A Novel Role for BDNF-TrkB in the Regulation of Chemotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Mechanisms of resistance for HNSCC to cisplatin (CDDP), the foundational chemotherapeutic agent in the treatment of this disease, remain poorly understood. We previously demonstrated that cisplatin resistance (CR) can be overcome by targeting Trk receptor. In the current study, we explored the potential mechanistic role of the BDNF-TrkB signaling system in the development of CDDP resistance in HNSCC. Utilizing an in vitro system of acquired CR, we confirmed a substantial up-regulation of both BDNF and TrkB at the protein and mRNA levels in CR cells, suggesting an autocrine pathway dysregulation in this system. Exogenous BDNF stimulation led to an enhanced expression of the drug-resistance and anti-apoptotic proteins MDR1 and XiAP, respectively, in a dose-dependently manner, demonstrating a key role for BDNF-TrkB signaling in modulating the response to cytotoxic agents. In addition, modulation of TrkB expression induced an enhanced sensitivity of cells to CDDP in HNSCC. Moreover, genetic suppression of TrkB resulted in changes in expression of Bim, XiAP, and MDR1 contributing to HNSCC survival. To elucidate intracellular signaling pathways responsible for mechanisms underlying BDNF/TrkB induced CDDP-resistance, we analyzed expression levels of these molecules following inhibition of Akt. Inhibition of Akt eliminated BDNF effect on MDR1 and Bim expression in OSC-19P cells as well as modulated expressions of MDR1, Bim, and XiAP in OSC-19CR cells. These results suggest BDNF/TrkB system plays critical roles in CDDP-resistance development by utilizing Akt-dependent signaling pathways

Sparse Positional Strategies for Safety Games

We consider the problem of obtaining sparse positional strategies for safety games. Such games are a commonly used model in many formal methods, as they make the interaction of a system with its environment explicit. Often, a winning strategy for one of the players is used as a certificate or as an artefact for further processing in the application. Small such certificates, i.e., strategies that can be written down very compactly, are typically preferred. For safety games, we only need to consider positional strategies. These map game positions of a player onto a move that is to be taken by the player whenever the play enters that position. For representing positional strategies compactly, a common goal is to minimize the number of positions for which a winning player's move needs to be defined such that the game is still won by the same player, without visiting a position with an undefined next move. We call winning strategies in which the next move is defined for few of the player's positions sparse. Unfortunately, even roughly approximating the density of the sparsest strategy for a safety game has been shown to be NP-hard. Thus, to obtain sparse strategies in practice, one either has to apply some heuristics, or use some exhaustive search technique, like ILP (integer linear programming) solving. In this paper, we perform a comparative study of currently available methods to obtain sparse winning strategies for the safety player in safety games. We consider techniques from common knowledge, such as using ILP or SAT (satisfiability) solving, and a novel technique based on iterative linear programming. The results of this paper tell us if current techniques are already scalable enough for practical use.Comment: In Proceedings SYNT 2012, arXiv:1207.055

Comment on ``Solidification of a Supercooled Liquid in a Narrow Channel''

Comment on PRL v. 86, p. 5084 (2001) [cond-mat/0101016]. We point out that the authors' simulations are consistent with the known theory of steady-state solutions in this system

Rheumatoid arthritis mimicking metastatic squamous cell carcinoma

We report a case of a cervical rheumatoid nodule in close relation to the hyoid bone mimicking a metastatic carcinoma. A 74-year-old female with a 15-year history of rheumatoid arthritis (RA) on treatment with methotrexate presented with tenderness of the right base of tongue. Imaging demonstrated a 1.4 cm cystic lesion at the hyoid bone. Biopsies were unsuccessful and the patient required surgical resection of the mass. A trans-cervical approach was used. Pathology revealed a necrotizing granuloma compatible with rheumatoid etiology. The clinician should be aware that, in a patient with a neck mass, in the presence of active RA, rheumatoid nodules should be part of the differential diagnosis

A Phase-Field Model of Spiral Dendritic Growth

Domains of condensed-phase monolayers of chiral molecules exhibit a variety of interesting nonequilibrium structures when formed via pressurization. To model these domain patterns, we add a complex field describing the tilt degree of freedom to an (anisotropic) complex-phase-field solidification model. The resulting formalism allows for the inclusion of (in general, non-reflection symmetric) interactions between the tilt, the solid-liquid interface, and the bond orientation. Simulations demonstrate the ability of the model to exhibit spiral dendritic growth.Comment: text plus Four postscript figure file

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment

Elastic theory of unconstrained non-Euclidean plates

Non-Euclidean plates are a subset of the class of elastic bodies having no stress-free configuration. Such bodies exhibit residual stress when relaxed from all external constraints, and may assume complicated equilibrium shapes even in the absence of external forces. In this work we present a mathematical framework for such bodies in terms of a covariant theory of linear elasticity, valid for large displacements. We propose the concept of non-Euclidean plates to approximate many naturally formed thin elastic structures. We derive a thin plate theory, which is a generalization of existing linear plate theories, valid for large displacements but small strains, and arbitrary intrinsic geometry. We study a particular example of a hemispherical plate. We show the occurrence of a spontaneous buckling transition from a stretching dominated configuration to bending dominated configurations, under variation of the plate thickness

Метод расчета теплообмена излучением в топке осесимметричной конфигурации на основе уравнений для компонент суммарного вектора потока лучистой энергии. Инженерная методика

На основе системы уравнений первой части статьи, получены разностные уравнения квазиодномерного метода расчета теплообмена излучением в топке котла осесимметричной конфигурации. Записаны уравнения и разностные формулы метода инженерного расчета теплообмена излучением при наличии экранной сетки около поверхности горелки. Методика пригодна для использования в инженерных расчетах при определении оптимальной конфигурации топки и определении оптимального расстояния экранной сетки до поверхности горелки

Discounting in LTL

In recent years, there is growing need and interest in formalizing and reasoning about the quality of software and hardware systems. As opposed to traditional verification, where one handles the question of whether a system satisfies, or not, a given specification, reasoning about quality addresses the question of \emph{how well} the system satisfies the specification. One direction in this effort is to refine the "eventually" operators of temporal logic to {\em discounting operators}: the satisfaction value of a specification is a value in $[0,1]$, where the longer it takes to fulfill eventuality requirements, the smaller the satisfaction value is. In this paper we introduce an augmentation by discounting of Linear Temporal Logic (LTL), and study it, as well as its combination with propositional quality operators. We show that one can augment LTL with an arbitrary set of discounting functions, while preserving the decidability of the model-checking problem. Further augmenting the logic with unary propositional quality operators preserves decidability, whereas adding an average-operator makes some problems undecidable. We also discuss the complexity of the problem, as well as various extensions