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Munshi Explains Staging, Prognosis, and Treatment for a Patient With Acute Graft-vs-Host-Disease – Targeted Oncology

By daniellenierenberg

During a virtual Targeted Oncology Case-Based event, Pashna N. Munshi, MD, associate clinical director, Stem Cell Transplant and Cellular Immunotherapy Program, assistant professor of Medicine, Georgetown University School of Medicine at MedStar Georgetown University Hospital, discussed the case of a 48-year-old male patient with acute graft-versus-host-disease (GVHD).

Targeted OncologyTM: What factors contribute to the risk of acute GVHD in a patient like this one?

MUNSHI: A lot of donor-recipient factors and other conditions increase the risk of acute GVHD. [These include] gender matching, human leukocyte antigen disparity, degree of mismatch, and having an older donor. Theres also [blood group] incompatibility and definitely CMV mismatched status. Though now that the FDA has approved letermovir [Prevymis] for patients who are undergoing allogeneic transplant if they have a CMV-positive donor,1 were seeing very little CMV reactivation. That has been a bit of a game changer for the good.

Patients have an increased risk of GVHD if they receive a transplant from a peripheral blood stem cell source versus a bone marrow graft, because the peripheral blood has more T cells in its composition. The myeloablative regimens [are associated with greater risk of GVHD than] reduced-intensity regimens.2

Do you agree with these poll results? Would you start with systemic therapy for this patient?

It can get a little tricky whether you want to give patients systemic steroids or wait and see if something gentler might work. I tend to agree that, at this point, the patient needs to immediately start with systemic steroids, because there are 2 organ systems involved. Once the lower gastrointestinal [GI] tract gets involved, it surely portends a poor prognosis if the grade becomes worse. And they become refractory to steroids very quickly: 50% of these patients will eventually not respond to steroids.

How would you stage this patients GVHD?

There are many criteria for staging GVHD. The criteria that most clinical trials use are the Mount Sinai Acute GVHD International Consortium [MAGIC] criteria.3 They are adapted from the Glucksberg criteria, which are very similar.4

Three organ systems [are involved in] acute GVHD: the skin, the liver, and the GI tract. Skin involvement is graded on the basis of the body surface area involved. Liver involvement is graded on the basis of the total bilirubin level. Upper GI involvement is graded on the basis of anorexia, nausea, and vomiting, and it just comes in stage 0 or stage I, depending on if its persistent or not. To determine lower GI tract involvement, we measure stool volume, especially when patients are admitted to the hospital. But once they go home, we cant do that, so we ask them how many times a day they have diarrhea. Is it watery? Is it muddy? Whats the volume? Is it large or small?

The patient can characterize the stool and tell their doctor how many times per day: 4 times, 5 times, 6 times. This patient is having 4 episodes per day; that puts them in stage I lower GI GVHD. But with a 60% body rash, that puts them in stage III skin GVHD. So really getting up there with skin, but not so much yet for GI. Once each organ [involvement is] staged, theres an aggregate score based on the combination of these organs. Then we come up with the grade.

In this patient, with a stage III rash, stage I upper GI, and stage I lower GI GVHD, they have a total score of a grade 2 acute GVHD. This is still in the mild to moderate zone. Anything above grade 2 is considered very severe GVHD.

Would you recommend that this patient receive systemic steroids?

In the scheme of things, somebody who didnt have symptoms and now is having active symptoms, especially with lower GI tract involvement, definitely needs high-dose steroids to get in there and [stop] the inflammation.

On what would you base a prognosis for this patient?

We can risk stratify these patients on the basis of the stage of organ involvement.5 Broadly, they can be at a standard risk or at a high risk [of poor response to treatment, mortality, and transplant-related mortality]. The patient is at high risk once they have very active GI involvement [or] if they have 2 organs involved. This is one more reason to think about starting these patients early on steroids. Why is this important? Because once a patient has high-risk GVHD, the chance of response to steroids is even lower, and once they dont respond to steroids, there is a higher [risk of] transplant-related mortality. The probability of transplant-related mortality is 44% for patients with high-risk acute GVHD flares, [versus] 22% for patients with low-risk GVHD [P < .001]. These are a few things to think about. Act very swiftly if a patient has 2-organ involvement, especially the lower GI tract.

Can biomarkers guide treatment decisions in this case?

In the field of GVHD, biomarkers are a very exciting advancement. We want a prognostic model of which patients will get GVHD. Can biomarkers in the blood [help] prevent GVHD and improve transplant outcomes?

A large prospective trial was done through the Bone and Marrow Transplant Clinical Trials Network where a set of 6 biomarkers were tested at several time points after the transplant.6 They saw that they could predict when GVHD happened by using these biomarkers. They could see that as the levels of these biomarkers increased, the patients had higher scores of GVHD. Once treatment was started, if specific biomarkers went down it was predictive of response at day 28 [56% vs 17%; odds ratio, 6.32; P = .001] and also predictive of [decreased] transplant-related mortality by day [180 (49% vs 87%; P < .0001)]. If all these biomarkers went up aggressively, overall survival was lower [P < .0001].

The MAGIC Consortium also tried to test biomarkers.7 They looked at 2 biomarkers, REG3Athe regenerating islet-derived 3-alpha, which is specific for the GI tract and ST2. Looking at these 2 biomarkers, they came up with an algorithm of prediction. On the basis of how these biomarkers responded at the time of GVHD and to treatment, they could predict mortality by 6 months. In clinical practice, it is difficult to use this day in and day out. We still use our clinical skills to assess the degree of GVHD. But all patients eventually get treated the same waywith high-dose steroidsdespite biomarkers being elevated or not.

At this point, [biomarker data] may tell us an association rather than a causality. Were not openly using biomarkers to guide our practice, but I think were learning to use them a bit more and knowing that theres something out there that could be used as a predictive tool. It is an exciting development.

Are there alternatives to systemic steroids?

Steroids remain the mainstay. We need to see if we can move to other therapies that are coming down the pipeline.

Data from the REACH1 [NCT02953678] and REACH2 [NCT02913261] trials led to ruxolitinib [Jakafi] approval.8,9 If we can use ruxolitinib in an up-front setting, [maybe we] can use the newly approved rho-kinase or ROCK2 inhibitors as well.10 We want to think about steroid-sparing agents. Maybe biomarkers can guide us in the future for that. But right now, in terms of, Do I start my patient on treatment? or Will they respond to this treatment, I find that [biomarkers are] still not a very useful tool because at the end of the day, the patients all still need to be started on steroids.

The minute you see that your patient is not responding to steroids, very quickly start them on a JAK2 inhibitor.

How do you dose steroids?

This patient received 2 mg/kg of prednisone per day for 14 days. Two mg/kg is a very high dose. The standard is 1 to 2 mg/kg.11 There are data to show that 2 mg isnt any different from 1 mg.12 But a lot of times, if its a very active, severe flare, we will use 2 mg/kg. Im not sure if I would have done 2 mg/kg in this case, but its certainly not out of the realm of treating these patients.

The goals of primary therapy for acute GVHD are to stabilize the organ manifestations, or improve them, and limit long-term treatment toxicity. We want to improve functional capacity and prevent any reduction in quality of life. First-line therapy is always with corticosteroids. Now ruxolitinib is approved for second-line therapy.8 There have been data to show that it can improve overall survival.

How do you taper glucocorticosteroids after achieving initial response?

If the patient is taking 2 mg/kg of steroids, an average 70-kg person, thats over 100 mg of steroids. After 2 weeks, they probably are not getting up from a seated position anymore with all the muscle wasting that can happen.

[As soon as they start to show improvement, it would be safe to start to taper the dose.] Traditionally, [the patient receives the full dose for] at least a week or 10 days. Then it is traditional to decrease the dose 10% every 5 to 7 days, gently coming down, making sure that the patient is not having any flares.

Describe the multidisciplinary teambased approach that you use for acute GVHD.

The incidence of acute GVHD in the patient population is anywhere from 30% to 50%, despite the best [efforts at] prophylaxis. Most patients will get some form of acute GVHDit can go up to even 80%. This [necessitates] a multidisciplinary team approach. If the patient is having diarrhea, theyre having malnourishment. Theres nausea or anorexia, so theyre not eating on top of that. Then theres skin rash, so the risk of infections and cellulitis. Theyre in pain. A dermatologist probably should be involved at some point. A nutrition team is also needed. If theyre on high-dose steroids, physical therapy should be involved up front. So early involvement of a whole team is very important. Thats usually how I treat my patients and usually how centers of excellence continue to treat active patients with GVHD after transplantation.

How do you determine if a patients GVHD is steroid refractory?

The strict definition of steroid refractoriness or resistance is if theres progression of acute GVHD within 3 to 5 days of starting high-dose steroids, or theres failure to improve within 1 week of starting these steroids, or theres incomplete response after more than 28 days of any immunosuppressive treatment.13 So, by and large, in 3 days or a maximum of 7 days, [it will be clear] if the patients GVHD is going to be steroid refractory or not.

Steroid dependence is [defined as when] the patients GVHD initially responded to steroids, but the disease flares when the dose is tapered, so they cannot be taken off the steroids.

Steroid intolerance is when the patient develops [unacceptable toxicity from steroids such as] uncontrolled diabetes or myopathies. Then it becomes hard to keep them on steroids.

What are the treatment options for patients with steroid-refractory GVHD?

Ruxolitinib now has been FDA approved for steroid-refractory acute GVHD, and its a category 1 definition.8,11 Ibrutinib [Imbruvica] has also been approvedits only FDA-approved indication is for chronic GVHD.14 There are many other treatment options [in the National Comprehensive Cancer Network guidelines].11 Oncologists always end up using some combination or other depending on which of these different immune suppression medications they are comfortable using.

What new treatments are in the pipeline?

In terms of BTK inhibitors, I dont think theres anything other than ibrutinib at this time point. There are many JAK inhibitors being studied.15 Baricitinib is another JAK inhibitor thats actively being studied for chronic GVHD, as well as for pulmonary GVHD.16 Then there are other rho-kinase inhibitors, called ROCK2 inhibitors. This is really making waves. Were very excited about this drug because the response rates are very high, about 70%.10 Its a smaller study, but clearly it has antifibrotic pathways. So I think thats going to be used much more in the up-front setting.

Then theres also alpha-1 antitrypsin, which targets the liver and macrophages and has very promising results from trials done at Dana-Farber Cancer Institute and Michigan.17 So I think were going to see very different characteristics of how to approach GVHD.

What data support the use of ruxolitinib in this setting?

The REACH1 study led to the approval of ruxolitinib for steroid-refractory acute GVHD.9,18 In this phase 2 trial, patients with steroid-refractory acute GVHD got ruxolitinib (5 mg twice a day) with or without a calcineurin inhibitor. They were allowed to remain on steroids. The primary end point of this trial was overall response rate [ORR] at day 28. They also looked at response rates at day 56 and day 100, biomarkers, failure-free survival, and durability of these responses. The ORR at day 28 was very high: 54.9%.18 The best ORR, which was at any given time during the treatment, which was as high as 73.2%. The median time to response was 7 days. So this was very quick. The median duration of response was 345 days, with more than 6 months follow-up. Nonrelapse mortality at 6 months was 44.4%. There were deaths from infections, etc, but not related directly to ruxolitinib.

Subsequently there was a phase 3 trial, REACH2.19 They looked at higher doses of ruxolitinib in steroid-refractory acute GVHD. They started off with 10 mg [of ruxolitinib] twice a day. This study had a similar primary end point of ORR at day 28. This was compared with best available therapy. This was done in Europe, so [the comparison was to the] best available therapy used in Europe, like anti-thymocyte globulin, sirolimus [Rapamune], etanercept [Enbrel], photopheresis, or other therapies; all things that we would use in the United States as well. They looked at similar key secondary end points, [including] duration of response at day 56.

The ORR for ruxolitinib was 62% at day 28, compared with the best available therapy arm, which was 39% [odds ratio, 2.64; 95% CI, 1.65 to 4.22; P < .001].19 Durable overall response at day 56 [was higher in the ruxolitinib group than it was in the control group (40% vs 22%, odds ratio, 2.38; 95% CI, 1.43-3.94; P < .001)].19

The lower grade acute GVHD, which was grade 2, had the highest complete response rate with ruxolitinib: 50.9% compared with just 26.4% with best available therapy.19 This is quite remarkable to have a complete response in GVHD so quickly. When you get to higher grades of GVHD, the complete response rate for ruxolitinib is not as impressive; its less than 30%. But its still much higher than the [response rates of] other therapies we would have otherwise treated these patients with in steroid-refractory disease. The key point is to diagnose steroid refractoriness early. Then get ruxolitinib in there to break the cycle and break the progression of organ grade to something higher.

The loss of response wasnt statistically significant. The estimated cumulative incidents for the loss of response at 6 months was 10% in ruxolitinib compared with 39% in the control arm.19 So patients continued to maintain responses, which, again, is what we want to see. We dont want to see flares if they come off steroids.

[Of the 4 organ systems involved in GVHD], the skin responses were the best with ruxolitinib. Lower GI and liver GVHD did have good responses, but the responses were not as remarkable. Ruxolitinib is an ideal drug in this setting, on the basis of the organ responses.

A secondary end point was failure-free survival, basically indicating a time point from randomization to either nonrelapse-related death or any new GVHD. This was not statistically significant because it was not designed to compare ruxolitinib survival outcomes with control therapy. But there were 5.0 months median failure-free survival with ruxolitinib compared with 1.0 month with control [hazard ratio for relapse or progression of hematologic disease, nonrelapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35-0.60]. That tells you that the responses were maintained, and the treatment was still working.

[Most of the adverse events associated with ruxolitinib] were expected; the bone marrow is recovering so its a bit fragile. [The most common was] thrombocytopenia. You can reduce the dose of ruxolitinib down to 5 mg adjusted accordingly or support patients with transfusions. CMV reactivation was also common. But again, with letermovir, that happens less and less.

References:1. Merck receives FDA approval of Prevymis (letermovir) for prevention of cytomegalovirus (CMV) infection and disease in adult allogeneic stem cell transplant patients. News release. Merck. November 9, 2017. Accessed April 7, 2021.

2. Scott BL. Long-term follow up of BMT CTN 0901, a randomized phase 3 trial comparing myeloablative (MAC) to reduced intensity conditioning (RIC) prior to hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplasia (MDS) (MAvRIC Trial). Biol Blood Marrow Transplant. 2020;26(3):S11. doi:10.1016/j.bbmt.2019.12.07

3. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001

4. Martino R, Romero P, Subira M, et al. Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow

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Lab-created heart valves grow with the recipient – Lab + Life Scientist

By daniellenierenberg

A groundbreaking new study led by the University of Minnesota, Twin Cities has shown for the first time that lab-created heart valves implanted in young lambs for a year were capable of growth within the recipient.

The valves also showed reduced calcification and improved blood flow function compared to animal-derived valves currently used when tested in the same growing lamb model.

Currently, researchers have not been able to develop a heart valve that can grow and maintain function for paediatric patients. The only accepted options for these children with heart defects are valves made from chemically treated animal tissues that often become dysfunctional due to calcification and require replacement because they dont grow with the child. These children will often need to endure up to five (or more) open heart surgeries until a mechanical valve is implanted in adulthood. This requires them to take blood thinners the rest of their lives.

Minnesota Professor Robert Tranquillo and his colleagues used a hybrid of tissue engineering and regenerative medicine to create the growing heart valves. Over an eight-week period, they used a specialised tissue engineering technique they previously developed to generate vessel-like tubes in the lab from a post-natal donors skin cells. To develop the tubes, the researchers combined the donor sheep skin cells in a gelatine-like material, called fibrin, in the form of a tube and then provided nutrients necessary for cell growth using a bioreactor.

The researchers then used special detergents to wash away all the sheep cells from the tissue-like tubes, leaving behind a cell-free collagenous matrix that does not cause immune reaction when implanted. This means the tubes can be stored and implanted without requiring customised growth using the recipients cells.

The next step was to precisely sew three of these tubes (about 16 mm in diameter) together into a closed ring. The researchers then trimmed them slightly to create leaflets to replicate a structure similar to a heart valve about 19 mm in diameter.

After these initial steps, it looked like a heart valve, but the question then became if it could work like a heart valve and if it could grow, Prof Tranquillo said. Our findings confirmed both.

This second generation of tri-tube valves was implanted into the pulmonary artery of three lambs. After 52 weeks, the valve regenerated as its matrix became populated by cells from the recipient lamb, and the diameter increased from 19 mm to a physiologically normal valve about 25 mm. The researchers also saw a 17 to 34% increase in the length of the valve leaflets as measured from ultrasound images. In addition, researchers showed that the tri-tube valves worked better than current animal-derived valves, with almost none of the calcification or blood clotting that the other valves showed after being implanted in lambs of the same age.

We knew from previous studies that the engineered tubes have the capacity to regenerate and grow in a growing lamb model, but the biggest challenge was how to maintain leaflet function in a growing valved conduit that goes through 40 million cycles in a year, said Zeeshan Syedain, a senior research associate in Prof Tranquillos lab. When we saw how well the valves functioned for an entire year from young lamb to adult sheep, it was very exciting.

This is a huge step forward in paediatric heart research, Tranquillo said. This is the first demonstration that a valve implanted into a large animal model, in our case a lamb, can grow with the animal into adulthood.

If confirmed in humans, the new heart valves could prevent the need for repeated valve replacement surgeries in thousands of children born each year with congenital heart defects. The valves can also be stored for at least six months, which means they could provide surgeons with an off the shelf option for treatment.

The study has now been published in the journal Science Translational Medicine, while the valve-making procedure has been patented and licensed to University of Minnesota start-up company Vascudyne. Prof Tranquillo said the next steps are to implant the tri-tube valve directly into the right ventricle of the heart to emulate the most common surgical repair and then start the process of requesting approval from the US Food and Drug Administration (FDA) for human clinical trials over the next few years.

If we can get these valves approved someday for children, it would have such a big impact on the children who suffer from heart defects and their families who have to deal with the immense stress of multiple surgeries, Prof Tranquillo said. We could potentially reduce the number of surgeries these children would have to endure from five to one. Thats the dream.

Image credit: Syedain, et al, Tranquillo Lab, University of Minnesota.

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A New CRISPR Tool Flips Genes On and Off Like a Light Switch – Singularity Hub

By daniellenierenberg

CRISPR is revolutionary. Its also a total brute.

The classic version of the gene editing wunderkind literally slices a gene to bits just to turn it off. Its effective, yes. But its like putting an electrical wire through a paper shredder to turn off a misbehaving light bulb. Once the wires are cut, theres no going back.

Why not add a light switch instead?

This month, a team from the University of California, San Francisco (UCSF) reimagined CRISPR to do just that. Rather than directly acting on genesirrevocably dicing away or swapping genetic lettersthe new CRISPR variant targets the biological machinery that naturally turns genes on or off.

Translation? CRISPR can now flip a light switch to control geneswithout ever touching them directly. It gets better. The new tool, CRISPRoff, can cause a gene to stay silent for hundreds of generations, even when its host cells morph from stem cells into more mature cells, such as neurons. Once the sleeping beauty genes are ready to wake up, a complementary tool, CRISPRon, flips the light switch back on.

This new technology changes the game so now youre basically writing a change [into genes] that is passed down, said author Dr. Luke Gilbert. In some ways we can learn to create a version 2.0 of CRISPR-Cas9 that is safer and just as effective.

The crux is something called epigenetics. Its a whole system of chemicals and proteins that controls whether a gene is turned on or off.

If that sounds confusing, lets start with what genes actually look like inside a cell and how they turn on. By turning on, I mean that genes are made into proteinsthe stuff that builds our physical form, controls our metabolism, and makes us tick along as living, breathing humans.

Genes are embedded inside DNA chains that wrap very tightly around a core proteinkind of like bacon-wrapped asparagus. For genes to turn on, the first step is that they need a bunch of proteins to gently yank the DNA chain off the asparagus, so that the genes are now free-floating inside their cellular space capsule, called the nucleus.

Once that chunk of bacon-y DNA is free, more proteins rush over to grab onto the gene. Theyll then roll down the genes nucleotides (A, T, C, and G) like a lawn mower. Instead of mulch, however, this biological machine spews out a messenger that tells the cell to start making proteinsmRNAs. (Yup, the same stuff that makes some of our Covid-19 vaccines.) mRNA directs our cells protein factory to start production, and voil, that gene is now turned on!

Anything that disrupts this process nukes the genes ability to turn into proteins, essentially shutting it off. Its enormously powerfulbecause one single epigenetic machine can control hundreds or thousands of genes. Its a master light switch for the genome.

The team started with a CRISPR system that has a neutered Cas9. This means that the protein normally involved in cutting a gene, Cas9, can no longer snip DNA, even when tethered to the correct spot by the other component, the guide RNA bloodhound. They then tacked on a protein thats involved in switching off genes to this version of CRISPR.

Heres the clever part: the protein is designed to hijack a natural epigenetic process for switching genes off. Genes are often shut down through a natural process called methylation. Normally, the process is transient and reversible on a gene. CRISPRoff commandeers this process, in turn shutting down any targeted gene but for a far longer period of timewithout physically ripping the gene apart.

Thanks to epigenetics enhancing power, CRISPRoff lets researchers go big. In one experiment targeting over 20,000 genes inside immortalized human kidney cells with CRISPRoff, the team was able to reliably shut those genes off.

Not satisfied with a one-way street, the team next engineered a similar CRISPR variant, with a different epigenetics-related protein, dubbed CRISPRon. In cells inside petri dishes, CRISPRon was able to override CRISPRoff, and in turn, flip the genes back on.

We now have a simple tool that can silence the vast majority of genes, said study author Dr. Jonathan Weissman. We can do this for multiple genes at the same time without any DNA damage and in a way that can be reversed.

Even crazier, the off switch lasted through generations. When the team turned off a gene related to the immune system, it persisted for 15 monthsafter about 450 cellular generations.

The edits also lasted through a fundamental transformation, that is, a cells journey from an induced pluripotent stem cell (iPSC) to a neuron. iPSCs often start as skin cells, and are rejuvenated into stem cells through a chemical bath, when they then take a second voyage to become neurons. This process often wipes away epigenetic changes. But to the authors surprise, CRISPRoffs influence remained through the transformations. In one experiment, the team found that shutting off a gene related to Alzheimers in iPSCs also reduced the amount of subsequently encoded toxic proteins in the resulting neurons.

What we showed is that this is a viable strategy for silencing Tau and preventing that protein from being expressed, said Weissman, highlighting just one way CRISPRoffand controlling the epigenome in generalcan alter medicine.

This isnt the first time someones tried to target the epigenome with CRISPR. The same team previously experimented with another set of CRISPR variants that tried the same thing. The difference between the two is time and stability. With the previous setup, scientists struggled to keep the light switch off for a single generation. The new one has no trouble maintaining any changes through multiple divisionsand transformationsin the genome.

A reliable CRISPR tool for epigenetics is insanely powerful. Although we have drugs that work in similar ways, theyre far less accurate and come with a dose of side effects. For now, however, CRISPRoff and CRISPRon only work in cells in petri dishes, and the next step towards genomic supremacy would be to ensure they work in living beings.

If thats the case, it could change genetic editing forever. From reprogramming biological circuits in synthetic biology to hijacking or reversing ones to prevent disease, epigenetic reprogramming offers a way to do it all without ever touching a gene, nixing the threat of mutationswhile leading to lasting effects through generations.

I think our tool really allows us to begin to study the mechanism of heritability, especially epigenetic heritability, which is a huge question in the biomedical sciences, said study author Dr. James Nuez.

Image Credit: nobeastsofierce/

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How stress causes hair loss | National Institute on Aging – National Institute on Aging

By daniellenierenberg

From NIH Research Matters

Long-term, or chronic, stress puts people at risk for a variety of health problems. These can include depression and anxiety, as well as problems with digestion and sleep. Chronic stress has also long been linked to hair loss, but the reasons werent well understood.

Hair growth involves three stages. In growth (anagen), strands of hair push through the skin. In degeneration (catagen), hair ceases to grow, and the follicle at the base of the strand shrinks. In rest (telogen), hair falls out and the process can begin again. Hair is among the few tissues that mammals can regenerate throughout their lifetime.

The hair growth cycle is driven by stem cells that reside in the hair follicle. During growth, stem cells divide to become new cells that regenerate hair. In the resting period, the stem cells are inactive. Until now, researchers hadnt determined exactly how chronic stress impaired hair follicle stem cells.

A team led by Dr. Ya-Chieh Hsu of Harvard University studied the underlying mechanisms that link stress and hair loss. The study was supported in part by NIHs National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Results appeared in Nature, on March 4, 2021.

The researchers began by testing the role of the adrenal glands, which produce key stress hormonescorticosterone in rodents and cortisol in humans. Removing the adrenal glands from mice led to rapid cycles of hair regrowth. Hair follicle regeneration didnt slow as these mice grew older, like it did in control mice. Rather, hair follicle stem cells continued to enter the growth phase and regenerate hair follicles throughout the animals lifespans. The team was able to restore the normal hair cycle by feeding the mice corticosterone.

Subjecting mice to mild stress over many weeks increased corticosterone levels and reduced hair growth. Hair follicles remained in an extended resting phase. Together, these findings supported the role of corticosterone in inhibiting hair regrowth.

The scientists next examined how corticosterone affects hair follicle stem cells. They found that the stress hormone was not regulating stem cells directly. By deleting the receptor for corticosterone from different cells, they determined that the hormone acts on a cluster of cells underneath the hair follicle called the dermal papilla.

Further studies revealed that corticosterone prevented the dermal papilla from secreting GAS6, a molecule they showed can activate hair follicle stem cells. Delivering GAS6 into the skin restored hair growth in mice fed corticosterone or undergoing chronic stress.

Last year, findings from Hsus team advanced the understanding of how stress causes gray hair. These results reveal a key pathway involved in hair loss from chronic stress. These findings may also lead to further insights into how stress affects tissue regeneration in other parts of the body.

In the future, the Gas6 pathway could be exploited for its potential in activating stem cells to promote hair growth, says first author Dr. Sekyu Choi of Harvard University. However, further study is needed to understand whether the same mechanism is at work in people.

by Erin Bryant

This research was supported in part by NIA grant R01AG048908.

Reference: Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence. Choi S, Zhang B, Ma S, Gonzalez-Celeiro M, Stein D, Jin X, Kim ST, Kang YL, Besnard A, Rezza A, Grisanti L, Buenrostro JD, Rendl M, Nahrendorf M, Sahay A, Hsu YC. Nature. 2021 Mar 31. doi: 10.1038/s41586-021-03417-2. Online ahead of print. PMID: 33790465.

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Cellino Biotech developing tech to help scale stem cell therapies – MedCity News

By daniellenierenberg

In response to emailed questions, Cellino Biotech CEO and Co-founder Dr. Nabiha Saklayen, talked about the formation of the company and its goal to make stem cell therapies more accessible for patients.

Why did you start this company?

I see a huge need to develop a technology platform to enable the manufacture of cell therapies at scale. We recently closed a $16 million seed financing round led by Khosla Ventures and The Engine at MIT, with participation from Humboldt Fund. Cellino is on a mission to make personalized, autologous cell therapies accessible for patients. Stem cell-derived regenerative medicines are poised to cure some of the most challenging diseases within this decade, including Parkinsons, diabetes, and heart disease. Patient-specific cells provide the safest, most effective cures for these indications. However, current autologous processes are not scalable due to extensive manual handling, high variability, and expensive facility overhead. Cellinos vision is to make personalized regenerative medicines viable at large scale for the first time.

How did you meet your co-founders?

Nabiha Saklayen.

I met my co-founder Marinna Madrid in my Ph.D. research group. We had worked together for many years and had a fantastic working relationship. I then met our third co-founder Matthias Wagner through a friend. Matthias had built and run three optical technology companies in the Boston area and was looking to work with a new team. I was thrilled when we decided to launch the startup together at our second meeting. Matthias built the first Cellino hardware systems in what I like to call Matthias garage. In parallel, I was doing hundreds of expert interviews with biologists in academia and industry, and it started to narrow down our potential applications very quickly. Marinna was doing our first experiments with iPSCs. We iterated rapidly on building new versions of the hardware based on the features that were important to industry experts, such as single-cell precision and automation. Its incredible to witness our swift progress as a team.

What specific need or pain point are you seeking to address in healthcare/life sciences?

In general, autologous therapies are safer for patients because they do not require immunosuppression. The next iteration of cell therapies would use patient-specific stem cells banked ahead of time. Anytime a patient needs new cells, such as blood cells, neurons, or skin cells, we would generate them from a stem cell bank.

Today, patient-specific stem cell generation is a manual and artisanal process. A highly skilled scientist sits at a bench, looks at cells by eye, and removes unwanted cells with a pipette tip. Many upcoming clinical trials are using manual processes to produce stem cells for about ten to twenty patients.

At Cellino, we are converging different disciplines to automate this complex process. We use an AI-based laser system comes to remove any unwanted cells. By making stem cells for every human in an automated, scalable way, we are working towards our mission at Cellino to democratize personalized regenerative medicine.

What does your technology do? How does it work?

Cellinos platform combines label-free imaging and high-speed laser editing with machine learning to automate cell reprogramming, expansion, and differentiation in a closed cassette format, enabling thousands of patient samples to be processed in parallel in a single facility.

In general, autologous, patient-specific stem cell-derived therapies do not require immunosuppression and are safer for patients. Today, patient-specific stem cells are made manually, by hand. To scale the stem cell generation process, Cellino converges different disciplines to automate this complex process. We train machine learning algorithms to characterize cells before our AI-based laser system removes any unwanted cells. By making stem cells for every human in an automated, scalable way, our mission at Cellino is to democratize personalized regenerative medicine. Thats why our vision statement is Every human. Every cell.

Whats your background in healthcare? How did you get to where you are today?

When I arrived at Harvard University for my Ph.D. in physics, I wanted to be closer to real-world applications. Biology is inherently complex and beautiful, and I was interested in developing new physics-based tools to engineer cells with precision. During my Ph.D., I invented new ways to edit cells with laser-based nanomaterials. I collaborated with many brilliant biology groups at Harvard, including the Rossi, Scadden, and Church labs. Working closely with them convinced me that lasers offer a superior solution to editing cells with high precision. That realization compelled me to launch Cellino.

Do you have clinical validation for your product?

Our immediate goal for the next year is to show that our platform can produce personalized, high-quality, R&D-grade stem cells for different patients, which has not been established in an automated manner in the regenerative medicine industry so far. There is significant patient-to-patient variability in manual cell processing, which we eliminate with our platform.

Photo: Urupong, Getty Images

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A Massive New Gene Editing Project Is Out to Crush Alzheimer’s – Singularity Hub

By daniellenierenberg

When it comes to Alzheimers versus science, science is on the losing side.

Alzheimers is cruel in the most insidious way. The disorder creeps up in some aging brains, gradually eating away at their ability to think and reason, whittling down their grasp on memories and reality. As the worlds population ages, Alzheimers is rearing its ugly head at a shocking rate. And despite decades of research, we have no treatmentnot to mention a cure.

Too much of a downer? The National Institutes of Health (NIH) agrees. In one of the most ambitious projects in biology, the NIH is corralling Alzheimers and stem cell researchers to come together in the largest genome editing project ever conceived.

The idea is simple: decades of research have found certain genes that seem to increase the chance of Alzheimers and other dementias. The numbers range over hundreds. Figuring out how each connects or influences anotherif at alltakes years of research in individual labs. What if scientists unite, tap into a shared resource, and collectively solve the case of why Alzheimers occurs in the first place?

The initiatives secret weapon is induced pluripotent stem cells, or iPSCs. Similar to most stem cells, they have the ability to transform into anythinga cellular Genie, if you will. iPSCs are reborn from regular adult cells, such as skin cells. When transformed into a brain cell, however, they carry the original genes of their donor, meaning that they harbor the original persons genetic legacyfor example, his or her chance of developing Alzheimers in the first place. What if we introduce Alzheimers-related genes into these reborn stem cells, and watch how they behave?

By studying these iPSCs, we might be able to follow clues that lead to the genetic causes of Alzheimers and other dementiaspaving the road for gene therapies to nip them in the bud.

The iPSC Neurodegenerative Disease Initiative (iNDI) is set to do just that. The project aims to stimulate, accelerate, and support research that will lead to the development of improved treatments and preventions for these diseases, the NIH said. All resulting datasets will be openly shared online, for anyone to mine and interpret.

In plain language? Lets throw all of our new biotech superstarswith CRISPR at the forefrontinto a concerted effort against Alzheimers, to finally gain the upper hand. Its an Avengers, assemble moment towards one of our toughest foesone that seeks to destroy our own minds from within.

Alzheimers disease was first recognized in the early 1900s. Ever since, scientists have strived to find the cause that makes a brain waste away.

The most prominent idea today is the amyloid hypothesis. Imagine a horror movie inside a haunted house with ghosts that gradually intensify in their haunting. Thats the amyloid horrora protein that gradually but silently builds up inside a neuron, the house, eventually stripping it of its normal function and leading to the death of anything inside. Subsequent studies also found other toxic proteins that hang around outside the neuron house that gradually poison the molecular tenants within.

For decades scientists have thought that the best approach to beat these ghosts was an exorcismthat is, to get rid of these toxic proteins. Yet in trial after trial, they failed. The failure rate for Alzheimers treatmentso far, 100 percenthas led some to call treatment efforts a graveyard of dreams.

Its pretty obvious we need new ideas.

A few years ago, two hotshots strolled into town. One is CRISPR, the wunderkind genetic sharpshooter that can snip way, insert, or swap out a gene or two (or more). The other is iPSCs, induced pluripotent stem cells, which are reborn from adult cells through a chemical bath.

The two together can emulate Dementia 2.0 in a dish.

For example, using CRISPR, scientists can easily insert genes related to Alzheimers, or its protection, into an iPSCeither that from a healthy donor, or someone with a high risk of dementia, and observe what happens. A brain cell is like a humming metropolitan area, with proteins and other molecules whizzing around. Adding in a dose of pro-Alzheimers genes, for example, could block up traffic with gunk, leading scientists to figure out how those genes fit into the larger Alzheimers picture. For the movie buffs out there, its like adding into a cell a gene for Godzilla and another for King Kong. You know both could mess things up, but only by watching what happens in a cell can you know for sure.

Individual labs have tried the approach since iPSCs were invented, but theres a problem. Because iPSCs inherit the genetic baseline of a person, it makes it really difficult for scientists in different labs to evaluate whether a gene is causing Alzheimers, or if it was just a fluke because of the donors particular genetic makeup.

The new iNDI plan looks to standardize everything. Using CRISPR, theyll add in more than 100 genes linked to Alzheimers and related dementias into iPSCs from a wide variety of ethnically diverse healthy donors. The result is a huge genome engineering project, leading to an entire library of cloned cells that carry mutations that could lead to Alzheimers.

In other words, rather than studying cells from people with Alzheimers, lets try to give normal, healthy brain cells Alzheimers by injecting them with genes that could contribute to the disorder. If you view genes as software code, then its possible to insert code that potentially drives Alzheimers into those cells through gene editing. Execute the program, and youll be able to observe how the neurons behave.

The project comes in two phases. The first focuses on mass-engineering cells edited with CRISPR. The second is thoroughly analyzing these resulting cells: for example, their genetics, how their genes activate, what sorts of proteins they carry, how those proteins interact, and so on.

By engineering disease-causing mutations in a set of well-characterized, genetically diverse iPSCs, the project is designed to ensure reproducibility of data across laboratories and to explore the effect of natural variation in dementia, said Dr. Bill Skarnes, director of cellular engineering at the Jackson Laboratory, and a leader of the project.

iNDI is the kind of initiative thats only possible with our recent biotech boost. Engineering hundreds of cells related to Alzheimersand to share with scientists globallywas a pipe dream just two decades ago.

To be clear, the project doesnt just generate individual cells. It uses CRISPR to make cell lines, or entire lineages of cells with the Alzheimers gene that can pass on to the next generation. And thats their power: they can be shared with labs around the world, to further hone in on genes that could make the largest impact on the disorder. Phase two of iNDI is even more powerful, in that it digs into the inner workings of these cells to generate a cheat codea sheet of how their genes and proteins behave.

Together, the project does the hard work of building a universe of Alzheimers-related cells, each outfitted with a gene that could make an impact on dementia. These types of integrative analyses are likely to lead to interesting and actionable discoveries that no one approach would be able to learn in isolation, the authors wrote. It provides the best chance at truly understanding Alzheimers and related diseases, and promising treatment possibilities.

Image Credit: Gerd Altmann from Pixabay

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Stress may be getting to your skin, but it’s not a one-way street – Harvard Health Blog – Harvard Health

By daniellenierenberg

Are you stressed out? Your skin can show it. Studies show that both acute and chronic stress can exert negative effects on overall skin wellness, as well as exacerbate a number of skin conditions, including psoriasis, eczema, acne, and hair loss.

But its not just a one-way street. Research has also shown that skin and hair follicles contain complex mechanisms to produce their own stress-inducing signals, which can travel to the brain and perpetuate the stress response.

You may already have experienced the connection between the brain and skin. Have you ever gotten so nervous that you started to flush or sweat? If so, you experienced an acute, temporary stress response. But science suggests that repeated exposure to psychological or environmental stressors can have lasting effects on your skin that go far beyond flushing and could even negatively affect your overall well-being.

The brain-skin axis is an interconnected, bidirectional pathway that can translate psychological stress from the brain to the skin and vice versa. Stress triggers the hypothalamus-pituitary-adrenal (HPA) axis, a trio of glands that play key roles in the bodys response to stress. This can cause production of local pro-inflammatory factors, such as cortisol and key hormones in the fight-or-flight stress response called catecholamines, which can direct immune cells from the bloodstream into the skin or stimulate pro-inflammatory skin cells. Mast cells are a key type of pro-inflammatory skin cell in the brain-skin axis; they respond to the hormone cortisol through receptor signaling, and directly contribute to a number of skin conditions, including itch.

Because the skin is constantly exposed to the outside world, it is more susceptible to environmental stressors than any other organ, and can produce stress hormones in response to them. For example, the skin produces stress hormones in response to ultraviolet light and temperature, and sends those signals back to the brain. Thus, psychological stressors can contribute to stressed-out skin, and environmental stressors, via the skin, can contribute to psychological stress, perpetuating the stress cycle.

Psychological stress can also disrupt the epidermal barrier the top of layer of the skin that locks in moisture and protects us from harmful microbes and prolong its repair, according to clinical studies in healthy people. An intact epidermal barrier is essential for healthy skin; when disrupted, it can lead to irritated skin, as well as chronic skin conditions including eczema, psoriasis, or wounds. Psychosocial stress has been directly linked to exacerbation of these conditions in small observational studies. Acne flares have also been linked to stress, although the understanding of this relationship is still evolving.

The negative effects of stress have also been demonstrated in hair. One type of diffuse hair loss, known as telogen effluvium, can be triggered by psychosocial stress, which can inhibit the hair growth phase. Stress has also been linked to hair graying in studies of mice. The research showed that artificial stress stimulated the release of norepinephrine (a type of catecholamine), which depleted pigment-producing stem cells within the hair follicle, resulting in graying.

While reducing stress levels should theoretically help to alleviate damaging effects on the skin, theres only limited data regarding the effectiveness of stress-reducing interventions. There is some evidence that meditation may lower overall catecholamine levels in people who do it regularly. Similarly, meditation and relaxation techniques have been shown to help psoriasis. More studies are needed to show the benefit of these techniques in other skin conditions. Healthy lifestyle habits, including a well-balanced diet and exercise, may also help to regulate stress hormones in the body, which should in turn have positive effects for skin and hair.

If you are experiencing a skin condition related to stress, see a dermatologist for your condition, and try some stress-reducing techniques at home.

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Leukemia Cutis: Symptoms and Treatment – Healthline

By daniellenierenberg

Leukemia cutis can happen when leukemia cells enter your skin. This rare condition causes patches of discolored skin to appear on the body.

In some cases, the appearance of leukemia cutis lesions on the skin is the first sign of leukemia a cancer of the blood and bone marrow.

Along with standard leukemia therapies, this complication can usually be addressed with topical treatments to help heal the damaged skin. If you have leukemia cutis, your outlook will usually depend on your age and the type of leukemia you have.

Leukemia cutis is an uncommon complication, affecting only about 3 percent of people with leukemia. However, it is often a sign that the cancer is at an advanced stage.

With leukemia, malignant leukocytes (white blood cells) are usually only present in the bloodstream. In the case of leukemia cutis, the leukocytes have entered the skin tissue, causing lesions to appear on the outer layer of your skin. The word cutis refers to the skin, or dermis.

Generally, leukemia cutis results in one or more lesions or patches forming on the outer layer of skin. This condition can mean that the leukemia is more advanced and may have spread to your bone marrow and other organs.

Because there are fewer healthy white cells to combat infections caused by other diseases, rashes and sores may be more common among people with leukemia. Low blood platelets from leukemia can cause damage to blood vessels that appear as red spots or lesions on the skin.

These may include:

However, these skin changes are different than those brought on by leukemia cutis.

While the legs are the most common area for leukemia cutis lesions to appear, they can also form on the arms, face, trunk, and scalp. These skin changes can include:

The lesions usually dont hurt. However, with certain types of leukemia particularly acute myeloid leukemia (AML) the lesions may bleed.

A dermatologist may initially diagnose leukemia cutis based on a physical examination of the skin and a review of your medical history. A skin biopsy is needed to confirm the diagnosis.

Leukemia cutis is a sign of leukemia. It wont develop if the body isnt already dealing with this type of blood cancer.

But leukemia isnt just one disease. There are multiple types of leukemia, each one classified by the kind of cell affected by the disease.

You can also have an acute or a chronic form of leukemia. Acute means it comes on suddenly and usually with more severe symptoms. Chronic leukemia develops more slowly and often with milder symptoms.

The types of leukemia that most commonly trigger leukemia cutis are AML and chronic lymphocytic leukemia (CLL).

Scientists arent sure why cancerous leukocytes migrate to skin tissue in some people with leukemia. It may be that the skin is an optimal environment for healthy leukocytes to transform into cancerous cells.

One possible risk factor that has emerged is an abnormality in chromosome 8, which has been found more often in individuals with leukemia cutis than in those without it.

Treating leukemia cutis usually includes treatment for leukemia as the underlying condition.

The standard leukemia treatment is chemotherapy, but other options may be considered depending on your overall health, your age, and the type of leukemia you have.

Other leukemia treatment options include:

For blood cancers, external beam radiation is a typical form of treatment. With this therapy, a focused beam of radiation is delivered outside the body from various angles. The goal is to injure the DNA in cancer cells to stop them from reproducing.

Immunotherapy, a type of biological therapy, uses the bodys own immune system to fight cancer. It is typically given by an injection that either stimulates immune system cells activity or blocks the signals cancer cells send to suppress the immune response.

Immunotherapy may also be given orally, topically, or intravesically (into the bladder).

Stem cell transplantation is more commonly known as a bone marrow transplant. Bone marrow is where blood stem cells develop. Stem cells can become any type of cell.

Through stem cell transplantation, healthy blood stem cells replace stem cells damaged by the cancer or by chemotherapy or radiation therapy. However, not everyone is a good candidate for this treatment.

Only treating the leukemia cutis lesions will not address the underlying disease of leukemia. That means treatments designed to remove or reduce lesions should be done in combination with systemic treatment for leukemia itself.

Treatments for leukemia cutis symptoms can include:

Again, these treatments will only treat the leukemia cutis lesions, but systemic treatment of the leukemia itself will be needed as well.

The length of time leukemia cutis lesions may last depends on many factors, including how well the leukemia itself is responding to treatment. If the leukemia goes into remission, its unlikely more lesions will appear.

With effective treatment, existing lesions could fade. However, other factors, including your age and overall health, can affect how widespread the lesions are and how long they may last.

There are encouraging trends in the treatment of leukemia, but it remains a challenging disease to treat and live with.

For people with AML who dont have leukemia cutis, research suggests that the survival rate at 2 years is about 30 percent. However, the survival rate drops to 6 percent among people with the skin lesions.

A separate study of 1,683 people with AML found that leukemia cutis was associated with a poor prognosis, and that those with AML and leukemia cutis may benefit from more aggressive treatment.

The outlook for people with CLL is better, with about an 83 percent survival rate at 5 years. The presence of leukemia cutis doesnt seem to change that outlook very much, according to a 2019 study.

Leukemia cutis is a rare complication of leukemia. It happens when malignant leukocytes invade the skin and cause lesions on the skins outer surface.

AML and CLL are more often associated with leukemia cutis than other types of leukemia.

While leukemia cutis usually means the leukemia is in an advanced stage, there are treatments for both the cancer and this uncommon side effect that may help extend life and improve its quality.

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We’re creating ‘humanized pigs’ in our ultraclean lab to study human illnesses and treatments – Alton Telegraph

By daniellenierenberg

(The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts.)

Christopher Tuggle, Iowa State University and Adeline Boettcher, Iowa State University

(THE CONVERSATION) The U.S. Food and Drug Administration requires all new medicines to be tested in animals before use in people. Pigs make better medical research subjects than mice, because they are closer to humans in size, physiology and genetic makeup.

In recent years, our team at Iowa State University has found a way to make pigs an even closer stand-in for humans. We have successfully transferred components of the human immune system into pigs that lack a functional immune system. This breakthrough has the potential to accelerate medical research in many areas, including virus and vaccine research, as well as cancer and stem cell therapeutics.

Existing biomedical models

Severe Combined Immunodeficiency, or SCID, is a genetic condition that causes impaired development of the immune system. People can develop SCID, as dramatized in the 1976 movie The Boy in the Plastic Bubble. Other animals can develop SCID, too, including mice.

Researchers in the 1980s recognized that SCID micecould be implanted with human immune cells for further study. Such mice are called humanized mice and have been optimized over the past 30 years to study many questions relevant to human health.

Mice are the most commonly used animal in biomedical research, but results from mice often do not translate well to human responses, thanks to differences in metabolism, size and divergent cell functions compared with people.

Nonhuman primates are also used for medical research and are certainly closer stand-ins for humans. But using them for this purpose raises numerous ethical considerations. With these concerns in mind, the National Institutes of Health retired most of its chimpanzees from biomedical research in 2013.

Alternative animal models are in demand.

Swine are a viable option for medical research because of their similarities to humans. And with their widespread commercial use, pigs are met with fewer ethical dilemmas than primates. Upwards of 100 million hogs are slaughtered each year for food in the U.S.

Humanizing pigs

In 2012, groups at Iowa State University and Kansas State University, including Jack Dekkers, an expert in animal breeding and genetics, and Raymond Rowland, a specialist in animal diseases, serendipitously discovered a naturally occurring genetic mutation in pigs that caused SCID. We wondered if we could develop these pigs to create a new biomedical model.

Our group has worked for nearly a decade developing and optimizing SCID pigs for applications in biomedical research. In 2018, we achieved a twofold milestone when working with animal physiologist Jason Ross and his lab. Together we developed a more immunocompromised pig than the original SCID pig and successfully humanized it, by transferring cultured human immune stem cells into the livers of developing piglets.

During early fetal development, immune cells develop within the liver, providing an opportunity to introduce human cells. We inject human immune stem cells into fetal pig livers using ultrasound imaging as a guide. As the pig fetus develops, the injected human immune stem cells begin to differentiate or change into other kinds of cells and spread through the pigs body. Once SCID piglets are born, we can detect human immune cells in their blood, liver, spleen and thymus gland. This humanization is what makes them so valuable for testing new medical treatments.

We have found that human ovarian tumors survive and grow in SCID pigs, giving us an opportunity to study ovarian cancer in a new way. Similarly, because human skin survives on SCID pigs, scientists may be able to develop new treatments for skin burns. Other research possibilities are numerous.

Pigs in a bubble

Since our pigs lack essential components of their immune system, they are extremely susceptible to infection and require special housing to help reduce exposure to pathogens.

SCID pigs are raised in bubble biocontainment facilities. Positive pressure rooms, which maintain a higher air pressure than the surrounding environment to keep pathogens out, are coupled with highly filtered air and water. All personnel are required to wear full personal protective equipment. We typically have anywhere from two to 15 SCID pigs and breeding animals at a given time. (Our breeding animals do not have SCID, but they are genetic carriers of the mutation, so their offspring may have SCID.)

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As with any animal research, ethical considerations are always front and center. All our protocols are approved by Iowa State Universitys Institutional Animal Care and Use Committee and are in accordance with The National Institutes of Healths Guide for the Care and Use of Laboratory Animals.

Every day, twice a day, our pigs are checked by expert caretakers who monitor their health status and provide engagement. We have veterinarians on call. If any pigs fall ill, and drug or antibiotic intervention does not improve their condition, the animals are humanely euthanized.

Our goal is to continue optimizing our humanized SCID pigs so they can be more readily available for stem cell therapy testing, as well as research in other areas, including cancer. We hope the development of the SCID pig model will pave the way for advancements in therapeutic testing, with the long-term goal of improving human patient outcomes.

Adeline Boettcher earned her research-based Ph.D. working on the SCID project in 2019.

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Frog skin cells turned themselves into living machines – Science News Magazine

By daniellenierenberg

Using blobs of skin cells from frog embryos, scientists have grown creatures unlike anything else on Earth, a new study reports. These microscopic living machines can swim, sweep up debris and heal themselves after a gash.

Scientists often strive to understand the world as it exists, says Jacob Foster, a collective intelligence researcher at UCLA not involved with this research. But the new study, published March 31 in Science Robotics, is part of a liberating moment in the history of science, Foster says. A reorientation towards what is possible.

In a way, the bots were self-made. Scientists removed small clumps of skin stem cells from frog embryos, to see what these cells would do on their own. Separated from their usual spots in a growing frog embryo, the cells organized themselves into balls and grew. About three days later, the clusters, called xenobots, began to swim.

Normally, hairlike structures called cilia on frog skin repel pathogens and spread mucus around. But on the xenobots, cilia allowed them to motor around. That surprising development is a great example of life reusing whats at hand, says study coauthor Michael Levin, a biologist at Tufts University in Medford, Mass.

And that process happens fast. This isnt some sort of effect where evolution has found a new use over hundreds of thousands of years, Levin says. This happens in front of your eyes within two or three days.

Xenobots have no nerve cells and no brains. Yet xenobots each about half a millimeter wide can swim through very thin tubes and traverse curvy mazes. When put into an arena littered with small particles of iron oxide, the xenobots can sweep the debris into piles. Xenobots can even heal themselves; after being cut, the bots zipper themselves back into their spherical shapes.

Scientists are still working out the basics of xenobot life. The creatures can live for about 10 days without food. When fed sugar, xenobots can live longer (though they dont keep growing). Weve grown them for over four months in the lab, says study coauthor Doug Blackiston, also at Tufts. They do really interesting things if you grow them, including forming strange balloon-like shapes.

Its not yet clear what sorts of jobs these xenobots might do, if any. Cleaning up waterways, arteries or other small spaces comes to mind, the researchers say. More broadly, these organisms may hold lessons about how bodies are built, Levin says.

With the advent of new organisms comes ethical issues, cautions Kobi Leins, a digital ethics researcher at the University of Melbourne in Australia. Scientists like to make things, and dont necessarily think about what the repercussions are, she says. More conversations about unintended consequences are needed, she says.

Levin agrees. The small xenobots are fascinating in their own rights, he says, but they raise bigger questions, and bigger possibilities. Its finding a whole galaxy of weird new things.

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The Next Generation of Living Machines: Xenobots 2.0 – Freethink

By daniellenierenberg

Last year, something new was grafted to the tree of life.

Somewhere between a living organism and a robot, these tiny, living machines were created from clumps of stem cells from the African clawed frog. Stem cells from the heart gave them muscle, while skin stem cells provided structure.

Dubbed "Xenobots" (after the frog's scientific name not, alas, xenomorphs), their creators found that the living machines that could complete simple tasks in Petri dishes, as Freethink's Amanda Winkler explained last year.

Those same researchers, from Tufts and the University of Vermont, have now developed a second iteration, Xenobots 2.0, if you will, which can "self-assemble a body from single cells, do not require muscle cells to move, and even demonstrate the capability of recordable memory," as Tufts Now explains.

These Xenobots are also faster, can make their way through more complex environments, live longer than their predecessors, work in concert, and heal themselves.

Yeah, that sounds a lot like the T-1000 to me, too.

First generation Xenobots were constructed with a "top-down" approach, as Tufts put it. The researchers manually placed and surgically sculpted the heart and skin cells to form tiny biological robots in a variety of shapes.

Their shapes chosen with the help of a digital Xenobots simulator then impacted their various movements.

The original Xenobots were capable of "crawling, traveling in circles, moving small objects or even joining with other organic bots to collectively perform tasks," Winkler reported.

But to create Xenobots 2.0, the researchers utilized a "bottom up" approach, published in the journal Science Robotics.

Rather than crafting the frog heart and stem cells, the researchers simply scraped off some skin stem cells from frog embryos. Left to their own devices, the cells glommed together into spheroids on their own.

They could survive for 10 days without food and even grow if some sugar's in the mix.

"We've grown them for over four months in the lab," Tufts' Doug Blackiston, study coauthor, told Science News. "They do really interesting things if you grow them," including forming new, balloon-like shapes.

Some of the cells adapted to grow cilia a few days in. Usually used by cells to push away pathogens and ensure a nice coating of protective mucus, the Xenobots used their cilia to move around, eliminating the need for heart stem cells.

It's an example of life's remarkable plasticity, the researchers say.

"In a frog embryo, cells cooperate to create a tadpole. Here, removed from that context, we see that cells can re-purpose their genetically encoded hardware, like cilia, for new functions such as locomotion," Michael Levin, professor of biology and director of Tufts' Allen Discovery Center and study corresponding author told Tufts Now.

"It is amazing that cells can spontaneously take on new roles and create new body plans and behaviors without long periods of evolutionary selection for those features."

Along with those new body plans came new abilities. Xenobots 2.0 can move around just like the first iteration did, but they are faster than what the researchers constructed. They're also better at sweeping up junk a swarm of them can round up iron oxide particles in a Petri dish and they can coat flat surfaces and shimmy through narrow capillaries.

Because they are biological, the Xenobots could also heal themselves, forming back together after injury even recovering from full-length lacerations halfway through their "bodies" in just 5 minutes.

"In a frog embryo, cells cooperate to create a tadpole. Here, removed from that context, we see that cells can re-purpose their genetically encoded hardware, like cilia, for new functions such as locomotion."

Just like before, the Tufts team turned to computer simulations to tease out the best Xenobot layouts. Researchers at the University of Vermont did the data crunching, using the Vermont Advanced Computing Core's supercomputer cluster, called Deep Green.

Deep Green comes in because "it's not at all obvious for people what a successful design should look like," UVM computer scientist and robotics expert Josh Bongard told Tufts Now. "That's where the supercomputer comes in and searches over the space of all possible Xenobot swarms to find the swarm that does the job best."

The hope is that eventually Xenobots will be able to perform tasks like clearing microplastics from the ocean, or decontaminating soil.

Performing those jobs would be a hell of a lot easier with the ability to retain and access memory for guiding their actions something the original Xenobots lacked. This time around, the researchers gave them the ability to hold on to one piece of information.

The researchers injected the frog stem cells with mRNA carrying the instructions for a protein called EosFP. This protein normally glows green, but when exposed to a specific wavelength of light, it turns red instead.

Armed with their little running light, the Xenobots could now keep a record of being exposed to certain wavelengths of blue light in their environment. Further work could potentially allow them to keep track of multiple variables, or even alter their behaviors accordingly.

"When we bring in more capabilities to the bots, we can use the computer simulations to design them with more complex behaviors and the ability to carry out more elaborate tasks," Bongard said. "We could potentially design them not only to report conditions in their environment but also to modify and repair conditions in their environment."

The researchers' original work already opened questions of what, exactly, Xenobots are. Are they lifeforms? Robots, but made of biological material, in lieu of nuts and bolts?

As you can imagine, these improved iterations which organize on their own are provoking more of the same.

Tel Aviv University evolutionary biologist Eva Jablonka, who is unaffiliated with the work, told Quanta Magazine that she considers them a new form of life "defined by what it does rather than to what it belongs developmentally and evolutionarily."

Armed with a special protein that changes color from green to red, the next generation Xenobots could keep a simple record of their exposure to blue light. Credit: Doug Blackiston & Emma Lederer, Tufts University

University of Melbourne digital ethics researcher Kobi Leins believes new ethical issues arise with the creation of new forms of life. "Scientists like to make things, and don't necessarily think about what the repercussions are," she told Science News.

(For what it's worth, Levin agrees, telling Science News the questions raised by the Xenobots are like "finding a whole galaxy of weird new things.")

Levin hopes that within that galaxy, the Xenobots will do more than perform tasks: they may help us understand how biological life itself develops.

We'd love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at [emailprotected]

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Fat grafting shows promise for cancer patients with radiation-induced skin injury – Newswise

By daniellenierenberg

Newswise March 30, 2021 As cancer survival rates improve, more people are living with the aftereffects of cancer treatment. For some patients, these issues include chronic radiation-induced skin injury which can lead to potentially severe cosmetic and functional problems.

Recent studies suggest a promising new approach in these cases, using fat grafting procedures to unleash the healing and regenerative power of the body's natural adipose stem cells (ASCs). "Preliminary evidence suggests that fat grafting can make skin feel and look healthier, restore lost soft tissue volume, and help alleviate pain and fibrosis in patients with radiation-induced skin injury after cancer treatment," says J. Peter Rubin, MD, MBA, FACS, American Society of Plastic Surgeons (ASPS) President-Elect and Chair of the Department of Plastic Surgery at University of Pittsburgh Medical Center. He is one of the authors of a new review of the clinical evidence on fat grafting for radiation-induced skin and soft tissue injury.

"But while promising, available research has some key weaknesses that make it difficult for us to determine the true benefits of fat grafting right now," Dr. Rubin adds. The review appears in the April issue of Plastic and Reconstructive Surgery, the official medical journal of the ASPS.

More than half of patients diagnosed with cancer receive radiation therapy. Because skin cells turn over rapidly, they are exquisitely sensitive to the damaging effects of radiation. In the first few months after treatment, many patients develop acute radiation injury with skin inflammation, peeling, swelling, pain and itching. In most cases, symptoms resolve over time. However, if inflammation continues, radiation-induced skin injury can become a chronic problem leading to tight, stiff skin (fibrosis) with a risk of poor wound healing, ulcers, and tissue loss.

Fat grafting procedures transferring the patient's own fat cells from one part of the body to another have become widely used in many cosmetic and reconstructive plastic surgery procedures. In their review, Dr. Rubin and colleagues round up promising research on fat grafting for patients with radiation-induced skin injury.

In studies of breast cancer patients, fat grafting procedures have reduced pain and other symptoms of radiation-induced skin injury backed up by more-normal cellular appearance of skin cells under the microscope. In other studies, fat grafting has led to reduced risks and better outcomes of breast reconstruction after mastectomy.

For patients with radiation-induced skin injury after treatment for head and neck cancer, fat grafting has led to improvements in voice, breathing, swallowing, and movement. Good outcomes have also been reported in patients with radiation-induced skin injury in the area around the eye or in the limbs.

"The good news is fat grafting has the potential to really help patients with discomfort and disability caused by radiation-induced skin damage," according to Dr. Rubin. While research is ongoing, the benefits of fat grafting seem to result from the wide-ranging effects of ASCs including anti-scarring, antioxidant, immune-modulating, regenerative, and other actions.

"However," he adds, "the available evidence has a lot of shortcomings, including small sample sizes, lower-quality research designs, and a lack of comparison groups." Variations in fat cell collection and processing, as well as the timing and "dose" of fat grafting, make it difficult to compare results between studies. There are also unanswered questions regarding potential risks related to ASC injection and concerns that fat grafting might affect cancer follow-up.

The reviewers outline some steps for further research to clarify the benefits of fat grafting for radiation-induced skin and soft issue injury, including approaches to clinical assessment and imaging studies, testing of skin biomechanics and circulation, and cellular-level analyses. For all of these outcomes, standardized measures are needed to achieve more comparable results between studies.

"We hope our review will inform efforts to establish the benefits of specific types of fat grafting procedures in specific groups of patients," says Dr. Rubin. "To do that, we'll need studies including larger numbers of patients, adequate control groups, and consistent use of objective outcome measures."

Click here to read Fat Grafting in Radiation-Induced Soft-Tissue Injury: A Narrative Review of the Clinical Evidence and Implications for Future Studies.

DOI: 10.1097/PRS.0000000000007705


Plastic and Reconstructive Surgery is published in the Lippincott portfolio by Wolters Kluwer.

About Plastic and Reconstructive Surgery

For more than 70 years, Plastic and Reconstructive Surgery ( has been the one consistently excellent reference for every specialist who uses plastic surgery techniques or works in conjunction with a plastic surgeon. The official journal of the American Society of Plastic Surgeons, Plastic and Reconstructive Surgery brings subscribers up-to-the-minute reports on the latest techniques and follow-up for all areas of plastic and reconstructive surgery, including breast reconstruction, experimental studies, maxillofacial reconstruction, hand and microsurgery, burn repair and cosmetic surgery, as well as news on medico-legal issues.

About ASPS

The American Society of Plastic Surgeons is the largest organization of board-certified plastic surgeons in the world. Representing more than 7,000 physician members, the society is recognized as a leading authority and information source on cosmetic and reconstructive plastic surgery. ASPS comprises more than 94 percent of all board-certified plastic surgeons in the United States. Founded in 1931, the society represents physicians certified by The American Board of Plastic Surgery or The Royal College of Physicians and Surgeons of Canada.

About Wolters Kluwer

Wolters Kluwer (WKL) is a global leader in professional information, software solutions, and services for the clinicians, nurses, accountants, lawyers, and tax, finance, audit, risk, compliance, and regulatory sectors. We help our customers make critical decisions every day by providing expert solutions that combine deep domain knowledge with advanced technology and services.

Wolters Kluwer reported 2019 annual revenues of 4.6 billion. The group serves customers in over 180 countries, maintains operations in over 40 countries, and employs approximately 19,000 people worldwide. The company is headquartered in Alphen aan den Rijn, the Netherlands.

Wolters Kluwer provides trusted clinical technology and evidence-based solutions that engage clinicians, patients, researchers and students with advanced clinical decision support, learning and research and clinical intelligence. For more information about our solutions, visit follow us onLinkedInand Twitter@WKHealth.

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Augustinus Bader and the making of a $70m phenomenon – Financial Times

By daniellenierenberg

The Augustinus Bader story hasbecome a beauty legend. Professor Bader, one of the worlds leading stem-cell experts, makes a groundbreaking wound gel that rehabilitates the skin of burns victims,without the need for grafts or scarring. At a dinner hosted by Robert Friedland, the self-made billionaire and long-time mentor to Steve Jobs, Bader meets Charles Rosier, a young French financier. They are kicking around ideas forfunding the necessary clinical trials forthe product, which would likely run intothetens of millions. Pharmaceutical companies arent interested because most burns victims are in emerging countries, where the market for sophisticated healing products is negligible.

Rosier has a flash of inspiration: couldBader use what he knows about wound healing to make an anti-ageing cream? Yes, answers Bader unhesitatingly. Two years and much cajoling later, the professor makes a prototype skincare cream, and pretty soon anyone who has ever had more than a passing interest in face cream is talking about it.

According to Deloitte, as many as 90per cent of beauty launches fail within ayear. By contrast, the Augustinus Bader skincare brand has grown from a turnover of $7m in 2018 to $70m in 2020. It has also shattered traditional conventions of luxury skincare along the way. For a start, the company launched with just two face products, The Cream (fornormal/oily skin) and The Rich Cream (dry skin) and insisted that apart from cleanser andSPF theyre all you need to use. No eye cream, no neck cream, no serum underneath, no primer ontop just one cream, and a very specific two pumps at that. This was intriguing. Most luxury-skincare brands (the creams retail at205 each) dont just sell you a dream they sell you a regime.

Charles Rosier believes that their inexperience in the beauty industry helpedat first. If Id known how complex and competitive the industry is, maybe Iwouldnt have had so much passion for it. But because I had seen what Augustinuss science could do, I was truly convinced thathe could create a product that was new, disruptive and of higher quality than whatever else was in the market.

As it turned out, it was. Celebrities normally paid handsomely to endorse beauty brands were not only recommending the Augustinus Bader cream unprompted butinvesting in the company too (Courteney Cox, Melanie Griffith and Carla Bruni to note). Usually cynical beauty editors discussed it with the fervour of addicts (myself included). And in February, a panel of more than 300 industry experts voted The Cream and The Rich Cream as Womens Wear Dailys Greatest Skincare Product ofAll Time (Crme de la Mer, launched in 1965, took second place and Este Lauder Advanced Night Repair, from 1982, took third), neatly capping off a pleasing statistic of 36 awards in 36 months.

Bader a softly spoken, bow tie-wearing 61-year-old German is both asthrilled and bemused by the brands success as youd hope. Before making the face cream, he says, he had never used a skincare product in his life. But he likes the fact that now, when he uses the cream before shaving, he no longer cuts himself. It would never have occurred to him to have created a cleanse/tone/moisturise-type regime. Beauty is always from inside, he says. You dont need a routine, as many people have been used to. The idea is that just after washing your face, you use The Cream or The Rich Cream. Everything is in that one product.

Before making the face cream, Bader had never used a skincare product inhis life

It would be tempting to paint Bader asthe sneery scientist, dabbling with the beauty world as a means to an end(close to10per cent of the brands profits in 201920 went to wound-healing research and other charities). The opposite is true: what finally convinced him to embark onthe project was his patients reaction tohisearly prototype: When I gave theproduct to patients with diabetic wounds, their skin became healthier-looking and stronger, and I could see how happy it made for me, even though it was just a skincare product, it developed a kind of medical meaning.

Also subversive is the brandsconspicuous lack ofmiracle ingredients. Baderswork is guided by theprinciple that your skin contains all it needs already its the communication between thecells thats important, notapplying endlessnew ingredients that your skin doesnt recognise. Conventional medicine very often tries to helpby treating symptoms, but what the patientreally wants is a healing process, he says. The creams themselves contain a complex called TCF8, which hesays is mainly made out of vitamins, amino acids and lipid structures.

$70mThe brands turnoverin2020

10%The profits in 20192020 thatwent towards wound-healing research and other charities

11The number of products in the Augustinus Bader line

50%The acceleration in healing time experienced by patientsusing Baders wound-healing gel

According to Charles Rosier, Bader isprobably the person in the team who is strictest about only using gentle ingredients which means the brand is able to satisfy the current appetite for clean skincare too. Thats why theres no SPF; because Bader is vehemently opposed to chemical sun filters and has so far found it hard to make sufficiently premium-feeling sun protection without them. And, says Bader, a little bit of sun is good for your skin as is a little bit of stress (and carrot juice: he says that people who eat a lot of carrots generally have good skin).

Last month the brand also launched avegan version of The Rich Cream, with original ingredients such as beeswax and lanolin removed and a slightly upgraded formulation. It has the same rich texture and the same uncanny ability which fans can eulogise about for hours to hug your skin within seconds of applying.

But is it getting harder to avoid the pull of the beauty mainstream? Some devotees have taken a recent spate of new launches to mean that the brand is moving away from its original one cream is all you need philosophy, and that as a result has lost some of its outsider charm. In the second half of 2020, launches came thick and fast: theres now anEssence, Face Oil, Cleansing Balm, Cleansing Gel and Lip Balm, plus body oils and lotions.

Rosier points outthat most of their competitors have around 200 products and that last years bottleneck of launches was largely due to hold-ups in the lab, as well as Covid-19. Perhaps our philosophy has switched a little from Well give you one cream to Wellgive you the essential basics of a skincare routine, he concedes. Well never do 20 serums, but well do products where we feel they can be better than otherthings that exist in the market, and allow you to have an Augustinus Bader routine and not have to mix our products with other brands.

Given how feverish the current Baderobsession is, it seems unlikely thatcustomers would need much convincingnot to mix other brands products into their routines. What isdebatable is how long this brand can remain a disrupter. Ever the renegade, Bader is less interested in being a beauty outsider than encouraging the rest of the field toraise its game.

This new beauty side of mywork is interesting because, ultimately, healthy skin contributes to beauty and for me, thats notsomething superficial, its something absolutely relevant to all the work that I do, including the medical research. In a way, Ihope that perhaps what we can do is be a little bit game-changing about what a skincare product may want to achieve. And that, to me, sounds like real hope in a jar.

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Augustinus Bader Launches Vegan Formulation of The Rich Cream | Review – Allure

By daniellenierenberg

While The Rich Cream is not the first vegan Augustinus Bader product (The Lip Balm, The Face Oil, The Essence, The Cleansing Balm, and The Body Oil have that designation as well), the upgrade features what cofounder Augustinus Bader (a famed stem-cell scientist) describes as "an advanced and smart formula resulting in deeper nourishment and hydration and, overall, a more immaculate complexion."

As a fan of both original and upgraded The Rich Cream versions, I can attest to that statement. The rich, buttery formula sinks in quickly and keeps my dry, stressed skin intensely hydrated overnight and well into the next day. "We merge a deep respect for nature and biology with knowledge-fueled targeting of skin repair needs," Bader tells Allure. "Now that our Rich Cream is vegan, it's an added bonus it is the ultimate sign of respect for nature." Another piece of exciting news: The brand says it's working on becoming entirely vegan.

The non-vegan ingredients cut from the formula include lanolin and beeswax. King (who is not affiliated with the brand) explains that lanolin is derived from wool grease and can cause long-term sensitivity and allergic reactions for some people. You also won't find lactic acid (a type of alpha hydroxy acid or AHA) in the upgraded formula, which King says is most likely created from fermented milk, and, therefore, not vegan.

On the flip side, the brand added moisture-binding hyaluronic acid, irritation-soothing hydrolyzed rice protein, and sisymbrium irio seed oil which, according to King, promotes cell turnover, firms the appearance of skin, and even helps reduce eczema. And despite the upgrades, this version keeps the essence of the original, fan-favorite The Rich Cream intact and for good reason; it works. Associate clinical professor of dermatology at Yale School of Medicine, Mona Gohara, counts herself among the legion of The Rich Cream's fans. "It's packed with peptides, a Trigger Factor Complex (which helps skin cells regenerate), vitamins [like panthenol, aka, vitamin B5], shea butter, and squalane," she praises, likening it to the cake and icing of skin care.

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Seven Innovative Skincare Brands That Deliver Clinical Results – Forbes

By daniellenierenberg

I find it hard to stay in the loop these days. When it comes to new consumer productsespecially in beauty, it seems like there is a new brand coming out daily. As a natural skeptic, I can be leery of new things.But, I rounded up seven innovative skincare brands that deliver clinical results that are definitely worth exploring.



Due to recent buzz, particularly in the K-Beauty space, snail slime as a hero ingredient may have popped up on your radar. But like so many trends, they are rooted in something much older. In fact,Hippocrates used to prescribe the mucusto clear up skin inflammation while small, rural communities used it to hydrate skin and to alleviate acnes and calluses.

In the spirit of its traditional use in skincare,Eskafilwas created in fall 2020. Founded by Jeffrey Lee and Marius Ronnov, Eskafil is a dermatologist-crafted beauty line of highly effective skincare products packed with ingredients found in nature. We are brand that revolves around the power of natural ingredients, in our case snail slime, Ronnov tells me. We believe ourselves to be gatekeepers of natures secrets and stewards of self-care. To us, skincare is self-care and we work to inspire our customers to commit to themselves everyday, with something as simple as a skincare routine.

Ancient Greeks coined snail mucin as the fountain of youth due to its ability to stimulate new cell repair and increase collagen production, the protein responsible for young healthy skin. What makes snail mucin so effective is one of its active ingredients, allatonin. It is this substance that repairs the snails shell when it accidentally becomes chipped or split. So just imagine what it can do for your skin, especially if you suffer from scarring caused by acne or from eczema, states Lee. The extract's healing properties are also known to heal cuts, soften scar tissue, fight infections, repair sun damage, regenerate skin cells and make skin look younger, tighter and brighter. Recognizing its hydrating properties and skin healing abilities, we wanted to introduce this miracle ingredient to users in the Western world.


Eskafils three-step skincare rangeis easy to use, packaged beautifully, and effective. After a few weeks of use, my skin definitely looks brighter. I would imagine this is due to the high levels of snail mucin concentrate in the products, which is 98%. I havent used eye creams in years since many of them felt heavy and often congested my eye area. But I love the way this light formula instantly cools and hydrates my eye area. It feels like you have nothing on your skin. We pride ourselves on using dermatologist-approved formulas that take supporting ingredients such as macadamia oil, shea butter and golden seaweed to enhance the healing nature of snail slime, explains Ronnov. This combination of ingredients across our products drives hydration, acne scar repair, reduction of fine lines and protection against signs of aging.

If you are wondering if any snails got injured in the whole process, the pair tells me that what makes their brand stand apart from the other snail slime products is there ethical sourcing. We obtain the snail slime through a system that places snails in an environment that makes them extremely pleasured and happy, Lee tells me. This environment is a room thats at the exact temperature and darkness for ultimate snail happiness. The snails then excrete their slime over a mesh covering then the slime is removed and placed into Eskafils skincare products.



Launched this past spring byAmir Nobakht MD, MBA, and Ben Van Handel, PhD,two of the top leading researchers on the topic of inflammaging,Herauxoffers a paradigm shift in skincare.

Inflammaging is the aging process that is attributable to chronic, low-grade inflammation in our bodies, explains Van Handel, PhD, who is a stem cell biologist at the University of Southern California. Inflammaging is actually caused by things like oxidative stress and environmental damage. These stressors cause our body to release inflammatory molecules, which harm the cellular environment and result in the visible signs of aging. Inflammaging specifically is what happens when this inflammatory process stays active on our body over a long period of time due to stressors like the environment, sun, and even our diets.

It is important to reduce chronic inflammation because once you have it Van Handel, PhD tells me your body just creates more inflammation. Thats how our cells work; by releasing some inflammatory molecules into our systems other cells respond by releasing more as well and the cycle, if left unchecked, continues. When we treat the inflammatory component of these conditions, we stop that cycle and allow the cellular environment to improve so our cells, including stem cells, can regenerate and function at an optimal level, continues Van Handel, PhD.

Heraux is the worlds first anti-inflammaging skin care product.It is the only skin care product to address inflammaging, Nobakht MD, MBA tells me. We are a science forward skincare brand that uses proprietary molecular technologies to improve our skin by combating the negative effects of inflammaging which is the aging caused by everyday chronic inflammation. Unlike most skin care products that only treat the symptoms of medical issues like acne, rosacea and the visible signs of aging,Heraux Molecular Anti-inflammaging Serumgets to the root of the problem by modulating the inflammatory pathway in the skin.


The serum is the brands first product release and is based on HX-1, a proprietary biomimetic lipid the pair discovered while researching arthritis for over a decade. Van Handel, PhD explains to me that the lipid is a major breakthrough in the fight against chronic inflammation and skin aging. This revolutionary one-of-a-kind molecule shields stem cells from the effects of stress and promotes their overall youthful function by modulating the protein that regulates regeneration versus inflammation. The lightweight formula also hashyaluronic acid, peptides, vitamins C + E, and red maple bark extract included to make it a well rounded face serum.

The formulation itself is patented, continuesVan Handel, PhD. Themain benefits includea reduction in wrinkles and fine lines, improved skin texture, increased brightness, reduction in hyperpigmentation and increased skin elasticity, all of which have been verified by an independent clinical trial. Results are seen in as little as 1 week with continued improvement with extended use. When I ask if there will be any other products to follow Nobakht MD, MBA responds, We are looking to launch a spot treatment version for acne and hyperpigmentation as well as a sunscreen very soon.I really like the way my skin feels and looks from using this product for the last few weeks. My vascular rosacea has definitely calmed down. A sunscreen would be a welcome new addition.

Pour Moi Skincare

Pour Moi Skincare

Skincare brandPour Moiwas created based on the premise that regardless of age, ethnicity, or gender that our skins appearance is affected by our exposure to daily, local weather. Founded by Ulli Haslacher, the company officially launched in 2020 (after a soft launch in 2017), shortly after receiving its first patent, with a second one issued a few months later, and several more on the way.

Climate-Smart Pour Moi is the worlds first climate-based skincare brand, changing everything you think you know about skincare, Haslacher tells me. Our brand offer products that are specifically formulated for six global and seasonal climates considering how each climates distinctive range of humidity, temperature, air pressure and light profoundly impacts the look and feel of skin. They are not created in the traditional way to only manage visible symptoms of aging skin. But rather scientifically designed to counteract the major cause of an aging complexionthe climate that you are in!

Not only did Haslacher change the approach to skincare based onclimate research, she even changed the way her products were tested. During R&D our formulas were not just tested in a controlled lab environment but tested on actual people in climate chambers, mimicking different climatic conditions and sudden changes to these conditions, explains Haslacher.

While each formula is based on one of six climate types, Haslacher tells me that there is one consistent principle across the entire ranges, the brands Geo-hydraDynamic Complex. Its the vital operating system of Climate-Smart skincare.It is the only complex in the world that intuitively aligns the upper layers of the skin with the various local atmospheric humidity conditions to achieve optimal hydration in each distinctive climate.Due to the adaptive nature of our complex, it has the unique ability to self-adjust to meet skins ever-changing hydration needs within the millions of nuances of specific climate.

Pour Moi Skincare

Customized for each specific climate, our patented complex is comprised ofingredientswith skin-identical properties including multi-size molecular hydra-actives and a French fungi, high in amino acids and valuable sugars, continues Haslacher. Together, they act as a biomimetic supramolecular network to uniquely boost the hydrating potential of the climate-specific creams and increase the efficiency of the entrapped actives. These include climate-specific antioxidants (for example the Red Snow Algae for Mountain climate and the ocean micro-algaeThermus Thermophilus Fermentfor Marine climate) as well as encapsulatedvitamins including A, C and E and anti-wrinkle peptidesfor an optimal release within the skin and a long lasting effect in each climate.

Haslacher tells me that the reason she has received both global and domestic patents is her three-step system of quenching, drenching, and geo-moisturizing. Step 1 is our Hydrating Balancer. It is an anti-aging liquefier that instantly hydrates, softens and preps skin for the next steps. Step 2 is our quenching serum that intelligently supports skins natural defense system against geo-climatic stressors in specific locations such as the mountains, beaches, plains and deserts. Step 3 is the geo-moisturizing game changer. Select the Day Cream that matches your daily weather to adapt, repair and protect skin in the climate you are in. This allows the customer tocustomize the systemfor their exact location. Think of it as anti-aging skincare for your zip code!

When I asked Haslacher if there is any sunscreen in her products, she tells me, We are working on an innovative sunscreen line which will launch in 2022. However, our formulas do account for how light impacts skin differently in different locations and seasons. While the formulas do not include SPF, they include climate-specific antioxidant strategies.I really like the concept of the brand. I just started using it, so I am excited to see what kind of changes my skin sees.



If you were under the impression that exfoliation means stripping your skin of moisture,Reflektis on a mission to change that with their 3-step hyaluronic acid-based products. Launched in 2017 and founded by Nancy Schnoll, Reflekt is a luxury skincare brand (for any skin type) thats rooted in pharmaceutical and medical principles and centered around simplifying your skincare routine, while delivering clinical results.

Reflekt is a skincare company that believes gentle daily exfoliation is the key to healthy balanced skin. We realize daily exfoliation is a novel concept, but it is the cornerstone of our brand, states Schnoll. The brands hero product,Reflekt 1is an exfoliating cleaner designed for all skin types and is gentle enough to use morning and night. Reflekt 1 was intentionally launched by itself to educate people about the benefits of a skincare regimen that consists of deliberate light exfoliation coupled with the infusion of hydrating actives.

This May, the brand will launch Reflekt 2 Brightening & Hydrating Serum, a silky serum that seals in moisture, brightens and gently exfoliates the skin, and Reflekt 3 Renewing & Hydrating Face Cream that gently exfoliates while moisturizing the skin to promote cell renewal and a firmer and even skin tone.


The entire Reflekt range is vegan, clean, and non-toxic and both exfoliates and hydrates the skin while not disturbing the skin barrier. Each product has unique characteristics. The exfoliating component in Reflekt 1 is the biodegradable jojoba esters that melt from the warmth of the water and your body as you cleanse, explains Schnoll. For Reflekt 2 and 3 the exfoliator is our unique fruit enzyme blend consisting of 9 different fruits (like pomegranate, passion fruit, and pineapple) and varies in percentage depending on the product. The hydrating aspect varies, but whether hyaluronic acid, aquaxyl, or squalene, each product packs a one-two punch of exfoliation and hydration.

I love the Reflekt collection. After using the 3-step system my skin looks dewy, brighter, smoother, and it feels hydrated. I also enjoy the light fragrance.

Saro de Re

Saro de Re

By now, most of us have heard about the benefits of hyaluronic acid for the skin. ButSaro de Retakes the experience to a whole new level. Founded by Mimi Kim, the brand launched last fall with their first product, the freeze-dried hyaluronic acid experience.

Saro de Re is a K-Beauty luxury brand rooted from the medical and pharmaceutical field for the professional results at the comfort of our own home and it is designed for any age, gender, any skin types, and skin conditions, Kim tells me. I have been sourcing ingredients and inventing beauty products for nearly three decades, and I have seen some very impressive technologies, products and unique ingredients that are not available to consumers. My goal over the years has been to make these discoveries available to the masses. When I partnered with a Korean Pharmaceutical R&D team and found something this ground-breaking, I knew we had something very unique.

Not all hyaluronic acids are made equal. Ourhyaluronic acid is 99.9% pure. Nowater, preservatives, fillers, additives, or chemicals. Each tablet is made up of 98.5% highly concentrated hyaluronic acid with a small amount of two additional ingredients for moisturizing: Squalene and Vitamin E.Clean beauty at its core, states Kim when I ask her what makes her formula unique.

Saro de Re

Other hyaluronic acid serums on the market contain primarily water as the number one top ingredient, which means the hyaluronic acid is not in its purest form. Our product has the patent on the method of preparing low molecular weight range that is small enough to permeate, but large enough to attract and retain the most abundant water, continues Kim. In fact, 1000 times its weight in water and the ability to release it for an immediate plumping and hydrating effect on skin with long-lasting results. No other brand has the capability to create HA in this molecular weight, which requires it to be in its purest form.

The ingredients are then freeze-dried and preserved until they are activated by the Saro de Re Pure Activator, which includes adenosine for wrinkle reduction, Niacinamide for skin brightening, and Allantoin and Hyaluronic Acid for hydration.Once activated and applied, it adds instant hydration that lasts up to 72 hours on skin with just one application. No competitive products can make this claim or be used once every other day or every three days, states Kim. Additionally, there are three botanicals included in the activator that synergistically work with the main active ingredients to achieve superior anti-aging benefits including purslane, pomegranate, and White Mulberry. Users can expect instant and accumulativeresultsincluding plumper skin, a brighter, tighter complexion, and improved tone and texture.

I have seen a huge difference in my skin with the addition of this product. I also like the alchemic process of activating the hyaluronic acid. I definitely feel like I am getting a lab-grade product when compared to other hyaluronic acid serums that I have used. It also works great with Reflekt skincare range. As for any follow up products, Kim tells me that the brand will be launching some new products soon.

The Nue Co

The Nue Co

Discussion about the gut microbiome and overall health have become mainstream and correlations between immunity and the gut have been supported clinically. But, the bodys skin is its largest first line of defense when it comes to immunity so it makes sense to treat it similarly. EnterThe Nue Co, a wellness brand launched in 2017 by founder and CEO, Jules Miller that approaches health holistically, as an entire ecosystem.

For too long health issues have been viewed as siloed issues. For example, breakouts are an issue with your skin, so the solution should be focused only on your skin. But actually, your skin is usually the mirror to our gut. Stress plays out on your skin and sleep affects your skin. To get to the root of an issue and drive real results, you have to view health as an ecosystem, states Miller. We definitely take that approach with our skincare - which we view as topical supplements. Whilst many brands focus on what we call, cosmetic ingredients, the kind which deliver on the instant glow and lovely scent but are proven to increase inflammation and erode the skin-barrier over time, every ingredient in our formulas delivers benefits to your skin health-long term.

The Nue Cosskincare formulations are grounded in clinical science and as such provides users with clinical results. They are a blend of natural ingredients, with the best of clinical research, which enables them to drive real, fast results, without compromising the health of your skin or the environment long-term, Miller tells me. There seems to be so much misinformation about skin health, with one of the biggest myths being that elaborate skincare regimes are the secret to healthy skin.Restoring the health of your skin and removing the complication of multiple products from your routine was part of a bigger shift we were noticing towards ending a culture of overconsumption, what some are calling skip-care or skin fasting. The impact of our beauty addiction has been profound, not only on our skin, but on our planet.

The Nue Co

This cycle of pollution, Miller tells me, is also a contributing factor to our skins barrier health. Our skin barrier, or the outermost layer of the skin, is responsible for defending against pollution, UV light, infection, and locking in hydration. The erosion of the skin barrier is identified as the number one cause of skin issues by dermatologists, causing premature ageing, breakouts, hyperpigmentation, sensitivity and dryness, explains Miller. And just like the gut, our skin is home to an ecosystem of microorganisms that help to keep the skin balanced. Our topical microbiome is just as important as our internal microbiome. In fact, its estimated that 21% of our microbiome lives on our skin whereas 26% lives in our gut. Like any ecosystem, it can be disrupted by outside forces and pollutants.

To support the skins barrier health and the skins microbiome, the brand is launching two newskincare products, BARRIER CULTURE Cleanser and BARRIER CULTURE Moisturizer on March 22ndon their website. Using patented, first to market technology, BARRIER CULTURE contains prebiotics, probiotics, and postbiotics to rebuild the skins microbiome. BARRIER CULTURE is the most comprehensive delivery of skin-barrier building ingredients in a two-step routine. In addition to its microbiome technology, BARRIER CULTURE uses anti-pollution ingredients to protect from external aggressors and boost the skins natural immune system; and hydrating actives to replenish and lock in moisture, states Miller.

The cleanser is designedto replace your double-cleanse, by removing dirt, pollution, and makeup without stripping or disrupting the skins PH. Almost immediately, we have found people have noticed a difference to the feel of their skin with a focus on deep-cleaning, rather than stripping. The application of pre, pro and postbiotics works to replenish the topical microbiome, whilst actively calming and conditioning the skin, Miller tells me.

The new moisturizer leaves skin instantly plumped and hydrated. The formula rebuilds and restores your skin barrier, containing ceramides and probiotics that rebuild and restore the skins natural defenses. Niacinamide activates the skins immune system, helping to repair dark marks, scarring and support natural healing and regeneration, whilst squalane protects against pollution and everyday stressors on the skin barrier. BARRIER CULTUREs microbiome technology also delivers an instant soothing effect to the skin, calming irritation and redness.

I just started using the products so I wont see all of the results for at least a month. But, I am already hopeful. I do love the way my skin feels squeaky clean, yet moisturized when I use the cleanser.

U Beauty

U Beauty

U Beauty launched in 2019 byTina Craig(aka. The Bag Snob) with the philosophy of less is more. U Beautyis tech-driven, science-backed, high-performance skincare, Craig tells me. Our strategic and singular products replace excess with essence and provide real results, without the risk of irritation. We're about amplifying your skin with a select, strategic edit of multifunctional products that streamline your routine and simplify your life.

What makes the brands three products, the Resurfacing Compound,The SUPER Hydrator, and the newest productThe SCULPT Arm Compound,is the brands proprietary technology called SIREN Capsule. Unlike most skincare that release actives all over the skin, SIRENS lures damage-causing free radicals to it like a magnet, explains Craig. By attracting only the compromised cells, healthy cells are preserved, while the Capsule releases age-reversing actives on free radicals (generated after exposure to pollution, secondhand smoke and sunshine), which materialize as vulnerable, damaged areas, instead of all over your skins surface. So your skin gets nothing but benefit.

While theResurfacing Compoundcontains the original SIREN Capsules, The Super and The Sculpt feature dual SIRENS. The SUPERs HYDRA-SIREN produces immediate hydration and with five unique types of hyaluronic acid, it continues to hydrate for up to 48 hours. Specifically designed for the arm area, the SCULPT-SIREN contains a targeted blend of marine extracts, probiotics and select ferments. It delivers oxygen and nutrients to the skin, increasing anti-aging ATP levels and boosting hydration, Craig tells me.

U Beauty

U Beautys latest formulation, The SCULPT Arm Compound, is a product of years of dreaming on behalf of Craig. No matter how often I work out, I was never able to change the fragile texture of the skin on my arms. Its not about being thin. Its about a healthy, bouncy skin consistency, says Craig. I can honestly say The SCULPT is unlike anything youve ever used. Thanks to a genius blend of peptides, marine extract, our signatureSIREN Capsule technologyand now the new SCULPT-SIREN, it visibly tightens, tones and sculpts the skin on the arms. Overall, skin is less subject to the effects of gravity and more resilient in its ability to address the visible signs of damage.

I just received The SCULPT so I cant say for certain what the accumulative results will be just yet. But, I can say that my arm skin feels much tighter immediately after applying the formulaso I am very hopeful. When I ask Craig if she will be creating any other body specific products she tells me, Were about taking a 360-degree approach to skincare, which means treating the whole body, not just the face. I will never create a product if theres not a white space in the industry and a personal need for it first. With that in mind, we have some exciting and revolutionary things coming out in the near future, so look out!

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Transform Your Skin Into That Of A Greek Goddess (on A Budget) –

By daniellenierenberg

Weve all heard of French beauty products and how amazing they are.

But what if I told you that certain Greek beauty products were just as good (if not better) than the high flying ones?

Think La Mere or LaPrairie. These cult favourite beauty brands cost will set you back several hundred dollars.

You dont have to spend a fortune to look good. I always say you can have great skin even if youre on a budget, no matter how old you are.

Greek women have long used natural products from the earth, plants and animals to beautify themselves and look at how immaculate their skin and beauty was.

Heck, one Greek woman launched a thousand ships! (You know her name)

These hand-picked items for skin-care are loaded with Greek olive oil, wine, figsand donkey milk. (Tried and tested by me, GCT Lifestyle Writer Despina Karp)


This nourishing cream-to-foam cleanser is good enough to eat and leaves the skin feeling clean, not stripped of everything. Its been formulated with incredible natural Greek Yoghurt and is gentle enough to be used on even the most sensitive of skin types, including psoriasis and acne-prone skin. It is super gentle, yet very effective at thoroughly cleaning the skin and removing daily impurities and makeup. After trying this cleanser, my skin was left feeling as smooth and supple as a babies bottom.

The key ingredients in this beauty are Greek yoghurt which delivers an almost instant dose of pre and probiotics to nourish the skin and kill surface bacteria.

Amaranth seed extract and honeysuckle: These two unique ingredients provide a soothing and calming comfort to the skin.

I always recommend using this twice per day, morning and night for the best results.

Buy here.

$110 (approximately)

Well, there are serums, and then theres this serum! A little pricey, but wait till I explain what this jar of ageless beauty contains.

This is one of the best antioxidant serums Ive tried and for good reason. For starters, its ingredients make it a high-end luxury antioxidant serum, but without the super costly price tag to match.

The heavenly golden fluid is infused with the famous antioxidant saffron, once known as the most expensive spice in the world.

The crimson threads of magic come from dried crocus flowers, grown in the Greek town ofKozani. It takes approximately 70,000 flowers to make one pound of saffron! Did I mention that they bloom only once a year? Plus they need to be picked exactly ONE day after theyve bloomed! Talk about time-sensitive.

The protecting power of the saffron, combined with the copper, peptides, and amino acids combine to make an incredibly effective collagen and elastin boost.

With consistent use, this serum will leave the skin feeling bright and glowing. I often use this serum on my mature-skinned clients before moisturiser and I massage it into the skin until it has been completely absorbed.

I highly recommend paying a little extra and indulging in this serum, it works wonders for mature skin.

Buy here.


Here comes the donkeys milk! Dont worry I wont make you drink it but it is a staple ingredient in this product.

It doesnt sound very luxurious or fancy, but Cleopatra allegedly bathed in donkeys milk for softer skin.

In 2013, a study by researchers at the University of Camerino discovered that donkeys milk is very close in structure and composition to human breast milk (Maybe thats why babies skin is so soft!).

EvenPope Francis even drank it as a babyin his native Argentina.

Are you convinced yet?

This cream provides antioxidant, antimicrobial, and anti-inflammatory moisturisation.

The best part of this incredible product are the key ingredients (which according to their website are 97.1% natural ingredients): donkey milk (obviously), aloe vera juice, St. Johns wort, Centella, carob, cotton stem cells, moringa peptides, red seaweed and cross-linked hyaluronic acid (a superacid for the skin).

The donkey milk and Cretan organic olive oil are rich in omega fatty acids, which the skin craves.

It also contains vitamins and trace elements, which deeply nourish and strengthen the skins natural defence against pollution and UVA/UVB light.

The St. Johns wort and Centella extract calm redness and skin irritations.

I highly recommend this daily moisturiser (as donkeys milk is non-comedogenic) for any skin type, except very congested and cystic acne skin types.

Its important to always apply SPF 30+ to protect your skin from the harmful rays of the sun (especially true if you live in Australia).

Buy here at

So, Ive give you an entire skin routine worthy of Aphrodite herself.

These 3 products can be used one after the other as a bedtime skin routine for mature and dry skin types.

If you are using these products in the morning, be sure to apply an SPF 30+ after all your products to protect your skin.

You dont have to use a large amount of the products too, a little goes a long way with these beauties.

My donkeys milk day cream lasted me 3 months! So it turns out to be a very economical investment.

Its worth investing in your skin as its the largest organ in your body and the amount of chemicals we are exposed to these days can leave our skin in terrible shape if not looked after.

Our skin is also the first thing people look at, healthy and hydrated skin can completely alter your appearance if youve had dehydrated skin for a while.

So, what are you waiting for? Lets get radiant, and prepare to launch a thousand ships! (More like a thousand compliments)

Note: always ask a Dermatologists advice when in doubt, these products arent suitable for all skin types or skin conditions.

Thesauri Greek Caviar: available in Australia for the very first time

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How New Yorkers Are Battling the Zoom Effect: 6 Cosmetic Treatments That Are on the Rise – PureWow

By daniellenierenberg

With more folks spending time inside, working from home and literally under wraps (i.e., masks), now is the time for many for some sneaky beauty procedures that would normally require taking time off work, hiding from your social circle and going dark on social media. But now, all your redness, swelling, and post-op symptoms can go undetectedsans burning your vacation days.

In fact, derms and plastic surgeons across the city are seeing skyrocketing increases in invasive and non-invasive cosmetic treatments since the start of the pandemic, thanks to the Zoom boom or Zoom effect.

What the heck is the Zoom effect, you ask? Basically, Zoom and other digital web conferencing platforms have led people to seek out ways to lift and tighten their faces after seeing themselves so often screens. (Note: If your computer camera is positioned lower and pointing up, it actually makes things look worse than they areinvest in a laptop stand, and you wont regret it.)

Laura Altman, a physician assistant at Tribeca Medspa, explains that since her clients are no longer spending money on travel, dinners out or fancy clothing, this disposable income allows them to spend on beauty proceduresnot to mention the added benefit of flexible downtime while WFH. Our clients are spending more per visit and we continue to see about the same number of new clients every month along with current clients who visit us for more treatments, says Altman.

Here are some of the most popular beauty treatments New Yorkers have been taking advantage of while WFH, plus some things to consider in case youre curious about giving them a go yourself.

RELATED: 9 Beauty Trends That Will Be Huge in 2021

In fact, requests for jawline filler are up as much as 2,133 percent at BeautyFix Medspa, a clinic with locations in Flatiron and on the Upper East Side. This non-surgical facial contouring enhances the jawline to give the lower face and neck a more defined and slimmer appearance by helping create a V-shape structure, BeautyFix CEO Mark Greenspan tells us. Jawline fillers are usually completed with one 30-minute treatment with no recovery time necessary.

Dr. Alexander Blinksi of NYCs Plump cosmetics and injectables bar has seen about a 25 percent increase in patients with general concerns about facial structure, aging and wrinkles over the last 12 months.

Consultations related to Botox have been requested in all the major treatment areas. The most common areas for Botox treatment remain horizontal forehead lines, 11 lines, and crows feet. We have seen a slightly greater number of patients consulted for TMJ Botox (TMJ is a medical jaw issue from grinding the teeth at night) likely due to increases in stress, and beauty trends of giving the face more angularity and a higher cheekbone, Dr. Blinski tells us.

Intrigued? Side effects from injectables include minor swelling and bruising. (Psst: Read up on our beginners guide to botox here.)


In fact, reports show that more women in the US are using facial skincare products today compared to one year ago, and that lifestyle changes including the effects of COVID-19 have in many ways altered skin care routines in a positive way, says master esthetician and CEO of Repechage, Lydia Sarfati.

At-home peels feature professional-grade ingredients and step-by-step instructions to boost a dull complexion and address specific skin concerns such as aging, discoloration and blemishes without having to go in to see an esthetician or dermatologist. These peels use low percent acids (like this one from PCA SKIN) and require no downtime for healing.

According to new survey data by healthcare marketplace RealSelf, 36 percent of respondents noted theyve seen an increase in the number of pimples since the pandemic started. And those who have had an increase in breakouts noted their chin was the most likely spot, followed by the jawline and cheeks.

Some acne breakouts are a result of wearing masks and the occlusion it causes (dubbed maskne), and other forms of acne are a result of hormonal stress or stress in general. Patients who have had acne scars are using this period to have laser treatments to finally address the treatment of their acne scars, now that they have the downtime, NYC-based cosmetic dermatologist Dr. Michele Green tells us.

One such treatment is eMatrix, a laser that works by stimulating collagen formation and healthy cells. eMatrix reduces the appearance of acne scars, enlarged pores and mild to moderate wrinkles in addition brightening the skin and improving skin texture. Downtime is approximately 48 hours with mild roughness remaining for three to five days. Results continue over three to five months after the final treatment and can be maintained annually (Dr. Green suggests patients receive three to five treatments).

PhotoAlto/Frederic Cirou/Getty Images

There are multiple ways to treat hair loss, but Dr. Greens preferred method is PRP (Platelet Rich Plasma), a treatment that uses your own blood to promote healing and stimulate the hair follicle to begin a new growth cycle while making hair stronger and thicker. Side effects of PRP may include some tenderness on the scalp after injections and a slight headache or pressure in the treated area. Depending on the severity, Dr. Green recommends four consecutive monthly treatments of PRP injections followed by maintenance treatments every four to six months.

Places like Tribeca Medspa have seen a 50 percent increase in microneedling with stem cells compared to last year. This treatment is designed to reduce the appearance of wrinkles and skin imperfections, with stem cells added to stimulate the regeneration and healing of the skin.

Typically, patients would experience mild redness and swelling for a day followed by possible mild dryness for a few days, at most. Bruising can happen but tends to heal quickly as it is generally fairly superficial, says Tribeca Medspa clinical lead medical aesthetician Holly Montgomery.

RELATED: We Ask a Derm: What Is the Best Derma Roller to Use at Home?

How New Yorkers Are Battling the Zoom Effect: 6 Cosmetic Treatments That Are on the Rise - PureWow

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Nvidia, Harvard researchers use AI to find active areas in cell DNA – ZDNet

By daniellenierenberg

Researchers from Nvidia and Harvard are publishing research this week on a new way they've applied deep learning to epigenomics -- the study of modifications on the genetic material of a cell.

Using a neural network originally developed for computer vision, the researchers have developed a deep learning toolkit that can help scientists study rare cell types -- and possibly identify mutations that make people more vulnerable to diseases.

The new deep learning toolkit, called AtacWorks, "allows us to study how diseases and genomic variation influence very specific types of cells of the human body," Nvidia researcher Avantika Lal, lead author on the paper, told reporters last week. "And this will enable previously impossible biological discovery, and we hope would also contribute to the discovery of new drug targets."

AtacWorks, featured in Nature Communications, works with ATAC-seq -- a popular method for finding the parts of the human genome that are accessible in cells.

Just about every cell in your body carries a copy of your genome sequence -- a sequence of your DNA about 3 billion bases long. However, only certain parts of the genome sequence are accessible to certain cells. Every cell type -- whether it's liver, blood or skin cells -- can only access the regions of DNA they need for their respective function.

"That allows us to understand what makes every type of cell different from each other, or how every type of cell is affected in disease, or in other biological changes," Lal said.

ATAC-seq finds those accessible parts by producing a signal for every base in the genome. Peaks in the signal denote accessible regions of DNA. This method typically requires tens of thousands of certain kinds of cells to get a clean signal. This makes it challenging to study rare cell types, like the stem cells that produce blood cells and platelets.

However, by applying AtacWorks to ATAC-seq data, the researchers found they could rely on just tens of cells, rather than tens of thousands. In the research described in their new paper, the Nvidia and Harvard scientists applied AtacWorks to a dataset of stem cells that produce red and white blood cells. They used a sample set of just 50 cells to identify distinct regions of DNA associated with cells that develop into white blood cells, as well as separate sequences that correlate with red blood cells.

AtacWorks is a PyTorch-based convolutional neural network that was trained on labeled pairs of matching ATAC-seq datasets -- one high quality and one "noisy." The model learned to predict an accurate, high-quality version of a dataset and identify peaks in the signal.

Running on Nvidia Tensor Core GPUs, the model took under 30 minutes for inference on a whole genome, a process that normally takes 15 hours on a system with 32 CPU cores.

Lal noted that the researchers were able to train the model on any type of cell and then apply it to any different type.

"That's a really wonderful thing because it means that we can train models using whatever data we have available and then apply it to entirely new biological samples," she said.

The model could help deliver insights into a range of diseases, including cardiovascular disease, Alzheimer's disease, diabetes or neurological disorders. It's available on the NGC Software Hub, Nvidia's hub of GPU-optimized software, where any researcher can access it.

"We are hoping that once our paper comes out, other scientists working with different diseases would also pick up this technique and be interested in using it," Lal said. "And we are excited to see what new research and new developments that can enable."

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Evolution: Lab-Grown ‘Mini Brains’ Suggest One Mutation Might Have Rewired the Human Mind – Singularity Hub

By daniellenierenberg

How we humans became what we are today is a question that scientists have been trying to answer for a long time. How did we evolve such advanced cognitive abilities, giving rise to complex language, poetry, and rocket science? In what way is the modern human brain different from those of our closest evolutionary relatives, such as Neanderthals and Denisovans?

By reintroducing ancient genes from such extinct species into human mini brainsclusters of stem cells grown in a lab that organize themselves into tiny versions of human brainsscientists have started to find new clues.

Most of what we know about human evolution comes from the study of ancient fossils and bones. We know that Neanderthals and Denisovans diverged from humans around 500,000-600,000 years ago, and that the last Neanderthals didnt disappear from Europe until about 40,000 years ago.

Research has also shown that humans and Neanderthals interbred, and that Neanderthals were a lot more sophisticated than previously thought.

From studying the size and shape of fossilized skulls, we also know that brains from archaic humans were roughly the same size as modern human skulls, if not bigger, and appear to be different shapes. However, although such variations might be correlated with different cognitive abilities and functions, the fossils cannot alone explain how the shapes affect function. Luckily, recent technological advances have provided a new path to understanding how we differ from our extinct relatives.

Homo Sapiens versus Neanderthals. Source: WikipediaCC BY-SA

Sequencing of ancient DNA has allowed scientists to compare genes of Neanderthals and Denisovans with those of modern humans. This has helped identify differences and similarities, revealing that we share most of our DNA with Neanderthals and Denisovans.

Still, in specific regions, there are gene variants exclusively carried by modern humans. These human-specific DNA regions may be responsible for traits that separate our species from our extinct relatives. By understanding how these genes work, we can therefore learn about the traits that are unique to modern humans.

Studies comparing archaic and modern DNA sequences have pinpointed differences in genes important for the function, behavior, and development of the brainin particular genes involved in cell division and synapses (which transmit electric nerve impulses between cells). These have suggested the human brain matures more slowly than the Neanderthal one did.

Specifically, the development of the orbitofrontal cortex in infants, which is thought to be involved in higher-order cognition like decision-making, might have changed significantly but subtly since the split from Neanderthals. Humans also reach sexual maturity later than their ancestors did, which can help explain why we live longer.

It has long been unclear which evolutionary changes have been the most important. A team of scientists led by Alysson Muotri at the University of California, San Diego, recently published a study in Science that shed some light on this question.

They did this by growing mini brainswhich are known scientifically as organoidsfrom stem cells derived from skin. Brain organoids arent conscious in the way we arethey are very simple and do not reach sizes larger than around five or six millimeters, due to a lack of blood supply. But they can emit brainwaves and grow relatively complex neural networks that respond to light.

The team inserted an extinct version of a gene involved in brain development in the organoids using the Nobel-prize winning CRISPR-Cas9 technology, often described as genetic scissors, which allows precise editing and manipulation of genes.

Human brain organoid. Image Credit: NIH/Flickr

We know that the old version of the gene was present in Neanderthals and Denisovans, whereas a mutation later changed the gene into the current version that modern humans carry.

The engineered organoids displayed several differences. They expanded more slowly than the human organoids and had altered formation of connections between neurons. They were also smaller and had rough, complex surfaces compared to the smooth and spherical modern human organoids.

The study identified 61 genes that are different between modern and archaic humans. One of these genes is NOVA1, which has an essential role in regulating other genes activity during early brain development. It also plays a role in the formation of synapses.

Altered activity of NOVA1 has previously been found to cause neurological disorders such as microcephaly (leading to a small head), seizures, severe developmental delay, and a genetic disorder called familial dysautonomia, suggesting it is important for normal human brain function. The version that modern humans carry has a change in one single letter of the code. This change causes the genes product, the NOVA1 protein, to have a different composition and possibly a different activity.

When analyzing the organoids, scientists found that the archaic NOVA1 gene changed the activity of 277 other genesmany of them are involved in creating synapses and connections between brain cells. As a result, the mini brains had a different network of cells to those of a modern human.

That means that the mutation in NOVA1 caused essential changes in our brains. A change in a single letter of the DNA code possibly sparking a new level of brain function in modern humans. What we dont know is how exactly this happened.

The team has said they will follow up their fascinating finding by investigating the other 60 genes in more detail, to see what happens when you alter each one or a combination of several.

Its no doubt an intriguing area of research, with the organoids giving important insight into these ancient species brains. But we are only at the beginning. Manipulation of a single gene will not capture the true Neanderthal and Denisovan genetics. But it could still help scientists understand how some human-specific genes work.

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

Image Credit: Wikimedia Commons

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Tissue regeneration: Reserve or reverse? – Science Magazine

By daniellenierenberg

A cross section of mouse small intestine, showing intestinal crypts and villi, is visualized with immunofluorescence microscopy (nuclei in red, and F-actin, which marks the cytoskeleton, in blue). Intestinal stem cells reside at the base of crypts, where they maintain cell turnover.

Tissues with high intrinsic turnover, such as the skin and intestinal lining, rely on resident stem cells, which generate all native cell types. Intestinal stem cells (ISCs) are highly sensitive to damage, although they recover quickly. It is unclear whether this recovery (i.e., regeneration) occurs from less sensitive pools of reserve stem cells (1) or whether ISC progeny undergo reverse differentiation into stem cells (2). Recent studies in diverse organs highlight that dedifferentiation of specified cell types is a pervasive and dominant means for tissue regeneration. The findings have broad implications because all tissues experience some cell attrition over a lifetime, and knowing how tissues replenish those losses may help in preventing or treating organ failure. Moreover, it remains unclear whether incomplete differentiation, a common feature of cancer, reflects normal tissue plasticity, and it is unclear whether stem cells that arise by dedifferentiation may spawn cancers.

ISCs expressing leucine-rich repeatcontaining G proteincoupled receptor 5 (Lgr5) lie at the bottom of small bowel crypts (3). In the course of homeostatic tissue turnover, their immediate progeny adopt alternative enterocyte or secretory fates, then fill the crypts with replicating progenitors that migrate away from ISCs. Cell division ceases at the crypt tops, where postmitotic cells begin a 3- to 5-day journey along intestinal villi. When ISCs sustain irreparable damage, some source in the crypt must regenerate new ISCs. Other adult epitheliasuch as airways, prostate, and liverare organized differently from the intestine and from each other (see the figure). These epithelia also restore cells lost by damage or attrition, even though at rest they turn over at least a hundred times more slowly than the intestinal lining.

Airway epithelial structure varies from trachea to small bronchioles, and distinct progenitors in different segments produce assorted secretory and ciliated cell types. In the lining of human and mouse upper airways, flat basal cells lie beneath a layer of columnar differentiated cells and adjacent to submucosal myoepithelial glands. Stem cell activity in normal tissue turnover maps to a subpopulation of keratin 5 (Krt5)expressing basal cells (4). The trachea and bronchi are vulnerable to diverse injuries, including targeted destruction of Krt5+ stem cells and pervasive mucosal damage from noxious inhalants or viruses.

Adult human and mouse prostate glands also contain columnar luminal and flat KRT5+ basal cells. Distinct unipotent progenitors maintain both populations, and castration induces massive luminal cell loss. Androgen reexposure restores prostate mass within weeks, which implies the presence of castration-resistant progenitors. However, an unequivocal stem cell pool has not been identified. The liver also has notable regenerative abilities after chemical or surgical injury. The emerging consensus is that this organ lacks a dedicated stem cell compartment and recovers from damage through dedifferentiation of mature hepatocytes and biliary cells (5, 6).

Stem cell activity in vivo is demonstrated most persuasively by introducing into a tissue a permanent color or fluorescent label whose expression depends on Cre recombinasemediated excision of a STOP cassette. When Cre activity is restricted to stem cells, all the progeny of those cells exclusively carry the label. ISCs and tracheal stem cells were thus identified because targeted Cre activity in LGR5+ or KRT5+ mouse cells labeled the respective full lineages (3, 4). Investigation of tissue regeneration requires ablation of a stem cell compartment, followed by tracking of the restored ability to produce sufficient numbers of all native stem cell progeny. The canon of tissue repair rests heavily on such lineage-tracing experiments, but one limitation is that Cre recombinase is not often confined to a single defined cell type. This challenge lies at the heart of competing models for tissue recovery after lethal cell injuries.

Dividing cells take up labels such as [3H]thymidine or fluorescent histone 2B and shed these labels as they replicate further or their daughters die. In the intestine, however, rare cells located near the fourth tier from the crypt base retain [3H]thymidine for weeks. Given once-popular ideas that stem cells must be few in number and retain one immortal DNA strand when they replicate, +4 label-retaining cells (LRCs) were described as ISCs. In support of that idea, lineage tracing from Bmi1, a locus thought to be restricted to nonreplicating +4 LRCs, elicited an ISC-like response in vivo (7).

Physiologic cell turnover and recovery from injury occur from different cellular sources in diverse epithelia (intestine, upper airway, and prostate gland). Homeostatic turnover is driven by the stem cell pool, and tissue restoration from injury occurs through transient expansion and dedifferentiation of specified mature cells.

To reconcile the evidence for ISC properties in both LGR5+ crypt base columnar cells (CBCs) and +4 LRCs, researchers postulated that abundant CBCs serve as frontline ISCs, whereas the smaller +4 LRC population contains dedicated reserves. Indeed, intestinal turnover is unperturbed when LGR5+ CBCs are ablated because other crypt cells' progeny continue to repopulate villi and an LGR5+ ISC compartment is soon restored (1). Multiple candidate markers of +4 LRCs that regenerate ISCs after injury have been proposed (8). Although these cells are too few to explain the typical scale and speed of ISC restoration, the prospect of two stem cell pools carried the additional allure of a sound adaptive strategy in a tissue that requires continuous self-renewal.

ISC differentiation is, however, not strictly unidirectional. Cre expression in absorptive or secretory cell types tags those cells selectively, but upon ablation of LGR5+ CBCs, the label appears throughout (9). These observations imply that differentiated daughter cells have reverted into ISCs. Moreover, Bmi1 expression was found to mark differentiated crypt endocrine cells (10), and putative +4 markers are expressed in many crypt cells including LGR5+ CBCs. Accordingly, when Cre is expressed from these loci, the traced lineage might simply reflect CBC activity in resting animals and reverse differentiation of crypt cells after ISC ablation. But is dedifferentiation a rare and physiologically inconsequential event or the predominant mode of stem cell recovery? Dedifferentiation may obviate the need to invoke a dedicated reserve population, or it is possible that ISC recovery may reflect both dedifferentiation and contributions from a reserve stem cell population.

To investigate these issues, researchers activated a fluorescent label in LGR5+ CBCs and waited for this label to pass into progeny cells before ablating CBCs (11). Thus, only the CBCs that recover by dedifferentiation should be labeled, and any cells arising from reserve ISCs should not. Nearly every restored crypt and CBC was fluorescent, with substantial contributions from both enterocytes and secretory cells (11). Cells captured early in the restorative process coexpressed mature-cell and ISC genes, which is compatible with recovery by dedifferentiation. Another study found that damaged ISCs are reconstituted wholly by the progeny of LGR5+ CBCs (8). Thus, dedifferentiation would seem to be the principal mode of ISC regeneration, and prior conclusions about +4 ISCs likely reflect unselective Cre expression.

Different tissues might deploy distinct regenerative strategies, and recent studies in mouse airway, prostate, intestinal, and liver epithelia provide insightful lessons. After ablation of KRT5+ airway stem cells, specified secretory and club cell precursors were found to undergo clonal multilineage expansion and accounted for up to 10% of restored KRT5+ cells in vivo (12). Chemical or viral damage was subsequently reported to induce migration and dedifferentiation of submucosal gland myoepithelial cells into the basal layer to reconstitute the surface lining, including KRT5+ stem cells (13). Thus, dedifferentiation into native stem cells occurs upon injury to both airway and intestinal linings in mice.

Single-cell RNA sequencing (scRNA-seq) analysis of mouse prostate glands recently revealed distinct gene expression profiles in 3% of luminal cells, which are more clonogenic than others, express putative stem cell markers, and hence qualify as a pool enriched for native stem-like cells (14). After androgen reexposure following castration, however, the scale and distribution of cell replication and the location of restored clones were incompatible with an origin wholly within that small pool. Rather, the principal source of gland reconstitution in vivo, including new KRT5+ basal cells, was the dominant population of differentiated luminal cells (14). These observations parallel those in the liver, where recovery of organ mass after tissue injury occurs by renewed proliferation of mature resting hepatocytes (5), abetted by expansion of bile duct cells that transdifferentiate into hepatocytes (6). Cell plasticity is thus widespread, whether tissues have or lack native stem cell compartments.

Reverse differentiation in the intestine, airways, and prostate gland was generally observed after near-total elimination of resident stem or luminal cells, an extreme and artificial condition. However, several observations suggest that this dedifferentiation reflects a physiologic process designed to maintain a proper cell census. Contact with a single KRT5+ airway stem cell prevents secretory and club cell dedifferentiation in vitro (12), and tracheal submucosal glands exhibit limited stem cell activity even in the absence of injury (13). Live imaging of intestinal crypts reveals continuous and stochastic exit from and reentry into the ISC compartment (15), implying that barriers for differentiation or dedifferentiation are inherently low. However, the primary purpose of dedifferentiating airway, intestinal, liver, and prostate cells is not to enable tissue recovery. Therefore, they should be regarded as facultative stem cells; that is, they have other physiologic functions and realize a latent stem cell capacity only under duress.

This distinction from reserve stem cells is not merely semantic. Emphasis in regenerative therapy research belongs on any cell population with restorative potential; in vivo findings now direct attention away from putative reserve cells and toward dedifferentiation as a common means for tissue recovery. The absence of dedicated reserves and the inherent cellular ability to toggle between stem and differentiated states also inform cancer biology. Because mutations realize oncogenic potential only in longlived cells, both frontline and reserve stem cells represent candidate sources of cancer, in contrast to differentiated cells, which are generally short-lived. However, oncogenic mutations that arise in differentiated cells could become fixed upon dedifferentiation, thus enabling tumor development.

Notably, stem cell properties and interconversion with their progeny are not stereotypic. ISCs divide daily into two identical daughters, whereas hematopoietic stem cell replication is infrequent and asymmetric. Severe loss of blood stem cells does not elicit substantial dedifferentiation and is rescued only by adoptive stem cell transfer. Immature secretory precursors dedifferentiate more readily than terminally mature airway cells (12), whereas fully differentiated cells fuel liver and prostate regeneration. Cell plasticity in each case is determined by local signals. Unknown factors from KRT5+ tracheal stem cells, for example, suppress secretory cell dedifferentiation (12), and specific factors secreted from the prostate mesenchyme stimulate luminal cell dedifferentiation (14). The intestinal mesenchyme probably senses ISC attrition to trigger tissue recovery, but the spatial and molecular determinants remain unknown. Outstanding challenges are to identify the signaling pathways that ensure a stable cell census and to harness diverse regenerative responses to ameliorate acute tissue injuries or prevent organ failure. Knowing the cellular basis for stem cell recovery in different contexts brings us closer to those goals.

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Tissue regeneration: Reserve or reverse? - Science Magazine

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