If You're Tired, Read This. Please.

If you're tired, read this. Please.

Hey, amigo.

It’s hard, isn’t it?

I know. Sometimes, it’s painful too.

Sometimes you really wanna give up, throw the books, hide in a corner and never take any action again.

I understand. I really do.

But I’m not here to collaborate on the pity party. I’m not going to join in on the groaning challenge, or complain about how hard it is.

First, get this though. It is hard. I won’t lie. It is worth groaning upon. Maybe one or two pity parties are affordable too.

Yet, there’s a pact we’ve make together, and I’d like to remind you of it, before we talk further. New here? We call it the Shush Pact.

Don’t do it. Don’t complain. Don’t whine. Don’t give in so easily. Don’t.

Go ahead. Make the pact. Now.

Go on! Do it.

Tell yourself, today’s hard. Tiring. But, I won’t give in to this. Nor will I complain and moan about it, and waste my energy. Not today, Amelia! Today’s not that day.

Done?

Sure?

Okay. Let’s go.

If you’re tired.

If you’re tired, exhausted of the hustle, and almost at your breaking point, I want you to remember how MUCH this means to you.

I don’t know what’s driving you nuts. Maybe it’s a math problem you just can’t crack. The presentation due next week that isn’t up to the mark. Maybe it’s 3 gigantic books you have to read up on before your next theology class. Perhaps your business has come at a standstill, and you can’t get it to grow. Or maybe you hate your job, and have finally, bravely, taken the step to work the 6 hours after you come home on building the art portfolio of your dreams, because in your heart, you’ve always been an artist. Maybe you’re juggling three jobs and working late nights to save enough money to catch the dream bus.

I don’t know. But I do know that it means a lot to you.

I know how passionate you’re about this, and how much it means to you.

And yet, you’re tired.

You’re tired of it!

You’re tired of studying so much. You’re tired of DMing every business in town, to have none reply back. You’re tired of working so much, handling so much, and you feel like you haven’t had a break since you were a kid. You’re tired of the pressure, you’re tired of the hustle and you just… wanna quit.

Don’t.

Please.

It’s hard to be positive in this dark, numb time and you’re starting to work mechanically, questioning your existence with every hour, but I have to make you understand! You’re worth this! You’re so worthy of this, my love.

Please don’t quit.

Don’t give up. It’s hard, but seal those lips, and trust your gut. I know you can make it. You’ve worked so hard for this! You’ve struggled so much, invested in so many weeks of work, and right now, at your breaking point, I want you to realise that you’re worthy. Of getting that grade, that degree, finding a job you love, your crazy ambitions of opening a flower shop… everything! All of it!

You deserve the world.

Listen to me. Open your ear and listen: you’re tired, yes. But here’s the truth. You’re not done yet.

You’ve got so much to prove to yourself. So many identities to identify yourself with. Exams to slay, jobs to get, money to make, dreams to build, people to meet and love to spread.

Listen. There’s more to this. There’s more to YOU.

Don’t give up now.

Not today.

You’re not done yet.

Tiredness will pass, and I want you to just try pushing through this. Just try. You’ll see you’re so capable of winning and it’ll blow your mind when you look back and realise the strength you truly possessed because you were able to push through.

Winning is your blood. It’s your oxygen.

Tiredness is a toxic. A poison. You’re not tired, you just think you are. When the human brain says it’s done, it’s actually got 70% more to give.

Don’t forget. Your legacy awaits. If this truly means everything to you, if you’ve already put in hundreds of hours of work into this, PUSH THROUGH! You’ve got to, because your future self deserves a better life! Don’t let them tell you that you need a break. A Hawaii vacation. They’ll say you’re getting nowhere and urge you to take a break.

You and me, we both know you don’t need one. You just needed a reminder of your capabilities.

And I’ve given you that now.

Just remember, you’re not done yet.

So fuck tiredness.

Go win.

Ugh #1

Fucking up when you knew you would is so funny.

Your depression is there to tell you you are a worthless piece of shit who has to fuck other people up.

But you are ready.

Anxiety already prepared you for fucking up. 😝 you knew that would happen

Anti-cancer drugs - DNA targeting

Include alkylating agents, intercalating agents, and chain cutters.

Alkylating agents

Highly electrophilic species, looking for nucleophilic sites to attack, and forming covalent bonds to bases in DNA

Prevent replication and transcription

Toxic side effects (e.g. alkylation of proteins)

Bind in the major groove of DNA

Both types cross-link DNA by covalently bonding to nitrogen of base pairs.

Binding of nucleic acid bases results in miscoding and distortion.

Distortion of DNA prevents excision by HMG proteins – permanent damage.

Transcription and replication prevented, tumour growth slows.

Two electrophilic sites on an anticancer drug can cause interstrand and intrastrand cross-linking.

Preference for 1,2-GG or 1,2-GC linkage sites, with interstrand or intrastrand linkage, is dictated by drug chemical structure

Other linkage adducts are possible. Eg 1,3-GCG, 1,2-GA.

Monofunctional adducts are also possible

Chlormethine (a nitrogen mustard)

Chlormethine is highly reactive, toxic side effects.

Lead compound for many less toxic mustard derivatives.

Methyl (CH3 ) group has positive inductive effect – promotes loss of chloride – see mechanism

Less toxic chlormethine analogues:

Melphalan: e- withdrawing ring lowers Nu strength of N, less reactive drug, less side effects, less toxic. Mimics PhAla, carried into cells by transport proteins.

Uracil mustard: Uracil ring is e-withdrawing, less reactive alkylating agent. Mimics a nucleic acid base, concentrates in fast growing cells.

Cyclophosphamide: Most commonly used alkylating agent, Non-toxic, orally active prodrug. Acrolein associated with toxicity.

Busulfan: Causes interstrand cross-linking. Sulphonate group withdraws electrons, adjacent carbon subject to Nu attack by DNA bases.

Dacarbazine – A diazine: Prodrug activated by oxidation in liver, decomposes to form methyldiazonium ion. Alkylates guanine groups

INTERCALATING AGENTS

Aminoacridines eg Proflavine

Antibiotics - Dactinomycin

Extra binding to sugar phosphate backbone by cyclic peptide

Intercalates via minor groove of DNA double helix

Prevents unwinding of DNA double helix

Blocks transcription, blocks DNA-dependent RNA polymerase

Anthracyclines eg Doxorubicin (adriamycin)

Extra binding to sugar phosphate backbone by NH3 Planar rings and Anthracyclines eg Doxorubicin (adriamycin)

Intercalates via major groove of DNA double helix

A topoisomerase poison - blocks action of topoisomerase II by stabilising DNA-enzyme complex

CHAIN CUTTERS

Calicheamicin g1 I antitumour agent

Nucleophilic attack on trisulphide chain starts a rearrangement process.

This interacts with DNA to generate a DNA diradical, which reacts with oxygen, resulting in chain cutting.

Bleomycins (BLM)

Highly active head, neck, testicular cancer (Hodgkin lymphoma)

Single and double-strand cleavage of DNA with several reduced metal ions and O2 , Fe(II) highest in vivo activity.

Three regions -

bithiazole DNA binding domain (DBD) locks BLM into the minor groove,

carbohydrate domain (CHD) H-bonds BLM to sugar phosphate of DNA

metal binding domain (MBD) bonds to Fe(II)

Mechanism

A reaction with hydrogen peroxide gives Fe(III) and hydroxyl radicals which abstract H atoms and cut the DNA chain.

Fe2+ + H2O2 Fe3+ + OH. + OH− Fenton mechanism

Lungs and skin have low levels of BLM hydrolase - higher sensitivity and toxicity. Pneumonitis occurs in about 10% of patients, progresses to pulmonary fibrosis. Over-expressed in malignant cells, resistance to bleomycin

Summary of Anti-Tumour Specificity for DNA

Major groove alkylators

GG interstrand - N-mustards, nitrosoureas.

GG intrastrand - methanesulphonates.

GC-interstrand - nitrosoureas, triazines.

Minor groove intercalators

GG interstrand – anthracyclines.

GC-interstrand – actinomycins, acridines.

Minor groove chain cutters

GC or GT intrastrand – bleomycins

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medintp

5 years ago

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medintp

6 years ago

I’m so happy for you!

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medintp

6 years ago

Ugh #2

Pros and cons of having a mental illness

Pros: nothing anybody ever tells you can really really get to you.

- professor telling you you are stupid and worthless. Dude dont worry ive been telling that myself for years

- grades telling you you suck and you should rethink being a student. Yeah yeah i know i should

- family telling you you are weird and tiring. Tell me something i dont know

Cons: literally everything else

tag yourself: note takers edition

Takes digital notes: tries to keep up with notetaking but eventually falls behind after 5 lectures, drinks coffee only to stay awake, tries the aesthetic of drinking hot tea while taking notes but fails, wakes up early once in a century and thinks they’ve reached their peak, wants a better organisation system but is too tired, worries about studyspo for 2 mins before saying fuck it

Takes handwritten notes: have really nice handwriting but they don’t realise it themselves, headers!! are!! everything!!, have a love-hate relationship with taking notes, studying only when they feel like it, only writes key points as notes because everything else is too much, drifts off a lot while notetaking to daydream

Doesn’t take notes: wears hoodies like 90% of the time, tries really hard to take care of themselves but it’s hard™, hair in a bun because hairstyles?? too much work, yells “fuck the system” as they study more than anyone else, studies straight from books and Knows what to study, can’t study for more than 45 mins at a time, is productive nonetheless, kinda exhausted but still carrying on

Takes notes only in class: take! notes! in! class! save! your! time! fuckers!, in a constant state of chaos but they’ll never admit, have a great relationship with the professors, raises eyebrows at everything it’s a Brand, likes lunch dates a lot, hates people who talk during lectures, wants a vacation already

Is still rotating between handwriting and typed notes: “did we have any homework” at the beginning of every lecture, is really friendly but tired of everything, likes laughing at stupid jokes, hates studying but is still doing it anyway, Major Chaos™, everyone loves them but they don’t have a lot of close friends, will fight for their friends to death, the mood: they’re just being their ball of anxiety, let them live thnx