AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells

In Vitro Investigations of miR-33a Expression in Estrogen Receptor-Targeting Therapies in Breast Cancer Cells

Background: Increased fatty acid synthesis leads to the aggressive phenotype of breast cancer and renders efficiency of therapeutics. Regulatory microRNAs (miRNAs) on lipid biosynthesis pathways as miR-33a have potential to clarify the exact mechanism. (2) Methods: We determined miR-33a expression levels following exposure of MCF-7 and MDA-MB-231 breast cancer cells to estrogen receptor (ER) activator (estradiol-17β, E2) or anti-estrogens (ICI 182,780, Fulvestrant, FUL) at non-cytotoxic concentrations. We related miR-33a expression levels in the cells to cellular lipid biosynthesis-related pathways through immunoblotting. (3) Results: miR-33a mimic treatment led to significantly downregulation of fatty acid synthase (FASN) in MCF-7 cells but not in MDA-MB-231 cells in the presence of estradiol-17β (E2) or Fulvestrant (FUL). In contrast to the miR-33a inhibitor effect, miR-33a mimic co-transfection with E2 or FUL led to diminished AMP-activated protein kinase α (AMPKα) activity in MCF-7 cells. E2 increases FASN levels in MDA-MB-231 cells regardless of miR-33a cellular levels. miR-33a inhibitor co-treatment suppressed E2-mediated AMPKα activity in MDA-MB-231 cells. (4) Conclusions: The cellular expression levels of miR-33a are critical to understanding differential responses which include cellular energy sensors such as AMPKα activation status in breast cancer cells

A temporal approach for morphological indices of the common sole (Solea solea Linnaeus 1758) from the coast of the Aegean Sea, Turkey

810-818Temporal changes of the morphological indices (Relative Gut Length (RGL), Fullness Index (FI), Hepatosomatic Index (HSI), Visceral Index (VSI), Gonadosomatic Index (GSI) and Fulton condition)) in 122 (♀: 94, ♂: 19, immature: 9) common sole were evaluated. Total length-weight relationships were calculated as W = 0.085TL3.01 and W = 0.0547TL2.40 in females and males, respectively, whereby isometric growth was observed in females and negative allometric growth was observed in males. While there was no statistically significant difference was observed between the FI, HSI, Viscerosomatic Index (VSI), RGL and GSI values of both sexes, however, there was a statistically significant difference in terms of Fulton K values (P < 0.05). In addition, there are statistical differences between the sexes total lengths and the values of RGL, FI, HSI, VSI, and Fulton-K (P < 0.05), as it is discernible in their HSI and VSI index values according to the month the specimens were obtained (P < 0.05). According to the results of the analysis, it has been determined that the female common sole along the Aegean coast adjust their energy temporally and store the energy they obtain from vegetative and carnivorous feeding. Contrary to the situation seen in females, the male individuals invest in energy through omnivorous feeding, according to the diet in the active process. Based on the results, it can be stated that the VSI and HSI are both important indicators of fish condition status. The results found here may be useful in both fishery research and fishery management

Plumo: An Ultralight Blockchain Client

Syncing the latest state of a blockchain can be a resource-intensive task, driving (especially mobile) end users towards centralized services offering instant access. To expand full decentralized access to anyone with a mobile phone, we introduce a consensus-agnostic compiler for constructing ultralight clients, providing secure and highly efficient blockchain syncing via a sequence of SNARK-based state transition proofs, and prove its security formally. Instantiating this, we present Plumo, an ultralight client for the Celo blockchain capable of syncing the latest network state summary in just a few seconds even on a low-end mobile phone. In Plumo, each transition proof covers four months of blockchain history and can be produced for just $25 USD of compute. Plumo achieves this level of efficiency thanks to two new SNARK-friendly constructions, which may also be of independent interest: a new BLS-based offline aggregate multisignature scheme in which signers do not have to know the members of their multisignature group in advance, and a new composite algebraic-symmetric cryptographic hash function

Abelian Chern-Simons Vortices and Holomorphic Burgers' Hierarchy

The Abelian Chern-Simons Gauge Field Theory in 2+1 dimensions and its relation with holomorphic Burgers' Hierarchy is considered. It is shown that the relation between complex potential and the complex gauge field as in incompressible and irrotational hydrodynamics, has meaning of the analytic Cole-Hopf transformation, linearizing the Burgers Hierarchy in terms of the holomorphic Schr\"odinger Hierarchy. Then the motion of planar vortices in Chern-Simons theory, appearing as pole singularities of the gauge field, corresponds to motion of zeroes of the hierarchy. Using boost transformations of the complex Galilean group of the hierarchy, a rich set of exact solutions, describing integrable dynamics of planar vortices and vortex lattices in terms of the generalized Kampe de Feriet and Hermite polynomials is constructed. The results are applied to the holomorphic reduction of the Ishimori model and the corresponding hierarchy, describing dynamics of magnetic vortices and corresponding lattices in terms of complexified Calogero-Moser models. Corrections on two vortex dynamics from the Moyal space-time non-commutativity in terms of Airy functions are found.Comment: 15 pages, talk presented in Workshop `Nonlinear Physics IV: Theory and Experiment`, 22-30 June 2006, Gallipoli, Ital

The Vela Pulsar and its Synchrotron Nebula

(Abridged) We present high-resolution Chandra X-ray observations of PSR B0833-45, the 89 ms pulsar associated with the Vela supernova remnant. We have acquired two observations separated by one month to search for changes in the pulsar and its environment following an extreme glitch in its rotation frequency. We find a well-resolved nebula with a toroidal morphology remarkably similar to that observed in the Crab Nebula, along with an axial Crab-like jet. Between the two observations the flux from the pulsar is found to be steady to within 0.75%; the 3 sigma limit on the fractional increase in the pulsar's X-ray flux is < ~10^-5 of the inferred glitch energy. We use this limit to constrain parameters of glitch models and neutron star structure. We do find a significant increase in the flux of the nebula's outer arc; if associated with the glitch, the inferred propagation velocity is > 0.7c, similar to that seen in the brightening of the Crab Nebula wisps. We propose an explanation for the X-ray structure of the Vela synchrotron nebula based on a model originally developed for the Crab Nebula. In a departure from the Crab model, the magnetization parameter "sigma" of the Vela pulsar wind is allowed to be of order unity; this is consistent with the simplest MHD transport of magnetic field from the pulsar to the nebula, where B < 4 X 10^-4 G. We review effects that may enhance the probability of alignment between the spin axis and space velocity of a pulsar, and speculate that short-period, slowly moving pulsars are just the ones best-suited to producing synchrotron nebulae with such aligned structures.Comment: 16 pages with 8 figures, uses LaTex, emulateapj.sty. Refereed version. To appear in The Astrophysical Journa

A study on the influencing parameters in developing construction and demolition waste-based geopolymer concretes and their sustainability assessment

YesConstruction and demolition waste (CDW) has been recently identified as a potential aluminosilicate source for geopolymers. However, the available research has mainly focused on developing CDW-based geopolymer pastes and mortars, while studies on geopolymer concretes sourced from CDW have been very limited. Thus, the current study aimed at experimentally identifying different CDW materials suitable for producing geopolymer concretes. Additionally, the study analysed the mechanical, microstructural, and environmental properties of CDW- based geopolymer concrete produced. In this regard, the effect of relevant parameters on the compressive strength development of CDW-based geopolymer concretes was comprehensively investigated, including those related to precursor types/fineness, alkali activator solution, aggregate type/size and curing regimes. Microstructural analyses were also conducted on the selected samples (100% brick waste, 100% tile waste, 100% concrete waste and 75% brick waste + 25% GGBS). Finally, the environmental impact of geopolymer concrete was assessed and compared with similar traditional concrete. Results showed that employing CDWs alone is not suitable to achieve sufficient strengths under all curing regimes. However, the inclusion of 25% GGBS significantly improved the strength performance of CDW-based geopolymer concrete, in comparison to other supplementary cementitious materials (SCMs) such as Class-C fly ash and calcium hydroxide. The particle size of CDWs and concentration of alkaline activators highly affect the performance of CDW-based geopolymer concretes. Utilization of CDWs with particles finer than 75 μm and high concentrations of NaOH (12 M) is recommended to achieve good performance. The results also indicate that almost similar energy is needed for producing CDW-based geopolymer and OPC-based traditional concrete, whereas a huge reduction in CO2 emission (∼40%) was estimated in the case of geopolymers. The outcomes of the current study are expected to contribute to the advancement of geopolymer concrete derived from CDW in addition to providing valuable insights into this type of concrete for practitioners and academics

Retinoid N-(1H-benzo[d]imidazol-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide induces p21-dependent senescence in breast cancer cells

Retinoids have been implicated as pharmacological agents for the prevention and treatment of various types of cancers, including breast cancers. We analyzed 27 newly synthesized retinoids for their bioactivity on breast, liver, and colon cancer cells. Majority of the retinoids demonstrated selective bioactivity on breast cancer cells. Retinoid 17 had a significant inhibitory activity (IC50 3.5 μM) only on breast cancer cells while no growth inhibition observed with liver and colon cancer cells. The breast cancer selective growth inhibitory action by retinoid 17 was defined as p21-dependent cell death, reminiscent of senescence, which is an indicator of targeted receptor mediated bioactivity. A comparative analysis of retinoid receptor gene expression levels in different breast cancer cells and IC50 values of 17 indicated the involvement of Retinoid X receptors in the cytotoxic bioactivity of retinoid 17 in the senescence associated cell death. Furthermore, siRNA knockdown studies with RXRγ induced decrease in cell proliferation. Therefore, we suggest that retinoid derivatives that target RXRγ, can be considered for breast cancer therapies. © 2016 Elsevier Inc. All rights reserved