Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed.     

Microbes versus microbes: control of pathogens in the food chain

Foodborne illness continues as a considerable threat to public health. Despite improved hygiene management systems and increased regulation, pathogenic bacteria still contaminate food, causing sporadic cases of illness and disease outbreaks worldwide. For many centuries, microbial antagonism has been used in food processing to improve food safety. An understanding of the mode of action of this microbial antagonism has been gained in recent years and potential applications in food and feed safety are now being explored. This review focuses on the potential opportunities presented, and the limitations, of using microbial antagonism as a biocontrol mechanism to reduce contamination along the food chain; including animal feed as its first link. © 2014 Society of Chemical Industry     

Influence of Sr2+ on Calcium‐Deficient Hydroxyapatite Formation Kinetics and Morphology in Partially Amorphized α‐TCP

Hydration of partially amorphized α‐TCP powders with Sr²⁺ concentrations ranging from 0 to 10 mol% substitution for Ca²⁺ was analyzed by isothermal calorimetry and quantitative in‐situ XRD. Hydration of both crystalline α‐TCP and amorphous TCP (ATCP) forming CDHA was retarded to an increasing extent with increasing Sr²⁺ content. Sr²⁺ slightly reduced the crystallite size (XRD coherent scattering domains) of the CDHA formed during hydration, while the size of crystals visible under SEM was not noticeably affected. Reaction enthalpies of ΔH_{R(Sr‐α‐TCP→Sr‐CDHA)} = 122 ± 8 J/g_TCP and ΔH_{R(Sr‐ATCP→Sr‐CDHA)} = 257 ± 8 J/g_TCP were determined for the hydration of crystalline α‐TCP and ATCP containing 5 mol% Sr²⁺ substitution for Ca²⁺. This is comparable with the corresponding reaction enthalpies previously obtained for undoped samples, which are 106 ± 7 J/g_TCP for α‐TCP and 250 ± 7 J/g_TCP for ATCP.     

Effects of display design on performance in a simulated ship navigation environment

Although automation is playing an increasing role on the ship's bridge, empirical research on the effectiveness of alternative bridge designs is limited. In this paper, we describe an experimental study of the benefits of integrated information display, using a computerized simulation of a highly automated ship's bridge. The study compared three types of interface design, which presented radar and electronic chart information to the operator in different ways: (a) integrated display, (b) functionally-separate display, and (c) spatially-separate display. Effects were examined in relation to time on watch and scenario complexity. Following extensive training on the task, 39 participants were tested over a 4-h experimental session, during which they encountered a sequence of collision scenarios of varying complexity. Using a dual-task methodology, a range of measures of primary and secondary task performance were taken, together with assessment of information sampling behaviour and subjective operator state (workload, fatigue, anxiety and situation awareness). The results indicated slight navigational advantages of the integrated display over the two alternative display types, although it also incurred higher levels of operator cost, particularly fatigue. There were no marked effects of time on watch, but more complex scenarios were associated with impaired performance, increased workload and reduced situation awareness. Overall, the findings have suggested some benefits of integrating primary information sources in a ship's bridge environment. The study further confirms the value of experimental simulations as tools for investigating design issues for ship's bridge automation.     

Reduction of stable differential–algebraic equation systems via projections and system identification

Most large-scale process models derived from first principles are represented by nonlinear differential–algebraic equation (DAE) systems. Since such models are often computationally too expensive for real-time control, techniques for model reduction of these systems need to be investigated. However, models of DAE type have received little attention in the literature on nonlinear model reduction. In order to address this, a new technique for reducing nonlinear DAE systems is presented in this work. This method reduces the order of the differential equations as well as the number and complexity of the algebraic equations. Additionally, the algebraic equations of the resulting system can be replaced by an explicit expression for the algebraic variables such as a feedforward neural network. This last property is important insofar as the reduced model does not require a DAE solver for its solution but system trajectories can instead be computed with regular ODE solvers. This technique is illustrated with a case study where responses of several different reduced-order models of a distillation column with 32 differential equations and 32 algebraic equations are compared.     

Density and Thermal Expansion of Liquid Au-Cu Alloys

The density of liquid Cu-Au alloys is measured using the technique of electromagnetic levitation, which entails producing a shadow image of the sample. The shadow is recorded by a digital CCD-camera, and the volume of the sample is calculated by an image processing algorithm. The density and thermal expansion of several alloys and the pure elements copper and gold are investigated at various temperatures above their melting points. In addition, the densities are also investigated as a function of the gold concentration at constant temperature. The measured values agree with literature data and with predictions obtained by molecular dynamics. It was found from data analysis that the ideal solution model applies.     

Polyplexes of polyethylenimine and per-N-methylated polyethylenimine-cytotoxicity and transfection efficiency

For non-viral gene delivery, the carriers for DNA transfer into cells must be vastly improved. The branched cationic polymer polyethylenimine has been described as an efficient gene carrier. However, polyethylenimine was demonstrated to mediate substantial cytotoxicity. Therefore, this study is aimed at investigating per-N-methylated polyethylenimine, which is thought to have a much lower cytotoxicity due to its lower charge density. Results from a gel retardation assay and laser light scattering indicated that per-N-methylated polyethylenimine condenses DNA into small and compact nanoparticles with a mean diameter <150 nm. Furthermore, polyplexes of polyethylenimine and per-N-methylated polyethylenimine with DNA had a positive zeta potential and the polymers protected DNA from nuclease-mediated digestion. The transfection efficiency of polyethylenimine and per-N-methylated polyethylenimine was tested in CHO-K1 cells. Using green fluorescent protein as reporter gene and flow cytometry analysis, we demonstrated that per-N-methylated polyethylenimine has a lower cytotoxicity, but also a significantly lower transfection efficiency. Using propidium iodide staining, we could additionally distinguish between viable and dead cells. At NP > or = 12, per-N-methylated polyethylenimine showed a much higher cell viability and the ratio of viable and transfected cells to dead and transfected cells was about 1.5 to 1.7 fold higher than for polyethylenimine. The results of cell viability from flow cytometry analysis were confirmed by the MTS assay. Using luciferase reporter gene for transfection experiments, the gene expression of per-N-methylated polyethylenimine was lower at NP 6, 12 and 18 as compared to polyethylenimine, but at NP 24 it yielded similar levels.     

A Semantics for Distributed Execution of Statemate

We present a semantics for the statechart variant implemented in the Statemate product of i-Logix. Our semantics enables distributed code generation for Statemate models in the context of rapid prototyping for embedded control applications. We argue that it seems impossible to efficiently generate distributed code using the original Statemate semantics. The new, distributed semantics has the advantages that, first, it enables the generation of efficient distributed code, second, it preserves many aspects of the original semantics for those parts of a model that are not distributed, and third, the changes made regarding the interaction of distributed model parts are similar to the interaction between the model and its environment in the original semantics, thus giving designers a familiar execution model. The semantics has been implemented in Grace, a framework for rapid prototyping code generation for embedded control applications.     

Process conditions in X-ray lithography for the fabrication of devices with sub-micron feature sizes

This article describes the fabrication of polymer structures with lateral dimensions in the sub-micron regime using hard X-rays (λ_c ≈ 0.4 nm) from the electron storage ring ANKA. Spincoated polymethylmethacrylate (PMMA) grades have been analyzed with respect to development rates and contrast. The contrast has been determined to be constant over a wide dose regime but rapidly decreases for dose values below 1 kJ/cm³. Films with a thickness from 2 to 11 μm have been patterned using a high resolution X-ray mask consisting of 2 μm thick gold absorbers on a suspended 1 μm thick silicon nitride membrane. The fabrication of sub-micron X-ray lithography structures with feature sizes down to 400 nm is confined by the mechanical parameters of the resist material and the process conditions. Surface tension after development limits the achievable aspect ratio of isolated pillars and walls, depending on the actual resist height. PMMA structures have been successfully used as template for electroplating of 1 μm thick gold to demonstrate the fabrication capability of sub-micron scale metal parts.     

Dynamic optimal experimental design yields marginal improvement over steady‐state results for computational maximisation of regulatory T‐cell induction in ex vivo culture

The isolation of T cells, followed by differentiation into Regulatory T cells (Tregs), and re‐transplantation into the body has been proposed as a therapeutic option for inflammatory bowel disease. A key requirement for making this a viable therapeutic option is the generation of a large population of Tregs. However, cytokines in the local microenvironment can impact the yield of Tregs during differentiation. As such, experimental design is an essential part of evaluating the importance of different cytokine concentrations for Treg differentiation. However, currently only single, constant concentrations of the cytokines have been investigated. This work addresses this point by performing experimental design in silico which seeks to maximize the predicted induction of Tregs relative to Th17 cells, by selecting an optimal input function for the concentrations of TGF‐β, IL‐2, IL‐6, and IL‐23. While this approach sounds promising, the results show that only marginal improvements in the concentration of Tregs can be achieved for dynamic cytokine profiles as compared to optimal constant concentrations. Since constant concentrations are easier to implement in experiments, it is recommended for this particular system to keep the concentrations constant where IL‐6 should be kept low and high concentrations of TGF‐β, IL‐2, and IL‐23 should be used.Inspec keywords: patient treatment, molecular biophysics, proteins, cellular biophysics, diseasesOther keywords: Tregs relative, optimal input function, dynamic cytokine profiles, optimal constant concentrations, IL‐23, computational maximisation, regulatory T‐cell induction, inflammatory bowel disease, viable therapeutic option, local microenvironment, Treg differentiation, single concentrations, predicted induction, dynamic optimal experimental design, interleukin‐2, IL‐6, transforming growth factor‐β