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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 433
22/07/2020 11:35 pm  

Wow! I mean are they saying no sonication? This is the same method as before, though this time it is just stir for a day or two? They treated at a dose 100 fold higher than in the earlier in vivo study with nanoMG which stopped tumor progression and they reported no safety issues. the technical requirements to create nanoMG appear to be declining.

https://pubmed.ncbi.nlm.nih.gov/32547022/


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 433
23/07/2020 1:59 am  

 

 

 

John, I am glad that you have taken an interest in MG. I remember diving into the research myself. It was quite memorable for me that MG is a cancer specific OXPHOS I inhibitor. That was quite interesting. Apparently one of the sub-components of subunit I is variant in cancer. It would be notable if this question were to be fully resolved.

The above show how powerful even seemingly simple molecules can be. The above are 3-BP, DCA and methylglyoxal.

 

 

 


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 433
23/07/2020 2:02 am  

D, I am having trouble finding the clinical trials for MG as well. As I remember it, you actually found these studies and they weren't even indexed in pubmed. I was not sure even at the time how you could find non-indexed articles. Are there competing scientific indexers in Asia etc.?


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Daniel
(@daniel)
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Posts: 841
23/07/2020 2:33 am  

@jcancom Hi J, you can find it in here https://www.cancertreatmentsresearch.com/methilglyoxal/ I made sure today the link its active so that John can access it.

The rest is work on your side to discover where the link is in the text. In this way you finally read my post.😀 

Kind regards,
Daniel


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 433
23/07/2020 2:42 am  

GgE, there are a lot of questions about Chitosan, I'll try to answer some of them. Chitosan is apparently  somewhat of a rarity in nanoparticles in that it can convert to cationic form in vivo. This is a very useful feature especially in cancer as cancer cells have negative surface electric charge. Chitosan would naturally, magnetically be attracted to cancer in the acidic environment around cancer cells.

Another interesting feature is that in acidic environments it will release its cargo. In one of my recent posts a figure illustrated this process. Considerable MG was released ~pH 5.5 not so much ~ pH 7. These are highly favorable characteristics when considering cancer. It is almost the perfect drug delivery system. However, as you noted it is not perfect, it is more like releasing the MG close and then seeing what happens.Chitosan is also generally regarded as safe. Online sellers offer chitosan with suggested daily intake of 5 grams as a health supplement. The order of magnitude estimate of nanoMg as a cancer treatment was ~~0.25 mg/kg.

Studies to date with nanoMg have shown that much of it does reach the tumor. This is why even reducing dosage by 400 fold still does not reduce efficacy over high dose bare MG. It can take some time to fully appreciate how powerful good formulations can be. I noted on the compass that minicells allow dose reductions of ~1 million times. This was thought to be hyperbolic, though I recall bringing out the slide rule and actually demonstrating the claim. Homeopathy might actually be on to something. Big problem is that weighing out doses in nanograms would require an expensive balance.

Chitosan certainly has some notable features that could make it a good delivery system. I also remember that MG has a chemical antidote which would also be a helpful treatment feature.  


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Jcancom
(@jcancom)
Joined: 3 years ago
Posts: 433
23/07/2020 2:53 am  

Hmm, yes, I am just not sure whether the one I want is there. I think it was the phase 2 trial. D, do you know if mega dose vitamin C would help or hurt MG? I believe I came across a mention that vitamin C is acting as an antioxidant in the MG combo, so upping the dosage into the millimolar zone and/or going metronomic might not be advised. Yet, if high dose vitamin C were recommended, then the MG protocol might be substantially enhanced using such doses.


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 215
23/07/2020 5:10 am  
Posted by: @rollandcoderre

I'm from Canada.  Can anyone tell me where I can obtain Syrosingopine?

Hi Roland, were you able to start the syrosingopine treatment? Please, let us know how it is going.

We wish you all the luck in the world from this forum!


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John Pizzuto
(@jpizzuto)
Joined: 1 year ago
Posts: 200
23/07/2020 5:36 am  

@gge

Shirley has been sleeping a lot more, and has decided to quit Piqray, saying it makes her feel very tired.

She also said it's killed what little appetite she had.  She said last week "she was able to eat half a hamburger, there's no way I could do that now."

I told her she's getting most of her nutrition from the shakes, but she says she can't live on them.  She's tolerated them really well, but now she says they are making her gag. 

I told her I don't know what's left, besides chemo.  I suggested she try taking it every other day, but she has her mind made up.

She has her monthly phone consultation with the oncologist tomorrow.


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 215
23/07/2020 6:21 am  
Posted by: @jpizzuto

Shirley has been sleeping a lot more, and has decided to quit Piqray, saying it makes her feel very tired.

Sorry about that. If Verzenio was working for her and she quit it because of diarrhea, she might want to go back to it but at a lower dose, or take another CDK with an estrogen antagonist. Many people stabilize their situation for a long time with CDK inhibitors; Verzenio seems to be a little better than the others. If she tolerates one and it works for her long enough there may be better things being approved by then.

CDKs are preferable to PI3K when there is a choice. PI3Ks and Everolimus are pretty much options of last resort at this time, so they better be saved for when you really have no other choice...


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 215
23/07/2020 7:08 am  
Posted by: @jcancom

I recall bringing out the slide rule

Well, now we all know you are in your twenties. LOL


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 12:26 am  
Posted by: @gge
Posted by: @jcancom

here is adifer's report on the lactate levels. Carefully contemplating how lactate changes, given especially metformin dosing, might be helpful. We need to step back and think about this.

Lactate doubled (!!) after starting syromet.

Do we know what happened to this patient clinically afterwards? Did they see a regression or any improvement? We need to know if the lactate could have risen due to a worsening of the condition. Then lactate could have gone up as more lactate was exported from larger or more numerous tumors rather than from cancer cells being killed by syromet. Couldn't it?

@daniel

What are your thoughts on this D. Was there any evidence of @jcancom's observation re syromet/lactate?


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Daniel
(@daniel)
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24/07/2020 1:06 am  
Posted by: @johan
Posted by: @gge
Posted by: @jcancom

here is adifer's report on the lactate levels. Carefully contemplating how lactate changes, given especially metformin dosing, might be helpful. We need to step back and think about this.

Lactate doubled (!!) after starting syromet.

Do we know what happened to this patient clinically afterwards? Did they see a regression or any improvement? We need to know if the lactate could have risen due to a worsening of the condition. Then lactate could have gone up as more lactate was exported from larger or more numerous tumors rather than from cancer cells being killed by syromet. Couldn't it?

@daniel

What are your thoughts on this D. Was there any evidence of @jcancom's observation re syromet/lactate?

I am not sure if I understand the question exactly, but Metformin is known to induce lactic acidosis or elevated lactate due to mito and gluconeogenesis inhibition, in patients with renal challenges.

MCT4 inhibitor such as we would expect from Syro should help reduce the lactate increase. This could actually help to identify if Syro its doing its job but in this case you would need a dynamic (time dependent analysis) as a function of Syro dose.

If that lactate doubled in my view this indicates also that overall syro may not be effective enough in blocking MCT4 (at least in that patient and dose) while Metfomin is doing it's job. But on the other hand we don't know what would have been the lactate level without Syro unless the patient has the data.

Metformin acts at multiple points at the same time, at least 3: reduce glycolisis due to reduced glucose level, increased glycolisis due to mito inhibitor, reduce gluconeogenesis at the liver site (all these have impact on lactate levels), and of course the renal condition just amplifies this.

Tumor was not necessary involved in the lactate increase, probably was just a systemic (typical) effect of Metformin.

Kind regards,

Daniel


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 1:25 am  

 

Tumor was not necessary involved in the lactate increase, probably was just a systemic (typical) effect of Metformin.

Kind regards,

Daniel

Thanks, I didn't know this was a typical effect of Metformin.


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Daniel
(@daniel)
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24/07/2020 1:34 am  

@johan You are welcome. I meant typical in patients with challenging renal conditions. 


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 1:42 am  

@daniel

Thanks. A month ago you said you spoke with adifer, any news since?


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Daniel
(@daniel)
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24/07/2020 1:58 am  

@johan Indeed, I had a call with him and the status was the tumor was very much reduced on two axes (reduced to half) after PhenylButyrate and a little extended on the other axis. Also at that time there was serious challenges (although while on PhenylButyrate  it was better) and the little extension on one axis was not helping. My impression based on discussions was that since before they started Syromet and until discussing last time, the situation was extreme. I should not that they are a family with medical doctors - so they had good support and info on that line all the time. Adi promised to give us an update here. If I get the chance I will heck with him and let you know.

Kind regards,
Daniel

This post was modified 2 weeks ago by Daniel

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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 2:05 am  

@daniel

thank you for the update. 

So they tried syrosingopine/metformin combination and that did not help and the situation was gradually getting worse, and then the tried phenylbutyrate and this produced a clear response in the tumor(diffuse intrinsic pontine glioma), do I have that right? 


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Daniel
(@daniel)
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24/07/2020 2:54 am  

@johan

About the first part I am not sure - I think they've seen some improvement with that too but not as evident as with PhenylBuryrate. I need to check. 

I think both worked to some extend, but PhenylBuryrate was clearly more effective than SyroMet in this specific case, according to the anecdotal report. Therefore, I would reformulate. However, both were not enough and Adi was searching for other options - this is why the phone call.

Kind regards,
Daniel


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 3:32 am  

It would indeed be important to know of syromet had any effect on tumor size.

After Phenylbutyrate treatment you say "status was the tumor was very much reduced on two axes (reduced to half) after PhenylButyrate and a little extended on the other axis". That's significant.

I agree PB isn't enough, a single-drug approach is unlikely to be a solution for most cancers.

A combination of PB with chemotherapy seems to me to be more likely to produce longer-lasting results.

 

 


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 3:43 am  

@daniel

Re: Metformin, in this study, it says " Metformin also increases lipolysis", isn't this a concern in later-stage cancer patients (cachexia)?


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GgE
 GgE
(@gge)
Joined: 2 years ago
Posts: 215
24/07/2020 3:46 am  
Posted by: @daniel

Metformin is known to induce lactic acidosis or elevated lactate due to mito and gluconeogenesis inhibition, in patients with renal challenges.

Do you know if there were renal challenges in this case?

When large quantities of cancer cells die from treatment-induced excess lactic acidosis and low pH, is their lactate released to the extracellular environment? Does this cause a detectable lactate level increase?


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 4:00 am  
Posted by: @daniel

@johan You are welcome. I meant typical in patients with challenging renal conditions

@gge

see above quote


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Daniel
(@daniel)
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24/07/2020 7:46 pm  
Posted by: @johan

It would indeed be important to know of syromet had any effect on tumor size.

After Phenylbutyrate treatment you say "status was the tumor was very much reduced on two axes (reduced to half) after PhenylButyrate and a little extended on the other axis". That's significant.

I agree PB isn't enough, a single-drug approach is unlikely to be a solution for most cancers.

A combination of PB with chemotherapy seems to me to be more likely to produce longer-lasting results.

 

 

It depends on the tumor type Johan. As with Metformin, sometimes it contributes sometimes not. But I agree, PhenylButyrate is one of the top repurposed metabolic drugs.

 


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Daniel
(@daniel)
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24/07/2020 8:00 pm  
Posted by: @johan

@daniel

Re: Metformin, in this study, it says " Metformin also increases lipolysis", isn't this a concern in later-stage cancer patients (cachexia)?

We need to look not at one data point or publication but clouds of knowledge to determine directions. Based on an overwhelming amount of literature, studies in humans and my experience, overall Metformin adds value (sometimes more, sometimes less). 

Actually, there are case reports indicating strong added value of Metformin alone in cancers such as Adrenal Cancer. Such cancer would be sensitive (in a negative manner) to increased lypo, yet Metformin induced tumor regression in a very aggressive cancer  https://journals.sagepub.com/doi/full/10.1177/2036361317749645

Like for Curcumin, there are many anticancer mechanism related to Metformin, both direct and indirect. 

Kind regards,
Daniel


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 8:01 pm  

It depends on the tumor type Johan. As with Metformin, sometimes it contributes sometimes not. But I agree, PhenylButyrate is one of the top repurposed metabolic drugs.

 

Interesting you refer to PB as a "metabolic" drug, in the scientific literature Phenylbutyrate (PBA) is known as a histone deacetylase inhibitor, known for inducing differentiation, cell cycle arrest, and apoptosis in various cancer cells.

Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from an amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation.


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Daniel
(@daniel)
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24/07/2020 8:07 pm  
Posted by: @gge
Posted by: @daniel

Metformin is known to induce lactic acidosis or elevated lactate due to mito and gluconeogenesis inhibition, in patients with renal challenges.

Do you know if there were renal challenges in this case?

When large quantities of cancer cells die from treatment-induced excess lactic acidosis and low pH, is their lactate released to the extracellular environment? Does this cause a detectable lactate level increase?

Hi @gge,

When Tumor Lysis occurs, typically there is a large jump in lactate dehydrogenase (LDH). About Lactate I do not know, it could be, but I would need to study this point to answer - about LDH I am sure based on literature and direct experience.

I very much suspect that the patient had renal challenges and other challenges, given the extremely difficult condition described by Adi. 

Kind regards,
Daniel


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 8:10 pm  
Posted by: @daniel
Posted by: @johan

@daniel

Re: Metformin, in this study, it says " Metformin also increases lipolysis", isn't this a concern in later-stage cancer patients (cachexia)?

We need to look not at one data point or publication but clouds of knowledge to determine directions. Based on an overwhelming amount of literature, studies in humans and my experience, overall Metformin adds value (sometimes more, sometimes less). 

Actually, there are case reports indicating strong added value of Metformin alone in cancers such as Adrenal Cancer. Such cancer would be sensitive (in a negative manner) to increased lypo, yet Metformin induced tumor regression in a very aggressive cancer  https://journals.sagepub.com/doi/full/10.1177/2036361317749645

Like for Curcumin, there are many anticancer mechanism related to Metformin, both direct and indirect. 

Kind regards,
Daniel

Thanks D. But in John's wife's case, cachexia is a great concern, that's why I asked, I totally agree there's a lot of information pointing to Met anti-cancer potential.


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Daniel
(@daniel)
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24/07/2020 8:22 pm  

@johan Johan. I knew that will be your reaction and this is why I added that word, which is correct as you are correct from the other perspective. It's a matter of perspective and bias at this point. Nobody has the 100% answer. 

You started to have a strong bias against metabolic options Johan and that doesn't help the discussions anymore. You changed a lot in the past few months and lost the constructive approach that you had for so long time. It's a step like change.

Don't forget, we are here to share and learn together in a constructive manner not to try to prove anything.

Starting to argue if PB is a HDAC inhibitor or a metabolic modulator dose not make sense at all.


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n/a
 n/a
(@johan)
Joined: 2 years ago
Posts: 494
24/07/2020 8:49 pm  

@daniel

I haven't changed D, just that I recently started noticing the HUGE bias on this website, and there's clearly a reason why this is happening. 

I wish you guys good luck.

 

 


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Daniel
(@daniel)
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Posts: 841
24/07/2020 9:50 pm  

@johan please let me know Johan why you think it happens. I am very transparent here, so I expect that from you too. 

Btw, I am not sure if you saw that but in my posts on this website, I zoomed in and out searching for different perspectives to address cancer (including modulating hormones, microtubule, various pathways, etc.), regardless if we speak about natural substances or chemo or radio or immuno-therapies. The goal was/is effectiveness not bias. This is one of probably the most unbiased website/platform addressing cancer treatments. There are various ways to address cancer, not just one and this is what this website reflects.

It started as a way to consolidate discussions from Cancer Compass and ended up to get attention and positive comments from some of the best experts in the medical world. Everything was and it is done with the most pure intentions. If you ever have doubts about that please let me know and I give you reference of any type where you could ask about who am I and what I am doing.

It's true that our discussions (I should say your because lately i did not had much time to participate) have been balanced more towards metabolic approaches because this is a perspective that is better understood and more controllable. It is also more actionable because of the modulators we can access, including so many repurposed drugs. 

I know we are not perfect and we don't know everything. But we can all comment and speak to each other in a constructive manner. That is the only aspect that I expect here. I appreciate different opinions and I like debates. But constructive ones not just for the sake of arguing. You have demonstrated for long time that you can do that but you have changed. 

You changed yourself since I started the supplement company. I did expected this will happen with some people. But I really did not expected this from you. I decided to answer to all people without asking coaching fee. I decided to continue to help others for free and do my best to do even more for the world. Starting the supplement company shows how hard I work to do something for this world. I had a great job and I can have one at any time anywhere in this world, that would require half of the work I do here for free. But I chosed to be unemployed and help people, and invest my saving in a company that will donate it's profits. If this is how you judge all this, and suggest there are other reasons, that's a pity.

Finally, I have many things to do and e-mails to answer but I respond to you because I care and I saw you as a friend.

Kind regards,
Daniel

 


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