"It is a complex disease whose etiology bridges biomechanics and biochemistry."
Dr David Felson - October 2000
ndeed this is the exploration we will be undertaking very soon, Trial 008. A true cross between the biomechanics and the biochemistry as the Great Doctor quotes above.
Are you new to us here at HotCopper - PAR HQ? Great Doctor? Doctor Who?
Less this...
More this...
(Not the TV series...the pre-eminent figure in OA....)
This 008 - My theory post will be a super long one, I was aiming to squeeze it into two parts, impossible...three parts minimum...so yes, it's really time to grab a coffee...perhaps a couple of glasses of that smooth red that you and I are BOTH eye'ing or a good jug of lemon water...whatever it might be...As an extension to my last BOND post...I tackle a theory on 008...but first some important caveats:
1) I am no scientist..I don't often wear a white lab coat..in fact even at fancy dress parties I haven't worn one, though I did once wear quite an outlandish afro-wig to a disco party, it was hilarious. 2) I am no medico... 3) The below work is only my own views and it is at times highly speculative musings...you must not in any way shape or form rely on any information and or misconstrue it as advice. 4) I could be completely...totally...unequivocally wrong about some or all of the below 5) If you agree to these terms and conditions, caveats...then read the below with these points in mind...If you have any views on the material...agree...disagree and hopefully with some reasons...then please do post your feedback in this thread.
008 MY THEORY - BREAKDOWN OF PARTS
Mate this will be quite a journey....
PART 1 We will tackle some background to prep you...I'll breakdown what exactly is 008, what it consists of and what exactly we are studying.
PART 2 I will cover why is it important, how it's to be used to our benefit and even some incredible diagrams that will depict just some of these biomarkers and their relevance to us.You will begin to get more of a sense of just how revealing and how pivotal little ol' 008 could be....so pivotal that it may just be worth waiting for in terms of any deal...in terms of any negotiations...
PART 3 We chat about a remarkable fact of timing and finally we will get into my theory of what we might (with some heavy caveats) just discover and observe.
References can be found at the end of Part 3.
EDITOR'S BLURB
You know me, I find it rather hard to sit down and not think about PAR. Heck I get excited by what we have when times are quiet, when there is no news...I do love to post at such times to keep up our interest, to motivate not only you, the reader, but myself as well! The good thing is that there is just oh so much to explore...it really is a whole new world.I'm always trying to think and project out our future...I know its a darned long term hold...I buy a few bits and pieces on dips but I'm mostly done...now it's the waiting game....but while we wait...I will explore...I will bolster my investment through sheer knowledge...and I'll pester where I can, to get insightful info.
The making of this post occurred over 2 months. I researched bits and pieces and figured out pretty soon after I started that this will be more of a project rather than doing the research, editing and posting in just one weekend. The research for this again was not simply and randomly pulled from the internet via copy and paste....I have talked to Doctors that are friends, Doctors that I bumped into...I even called up one of the analysts that did some research on us a while ago, I've sent emails and bugged people to come up with some of this material...
There is some material here that I was stunned by...Paradigmers - I will try in words to express to you what we have, It is easy to get excited by the larger font headlines we get from PAR and the ASX...but it is underneath the surface, the science stuff that tells us even more...we are in front of the queue here...it is still early days and it is only a small tiny fraction of investors that know the stuff you and I know....we just need to work out how to translate and decipher the research and the evidence...it's literally gold.
As always, please enjoy this most amazing journey, one in which I really believe will result in some great success (my views).
Thank you to my many contacts, you know who you are, after all, it is for ourcombined benefit.
008 - MY THEORY - PART 1
BACKGROUND
OA affects many, a solution is desperately required as the numbers grow every year....inflation in most of the world runs at around 2%...perhaps a bit less in these times...the CAGR of OA marches on at 8% per year.... the challenge indeed is to find a solution that is not only effective but has some chondroprotective properties. It should not come at a cost of further destruction of cartilage and it should do so, safely.
008 is what I like to think of a sampler trial to investigate what is happening within the joint itself focusing in on the synovium.
The synovium can be thought of as an encompassing bubble/envelope over a given joint such as the knee or elbow...even joints like the wrist, foot and ankle have a synovium. So what can go wrong? Well as your cartilage degrades you can get particles of cartilage that float within the fluid...a quaint way of putting it, is that the body doesn't like this....in fact it elicits inflammation (Synovitis) and irritation.... But it's not this state of synovitis that directly causes dangerous complications, it's the aftermath...the subsequent chain reactions if the pain and swelling doesn't go away.
Now we know there are ways to get rid of the inflammation...but a lot of these can have side effects and may not be a permanent situation...it depends on the nature of the inflammation and injury.There have been many observational studies that link synovial inflammation to early OA symptoms and later, structural deterioration.2
Those broken bits of cartilage can lead to inflammation.
We then find cytokines both in the Serum (Blood) AND the Synovial Fluid (the bit that swims around in our joints that reduce friction, see above diagram). But first, what are these little buggers, the cytokines?
The actual definition from the Oxford dictionary 3 is fairly simple, it's simply a type of secretion from certain cells of the immune system. These secretions thus have a cause and an effect on other cells.Let's Mozzify ® this (make it simple!) It's like I make a funny statement (that's my verbal secretion), our friend AF picks up on it, does his quick construction/reconnaissance work (he is lightning quick, so are some of the cellular reactions by the way) and he comes back with a reaction, namely an amazing moving gif that makes us laugh.
Perhaps an oversimplification but it's this chain reaction that's important. Some are good reactions, others are evilly destructive. The point here is that we are utilising the numbers, the quantities of these cytokines to observe what effect our Magic Juice (iPPS) is having on these certain cytokines. They are also labelled or thought of as biomarkers. If these biomarkers are present we can say with some confidence that the destructive nature of OA is at work. A reduction of these means that the disease is slowing. Therein lies the clue.
THE MECHANICS
Certainly and completely beyond the scope of this post (I'd need about 10 posts I reckon) is the biomechanical action of what happens in the gradual destruction of the joint. At a high level it appears to be the disrupting role that cytokines have in terms of a balance between catabolic and anabolic processes. 4
Whoa...stop...Definition time
Catabolic = Energy required to break something down (usually a tissue...no not Klenix, I mean cellular, think streams or clusters of cells) Anabolic = Energy required to build and grow cells and/or cell tissues.There are four types of cell tissues 5:
Epithelial
Connective
Neural
Muscular
Ok back to the story, so when this disruption in terms of the balance occurs we get progressive degeneration of articular cartilage.The result?
1) Inflammation 2) Degradation 3) Interruption of joint function 4) Pain
HOW DOES THIS HAPPEN?
Well there are a number of factors, disposition to it (genetic), physical injury/damage, excessively high mechanical load (obesity or continuous heavy workload on a given joint, think factory worker or farmer doing the same action over and over again), natural aging."...clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity." 6 OA occurs and as we know, there are four main grades of it, the final one eventually leading in most cases to surgery. There are currently NO available solutions...we are about to change all that (my view).Let's go to a diagram to see this degeneration as a flow chart:
A number of factors leading a flow of degradation of quality of life.
THE ACTIVITY
Ok so we know certain cytokines present themselves when there is inflammation going on, when there is cartilage destruction taking place, when OA is present. We know that this is effectively a biomarker that can be observed and tested for. So Mozz, how many biomarkers are there?Well lots.The best clue I got was from the heat map, I was blown away the first time I saw it because I didn't know there were that many. When PAR announced way back in late 2019 that they looked at two, namely COMP and ADAMTS-5, I didn't think there were many more...turns out there are a stack...recap?
Take a look at this post for the details ----> HEAT MAP!
But to save you some time, here is the main pic which I managed to get a clearer version compared to the original post. The original post (See link above) gives a bit of a description and interpretation of what you are seeing below.
Look at the difference between the number of cytokines in a healthy person and one with OA and then further with an RA patient. So we have heaps of biomarkers....in fact in the above diagram there are some 42 biomarkers mentioned! In the case of an OA and a RA patient, the more red you see, the more the cytokine activity that is taking place. Remember this point , we'll come back to it in part 3.Indeed there is a clear association between the presence of some biomarkers like the illustrative and PAR-observed COMP and the onset of OA:
"...the synovial fluid aggrecan or COMP was several times higher than serum levels. This result suggests that aggrecan and COMP are locally produced in the joint and high synovial fluid of these biomarkers are associated with rapid cartilage turnover."7
...in fact so rapid that our bodies just can't keep up with the formation of new cartilage and we start to experience net loss.
ndeed this is the exploration we will be undertaking very soon, Trial 008. A true cross between the biomechanics and the biochemistry as the Great Doctor quotes above.
(20min delay)