162,384 research outputs found
Design and optimization of nano-formulations for a novel colchicine derivative
No full textIntroduction: Chemotherapy is the most reliable approach to cancer treatment, but it is often
associated with side effects due to anti-cancer compounds' toxicity and non-selectivity [1]. CCI-
001 is a novel colchicine derivative, computationally designed by modifying colchicine’s basic
structure, that exploits the affinity with βIII-tubulin to impair the mitosis of cancer cells [1]. CCI-
001 showed lower general toxicity, increased selectivity and specificity [1]. Despite this, its
applications are limited by low water solubility and poor tumor uptake. [1]. This may reduce CCI-
001 efficacy and produce undesirable side effects. To solve this issue, this contribution describes
the design of new efficient transporters of CCI-001 (polymeric nanoparticles, NPs) to enhance
target accumulation and reduce the off-target effects.
Methods: CCI-001 was successfully loaded in core-shell pegylated NPs, using the
nanoprecipitation method [2]. In detail, a poly-ε-caprolactone (PCL)-based polyurethane
(NHSC2000) was solubilized in acetonitrile and precipitated in water containing a mix of
phospholipids (L-α- phosphatidylglycerol, PG and 1,2 – Distearoyl- sn – glycerol – 3 –
phosphoethanolamine – Poly (ethylene glycol), DSPE-PEG). In vitro efficacy of CCI-001 loaded-
NPs was analyzed against 2D and 3D cultures (spheroids) of three cell lines: U87MG (glioblastoma
multiforme), Mia-PaCa-2 (pancreatic adenocarcinoma) and OVCAR-3 (ovarian cancer).
Results: NPs of small size (~170 nm), narrow size distribution (PDI<0.3), high stability in aqueous
solution, and satisfying encapsulation efficiency (6 %) were obtained [3]. CCI-001-loaded NPs
caused a significant decrease in the viability of each cell line tested. The maximum effect was
exerted after 72h, at a concentration of 2,5 μM, where residual viabilities of 50%, 30%, and 26%
were reached for 2D culture of U87MG, Mia-PaCa-2, and OVCAR-3, respectively (Figure 1a). NPs
exhibited similar results on U-87 and Mia-PaCa-2 spheroids, while OVCAR-3 spheroids' viabilities
are higher than the corresponding 2D culture (as shown in Figure 1b). Also, empty NPs did not
elicit signs of toxicity on these cell lines, up to a concentration of 1 mg/ml.
Conclusions: Overall, our results demonstrate that nano-formulations of CCI-001 can be obtained
with satisfying loading efficacy without altering the anti-cancer effect of the drug, warranting
their further investigation
Ion channel and neurotransmitter modulators as electroceutical approaches to the control of cancer
No full textThe causal roots of integration and the unity of consciousness
No full textA fundamental feature of consciousness is unity. The problem is whether unity is compatible both with the physical underpinnings of conscious experience and with the fabric of the physical world in general
[Report to Chief J. E. Curry, by an unknown author #1]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
[Report to Chief J. E. Curry, by an unknown author #2]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
sj-pdf-1-tmj-10.1177_03008916221146208 – Supplemental material for Demystifying neuroblastoma malignancy through fractal dimension, entropy, and lacunarity
No full textSupplemental material, sj-pdf-1-tmj-10.1177_03008916221146208 for Demystifying neuroblastoma malignancy through fractal dimension, entropy, and lacunarity by Irene Donato, Kiran K Velpula, Andrew J Tsung, Jack A Tuszynski and Consolato M Sergi in Tumori Journal</p
Discovery and Characterization of the Laulimalide-Microtubule Binding Mode by Mass Shift Perturbation Mapping
No full textSummaryConventional approaches to site mapping have so far failed to identify the laulimalide binding site on microtubules. Using mass shift perturbation analysis and data-directed docking, we demonstrate that laulimalide binds to the exterior of the microtubule on β-tubulin, in a region previously unknown to support ligand binding and well removed from the paclitaxel site. Shift maps for docetaxel and laulimalide are otherwise identical, indicating a common state of microtubule stability induced by occupancy of the distinct sites. The preferred binding mode highlights the penetration of the laulimalide side chain into a deep, narrow cavity through a unique conformation not strongly populated in solution, akin to a “striking cobra.” This mode supports the development of a pharmacophore model and reveals the importance of the C1–C15 axis in the macrocycle
Cytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?
No full textMemory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and 'hard-wired' elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP), a cellular and molecular model for memory, post-synaptic calcium ion (Ca²⁺) flux activates the hexagonal Ca²⁺-calmodulin dependent kinase II (CaMKII), a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit). Thus each set of extended CaMKII kinases can potentially encode synaptic Ca²⁺ information via phosphorylation as ordered arrays of binary 'bits'. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs), cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six "bits", and thus "bytes", with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells
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