sarahconstantin
Posts
Wiki Contributions
links 10/29/2024: https://roamresearch.com/#/app/srcpublic/page/10-29-2024
- https://www.theguardian.com/news/2024/oct/29/acute-psychosis-inner-voices-avatar-therapy-psychiatry a therapist acting out the voices in your head might be an effective treatment for psychosis
- https://www.futurehouse.org/research-announcements/wikicrow SOTA (?) paper summarization from FutureHouse
"weak benevolence isn't fake": https://roamresearch.com/#/app/srcpublic/page/ic5Xitb70
- there's a class of statements that go like:
- "fair-weather friends" who are only nice to you when it's easy for them, are not true friends at all
- if you don't have the courage/determination to do the right thing when it's difficult, you never cared about doing the right thing at all
- if you sometimes engage in motivated cognition or are sometimes intellectually lazy/sloppy, then you don't really care about truth at all
- if you "mean well" but don't put in the work to ensure that you're actually making a positive difference, then your supposed "well-meaning" intentions were fake all along
- I can see why people have these views.
- if you actually need help when you're in trouble, then "fair-weather friends" are no use to you
- if you're relying on someone to accomplish something, it's not enough for them to "mean well", they have to deliver effectively, and they have to do so consistently. otherwise you can't count on them.
- if you are in an environment where people constantly declare good intentions or "well-meaning" attitudes, but most of these people are not people you can count on, you will find yourself caring a lot about how to filter out the "posers" and "virtue signalers" and find out who's true-blue, high-integrity, and reliable.
- but I think it's literally false and sometimes harmful to treat "weak"/unreliable good intentions as absolutely worthless.
- not all failures are failures to care enough/try hard enough/be brave enough/etc.
- sometimes people legitimately lack needed skills, knowledge, or resources!
- "either I can count on you to successfully achieve the desired outcome, or you never really cared at all" is a long way from true.
- even the more reasonable, "either you take what I consider to be due/appropriate measures to make sure you deliver, or you never really cared at all" isn't always true either!
- some people don't know how to do what you consider to be due/appropriate measures
- some people care some, but not enough to do everything you consider necessary
- sometimes you have your own biases about what's important, and you really want to see people demonstrate a certain form of "showing they care" otherwise you'll consider them negligent, but that's not actually the most effective way to increase their success rate
- almost everyone has a finite amount of effort they're willing to put into things, and a finite amount of cost they're willing to pay. that doesn't mean you need to dismiss the help they are willing and able to provide.
- as an extreme example, do you dismiss everybody as "insufficiently committed" if they're not willing to die for the cause? or do you accept graciously if all they do is donate $50?
- "they only help if it's fun/trendy/easy/etc" -- ok, that can be disappointing, but is it possible you should just make it fun/trendy/easy/etc? or just keep their name on file in case a situation ever comes up where it is fun/trendy/easy and they'll be helpful then?
- it's harmful to apply this attitude to yourself, saying "oh I failed at this, or I didn't put enough effort in to ensure a good outcome, so I must literally not care about ideals/ethics/truth/other people."
- like...you do care any amount. you did, in fact, mean well.
- you may have lacked skill;
- you may have not been putting in enough effort;
- or maybe you care somewhat but not as much as you care about something else
- but it's probably not accurate or healthy to take a maximally-cynical view of yourself where you have no "noble" motives at all, just because you also have "ignoble" motives (like laziness, cowardice, vanity, hedonism, spite, etc).
- if you have a flicker of a "good intention" to help people, make the world a better place, accomplish something cool, etc, you want to nurture it, not stomp it out as "probably fake".
- your "good intentions" are real and genuinely good, even if you haven't always followed through on them, even if you haven't always succeeded in pursuing them.
- you don't deserve "credit" for good intentions equal to the "credit" for actually doing a good thing, but you do deserve any credit at all.
- basic behavioral "shaping" -- to get from zero to a complex behavior, you have to reward very incremental simple steps in the right direction.
- e.g. if you wish you were "nicer to people", you may have to pat yourself on the back for doing any small acts of kindness, even really "easy" and "trivial" ones, and notice & make part of your self-concept any inclinations you have to be warm or helpful.
- "I mean well and I'm trying" has to become a sentence you can say with a straight face. and your good intentions will outpace your skills so you have to give yourself some credit for them.
- like...you do care any amount. you did, in fact, mean well.
- it may be net-harmful to create a social environment where people believe their "good intentions" will be met with intense suspicion.
- it's legitimately hard to prove that you have done a good thing, particularly if what you're doing is ambitious and long-term.
- if people have the experience of meaning well and trying to do good but constantly being suspected of insincerity (or nefarious motives), this can actually shift their self-concept from "would-be hero" to "self-identified villain"
- which is bad, generally
- at best, identifying as a villain doesn't make you actually do anything unethical, but it makes you less effective, because you preemptively "brace" for hostility from others instead of confidently attracting allies
- at worst, it makes you lean into legitimately villainous behavior
- which is bad, generally
- OTOH, skepticism is valuable, including skepticism of people's motives.
- but it can be undesirable when someone is placed in a "no-win situation", where from their perspective "no matter what I do, nobody will believe that I mean well, or give me any credit for my good intentions."
- if you appreciate people for their good intentions, sometimes that can be a means to encourage them to do more. it's not a guarantee, but it can be a starting point for building rapport and starting to persuade. people often want to live up to your good opinion of them.
- not all failures are failures to care enough/try hard enough/be brave enough/etc.
2links 10/28/2024: https://roamresearch.com/#/app/srcpublic/page/10-28-2024
- Vincent deVita, chemotherapy pioneer, reflecting on how cancer research has changed (and become more bureaucratic) since the 1960s:
- https://www.nature.com/articles/nrclinonc.2009.51
- https://aacrjournals.org/cancerres/article/68/21/8643/541799/A-History-of-Cancer-Chemotherapy
- https://cancerhistoryproject.com/article/vince-devita-on-the-history-of-chemotherapy/
- https://www.yalemedicine.org/podcasts/cancer-answers-the-history-of-chemotherapy-july-6-2008
- https://www.sciencefriday.com/articles/where-we-are-in-the-war-on-cancer/
- https://vincenttdevitajrmdoncancer.blogspot.com/
- Michael Levin has his own team (of ~20) at Tufts working on morphogenetics: https://allencenter.tufts.edu/
- with a $10M founding grant from the Allen Foundation, which I expect will not be enough to complete this research program. https://alleninstitute.org/news/the-paul-g-allen-frontiers-group-announces-allen-discovery-center-at-tufts-university/
links 10/25/24: https://roamresearch.com/#/app/srcpublic/page/10-25-2024
- https://theoryandpractice.org/2024/10/Yes,%20we%20did%20discover%20the%20Higgs!/ CERN's statistical methods are good actually. compare this to any other stats-heavy area of natural or social science and they come out impressively rigorous. blinded data analyses? whoa.
- https://en.m.wikipedia.org/wiki/Siege_engine a siege engine is any machine you use against the city you're besieging -- from towers to catapults to flamethrowers to artillery.
- there's a new field of "pan-cancer" where you make (mostly molbio) comparisons across cancers, including vulnerability screens where you use CRISPR or RNAi to knock down each gene and see which ones kill the cancer cells when absent.
- https://aacrjournals.org/clincancerres/article/24/9/2182/81290/Pan-Cancer-Molecular-Classes-Transcending-Tumor representative paper
- https://www.nature.com/articles/s41467-019-13528-0 you can also do it with the proteome
- https://www.nature.com/articles/s41422-020-0355-0 you can single-cell it
- https://www.science.org/doi/10.1126/science.abe6474 you can profile the TILs cell by cell
- https://link.springer.com/content/pdf/10.1186/s13059-023-03020-w.pdf CRISPR and RNAi both have their strengths and weaknesses but if you look at the overlap there are still a bunch of "pan-essential" genes that all cancers need to survive. (do healthy cells also need those, or are they good therapeutic targets? we just don't know.)
- https://www.researchgate.net/profile/Yize-Li/publication/354641293_Moving_pan-cancer_studies_from_basic_research_toward_the_clinic/links/615f5d570bf51d4817512465/Moving-pan-cancer-studies-from-basic-research-toward-the-clinic.pdf?_sg%5B0%5D=started_experiment_milestone&_sg%5B1%5D=started_experiment_milestone&origin=journalDetail by "towards the clinic" we mean "very gingerly", apparently
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30656-5 when you target pan-essential genes you are in the chemo zone, where by default the therapeutic index is low (kills cancer AND healthy cells) and you need to put more work in to handling toxicity.
- tumors -- most tumors -- get coated with IgG, much more than other tissues. is this a systemic defense against cancer or a tumor-secreted IgG? hard to say.
- https://www.cell.com/cell/pdf/S0092-8674(22)00192-1.pdf mostly ovarian carcinoma but they also compare to a bunch of other tumor types
- https://www.mdpi.com/1422-0067/22/21/11597 could be tumor-derived
- https://www.nature.com/articles/srep05088.pdf this is Sanford Simon -- endogenous IgG concentrates around mouse tumors of many types
- James Watson's vision for cancer research -- this is what he originally became a "controversial figure" for, before the race thing. https://royalsocietypublishing.org/doi/full/10.1098/rsob.120144
- basically, this is a few things:
- a call to work harder dammit and treat it like a true war on cancer, not a sedate and bureaucratic academic field
- a call for more pan-cancer RNAi vulnerability screens
- a call to focus on transcription factors as targets, particularly things like Myc and BRD4 that are particularly involved in the transition to metastasis -- we don't yet have any good drug therapies that work well on metastatic cancers
- transcription factors are obviously causally upstream of what makes cancer cancer -- its invasiveness, its metastatic potential, its evasion of immune surveillance, etc
- they are hard to drug though, because they're in the nucleus, not on the cell surface. but we can start to do hard things now!
- cell surface growth factors (think EGFR) are the easiest to target but the associated drugs have unimpressive clinical effects in most patients because targeting growth factors only slows growth, it doesn't kill cancer cells. usually just slightly delays the inevitable.
- a statement of his redox hobbyhorse -- ROS is good, ROS is how the body fights cancer, etc.
- not sure how to operationalize this as a strategy. it might, as it turns out, be redundant with immunotherapy.
- a couple specific targets/mechanisms he thinks deserve more attention -- apparently the circadian regulator PER2 is a tumor suppressor. i'm always down for more attention to circadian stuff.
- basically, this is a few things:
- the Halifax Project researched the hypothesis that low-dose combinations of environmental carcinogens might synergistically increase cancer risk:
- https://en.wikipedia.org/wiki/CpG_oligodeoxynucleotide this is the inflammatory molecule on bacteria that's the reason bacterial infections sometimes cause complete regressions of very difficult tumors (like sarcoma -- we have no drugs for sarcoma! it's either surgery or death!). fortunately the immunooncology people are On It and researching this as an immunostimulant.
- if you've heard of "Coley Toxins", they're kind of an alt-med thing with a tantalizing grain of truth -- but we don't need to inject bacteria into tumors any more, we know how they work, we can replicate the effect with well-defined compounds now.
- https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00221-0?rss=yes#mmc1 this is AOH1996, the mindblowingly selective new pan-cancer drug candidate.
- basically this is using the same principle as old-fashioned chemo -- hit it in the DNA replication -- but with a new target, and with modern structural-biology-based rational drug design to hit the cancer version of the target rather than the healthy-cell type.
- would I have guessed there was room for optimism here a priori? no way.
- but apparently we have not explored this space sufficiently. now try it with AlphaFold.
- https://www.science.org/content/blog-post/new-mode-cancer-treatment and Derek Lowe is impressed.
- basically this is using the same principle as old-fashioned chemo -- hit it in the DNA replication -- but with a new target, and with modern structural-biology-based rational drug design to hit the cancer version of the target rather than the healthy-cell type.
- https://www.nature.com/articles/s41419-021-04468-z inducible caspase 9 allows conditional apoptosis. it's incredibly powerful. unfortunately it doesn't always work and this raises drug resistance concerns.
- I haven't yet seen many examples of "put the iCasp9 in the cell if-and-only-if the cell has some molecular marker" but that's the obvious place to go.
- you can kinda reduce the drug resistance thing by putting a promotor to increase iCasp9 expression. buddy if this is where we are in 2022 i'm going to predict there is a LOT of potential value in continuing to work out the kinks in this system. get in on the ground floor!
- https://en.wikipedia.org/wiki/Proteolysis_targeting_chimera a PROTAC is "this protein? kill it." uses the ubiquitin system.
- sadly, the Warburg Effect is not as cool as I once thought.
- glucose deprivation is just not that deadly across tumor lines: https://www.sciencedirect.com/science/article/abs/pii/S0899900720300319
- https://pmc.ncbi.nlm.nih.gov/articles/PMC3237863/ i mean, 2DG + metformin might do a thing?
- https://pmc.ncbi.nlm.nih.gov/articles/PMC5095922/#BST-2016-0094C20 yeah...it's not what you think.
- https://www.sciencedirect.com/science/article/abs/pii/S0006291X0302504X if you actually measure what % of ATP comes from glycolysis, cancers cover a wide range, and the distribution overlaps substantially with the distribution of healthy cells. glycolysis dominance is not a distinguishing characteristic of all or even most cancers.
- https://journals.sagepub.com/doi/pdf/10.2310/7290.2015.00021 heavy glucose uptake is enough of a thing for PET imaging to be used clinically though
- are cancer cells selectively vulnerable to mechanical stress? kinda, but also it sometimes stimulates them to go metastatic so beware.
- https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/elsc.201900154 vibrate em and they apoptose
- https://www.sciencedirect.com/science/article/abs/pii/S0168365915302819 just mcfuckin spin some tiny magnets around in your brain tumor. apparently it works in rodents but aaaaaah
- https://www.sciencedirect.com/science/article/pii/S0167488913003224 laminar but not oscillatory shear stress kills em? no non-cancer comparison
- https://www.sciencedirect.com/science/article/pii/S2949907024000585 vibrations to kill prostate cancer? no non-cancer comparison
- https://pubs.rsc.org/en/content/articlelanding/2015/nr/c5nr03518j/unauth magnetic particle vibration against renal cancer? no non-cancer comparison
- https://www.nature.com/articles/s41557-023-01383-y.epdf?sharing_token=jICYt2mKBMQ0GsetiWodv9RgN0jAjWel9jnR3ZoTv0PPtLuduvirY9e9lvJJx5Q_iJTfP9UCvLlXVOkNBly5J-gi3DlHLxMYWqsmEJBOrH0s7RbtQm1UREc3FbrfF2vDNLzTfS250KEAwBdVsczhxamax0pSp4TP23jM_ehG703560use7dJ6hnsaVLpnXsWU1n14UplHLGvaXHsJ444z96C3IEcjmnjMZvijAgkKsQ%3D&tracking_referrer=www.genengnews.com "vibronic molecular jackhammers"? still no non-cancer comparison, but at least they tried some mice
- https://www.nature.com/articles/s41413-020-00111-3 vibration to reduce metastatic potential of breast cancer cells. no non-cancer comparison.
- https://www.science.org/doi/10.1126/science.adp7206 gently ultrasound the tumor to sensitize it to chemo or induce an immune anti-tumor response.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10068349/ Piezo1 might be involved in an apoptotic response to mechanical stress?
- https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/elsc.201900154 vibrate some cancer cells and they go apoptotic but not necrotic. no non-cancer comparison.
- https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4703126 more ultrasound, including in vivo, Piezo1 mediated.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8274378/ mechanical stress is also a natural feature of cancer -- tumors get more rigid and experience pressure. in fact this stress can be a trigger for increased proliferation or metastasis, so watch out!
- https://pmc.ncbi.nlm.nih.gov/articles/PMC5992512/ oops shear stress can promote metastasis
- https://www.cell.com/biophysj/fulltext/S0006-3495(22)00367-8 substrate stiffness promotes invasion and metastasis
- https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.955595/full "mechanoptosis" (mechanical pressure causing cancer apoptosis)
- https://elifesciences.org/for-the-press/12916d1e/migrating-through-small-spaces-makes-cancer-cells-more-aggressive squish cancer cells through tight spaces (eg on a microfluidic chip) and you get more invasive/metastatic potential
- are cancer cells selectively vulnerable to electrical stress? also kinda yeah
- https://www.mdpi.com/2072-6694/13/9/2283 "tumor treating fields", just an oscillating electric field, are actually an approved therapy in glioblastoma that extends life a few months. (not saying much though...glioblastoma is so deadly that it's easy mode from an FDA standpoint)
- of course you can just kill *cells* with pulsed electric fields, cancer or not: https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.02-0859fje
- https://jamanetwork.com/journals/jama/article-abstract/2475446 more electrical fields for glioblastoma
- https://aacrjournals.org/cancerres/article/64/9/3288/517864/Disruption-of-cancer-Cell-Replication-by ah this actually IS a differential effect in tumor vs. non cancer cell lines. plus in vivo, in mice.
- i don't even know man. somebody who knows physics explain this. little nanoelectrodes with some chemical functionalization kill cancer cells? "quantum biological tunneling?" https://www.nature.com/articles/s41565-023-01496-y
- https://nyulangone.org/news/coping-mechanism-suggests-new-way-make-cancer-cells-more-vulnerable-chemotherapies "stress granules" as a form of chemo resistance, driven by KRAS?
- https://www.nature.com/articles/s41420-022-01202-2 cancer can be selectively vulnerable to proteotoxic stress. they're worse at expressing heat shock proteins.
- https://www.researchgate.net/profile/Pietro-Taverna-2/publication/221748736_The_Novel_Oral_Hsp90_Inhibitor_NVP-HSP990_Exhibits_Potent_and_Broad-spectrum_Antitumor_Activities_In_Vitro_and_In_Vivo/links/56d0a18708ae059e375d4920/The-Novel-Oral-Hsp90-Inhibitor-NVP-HSP990-Exhibits-Potent-and-Broad-spectrum-Antitumor-Activities-In-Vitro-and-In-Vivo.pdf heat shock protein inhibitor reduces tumor growth in many cell lines
- cancer cells have depolarized membranes -- you can literally distinguish them from healthy cells by voltage alone.
- this is a Michael Levin thing. https://pmc.ncbi.nlm.nih.gov/articles/PMC3528107/ you can give a frog a tumor -- or make the tumor go away -- through manipulating voltage alone! it does not matter what ion channel you use, it's about the voltage.
- more Michael Levin https://pmc.ncbi.nlm.nih.gov/articles/PMC4267524/#R250
- apparently Wnt signaling is involved. https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP278661 in general you get alterations in membrane voltage potential by changing the behavior of ion channels
- https://jamanetwork.com/journals/jamasurgery/article-abstract/591620#google_vignette depolarization occurs early in the development of colon cancer in mice exposed to a carcinogen.
- https://www.medigraphic.com/pdfs/hepato/ah-2017/ah172s.pdf cancer stem cells are depolarized relative to normal stem cells
- https://www.nature.com/articles/s41598-021-92951-0.pdf here's math modeling if you care.
- https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2013.00185/full a lot of ion channels are involved
- https://karger.com/tbi/article-abstract/15/3/147/299607/Electrical-Potential-Measurements-in-Human-Breast breast cancers vs non-cancer tumors show up differently on an external volt meter!!!!
- literally, you can try this at home! stick a voltmeter across your boob!
- https://aacrjournals.org/cancerres/article/40/6/1830/484668/Cellular-Potentials-of-Normal-and-cancerous cancerous cells have lower membrane potential than their healthy counterparts
- https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1974.tb26808.x even in non-cancer cells membrane potential correlates negatively with proliferation
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9652252/ cancer membrane potentials also fluctuate more than healthy cell membrane potentials
- https://aacrjournals.org/amjcancer/article/32/2/240/679553/Bio-Electric-Properties-of-Cancer-Resistant-and going back to 1938, if you put a volt meter across a mouse's body you can tell the ones with tumors from the ones without. it is literally that simple and has been known that long.
- this is a Michael Levin thing. https://pmc.ncbi.nlm.nih.gov/articles/PMC3528107/ you can give a frog a tumor -- or make the tumor go away -- through manipulating voltage alone! it does not matter what ion channel you use, it's about the voltage.
- something in (some of?) the neutrophils in (some) humans and a cancer-resistant strain of mice can kill cancer, including when transferred. a Zheng Cui research program.
- my take is, he's not an immunologist and modern methods could elucidate the specific clonal population a LOT better than this, but I like the thought process.
- https://www.cell.com/heliyon/fulltext/S2405-8440(17)31693-6 they did some infusions from young blood donors into 3 patients with advanced metastatic cancer got a bunch of tumor necrosis and a cytokine release syndrome. all died within 3 months though.
- https://link.springer.com/article/10.1186/1475-2867-11-26 healthy controls' leukocytes are better at killing cancer in vitro than cancer patients'. this is as expected.
- https://link.springer.com/article/10.1186/1471-2407-10-179 SR/CR cancer resistant mice seem to need the leukocytes to physically home to the cancer cells. again, not news; neutrophils infiltrate tumors.
- Cui has been beating this drum since before immunotherapy was cool, so let's not blame him too much, but we do very much know this bit independently
- eg https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01710/full -- sometimes neutrophils promote cancer actually!
- eg https://www.cell.com/cell-reports/pdfExtended/S2211-1247(22)00984-6 we can determine the "good guy" neutrophil subpopulation that infiltrates tumors and promotes an anti-tumor immune response: it's HLA-DR+CD80+CD86+ICAM1+PD-L1-. in metastasis these guys become PD-L1+ and immunosuppressive.
- so like...the secret to replicating Zheng Cui's miracle mice...might be nivolumab?? don't get me wrong it's a good drug but this is anticlimactic.
- a great example of the mundanity of success
- https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0059995&type=printable the Danes do not replicate quite as much cancer resistance from SR/CR mice as Cui's lab
- https://www.pnas.org/doi/pdf/10.1073/pnas.0602382103 whatever the SR/CR mice are doing, you can transfer it to other mice and get cancer resistance. Lloyd J. Old is a coauthor!!!
- https://pmc.ncbi.nlm.nih.gov/articles/PMC4544930/ independent description of anti-tumor neutrophils extracted from mice
- https://www.sciencedirect.com/science/article/abs/pii/S0171298510000033 more evidence of anti-tumor granulocytes(which include neutrophils)
- https://www.tandfonline.com/doi/abs/10.4161/cbt.7.9.6417 cancer patients' granulocytes are less active
- more Zheng Cui: cancer cells are negatively charged, such that positively charged nanoparticles can detect them VERY specifically. this is legit IMO.
- https://link.springer.com/article/10.1007/s41048-018-0080-0 works on 22 different cancer cell lines. absolutely no affinity for healthy cells, quite a bit for all cancer cells.
- https://www.thno.org/v06p1887.htm
- can't do it in vivo though
- https://link.springer.com/article/10.1186/s12951-019-0491-1?fromPaywallRec=false detects four CTCs per 1 mL blood!!!!
- https://www.science.org/doi/10.1126/science.abm5551#supplementary-materials sadly these guys think positive nanoparticles are too toxic to use as treatments -- the entire paper is about negative nanoparticles, which do sometimes add to the tumor uptake of chemotherapies
- https://www.sciencedirect.com/science/article/abs/pii/S1879625715000413 oncolytic virus BHV1 kills cancer cells in a variety of tumor types?
- https://www.nature.com/articles/s41598-023-47478-x.pdf broad-spectrum metastasis suppressing compounds targeting a lncRNA. scary-big chemical structures though.
- https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2010.01834.x broad spectrum effectiveness of a survivin inhibitor + tumor regressions in vivo.
- survivin is pan-essential, i got a good feeling about this
- https://aacrjournals.org/cancerimmunolres/article/2/6/510/467367/VISTA-Is-a-Novel-Broad-Spectrum-Negative VISTA is another negative checkpoint regulator like PD1 and CTLA4 (which are both major successful drug targets)
- https://www.science.org/doi/abs/10.1126/scitranslmed.3007646 alkylphosphocholine is a type of lipid especially present in cancer cells, across cancer types, via lipid rafts. a synthetic analog has preferential uptake in basically all rodent & human tumors. usable for imaging and radiotherapy.
- https://www.nature.com/articles/s41568-023-00554-w Sanford Simon's personal journey against fibrolamellar hepatocellular carcinoma
- they found a fusion transcript and a corresponding fusion protein -- the root cause
- they did the reasonable thing: screen a compound library against tumor samples.
- one hit is napabucasin, usually known as a STAT3 inhibitor (but that's not the mechanism here) but somebody owns it
- another was irinotecan. and navitoclax...but navitoclax has platelet toxicity
- irinotecan + a BcrX PROTAC is being investigated though
- or you can just. shRNA the fusion transcript. that's a thing you can do now.
- apparently Elana wanted to do that in 2013 but her dad said "pshaw RNA breaks down in the body." now Spinraza is a thing (antisense oligonucleotide.) not to mention the mRNA world. truly these are the days of miracle and wonder.
- https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00126/full redox balance is tricky, since cancers are both more prone to ROS and prone to develop coping mechanisms to regain redox balance.
- https://www.nature.com/articles/cdd2017180 there's nothing like TP53. mutated in 50-60% of cancers. the tumor suppressor gene par excellence.
- https://nousresearch.com/wp-content/uploads/2024/08/Hermes-3-Technical-Report.pdf the Hermes 3 model is fine-tuned to be more responsive to prompts, such that prompt engineering suffices for "in-character" writing style (which IME does not work on most Instruct models)
links 10/23/24:
https://roamresearch.com/#/app/srcpublic/page/10-23-2024
- https://eukaryotewritesblog.com/2024/10/21/i-got-dysentery-so-you-dont-have-to/ personal experience at a human challenge trial, by the excellent Georgia Ray
- https://catherineshannon.substack.com/p/the-male-mind-cannot-comprehend-the
- I...guess this isn't wrong, but it's a kind of Take I've never been able to relate to myself. Maybe it's because I found Legit True Love at age 22, but I've never had that feeling of "oh no the men around me are too weak-willed" (not in my neck of the woods they're not!) or "ew they're too interested in going to the gym" (gym rats are fine? it's a hobby that makes you good-looking, I'm on board with this) or "they're not attentive and considerate enough" (often a valid complaint, but typically I'm the one who's too hyperfocused on my own work & interests) or "they're too show-offy" (yeah it's irritating in excess but a little bit of show-off energy is enlivening).
- Look: you like Tony Soprano because he's competent and lives by a code? But you don't like it when a real-life guy is too competitive, intense, or off doing his own thing? I'm sorry, but that's not how things work.
- Tony Soprano can be light-hearted and always have time for the women around him because he is a fictional character. In real life, being good at stuff takes work and is sometimes stressful.
- My husband is, in fact, very close to this "Tony Soprano" ideal -- assertive, considerate, has "boyish charm", lives by a "code", is competent at lots of everyday-life things but isn't too busy for me -- and I guarantee you would not have thought to date him because he's also nerdy and argumentative and wouldn't fit in with the yuppie crowd.
- Also like. This male archetype is a guy who fixes things for you and protects you and makes you feel good. In real life? Those guys get sad that they're expected to give, give, give and nobody cares about their feelings. I haven't watched The Sopranos but my understanding is that Tony is in therapy because the strain of this life is getting to him. This article doesn't seem to have a lot of empathy with what it's like to actually be Tony...and you probably should, if you want to marry him.
- https://fas.org/publication/the-magic-laptop-thought-experiment/ from Tom Kalil, a classic: how to think about making big dreams real.
- https://paulgraham.com/yahoo.html Paul Graham's business case studies!
- https://substack.com/home/post/p-150520088 a celebratory reflection on the recent Progress Conference. Yes, it was that good.
- https://en.m.wikipedia.org/wiki/Hecuba in some tellings (not Homer's), Hecuba turns into a dog from grief at the death of her son.
- https://www.librariesforthefuture.bio/p/lff
- a framework for thinking about aging: "1st gen" is delaying aging, which is where the field started (age1, metformin, rapamycin), while "2nd gen" is pausing (stasis), repairing (reprogramming), or replacing (transplanting), cells/tissues. 2nd gen usually uses less mature technologies (eg cell therapy, regenerative medicine), but may have a bigger and faster effect size.
- "function, feeling, and survival" are the endpoints that matter.
- biomarkers are noisy and speculative early proxies that we merely hope will translate to a truly healthier life for the elderly. apply skepticism.
- https://substack.com/home/post/p-143303463 I always like what Maxim Raginsky has to say. you can't do AI without bumping into the philosophy of how to interpret what it's doing.
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I don't think it was articulated quite right -- it's more negative than my overall stance (I wrote it when unhappy) and a little too short-termist.
I do still believe that the future is unpredictable, that we should not try to "constrain" or "bind" all of humanity forever using authoritarian means, and that there are many many fates worse than death and we should not destroy everything we love for "brute" survival.
And, also, I feel that transience is normal and only a bit sad. It's good to save lives, but mortality is pretty "priced in" to my sense of how the world works. It's good to work on things that you hope will live beyond you, but Dark Ages and collapses are similarly "priced in" as normal for me. Sara Teasdale: "You say there is no love, my love, unless it lasts for aye; Ah folly, there are episodes far better than the play!" If our days are as a passing shadow, that's not that bad; we're used to it.
I worry that people who are not ok with transience may turn themselves into monsters so they can still "win" -- even though the meaning of "winning" is so changed it isn't worth it any more.
20
I thought about manually deleting them all but I don't feel like it.
1- https://milton.host.dartmouth.edu/reading_room/pl/book_1/text.shtml [[John Milton]]'s Paradise Lost, annotated online [[poetry]]
- https://darioamodei.com/machines-of-loving-grace [[AI]] [[biotech]] [[Dario Amodei]] spends about half of this document talking about AI for bio, and I think it's the most credible "bull case" yet written for AI being radically transformative in the biomedical sphere.
- one caveat is that I think if we're imagining a future with brain mapping, regeneration of macroscopic brain tissue loss, and understanding what brains are doing well enough to know why neurological abnormalities at the cell level produce the psychiatric or cognitive symptoms they do...then we probably can do brain uploading! it's really weird to single out this one piece as pie-in-the-sky science fiction when you're already imagining a lot of similarly ambitious things as achievable.
- https://venture.angellist.com/eli-dourado/syndicate [[tech industry]] when [[Eli Dourado]] picks startups, they're at least not boring! i haven't vetted the technical viability of any of these, but he claims to do a lot of that sort of numbers-in-spreadsheets work.
- https://forum.effectivealtruism.org/topics/shapley-values [[EA]] [[economics]] how do you assign credit (in a principled fashion) to an outcome that multiple people contributed to? Shapley values! It seems extremely hard to calculate in practice, and subject to contentious judgment calls about the assumptions you make, but maybe it's an improvement over raw handwaving.
- https://gwern.net/maze [[Gwern Branwen]] digs up the "Mr. Young" studying maze-running techniques in [[Richard Feynman]]'s "Cargo Cult Science" speech. His name wasn't Young but Quin Fischer Curtis, and he was part of a psychology research program at UMich that published little and had little influence on the outside world, and so was "rebooted" and forgotten. Impressive detective work, though not a story with a very satisfying "moral".
- https://en.m.wikipedia.org/wiki/Cary_Elwes [[celebrities]] [[Cary Elwes]] had an ancestor who was [[Charles Dickens]]' inspiration for Ebenezer Scrooge!
- https://feministkilljoys.com/2015/06/25/against-students/ [[politics]] an old essay by [[Sara Ahmed]] in defense of trigger warnings in the classroom and in general against the accusations that "students these days" are oversensitive and illiberal.
- She's doing an interesting thing here that I haven't wrapped my head around. She's not making the positive case "students today are NOT oversensitive or illiberal" or "trigger warnings are beneficial," even though she seems to believe both those things. she's more calling into question "why has this complaint become a common talking point? what unstated assumptions does it perpetuate?" I am not sure whether this is a valid approach that's alternate to the forms of argument I'm more used to, or a sign of weakness (a thing she's doing only because she cannot make the positive case for the opposite of what her opponents claim.)
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080017/ [[cancer]][[medicine]] [[biology]] cancer preventatives are an emerging field
- NSAIDS and omega-3 fatty acids prevent 95% of tumors in a tumor-prone mouse strain?!
- also we're targeting [[STAT3]] now?! that's a thing we're doing.
- ([[STAT3]] is a major oncogene but it's a transcription factor, it lives in the cytoplasm and the nucleus, this is not easy to target with small molecules like a cell surface protein.)
- https://en.m.wikipedia.org/wiki/CLARITY [[biotech]] make a tissue sample transparent so you can make 3D microscopic imaging, with contrast from immunostaining or DNA/RNA labels
- https://distill.pub/2020/circuits/frequency-edges/ [[AI]] [[neuroscience]] a type of neuron in vision neural nets, the "high-low frequency detector", has recently also been found to be a thing in literal mouse brain neurons (h/t [[Dario Amodei]]) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055119/
- https://mosaicmagazine.com/essay/israel-zionism/2024/10/the-failed-concepts-that-brought-israel-to-october-7/ [[politics]][[Israel]][[war]] an informative and sober view on "what went wrong" leading up to Oct 7
- tl;dr: Hamas consistently wants to destroy Israel and commit violence against Israelis, they say so repeatedly, and there was never going to be a long-term possibility of living peacefully side-by-side with them; Netanyahu is a tough talker but kind of a procrastinator who's kicked the can down the road on national security issues for his entire career; catering to settlers is not in the best interests of Israel as a whole (they provoke violence) but they are an unduly powerful voting bloc; Palestinian misery is real but has been institutionalized by the structure of the Gazan state and the UN which prevents any investment into a real local economy; the "peace process" is doomed because Israel keeps offering peace and the Palestinians say no to any peace that isn't the abolition of the State of Israel.
- it's pretty common for reasonable casual observers (eg in America) to see Israel/Palestine as a tragic conflict in which probably both parties are somewhat in the wrong, because that's a reasonable prior on all conflicts. The more you dig into the details, though, the more you realize that "let's live together in peace and make concessions to Palestinians as necessary" has been the mainstream Israeli position since before 1948. It's not a symmetric situation.
- [[von Economo neurons]] are spooky [[neuroscience]] https://en.wikipedia.org/wiki/Von_Economo_neuron
- only found in great apes, cetaceans, and humans
- concentrated in the [[anterior cingulate cortex]] and [[insular cortex]] which are closely related to the "sense of self" (i.e. interoception, emotional salience, and the perception that your e.g. hand is "yours" and it was "you" who moved it)
- the first to go in [[frontotemporal dementia]]
- https://www.nature.com/articles/s41467-020-14952-3 we don't know where they project to! they are so big that we haven't tracked them fully!
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953677/
- https://www.wired.com/story/lee-holloway-devastating-decline-brilliant-young-coder/ the founder of Cloudflare had [[frontotemporal dementia]] [[neurology]]
- [[frontotemporal dementia]] is maybe caused by misfolded proteins being passed around neuron-to-neuron, like prion disease! [[neurology]]
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838634/
- https://www.nature.com/articles/s41467-018-06548-9.pdf inject the bad protein into a mouse and it really does spread!
- https://researchfeatures.com/cell-cell-transmission-proteins-core-neurodegenerative-disease/ something similar might be happening in [[Alzheimer's]] as well
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943211/ the spread of [[ALS]] through the brain is consistent with cell-to-cell transmission of misfolded proteins
40
Therefore, do things you'd be in favor of having done even if the future will definitely suck. Things that are good today, next year, fifty years from now... but not like "institute theocracy to raise birth rates", which is awful today even if you think it might "save the world".
1
links 10/30/2024: https://roamresearch.com/#/app/srcpublic/page/10-30-2024