EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells

<p>Abstract</p> <p>Background</p> <p>Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.</p> <p>Results</p> <p>Here we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC₅₀'s ranging from 4-50 μM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.</p> <p>Conclusion</p> <p>These <it>in vitro </it>data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.</p

Ignorance based inference of optimality in thermodynamic processes

We derive ignorance based prior distribution to quantify incomplete information and show its use to estimate the optimal work characteristics of a heat engine.Comment: Latex, 10 pages, 3 figure

A Frequency Reconfigurable Compact Planar Inverted-F Antenna for Portable Devices

In this paper, a low-profile, compact size, inexpensive, and easily integrable frequency reconfigurable antenna system is proposed. The proposed antenna consists of an inverted-F shape antenna, capacitors, and switching PIN diodes. The designed antenna element is fabricated on easy available and less expensive FR-4 substrate (epsilon(r) = 4.4, tan delta = 0.02). The switching diodes are incorporated within the radiating structure of the antenna design, and by changing the different states of PIN diodes, frequency reconfigurable response is achieved. While adjusting the different states of the diodes, the antenna resonates between 0.841 GHz and 2.12 GHz and covers six different frequency bands. The proposed system has compact size of 44x14x3.2 mm(3). The gain of the antenna is between 1.89 and 2.12 dBi. The measurement results shows the good agreement with simulated results for different key performance parameters. Additionally, the proposed antenna shows omni-directional far-field characteristics for various different frequencies

Computation of electroconductive gyrotactic bioconvection from a nonlinear inclined stretching sheet under non-uniform magnetic field : simulation of smart bio-nano-polymer coatings for solar energy

Incompressible, steady-state, boundary layer magneto-bioconvection of a nanofluid (containing motile gyrotactic micro-organisms) over a nonlinear inclined stretching sheet subjected to non-uniform magnetic field is studied theoretically and numerically. This regime is encountered in novel bio-nano-material electroconductive polymeric processing systems currently being considered for third generation organic solar coatings, anti-fouling marine coatings etc. Buongiorno’s two-component nanofluid model is deployed with the OberbeckBoussinesq approximation. Ohmic dissipation (Joule heating) is included. The governing nonlinear partial differential equations are reduced to a system of ordinary differential equations and appropriate similarity transformations. The normalized system of equations with associated boundary conditions features a number of important dimensionless parameters including magnetohydrodynamic body force parameter (M), sheet inclination (δ), Brownian motion nanoscale parameter (Nb), thermophoresis nanoscale parameter (Nt), Richardson number (Ri=GrRe2 , where Gr is thermal Grashof number and Re is Reynolds number), buoyancy ratio parameter (Nr), Eckert (viscous dissipation) number (Ec), bioconvection Rayleigh number (Rb), Lewis number (Le), bioconvection Lewis number (Lb), Péclet number (Pe), nonlinear stretching parameter (n) are solved with a variational Finite Element Method (FEM). Validation is conducted with earlier published studies of Khan and Pop (2010) for the case of non-magnetic stretching sheet nanofluid flow without bioconvection. Further validation of the general magnetic bioconvection nanofluid model is achieved with a generalized differential quadrature (GDQ) numerical technique developed by Bég and Kuharat (2017). The response of non-dimensional velocity, temperature, nanoparticle concentration, motile microorganism density function, local skin friction coefficient, Nusselt number, Sherwood number, wall motile density gradient function to variation in physically pertinent values of selected control parameters (representative of real solar bio-nano-magnetic materials manufacturing systems) are studied in detail. Interesting features of the flow dynamics are elaborated and new future pathways for extension of the study identified in bio-magneto-nano polymers (BMNPs) for solar coatings

Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC

Manic Symptoms and Behavioral Dysregulation in Youth with Velocardiofacial Syndrome (22q11.2 Deletion Syndrome).

Mania and bipolar disorder have been reported in adolescents and adults with velocardiofacial syndrome (VCFS; also known as 22q11.2 deletion syndrome). Children with VCFS have a high prevalence of attention-deficit/hyperactivity disorder (ADHD), which may constitute a risk factor for the eventual development of bipolar disorder in this population. Therefore, we sought to determine whether children with VCFS exhibit more manic symptoms than community controls that also may have learning disorders and ADHD. The study population consisted of 86 children with VCFS and 36 community controls from ages 9 to 15 years, using measures of Young Mania Rating Scale-Parent Version, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), Child Behavior Checklist (CBCL), and Wechsler Intelligence Scale for Children-3rd edition (WISC-III). The results indicate that manic symptoms were not more prevalent in VCFS than in a community sample of children with learning disorders and ADHD. However, after accounting for symptoms of depression and ADHD, we found that manic symptoms in VCFS predicted uniquely to scores on four Child Behavior Checklist (CBCL) subscales, including anxiety, somatization, thought, and conduct problems. In contrast, manic symptoms in controls predicted uniquely to conduct problems only. Accordingly, our findings of severe behavioral impairment in youth with VCFS and manic symptoms suggest that these children may warrant more intensive monitoring and treatment relative to youth with VCFS and ADHD only