Recent submissions

Comment · 2 years ago
The mitochondria in many cancer cell behave abberantly. For example, in many cases, they can start promoting glycolysis, in process known as the Warburg effect. They're also involved in other processes such as apoptosis and cell migration. I'd hypothesize that these drugs target pathways or processes that are dysregulated in the mitochondria of those cancers.
Comment · 2 years ago
I think this is a very cynical take. Patients with gastric cancer are often in a dire situation: many of them have had their stomach removed and have generally significant difficulties with digestion, which makes consuming specific foods very difficult. The therapeutically effective doses of ATRA are also high compared to what you'd get from foods, meaning that injections are nearly the only solution for these patients. Finally, naturally derived compounds generally have the weakest patents, so if anything, we should thank these researchers for looking into the therapeutic potential of these drugs. I can assure you that few pharmaceutical companies would research this, as the commercial incentives are really weak to do so.
Comment · 2 years ago
I work in drug discovery (including in oncological indications), so it's always great to see new research with early, promising results!

To summarize the paper: some gastric cancer models are sensitive to all-trans retinoic acid (ATRA). ATRA is an active metabolite of vitamin A, and is already used clinically to treat some hematological cancers. The researchers tested the compound at several concentrations on a number of gastric cancer cell lines, where they show moderate to significant reductions in growth (from 30% to 60% reduction). Next, they tested ATRA on xenografted tumor cells on immuno-compromised mice, where they also show a reduction in tumor size. They hypothesize that ATRA exerts its effects through immuno-modulation.

Firstly, very cool, and congrats to the authors - I definitely see first evidence of the potential of ATRA to treat gastric cancer.

While I might have misunderstood some parts, I do think there are some elements that warrant precautions here: 1. we can see that some of the untreated mice also show reduction in tumor size, albeit less significant, meaning there could be issues with the cells or protocol, 2. I find it hard to conclude anything about ATRA exerting its effect through the immune system in a study of cell models and immuno-compromised mice.

Nevertheless, given the frankly poor prognosis of gastric cancer (many patients in early stages of the disease now get their stomach removed, and more often than not, these tumors metastize aggressively), and the well known safety profile of ATRA, I think the study is very welcome, and should warrant further investigation. Given the hypothesized mechanism of action, I think testing on humanized mice, using more and more distinct patient-derived cells would bring convincing proof to move ATRA forward to clinical trials.

Comment · 3 years ago
Comment · 4 years ago
It can do both - I've edited my original post to show the translation task.
Comment · 4 years ago
I just tested the model [1] using an RTX3090, trying to translate a french text I found here [2].

Some observations:

- The full translation of the 6:22 minute video takes about 22 seconds (17x real time)

- It recognizes the language by default (and did a good job to recognize it was french audio)

- MIT License [3]!

- The quality of the transcription is good, but not perfect.

- The quality of the translation (if you don't consider transcription errors as a translation error) is generally very good.

---

The transcription:

> Bonjour à tous, <error>j'suis</error> espère que vous allez bien, c''est ENTI. Et aujourd', <error>aujourd',</error> on se retrouve <error>un peu physique</error> pour parler de la termo dynamique. Vous ne vous inquiétez pas, ça va bien se passer. On va y aller ensemble, <error>être à par exemple,</error> je vous accompagne à travers une série de vidéos pour vous expliquer les principes de base en termo dynamique. Et bah, c''est parti, on va y aller tranquillement. Lidée, c''est vous puissiez comprendre la termo dynamique dans son ensemble. Donc, je vais vraiment prendre mon temps pour <error>couplisser</error> bien comprendre les notions,

The translation:

> Hello everyone, I hope you're doing well, it's NT and today we find ourselves a little physical to talk about the thermo dynamic. Don't worry, it's going well, we're going to go together and be the same. I'm going to accompany you through a series of videos to explain the basic principles in thermo dynamic. Well, let's go, <error>we're going to go quietly</error>. The idea is that you can understand the thermo dynamic <error>in sound together</error>. So I'm really going to take my time to understand the notions,

---

All in all very happy that OpenAI is publishing their models. If Stable Diffusion is any guide, people will hack some crazy things with this.

[1] https://github.com/openai/whisper [2] https://www.youtube.com/watch?v=OFLt-KL0K7Y [3] https://github.com/openai/whisper/blob/main/LICENSE

Comment · 4 years ago
Comment · 4 years ago
You can order these drugs in bulk from chemical vendors for research purposes (i.e. non-human use). Chemscene, to name just one, sells Rapamacyn at 1440 USD for 5g.

EDIT: I clearly don't recommend you buying this and taking it by the way. You're never quite sure about the purity nor about how to dose this effectively as a layperson without access to a lab. It's also possibly completely illegal, depending on your local laws.

Comment · 4 years ago
Regarding the biology:

- One of the strategies in drug development is to find a protein that is more present in people who have a disease versus those who don't (called "overexpressed" proteins), and attempt to stop this protein from work correctly (called "inhibition") by having a small molecule drugs that binds to a specific site of the protein (called the "allosteric site") in order to make it mechanically unable to execute its function.

- Cyclin-dependent protein kinases (CDKs) are a family of proteins that seem to play important roles in controlling cell division. CDK20 is overexpressed in a number of cancers.

Regarding the novelty:

- Discovering new inhibitors of proteins based on AI is definitely less novel than it was 5 years ago - while it's definitely still not the norm, AI is making big waves in the pharmaceutical industry. However, I think this might be the first publication validating the use of Alphafold for small molecule drug development, which is a major step forward.

- While it's interesting to see that it's possible to design a small-molecule CDK20 inhibitor, it's currently still very uncertain whether this is a promising drug: i. the compound could be insufficiently specific to CDK20 and could bind to other important proteins and cause unwanted and potentially serious side-effects, ii. the compound could have bad "drug-like" properties (e.g. bioaccumulate in the liver) or be toxic in some way, iii. the compound could interact badly with other drugs that cancer patients receive, iv. the compound could induce resistance (a common problem in small molecule drugs in oncology), and finally, and most importantly, v. the drug might just not be effective at treating cancer or any other diseases - it's not because a protein is over-expressed that it's the cause of a cancer, but rather a symptom of another biological dysregulation.

Still, it's definitely an achievement, and I applaud the efforts of the team and hope they'll find successful treatments.

Comment · 4 years ago
You can also say that blockchains have mechanisms that prevent a government from coercing third parties from handing over your NFTs to someone else.

I'll agree that the analogy wasn't perfect though - I added an edit for another analogy (still as imperfect as it may be).

Comment · 4 years ago
Comment · 5 years ago
I worked in the same co-working space as Wietse, Aline and Koen, the three co-founders of Citizenlab, when they were launching their service. They're a super competent team with a fantastic vision and execution - I'm excited to see this new step in their story.
Comment · 5 years ago
Comment · 5 years ago
Comment · 6 years ago
Incredibly interesting research: hopefully this pans out in human studies too.

If I understand correctly, in order to achieve this:

  1. a nanotube is created that contains a chemical compound (SHP1i) that inhibits the the "don't eat me" (antiphagocytic) signal of plaque.
  2. These nanotubes are engineered to be taken up by white blood cells.
  3. White blood cells tend to be more present at areas of inflammation (such as plaque), which in turn increases the chance that the chemical compound mentioned above will be released in areas where plaque is present.
  4. This presence of nanotube-loaded white blood cells at areas of plaque will turn off the antiphagocytic signals of all cells in this area,
  5. which induces plaque (and all other antiphagocytic cells in the area) to be removed through traditional cellular activity.
Assuming what I said above is correct, what I still don't understand:

  - How do the nanotubes bind to the white blood cells? Is there a specific technique to achieve this?
  - If I understand correctly, the chemical compound (SHP1i) removes antiphagocytic signals indiscriminately, which causes issues with toxicity of most therapies that attempt to use this technique without tightly controlling delivery (because organs might become a target of white blood cells). What happens however if a patient has other areas of inflammation? Does this exclude patients with auto-immune diseases from benefiting from these approaches, for example?
Any insight would be greatly appreciated!

Other sources: [1] https://www.nature.com/articles/s41565-019-0619-3 (Original article)

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