I used VSCode as my default IDE so the switch was very natural.
I am working on machine learning in bio, and many of the tools, methods, and data structures are very domain specific. Even so, the agent feature is good enough that for most tasks, I can describe the functionality I want and it gets me 80% of the way there. I pay $20 a month for Cursor and it has quickly become the last subscription I would cancel.
Not 100% — live share doesn’t work for realtime paired programming. There is an open source alternative extension that works though, albeit even more buggy and slightly more clunky than the official Microsoft extension.
devcontainers extension was a year out of date up until the last month or something? sorry, this is from memory, but definitely not 100% compatibility.
Strongly disagree. My son is going to be born into a county with an active measles outbreak caused entirely by misinformation and stupidity. We can’t vaccinate until 6 months. Absolutely preventable. Zero arguments against vaccination for measles. Public health is everyone’s problem.
> Absolutely preventable. Zero arguments against vaccination for measles. Public health is everyone’s problem
I sympathise with you. I'm not seeing a solution outside suspending this moronic minority's right to make decisions for themselves and their children or leaving the parts of the country that have chosen this fate to their own devices. In that framing, the question is which is leakier: suspending civil rights or literal viruses?
While it’s easy to blame anti-vaxxers, a large contributor are people who saw waning immunity and immigrants from countries with poor immunization rates.
Even with 100% immunization youll still have outbreaks occasionally as people come in and out and the vaccine just doesn’t “take” in some small percentage.
I am curious about the same thing. I worked as a ML engineer for several years and have a couple of degrees in the field. Skimming over the document, I recognized almost everything but I would not be able to recall many of these topics if asked without context, although at one time I might have been able to.
What are others' general level of recall for this stuff? Am I a charlatan who never was very good at math or is it just expected that you will forget these things in time if you're not using them regularly?
There's a decent amount of cynicism in the comments, which I understand. I think this is a really cool and novel study, though.
Historically, cancer was treated with therapies that are toxic to all cells, relying on the fact that cancer cells divide quickly and are unable to handle stress as well as normal cells (chemotherapy, radiation).
The last couple of decades we've seen many targeted cancer therapies. These drugs generally inhibit the activity of a specific protein that lets the cancer cells grow (e.g. EGFR inhibitors) or prevents the immune system from killing the cancer cells (e.g. PDL1 inhibitors).
This mechanism is way more interesting. The gene BCL6 is usually turned on in immune cells when they are mutating to recognize foreign invaders. This process involves lots of DNA damage and stress, but BCL6 stops the cells from dying and is therefore important for normal immune function. Unfortunately, this makes BCL6 a gene that is often co-opted in cancer cells to help them survive.
The method cleverly exploits the oncogenic function of BCL6 not by inhibiting it, but by turning it into a guide, enabling the delivery of activating machinery to the targets of BCL6 and reversing the inhibitory effects on cell death.
The whole field of targeted degraders, molecular glues, and heterobifunctional molecules is a growing area of interest in cancer research.
This comment hits the nail on the head. Another big consideration with the technology in this paper that hasn't been mentioned in this thread is that it opens up a huge range of possibilities for targeting "undruggable" protein targets. Most drugs are small molecules that bind to sites an (relatively much larger) proteins, thereby getting in the way of their function. Unfortunately the vast majority of proteins do not have a site that can be bound by a molecule in a way that 1) has high affinity, 2) has high specificity (doesn't bind to other proteins) and 3) actually abolishes the protein's activity.
With "induced proximity" approaches like the one in this study, all you need is a molecule that binds the target protein somewhere. This idea has been validated extensively in the field of "targeted protein degradation", where a target protein and an E3 ubiquitin ligase, a protein that recruits the cell's native proteolysis machinery, are recruited to each other. The target protein doesn't have to be inactivated by the therapeutic molecule because the proteolysis machinery destroys it, so requirement #3 from above is effectively removed.
The molecule in this study does something similar to targeted protein degradation, but this time using a protein that effects gene expression instead of one that recruits proteolysis machinery. The article focuses on the fact that cancers are addicted to BCL6. This is an important innovation in the study and an active area of research (another example at [1]), but leaves out the fact that these induced proximity platforms are much more generalizable than traditional small molecules because it's the proteins that they recruit that do all the work rather than the molecules themselves. This study goes a long way to validate this principle, pioneered by targeted protein degradation and PROTACs, and shows that it can be applied broadly.
I haven’t read the paper yet but the news article seemed a bit, meeh.
BCL-2 inhibitors, mainly Venetoclax, is used in cancer therapies quite often which also triggers cell apoptosis and it’s very effective. It was also designed to target B-cell related cancers, but it found to be so effective that FDA approved it to be used in primary cases of Acute Myeloid Leukemia. So, killing cancer with triggerring apoptosis is very well known. I think the novel part might be the two protein, so it is probably more targeted for metabolic activities… but yeah didn’t read the paper yet.
Anyways, for the side effects a major one could be Tumor Lysis Syndrome (TLS). Basically, if you apoptose the cancer cells super fast, the molecules from those cells spread everywhere and it becomes toxic for the patient. This is at least the case for Venetoclax.
Cancerous cells are fairly diverse across individuals, or even within a single individual, and many biological treatments require precise sequencing of the tumor DNA of that individual patient to adjust and work. In some cancers, there is a nasty "Russian roulette" effect in play, where a certain treatment may be extremely efficient (in practice a cure, even though oncologists avoid that word) in people with a certain mutation and totally useless in others, even though from the macroscopic point of view, their tumors look the same.
Then, basically, each cancer, cancer cells should be sequenced, then based on the type of cell and DNA sequencing, we have a list of "tools" to deliver payload to those very cells (without delivering such payload to sane cells, ofc)?
In practice, we can only make use of some known mutations. Not just for delivering chemicals, but also for "teaching" the immune system to attack such cells, which, once it is able to recognize them, it will do vigorously.
Let's hope that this catalogue will grow until it covers at least all the typical cases.
My understanding is that even though immunotherapy's mechanism may seem more natural than chemotherapy and radiation, and in some instances may be a magic bullet, up-regulating the immune system can have serious consequences. I remember reading about a clinical trial showing similar progression free survival but increased grade 4-5 toxicities (requiring hospitalization or being fatal). My assumption was that these are autoimmune conditions that are aggravated in some of the patient population.
oop talked about mechanism, so we can't know side effects here. someone will publish a new drug that relies on this mechanism, and then they will check the side effects of the specific drug on cells, rats, or other experimental species.
It’s fairly common for private companies to have non-transferability clauses for both options and stock.
IANAL, but this sounds pretty standard and I doubt OP will be able to fight the legitimacy of the claim. Re: a forward sale, sounds like it blatantly violates the agreement and would expose OP to some obvious risks. Agreed OP should talk to a lawyer.
Is anyone else surprised by OP’s indignation? Startups are risky, options aren’t a guaranteed payday, exercising is gamble, and liquidity events are regulated for a reason. Sometimes you lose money. Have we forgotten this?
> Startups are risky, options aren’t a guaranteed payday, exercising is gamble, and liquidity events are regulated for a reason. Sometimes you lose money. Have we forgotten this?
I spent around $100k to purchase this stock and paid tax on the gain. They are now worth millions of dollars on the open market, but the company will not allow me to sell them... I understand it's risky, but at this point they just aren't letting me get a payday...
> They are now worth millions of dollars on the open market
No, they aren't, because there is no open market for private company shares.
You have a private company valuation you can base the share price on, but that's it. And even that is typically based on black magic and accounting tricks since, at the risk of repeating myself, there's no open market in which those shares are trading and thus no method for price discovery.
And any theoretical transfer of ownership would occur in a private transaction or on a private marketplace that specializes in matching buyers and sellers in private company shares.
<chopped this bit out since the dead horse is beaten>
Edit: And to provide something a bit more constructive, here: unless some lawyer comes up with something clever--and certainly it's worth exploring your options--my bet is your only real move is to just hold onto those shares and wait.
Eventually there may be a liquidity event--probably an acquisition--and hopefully you'll net out positive. You basically bought a 100k lottery ticket. I suspect all you can do now is move on and hope it pays off.
>> They are now worth millions of dollars on the open market
> No, they aren't, because there is no open market for private company shares.
I do have offers to purchase my stock. In a bygone era, I could simply instruct the company to transfer my shares and broker the transaction myself.
I get what you're saying though.
The purpose of my post here isn't to complain so much as inquire about people who have executed forward sales and are willing to speak about the experience. From what I understand, this is being done quite a bit and I guess the idea is that company never has to find out...
> I spent around $100k to purchase this stock and paid tax on the gain.
Yes, that’s how options exercises work.
> They are now worth millions of dollars on the open market, but the company will not allow me to sell them...
But you were prrsumably aware of that limitation when you entered into the agreement under which you purchased them (if you dispute that that is the agreement you agreed to, thebmn, definitely, you need a lawyer.) So, even insofar as you describe the “open market” accurately, that market isn’t open to you.
> I understand it's risky, but at this point they just aren't letting me get a payday...
Perhaps not. Are they obligated to let you get a payday? Is it in their interests to do so? If neither of those is the case, why do you expect they would?
Trying to take this in a more constructive direction though: what happens if I go bankrupt? I have no idea how all of that works, but I can imagine a judge saying this limited transferability clause isn't legal or something. How can I go bankrupt when I kinda-sorta own millions of dollars worth of company stock?
> Trying to take this in a more constructive direction though: what happens if I go bankrupt?
If that is an important real consideration, you should consult an attorney; my general understanding, whixh yoi should not rely on, is that non-transferrability clauses mostly are not enforceable in bankruptcy, with some particular exceptions.
It's a theoretical question, and I'm not trying to be annoying here, just genuinely curious.
If this stock is non-transferable, does that mean it has an inherent value of zero? Does that mean I can file for bankruptcy and still keep the stock? I just feel like the nature of property rights in this country doesn't square with transferability restrictions. :shrug:
> For example, in a U.S. case, Associated Grocers of Maine, Inc., the Bankruptcy Court for the District of Maine ruled that federal bankruptcy law preempted a restriction on the transfer of the debtor's stock, thereby permitting a sale of the stock free and clear of the restriction.
> If this stock is non-transferable, does that mean it has an inherent value of zero?
The value of stock comes from the claim against the assets in the case of dissolution, the ability ot sell in the market just enables one to realize that value without the company dissolving in whole or (as by issuing dividends) in part.
This is not true. Some cancers are caused by viruses. Many oncogenes were initially discovered in viruses. But the majority of tumors are definitely not caused by viruses.
This was a hypothesis in the field for a number of years, and has been disproven. If you want a good overview of the history of cancer, I recommend “The Emperor of All Maladies” by Siddhartha Mukherjee.
* that science has proven the majority of tumors are definitely not caused by viruses.
could you kindly share a few of the studies disproving the majority case? in particular, i'm interested in the sample size and diversity powering these refutations.
to clarify, i'm not saying you're wrong. simply seeking to learn more.
my research has uncovered misleading conclusions based on studies with flawed methodology/logic. for example, this study [0] states, "epstein-barr virus plays no role in the tumorigenesis of small-cell carcinoma of the lung." based on a sample size of 23.
I'm not saying that there aren't other mechanisms (sustained inflammation, etc) that might contribute to the aetiology of some other cancers, even without clear viral integrations, but we can state pretty strongly that many cancers are not directly caused by cancer.
Sure, a 2020 study from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, looking for viral evidence in thousands of tumor genomes and transcriptomes[0]. Part of a massive, cross-institutional effort.
"Searching large pan-cancer genome and whole-transcriptome datasets enabled the identification of a high percentage of virus-associated cases (16%)".
based on ebv studies i have read (happy to share if you want), some papers use flawed methodologies for viral detection (e.g., checking for limited set of viral proteins).
to reiterate, we mostly agree, except i adopt a more restrained stance: the conclusion supported by science is that viral causation is provable in some cancers -- but not a majority.
which is a subtle, but crucial difference, from concluding that viruses do not cause a majority of cancers (much higher bar IMO).
for instance, past studies may have used flawed detection methods or extrapolated from unrepresentative samples like the lung cancer study shared earlier.
Sure, absence of evidence is not evidence of absence. But these PCAWG results have been discussed to death since they were published, and its pretty sound science.
You could also take the bottom-up approach of asking what DOES cause certain cancers. That's a whole other discussion.
Considering all this, if you still have doubts that "viruses do not cause the majority of cancers", I think you will likely be skeptical about pretty much all of biology.
i do think flawed studies are more common than people realize (e.g., lung cancer one linked above, ebv ones referenced).
i wouldn’t say i’m skeptical.
more willing to say “unsure” until the underlying methods and logic have been validated.
based on personal anecdotes only, scientists seem too rushed and overworked, forced by our broken system to cite without verifying logic or methods first.
to be honest, part of me hopes you are right and all the virus science is sound. it would save me a lot of time and money.
thanks for sharing your thoughts and providing resources to check out.
Tl;dr from the article, they used flow cytometry to quantify different cell populations in the blood, and noted that the proportion of CD8+ T cells (cytotoxic, the kind of immune cells that recognize and kill cancer cells, among other things) increases after exercise and returns to baseline 30 min later.
Claiming that this supports the idea that cancer patients could benefit* from exercise is a pretty big overstep of scientific inference.
There's simply not enough here to say if it's just an interesting artefact of exercise or an actual helpful response. It may be a useful starting point for further studies, but the comment section is frightening in how quickly people are jumping on this to confirm their biases on health and disease.
If we were to extrapolate from this logic, we would wrongly conclude that people with autoimmune diseases should never exercise.
If they return to baseline in 30 minutes, was there even an increase to begin with? What is the mean lifetime of those cytotoxic cells, and would one expect such a decay in so short a time?
I understand that it is a very dynamic system but 30 minutes seems very short to me. So is the return a die-off or where do they go?
The lifespan of T cells varies from months to years (memory T cells). T cell development begins in the bone marrow and continues in the lymphatic tissue and periphery. During their lifespan, these cells circulate in the body and migrate based on chemical gradients.
What happens when you exercise? Blood pressure increases, blood vessels dilate. I honestly would not be surprised if what these authors observed was just existing T cells in capillary beds being kicked up into circulation, only to adhere and begin to intravasate a couple minutes later.
That seems to translate well to my layman intuition. Would there actually be a health benefit with respect to cancer (or pathogenic disease) from this "T cell migration"? Is there a sense in which migration of T cells spread information to different parts of the body or is this just not how it works?
Just finished assignment 2 of cs224n[1], which has you derive gradients and implement word2vec. I thought it was a pretty good exercise. You could read the glove paper and try implementing that as well.
Knowing how to step through backpropagation in a neural network gets you pretty far in conceptual understanding of a lot of architectures. Imo there’s no substitute for writing out the gradients by hand to make sure you get what’s going on, if only in a toy example.
I have had friends tell me forecasts like this with complete confidence. Just curious- what industry? What info do you know that convinced you to believe this? Eager to hear whatever you're willing to share.
Look at the last 12 months. Multiple sub-sectors of public equities down >80%. Do you think people saw that coming? If they believed it enough to bet on it, the opportunity to profit was huge. That's to say nothing of private valuations.
And yet every startup with some traction and a proof of concept PMF seems confident an exit is on the horizon. Maybe for parts of the last decade this was true, but now...
I used VSCode as my default IDE so the switch was very natural.
I am working on machine learning in bio, and many of the tools, methods, and data structures are very domain specific. Even so, the agent feature is good enough that for most tasks, I can describe the functionality I want and it gets me 80% of the way there. I pay $20 a month for Cursor and it has quickly become the last subscription I would cancel.