by qualified physicians, are violating FDA protocols, and are a waste of money. They may also adversely affect your health.

BM-MSCs are not hematopoietic stem cells derived from blood platelets for treatments such as leukemia.

Dr. Atluri, who has successfully treated over 400 patients over the last five years at his clinic, also pointed out that by making the treatment more accessible to chronic pain sufferers, more patients can wean themselves off prescription painkillers. The consequences of that could significantly impact this country's opioid addiction problem.

"These results of this treatment are astonishing and now, irrefutable," said Dr. Atluri. "I travel around the world educating and teaching other physicians about BM-MSCs and now I can do it with scientific proof in hand. Every physician treating chronic pain patients should be identifying their BM-MSC candidates, which are those who suffer from arthritis or joint degeneration for more than six months and don't have contraindications such as cancer.

"It's changing people's lives and in many cases, giving them a future to look forward to for the first time in years."

For more information about the study and bone marrow mesenchymal stem cells treatment, contact Dr. Atluri at hisStemCures clinic at 513-624-7525. The clinic address is 7655 Five Mile Rd., Ste. 117, Cincinnati.

Cision

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SOURCE Dr. Sairam Atluri

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Cincinnati Pain Management Physician Leads First Successful Stem Cell Controlled Trial with 70% of Participants Seeing Positive Results - Yahoo...

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Symptoms of the disease are usually visible at the age of 5 months and change over time. Some of the common symptoms include pain, anaemia, frequent infections, swelling of hands and feet and vision problem

Sickle-shaped cells and normal blood cells in human blood. Image courtesy: Wikimedia Commons/Dr Graham Beards

World Sickle Cell Day is marked every year on 19 June with an aim to raise awareness about sickle cell disease. Sickle Cell Disease is a group of disorders that impact haemoglobin, the molecule in red blood cells which deliver oxygen to cells throughout the body.

Individuals who live with this disease have haemoglobin S, an atypical haemoglobin molecule which distorts red blood cells into a sickle or a crescent shape. The disease is usually transmitted from parents to children.

What are the symptoms?

Symptoms of the disease are usually visible at the age of 5 months and change over time. Some of the common symptoms include pain, anaemia, frequent infections, swelling of hands and feet and vision problem.

What are the different types of Sickle Cell Disease?

If one of the parents has a problem gene, then the child will not have symptoms but will possess sickle cell trait.

What is the treatment?

The disease can be detected in an infant during the screening process of a newborn. In case, there is a family history of the Sickle Cell disease, it can even be diagnosed at the time of pregnancy.

The only way to cure it is either stem cell or a bone marrow transplant. The symptoms can also be dealt with the use of antibiotics, periodic blood transfusion, pain killers, and vaccinations.

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World Sickle Cell Day 2022: Know all about symptoms and treatment of the disease - Firstpost

Bone Marrow Stem Cells Comments Off on World Sickle Cell Day 2022: Know all about symptoms and treatment of the disease – Firstpost | June 20th, 2022