This is a follow up to our earlier post revealing the dangers of fat stem cells secretions as the basis of daily application cosmeceuticals. To be clear, we are not talking about fat transfers augmented by stem cells, or autologous adipose stem cell injections as used in orthopedics. Those are one time procedures, in which inflammation will occur briefly, leaving behind viable (hopefully) fat cells. What we are talking about is topically applied products based on the growth of adipose (fat) stem cells in laboratory culture, then taking those secretions and putting them in face creams and serum.
So, what’s the difference, you say? The difference is timing, or more specifically chronicity.
We do not worry about the brief episodes of inflammation occurring at a point in time, followed by a long period in which the skin (and mesenchymal stem cells traveling to skin from the bone marrow) can use its own innate reparative process to recover, including overcoming inflammation by secreting anti-inflammatory cytokines. In fact, many of the successful procedures used in clinical aesthetics (lasers, RF, microneedling) cause controlled damage (micro wounds) in order to kick off the cascade of healing. In adults, that includes some inflammation in the earliest phase. But you don’t have a procedure like that every day. You may have a series of 3, but at spaced intervals of weeks to months. So that your skin has a chance to heal – to move from inflammation rich to an inflammation free healing environment.
What we do worry about is the daily application of low level inflammatory molecules which can result in a slow, insidious burn like the embers of a fire rather than the flames. This results in what we call fibrosis. Fibrosis is like scar tissue, although it can be under the visible part of your skin. May look fine on the surface, in fact the slight edema and cellular proliferation that accompanies this may even disguise fine lines and wrinkles. But fibrosis eventually catches up with you. it is not anti-aging, it is pro-aging. In some ways it would be like having your skin lasered every day. No chance to ever catch up.
By the way, the older you get, the longer it takes to move from inflammation to anti-inflammation, no matter what the stimulus. This is why inflammation and aging are tightly bound. Eventually we cannot keep up with the minor insults of life (sun, etc). Inflammation, ultimately, is fatal.
Why do companies persist in marketing skincare products based on laboratory culture of fat stem cells? Because they’re plentiful, they’re cheap, and they’re very easy to grow. Plus, thousands of gallons of fat are available daily from middle-aged women (and some men) undergoing liposuction so the raw material is in abundant supply.
Sure, a little extra edema fluid can make fine lines less visible and the skin appear plumper, but what is the long term effect when it is well known that inflammation is pro-aging? Seems counter-productive to us in the long run – actually pro-aging. There are better choices, including our favorite – bone marrow stem cells.
But, what about those cosmetic physicians who inject autologous fat stem cells for aesthetic procedures? For starters, there’s a difference between an injection during a procedure versus a product intended for daily indefinite topical use. A little inflammation and enhanced angiogenesis (new blood vessel formation) can be of benefit during fat grafting. But even injected fat stem cells may be problematic.
We are quite certain most practitioners are not up to speed on the growing bad rap scientists are giving adipose derived stem cells. Some of the research is very new, with additional studies published frequently. The areas of most concern have to do with the role of fat and fat stem cells in the genesis and progression of certain cancers, and their well-established role in systemic inflammation, metabolic syndrome, insulin resistance and diabetes. Their profoundly pro-inflammatory behavior is not in dispute.
The studies below are just a few of the many that raise our concerns and our eyebrows. The text is adopted directly from the articles with minor deletions of super high science jargon, but you’ll get the idea. How long will it be before companies pitching the “benefits” of products made using adipose derived stem cell conditioned media are forced to address the elephant in the room.
Obesity, Inflammation, and Cancer.
Annual Review of Pathology 2016 May 23;11:421-49.
Obesity confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism that stems from obesity, including insulin resistance, hyperglycemia, and dyslipidemia, can further impact tumor growth and development.
Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates.
Tissue Engineering Part A. 2011 Jan;17(1-2):93-106
Adipose-derived stem cells (ASCs) have been proposed to stabilize autologous fat grafts for regenerative therapy, but their safety is unknown in the setting of reconstructive surgery after mastectomy. Here, we ask whether ASC promote the in vitro growth and in vivo tumorigenesis of metastatic breast cancer clinical isolates. Metastatic pleural effusion (MPE) cells were used for coculture experiments. ASC enhanced the proliferation of MPE cells in vitro (5.1-fold).
The secretome profile of ASC resembled that reported for MSC, but included adipose-associated adipsin and the hormone leptin, shown to promote breast cancer growth. Our data indicate that ASC enhance the growth of active, but not resting tumor cells. Thus, reconstructive therapy utilizing ASC-augmented whole fat should be postponed until there is no evidence of active disease.
The White Adipose Tissue Used in Lipotransfer Procedures Is a Rich Reservoir of CD34+Progenitors Able to Promote Cancer Progression
Cancer Res; 72(1); 325–34. 1 January 2012
Previous studies have suggested a “catalytic role” in neoplastic angiogenesis and cancer progression for endothelial progenitor cells (EPC). We have found that human and murine (mouse) white adipose tissue (WAT) is a very rich reservoir of EPCs with endothelial differentiation potential, containing a mean of 263 times more EPC cells/mL than bone marrow. Compared with marrow-derived cells, purified WAT-CD34+ cells expressed similar levels of stemness-related genes, significantly increased levels of angiogenesis-related genes, and increased levels of fibroblast activation protein-α, a crucial suppressor of antitumor immunity. In vitro, WAT-CD34+ cells generated mature endothelial cells and capillary tubes as efficiently as mature mesenchymal cells. The coinjection of human WAT-CD34+ cells from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient mice. Endothelial cells derived from human WAT-CD34+ cells lined the lumen of cancer vessels. These data indicate that CD34+ WAT cells can promote cancer progression and metastases. Our results highlight the importance of gaining a better understanding of the role of different WAT-derived cells used in lipotransfer for breast reconstruction in patients with breast cancer.
Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling.
Cancer Letters 2016 Jun 16;380(1):114-121
Obesity increases the incidence and progression of multiple myeloma (MM), yet the molecular mechanisms by which adipocytes contribute to cancer development and patient prognosis have yet to be fully elucidated. Here, we obtained human adipose-derived stem cells (ASCs) from twenty-nine normal (BMI = 20-25 kg/m2), overweight (25-30 kg/m2), obese (30-35 kg/m2), or super obese (35-40 kg/m2) patients undergoing elective liposuction. Upon differentiation, adipocytes were co-cultured with RPMI-8226 and NCI-H929 MM cell lines. Adipocytes from overweight, obese and super obese patients displayed increased PPAR-gamma, cytochrome C, interleukin-6, and leptin protein levels, and decreased fatty acid synthase protein. 8226 MM cells proliferated faster and displayed increased pSTAT-3/STAT-3 signaling when cultured in adipocyte conditioned media. Further, adipocyte conditioned media from obese and super obese patients significantly increased MM cell adhesion, and conditioned media from overweight, obese and super obese patients enhanced tube formation and expression of matrix metalloproteinase-2. In summary, our data suggest that adipocytes in the MM microenvironment contribute to MM growth and progression and should be further evaluated as a possible therapeutic target.
New Piece in the Jigsaw Puzzle: Adipose Tissue–Derived Stem Cells From Obese Subjects Drive Th17 Polarization
Diabetes 2015 Jul; 64(7): 2341-2343.
Obesity fuels the development of metabolic syndrome which includes elevated glucose levels, insulin resistance, elevated blood pressure, and increased levels of triglycerides. Obesity and metabolic syndrome increase the risk of metabolic diseases, such as type 2 diabetes (T2D), cardiovascular disease, and atherosclerosis, and contribute to a reduction in life expectancy. In the U.S., the obesity rate in adults has reached 36% and obesity affects more than 1 billion people worldwide. Currently, 9.3% of the U.S. population has diabetes. In adults, T2D accounts for 90–95% of all diagnosed cases of diabetes, and the estimated total economic burden of diabetes in the U.S. is $245 billion.
Adipose tissue is a perplexingly complicated endocrine organ that contains a multitude of cell types, such as adipocyte-derived stem cells (ASCs), adipocytes, vascular cells, and immune cells, that all play a role in obesity-induced inflammation. Excess calorie intake induces adipose tissue enlargement and causes adipocyte dysfunction. Enlarged adipocytes produce cytokines and chemokines that include TNF-α and chemokine (C-C motif) ligand-2, which, in turn, promote immune cell accumulation in the adipose tissue. Immigrated inflammatory immune cells enhance adipose tissue inflammation, which further exacerbates adipocyte dysfunction. TNF-α secreted by inflammatory cells interferes with insulin receptor signaling pathways in adipocytes and causes peripheral insulin resistance.
Co-culturing human ASCs (from obese donors) with human mononuclear cells (MNCs), drastically changes the phenotype of MNCs. IL-1β and IL-6 production are both elevated in coculture experiments using ASCs and MNCs. Altogether, these results suggest that the triumvirate of monocytes, ASCs, and T cells controls adipose tissue inflammation.
Inflammasomes are caspase-1–containing multicomponent protein complexes, which proteolytically cleave IL-1β and IL-18 to induce the secretion of these cytokines by adipose tissue macrophages. Signals derived from ASCs or MNCs induce inflammasome activation and IL-1β secretion by monocytes.
Adipose Tissue–Derived Stem Cells from Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation
Diabetes 2015 Jul; 64(7): 2477-2488.
Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs—with a contribution of intracellular adhesion molecule-1—and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.
Hi I have had a skin flap around nostril area this was for a cosmetic surgery gone wrong and then the flap also went wrong and was removed. There is so much fibrotic scar tissue and skin tension and a shortage of skin from where the flap was taken from. Would the mechesyml bone marrow derived stem cells help? Can they replace the lost tissues? I also have fibrotic scar tissue deep inside not visible scar tissue from the original procedure. It’s not visible but changed the shape of the area because of contracture inside. Can the bone marrow derived stem cells be injected there? The needling doesn’t go down as far as the muscle right?
Kim, it is troubling when the desired goal of surgical repair is not achieved – troubling for the patient and for the physician. If you read BFT regularly, you know our opinion is any effort to reduce inflammation during the healing process is a good thing. Some of what you describe will likely require plastic surgery revision. Seek professioanal advice from two or three experts.
For your fibrotic scar contracture, there may be a role for medical needling and we would certainly suggest you consider using our microneedling product to help tamp down inflammation if that is the route you elect to go. There is a specialist in dermal needling of burn contractures who has been using our products for two years who reports improved results. Certainly replacement of “missing” tissue is something that needs more than dermal needling to address. Good luck.
Just wondering how long the mechesyml derived stem cells last in their bottle (in Anteage & Procell). Is there a shelf life for them?
Looks like we have to step up our educational mission. We’ll answer your question straight away but want to remind you there is deep science, even PhD level material, in Drjohn’s excellent series on cytokines. Use the keyword categories on the right and you’ll soon have your answer, and then some.
The short answer is there are no stem cells in the bottle, so how long they last has no answer – the cells are long gone. Read on.
There is no worry about how long the stem cells survive in cosmeceutical products since they have long ago been discarded (no so for one class of products we’ll mention in a moment.) We will dispense with the notion of plant stem cell products since we consider them a marketing ruse, purloining the words “stem cell” to fleece unsuspecting consumers of their hard earned money. Plant stem cells come from a different biologic kingdom, one with its own chemical signalling molecules, entirely different from those of the animal kingdom, particularly higher animals like humans.
There are more than 500 published articles in the world’s literature that address the clinically verifiable benefits of cell culture derived bio-signals (cytokines and growth factors) on human skin. The kernel of truth we want you to grasp is that the bio-signals, not the cells that produce them, are the key to skin improvement. The cells cultured are simply the “factory” used to obtain the bio-signals. A recurring message on BFT is the effect of a given cell type’s bio-signals can vary greatly, particularly with regards to its impact on stimulating or inhibiting an inflammatory response. Our readers know that we are huge proponents of bone marrow stem cell derived bio-signals because they are the commander-in-chief of healing in all injured tissues, and produce a pattern of bio-signals that tamps down the fires of inflammation.
Other cell types cultured are adipose (fat) stem cells (highly pro-inflammatory bio-signal pattern) and fibroblasts (very impotent producers of bio-signals.) We are not fans of those cells as a source of bio-signals ESPECIALLY if use in a product intended for daily, chronic use. One tends to inflame the skin, the other just no “oomph”.
One type of cell-culture derived skincare product makes no scientific sense to us – those where the cells are actually saved, ruptured by repeat freeze/thaw cycles, and blended into a final product…that just sounds like slathering hamburger on the skin. Cell remnants cannot penetrate the skin/ They sipl sit on the surface until later rinsed down the drain.
Dermpen 3MD microneedling or Venus Viva Fractional treatments didnt really help much with my ACNE scars and large pores. i only had one of each treatment but I felt discouraged to continue.
I am so glad I came across this website as they didn’t applie HA or HGF during or after the Microneedling treatment. When you say high weight molecule HA, does juvederm count? The place also sell Skin medica product that is called HA5 which is a topical moisturiser made of HA(not sure about HMW) what do you think about HA5 or Juvederm for the treatments? Is it best to applied before the tx? During? Right after? My main concerns are poresizes and ACNE scars rathers than wrinkles.
I also found a comment here that TNS Repair Complex should be avoided following microneedling. So I am very interested in getting your product. Would you do wholesale? I will test on myself and see the result. Please email me on info on how to get the HA and HGF. I found Anteage website but it didn’t sell products.
Viva Venus Fractional treatment followed with application of venus viva RF cream, which is explained it has HGF and is perfect for boosting collagen production even further. Should I ask for that cream after microneedling?
So do I apply HA during the procedure or right after? When do I apply HGF?
Microneedling and Viva treatments provide accumulative improvement over a series of treatments. This is particularly true the worse the scarring problem. There is incremental improvement with each treatment. The HA5 ingredient in SkinMedica refers to five forms of HA in this product: time release HA, sodium hyaluronate, uncross-linked HA, nano-HA, and cross-linked HA. Interesting twist on HA delivery and not so sure this isn’t more of a marketing ploy than a great leap forward in HA science. After all, the purpose of HA, regardless of delivery form is to provide something that absorbs lots of water. TNS Recovery Complex contains as its first ingredient conditioned media from culture of human fibroblasts. BFT readers know that fibroblasts are poor producers of cytokines and growth factors when compared to our favorites, bone marrow mesenchymal stem cells, which, depending on the bio-signal in question, produces 15 to 50 times the amount produced by fibroblasts. To be frank, the most impressive microneedling and Viva results we have seen used our products as immediate and daily aftercare. Our microneedling solution contains HA and bio-signals from bone marrow stem cells. Our MD version also has additional synthetic bio-identical growth factors.
I would love to! I am thinking of dermapen 3MD tx every 3 weeks, going in with .5mm for everywhere except for my cheeks with large pores and icepick scars. I would really appreciate if you have an instruction so that I can give it to the technician. I am sure they will be thrilled to implement new products if it leaves a good result.
Thank you so much!! Your thoughts on those products clarified my doubts. I would love to try your products and if there are any medical graded or clinic use products, pkease introduce me to those as well. Thank you and I am so glad I found this website!!
Hi doctors, I have to start by saying just how much I love your posts! I’m bordering on obsession.
So I just purchased the anteAge MD microneedling solution, accelerator and serum; I’m in Australia and can’t wait for them to arrive. However I have had a bad experience with microneedling before where the skin beneath my lashes was needled at 0.25mm using active ingredients (vitamin C and A) and I actually ended up with wrinkles; very depressing! That was more than a year ago and I haven’t had another treatment since. But I’m going to brave out another treatment using the anteAge MD microneedling solution and was just wondering if you have any advice to put my mind at ease?
Also, prior to that experience I’d had many successful microneedling sessions which’d done wonders for my acne scars however for some reason immediately post treatment my face looks like it’s aged 20 years. – no joke I’m talking deep folds all over. The first time I saw it I freaked out but it only lasts about a half hour or so and then goes back to normal. Do you know why this happens? The nurse performing my treatment said she’d seen this happen on one other patient but had no idea why and just assured me that it was a temporary effect. This happens before she uses any active products on my skin and therefore seems to be a result of the needling itself. Dr google has nothing to say on it so I’d be really interested to hear your opinion please.
Deep folds appearing immediately? I would suspect a sudden edema. To happen that quickly, I might also suspect an allergic chemical reaction to something. Mystery here as to what. Perhaps the needles themselves (rare metal allergy, some left over chemical?). In any event the fact that it is brief and seems to do no harm is reassuring. We do of course worry about vitamins C and A, as we have seen multiple reactions to those, including full on granulomas reported in the medical literature. As we are fond of saying, during and after microneedling do not put anything on your skin that the body does not itself make. Even vitamins (made by plants and used by humans). So stick to HA & human growth factors.
I concur with Drjohn on the edema etiology. There is enough trauma from dermal needling, especially with longer needles, lots of passes, and perhaps HA topically applied, to cause substantial and significant increased in hydration in the upper layers of the skin. The phenomenon you describe, if caused by lots of sudden fluid accumulation within the superficial tissues of the face, is akin to what one see when they linger in the bath tub too long – wrinkled finger tips. When the edema fluid reabsorbs and/or redistributes, wrinkles disappear. Drjohn’s suggestions about possible allergic reactions are plausible but I would expect the wrinkling to persist for a while and have associated itching.
Thanks so much for the response docs. The edema/increased hydration theory makes total sense as she does usually needle with HA at 2.5mm (the bathtub analogy brought it home).
Can’t wait to try your microneedling solution!
Hi docs, I have purchased the set of anteage and it just arrived today. I am excited to try them out. Just some questions: is there any money back guarantee incase we are not satisfied with the products? I see no expiration date on it. How long can I keep them for? And can you tell me more about the major differences between anteage and some other stem cells serum like jeunesse? Thanks!
Yes, Karen, your satisfaction is of key importance, with a money back guarantee. It has a two-year expiration. Jeunesse is based on adipose (fat) stem cells, as are most others. These are decidedly inferior for regenerative skin care. Others are based on fibroblasts, which are not actually stem cells at all. And then there is the folks who want you to believe that plant stem cells are somehow communication with your cells (not true).
Hello docs! I’m guessing I’m one of the younger people here at 22, but I’m a skincare enthusiast and have thoroughly enjoyed reading your blog. As a mere law student I am far from a scientist, but I have an unorthodox theory that I want to run by you based on information I have come across throughout my research.
I have noticed a growing amount of young tretinoin users complaining of subcutaneous fat loss. While I’m aware of Retin-A’s proven efficacy in up-regulating collagen production and mitigating fine line formation, I have come across several studies stating that retinoic acid directly inhibits adipogenesis both in vitro and in vivo. While conventional wisdom and research state that tretinoin is unable to penetrate the subcutaneous fat layer of the skin, I still find this to be incredibly unsettling. I would be happy to link you to both anecdotes and research I have come across.
I am aware that there are no clinical trials supporting this idea, but I also feel it necessary to point out that most studies involving Retin-A have featured middle-aged females as test subjects. Perhaps because people in this age group have less subcutaneous fat, any change would be less noticeable than in a younger subject. I also frankly do not trust pharmaceutical companies to explore this potential flaw nor be forthcoming with any research on it.
I suppose what I am asking is do you think that this is somehow possible? Perhaps not in the majority of cases or skin types given tretinoin’s success, but would it be theoretically possible in any way given that there is substantial evidence suggesting that retinoic acid affects the process of fat production? Preserving subcutaneous facial fat is important to me as I feel that while there are many ways of up-regulating collagen production, there are no topical methods of addressing loss of fat.
Sam, it is well known that all trans retinoic acid reduces expression of adipogenic transcription factors (e.g. PPAR-gamma) and increases fat oxidation. Short-term administration of isotretinoin can even elevates plasma triglyceride concentrations. Suspicious huh? The effect on subcutaneous fat is not at all clear (mostly “ignored” in the medical literature), but switching to an oxidative metabolism is surely suggestive of disrupted lipogenesis, which would at the least interfere with normal tissue maintenance. So your theory may not be all that unorthodox, although poking the sleeping bear (retinoids being all that many dermatologists believe in for anti-aging) could earn you a reputation as a muckraker. Please share your data or observations. Even if the world comes to hate you, you can always set your sights on a specialty in toxic skin torts, which would guarantee you induction into the BFT hall of fame.
P.S. Sam Certain native human growth factors can contribute to restoration of fat stores. Facial adipose fat cells have receptors for e.g. IGF-1, and TGF-B3. The response to topical signaling is is growth (mitogenic) and differentiation. Plastic surgeons are gaining experiencing in using GF and cytokine stimulation, typically through autologous stem cell enrichment, to aid in the engraftment of transplanted fat for facial volume enhancement.
What your thoughts are on DHA or erythrulose-based topical false tanners and whether or not the Maillard reaction through which they function could damage skin. Glycation is unsettling and as much as I want to embrace the fake tan as a healthier sun-tanning alternative, I don’t want to potentially endanger my skin!
DHA (dihydroxyacetone) and erythrulose-based “tanners” indeed cause the Maillard reaction resulting in artificially colored skin. DHA tends to produce orange colored skin tones which is “balanced” with the red color produced when erythrulose is added. In some products other added pigments may include beet root, blue green algae, caramel, and cocoa powder. The reaction of sugars with amino acids occurs in the keratin on the skin surface, producing pigments call meanoidins. The reaction occurs in the keratinocytes of the outermost layers of the stratum corneum; these cells are dead and shed over time, making it necessary to reapply the artificial tanning products every couple weeks or so.
The phenomenon of skin coloration was discovered in the 1950s, while studying the effect of large oral doses of DHA in children with glycogen storage disease. The skin of the children that casually and accidentally came into contact with DHA in solution turned brown, whereas textiles did not.
Fifty five years later (in 2015), driven by consumer demand for a fashionable tan throughout the whole year and by concomitant increasing awareness of UV photodamage hazards, one of the leading self‐tanning product manufacturers sold out a year’s worth of stock of its in‐shower tanning lotion in only one day. In 2011, 41% of women in the UK were reported to use self‐tanning products.
In the EU, for example, the Scientific Committee on Consumer Safety evaluated the safety of DHA as a self‐tanning ingredient in cosmetic formulations, in 2010, and concluded that the use of DHA in skin formulations at concentrations up to 10 % will not pose a risk to the health of the consumer. Several medical associations recommend it as a safer alternative to UV radiation from the sun or from hazardous tanning beds (“we don’t call those UV tanning booths; we call them tanning coffins”).