A Mean change cT1 - 700 mg group (-2.73 ms vs +27.64 ms, p = 0.059). Really?
If we were trying to achieve -80 ms cT1, and conditions remained the same, it would take nearly (30), 14 week iterations at 700mg to achieve it. Real good reduction of fibrosis and inflammation using 700mg. This is NOT good at all. Nobody would care about this at all if all we were able to achieve was just a -2.73ms cT1.
What are your inflammatory Biomarkers?
1) Interleukin 1 beta is PRO-INFLAMMATORY: Interleukin 1 beta is ONLY increased in the 700mg HM group. Here cT1 was reduced by 45.4 ms and PDFF was reduced by 28%. 700mg worked very well in HM group. Why were these 5 HM patients INFLAMED at the end of 14 weeks? Because, with their extra CCR5 receptors, the 700mg LRM was not too much of a burden and worked well in reducing both fibrosis and PDFF such that at the end of the 14 week period, these patients had lost an order of magnitude in their NAS stage and were more in a stage of NAFLD, rather than NASH. With NAFLD, the percentage of Fat to Fibrosis is increased because there is less Fibrosis. Since scarring is actually an anti-inflammatory mechanism, and Steatosis has only an inflammatory mechanism associated with it, and since the level of disease actually went down, these 5 HM patients had increased Interleukin 1 beta at the end of the 14 weeks.
2) Intercellular Adhesion Molecule 1 was increased in all the 350mg group because this adhesive molecule is increased in the Fibrotic Remodeling Pathway when the Macrophages are being Activated by IL-4 and IL-13 to remain in the metabolism of Fibrotic Remodeling. When scar tissue is being remodeled, the macrophages are activated by IL-4 and IL-13 which increases the Intercellular Adhesion Molecules which helps in the remodeling of scar tissue. The 350mg dose is the appropriate dose to do this at because it does not overburden the system and consistently does it at a measured rate.
In the Placebo and the 700mg normal group, the Intercellular Adhesion Molecule was decreased because in the Placebo group, the patients were always in the M1 Pathway and hardly entered the Fibrotic Remodeling Pathway. In the 700mg normal group, the dosing was an extreme slamming of the systems out of the Fibrotic Remodeling Pathway and into the M1 pathway of Steatosis. Steatosis increased and the maintenance of the Fibrotic Remodeling Pathway was lost. The systems resorted back to the M1 pathways leading to inflammation and the escalation of steatosis.
3) Tumor Necrosis Factor Alpha and Beta were both unchanged in the Placebo group yet had significant increases in cT1, but the Placebo immune systems kept their regulation in M1 and did not switch to the Fibrotic Remodeling Pathway. That is why TNF was unchanged, because in the Placebo group, their systems remained in the M1 Pathway; Both TNF Alpha and Beta increased in 700 mg normal because although 700mg was used, an increase in cT1 still occurred because of inappropriate dosing, but because LRM was on board, the patient's immune system was capable of recognizing that, unlike what happens in Placebo; therefore, because of LRM, they switched from M1 to Fibrotic Remodeling Pathway as evidenced by increases in TNF Alpha and Beta.
Both Tumor Necrosis Factor Alpha and Beta were decreased in 700mg HM because scar tissue was dramatically reduced with cT1 decreasing by 45.4 ms cT1 and since there was less scar tissue, the system reverted back to the M1 Pathway. It switched back to the M1 Pathway when the level of fibrosis was reduced and subsequently decreased TNF alpha and beta. When LRM is onboard, the system is capable of detecting scar tissue levels while in Placebo, regardless of increasing scar tissue, system seems to remain in M1 Pathway.
The 2 milder 350 mg levels, <875 and <950, both had similar findings as did the 700mg HM regarding TNF alpha and beta. TNF alpha and beta were both reduced in these 350 mg groups because the overall level of fibrosis was either low or had come down to the point, that their systems had switched from the Fibrotic Remodeling Pathway to the M1 pathway where there was less TNF. TNF seems like it is a great tool to determine whether a patient is in the M1 Pathway or the Fibrotic Remodeling Pathway.
In the 350mg > 950 cT1 group, TNF was unchanged, because that group stayed in the Fibrotic Remodeling Pathway and had the same TNF output. They were in the Fibrotic Remodeling Pathway to begin with because their scarring was so bad to begin with and they remained in the Fibrotic Remodeling Pathway with 350mg dosing, even after 14 weeks, but, all the while, they were metabolizing the fibrous tissue, and removing it at a faster rate than they were forming it. It would probably be helpful to get actual quantities of TNF alpha and beta, rather than just looking at increased or decreased so we can see what the starting value was, what the ending value was and if the actual levels correlate to whether patient is in M1 Pathway or Fibrotic Remodeling pathway.
4) Interferon Gamma is increased in Placebo, 700mg normal and mildly increased in 700mg HM. Interferon Gamma says that Macrophages and Leucocytes are in the M1 Pathway. Since 700mg HM did so well with reducing fibrosis, the level of Interferon Gamma increase was less than when fibrous tissue significantly increased in Placebo and 700mg normal. The more fibrous tissue increase there is, the greater the increase in Interferon Gamma.
Interferon Gamma decreased in 350mg across the board because there was significant fibrous metabolism occurring, both in the formation as well as resorption phase while the Macrophages were in the Fibrotic Remodeling pathway.
5) Interleukin 4: Unchanged in Placebo. In Placebo, Scar tissue tremendously increased by 27.64 cT1. Immune System was not doing anything about it. It just left the macrophages in M1 pathway. What were the levels of IL-4? Yes, they did not change, but overall, did they correlate with the patients being in the M1 Pathway, that would mean the IL-4 levels would tend to be lower. In the Fibrotic Remodeling Pathway, both IL-4 and IL-13 increase.
In 700mg normal, IL-4 was slightly decreased. IL-4 was consumed by the Macrophages attempting to switch from M1 to Fibrotic Remodeling Pathway which thereby reduced IL-4. This resulted in the loss of a modest -2.73 cT1 which was better than Placebo.
In 700 mg HM, IL -4 was sharply increased. In this group cT-1 was reduced by a significant 45.4 cT1, evidencing a system, strongly seated in the Fibrotic Remodeling Pathway. IL-4 was being produced and consumed while in the Fibrotic Remodeling pathway and since it was effective at consuming the scar tissue, it remained in that pathway. There was probably more scar tissue to remodel in this patient population.
In the 350 group, the >950 cT1, IL-4 was slightly decreased. Similar to the 700mg normal, because of the increased remodeling, there was increased uptake of IL-4 by the macrophages and because of the reduced dosage, it wasn't trying to remodel at a super fast pace, so the BALANCE between re-uptake and reformation of IL-4 was stronger in the uptake, so there was a slight decrease. I believe IL-4 is autocrine so it is produced and consumed by the macrophage and lymphocytes and the rate at which that occurs, both production and consumption, is what is seen in the serum levels.
For the 350mg >875 cT1, IL-4 was increased. In this group, There was a mix of both patients. Some having severe disease (those in the 950 camp) and some more mild disease, (between 875 and 950). So, giving the 350mg ramped up the rate of metabolism of the scar tissue, but since the disease was rather modest, the systems were going into M1 Pathway, so there was no uptake resulting in an excess of IL-4. As the systems switch to the Fibrotic
Remodeling Pathway, IL-4 is produced. Provided there exists more scar tissue to metabolize, the systems remain in the Fibrotic Remodeling pathway producing more IL-4. When scar tissue levels are consumed or are reduced, less and less IL-4 is produced by the macrophages, and the systems then start switching to the M1 pathway.
If we were trying to achieve -80 ms cT1, and conditions remained the same, it would take nearly (30), 14 week iterations at 700mg to achieve it. Real good reduction of fibrosis and inflammation using 700mg. This is NOT good at all. Nobody would care about this at all if all we were able to achieve was just a -2.73ms cT1.
What are your inflammatory Biomarkers?
1) Interleukin 1 beta is PRO-INFLAMMATORY: Interleukin 1 beta is ONLY increased in the 700mg HM group. Here cT1 was reduced by 45.4 ms and PDFF was reduced by 28%. 700mg worked very well in HM group. Why were these 5 HM patients INFLAMED at the end of 14 weeks? Because, with their extra CCR5 receptors, the 700mg LRM was not too much of a burden and worked well in reducing both fibrosis and PDFF such that at the end of the 14 week period, these patients had lost an order of magnitude in their NAS stage and were more in a stage of NAFLD, rather than NASH. With NAFLD, the percentage of Fat to Fibrosis is increased because there is less Fibrosis. Since scarring is actually an anti-inflammatory mechanism, and Steatosis has only an inflammatory mechanism associated with it, and since the level of disease actually went down, these 5 HM patients had increased Interleukin 1 beta at the end of the 14 weeks.
2) Intercellular Adhesion Molecule 1 was increased in all the 350mg group because this adhesive molecule is increased in the Fibrotic Remodeling Pathway when the Macrophages are being Activated by IL-4 and IL-13 to remain in the metabolism of Fibrotic Remodeling. When scar tissue is being remodeled, the macrophages are activated by IL-4 and IL-13 which increases the Intercellular Adhesion Molecules which helps in the remodeling of scar tissue. The 350mg dose is the appropriate dose to do this at because it does not overburden the system and consistently does it at a measured rate.
In the Placebo and the 700mg normal group, the Intercellular Adhesion Molecule was decreased because in the Placebo group, the patients were always in the M1 Pathway and hardly entered the Fibrotic Remodeling Pathway. In the 700mg normal group, the dosing was an extreme slamming of the systems out of the Fibrotic Remodeling Pathway and into the M1 pathway of Steatosis. Steatosis increased and the maintenance of the Fibrotic Remodeling Pathway was lost. The systems resorted back to the M1 pathways leading to inflammation and the escalation of steatosis.
3) Tumor Necrosis Factor Alpha and Beta were both unchanged in the Placebo group yet had significant increases in cT1, but the Placebo immune systems kept their regulation in M1 and did not switch to the Fibrotic Remodeling Pathway. That is why TNF was unchanged, because in the Placebo group, their systems remained in the M1 Pathway; Both TNF Alpha and Beta increased in 700 mg normal because although 700mg was used, an increase in cT1 still occurred because of inappropriate dosing, but because LRM was on board, the patient's immune system was capable of recognizing that, unlike what happens in Placebo; therefore, because of LRM, they switched from M1 to Fibrotic Remodeling Pathway as evidenced by increases in TNF Alpha and Beta.
Both Tumor Necrosis Factor Alpha and Beta were decreased in 700mg HM because scar tissue was dramatically reduced with cT1 decreasing by 45.4 ms cT1 and since there was less scar tissue, the system reverted back to the M1 Pathway. It switched back to the M1 Pathway when the level of fibrosis was reduced and subsequently decreased TNF alpha and beta. When LRM is onboard, the system is capable of detecting scar tissue levels while in Placebo, regardless of increasing scar tissue, system seems to remain in M1 Pathway.
The 2 milder 350 mg levels, <875 and <950, both had similar findings as did the 700mg HM regarding TNF alpha and beta. TNF alpha and beta were both reduced in these 350 mg groups because the overall level of fibrosis was either low or had come down to the point, that their systems had switched from the Fibrotic Remodeling Pathway to the M1 pathway where there was less TNF. TNF seems like it is a great tool to determine whether a patient is in the M1 Pathway or the Fibrotic Remodeling Pathway.
In the 350mg > 950 cT1 group, TNF was unchanged, because that group stayed in the Fibrotic Remodeling Pathway and had the same TNF output. They were in the Fibrotic Remodeling Pathway to begin with because their scarring was so bad to begin with and they remained in the Fibrotic Remodeling Pathway with 350mg dosing, even after 14 weeks, but, all the while, they were metabolizing the fibrous tissue, and removing it at a faster rate than they were forming it. It would probably be helpful to get actual quantities of TNF alpha and beta, rather than just looking at increased or decreased so we can see what the starting value was, what the ending value was and if the actual levels correlate to whether patient is in M1 Pathway or Fibrotic Remodeling pathway.
4) Interferon Gamma is increased in Placebo, 700mg normal and mildly increased in 700mg HM. Interferon Gamma says that Macrophages and Leucocytes are in the M1 Pathway. Since 700mg HM did so well with reducing fibrosis, the level of Interferon Gamma increase was less than when fibrous tissue significantly increased in Placebo and 700mg normal. The more fibrous tissue increase there is, the greater the increase in Interferon Gamma.
Interferon Gamma decreased in 350mg across the board because there was significant fibrous metabolism occurring, both in the formation as well as resorption phase while the Macrophages were in the Fibrotic Remodeling pathway.
5) Interleukin 4: Unchanged in Placebo. In Placebo, Scar tissue tremendously increased by 27.64 cT1. Immune System was not doing anything about it. It just left the macrophages in M1 pathway. What were the levels of IL-4? Yes, they did not change, but overall, did they correlate with the patients being in the M1 Pathway, that would mean the IL-4 levels would tend to be lower. In the Fibrotic Remodeling Pathway, both IL-4 and IL-13 increase.
In 700mg normal, IL-4 was slightly decreased. IL-4 was consumed by the Macrophages attempting to switch from M1 to Fibrotic Remodeling Pathway which thereby reduced IL-4. This resulted in the loss of a modest -2.73 cT1 which was better than Placebo.
In 700 mg HM, IL -4 was sharply increased. In this group cT-1 was reduced by a significant 45.4 cT1, evidencing a system, strongly seated in the Fibrotic Remodeling Pathway. IL-4 was being produced and consumed while in the Fibrotic Remodeling pathway and since it was effective at consuming the scar tissue, it remained in that pathway. There was probably more scar tissue to remodel in this patient population.
In the 350 group, the >950 cT1, IL-4 was slightly decreased. Similar to the 700mg normal, because of the increased remodeling, there was increased uptake of IL-4 by the macrophages and because of the reduced dosage, it wasn't trying to remodel at a super fast pace, so the BALANCE between re-uptake and reformation of IL-4 was stronger in the uptake, so there was a slight decrease. I believe IL-4 is autocrine so it is produced and consumed by the macrophage and lymphocytes and the rate at which that occurs, both production and consumption, is what is seen in the serum levels.
For the 350mg >875 cT1, IL-4 was increased. In this group, There was a mix of both patients. Some having severe disease (those in the 950 camp) and some more mild disease, (between 875 and 950). So, giving the 350mg ramped up the rate of metabolism of the scar tissue, but since the disease was rather modest, the systems were going into M1 Pathway, so there was no uptake resulting in an excess of IL-4. As the systems switch to the Fibrotic
Remodeling Pathway, IL-4 is produced. Provided there exists more scar tissue to metabolize, the systems remain in the Fibrotic Remodeling pathway producing more IL-4. When scar tissue levels are consumed or are reduced, less and less IL-4 is produced by the macrophages, and the systems then start switching to the M1 pathway.
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