The PhD - NO and the DMOAD magic of iPPS... PART 2In Part 1 we learnt a bit more about the properties of iPPS via a paper submitted as part of a pHD. We read through Study 1 depicting for the first time that it acts as an inhibitor to various biomarkers such as NO ..In part 2 we journey through other studies covered in the PhD paper along with a very clear picture which will give you insight into the workings of the drug that you have invested in.STUDY 2Mate, I thought Study 1 was good...The current std of care as we know involves a number of treatments all of which really just results in the temporary reduction of pain and aren't really designed to be on going longer term application. They can result in unwanted side effects and some courses can be addictive. Finally. surgery is proposed when it becomes too much in terms of pain and lack of function. "For isolated focal OA cartilage lesions, several surgical treatment options that reduce pain and extend the useful life of the joint, prior to total joint replacement, are available". New guys to us, there are some instances where the usage of iPPS can not only delay potential surgery, it may CIRCUMVENT it altogether!The paper then refers to Ghosh's work in terms of "PPS was recently shown to promote proliferation and chondrogenesis of human bone marrow-derived mesenchymal precursor cells (MPCs) while suppressing osteogenic expression and bone formation in micromass cultures". The paper went on to assert that follow up studies in this area were lacking, thus Study 2 attempted to "investigate the chondroinductive potential of PPS to completely restore the phenotype of dedifferentiated monolayer articular chondrocyte ".This study again involved dogs, two were chosen .The findings of this study confirms PPS as novel chondro inductive factor with the potential to offer a solution to the major challenges that exist at the front-end of cartilage tissue engineering."This second study's results effectively confirmed what was originally observed by the two scientists, Collier and Ghosh back in 1989, "These observed positive chondroinductive effects of PPS are in agreement with previous studies ".Ok before the next quote, let me explain some terminology, dedifferentiated is a concept in Biology meaning to undergo a reversal of differentiation, in other words a cell might have had some specialised function it now does not have this function. Monolayer simply means closely packed, dense cells for example. CACs are canine articular chondrocytes, ok this one needs another level of Mozzifing.... Canine - dogs, Articular Chondrocytes are highly specialised cells which secrete the matrix (scaffolding and network) of cartilage and becomes embedded into it.*whew* sorry we had to go into that detail as I want you to understand the ramifications of the next quote...we are ready now...."The study presented in this chapter demonstrated for the first time that the phenotype of dedifferentiated monolayer CACs is completely restored by combining alginate beads with culture in standard medium supplemented with only PPS without the addition of established chondroinductive growth factors."Paradigmers, they are saying that though the sample size was small, they are saying that more research and experimentation needs to be conducted to show this, but this study found that for the first time it was observed that PPS can play a major role inCOMPLETELY RESTORINGthis cartilage matrix.Now don't get me wrong, I'm not inferring that iPPS will re-grow your entire cartilage from nothing. All I am deducing is that iPPS can help, perhaps not in all circumstances, maybe not in every patient. BUT I am saying there is some percentage , some chance, that SOME patients MAY get some amazing DMOAD result at least to some extent? Highly speculative remarks and conclusions and you know I'm not a scientist, so please do your own research, all I want to bring to the table is that there is more to discover and I personally I think we really are just getting started here, there are grounds for further study, when they do, we may just one day be astounded by the results.We have seen the wonderful results it CAN have on SOME animals and human patients alike, 900 plus SAS patients so far with what, about 90% of them showing at least some improvement with a large 50% or so showing 50% reduction of pain and a great 75% or so showing at least 25% reduction in pain. I can't wait till we get more peer reviewed material and more trials to test and focus on the DMOAD properties of iPPS and it's potential.
Here is another quote from the same study..."...the findings of this study confirmed PPS as a novel suitable alternative chondroinductive factor to known chondrocytic growth factors that may offer a solution to the inherent challenges faced in cartilage tissue regeneration and repair of small OA cartilage lesions."
These words mean a lot to us. Even if there is only just a small amount of cartilage tissue regeneration and repair of small OA cartilage lesions, it is transformatory. Leave aside the pain reduction, the safety profile...it is these mirco chain reactions that will disrupt and on what scale.
Ok on to another study covered by the some paper.STUDY 4
In the next experiment they again took samples from dogs and this time they compared the effect of PPS and a compound known as PSGAG. The evidence and action which we will cover shortly also serves to depict just how vastly different a change to the underlying molecule can have as quoted in the paper: "...the study in this chapter demonstrated that while PPS and PSGAG share a similar chemical structure, their effects on chondrogenesis of cBMSCs varies significantly."
PSGAG stands for polysulfated glycosaminoglycan. Now the science is borderline/on the fringe for me to understand but from what I gather, there are differences between PSGAG and PPS in that they both do belong to the same family of polysulfated polysaccharides BUT the PSGAGS are primarily derived from "chondroitin sulfate (CS), and the product is made from an extract of bovine lung and trachea modified by sulfate esterification. " 10 This observation confirms the results of a previous study which demonstrated that "PPS promotes proliferation and chondrogenic differentiation of human MPCs s (Ghosh et al., 2010)".
Now as I mentioned, the interesting part was that despite these two molecules belonging to the same family, they act in vastly different ways, "PPS synergistically enhanced chondrogenesis and PG deposition whereas PSGAG inhibited chondrogenesis ".
Again, read those words carefully...'PG' is promotion growth....this is key, this is what we want, this is the underlying biology and this is what I understand to be INSIDE the black box of what is the workings of our iPPS. For you to drive your car to the supermarket, to the pub...to the shopping centre, it makes very little difference if you know how your car works... but let me say this, if you want to have an edge and you are a professional racing car driver, you need to know how the car works, every component what is it's capacity, what it can do, how it is held together, what problems can arise, what are the co-dependencies...what are the limitations, when will it not work, how does it function and the list goes on.
In the same way it is for me. I cannot have even a slightly over exposure to an investment to any significant degree if I know this stuff works but I do not know HOW...I want to know the WHY...the workings under the hood....I want to know that this is not just random miracles happening here....yes it is magical, I cannot deny it...but Mozz wants to know what is the trick behind the magic...when and in how many cases it may not work...and when and what proportion it prob. will work. Yes of course the FDA will go through this is much greater detail than I ever could...but in a way, I'm front-running them...There is no point in me just passively waiting for them to approve it, some instos come in with their BILLIONS of backing US dollars and buying up every share in existence and then me coming in and buying after they have gone through like some freak category 5 cyclone , it is just TOO LATE! I'm sneaking in Paradigmers, under the radar, crawling under the barb'ed wire...shhhh....before the world finds out.This is a party Im preparing for.
The professionals know what's under the hood, the way it works, the dynamics....I want to be a professional when it comes to 'under the hood' of possibly my greatest investiture of all time. PHOTOGRAPHIC PROOF
Sometimes words on a screen gets a bit dry...especially when it is paragraphs of science....to further illustrate and enhance our understanding of some of these experiments at a most fundamental level....let's take a look at some photographs. But I will need to explain what we are looking at:
1) Ok so these researchers took 8 samples of a cluster of cells (known as micromass culture) and subjected them to the following over 20 days.
2) PSGAG is a similar compound but still obviously different to iPPS with its own molecular composition.
3) A negative control is a control group that isn't expected to produce any results, a positive is the converse, ie it is known to produce results.
The following 'tests were conducted and relate to the picture we will see below.
A) Negative Control
B) Positive Control
C) 1.0 micro grams/mL of PPS
D) 3.0 micro grams/mL of PPS
E) 5.0 micro grams/mL of PPS
F) 1.0 micro grams/mL of PSGAG
G) 3.0 micro grams/mL of PSGAG
H) 5.0 micro grams/mL of PSGAG
They then used a Blue stain that shows up bluer when there is PG Deposition. PG deposition is yet another biomarker. Remember that Paul mentioned there are at least 10 of these kinda markers like ADAMTS 5 , MMS 3 and 31 I believe is what he gave as some examples. Remember, PG stands for proteoglycan. The more of this, the healthy things are, to simplify it, think of it as connective tissues that form bridges (tetrasacaccharide bridges).
Right..let's get to the pictures please Mr Mozz.
Oh one more thing before I show you, remember, the more the blue, the better it is...this is the dye showing up the PG.
Use the above Letters A - H to see what resulted in the MOST blue dye.
Ok Par_Peeps...what's the verdict, which ones look the bluest to you?
If you said anything other than C, D or E, I would order a colour blindness test. If you now scroll up a fraction and cross reference what exactly was C, D and E were, you will find that all quantities of PPS showed efficacy and yes, the highest dose E happened to be the best result.
This is what it fundamentally looks like under the hood of our amazing PAR VEHICLE. I understand the science is heavy and can be dry but do me a favour, just flick through Reference 1 when you get a chance. No need to even skim through it...just have a glance and almost pick any paragraph at random and you will get a sense of what the science is telling us. CONCLUSION
iPPS we now know is multi actionary.
1) It has a positive anabolic effect on articular chondroctyes
2) It reduces cartilage destruction via inhibition of the activities of cytokine driven facilitators of Osteoarthritis
3) It increases the anti-inflammatory cytokines (more on this later in a new series of posts I will be doing)
4) It has been recently shown to promote chondrogenic differentiation of human MPC cells.
5) We now have seen via this pHD study the positive effect of yet another biomarker, the production of Nitros Oxide (represented in chemistry as 'NO').
6) Again via these studies we have witnessed, "for the first time that PPS is a novel inhibitor of IL-1-induced iNOS, c-Jun, and HIF-1α mRNA upregulation, and iNOS protein-induction and thus may translate to it's beneficial effects in treatment OA and prevention of disease progression."
Yes Paradigmers, you are reading these quotes, these statements BEFORE MOST of the world. This is not some comment from a celeb. and is merely just an opinion. These are statements, quotes from science. These are facts, observations and soon to be FDA/EMA endorsed evidence. (My views).
I can only simplify so much, read this quote, yes it gives you an idea of the technicalities but Paradigmers, read it anyway, you will get the underlying message:
"For successful cartilage tissue regeneration and repair of OA defects by autologous chondrocyte transplantation (ACT), redifferentiation of dedifferentiated articular chondrocytes following in vitro monolayer expansion has long been proposed as the best hope for returning chondrocytes to their native articular cartilage mode of expression prior to implantation. Dedifferentiated monolayer P1 CACs cultured for 18 days by encapsulation in alginate beads under normoxia condition in 20% DMEM supplemented with only PPS demonstrated a full retain to their ‘native’ cartilage phenotype as verified by enhanced synthesis of cartilage-specific gene markers, type II collagen and aggrecan mRNA with complete suppression of type I and X collagen.""Full retain to their native cartilage phenotype" kinda did it for me.
In concluding, the paper went on to state quite clearly: "...this study verifies that PPS is a novel alternative chondro inductive factor with the potential to offer a solution to the major challenges that exist in cartilage tissue engineering efforts ". Mate...study after study is showing me the science behind what we have.
1) It is occurring at a fundamental level
2) Others in the industry have noticed this
3) The market in Australia is TOTALLY unaware of this (leave aside the Global market)...they have no time and very little foresight to observe and understand the ramifications of this.
4) We are darned early to the party.
Yes I know we have had some drama last week...the science really doesn't care. I also know that's an unfair statement as the corporate side is married to the science with any company....my point is:
Do not feel like WISHY WASHY Charlie brown (friend of Snoopy)....
"I think I have missed the boat"...
"I COULD'VE got in at $1.08"....
"I missed the raise at $1.30"
...."I should've bought more at $2".
"It was only $2.55 the other day but I didn't have funds ready".
Mate...YOU could kick yourself many times over if you have some finds and haven't bought and you look at the share in 2024 and it is $45 ...a share....(my views). As I often say, no matter how few or how many shares you have, it is in MY OWN OPINION you should keep some fraction for the super long term.
Do not feel you have missed the boat now, get SOME exposure (not advice, you must weigh this up for yourself, do not over invest in one investment vehicle, this is in no way advice...)...I don't really care if you just have 300 shares..in my strict view, even 300 shares could actually be worth something half decent in a mere 5 years (yes it has to be a longer time if you have a smaller exposure). I have some people (I want to call them Super PAR holders) let's call them bedrock shareholders, that I'm in touch with that have in excess of 1 millions shares each, I do not joke...you know who you are....these people DO not have to wait for 8 years...3 years and they will be already fantastically wealthy (if they aren't already). But how about this for an insight...they have even longer term personas than ME. They are calm...they are collected, they care not what the share price does on a day to day basis, yes, they are here for the long term, they are here to stay.
My fellow shareholders, the underlying science does not lie.REFERENCESMAIN REFERENCE - pHD paper:
1) https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/71681/1/EUGENE_CHISELA_BWALYA.pdf
2) https://pubmed.ncbi.nlm.nih.gov/20199396/#:~:text=OA%20occurs%20when%20the%20equilibrium,to%20major%20drug%20development%20challenges.3) https://www.cellapplications.com/human-chondrocytes-osteoarthritis-hc-oa#:~:text=Applications%20Inc%20Brochure-,Description,enzymes%20degrading%20the%20extracellular%20matrix.
4) https://www.prospecbio.com/cytokines#:~:text=Cytokines%20include%20Interleukins%2C%20Lymphokines%2C%20Monokines,by%20Th2%20T%2Dhelper%20cells.
5) https://www.nature.com/articles/bjc20124295.5) https://dermnetnz.org/topics/nitric-oxide/
6) https://adf.org.au/drug-facts/nitrous-oxide/
7) https://www.nature.com/articles/7290106
8) https://www.sciencedirect.com/science/article/abs/pii/S0003996916300619
9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445147/#:~:text=the%20interterritorial%20zone.-,Chondrocytes,and%20repair%20of%20the%20ECM.10) https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/glycosaminoglycan-polysulfate#:~:text=Second%20Edition
11) https://dalchem.com.au/how-to/what-is-alginate
12) https://www.sciencedirect.com/science/article/pii/S0091679X08606317#:~:text=The%20micromass%20culture%20technique%20was,of%20dissociated%20limb%20bud%20cells.&text=In%20the%20limb%2C%20the%20first,the%20core%20of%20the%20limb.
13) https://www.thermofisher.com/au/en/home/life-science/cell-culture/mammalian-cell-culture/classical-media/dmem.html#:~:text=Gibco%20Dulbecco's%20Modified%20Eagle%20Medium,7%2C%20and%20PC%2D12.
14) https://www.news-medical.net/life-sciences/Structure-and-Function-of-Proteoglycans.aspx
15) https://www.sciencedirect.com/science/article/pii/S0091679X08606317#:~:text=The%20micromass%20culture%20technique%20was,of%20dissociated%20limb%20bud%20cells.&text=In%20the%20limb%2C%20the%20first,the%20core%20of%20the%20limb.
(20min delay)