The key is this: "statistically significant."
That means there were at least 3 mice per group. You need to have 3 to have statistical significance.
By the way. It wasn't rats, it was mice. Read the PR.
I do agree, though, that they need more information in the PR. After the pump over the summer that wasn't substantiated, they should have learned their lesson. I do believe not releasing the actual data is holding the big boys back (Unless they are sharing data behind closed doors. And don't take this as they are doing something wrong. They issued the PR. They let the world know they have statistically significant data. They don't have to share the numbers with everybody if they don't want to.
Just had time to quickly scan his paper. His small molecule screen is based on inhibition of caspase cleavage (a marker that apoptosis may occur) in neurons following endoplasmic reticulum stress. So he found certain molecules may prevent ER stress induced cell death. Most of those molecules have been found by others before, including dantrolene.
Dantrolene works in vivo in rats to prevent traumatic brain injury induced nerve apoptosis because it is a calcium channel blocker. Shifts in calcium occur very early after injury in cells and mediates, in part, the cell death. People are also looking at calcium channel blockers for Alzheimer's disease.
He used a simple approach, that resulted in a simple outcome. All of those inhibitors that he used make sense as they have been previously shown to inhibit apoptosis, except the Cox-2 inhibitor (NS-398). In some models COX-2 inhibition (like by celebrex) can make apoptosis worse, and in others it can make it better.
From my experience, its not that simple.
The other thing about why he is looking at these inhibitors (likely) is that the NIH has a big initiative for giving grants for drugs that have been "retired" and repurposing them/giving them new uses. They have a large funding pool available for this kind of research. Just my 2 cents.
I bought MANF made in CHO cells, which should have the correct post-translational modifications. I spoke to the company, and they said they test and guarantee all of their recombinant proteins for the function listed.
The function listed was the ability to stimulate rat neural cell proliferation. So I figured if a human protein can make rat cells proliferate (meaning it possesses neurotrophic/cytokine properties), it should be able to function in human macrophages (if the macrophages express the receptor for it). Well I used 0.1, 1, and 10 x, and 100x the concentration that was previously shown to work in heart cells, brain cells, and retinal cells.
Either I bought a dud from the company (possible) or the macrophages don't express the receptor for it (possible) or MANF doesn't possess anti-inflammatory effects (possible).
I could try to purify the receptor, but since it didn't do what I was hoping it would, I figured, there is no point in looking at it any more. Plus I ran out of the protein after trying it out twice. Not worth me putting any more lab money into it.
This does not impact my opinion of MANF or Amarantus at all. It just didn't work in my model. I was hopeful because of the effects in type I diabetes (an immune disease), but no dice...
Sorry I have been really busy.
I actually agree with zoomboom on this. You should understand anything you invest in.
For scasperavich, check my post history (some prob a year old) I have numerous posts on why I think AMBS could be worth a speculative investment. It has nothing to do with LymPro. Its all MANF, and a little eltoprazine sprinkled in there.
Now back to the first sentence of the above paragraph. So in the GDNF MANF article that I wrote a summary about last week, basically it proved that different neurons respond to different neurotrophic factors. In the substantia nigra, MANF/GDNF clearly play roles that can result in synergy, whereas CDNF clearly plays a role in the striatum. In the eye, MANF seems to be able to fix the retinal cells. My guess is that all of these cells express the receptor for MANF, and those are the indications that should be targeted for treatment with recombinant MANF. Eyes/retina, and substantia nigra based disease. So I do believe that MANF administration may help retinitis pigmentosa in wolfram's disease, or any other disease that patients develop retinitis pigmentosa in.
I have tried pretreating mouse macrophages (immune cells) with (murine) MANF prior to stimulating them with an immune activator (lipopolysaccharide). It did not prevent activation of the immune system. By itself, MANF also didn't cause any discernable changes in a limited panel of genes that I tested compared to vehicle control. That just tells me that macrophages probably don't express the receptor for MANF. I was hoping that it would have some anti-inflammatory effect. But it did not in that particular model.
I think someone needs to find the receptor for extracellular MANF so that real progress can be made to identify how extracellular MANF works.
Fibonacci has deleted every post over a couple of weeks old, so you can no longer see his 100 other predictions that were completely wrong. His Spec/Sens predictions never made any sense, and he doesn't even understand there is only two inducible genes in LymPro that can possibly go up in lympro (he said 8 in his last tweet), so when I tweeted him that, he deleted that "prediction" tweet as well. That's all I'm going to say about that.
As far as the small molecules, I have to see what the small molecules are and then I can assess whether they may work.
As far as the efficacy of MANF, it all depends on which neurons/cells are responsive to MANF. Wolframin is a related gene/protein (to MANF- they are both involved in endoplasmic reticulum stress pathways) mutated in Wolfram's disease that plays a role in diabetes. Both MANF and WFS1 knockout mice display diabetes and death of pancreatic beta cells. What that tells me, is that pancreatic beta cells are exquisitely sensitive to endoplasmic reticulum stress. In Wolfram's disease, will MANF be able to fix the beta cells that are dying because they don't express wolframin? My opinion, no. It doesn't make sense. Remember, intracellular MANF protects cells from ER stress. Extracellular MANF acts as a neurotrophic factor (hence its name) mainly acting like a cytokine and causing cell signaling. So will adding extracellular MANF to patients who don't make intracellular wolframin fix the dying beta cells that lack wolframin? My opinion, no. Now if there were MANF deficient humans, extracellular MANF still may be able to fix the beta cells. I think you still need to get the beta cells to make it intracellularly, to block the ER stress pathway from being activated and killing those cells.
KITE catalysts, CAR-T cells
JUNO IPO should be big when it hits. Also CAR-T, furthest along (along with NVS).
JCAR015, now in a Phase I clinical trial, has seen a "91% complete remission rate in 22 evaluable adult patients with relapsed/refractory B cell acute lymphoblastic leukemia, or r/r ALL, as of the most recent data cutoff date of July 1, 2014. Historical complete remission rates without JCAR015 in a similar population are less than 10%." Juno plans to start a Phase II trial in mid-2015 exploring JCAR015 in adult r/r ALL that could support accelerated U.S. regulatory approval.
JCAR017 has achieved an 83% complete remission rate in 6 evaluable patients with pediatric r/r ALL as of August 1. "We plan to continue the ongoing Phase I/II trial in pediatric r/r ALL in 2015. Based upon data to date, we also plan to initiate a multicenter Phase I trial exploring JCAR017 in relapsed/refractory B cell non-Hodgkin's lymphoma, or r/r NHL, in 2015, with the potential to advance to a registration trial in 2016 that may support accelerated U.S. regulatory approval."
NVAX and CCXI got orphan drug designation. NVAX already up. Flu season coming. I see NVAX and BCRX going up if its a bad flu season. Watching those.
Also of note. Good luck with the kitchen/dishwasher. That sucks. I just moved, so haven't been so active. Moving tough with a 2 and a 4 year old.
PHMD potential bottom play. Had a nice bump yesterday. It will settle in the 2.30s- 2.40s today before next leg up. I am hoping to get more at 2.20ish...
Awesome. I'll email you next time I see something good. PED finally looks like a bottom. Tricked me with that morning bump to $1.00, then fade back to .67... I think .60 is the bottom there. Company way undervalued. LNCGY, a pick of a friend of mine. Another energy pick in Australia. Huge potential.
MB. Good to see you my man. I am adding here at these levels. After Ken recommended looking into this, I bought a small position. Getting in larger now. I do think this downturn is because of the warrants. It should go up soon. Potential game changer.
I am in same boat with AMBS. Letting it play out. That's why I haven't posted much here in a while. No need to worry about a free investment.
Haven't heard from you in a while... I got in some JNUG at 4.55 earlier this week. Sold half at 5.67 this am... I haven't heard from you. Thought you may have not liked my last call with AMZG, so didn't want to bother you.
There is one way to do this. You can make smaller and smaller mutants of recombinant MANF and use an assay where you apply those MANF mutants to neurons, and have a reporter that lights up when the neurons are dividing, you can compare full length MANF to the fragments and find the portion that is responsible for activating the receptor.
That will give you an amino acid sequence that binds to the receptor, then you can use that small MANF sequence as your "small molecule" or use it to narrow down your choices for what the actual receptor are.
What's the receptor for MANF?The receptor for extracellular MANF has never been found. There was one manuscript a while back that hinted at KDEL receptors, (receptors that bind to proteins that contain that 4 amino acid sequence K-D-E-L), but this has never been verified.
If he can find a small molecule to activate a, to this date, unknown receptor, he's a much much better scientist than I.
I don't think he will find a small molecule that induces MANF production that is not cytotoxic. Basically, it would be very difficult to find a molecule that selectively induces MANF production.