31Aug/16

Why “Starving Cancer” May Not Be So Bogus Of An Idea After All

It is well known that cancer cells switch their metabolism from a normal utilization of glucose and fats (glucose and fatty acid oxidation) to an abnormal, less efficient but more rapid, utilization of glucose. This abnormal utilization is referred to as glycolysis. When oxygen is not available, this is the pathway that is triggered.1 Glycolysis in itself doesn’t cause cancer per se, but it is a necessary consequence (i.e. necessary for cancer to develop). For example, our immune cells, red blood cells, cells lining the gut, and fast twitch muscle fibers, are all glycolytic, and they aren’t cancerous. They are glycolytic in order to rapidly proliferate (immune cells in response to infection, or gut cells to continuously be an effective barrier in the stomach), or in order to provide rapid energy when oxygen isn’t available in an adequate amount of time (e.g.… Read More...
30Aug/16

“AMPK modulates Hippo pathway activity to regulate energy homeostasis” – A Review

I’m on a YAP kick lately! This is another paper about the Hippo pathway and YAP but in relation to glucose homeostasis and cellular energy stress. In summary, the Hippo pathway is a tumor suppressor pathway. Energy stress, defects in glucose metabolism, and glucose starvation, all activate this pathway and decrease oncogenic downstream components (specifically YAP). The implications? Metabolic regulation and glucose homeostasis are integral pieces in the puzzle that is “What causes cancer?” Summary & Key Points: The Hippo pathway is a signaling pathway that is involved in the control of tissue and organ size in the body. Loss of the Hippo path components leads to tumor formation, which suggests that the Hippo path is crucial for suppressing tumors.… Read More...
26Aug/16

“Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension” – A Review

This was a very interesting and exciting paper that I discovered today via Pulmonary Hypertension News: “Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension”. I’m a large proponent of the hypothesis that metabolic dysregulation and immune dysfunction are key drivers in the development of pulmonary hypertension. This paper adds weight to my case that the former is most likely a key element in PH pathogenesis. I’ve also always believed that due to the enigmatic nature of the disease, and presence of “cancer”, “autoimmune”, and “metabolic dysregulation” like features, solving PH can potentially solve problems like cancer and autoimmunity. A few examples from the paper as it pertains to cancer: “Here, the identification of glutaminolysis as a mechanoactivated process coregulated with aerobic glycolysis advances our understanding of the regulatory hierarchy seen in the metabolic reprogramming in PH.… Read More...
25Aug/16

“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 in PH (IPAH, Scleroderma, etc.), we should start with Schistosomiasis, which is something where we know what the culprit is: an egg nesting around vasculature that causes vasculopathy.… Read More...
24Aug/16

“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 to glycolysis in the heart.… Read More...
13Aug/16

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, increasing risk of lipotoxicity.… Read More...
12Aug/16

“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 antigen or de novo antigens) There are no drugs out there that induce tolerance to a specific antigen that we want to down-regulate Overall goal: tone down specific immune responses without completely suppressing immunity.… Read More...
09Aug/16

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 does the heart not need to do this, but is in glycolysis mode anyway, perhaps because of the sick lung circulation?… Read More...
08Aug/16

“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 shut down and another pathway occurs through the receptor that leads to growth and priming functions as well as survival.… Read More...
06Aug/16

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 also has larger repercussions if done incorrectly.… Read More...