Old interview with Cotsarelis (must read IMHO)

waynakyo

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http://www.aad.org/dw/monthly/2012/june/can-blocking-pgd2-prevent-androgenetic-alopecia-#page1

By Abby Van Voorhees, MD, June 01, 2012
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with George Cotsarelis, MD, about his recent Science Translational Medicine article, “Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia.â€
Dr. Van Voorhees: What have we known about androgenetic alopecia (Androgenetic Alopecia) up until your most recent findings?
Dr. Cotsarelis: We know a lot about Androgenetic Alopecia from studies a long time ago, in the ’50s, by Dr. James Hamilton. He was the first one to coin the term androgenetic alopecia. He noticed that men who had been castrated before puberty never went bald, and realized that baldness was androgen-dependent. He did some experiments where he gave men who had been castrated testosterone; the ones who had a family history of baldness started to go bald, so that was how he identified the genetic component. He originally called it androchronogenetic alopecia because you needed androgens, time, and genetics. We’ve known it’s androgen-dependent since then.
Next we learned more from studies by Imperato-McGinley, who studied families in the Dominican Republic who were pseudo-hermaphrodites — they were born looking like girls, with female genitals, and then at puberty they virilized, developing musculature, lower voices, and hair, and would actually develop a penis and could be fertile if they had their undescended testes surgically corrected. They were found to have a deficiency of type-2 5- reductase, the enzyme that converts testosterone into dihydrotestosterone. This was when we understood the importance of dihydrotestosterone in the process. Of course that’s what finasteride blocks; Merck developed that drug based on those studies.


Dr. Van Voorhees: What is the mechanism that accounts for the miniaturization of hair?
Dr. Cotsarelis: We know that inhibiting the testosterone pathway slows down the miniaturization of the follicle. Jaworsky, Kligman, and Murphy had a paper 20 years ago showing that half the time there is also inflammation around the hair follicle, which led to some thought that maybe inflammatory cells including mast cells were contributing to hair loss. Studies and case reports of transgender operations where men become women and receive high doses of estrogen show that a scalp that was almost completely bald can have, after castration and high estrogen supplementation, a tremendous amount of hair growth.
The overall feeling is that the follicles can be thought of as being in three states. Either they’re terminal, and they’re large, or they’re miniaturized, and they’re small, and the hair they’re creating is microscopic, or they’re in between, called indeterminate. It’s thought that follicles reach a point where they’re producing a hair so small that at that point the chance of reversing that follicle is small. There seems to be a point of no return with respect to androgen removal; even if you castrate someone who’s bald he won’t regrow all his hair. If you give him estrogen, too, he might.


Dr. Van Voorhees: Do resting stem cells remain in Androgenetic Alopecia? Do current medications used to treat Androgenetic Alopecia help us understand this process? What did this research demonstrate about the mechanism of Androgenetic Alopecia?
Dr. Cotsarelis: About a year ago Luis Garza, MD, did another study in my lab and looked at the stem cells in balding scalps of men undergoing transplants. He got tissue from the donor site and the recipient site and he actually quantitated the number of hair follicle stem cells using flow cytometry, a very accurate cutting-edge technique for quantitating the number of stem cells. And he showed that the percentage of stem cells was very similar in both areas. So the stem cells were still there even in the balding scalp where the follicles were miniaturizing.
However, he did find a population of cells that was markedly diminished in the balding scalp, and those resembled progenitor cells, the immediate progeny of stem cells. At that point we thought there must be either a lack of an activator of the stem cells preventing them from proliferating and doing their job and making hair, or maybe an inhibitor present. Using microarrays of bald and non-bald scalp in the same people, we looked at all 30,000 genes to see whether their expression levels were increased or decreased in the bald scalp. One of the genes that was markedly elevated in the bald scalp was PTGDS, prostaglandin D2 synthase.
We collaborated with Garret FitzGerald, MD, who’s an expert in prostaglandins and has done a lot of work with the COX-2 inhibitor he’s the one who actually showed that the COX-2 inhibitors have dangerous side effects. We gave him tissue from balding and non-bald scalp and he looked at the levels of PGD2 with mass spectrometry and showed that the PGD2 levels were quite high in the bald scalp. That was still just a correlation showing that there were higher levels of the genes and the lipid products in the bald scalp — we didn’t really know functionally whether that meant anything.
So then Luis worked with mouse models to assess the function of PGD2. Luis applied the PGD2 and another breakdown product, PGJ2, topically to the back of a mouse and he showed that hair growth slowed. Next, we collaborated with another group that was good at growing human hair follicles in culture. They showed that PGD2 in the culture media slowed down hair growth. So now we had functional evidence that prostaglandins played a role in hair growth. Luis also looked in the mouse, which has a better-defined hair cycle than humans because all of the hairs tend to be in the same stage whereas humans have mixtures of hair follicles in different stages of growth. In that model we showed that PGD2 started to go up during the end of the growing phase and was highest at catagen, the stage of regression. That, again, was good correlative evidence that PGD2 was inhibiting hair growth and even in a spontaneous hair cycle played a role in controlling hair growth.
There was a mouse that was made in the ’90s by Sue Fisher, who studies skin cancer; it’s a transgenic mouse that makes the COX-2 enzyme in the skin, so you drive COX-2 gene expression with keratin K14 promoters. It’s up higher in the pathway so if you overexpress COX-2 you get increases in PGD2 and also PGE2. E2 and F2 are actually known to promote hair growth — bimatoprost (Latisse) is an F2 analog. We looked at levels of D2 in that mouse, which develops alopecia, and they were sky high. E2 was also higher than the control but D2 levels were much higher. What’s amazing is if you looked at that mouse’s skin histologically the hair follicles were miniaturized and the sebaceous glands were enlarged, just like in androgenetic alopecia.
Finally, in genetic experiments done in collaboration with FitzGerald, we applied D2 to mice that lacked two different receptors that D2 binds to. The DP-1 knockout mouse had suppressed hair growth. The DP-2 (or GPR44) knockout mouse did not have inhibited hair growth.


Dr. Van Voorhees: Does this research open up possible avenues for treatment approaches that have not yet been considered? Are there currently drugs under development which might be utilized?
Dr. Cotsarelis: This work suggested that D2 was working through the GPR44 receptor to inhibit hair growth. It turns out that there are compounds under development by a number of companies to inhibit this receptor. They are being developed for asthma and allergic rhinitis. PGD2 causes bronchoconstriction — when you inhibit its receptor you relax smooth muscle so it helps with lung disorders. No one is developing a topical formulation, but we think if you did, it would be a potential treatment for alopecia.
Dr. Van Voorhees: Should this allow for reversal of previously lost hairs or do you expect that it will only play a role in retaining hairs that have not yet miniaturized?
Dr. Cotsarelis: We don’t know. Like anything you’d have to test a large number of people to see how they respond. We don’t know if people who are already completely bald will regrow hair. We do know that the stem cells are present in men who are balding so if this is indeed the inhibitor preventing stem cells from making progenitor cells, there’s a possibility this would help there as well.
Dr. Van Voorhees: Why do you think there’s that threshold where miniaturization becomes non-reversible?
Dr. Cotsarelis: That’s an interesting question. There might be other genes downstream of testosterone playing a role. We already know that if you inhibit testosterone that hair doesn’t revert once it’s completely miniaturized. The fate of the hair follicle is determined very early on during development; there’s patterning, that’s why you have follicles responding to androgens on the top of the scalp and in the beard area in completely different ways. Androgen receptors are set up very early in development; I think the more we understand about that patterning the more we’ll likely be able to figure out what’s going on with hair loss.
 

casperz

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Studies and case reports of transgender operations where men become women and receive high doses of estrogen show that a scalp that was almost completely bald can have, after castration and high estrogen supplementation, a tremendous amount of hair growth.

I just mentioned this today elsewhere. Estrogen clearly plays a role.
 

saintsfan92344

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Ok so we need volunteers to take estrogen in a trial and then we need to take donations to buy them bras
 

opti

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if estrogen wouldnt go systematic it would be a cure indeed.No more temples etc.

Injecting fat cells in to the scalp could be a cure too. Fat cells are rich of aromatase which produces estrogen.Women have more fat cells than men do ,especially at temples,thats why they dont have balding temples.
But who knows how long this fat cells are living...
 

squeegee

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Ok so we need volunteers to take estrogen in a trial and then we need to take donations to buy them bras

I'll stick to the derma roller. There is still men out there with their balls with plenty of hair. Estrogen is a cause of breast cancer! Female have their problems too!

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Time to cut off my balls, brb.

youtube it.

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I think that we can fix the problem locally, no systematically. The skin has his own endocrine system, one of my theory about hairloss is that the steroidogenic enzymes are overactive.

Steroidogenic isoenzymes in human hair and their potential role in androgenetic alopecia.

Hoffmann R.
Source

Department of Dermatology, Philipp University, Marburg, Germany. rolf.hoffmann@mailer.uni-marburg.de

Abstract

Androgenetic alopecia (Androgenetic Alopecia) is the most common type of hair loss. The relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait, and a polygenic basis is considered to be most likely. So far, the predisposing genes for Androgenetic Alopecia are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but Androgenetic Alopecia can be defined as a dihydrotestosterone (DHT)-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5alpha-reductase plays a central role by the intrafollicular conversion of testosterone to DHT. However, due to the increasing knowledge in this field, we now know that there are many more steroidogenic enzymes involved in the onset and development of Androgenetic Alopecia, and this article shall provide a critical overview of recent discoveries.
Copyright 2003 S. Karger AG, Basel





Steroidogenic enzymes in skin.

Andersson S.
Source

Department of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA. stefan.andersson@UTSouthwestern.edu

Abstract

The gonadal synthesis of testosterone from cholesterol involves four enzymes, namely, cytochrome P-450 side-chain cleavage enzyme, cytochrome P-450 17a-hydroxylase/lyase, 3b-hydroxysteroid dehydrogenase, and 17b-hydroxysteroid dehydrogenase. A significant part of the plasma-borne testosterone is converted in androgen target tissues, such as the skin, to the more potent androgen dihydrotestosterone by the steroid 5a-reductase type 1 and type 2 isoenzymes. Dihydrotestosterone, which binds to the nuclear androgen receptor with much greater affinity than testosterone, is the androgen responsible for a process leading to androgenetic alopecia. Consequently, the 5a-reductase inhibitor finasteride was developed and has proven efficacious in promoting hair growth as a consequence of lowering scalp and plasma dihydrotestosterone levels. In contrast to the direct synthesis of dihydrotestosterone from testosterone, biologically inactive C19-steroids produced by glandular and peripheral tissues may also feed into the scalp skin production of dihydrotestosterone by the local expression of reductive 17b-hydroxysteroid dehydrogenase, oxidative 3a-hydroxysteroid dehydrogenase, and 3b-hydroxysteroid dehydrogenase enzymes. Aberrant expression of one or more of these enzymes, could conceivably result in increased scalp dihydrotestosterone levels, and possibly, acceleration of the balding process in genetically predisposed men and women.



J Invest Dermatol. 2003 Jun;120(6):905-14.
Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1).

Thiboutot D, Jabara S, McAllister JM, Sivarajah A, Gilliland K, Cong Z, Clawson G.
Source

Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. dthiboutot@psu.edu

Abstract

Although the human sebaceous gland can synthesize cholesterol from acetate and can further metabolize steroids such as dehydroepiandrosterone into potent androgens, the de novo production of steroids from cholesterol has not been demonstrated in human skin. The goal of this study was to delineate the steroidogenic pathway upstream from dehydroepiandrosterone by documenting the presence of members of the P450 side chain cleavage system (P450scc). This system catalyzes the initial step in steroid hormone synthesis following translocation of cholesterol to the inner mitochondrial membrane. In concert with its cofactors, adrenodoxin and adrenodoxin reductase, and the transcription factor steroidogenic factor 1, P450scc converts cholesterol to pregnenolone. An SV40 immortalized human sebaceous gland cell line (SEB-1) was established in order to facilitate investigation of the P450scc system. The sebaceous phenotype of SEB-1 sebocytes was confirmed using immunohistochemistry, Oil Red O staining, and gene array expression analysis. Presence of P450scc, adrenodoxin reductase, cytochrome P450 17-hydroxylase (P450c17), and steroidogenic factor 1 was documented in human facial skin, human sebocytes, and SEB-1 sebocytes. Using immunohistochemistry, antibodies to the above proteins localized to epidermis, hair follicles, sebaceous ducts, and sebaceous glands in sections of facial skin. Results of immunohistochemistry were confirmed with Western blotting. Biochemical activity of cytochrome P450scc and P450c17 was demonstrated in SEB-1 sebocytes using radioimmunoassay. The relative abundance of mRNA for P450scc, P450c17, and steroidogenic factor 1 in SEB-1 sebocytes and sebaceous glands was compared to mRNA levels in ovarian theca and granulosa cells using real-time quantitative polymerase chain reaction. Gene array expression analysis and quantitative polymerase chain reaction indicated that mRNA for P450scc is more abundant than mRNA for both P450c17 and steroidogenic factor 1 in sebaceous glands and SEB-1 cells. These data demonstrate that the skin is in fact a steroidogenic tissue. The clinical significance of this finding in mediating androgenic skin disorders such as acne, hirsutism, or androgenetic alopecia remains to be established.




Higher Levels of Steroidogenic Acute Regulatory Protein and Type I 3
-Hydroxysteroid Dehydrogenase in the Scalp of Men with Androgenetic Alopecia



http://www.nature.com/jid/journal/v126/n10/full/5700442a.html
 

odalbak

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Human skin is a steroidogenic tissue

How come bald men have higher risks of other pathologies that are irrelevant to the skin? Does the excessive DHT produced in the skin affect other areas of the body?
 

waynakyo

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You guys got distracted with balls and bras, amazing.

I think we know that feminization=more hair, the is a lot of other useful info, including the fact that he think TOPICAL pgd2 inhibitor could be a potential treatment.

He also mentioned that inhibiting cox has bad effects (probably on our c****), but my understanding is that OC acts directly on pgd2 not cox right?

There is so much distraction and obsession on this forum, the pgd2 discussion was going well, it stopped too quickly i think.
I am not the only one who experienced a persistent halt to the daily and seasonal shedding, no other drug has done that.

I will also post pics soon, i think after 6 months i am starting to see some coverage on the crown and some more minor in the front (i am talking about cosmetic not a microscopic hair).

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How come bald men have higher risks of other pathologies that are irrelevant to the skin? Does the excessive DHT produced in the skin affect other areas of the body?
My sense is that many non-balding men are slightly thinning, and their hair is not necessarily resistant to dht but they have low dht. A friend of mine falls in this category, he told me he has very low T, he is older than me, has almost a full head of hair, yet on both sides of his family people bald early. The point is that this makes that on average people who are bald have higher DHT with its negative consequences when it comes to health as people age (implicated in cancer and heart disease)...

i could be wrng..
 

saintsfan92344

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I got distracted on the growing boobs part, just doesn't do it for me, I did pick up on the pgd2 inhibitor but aren't we waiting on a way to get it in something that can be absorbed effectively
 

squeegee

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How come bald men have higher risks of other pathologies that are irrelevant to the skin? Does the excessive DHT produced in the skin affect other areas of the body?

Androgen receptors are present in a variety of tissues like skeletal muscles, skin, gastrointestinal tract, genitourinary tract, bone, brain, cardiovascular system, placenta, and adipose tissues.....etc.

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J Steroid Biochem Mol Biol. 2013 Sep;137:107-23. doi: 10.1016/j.jsbmb.2013.02.006. Epub 2013 Feb 19.
Steroidogenesis in the skin: implications for local immune functions.

Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, Li W, Janjetovic Z, Postlethwaite A, Zouboulis CC, Tuckey RC.
Source

Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: aslominski@uthsc.edu.

Abstract

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.

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Human Skin: An Independent Peripheral
Endocrine Organ

Human Skin: An Independent Peripheral
Endocrine Organ
Christos C. Zouboulis
Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin,
Berlin, Germany
Prof. Dr. Christos C. Zouboulis
Department of Dermatology, University Medical Center Benjamin Franklin
The Free University of Berlin, Fabeckstrasse 60–62
D–14195 Berlin (Germany)
Tel. chrome://skype_ff_extension/skin/numbers_button_skype_logo.png
ABC
Fax + 41 61 306 12 34

www.karger.com
© 2001 S. Karger AG, Basel
0301–0163/00/0546–0230$17.50/0
Accessible online at:
www.karger.com/journals/hre
Key Words
Endocrinology
W
Hormone synthesis
W
Hormone
receptors
W
Hormone metabolism
W
Hormone activity
Abstract
The historical picture of the endocrine system as a set of
discrete hormone-producing organs has been substi-
tuted by organs regarded as organized communities in
which the cells emit, receive and coordinate molecular
signals from established endocrine organs, other distant
sources, their neighbors, and themselves. In this wide
sense, the human skin and its tissues are targets as well
as producers of hormones. Although the role of hor-
mones in the development of human skin and its capaci-
ty to produce and release hormones are well estab-
lished, little attention has been drawn to the ability of
human skin to fulfil the requirements of a classic endo-
crine organ. Indeed, human skin cells produce insulin-
like growth factors and -binding proteins, propiomelano-
cortin derivatives, catecholamines, steroid hormones
and vitamin D from cholesterol, retinoids from diet caro-
tenoids, and eicosanoids from fatty acids. Hormones
exert their biological effects on the skin through interac-
tion with high-affinity receptors, such as receptors for
peptide hormones, neurotransmitters, steroid hormones
and thyroid hormones. In addition, the human skin is
able to metabolize hormones and to activate and inacti-
vate them. These steps are overtaken in most cases by
different skin cell populations in a coordinated way indi-
cating the endocrine autonomy of the skin. Characteristic
examples are the metabolic pathways of the corticotro-
pin-releasing hormone/propiomelanocortin axis, ste-
roidogenesis, vitamin D, and retinoids. Hormones exhib-
it a wide range of biological activities on the skin, with
major effects caused by growth hormone/insulin-like
growth factor-1, neuropeptides, sex steroids, glucocorti-
coids, retinoids, vitamin D, peroxisome proliferator-acti-
vated receptor ligands, and eicosanoids. At last, human
skin produces hormones which are released in the circu-
lation and are important for functions of the entire organ-
ism, such as sex hormones, especially in aged individu-
als, and insulin-like growth factor-binding proteins.
Therefore, the human skin fulfils all requirements for

being the largest, independent peripheral endocrine or-
gan

http://www.klinikum-dessau.de/fileadmin/user_upload/Hautklinik/PDF-Files/110_hormres.pdf




 

mlb

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This study has always fascinated me. All three treatments helped significantly. That tells me the delivery method is the key (iontophoresis). We spend 99.9% of our time worrying about WHAT we put on our head, when in fact, it may may be HOW we put it on our head, that matters.

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We knew estrogen was good for hair.

Cosmo study shows good results with 17a-estradiol:
http://www.cosmopharmaceuticals.com/news/press/pr2010/2010-10-06.aspx


This study has always fascinated me. All three treatments helped significantly. That tells me the delivery method is the key (iontophoresis). We spend 99.9% of our time worrying about WHAT we put on our head, when in fact, it may may be HOW we put it on our head, that matters.
 

brunobald

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This study has always fascinated me. All three treatments helped significantly. That tells me the delivery method is the key (iontophoresis). We spend 99.9% of our time worrying about WHAT we put on our head, when in fact, it may may be HOW we put it on our head, that matters.

Hopefully the same can be said for Yorams pilox device from Israel and his method of applying zinc ions to the scalp. As far as I know zinc has never worked well as a topical but tests show zinc can inhibit DHT production upto 90%.
 

odalbak

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Why the **** do I have excessive DHT in my scalp ! I ****ING WANT TO KNOW THE REASON !

(this is not a question)
 

squeegee

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Why the **** do I have excessive DHT in my scalp ! I ****ING WANT TO KNOW THE REASON !

(this is not a question)

I would say that cholesterol is part of the problem!
 

brunobald

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Sorry I don't have the study link but I read somewhere that follicles in the male pattern baldness scalp upregulate their T -> DHT conversion sites?
 
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