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Your Moves - April 07 by AutoModerator in wallstreetdd

[–]SirT6 0 points1 point  (0 children)

SGYP: http://ir.synergypharma.com/press-releases/detail/1840/synergy-pharmaceuticals-launches-the-poop-troop-the-first

Poop troop emojis 😂💩

RIP longs

Your Moves - April 07 by AutoModerator in wallstreetdd

[–]SirT6 0 points1 point  (0 children)

Got a starter position in NBIX filled below $40, which I am pretty happy about. PDUFA next week presents a mini-catalyst, and the pipeline remains intriguing.

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A study by the Cneters for Disease Control finds that close to half of all American adults are infected with genital HPVMedicine (nytimes.com)

submitted by SirT6 to r/science

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Autoantibodies to GPIHBP1 as a new cause of severe hypertriglyceridemia (nejm.org)

submitted by SirT6 to r/Immunology

"Male contraceptive blocked by drug companies who make billions from the female pill" by SoFemale in TwoXChromosomes

[–]SirT6 0 points1 point  (0 children)

I work in drug development. Sadly, whether a drug works in animal models is poorly prognostic of whether it will work in humans. If it was, then 90% of all drugs wouldn't fail to make it through clinical trials.

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease — NEJM by HFpEF in medicine

[–]SirT6 2 points3 points  (0 children)

The study wasn't designed or powered to evaluate the impact on mortality. Given, though, that the primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization I would be surprised if a mortality benefit did not emerge over time.

The results from the ODYSSEY trial (investigating a different PSCK9 mab in atherosclerotic cardiovascular disease), which are anticipated later this year, may provide further clarity on the benefit of PCSK9 targeting agents. The patients in this trial had higher LDL-c levels and were generally higher risk than the patients enrolled in the FOURIER study.

LSD reduces activity in the amygdala, the region of the brain related to the handling of negative emotions like fear, compared to placebo, in a double-blind, randomised, cross-over study. This may explain it's therapeutic action in addiction, depression and anxiety, especially with psychotherapy. by mvea in science

[–]SirT6 14 points15 points  (0 children)

Sounds interesting. Do you have a link to the report?

LSD reduces activity in the amygdala, the region of the brain related to the handling of negative emotions like fear, compared to placebo, in a double-blind, randomised, cross-over study. This may explain it's therapeutic action in addiction, depression and anxiety, especially with psychotherapy. by mvea in science

[–]SirT6 43 points44 points  (0 children)

Abstract: Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

A couple of thoughts on this:

  1. Is 100ug of LSD a lot? Also, I'm a bit surprised that they didn't attempt to normalize the ammount of drug given by body weight or some other parameter - the study had 9 men and 11 women, I would guess that dose would matter in this context.

  2. I am generally a fan of double blind studies, but are they necessary for something like this? I would guess that you'll know pretty quickly whether they just gave you LSD or a placebo.

  3. How can you tell whether the response to fearful faces is different because LSD is modulating the biology of the fear response versus LSD is causing the person to trip, and not really pay attention to the faces they are being shown?

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 1 point2 points  (0 children)

The MHCs are agnostic about the origin of the peptides they bind. They will bind any peptide (host or foreign) that fits within their groove. The MHC-peptide complex is then ransported and presented at the cell surface, where TCRs from T-cells are able to monitor them.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 1 point2 points  (0 children)

See below ;)

I was hoping u/funkmccool might push themselves a bit to elaborate on their answer.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 1 point2 points  (0 children)

The recipients adaptive immune cells therefore recognize transferred cells as foreign and a potential threat.

This would be the situation in a graft rejection. This article is more about GvHD - where the grafted immune cells recognize the new host as foreign and initiate an immune response.

In any case, the reason mismatched MHCs in a transplant setting are a problem is because (as you allude to) the engrafted T-cells have been trained on a separate set of peptides. What many people don't appreciate is just how different these sets can be. They are different in part because different humans have different variants for genes across the genome. But these "neo-epitopes" are only a small contributor to GvHD. The bigger contribution is the fact that different MHC alleles load different portions of the proteome, and they do so in different ways (i.e. one MHC type may load 9-mers, while another may load 10-mers). So different MHCs are problematic because of almost everything will be recognized as foreign in a transplant setting without good matching.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 0 points1 point  (0 children)

As described, I have to imagine it would be restricted to pure HSC replacement. Most HSC transfers, though, occur in an oncology setting.

But would it not be more expedient to modify stem cells with (1) matched MHC alleles and (2) and inducible CAR-T receptors that can be triggered with a pharmacological switch?

I'm not sure I'd use the word "expedient" - that sounds like a lot of genome engineering. But people are certainly investigating similar strategies. I'm not sold on the idea though that the answer is a highly personalized medicine - it seems like that would be very difficult to scale efficiently. It's also unclear what CAR would be best - there is still lots of research being done in this field.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 0 points1 point  (0 children)

In the leukemia setting, one of the main reasons you do allo transplant is to induce a graft versus tumor response. If you somehow perfectly match MHC alleles, you are likely to reduce the GvT component of the transplant, leading to worse patient outcomes.

Finding a therapy that can thread the needle between retaining GvT effects and sidestepping GvHD is highly desired in the clinic.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 3 points4 points  (0 children)

They probably would be required. Most transplants try their best to match HLAs when possible. Even still, GvHD is a problem. I think the consensus is that while MHC mismatch contributes to a large fraction of GvHD in an allo setting, other factors do as well.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 0 points1 point  (0 children)

MHC genes do not undergo somatic recombination like the TCR and BCR loci.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 0 points1 point  (0 children)

MHC I are expressed on the surface. How else would they present antigens to T-cells?

It's that time of year again. We just published our 2016 Transparency Report. by spez in announcements

[–]SirT6 0 points1 point  (0 children)

If anyone is interested in implementing it, just message glr123 or the r/science modmail and I am sure they will share the code if possible.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 0 points1 point  (0 children)

MHC type II are.

GvHD, though, is mostly mediated by differences in MHC type I molecules and the antigens they present. MHC I are expressed on almost all cells.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 3 points4 points  (0 children)

Lacking from this explanation, though, is an indication of why reprograming MHC molecules can potentially attenuate GvHD.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 1 point2 points  (0 children)

In the case of viral infection, 'self' peptides aren't replaced by viral peptides. Rather, viral peptides are also loaded into MHC and presented at the cell surface.

And for MHC polymorphisms, the polymorphic MHC peptides are generating only a very, very small portion of the immunogenic response. Most of the response comes because different peptides i) sample different portions of the proteome and ii) the peptides loaded into different MHCs vary in length (and some other properties). These differences drive the bulk of the immunogenic reaction.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 5 points6 points  (0 children)

That's a holy grail of transplantation biology - find a therapy that reduces the patient's risk of GvHD while preserving the capacity of the graft to initiate an anti-tumor response.

I would predict that the strategy described by the authors would result in an attenuated anti-tumor response. If so, this will not be used in most oncology settings.

Scientists reprogram so-called MHC molecules, responsible for displaying antigens, to match donor to receipient for Transplantation surgery, using CRISPR/Cas9. After breakthroughs in allogenic iPSC treatment of AMD in Japan, this technique could help prevent GvHD in allogeneic transplantation. by Royddit_com in science

[–]SirT6 14 points15 points  (0 children)

GvHD is graft versus host disease. This occurs when T-cells derived from a bone marrow transplant recognize the new body they are implanted in as foreign and begin to attack it.

This most often happens because the grafted T-cells and the new host have mismatched MHC alleles.

MHC, the major histocompatibility complex, is a part of a pathway that is constitutively sampling proteins made by the cell and then loading them into a receptor (the MHC) where they can be "analyzed" by T-cells. During development, T-cells are trained to ignore all normal human proteins presented in this way. So if they see something new, they assume it is cancer/a virus/pathogen and kill the cell presenting the peptide.

MHC mismatch is important because through a quirk of evolution, different humans have different MHC proteins. Functionally, they do the same basic task, but they do it in different ways. One MHC type, for instance may only show peptides in nine amino acid segments. Another may show them in ten amino acid segments. In this context of GvHD, this is important because a T-cell that was trained on ten amino acid segments will recognize all nine amino acid segments as foreign and try to kill cells presenting peptides this way.

I tried to simplify this as much as possible, but you can dig much deeper into this topic if you are interested. Many factors beyond imple MHC matching go into whether a transplant will work and whether GvHD will ensue. The tl;dr would be immunology is hard but sweet.

It's that time of year again. We just published our 2016 Transparency Report. by spez in announcements

[–]SirT6 0 points1 point  (0 children)

Wow. Very cool - I never would have even thought to implement something like that on Netflix.

It's that time of year again. We just published our 2016 Transparency Report. by spez in announcements

[–]SirT6 9 points10 points  (0 children)

Needs to be peer reviewed and published in a reputable journal 😜

It's that time of year again. We just published our 2016 Transparency Report. by spez in announcements

[–]SirT6 29 points30 points  (0 children)

Credit goes to u/glr123 for having the idea and for coding the bot. A number of other r/science mods have played important roles in establishing parameters for what the bot should recognize, monitoring the bot's outputs and deciding how to handle this information.

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