Dave's Blog

“Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension” – A Synopsis

Below is a synopsis of this video “Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension”, a talk by Rubin Tuder given at the Vera Moulton Wall Center for Pulmonary Vascular Disease: Summary He has shown the first statistical correlation of perivascular inflammation with mPAP and vascular remodeling (~60 lungs from IPAH, hereditary PAH, scleroderma associated PH) despite current PH drugs: Schistosomiasis – 200 million people infected by parasite – in temperate areas like China, Brazil, Sudan, etc. 1-10% of people infected will develop PH Rather than talking about things where we don’t know what the cause/effect relationship is

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“Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy” – A Review

In the below I will be referencing and discussing quotes from the paper “Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy” by M. Talati. Basically, I’m distilling the key points that I’ve learned, summarizing them, and including any thoughts I may have. Overall it appears that the running thread through this paper is the following: Can metabolic syndrome or insulin resistance in PH cause RV dysfunction? Or is the dysfunction a result of PH? In sum, there is a dysregulation in fatty acid oxidation and glucose oxidation, with increased intracellular lipid accumulation, and an overall switch

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Pulmonary Hypertension – Atherosclerosis of the Lungs?

The passage below is from “Metabolic Regulation: A Human Perspective”, by Keith N. Frayn. I sometimes read things with a “PH filter” (and sometimes with a more global filter depending on context), and this particular passage was read with my “PH filter”… It got me thinking about the relationship of elevated non-esterified fatty acid concentrations in the plasma, adipose tissue, atherosclerosis, and if there is any connection between those and pulmonary hypertension. For some perspective, fatty acid metabolism is dysregulated in PH patients, with decreased fatty acid oxidation in myocardium and potentially increased lipid accumulation in myocardium and other tissues,

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“Role Of T-Regulatory Cells In Immune Modulation” – A Synopsis

Below is a video and synopsis of the talk “Role Of T-Regulatory Cells In Immune Modulation” by Dr. Maria Roncarolo at the Vera Moulton Wall Center for Pulmonary Vascular Disease: Summary Standard treatment of immune mediated diseases involves anti-inflammatory and immunosuppressive drugs. By doing this, you downregulate the physiological mechanism to counteract inflammation and adaptive immune responses to self-antigens. Almost all immunosuppressive drugs block T-regulatory cell induction and function. Tolerance is not a lack of immune response, it is just a different type of immune response that the immune system puts in place when we want to tolerize an antigen (self

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Thought Of The Day – Metabolism in PH, Heart v. Skeletal Muscle

Fatty acid oxidation is a slower but more energy producing process than glycolysis, but glycolysis is a much faster process. In slow twitch muscle fibers (predominantly present in marathon runners, for example), complete glucose and fatty acid oxidation occurs, but in fast twitch muscle fibers (predominantly present in sprinters, for example), glycolysis predominates.  Glycolysis is upregulated and present in the heart (myocardium), pulmonary vasculature, immune cells, and bone marrow progenitor cells in PH. Is the heart (which primarily relies on fatty acid oxidation) in PH switching to glycolysis to compensate (i.e. to build muscle to compensate for increased afterload)?  Or

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“Regulation Of Pulmonary Macrophage Function In Health And Disease” – A Synopsis

Below is a video and synopsis of the talk “Regulation Of Pulmonary Macrophage Function In Health And Disease” by Dr. Bruce Trapnell at the Vera Moulton Wall Center for Pulmonary Vascular Disease: Summary GM-CSF is important for macrophages to clear adenovirus transfections Normally, an adenovirus exits the endosome and is targets the nucleus of the cell and dumps its DNA into the nucleus In cells, GM-CSF redirects adenovirus to lysosomes via PU.1 GM-CSF receptor has pleiotropic effects on macrophages: low concentrations of GM-CSF leads to signaling that induces differentiation and survival of macrophages, and at higher concentrations, that pathway is

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The First CRISPR Trial In China

This month Chinese scientists are using the CRISPR method to target metastatic non-small cell lung cancer in patients. The specific technology employed will reprogram T-cells from the patients to remove the PD-1 gene. The PD-1 gene serves as a check on the cell’s ability to generate an immune response and thus prevents healthy cells from being attacked during an immune response. CRISPR is more specific than alternative immunotherapy methods (which are typically antibody based) because you are going into the cell’s genome and editing the genes. This makes CRISPR a potentially more effective method at targeting cancer cells, but it

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An Evolutionary Perspective On Macronutrient Profiles – A Case For Low Carb, Low Fat, and High Protein?

A thought experiment (and ONLY a thought experiment): If you think about it, when do we typically encounter something in this universe (in nature, or in the modern world) that requires a storage mechanism? Typically when the thing we encounter, the input, is rare, or when we anticipate that in the future, it will be rare or it will most likely be needed (an analogy is saving money in a bank)… Mother nature gave us storage mechanisms for things that were rarely encountered or for the anticipation that in the future, these stored things would most likely be needed. We

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“Novel Insights Into Lung Autoimmunity Through Research In Rare Mendelian Diseases” – A Synopsis

This is a video by Dr. Anthony Shum from an excellent series of talks by the Vera Moulton Wall Center for Pulmonary Vascular Disease (a brief summary of which is below): Summary Exome sequencing (similar to what 23andMe does) can provide insight into rare Mendelian diseases. Specifically, Dr. Shum has used this to analyze patients with autoimmune interstitial lung disease patients (typically patients who present at a young age, have pulmonary hemorrhage, arthritis, and presence of the autoantibodies ANCA and ANA) and has found that they all contain a mutation in the COPA gene, which was predicted to be damaging.

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The Cholesterol Paradox, Part I

Here is the quote from the above diagram from Metabolic Regulation: A Human Perspective by Keith N. Frayn, regarding cholesterol regulation (emphasis added): “The full length SREBP protein is located in the ER. It is associated with the SREBP cleavage activating protein (SCAP), which “senses” the level of cholesterol, or related sterols, within the membrane of the ER. When the cholesterol content is low, the SCAP-SREBP complex migrates to the Golgi complex, where specific proteases cleave SREBP to release the N-terminal portion, “mature” SREBP. Mature SREBP moves to the nucleus where it binds to sterol response elements in the promoter

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