Replies to post #188541 on Avid Bioservices Inc (CDMO)

[biopharm]

but I'm sitting here tossing the basketball around and walking over to find a magnet buried under some dirt and what do I think? you have it... thinking of PS ! lol

more than a few articles I come across mentioning that PS is "negatively" charged...

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Notch Signaling, Phosphatidylserine, generation of cell polarity, negative charges..etc..etc..etc... gets me positively all charged up. What happens though when normal cell division goes awry and we end up with cell invasion, flipped PS, migration and metastasis till something gives and I say give Bavituximab and target that flipping, flipped PS, before the immune system has no idea how to do its job.

Hell... maybe Alison Stopeck goes to Stony Brook to help them finish and complete this puzzle, because she seems to certainly be in the position to know if Bavituximab works well and once we know it works, it is sort of like you only need to reverse engineer and notice what is changing to complete the MOA of Bavituximab and PS Targeting.

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Junyi Wu
Stony Brook University

(**Note.. some interesting responses to this question )

Why is the cell membrane negatively charged?

I know it's due to phospholipids bi-layer structure. It was reported that the head groups of both phosphatidylserine and phosphatidylinositol are negatively charged. Are the head groups of phosphatidylcholine and sphingomyelin (make up the outer layer of the bi-layer structure) also negatively charged?

http://www.researchgate.net/post/Why_is_the_cell_membrane_negatively_charged

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Phosphatidylserine polarization is required for proper Cdc42 localization and for development of cell polarity.

Abstract:
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Remarkably, PS was polarized, accumulating in bud necks, the bud cortex and the tips of mating projections. Polarization required vectorial delivery of PS-enriched secretory and recycling vesicles. Rapid dissipation of the PS gradient is prevented by the slow diffusion of lipids along the plasmalemmal inner leaflet, estimated by photobleaching recovery measurements to be over an order of magnitude slower than in mammalian cells. In mutants lacking PS-synthase the absence of PS was associated with, and likely responsible for impaired polarization of the Cdc42 complex, leading to inhibition of bud emergence, diminished growth rate and abolishment of mating. The results indicate that PS polarization is required for optimal Cdc42 targeting and activation during cell division and mating.
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http://www.researchgate.net/publication/41546517_Phosphatidylserine_polarization_is_required_for_proper_Cdc42_localization_and_for_development_of_cell_polarity

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Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application

Dec 5, 2014

Overwhelming evidence has proven that Notch signaling is crucial for the development and homeostasis of most tissues. Notch signaling has been known to participate in cell proliferation, differentiation and apoptosis. Earlier studies discovered that deregulated Notch signaling leads to various diseases, such as T cell leukemia and breast cancer

The involvement of Notch on lung cancer was experimentally proved in transgenic mouse model by the alveolar epithelium specific expression of activated Notch [50]. The mice developed alveolar hyperplasias as early as 7 days’ induction of Notch and the lesions progressed to pulmonary adenomas after 8 months’ induction. Molecular analyses revealed that Notch1 activation leads to dysregulated expansion of type II lung epithelial cells. When crossed with mice conditionally overexpressing MYC in the alveolar epithelium, mice developed adenocarcinomas. Those pathological processes mimic progression of human adenocarcinoma. Using an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic Kras and deletion of Notch1, Dr. Kissil’s group found that Notch1 function was required for tumor initiation via suppression of p53-mediated apoptosis through the regulation of p53 stability [51]. Molecular analyses defined subpopulation of CD24 (+) ITGB4 (+) Notch (hi) cells were capable of propagating tumor growth in both clonogenic and an orthotopic serial transplantation assays. While all four Notch receptors represented tumor-propagating cells, Notch3 plays a nonredundant role in Kras models and in human NSCLC [52]. Interestingly, in K-Ras mouse model, inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2 (+), Sox9 (+), and CC10 (+) papillary adenocarcinomas throughout the bronchioles [53]. Those researches supported a strong and direct role of Notch signaling in NSCLC. Other studies had shown that under hypoxic conditions, Notch1 stimulated NSCLC tumor growth through direct upregulation of IGF1-R [54] and survivin [55], both of which enhanced cell proliferation and survival.
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Elevated levels of Notch-1, 3 and their ligand Jagged 1–4 expressions were found to be associated with tumor progression and predicted poor prognosis in NSCLC, suggesting a promising biomarker for NSCLC..
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Targeting Notch Signaling in NSCLC:

Currently, several classes of investigational Notch inhibitors have been developed. These include monoclonal antibodies against Notch receptors or ligands, decoys to soluble forms of the extracellular domain of Notch receptor or Notch ligands, blocking peptides, and gamma-secretase inhibitors (GSIs) or natural compounds [98].

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Inhibitors of Notch signaling can be used not only as direct anti-cancer agents but also as a sensitizer to current therapy.
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Conclusion:

As a well known driving force of cell invasion, migration and metastasis, EMT has been shown to induce resistance of cancer cells to conventional chemotherapy and radiotherapy. Notch signaling not only activates cell proliferation, antagonize apoptosis but also cross-talks with several transcriptional factors to promote EMT, leading to enhanced motility in vitro and invasion and metastasis in vivo. Theoretically, combination of chemotherapy or radiotherapy with Notch inhibitors might acquire synergistic effect and improve chemotherapy response.

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http://www.jhoonline.org/content/7/1/87

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No wonder why we have the MD of MDSC and one that visits Greece for the occasional Notch Signaling conferences and Peregrine KOL Dmitry Gabrilovich and just as important David Carbone, Hakan Mellstedt and Scott Antonia that all came on to see the Sunrise.