English Language & Usage: Multi-Layered Discourse Room

2:19 AM

@FaheemMitha Two of my uncles died of cancer. Stomach cancer, pancreatic cancer.

M.A.R.

4:07 AM

There's a bit of a . . . survivorship bias here, despite the unfortunate name. People generally no longer die from diseases that we have eradicated, or can treat, control or cure, so they die more from things we can't cure yet.

Maybe the question is whether there is an illness out there that's impossible to cure or treat, but science doesn't look at it that way

@FaheemMitha exciting stuff, isn't it? In about a decade, we'll know much more about it

@FaheemMitha no, cancer cells differ from normal cells in quite a lot of ways. They do have different antigens, but, especially the more vicious types can even stimulate specific types of immune cells not to attack the malignant tissue

The treatments already available are a lot different than just nuking everything so that maybe cancerous cells die (that was like 60 years ago), but clearly we could do a lot better. For example, cancerous cells often divide at a crazily high rate, so they uptake a lot of glucose, and can't burn that properly, like when you get sore from strenuous exercise. Acid buildup leads to a lower pH in malignant tissue.

If you administer a drug that penetrates tissue better at lower pH, or is activated by a more acidic environment, then you've kinda sorta targeted the cancer cells. More recent drugs tend to have specific portions in their molecule so that they're either (1) only activated by enzymes inside cancerous cells, at least theoretically, or (2) match a receptor on the cancerous cells, so they uptake the drug at much much higher rates.

Even more recent drugs are biological drugs that target either receptors that are very highly expressed on cancerous cells, or are unique to cancerous cells, thus either deactivating them or activating the immune system to destroy them or both. Biological drugs have a long way to go in terms of specificity, especially given their potential to be much more specific than conventional drugs.

CowperKettle

4:26 AM

And there are specialized markers that latch on to receptors on cancerous cells, and glow during an operation, so that the surgeon can remove all cancerous tissue.

Pafolacianine

Pafolacianine, sold under the brand name Cytalux, is an optical imaging agent used in fluorescence-guided surgery.The most common side effects of pafolacianine include infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity.It was approved for medical use in the United States in November 2021.Pafolacianine is a fluorescent drug that targets the folate receptor alpha (FRa). == Medical uses == Pafolacianine is indicated as an adjunct for intraoperative identification of malignant lesions in people with ovarian cancer...

M.A.R.

Unfortunately, anti-cancer drugs are still some of the most potent toxins out there, and their very job is to wreak havoc in cells. So even if a drug is 10000 times more likely to go where it's supposed to, especially more susceptible cells and individuals and cells will suffer quite a lot of damage.

Another problem is they're sometimes not as specific as we want them to. Because conventional drugs are 'small' molecules, and there are a myriad of enzymes in the body, especially in the liver, you can't guarantee that, should you design a drug that is supposed to be activated only by an enzyme inside cancerous cells, the drug won't be activated by another enzyme in the blood or especially in the liver.

This is the case for cyclophosphamide, which is AFAIK still a major drug in most cancer therapy regimens. It was designed to be activated only in cancerous cells, by an enzyme than doesn't exist in normal cells. Turns out several microsomal enzymes in the liver metabolize it, and the toxic metabolites enter the bloodstream and cause adverse effects

@M.A.R. *poison, not toxin

@CowperKettle haha awesome stuff

Ah, I love the smell of pharmacology in the morning

Well, more like pharmacotherapy.

Medicine chemistry if you wanna be fussy about it

Xanne

7:14 AM

Wordle 468 5/6

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jlliagre

7:34 AM

Wordle 468 3/6

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https://worldle.teuteuf.fr

🌎 Sept 30, 2022 🌍
🔥 4 | Avg. Guesses: 7.18
🟨🟥🟧🟥🟩 = 5

#globle

Faheem Mitha

9:03 AM

@M.A.R. The medications they gave my mother appeared to do nothing whatever. The first one they tried targeted some hormone. And supposedly the tumor was hormone sensitive, but it still didn't do anything. Then we tried some other medication, all very expensive, and that didn't seem to do anything either. Then she got fluid outside her lungs (pleural effusion or something), we took her to hospital, she picked up a secondary infection, and she died there.

There was basically no testing of the tumor in order to target it. It seemed pretty stone age to me.

Of course my mother was 83, which probably meant that some treatments were off the table.

@M.A.R. What is the meaning of 'small' in this context?

M.A.R.

10:44 AM

@FaheemMitha I'm sorry to hear that. Under physiological conditions (meaning normal, as opposed to 'pathological') estrogen makes certain cells in the breasts and endometrium proliferate (just like testosterone does in the testes). Estrogen has a receptor. There are many ways for cells to go cancerous, some of which involve this receptor. Maybe a regulatory protein has mutated and is no longer functional, so the number of estrogen receptors skyrockets. Maybe more estrogen than normal is secreted.

Rarely, postmenopausal hormone replacement therapy is the culprit. Either way, the cell receives a very strong signal to proliferate. The cell is not removed by the immune system and develops into cancerous tissue.

In these cases, and cases similar to these, if you prevent that strong signal from making the cells proliferate further, you can control the cancer. Thus, a compound that looks similar to estrogen, and thus binds the receptor, but is different enough that doesn't initiate the signal, or initiates it weakly, can help. Tamoxifen is one such drug.

As long as the clinical diagnosis is correct, there is no need for biopsy to obtain a sample of the cancer tissue, because it's an invasive and stressful process.

For geriatric patients, many types of surgery are off the table. I don't know about the restrictions in administering anti-cancer drugs. And what I said is rather general as well; different cancer types and different cases demonstrate a wide range of drug resistances, potential for metastasis etc.

@FaheemMitha conventional or 'small-molecule' drugs are drugs we're familiar with: Administered by oral, sublingual, parenteral, ophthalmic etc. routes, they have a definite chemical structure which you can find out about with a Google, they have molecular weights around 500, very rarely more than 2000 g/mol.

Faheem Mitha

11:03 AM

@M.A.R. In my mother's case, it was approximately stage 4 when discovered, so probably hopeless anyway. But my main point is that I expected a rather more high-tech approach than I in fact experienced with regard to targeting the tumor.

M.A.R.

'Conventional' is as opposed to biological, because biological drugs have different properties, and require special conditions for manufacture, storage, and administration. They're much larger molecules, and if you Google them, you'll get an inscrutable 3D model, similar to proteins. Antibodies have molecular weights of around 150000 g/mol.

Faheem Mitha

@M.A.R. Yes, it was likely that drug or something similar. I would have to dig it out of the records.

It's also possible that the latest technology is simply not available in India or is unaffordably expensive. Being under patent or whatever.

@M.A.R. It sounds like these biological drugs are also much more expensive, probably. And hard to manufacture.

M.A.R.

@FaheemMitha well, all the science is embedded in the dull-looking pill, and the exact therapy regimen. The doctor's role is monitoring the effectiveness of the therapy, managing the side effects, and smiling and looking presentable

@FaheemMitha some can be tens of thousands of dollars per vial

Of course, this knowledge is outdated. As we get better at making them, and coming up with better drugs, we can drastically reduce the costs.

CAR-T and similar methods are very new. They're rapidly improving, and they require a lot of 'field experience' before they're fully incorporated as cancer therapies

Faheem Mitha

11:19 AM

@M.A.R. It sounds like this is something that you are familiar with. It is part of your studies?

M.A.R.

@FaheemMitha just as part of an introductory course (like most other undergrad courses)

Faheem Mitha

@M.A.R. OK. If it's part of an undergrad course it can't be that cutting edge.

M.A.R.

It's I think around 7 or 8 years old

Some courses are less outdated than others

Faheem Mitha

@M.A.R. I suppose a pharmacist needs to know something about everything as part of the job. It must be a big job.

I mean, there are a ton of diseases. And some of them are really a family of diseases, like cancer.

M.A.R.

For example, immunology is exploding as a field, and the lecturers are often young and energetic, while pharmacology often deals with drugs we have known for half a century, because you need decades to really trust most drugs

@FaheemMitha oh definitely. Of course, once I specialize in a field, I'm gonna forget most of it, except the stuff I like to revisit

I'm a year four student, and I've already forgotten more than I already know, even from these introductory courses

Robusto

11:37 AM

@M.A.R. Yeah, that's the way it goes. You don't remember what you studied, only what you use.

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🟩🟩🟩🟩🟩🎉
https://worldle.teuteuf.fr

🌎 Sept 30, 2022 🌍
🔥 30 | Avg. Guesses: 6.13
🟨🟥🟥🟩 = 4

#globle

Wordle 468 3/6

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Everything is easy today.

I spoke too soon. Spelling Bee is a bitch today.

Faheem Mitha

12:13 PM

@M.A.R. Yes, if you don't use it, you lose it.

Robusto

1:11 PM

> The population of the United States had doubled in my lifetime, and the old simple world that I had known as a boy was gone. India was a reminder to me of what was in store for us all, a glimpse of the future. Trillions of dollars were spent to keep people breathing, to cure disease, and to extend human life, but nothing was being done to relieve the planet of overpopulation, the contending billions, like those ants on the rotting fruit.

Footage shows harsh conditions of military call-up centres in Russia - BBC News

►

CowperKettle

1:41 PM

Happiness galore

Faheem Mitha

@Robusto Another quote from the Theroux book?

@M.A.R. Is any work being done on preventative measures - trying to help the body stay free of tumors in the first place?

Robusto

2:05 PM

@FaheemMitha Yup.

SmokeDetector

2:40 PM

[ SmokeDetector | MS ] Few unique characters in body, no whitespace in body, repeating characters in body (255): What adverb would fit in the blank? ✏️‭ by redhead456‭ on english.SE

CowperKettle

Mongolia has said it will provide right of residence to any Russian who asks.

Whew.

M.A.R.

@FaheemMitha nothing serious AFAIK, if you mean some sort of drug or therapy that quantifiably or reliably reduces the chance of getting cancer. Well, it's complicated.

CowperKettle

Cancer often comes from faulty gene replication, and you probably can't help it. Every second, a lot of errors are made inside cells while copying/expressing genes.

M.A.R.

2:55 PM

The body makes heavy use of the oxygen atom (obviously), and oxygen has a tendency to form radicals, oxidizing agents and other sorts of very reactive compounds. Most cells in the body also contain machinery (supremolecular complexes) and molecules that convert these reactive byproducts of enzymatic activity to harmless substances like water. If they don't, and the cell is damaged, there's some possibility that it will gain the potential to become a cancerous cell.

Even then, T cells, the ones that kill, come and kill the cell (rather, tell it to go kill itself). There are dozens of checks and balances here.

CowperKettle

> I wish I had the voice of Homer
To sing of rectal carcinoma,
Which kills a lot more chaps, in fact,
Than were bumped off when Troy was sacked.
("Cancer's a funny thing", John Haldane)

M.A.R.

One of these protective molecules are the reducing agents that prevent proteins from being oxidized. Glutathione is one of the main anti-oxidants of the cell. Vitamin C, for example, helps replenish the supply of glutathione in the cells, because Vit C itself is a reducing agent. Lycopene, some carotenoids, generally all those nice anti-oxidants in plants reduce the possibility of the depletion of glutathione.

CowperKettle

Glycine + N-acetylcysteine can significantly elevate glutathione

M.A.R.

Can you say though, that tomatoes prevent cancer? It's such a loose definition of 'prevent'. The best you can do is gather some data from a population that says tomato eaters get, I dunno, prostate cancer 10 percent less.

CowperKettle

GlyNAC supplementation reverses aging hallmarks in aging humans

M.A.R.

3:01 PM

So we kinda already have all sorts of herbal supplements rife with cheap antioxidants that are marketed as preventing cancer or autoimmune diseases blah blah blah

CowperKettle

Curcumine

M.A.R.

But, to borrow your wording, it all feels very "Stone Age".

As @Cowp mentioned, one potential cause of cancer we could investigate and are investigating are gene defects.

CowperKettle

The famous p53 gene for example

> The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.[6]

And a huge host of genes that make this or that subtype of cancer aggressive, like CIC, which forms chimeric proteins with other genes to make tumors aggressive and resistant to treatment.

M.A.R.

"Gene fancy-name on chromosome 13 is linked to CLL" "Deletions at the ass area of chromosome 20 lead to susceptibility to viral infections that increase the incidence of cervical cancer"

CowperKettle

For instance, if you have a CIC-DUX4 chimeric protein in your tumor, it's curtains.

M.A.R.

3:06 PM

But these are rather . . . preliminary. Years away from suitable gene therapy, if it was ever funded

Then you have conditions that are prevalent in a large portion of the population that make one susceptible to cancer. Hyperplasia and neoplasia in one or more lobes of the thyroid gland are really common. Benign prostate hyperplasia is very common in men. Does it make any economical sense to have half the men in the world take these hypothetical cancer prevention pills? Probably not.

So the best we got is tomatoes

And will be for a long time.

CowperKettle

Maybe there will be found some highly-specific biomarkers, so you just go and take a blood test once a year to help catch a cancer at an early stage.

M.A.R.

@CowperKettle for a lot of cancer types we do know these markers.

Current guidelines indicate that all people above 50 years of age undergo colonoscopy for screening of early stages of colorectal cancer. And it works wonders, but how many people are willing to undergo that?

CowperKettle

Yes, unfortunately, colonoscopy is expensive and it takes a bit of time.

M.A.R.

No solid food for two days, and maybe some horrific laxative before the test.

I'd recommend going to the movies instead

CowperKettle

I've downloaded 100+ movies in the last 7 days.

M.A.R.

3:17 PM

Man I wish I was ready for the internet outage

CowperKettle

I don't think there will be outage in Russia until October 4, when Putin finally signs the paper to admit the four regions into Russia.

M.A.R.

These chats are one of the few sites that I reliably know aren't down

I heard the news, which regions are these?

CowperKettle

Even then, he might not drop the nuke right away, but start with an ultimatum.

@M.A.R. The four regions of Ukraine. The initial papers have been just signed 2 hours ago.

Putin gave a 40 minute speech in the Kremlin 3 hours ago

And now they are all celebrating.

M.A.R.

Too much like the Iran-Iraq war. Too, too much.

CowperKettle

M.A.R.

3:21 PM

Except the crackdown on his own citizens began earlier

@CowperKettle the mafia boss will only give a slight smile of approval

Also, I'm trying to figure out how many hands are there

It looks like Putin has three or four hands

Wait

CowperKettle

haha

M.A.R.

Seriously, I can't account for the hands there

Faheem Mitha

@M.A.R. Yes, that's what I mean.

I wasn't suggesting it would be easy or even possible.

@CowperKettle I was thinking more of the mechanisms which nip incipient tumors in the bud - kill them before they pose a real threat.

@CowperKettle Those already exist. One doctor I went to see with my mother in 2017 tried to sell them to me.

@M.A.R. Is a colonoscopy a good idea as part of a regular checkup regimen?

@CowperKettle Why?

A sudden urge to watch lots of movies offline or some other reason?

CowperKettle

3:57 PM

@FaheemMitha Venlafaxine suddenly started working on September 24, and I started enjoying movies.

But the couple days before that, my vision got worse, so I decreased the dose. So it has stopped working again.

I've read that it may increase intraocular pressure. Might be that.

Faheem Mitha

@CowperKettle You couldn't watch movies before?

CowperKettle

@FaheemMitha Yes, I got quickly tired mentally

And now I can't watch them again, because I decreased the dose from 187 to 75 mg/day

Because on 187 mg/day, my vision got worse.

Faheem Mitha

@CowperKettle Oh. So you have vision problems, or something else? My eyes are pretty bad. Congenital defect - severe myopia.

CowperKettle

@FaheemMitha Both my corneas are tranplanted, so I have some issues with vision ))

And now it's hard to read, the letters get a bit distorted.

Faheem Mitha

@CowperKettle Oh yes, I remember you mentioning that.

@CowperKettle Oh, that's awful.

CowperKettle

4:04 PM

I got an appointment with the eye doc to check my ocular pressure on October 6.

Faheem Mitha

@CowperKettle OK.

CowperKettle

It's amazing that it did not work for the first couple weeks, and just started working several days after a dose increase, and did that instantly. But if the vision deterioration is indeed caused by it, I would have to try a different drug.

Other people ramp the dose as high as 300+ mg/day, so it must be a rare side effect.

Another side effect was increased perspiration, but it was tolerable for the sake of a better mental condition.

Faheem Mitha

4:26 PM

@CowperKettle What does the drug actually do?

CowperKettle

@FaheemMitha It increases the concentration of serotonin and noradrenaline in synapses between neurons

Faheem Mitha

@CowperKettle Oh.

CowperKettle

The first-choice antidepressants increase only serotonin, and Venlafaxine increases two neurotransmitters.

Noradrenaline sometimes works to make a person more active.

Thus helping more than the usual antidepressants, but sometimes causing the loss of sleep.

So it's kind of try-and-see.

I did not expect it to work so powerfully, because a friend told me it was like eating chalk even at the dose of 300 mg/day, only with a slightly elevated mood.

Every person's reaction is different though.

Antidepressants fail to work in about 30% of patients.

tchrist

5:00 PM

@CowperKettle I believe that the central nervous stimulants unselectively increase the production of multiple neurotransmitters, but often at the cost of sleep.

Kомментарий | Алексей Навальный: Вот как должна выглядеть постпутинская Россия.

Faheem Mitha

5:41 PM

@CowperKettle I'm aware that serotonin has something to do with depression. Lack of it helps to cause depression, or something. But I don't understand how that is connected to your eyesight.

M.A.R.

@FaheemMitha regular? I don't think any clinical procedure requires endoscopy or colonscopy (which is worse) for follow-up. Colorectal cancer screening should ideally be done every 10 years or so.

@tchrist you have a family of anti-depressants called SSRIs (Selective Serotonin Reuptake Inhibitor), and another called SNRIs (Serotonin-Norepinephrine Reuptake Inhibitor). Both very commonly prescribed with more tolerable side effects.

They have a bit of specificity, due to both a mechanism I don't remember, and the arrangement of neurons that secrete these neurotransmitters

But yeah, they're overall very non-specific

You have anxiolytics that work on GABA receptors (GABA is an inhibitory neurotransmitter and decreases the overall excitability of the brain), e.g. Xanax

The abuse potential and LD50 (more specifically, how likely is an overdose to be lethal) are the main considerations regarding their adverse effects, so for most other adverse effects, there's a general attitude of "deal with it"

Mitch

6:38 PM

@M.A.R. Not exactly totally irrelevant but maybe far afield, but I just saw the movie 'Awakenings' about using L-Dopa (a dopamine precursor) to treat some very specific kinds of catatonia, and the way the movie made it seem it was like magic, these people had been 'awakened'. But at the end of the movie... well it wasn't clear but it wasn't a 'cure', they had to stop giving the L-Dopa because of side effects (?...it wasn't clear... did I say that?).

So I'm wondering what the current status of L-Dopa is.

M.A.R.

7:39 PM

@Mitch L-Dopa is unsurprisingly a dopamine agonist. The main indication is for Parkinsonism, where dopaminergic pathways in the brain have diminished activity. It's administered with carbidopa, because otherwise it would be immediately metabolized in the periphery and never reach the brain. Carbidopa is an inhibitor and substrate for peripheral DOPA decarboxylase, so levodopa can reach the brain and boost the dopamine pathways there.

AFAIK catatonia is a manifestation of some specific forms of psychoses. In psychosis, most areas of the brain have increased dopaminergic activity (alongside increased glutamatergic and serotonergic activity), but studies show some parts, for example certain nuclei in mesencephalon, if I'm not mistaken, have diminished dopaminergic activity, so levodopa is not the first choice for most (all?) types of psychoses but may be administered for catatonia

Faheem Mitha

@M.A.R. I'm not sure I follow that. Are you saying that one should not do a colonoscopy as part of a checkup?

M.A.R.

I dunno, psychosis treatment is a mess. Sometimes they try anything that works, just throw in drugs there, antidepressants, anticholinergics, lithium, etc. until something sticks

@FaheemMitha a colonoscopy is administered for diagnosis of certain diseases, and also the screening of certain chronic diseases. It's not regular though, people at most undergo colonoscopies every six months, I think

Faheem Mitha

@M.A.R. Well, a checkup might be yearly.

M.A.R.

But, say, if the doctor wanted to monitor the effectiveness of therapy at regular intervals, they would order a stool or a blood test

@FaheemMitha I don't think it's necessary, unless one has some underlying condition

Of course, this advice should be taken with three tablespoonfuls of salt.

Faheem Mitha

@M.A.R. Meaning if the patient has certain symptoms that suggest an underlying problem?

M.A.R.

7:49 PM

I'm not a medical practitioner

@FaheemMitha yep. For Crohn's disease, for example.

Faheem Mitha

@M.A.R. Ah.

@M.A.R. Well the medical practitioners here are barely practitioners.

M.A.R.

@Mitch anyway levodopa itself is kinda a safe drug, it can rarely cause severe hypotension but that's about it. Unfortunately, in chronic use, dopamine agonists can exacerbate or precipitate symptoms of psychosis, varying from certain involuntary movements to more severe behavioral issues. The reverse is also true: Dopamine antagonists are the main drugs used in psychotic disorders, and they cause or exacerbate Parkinson-like syndromes (such as nervous ticks)

Kinda like two ends of a spectrum. The reality is of course much more complicated, but it's generally like that

Well, WebMD is blocked so I can't check for other adverse effects of levodopa. I would need to consult a textbook, but that's booooring

Mitch

8:34 PM

@M.A.R. got it. the movie did hint that it can go both ways, repressing tics or exacerbating them considerably.

@M.A.R. I used the word 'catatonia'...I'm not sure if that was what they used in the movie (or original book) or if I just thought that's what it looked like from how the actors acted.

M.A.R.

8:47 PM

@Mitch well, there are several types of tics

And several slower types of involuntary movement that resemble writhing

Some types of seizures resemble tics.

I don't remember how much levodopa lowers the seizure threshold, if it does

I'm gonna watch that movie

I dunno when, but I will!

Mitch

9:16 PM

@M.A.R. It was made in 1990 from a book in the 70's about a psychiatric hospital in the 60's. It looks dated but I can't tell if it because the movie was good at the 1960's period decor, or if was just ... 1990's old.

Also, they really relied a lot on EEGs in the movie, and I realized afterwards that I haven't seen much of those lately and wonder if imaging (CT and MRI) has totally taken away the need for EEGs or at least eclipsed EEGs considerably.

Robusto

@Mitch Lotta that going around. Look at One Flew Over the Cuckoo's Nest.

SmokeDetector

9:58 PM

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M.A.R.

10:28 PM

@Mitch EEGs are still very important AFAICT. The biggest change since 50 years ago would be that most psychotic patients no longer require hospitalization for long periods, only during acute episodes due to draw withdrawal, or a suicide attempt, things like that.

We have since developed entirely new class of drugs that are more effective and with fewer side effects, but as I said we have a long way to go. Oftentimes the patients don't get better with monotherapy, so the doctor theorizes some based on the symptoms and tries another drug, then another, until one provides significant behavioral or mood improvements

There's also an aspect of psychotic disorders that has to do with cognitive impairment, which is a very active area of research. Most places in the brain become overactive, so how come the patient becomes cognitively impaired? For this cognitive impairment, a huge range of drugs can be administered, antidepressants, for example, until one drug seems to help the most

@M.A.R. *classes

EEGs are most important with regards to seizures AFAIK. Some drugs that affect the brain can worsen seizures, or even induce seizures. Monitoring that is best done with an EEG.

Seizures themselves, regardless of origin, are characterized by the appearance of EEG waves. And there are other applications too, like analyzing sleep patterns and wacky research stuff

So all in all I suppose brain activity is monitored best using EEGs.

If you don't have an anatomical change, CT or MRI won't do much good

MRI tends to be more expensive than CT, but it's a more versatile tool, often able to provide more contrast and fewer artifacts

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