Follica - Good News!

[Moomin]

Well I think there is some regulation of the pathway by some tyrosine kinases but I think the wnt pathway has a much greater importance in regulating beta-catenin levels and there is no tyrosine kinase involved in this signalling pathway as far as I can tell. If you see otherwise please let me know.

I don't know how you can say that, Wnt works on Tyrosine Kinase and GSk-3 which communicate downstream to upregulate beta catenin adhesion and neutralise/limit phosphorylation of beta catenin, respectively. Its not a case that Wnt upregulates beta-catenin all by itself as if by magic but works via intermediaries. This information is not esoteric, it is plastered all of the internet.

This quote is not saying that EGCG inhibits tyrosine kinase - EGCG "directly blocks EGF binding to the EGFR" and it is only subsequently ie. indirectly that the EGFR mediated tyrosine kinase inhibitor is blocked. So the mechanism of EGCG inhibiting EGFR is not related to EGFR tyrosine kinase.

I do not understand what you mean by this. If Tyrosine Kinase has an an EGFR site and ECGC blocks EGF from binding to those sites, and EGF - EGFR binding is necessary, at least in part, for beta catenin binding/adhesion then wouldn't BCGC negatviely affect beta catenin production if TK played any role in that production (which it does).

I dont recall saying how EGCG works but as the quote above shows it works as an EGFR inhibitor by directly stopping EGF from docking at the receptor.

No you said how it didn't work, and also I already explained how EGCG worked in my post prior to this. But repetition never harmed anyone.

I feel as though we are just going back and forth here.

Fundamentally I believe TK plays an important role in Beta-Catenin binding as do other proteins. Further you speak as though EGF only affects certain TK but not others, which isn't the case. You also don't seem to appreciate the difference between Wnt Proteins and signalling, as TK as well as GSK-3 all play their part in Wnt signalling, making it impossible to say TK nor GSK isn't important for our purposes. Finally, on this matter it is because EGF affects TK and GSK-3, as well as others, that so far their hasn't been a single suggestion of an EGF inhibitor that doesn't affect Wnt signalling. GO FIGURE.

Nevertheless, as much as I enjoyed and learnt from this conversation, it clearly isn't going to be developed any futher. My reason for this discussion was to see if any practical information could be garnered from the theory and I believe there has been some. Has anyone considered upregulating Wnt signalling over an extended period of time. As in applying Lithium Chloride for a month prior to the wounding, during the wounding and then applying an EGFR inhibitor and lithium chloride 3 days prior to the wounding. My thinking is that the ability for beta-catenin to bind and the lack/limitation of it being phosphorylated would make the beta-catenin more potent in its ability to pair with Lef1. This should obviate the affect of the EGFR-inhibitor on Wnt signalling, or at least it should limit the effect. Also the mice that over expressed Wnt signalling, were they genetically engineered (i seem to remember it was) to do this or was it done through some sort of feed and were they overexpressing Wnt before wounding or only prior to wounding? Of course this is just a theory. I'll be trying this out on myself soon.

 

[Kestrel]

I don't think anyone is suggesting they'd be miraculously spared from succumbing to DHT, but if they can grow out to full terminal hair (like the re-awokened hair that I have gotten), chances are they'll atleast stick around for a full hair-cycle, and most likely longer still before becoming very thin again.

So all in all you will, at worst, buy a few years - at which point you should be able to do the procedure again. It's also possible that hair that grow to terminal under very little bombardment of DHT, might be able to endure longer, than the hair that's been bombarded by DHT since you were... I dunno, 14-15 or so?

Thanks for the follow-up. At worst, even if the new follicles do succumb to DHT over time, as you suggest, minoxidil and/or Propecia may have enough of a mitigating effect. Also, you have an infinite supply of genetically immune follicles from the back and sides of the head. Maybe if the wounding is done close enough to the existing hairline, the new growth can be coaxed into moving toward the vertex of the scalp.

I need to read through all your previous posts. Please keep us updated on your progress.

This excerpt from a question & answer session seems to suggest that DHT susceptibility in newly generated HF may not be much of a problem, or a problem at all.

It is cut from http://www.xconomy.com/boston/2008/01/0 ... reatment/2

David Steinberg claims to be with Follica.

Erik Sebesta 1/4/08 10:05 am:
Seems, um, hair-brained. Even if they can get enough new hair to grow, won’t it just thin out again because of the same things that cause male pattern baldness in the first place?

David Steinberg 1/4/08 2:12 pm:
I am with the company. While we have not tested this in humans yet we fully expect that hair will persist. There are multiple reasons for this. First of all, consider hair transplants - while they have other flaws, the hair does indeed persist despite the presence of circulating DHT. In a distinct, but similar way, the Follica treatment changes the microenvironment of the follicles. Further, a single hair cycle lasts several years, and at the very least the new hair should last one full cycle (because of the underlying physiology of the condition). Also, circulating levels of DHT actually drop over a man’s life. We have seen numerous clinical reports of patients showing sustained hair cycling when exposed to conditions similar to the treatment Follica is pursuing (in a carefully directed and controlled way).

 

[Matt27]

We have seen numerous clinical reports of patients showing sustained hair cycling when exposed to conditions similar to the treatment Follica is pursuing (in a carefully directed and controlled way).

That one sentence makes it sound like they are very well aware of other cases of human head hair follicle regeneration. If it's true that these other (accidental??) cases resulted in continued hair cycling then there really is no reason to think the Follica method will be any different.

 

[harold]

Well I think there is some regulation of the pathway by some tyrosine kinases but I think the wnt pathway has a much greater importance in regulating beta-catenin levels and there is no tyrosine kinase involved in this signalling pathway as far as I can tell. If you see otherwise please let me know.

I don't know how you can say that, Wnt works on Tyrosine Kinase and GSk-3 which communicate downstream to upregulate beta catenin adhesion and neutralise/limit phosphorylation of beta catenin, respectively. Its not a case that Wnt upregulates beta-catenin all by itself as if by magic but works via intermediaries. This information is not esoteric, it is plastered all of the internet.

No. Wnt inhibits the action of Gsk3-Beta which is not a tyrosine kinase. As far as I am aware I have not seen anything about a tyrosine kinase in the wnt signalling pathway. If you find something please post a link to it.
Here is a link showing that at least one non-canonical wnt ligand does activate a tyrosine kinase. But this has nothing to do with beta-catenin.
http://www.ncbi.nlm.nih.gov/pubmed/1861 ... d_RVDocSum
At any rate none of this is really important for the reason that I gave before - there are different tyrosine kinases. Even if what you were saying were true it doesnt mean that an EGFR inhibitor that interfered directly with the EGFR tyrosine kinase would affect beta-catenin levels.

[quote:2i9y1nmg]This quote is not saying that EGCG inhibits tyrosine kinase - EGCG "directly blocks EGF binding to the EGFR" and it is only subsequently ie. indirectly that the EGFR mediated tyrosine kinase inhibitor is blocked. So the mechanism of EGCG inhibiting EGFR is not related to EGFR tyrosine kinase.

I do not understand what you mean by this. If Tyrosine Kinase has an an EGFR site and ECGC blocks EGF from binding to those sites, and EGF - EGFR binding is necessary, at least in part, for beta catenin binding/adhesion then wouldn't BCGC negatviely affect beta catenin production if TK played any role in that production (which it does).
[/quote:2i9y1nmg]

EGF is not necessary for functional levels of beta-catenin. But again there are many types of tyrosine kinase. Stop referring to them as if they are all the one protein and it might become clearer as to why what you are proposing is not the case.

[quote:2i9y1nmg]I dont recall saying how EGCG works but as the quote above shows it works as an EGFR inhibitor by directly stopping EGF from docking at the receptor.

No you said how it didn't work, and also I already explained how EGCG worked in my post prior to this. But repetition never harmed anyone.
[/quote:2i9y1nmg]

OK I see that I didnt say how EGCG works as an EGFR inhibitor before but I did say how it "doesnt work" in the sense of not working out well for us as an inhibitor of wnt signalling.

Anyway as to EGCG inhibiting wnt signalling via the way I proposed and the way you proposed:
Read the below abstract/study - EGCG blocks wnt signalling but has no effect on beta-catenin levels. Because it blocks the signal downstream of beta-catenin.
J Biol Chem. 2006 Apr 21;281(16):10865-75. Epub 2006 Feb 22.Click here to read Links
Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1.
Kim J, Zhang X, Rieger-Christ KM, Summerhayes IC, Wazer DE, Paulson KE, Yee AS.

Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Genetic and biochemical de-regulation of Wnt signaling is correlated with breast and other cancers. Our goal was to identify compounds that block Wnt signaling as a first step toward investigating new strategies for suppression of invasive and other breast cancers. In a limited phytonutrient screen, EGCG ((-)-epigallocatechin 3-gallate), the major phytochemical in green tea, emerged as an intriguing candidate. Epidemiological studies have associated green tea consumption with reduced recurrence of invasive and other breast cancers. Wnt signaling was inhibited by EGCG in a dose-dependent manner in breast cancer cells. The apparent mechanism targeted the HBP1 transcriptional repressor, which we had previously characterized as a suppressor of Wnt signaling. EGCG treatment induced HBP1 transcriptional repressor levels through an increase in HBP1 mRNA stability, but not transcriptional initiation. To test functionality, DNA-based short hairpin RNA (shRNA) was used to knockdown the endogenous HBP1 gene. Consistently, the HBP1 knockdown lines had reduced sensitivity to EGCG in the suppression of Wnt signaling and of a target gene (c-MYC). Because our ongoing studies clinically link abrogation of HBP1 with invasive breast cancer, we tested if EGCG also regulated biological functions associated with de-regulated Wnt signaling and with invasive breast cancer. EGCG reduced both breast cancer cell tumorigenic proliferation and invasiveness in an HBP1-dependent manner. Together, the emerging mechanism is that EGCG blocks Wnt signaling by inducing the HBP1 transcriptional repressor and inhibits aspects of invasive breast cancer. These studies provide a framework for considering future studies in breast cancer treatment and prevention.

From the study itself
"HBP1 Contributes to the Suppression of Wnt Signaling and Gene Expression by EGCG—The experiments of Fig. 1 suggested two testable mechanisms for EGCG blocking Wnt signaling: 1) EGCG might trigger a reduction in beta-catenin levels, or 2) EGCG might increase the levels of HBP1. Previously, we showed that HBP1 is a suppressor of Wnt signaling by inhibiting the LEF/TCF/beta-catenin transcriptional activation complex (7). As shown in Fig. 2A, endogenous beta-catenin levels were unchanged with EGCG treatment. In addition, both the phosphorylation of beta-catenin by GSK-3beta, as well as total, cytoplasmic and nuclear beta-catenin levels were unchanged (Fig. 2B), further supporting the lack of change in beta-catenin levels with EGCG. However, we observed that in 293T cells (Fig. 2A) and in MDA-MB-231 cells (Fig. 4A), endogenous HBP1 protein levels increased with EGCG treatment. These results were extended with the observation that EGCG treatment increased HBP1 mRNA, as measured by real-time RT-PCR (Fig. 3A). Thus, EGCG increased expression of HBP1, suggesting that HBP1 may be a plausible target of EGCG action in the inhibition of Wnt signaling."

So EGCG did not effect beta-catenin levels despite being a potent inhibitor of EGFR.

I feel as though we are just going back and forth here.

Fundamentally I believe TK plays an important role in Beta-Catenin binding as do other proteins. Further you speak as though EGF only affects certain TK but not others, which isn't the case. You also don't seem to appreciate the difference between Wnt Proteins and signalling, as TK as well as GSK-3 all play their part in Wnt signalling, making it impossible to say TK nor GSK isn't important for our purposes. Finally, on this matter it is because EGF affects TK and GSK-3, as well as others, that so far their hasn't been a single suggestion of an EGF inhibitor that doesn't affect Wnt signalling. GO FIGURE.

So you are implying that the EGFR is functionally linked to every type of tyrosine kinase? Can you provide some evidence for this?
I appreciate the comment that I dont understand the difference between wnt proteins and wnt signalling but so far you havent shown a single link between wnt proteins and beta-catenin via a tyrosine kinase. ie you havent shown how they are relevant to the discussion of the canonical wnt pathway. Which is the type of wnt signalling that we are interested in. And even if you did show this then it wouldnt be important unless you could show that these same tyrosine kinases would be effected by gefitinib or whatever other EGFR inhibitor we are talking about. And even then your central concern is not important since Follica showed that EGFR inhibitors increased both hair follcile density and size.
And quercetin was more or less hown not to effect wnt signalling.

Nevertheless, as much as I enjoyed and learnt from this conversation, it clearly isn't going to be developed any futher. My reason for this discussion was to see if any practical information could be garnered from the theory and I believe there has been some. Has anyone considered upregulating Wnt signalling over an extended period of time. As in applying Lithium Chloride for a month prior to the wounding, during the wounding and then applying an EGFR inhibitor and lithium chloride 3 days prior to the wounding. My thinking is that the ability for beta-catenin to bind and the lack/limitation of it being phosphorylated would make the beta-catenin more potent in its ability to pair with Lef1.

...how would it become "more potent in its ability to pair with Lef1"? It either binds or it doesn't - having elevated levels for a long time is not going to make a difference anymore than holding your keys in your hand for a few days is going to make them any more likely to open your car when you try. Besides which there is a critical period where wnt signalling is required to be upregulated outside of which it is unimportant. There is also a critical period in which you probably want it downregulated also in order to create pigmented hairs.

This should obviate the affect of the EGFR-inhibitor on Wnt signalling, or at least it should limit the effect. Also the mice that over expressed Wnt signalling, were they genetically engineered (i seem to remember it was) to do this or was it done through some sort of feed and were they overexpressing Wnt before wounding or only prior to wounding? Of course this is just a theory. I'll be trying this out on myself soon.

They were genetically engineered to overexpress wnt7a. They overexpressed wnt7a all the time but later Follica work has further identified the existence of a critical post-wounding period where wnt signalling is important (though the original work hinted at this).
hh

 

[Moomin]

LOL, I could respond to this AGAIN (and to be fair i've only skimmed what you said in about 15 seconds) and any reply would only be a more protracted possibly slightly more lucid explanation of what i've already said many times before, what I believe to be the case and why I don't agree with some of the points you've made. But really that isn't going to get us very far.

But just for the sake of it, you keep making the point that I refer to tyrosine kinase as all being all the same protein, this is something i've never said. The only thing i'm interested in is whether TK ,in all its multifarious forms, have EGF receptor sites, and as far as i'm aware they do. END OF.

But please don't think I don't appreciate your input.

Anywho I'm going to be ordering my products this week to begin self testing (self harming :freak: ). I've found a source of powered lithium orotate and another for DMSO (you guys don't seem to mention DMSO often in your routines, is there a reason for this). What I am looking for now is a source for THC preferably 50% and a potent EGFR inhibitor regardless of its Wnt affecting ability, if anyones got any suggestions lemme 'ave 'em.

 

[harold]

LOL, I could respond to this AGAIN (and to be fair i've only skimmed what you said in about 15 seconds) and any reply would only be a more protracted possibly slightly more lucid explanation of what i've already said many times before, what I believe to be the case and why I don't agree with some of the points you've made. But really that isn't going to get us very far.

But just for the sake of it, you keep making the point that I refer to tyrosine kinase as all being all the same protein, this is something i've never said.

Well you always seemed to assume that if something interfered with the EGFR and/or the tyrosine kinase portion of the receptor that it was guaranteed to interfere with all tyrosine kinases. And since you never referred to specific tyrosine kinases but only to the singular "tyrosine kinase" I could only assume that this was the impression you had.

The only thing i'm interested in is whether TK ,in all its multifarious forms, have EGF receptor sites, and as far as i'm aware they do. END OF.

OK I understand now.
They dont.
http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase
Many tyrosine kinases dont even have a receptor portion let alone an EGF receptor.
hh

But please don't think I don't appreciate your input.

Anywho I'm going to be ordering my products this week to begin self testing (self harming :freak: ). I've found a source of powered lithium orotate and another for DMSO (you guys don't seem to mention DMSO often in your routines, is there a reason for this). What I am looking for now is a source for THC preferably 50% and a potent EGFR inhibitor regardless of its Wnt affecting ability, if anyones got any suggestions lemme 'ave 'em.

 

[Moomin]

I don’t see the relevance of your post, if you follow the links on the link you’ve sent me you’ll see why and I’ll explain here. Nevertheless I have to take part of the blame, in that it has become evident that I will have to specify exactly which srucutres I’m talking about and refer to them in all posts, I don’t do this because it would take too bloody long. So I’m going to refer to them once here for the avoidance of confusion, they are EGFR (ErbB-1), Her2, Her 3 and Her 4, which are all affected by EGF and play a role in Beta-Catenin (and incidentally are tyrisone kinases). I did not mean every Tyrisone Kinase in existence, such as those which have a function in insulin regulation or those TKs that play a role in the formation of blood vessels or even those TKs that play their role in skeletal muscle development. Oddly, I’m referring to those TKs that affect Beta Catenin (and therefore HF Neo Genesis), partly because I didn’t think it was necessary to spell this out (especially since this whole conversation revolved around EGF, why would i be discussing TKs that are affected by FGF or anything else), also because I know very little about the others (theres no reason for me to know anything about them) but most importantly because this argument over TK that you focussed on isn’t particularly important as I see it.

And even if you did show this then it wouldnt be important unless you could show that these same tyrosine kinases would be effected by gefitinib or whatever other EGFR inhibitor we are talking about. And even then your central concern is not important since Follica showed that EGFR inhibitors increased both hair follcile density and size.
And quercetin was more or less shown not to effect wnt signalling.

In response to your first sentence, I already have in links in previous posts, the ones you said you didn't read.

In response to your second setence, yes i know, i've said this myself (its simply what the findings of follica have said) but people have tried wounding and quercetin with no results so clearly there has to be something else invovled. If it was a simple case of wounding and applying EGFR inhibitor then we'd all be well on our way to growing a fancy new mullet. I am trying to find out what that something else is, and repetition of a patent like its some holy text isn't helping

how would it become "more potent in its ability to pair with Lef1"? It either binds or it doesn't - having elevated levels for a long time is not going to make a difference anymore than holding your keys in your hand for a few days is going to make them any more likely to open your car when you try.

Your right they do either bind or they don't, but maybe more bind than don't bind or vice versa. Your key and lock analogy, other than inappropriate doesn't take in to account the vast numbers of processes that have to be carried out relatively simoultaneously. Its not one key and one lock. But millions of keys and millions of locks.

Finally you said:

They were genetically engineered to overexpress wnt7a. They overexpressed wnt7a all the time but later Follica work has further identified the existence of a critical post-wounding period where wnt signalling is important (though the original work hinted at this).
hh

Thanks for clearing that up, i knew i had read it somewhere but wasn't sure. Would you point in my direction of where you found this information.

by the way:

There is also a critical period in which you probably want it downregulated also in order to create pigmented hairs.

I seem to remember the mice that grew the grey hair, had very little pigment in their skin and this was the reason for the hairs lack of colour.

 

[harold]

I don’t see the relevance of your post, if you follow the links on the link you’ve sent me you’ll see why and I’ll explain here.

Follow what links on what link I sent you? You seem to be addressing the first post I wrote to you and not the second. I sent you a link showing that some wnt ligands did go on to effect tyrosine kinases but not as part of the the canonical pathway and thus this was irrelevant. And I sent a link to Wikipedia that showed that not all tyrosine kinases had EGF receptor sites. I assume you meant this link.

Nevertheless I have to take part of the blame, in that it has become evident that I will have to specify exactly which srucutres I’m talking about and refer to them in all posts, I don’t do this because it would take too bloody long.

well if you are going to make sweeping statements and inferences about tyrsoine kinases when you really mean only one/a few then it helps to be specific. But your earlier idea seemed to rely on all tyrosine kinases being the same or as you later clarified all tyrosine kinases having a EGF receptor binding site.

So I’m going to refer to them once here for the avoidance of confusion, they are EGFR (ErbB-1), Her2, Her 3 and Her 4, which are all affected by EGF and play a role in Beta-Catenin (and incidentally are tyrisone kinases).

...can you elaborate on the role that they play in regards to beta-catenin? You have previously stated that there is a big role played by tyrosine kinases in beta-catenin regulation but mentioned nothing about these specific kinases that you now mention. EGF is only a ligand for the first of these receptors (EGFR).

I did not mean every Tyrisone Kinase in existence, such as those which have a function in insulin regulation or those TKs that play a role in the formation of blood vessels or even those TKs that play their role in skeletal muscle development. Oddly, I’m referring to those TKs that affect Beta Catenin (and therefore HF Neo Genesis), partly because I didn’t think it was necessary to spell this out (especially since this whole conversation revolved around EGF, why would i be discussing TKs that are affected by FGF or anything else),

Well since as recently as your last post you were convinced that every tyrosine kinase had a EGF receptor you can see how it would be easy to be confused since that seems to absolutely contradict what you are saying here. "The only thing i'm interested in is whether TK ,in all its multifarious forms, have EGF receptor sites, and as far as i'm aware they do. END OF."

also because I know very little about the others (theres no reason for me to know anything about them) but most importantly because this argument over TK that you focussed on isn’t particularly important as I see it.

I dont think its particularly important either and its not something that was a big interest/area of knowledge for me either but this all started because you proposed that inhibiting the EGFR seemed likely to have a strong effect on beta-catenin levels.

[quote:5meo7kzm]And even if you did show this then it wouldnt be important unless you could show that these same tyrosine kinases would be effected by gefitinib or whatever other EGFR inhibitor we are talking about. And even then your central concern is not important since Follica showed that EGFR inhibitors increased both hair follcile density and size.
And quercetin was more or less shown not to effect wnt signalling.

In response to your first sentence, I already have in links in previous posts, the ones you said you didn't read.
[/quote:5meo7kzm]

I have read them now and they dont show that at all. For one they only discuss EGCG, secondly there is no mention of any tyrosine kinases involved in the wnt pathway. One abstract said something about EGCG interfering with tyrosine kinase but was clear that it did so in malignant cells but not in normal cells.

In response to your second setence, yes i know, i've said this myself (its simply what the findings of follica have said) but people have tried wounding and quercetin with no results so clearly there has to be something else invovled.

Who has tried wounding and quercetin? There are maybe a dozen at most people who have had a go at this process thusfar, many only within the past few weeks.
How much wounding did they do? How potent is quercetin as an EGFR inhibitor (almost certainly not very)? how well does it work as a topical?

If it was a simple case of wounding and applying EGFR inhibitor then we'd all be well on our way to growing a fancy new mullet.

We dont know if the process works in balding/bald scalp at all let alone how well. We dont know how deep we need to wound and nobody has access to a robust EGFR inhibitor yet apart from the backyardstuff we are trying. So IMO at least its abit ealy to say "there has to be something else involved" and that the scattered half-assedattempts of myself and a few others say much either way.

I am trying to find out what that something else is, and repetition of a patent like its some holy text isn't helping

[quote:5meo7kzm]how would it become "more potent in its ability to pair with Lef1"? It either binds or it doesn't - having elevated levels for a long time is not going to make a difference anymore than holding your keys in your hand for a few days is going to make them any more likely to open your car when you try.

Your right they do either bind or they don't, but maybe more bind than don't bind or vice versa. Your key and lock analogy, other than inappropriate doesn't take in to account the vast numbers of processes that have to be carried out relatively simoultaneously.
[/quote:5meo7kzm]

Well a key lock analogy is the classic analogy for enzyme/ substrate and receptor/ligand interactions so I dont think its particularly inappropriate. Then again I dont entirely understand what it is that you are proposing and how it might work so its just how it seems to me.

Its not one key and one lock. But millions of keys and millions of locks.

OK but I dont think this makes what you were proposing any more likely.

Finally you said:

[quote:5meo7kzm]They were genetically engineered to overexpress wnt7a. They overexpressed wnt7a all the time but later Follica work has further identified the existence of a critical post-wounding period where wnt signalling is important (though the original work hinted at this).
hh

Thanks for clearing that up, i knew i had read it somewhere but wasn't sure. Would you point in my direction of where you found this information.
[/quote:5meo7kzm]

The original wounding follicular neogenesis paper and the supplementary materials:
http://www.ncbi.nlm.nih.gov/sites/entrez

by the way: [quote:5meo7kzm]There is also a critical period in which you probably want it downregulated also in order to create pigmented hairs.

I seem to remember the mice that grew the grey hair, had very little pigment in their skin and this was the reason for the hairs lack of colour.[/quote:5meo7kzm]

Both patents go on to report that pigmented hair can be grown if a wnt antagonist is expressed/applied shortly after wounding.
hh

 

[Moomin]

Yeah... I think this has turned into a war of egos which i'm happy to lose, if not simply because i have other things i can be doing with my life, but seeing as i'm here...

Follow what links on what link I sent you? You seem to be addressing the first post I wrote to you and not the second. I sent you a link showing that some wnt ligands did go on to effect tyrosine kinases but not as part of the the canonical pathway and thus this was irrelevant. And I sent a link to Wikipedia that showed that not all tyrosine kinases had EGF receptor sites. I assume you meant this link.

Spot on bud.

well if you are going to make sweeping statements and inferences about tyrsoine kinases when you really mean only one/a few then it helps to be specific. But your earlier idea seemed to rely on all tyrosine kinases being the same or as you later clarified all tyrosine kinases having a EGF receptor binding site.

Yeah i thought this was obvious seeing as we were having a specific conversation about EGF, not really much point in me discussing those affected by FGF, but i'll spell it out in future.

can you elaborate on the role that they play in regards to beta-catenin? You have previously stated that there is a big role played by tyrosine kinases in beta-catenin regulation but mentioned nothing about these specific kinases that you now mention. EGF is only a ligand for the first of these receptors (EGFR).

Yeah I have elaborated on how TK affects BC in previous posts, go back and check them out.

Well since as recently as your last post you were convinced that every tyrosine kinase had a EGF receptor you can see how it would be easy to be confused since that seems to absolutely contradict what you are saying here. "The only thing i'm interested in is whether TK ,in all its multifarious forms, have EGF receptor sites, and as far as i'm aware they do. END OF."

Yes it is contradictory if what i was saying was misunderstood as you misunderstood it. Nevertheless i thought i cleared that up, do i have to through it again??

I dont think its particularly important either and its not something that was a big interest/area of knowledge for me either but this all started because you proposed that inhibiting the EGFR seemed likely to have a strong effect on beta-catenin levels.

Yup and I still think it might, you haven't so far suggested anything to contradict this.

For one they only discuss EGCG, secondly there is no mention of any tyrosine kinases involved in the wnt pathway. One abstract said something about EGCG interfering with tyrosine kinase but was clear that it did so in malignant cells but not in normal cells.

Are you seriously telling me you cannot find any link between TK and Wnt and BC. I've provided links an explanation in previous posts, repeating myself and reposting is just wasting my time on something i've already done at the expense of learning something new, if you don't want to accept this then that is your perogative.

Who has tried wounding and quercetin? There are maybe a dozen at most people who have had a go at this process thusfar, many only within the past few weeks.
How much wounding did they do? How potent is quercetin as an EGFR inhibitor (almost certainly not very)? how well does it work as a topical?

This isn't the only forum trying this, i think i read someone trying this process on hairloss forum. Abrasion of THC followed by a cocktail followed by quercetin.

We dont know if the process works in balding/bald scalp at all let alone how well. We dont know how deep we need to wound and nobody has access to a robust EGFR inhibitor yet apart from the backyardstuff we are trying. So IMO at least its abit ealy to say "there has to be something else involved" and that the scattered half-assedattempts of myself and a few others say much either way.

Yeah you might be right on this one, but at the same time, you might be wrong i honstly can't say one way or the other, which is why its just a THEORY.

Well a key lock analogy is the classic analogy for enzyme/ substrate and receptor/ligand interactions so I dont think its particularly inappropriate. Then again I dont entirely understand what it is that you are proposing and how it might work so its just how it seems to me.

yeah although didn't actually mention locks, you did mention car doors and length of time keys are to be held in ones hand though. Not that any of that is important, but since you mentioned it.

In relation to applying lithium prior to wounding. I was going along the line of thought that if beta catenin was being upregulated and its phosphorylation prevented / limited couldn't that increase the chances of BC binding; prior during and post wounding. Nevertheless if you say there are reasons for applying it post wounding im going to have to look in to it, but thats was the theory anyway.

Now i'm sure you'll reply, you can have the last word on this as I want to move on to something else.

 

[Moomin]

What were your views on DMSO. I hear its an excellent carrier agent so the Lithium Orotate should dissolve nicely in that and also it apparently does "something" to Beta-Catenin.

There also seems to be some anecdotal evidence of DMSO and Lithium being applied without any form of wounding producing regrowth

http://www.freewebs.com/immortalhair/topicals.htm

 

[Moomin]

Also view the patent onthe above site, for easy reference, seems similar to Follica no??

http://www.pharmcast.com/Patents100/Yr2 ... 080205.htm

 

[NicholasLim]

This thread is getting too scientific , can someone explain in easier terms what is going on ?

 

[Moomin]

Your right it is. You can forget everything Harold and I said for now, its of no practical significance yet.

The posts before ours were well put together and easily understandable I would stick to digesting those.

 

[Orin]

I think everything has significance. Just because I can't understand it, doesn't mean someone else can't pick apart something useful from it, that might add to the ongoing sharpening of this treatment.

Other than I really don't have anything to add... other than that I kinda don't want to go on vacation anymore. I kinda want to stay home, pluck large parts of my hair, dermabrade and put lithium on it.

But that's just crazy talk I suppose, and more of an expression of me wanting to add as much growth as possible now that I'm thinning out more than before (due to shift from dutasteride to propecia).

I'm very curious how a larger-scale treatment will pan out if you add plucking to it, and would be cool to see what other people can get from it. There seem to be very few people that (publically announce) experiment with this, which feeds into the self-perpetuating idea that nothing can substantially be done about hair-loss.
It also takes quite some time (a month or so) to fully evaluate anything, which probably adds to mindset.

Anyway, just a stray thought; I in no ways want to encourage an endless meta-discussion, about how other people seem to talk rather than get active.

 

[harold]

Yeah... I think this has turned into a war of egos which i'm happy to lose, if not simply because i have other things i can be doing with my life, but seeing as i'm here...

Follow what links on what link I sent you? You seem to be addressing the first post I wrote to you and not the second. I sent you a link showing that some wnt ligands did go on to effect tyrosine kinases but not as part of the the canonical pathway and thus this was irrelevant. And I sent a link to Wikipedia that showed that not all tyrosine kinases had EGF receptor sites. I assume you meant this link.

Spot on bud.

[quotembwu780]well if you are going to make sweeping statements and inferences about tyrsoine kinases when you really mean only one/a few then it helps to be specific. But your earlier idea seemed to rely on all tyrosine kinases being the same or as you later clarified all tyrosine kinases having a EGF receptor binding site.

Yeah i thought this was obvious seeing as we were having a specific conversation about EGF, not really much point in me discussing those affected by FGF, but i'll spell it out in future.
[/quotembwu780]

So before you were saying "all tyrosine kinases have an EGF receptor except for those that dont"? How profound.
If that was what you were saying why then did you refer to "TK ,in all its multifarious forms," as having EGF receptors? Indeed wh did you say "Further you speak as though EGF only affects certain TK but not others, which isn't the case." I guess its not important.
Also of the 4 receptors you explicitly mention only one actually binds to EGF and is targeted by EGFR inhibitors like gefitinib.

[quotembwu780]can you elaborate on the role that they play in regards to beta-catenin? You have previously stated that there is a big role played by tyrosine kinases in beta-catenin regulation but mentioned nothing about these specific kinases that you now mention. EGF is only a ligand for the first of these receptors (EGFR).

Yeah I have elaborated on how TK affects BC in previous posts, go back and check them out.
[/quotembwu780]

I checked everything that you have written out and all your links and there is nothing about this. Perhaps you misplaced it.

[quotembwu780]Well since as recently as your last post you were convinced that every tyrosine kinase had a EGF receptor you can see how it would be easy to be confused since that seems to absolutely contradict what you are saying here. "The only thing i'm interested in is whether TK ,in all its multifarious forms, have EGF receptor sites, and as far as i'm aware they do. END OF."

Yes it is contradictory if what i was saying was misunderstood as you misunderstood it. Nevertheless i thought i cleared that up, do i have to through it again??
[/quotembwu780]

No I guess I have it down now though your various statements do seem to contrdict one another, sometimes blatantly so.

[quotembwu780]I dont think its particularly important either and its not something that was a big interest/area of knowledge for me either but this all started because you proposed that inhibiting the EGFR seemed likely to have a strong effect on beta-catenin levels.

Yup and I still think it might, you haven't so far suggested anything to contradict this.
[/quotembwu780]

Well you havent given any evidence that it would.You had an argument before that seemed to revolve around a misunderstanding. Now apparently that was all my misunderstanding. But now that I have understood/you have changed what you were saying there isnt really an argument as to why that might happen. Unless you showed that EGF had a significant role to play in regulating beta-catenin levels. Which from reading everything you have written and linked to is not the case.

[quotembwu780]For one they only discuss EGCG, secondly there is no mention of any tyrosine kinases involved in the wnt pathway. One abstract said something about EGCG interfering with tyrosine kinase but was clear that it did so in malignant cells but not in normal cells.

Are you seriously telling me you cannot find any link between TK and Wnt and BC. I've provided links an explanation in previous posts, repeating myself and reposting is just wasting my time on something i've already done at the expense of learning something new, if you don't want to accept this then that is your perogative.
[/quotembwu780]

...you gave some links on EGCG and EGF. You said "If I’m not mistaken Wnt is used to signal Tyronise Kinase (TK) activation, for the purpose of upregulating Beta Catenin (BC)." but when I asked for a source you told me to google it.

[quotembwu780]Who has tried wounding and quercetin? There are maybe a dozen at most people who have had a go at this process thusfar, many only within the past few weeks.
How much wounding did they do? How potent is quercetin as an EGFR inhibitor (almost certainly not very)? how well does it work as a topical?

This isn't the only forum trying this, i think i read someone trying this process on hairloss forum. Abrasion of THC followed by a cocktail followed by quercetin.
[/quotembwu780]

I know this isn't the only forum but out of the guys at regrowth and hairsite there aren't that many who have actually tried it and reported back. Plenty who have been interested in it and have talked about trying it soon. but not many have done so and I can think of maybe one guy who said nothing much happened for him though it was only a couple of weeks at most. I can think of three who claim to have gotten some result.

We dont know if the process works in balding/bald scalp at all let alone how well. We dont know how deep we need to wound and nobody has access to a robust EGFR inhibitor yet apart from the backyardstuff we are trying. So IMO at least its abit ealy to say "there has to be something else involved" and that the scattered half-assedattempts of myself and a few others say much either way.

Yeah you might be right on this one, but at the same time, you might be wrong i honstly can't say one way or the other, which is why its just a THEORY.

[quotembwu780]Well a key lock analogy is the classic analogy for enzyme/ substrate and receptor/ligand interactions so I dont think its particularly inappropriate. Then again I dont entirely understand what it is that you are proposing and how it might work so its just how it seems to me.

yeah although didn't actually mention locks, you did mention car doors and length of time keys are to be held in ones hand though. Not that any of that is important, but since you mentioned it.
[/quotembwu780]

Because you were talking about the beta-catenin somehow "building up" binding affinity by "upregulating Wnt signalling over an extended period of time". At least thats as near as I can make out is what you meant.

In relation to applying lithium prior to wounding. I was going along the line of thought that if beta catenin was being upregulated and its phosphorylation prevented / limited couldn't that increase the chances of BC binding; prior during and post wounding. Nevertheless if you say there are reasons for applying it post wounding im going to have to look in to it, but thats was the theory anyway

.

From what we know the only time that beta-catenin, minoidil or any of the other growth factors are helpful is during the critical period of re-epithelialization that takes place about a week to 10 or so days after the wound. This is the period when it is possible to influence what type of cells the new tissue becomes. I dont think Cotsarelis looked at a pre-wounding regimen but they have/will be looking at the timing of the compounds applications post-wounding in relation to the results achieved.

Now i'm sure you'll reply, you can have the last word on this as I want to move on to something else.

Yeah the preceeding discussion did get a little....tense. Sorry if I was a little brusque or maybe even rude towards the beginning but you came here with a question/theory and I tried to give you the best response I could as in your initial post you asked for someone to point out where you had gone wrong if possible. Anyway, no it wasnt very fruitful in the larger scheme of things....though I think we all know a little more about tyrosine kinases than we did at the beginning for what its worth.
hh

 

[masculineyourheart]

....though I think we all know a little more about tyrosine kinases than we did at the beginning for what its worth.

For all the reading I've just done, they still seem about as relevant to experimenting with the Follica method as studying up on my logarithms to buy a round of drinks with a side of souvlaki. At least I feel dumb enough to feel the need to improve. :beer:

 

[Orin]

Anything new on the natural EGFR-inhibitors regarding their efficiency and tendency to inhibit WnT?

I tried my google-paws at Tannic Acid, but found nothing about WnT. Though that is basically meaningless, as I'm bad at deciphering studies.
It's a polyphenol though, and most other polyphenols also inhibit WnT. I don't know if that is a much too simplified approach though, but I thought I'd mention it anyway.

On another forum there are talks about some serious side-effects of Gefitinib (which I also noticed independantly as I browsed a list of them), so if anyone is using that drug - be careful.

It could explain why Follica is taking their time with this. If you can make a topical solution that side-steps the side-effects from taking it orally (1 in 100 get a potentially fatal scarring of their lung, which apparently can happen within hours), you'd take the time to do so.

Gefitinib might still be very effective, and indeed key. It just seem to need some tempering.

I guess the up-side to this is that natural EGFR-inhibitors, though apparently both weaker and less effective than Gefitinib, are also for the most part much less severe in side-effects (though they surely, like all medicine, has those too).

Anyway, just a heads up for home-experimenters.

 

[michael barry]

Soy isoflavones are mentioned as egf-inhibitors in this patent, http://www.freepatentsonline.com/6638543.html

These side effects can be reduced or eliminated by the topical administration of an inhibitor, especially a natural inhibitor, of the epidermal growth factor receptor (EGFR), administered concomitantly with the retinoid, separately from the retinoid (such as on an as needed basis), or both. Administration of the two together is facilitated by a composition suitable for topical application and comprising both the retinoid and a natural EGFR inhibitor. Preferred natural inhibitors are genistein and other isoflavones extracted from natural occurring substances, or simple derivatives of such substances

Getfitinib, erlonitib, and lefloumonide are all associated with a lung disease in a relatively rare side effect. The thing is, is that it can eventually be fatal if you get it bad enough (scarring of the lung due to inflammation). TAGOHL posted the info for everybody at hairsite. Something like 1 in 82 men got it with Lefloumonide and 1 in 100 with getfitinib. By the time you notice the damage its already too late, and if you get the side effect you can have it within days of your first dose. Asians who smoke were most likely to get it. Here is what TAGOHL was able to find concering this and posted at HS:

. While most of the side-effects are simply annoying (acne, rash, diarrhea, etc.), there's one side-effect associated with its use called interstitial lung disease. It's a scarring lung disease. Particularly if you are Asian...about 3 Asians in 100 get this side-effect (3%), and it's fatal about a 1/3 of the time, which means for every 100 people who take gefitinib, one of them dies of this side-effect. The incidence is about 1% for other populations. Perhaps even more concerning is the speed at which this side-effect happens -- your lungs can start to scar within hours of the first dose, and within 48 hours the scarring can show up on CT scans. Within a week, you could be dead from it. Granted, this is a rare side-effect, but I always felt that 10 days use would avoid serious side-effects, but this is not true in the case of gefitinib.


Ive wondered if getfitinib can be mixed with dermovan or cetaphil creams and topically delivered without systemic absorbtion?



This is almost certainly the "holdup" at FOllica and why they aren't just rushing into a trial. 1 in 100 men getting lung disease is not going to be feasible. The lawsuits would be too many. They are almost undboutably trying to make a topical formulations for the EGF-antagonists, the most important part of their patent, that dont get systemically absorbed but still are topically effective in inhibiting EGF. This would take time and tests with human skin models, etc. No wonder they have backed off the early-release projections.


I went back over experiment 7 in their patent and it mentions that subsequent experiments with the human skin model also produced hair.....................meaning they were able to replicate the hair-growing result more than once. This is a good indication that this will work in us unless our immune systems interefere in some unforseen way (Its hard to imagine it would though, I mean hell its your own cells it would be attacking but I suppose one could point out that baldness itself has an autoimmue component, etc).



Lidocaine is supposedly an EGF inhibitor. I have a tube of that. Its a pain-relief cream. I'll try and post that info. TAGOHL found that also.

 

[michael barry]

As posted by TAGOHL at hairsite: Lidocaine is an egf inhibitor



Anesthesiology. 2004 May;100(5):1206-10.

Lidocaine inhibits tyrosine kinase activity of the epidermal growth factor receptor and suppresses proliferation of corneal epithelial cells.

BACKGROUND: Although lidocaine is recognized as an excellent topical corneal analgesic, its toxic effect on corneal epithelial cells limits its use during corneal epithelial wound healing. Mechanism of the impairment of corneal reepithelialization with lidocaine, however, has not been evaluated. The authors' previous study revealed that lidocaine inhibits the activity of tyrosine kinase receptors through the interaction with specific amino acid sequences around autophosphorylation sites, including acidic, basic, and aromatic amino acids. Epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with an important role in epithelial cell proliferation after corneal wounding, also possesses these amino acids sequences around autophosphorylation sites. The authors hypothesized that lidocaine would suppress tyrosine kinase activity of EGFR and would impair corneal epithelial cell proliferation. METHODS: To investigate the effect of lidocaine (4 microM-40 mM) on epidermal growth factor (EGF)-stimulated autophosphorylation of EGFR, the authors studied purified EGFR in microtubes. They cultured human corneal epithelial cells (HCECs) with EGF and lidocaine to investigate the effect of lidocaine on cell proliferation and on autophosphorylation of EGFR in HCECs. RESULTS: Lidocaine (> or =400 microM) significantly suppressed EGF-stimulated autophosphorylation of the purified EGFR. In the HCEC study, EGF alone stimulated cell proliferation and increased autophosphorylation of EGFR in HCECs. Lidocaine (> or = 400 microM) significantly suppressed both the proliferation of HCECs promoted by EGF and EGF-stimulated autophosphorylation of EGFR. CONCLUSION: Lidocaine directly inhibits tyrosine kinase activity of EGFR and suppresses the corneal epithelial cell proliferation.

PMID: 15114219 [PubMed - indexed for MEDLINE]



I highlighted the one part of that info that might be of some concern. Whether the effect on epilithial cells would impair the whole proess in some unforseen way..... You can buy lidocaine gels though. I have a tube.

 

[Orin]

Great work. Interesting to hear about that lidocaine. As far as I can tell, it's used for pain-relief. It would be a match made in heaven if it worked the way we wanted it.

Great job, keep the investigation of things I cannot comprehend going. Anything new about tannic acid? That potato-thing? It's hard to keep up with all the things that inhibit EGFR. I guess that's some comfort though; the sheer volume of things to try.

And also - be careful for everyone trying this. Do read the side-effect papers regardless of what you're about to test. We're all *very* excited at the prospect of things creating new hair, but sometimes we have to reel back that excitement and realize that this is pretty bleeding edge (in terms of new:ness).

It rarely gets more hardcore than trying to independantly keep up with on-going medical trials for medicine that has not been cleared as safe yet. Remember, gefitinib, however effective it may be at growing hair, is given to lung-cancer patients as a last-resort kind of thing.

I have read (admittedly) little about the clinical use of the drug, but my understanding of it is that it is given as a last resort. It's given because it shows promise, but it's not administered casually because of how double-edged it is. Outside of potential hair-growing, I wouldn't be surprised if in 5-10 years it will be gone from lung-cancer treatments.

It seems like the first batch of medicines used for alternatively treating an ailment. The whole EGFR-inhibitor angle is quite new in terms of lung cancer (and perhaps cancer in large).