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Samira Farouk, MD, MS, FASN
@ssfarouk
, 11 tweets, 9 min read Read on Twitter
1/ Continuing the #immunosuppression #tweetorial series...@MedTweetorials

Today's player: #mTORi, mammalian/mechanistic target of rapamcyin inhibitors

Rapamcyin was @US_FDA approved for #kidneytransplant in 2003.

It was isolated from a soil sample from which island in 1975?
2/ Meet mTOR, a phosphatidylinositol 3-kinase (PI3)-related kinase (adds a phos). mTOR adds a phosphoryl group to serine/threonine residues.

It is a key component of the complexes mTORC1 and mTORC 2 - which regulate processes including cell growth, proliferation, and survival.
3/ mTOR inhibition blocks "Signal 3" of #TCell activation - reducing cytokine dependent cell proliferation and activation.

Take a look at all 3 signals below 👇🏽

nejm.org/doi/full/10.10…
4/ Rapamycin (sirolimus) and everolimus are macrolides & 1st generation mTORi.

Rapamycin was isolated in 1975 from a soil bacterium, S. hygrocopicus, on Easter Island (Rapa Nui). Anti-fungal properties were described before immunosuppressive activity.

nejm.org/doi/full/10.10…
5/ Like tacrolimus, rapamycin binds FK binding protein. Instead of inhibiting calcineurin, the main action of the rapamycin-FKBP complex is 🛑 of mTORC1 (with some effect on mTORC2)

For 🦕 fans, an important component of the mTORC1 complex is RAPTOR

ncbi.nlm.nih.gov/pubmed/20234352
6/ Worth mentioning now that mTOR signaling pathways are COMPLEX! Do you see mTORC1 & RAPTOR? 🦖🦕🦖 @CellSignal

cellsignal.jp/contents/scien…
7/ As dysregulation of #mTOR pathways has been shown in numerous malignancies, it is not surprising that post-transplant patients have a lower incidence of malignancy when treated with an mTORi - no matter if it is used with or without a #CNI.

journals.plos.org/plosone/articl…
8/ What about the kidneys?

#CNI nephrotoxicity may be enhanced mTORi-mediated inhibition of P-glycoprotein efflux of CNI ➡️ increased intracellular CNI concentrations.

mTORi have been also shown to induce or aggravate proteinuria 😭

ncbi.nlm.nih.gov/pubmed/22137729
9/ The lungs are not spared...another feared complications of mTORi use is interstitial lung disease #ILD

hindawi.com/journals/jtran…

radiopaedia.org/cases/drug-ind… @Radiopaedia
10/ To keep this #tweetorial short & sweet, here's a graphic to summarize adverse effects of #mTORi

ncbi.nlm.nih.gov/pubmed/30868436
11/ In summary:

1. #mTOR signaling pathways are complex
2. Rapamycin (mTORi) binds to FKBP ➡️ inhibit mTORC1 🛑 #Tcell proliferation/activation
3. The good: Immunosuppression, anti-cancer
4. The bad: hyperTG, ILD, DM, HTN, proteinuria, CNI tox

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Related hashtags

#immunosuppression #tweetorial #mTORi #kidneytransplant #Tcell #mTOR #CNI #ILD

More from @ssfarouk see all

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Samira Farouk, MD, MS, FASN
@ssfarouk
1/

Here's another #immunosuppression #tweetorial. This time, a focus on mycophenolic acid (MPA). #MMF #Mycophenolate

The main mechanism of action of MPA is inhibition of which of the following:
2/ Let's meet the players. Mycophenolate mofetil (MMF, left) is a prodrug of MPA while mycophenolate sodium (MPS, right) is an enteric-coated salt of MPA.

MMF administration releases MPA in the stomach, while mycophenolate sodium (MPS) releases it in the small intestine.
3/ MPA is often referred to as an "anti-metabolite", which means a substance that interrupts a metabolic process within cells.

The process that MPA interrupts here: PURINE SYNTHESIS
Read 9 tweets
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Samira Farouk, MD, MS, FASN
@ssfarouk
1/
A brief #tweetorial on the calcineurin inhibitors #CNI and their toxicities. Let's start with a quick poll.

Which of the following describes the main mechanism of action of #CNI?
2/

On to the mechanism of #CNI. Calcineurin inhibitors bind to the "immunophiliins" for which they are named. Cyclosporine (CsA) binds cyclophilin and tacrolimius(FK506) binds FK binding protein.

The CNI-immunophilin complex is the superhero which then inhibits calcineurin
3/
 Meet calcineurin, whose superpower is a calcium-dependent PHOSPHATASE: enzyme that uses H2O to cleave phosphoric acid into a phosphate ion and an alcohol (read: removes phos)

Normally, calcineurin dephosphorylates NFAT - allowing it to freely swim into the nucleus.
Read 10 tweets

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Nick Ingraham
@Nick_Ingraham
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Pauli Ohukainen
@POhukainen
#Tweetorial time! 🚨 Looks like there’s another misconception about #cholesterol and #atherosclerosis making rounds again. This one has to do with the process of #LDL particles entering the arterial wall. So gather round friends and let me science the s*it out of this 🤓 (1/24)
For background, here’s a widely cited series of figures by Nakashima et al. (2007). They performed autopsies on 38 people aged 7-49, who died of non-#cardiovascular causes (2/24)
ncbi.nlm.nih.gov/pubmed/17303781
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Read 25 tweets
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Scott Gottlieb, M.D.
@SGottliebFDA
Today’s #FDA #SundayTweetorial is personal. I look back at what we've accomplished at FDA to advance innovations to benefit patients, promote policies to protect consumers, and address public health challenges during the two years I've shared these experiences with my colleagues.
I was truly fortunate to arrive at #FDA at an inflection point in medicine, health, and science – during a time when new discoveries, made right down to the molecular level, offer the potential to transform health, protect consumers, and cure disease in fundamentally novel ways.
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Read 46 tweets
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Scott Gottlieb, M.D.
@SGottliebFDA
Compounded drugs serve an important medical need for patients who can’t use an FDA-approved medication. In today’s #FDA #SUNDAYTWEETORIAL, I’m going to talk about what FDA is doing to preserve access to appropriately compounded drugs while protecting patients from serious risks.
In drug compounding, ingredients are combined, mixed or altered to create a sterile or non-sterile medication tailored to a patient - such as those with an allergy who need a drug without a certain dye or a child who can’t swallow a tablet and needs medicine in a liquid form.
But compounded drugs, which aren’t FDA-approved, may pose serious risks if not produced properly, potentially resulting in contamination or medications that do not possess the strength, quality or purity they are supposed to have bit.ly/2G7IpjB
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Scott Gottlieb, M.D.
@SGottliebFDA
For this week’s #FDA #SUNDAYTWEETORIAL, I want to talk about #biosimilars. It's a critical moment in the development of the market for these products. We'll advance major policy changes in this area soon. Enhancing biosimilar competition is a key to reducing overall drug spending
Congress charged #FDA with maintaining balance between encouraging and rewarding innovation and facilitating robust and timely competition. We must ensure that this balance exists across the spectrum of pharma products; from small molecules to more complex products to biologics
Biologics play a key role in treating many serious illnesses like cancer or genetic disorders. While they offer many therapeutic benefits, biologics often come at high expense. While <2% of US patients use biologics, they represent ~40% of total Rx spend bit.ly/2EsWDOr
Read 19 tweets
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Scott Gottlieb, M.D.
@SGottliebFDA
SUNDAY TWEETORIAL: For those who follow me, you’ll know that the topic of this week’s #FDA Sunday Tweetorial is among the most critical: food safety. FDA takes our responsibility for assuring safety of the food supply seriously, and food safety is one of my highest priorities
The US has one of the safest food supplies in the world. #FDA continues to make sure the abundant, diverse, and complex global food supply is safe, and that food imported into the US is held to the same standards as food produced at home
FDA uses several tools to better identify foodborne illnesses and outbreaks. These advances in technology protect consumers, so let’s look deeper at some of these groundbreaking tools and their public health benefit
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