Gas6?

[Cycle Chic]

Maybe that's why Froome was about to be dropped from Sky in 2010 because he wasn't responding to Epo...due to the Bilharzia. In an article I read, cant remember which one, he says the disease was discovered by the testers for the bio-passport..when they saw him in Africa.

+agree ..needle marks are not a concern.

and Thomas Frei tweeting that is a Heads Up or what ?? !!

 

[King Boonen]

As to speculation, that's the point of the clinic, isn't it? Otherwise we would need to sit on our hands for a decade waiting for Froome to show up on Oprah's couch.

I said speculation based on unfounded opinions. These's no evidence GA S6 will aid EPO doping, the current evidence suggests otherwise.

Speculation about using it as a recovery aid though I wouldn't complain about, evidence seems to suggest that is possible.

Needle marks? Sure, they found plenty of those after refill day in the past ... not.

And to imagine WADA checks every square inch of every gluteus maximus they get their hands on (where do they recruit the chaperons for that job, btw?). Think of the conversation: Is that a pimple or a needle mark? Let's take a photo and send it to the lab. Or the excuses: no, I drove into a barbed wire yesterday, so that's not a needle mark, I swear.

Well they should be checking, after all airport staff are trained to do full body searches, I don't see why drugs testers can't be.

Intravenous needle marks are obvious, they can't really be mistaken for anything else. The barbed wire part is hyperbole, we've all seen what that can do to a pro travelling at high speed, to suggest that it would leave a single, small, needle like mark is disingenuous.

Other subcutaneous injections are not obvious though. I recently had a tetanus shot after a crash, didn't leave a mark, but that's more dependent on the size of the needle.


As a general point, if Froome is still being treated for anemia it is perfectly possible it will aid his recovery between stages, but I would like to think this has already been determined and his treatment has been determined to stay in line with what would naturally happen. Unfortunately there is no way for us to know this though.

 

[taiwan]

I'm sorry, I'm not sure what you are implying with this but it is not talking about doping. It is talking about helping people who are poor responders to EPO when used as a treatment for anemia. There is no proof that GA S6 will either boost RBC production in healthy individuals, in fact the research shows the opposite, or will increase the effect of EPO doping in healthy individuals.

GA S6 looks like it may aid recovery, which would certainly be a concern, but again there is no proof for this.

Read much of this report on the drug and can't really find an indication of it's effect on patients with healthy rbc levels. It does say "the protein normalised hct levels without causing ethrythrocytosis" but I can't find the details of that claim.

Seemed to affect positively a type of mouse with a naturally low hematocrit.

Anyway, to say that on it's own or in synergy with EPO, it won't raise hct to a high normal level in a way that would be useful for an athlete - it's a reach. Particularly under the 50% rule. Noone's talking about jacking up to 90s levels.

 

[King Boonen]

Maybe that's why Froome was about to be dropped from Sky in 2010 because he wasn't responding to Epo...due to the Bilharzia. In an article I read, cant remember which one, he says the disease was discovered by the testers for the bio-passport..when they saw him in Africa.

+agree ..needle marks are not a concern.

and Thomas Frei tweeting that is a Heads Up or what ?? !!

To the bolded part, this is the second most likely time it would be identified, probably the most likely for a professional athlete.

I'm not sure how many people are poor/non-responders to EPO as a percentage, but I don't think Bilharzia is the cause, if you are a poor/non-responder you are a poor/non-responder. Even is GA S6 was being used and worked it would only return him to normal hematocrit levels, he would still then require the same amount of EPO as everyone else does to dope and that would be detectable.


As to Thomas Frei, I'm unsure, it's perfectly possible he follows the same news we do here and draws the same overreaching conclusions people here are. That's not to say they are wrong, just currently completely unfounded and against the available evidence.

 

[Cycle Chic]

How funny is this !! and I,m just jokin..

Role of Gas-6
Abstract

Objective— A potential role of growth arrest-specific gene 6 (Gas-6) in energy storage in adipose tissue was investigated in murine models of obesity. Gas-6 is a ligand for the Axl, C-Mer, and Sky family of tyrosine kinase receptors.
Methods and Results— Whereas Gas-6, C-Mer, and Sky were expressed in mature murine adipocytes, the expression of Axl was restricted to the stromal-vascular fraction, which includes pre-adipocytes

http://atvb.ahajournals.org/content/25/5/1002.abstract

 

[blackcat]

Pure speculation based on unfounded opinions is not helpful to a discussion. There are much easier ways to dope and win as has been shown.


By the way, GA S6 is a protein so would have to be taken subcutaneously, probably intravenously. Needle marks are pretty obvious and I'm guessing doping control check for them?

i reckon goes in the belly in one of those narrow gauge insulin hypodermics. not spotting that puncture. would disappear immediately

 

[King Boonen]

Read much of this report on the drug and can't really find an indication of it's effect on patients with healthy rbc levels. It does say "the protein normalised hct levels without causing ethrythrocytosis" but I can't find the details of that claim.

Anyway, to say that on it's own or in synergy with EPO, it won't raise hct to a high normal level in a way that would be useful for an athlete - it's a reach. Particularly under the 50% rule. Noone's talking about jacking up to 90s levels.

That's because it was done on mice, unless you are referring to WT mice as healthy patients, which I'll do my conclusions.

From the article:

Conversely, treatment with rGas6 stimulates hematocrit recoveries and protects WT mice against the development of anemia, induced by hemolysis or in part by blood loss

Stimulates recoveries, not overproduction. That's why I think it's perfectly reasonable to suggest it could be used as a recovery aid.

In fact, the article does not go into much detail about the effect of Gas6 in WT mice, suggesting they didn't find much.

Figure 3 shows the Axl + rGas6 mutant returning to natural hematocrit at a similar rate to the WT, but they have not included WT +rGas6.

Figure 8 shows a similar response between EPO only and EPO+Gas6 in the WT (+/+)mouse.

Figure 10 shows Gas6 treated WT mice have a slightly higher hematocrit baseline and a much quicker return, which is why it's reasonable to draw the conclusion it could be used to aid recovery.

In an EPO non-responder Gas6 + EPO is worse at increasing hematocrit than EPO only in WT, meaning if Froome were an EPO non-responder and he was being treated with Gas6+EPO, he would probably need significantly higher doses of EPO to match a "healthy" doper.

This conversation is getting messy talking to two people, mainly for me trying to keep the two threads separate!



So, in conclusion, and this is all based on one study in mice, which is kind of important;

if Froome were a non-responder to EPO, treatment with Gas6+EPO would have less effect than treating an EPO-responder with EPO only.

The research seems to show little to no benefit in combination treatment of Gas6 and EPO for healthy individuals. The lack of much information on this also indicates these findings.

Gas6 treatment aids recovery of hematocrit in both healthy and EPO non-responders, but this recovery is back to baseline. So it has a possible use as a recovery aid.


You mention slight increases. Do we know how much of an increase is required for a perfrmance gain? 1% hematocrit relates to 1% improvement? I'm guessing it isn't that simple. And what is the spread of hematocrit percentages across the normal population? Do they vary by 10%, 20%, 30% etc. (at normal times, not within a GT).

 

[King Boonen]

i reckon goes in the belly in one of those narrow gauge insulin hypodermics. not spotting that puncture. would disappear immediately

This is really beyond my biological level but I don't believe that would work. Gas6 is produced at the cellular level so I think it would have to be intravenously administered.

 

[Catwhoorg]

Pretty good read: "Measuring the Impact of Schistosomiasis Infection on Different Blood Parameters"

Full text

Thanks for that link. Printed a copy to read on a plane ride this week.

 

[Mr.38%]

Thanks for that link. Printed a copy to read on a plane ride this week.

In a nutshell: If Sir Brailsford could produce consistent evidence that the current best rider in the world had -15% Hb/Hct (as expected from a severe infection) up until mid of 2011 and then went back to his normal values, I would be inclined to believe him.

However I would question Sir B's qualification as director for signing a rider with such a bad state of health. Maybe he just looked him in the eye?

 

[taiwan]

In an EPO non-responder Gas6 + EPO is worse at increasing hematocrit than EPO only in WT, meaning if Froome were an EPO non-responder and he was being treated with Gas6+EPO, he would probably need significantly higher doses of EPO to match a "healthy" doper.

Where was this btw?

Anyway in the last section of the results it says that rGAS6 amplifies the response to EPO treatment. Couple this with quicker recovery from anemia and you poyentially have a very useful tool for blood management. The fact (which I eventually found in the report) that htc will not reach "supraphysiologic" levels: not necessarily a problem under the ABP, although I'd need someone to explain whether that refers to the individual's level or the expected level of the genotype of mouse or whatever.

From another cycling forum I got FTP increase = 0.6 x hct increase in response to your question.

Edit - I'm not really thinking about Froome, for me the bilharzia thing just fudges his biopassport and gives him a freer hand with blood values. Equivalent to Bert/Ricco/Rob Hayles having a doctors note for a high hct.

 

[timbo25]

Pure speculation based on unfounded opinions is not helpful to a discussion. There are much easier ways to dope and win as has been shown.


By the way, GA S6 is a protein so would have to be taken subcutaneously, probably intravenously. Needle marks are pretty obvious and I'm guessing doping control check for them?

I think you have too much faith in the testing org's

 

[Catwhoorg]

In a nutshell: If Sir Brailsford could produce consistent evidence that the current best rider in the world had -15% Hb/Hct (as expected from a severe infection) up until mid of 2011 and then went back to his normal values, I would be inclined to believe him.

However I would question Sir B's qualification as director for signing a rider with such a bad state of health. Maybe he just looked him in the eye?

He needed rider numbers, and more than a few ex-Barloworld riders were available.

Looking back at articles from that time, people were more excited about John-Lee Augustyn's possible contributions than Froomes.

 

[Cobblestones]

Read much of this report on the drug and can't really find an indication of it's effect on patients with healthy rbc levels. It does say "the protein normalised hct levels without causing ethrythrocytosis" but I can't find the details of that claim.

Seemed to affect positively a type of mouse with a naturally low hematocrit.

Anyway, to say that on it's own or in synergy with EPO, it won't raise hct to a high normal level in a way that would be useful for an athlete - it's a reach. Particularly under the 50% rule. Noone's talking about jacking up to 90s levels.

I would agree with you here. In particular, I found the following quote from the article intriguing:

Furthermore, whereas Epo regulates embryonic and adult erythropoiesis, Gas6 is more important for switching on erythropoiesis in pathological conditions in adulthood and thus may also be an attractive therapeutic target (see below). Considering that the role of Gas6 might be more important in disease than in normal health, it will be interesting to examine whether abnormal Gas6 signaling contributes to the development of anemia associated with renal disease, cancer, arthritis, and other common disorders.

One should remember that the two models tested in the study were (i) GAS6-/- and one with low EPO levels. In the GAS6-/- model, acute anemia was induced by different methods and recovery under different scenarios was tested. The other model is one of chronic anemia due to low EPO levels.

Neither model is particularly relevant with respect to Bilharzia. Here, the patient is anemic neither because of low EPO levels nor because of defects in relation to the GAS6 complex (receptors or protein production or whatever).

What is more likely is that the body's own regulatory response includes elevated endogenous EPO levels just to keep up a marginal Hct level. Extrageneous GAS6 (the protein) then might boost Hct up to a level corresponding to the presumably already elevated endogeneous EPO level until it is downregulated naturally. To prove or disprove this would require an entirely different model (which I don't think exists), and to look at the detailed kinetics of the whole shebang. There's just no way of knowing based on the present study.

And of course, the recovery aspect is a different route, but it seems everybody here is on the same page when it comes to that.

 

[King Boonen]

Where was this btw?

It's in figure 10. The blue line in A (EPO only treatment in WT) compared to the red line in B (EPO and Gas6 treatment in -/-). It clearly shows the WT is much more responsive to EPO than the mutant, even when Gas6 and EPO are used in combination.

Anyway in the last section of the results it says that rGAS6 amplifies the response to EPO treatment. Couple this with quicker recovery from anemia and you poyentially have a very useful tool for blood management.

Yes, but only in the -/- mouse, they don't include results for WT which would suggest they either didn't do them, they weren't reproducible or they weren't significant. The western blot in figure 8 suggests they were not significant. Combination treatment of a healthy individual seems to offer no benefit, in terms of doping, compared to just EPO treatment. Combination treatment of a mutant still won't match just EPO use in a WT.

This suggests Gas6 is useless for a healthy individual if they are using EPO and for a EPO non-responder combination treatment would give less of a boost than just EPO in a healthy individual.

Basically, if Froome needed Gas6 to respond to EPO, based on the evidence in the paper, he could not reach the level of a healthy individual doping to the same level. There also seems to be a plateau for a non-responder using combination therapy, possibly even a drop off during prolonged treatment.

The fact (which I eventually found in the report) that htc will not reach "supraphysiologic" levels: not necessarily a problem under the ABP, although I'd need someone to explain whether that refers to the individual's level or the expected level of the genotype of mouse or whatever.

From what I can make out it is an average across the population as a comparison to WT.


Gas6 therapy replacing EPO in anemia treatment would be beneficial, purely because it would remove one of the uses of EPO and possibly make it harder to come by, there would be less excuses doctors could use from false prescriptions etc.

Based on the evidence in the paper, it's pretty useless for doping except to help non-responders get some boost from EPO.

 

[Red Rick]

Great thread! Very interesting. I'm surrounded by geniuses

 

[King Boonen]

One should remember that the two models tested in the study were (i) GAS6-/- and one with low EPO levels. In the GAS6-/- model, acute anemia was induced by different methods and recovery under different scenarios was tested. The other model is one of chronic anemia due to low EPO levels.

Neither model is particularly relevant with respect to Bilharzia. Here, the patient is anemic neither because of low EPO levels nor because of defects in relation to the GAS6 complex (receptors or protein production or whatever).

You're looking to the wrong data here.

In this case, the WT, not the mutant, with induced anemia is more representative of Bilharzia, the mouse neither lacks EPO or Gas6. In this case, also from figure 10, Gas6 treatment only returns hematocrit levels to those before anemia. This figure doesn't include Gas6+EPO for wild-type after induced anemia.

In figure 8 B, ATK phosphorylation appears to be the same for both EPO only and Gas6+EPO in the WT, with total ATK also remaining constant. This is being used a measure of activity and, I'm assuming, can therefore be used to elicit a similar response in hematocrit level.

Again, this suggests no benefit from combination treatment of an anemic WT.

 

[taiwan]

Based on the evidence in the paper, it's pretty useless for doping except to help non-responders get some boost from EPO.

Quicker recovery from blood extraction?

Fig 10 also shows the GAS6-/- mouse and the Epo-TAgH mice getting up to almost 60% when treated with both substances. From baselines of ~50 and ~30%. That is a handy increase, despite not having data for WT mice on that programme.

 

[Cycle Chic]

So Recovery - when they take out a blood bag for transfusing - the body is depleted of RBC - could that be a state of anemia ? and that's why they need the 3 week window to let the blood replenish. If Gas6 can be applied with Epo during this window wont that allow the body to recover quicker ?

 

[King Boonen]

Quicker recovery from blood extraction?

Yes, good point, looks like it would help with that in a similar way it would help recovery during a GT (which should have been repeated in the post you quoted but I forgot!).

 

[King Boonen]

So Recovery - when they take out a blood bag for transfusing - the body is depleted of RBC - could that be a state of anemia ? and that's why they need the 3 week window to let the blood replenish. If Gas6 can be applied with Epo during this window wont that allow the body to recover quicker ?

Based on the paper, yes. Full recovery takes the same time but it reduces the fall in hematocrit quite dramatically.


Applied with EPO? We don't know, the data in the papers suggests it offers no benefit at 6 days, but we don't have any time-course data for this, unless it's in the supplementary material, I haven't checked.

 

[Cycle Chic]

Taiwan and I posted at the same time same thinking

 

[King Boonen]

Great thread! Very interesting. I'm surrounded by geniuses

Maybe I'm jaded. I can't tell if this is sarcastic or not!

 

[Cobblestones]

You're looking to the wrong data here.

In this case, the WT, not the mutant, with induced anemia is more representative of Bilharzia, the mouse neither lacks EPO or Gas6. In this case, also from figure 10, Gas6 treatment only returns hematocrit levels to those before anemia. This figure doesn't include Gas6+EPO for wild-type after induced anemia.

In figure 8 B, ATK phosphorylation appears to be the same for both EPO only and Gas6+EPO in the WT, with total ATK also remaining constant. This is being used a measure of activity and, I'm assuming, can therefore be used to elicit a similar response in hematocrit level.

Again, this suggests no benefit from combination treatment of an anemic WT.

I don't agree, because they're only looking at acute anemia in WT. What they would need is a model for chronic anemia with WT. There will be some physiological adjustment to the chronic anemia which might be exploited.

 

[taiwan]

Agree it's an interesting thread, but I'm clearly no experts. Posters with (genuine ) specialised knowledge would be very welcome to keep the thread realistic.