Efficient primal-dual heuristic for a dynamic location problem

In this paper the dynamic location problem with opening, closure and reopening of facilities is formulated and an efficient primal-dual heuristic that computes both upper and lower limits to its optimal solution is described. The problem here studied considers the possibility of reconfiguring any location more than once over the planning horizon. This problem is NP-hard (the simple plant location problem is a special case of the problem studied). A primal-dual heuristic based on the work of Erlenkotter [A dual-based procedure for uncapacitated facility location. Operations Research 1978;26:992–1009] and Van Roy and Erlenkotter [A dual-based procedure for dynamic facility location. Management Science 1982;28:1091–105] was developed and tested over a set of randomly generated test problems. The results obtained are quite good, both in terms of the quality of lower and upper bounds calculated as in terms of the computational time spent by the heuristic. A branch-and-bound procedure that enables to optimize the problem is also described and tested over the same set of randomly generated problems.     

3D Micro-PIXE at atmospheric pressure: A new tool for the investigation of art and archaeological objects

The paper describes a novel experiment characterized by the development of a confocal geometry in an external Micro-PIXE set-up. The position of X-ray optics in front of the X-ray detector and its proper alignment with respect to the proton micro-beam focus provided the possibility of carrying out 3D Micro-PIXE analysis. As a first application, depth intensity profiles of the major elements that compose the patina layer of a quaternary bronze alloy were measured. A simulation approach of the 3D Micro-PIXE data deduced elemental concentration profiles in rather good agreement with corresponding results obtained by electron probe micro-analysis from a cross-sectioned patina sample. With its non-destructive and depth-resolving properties, as well as its feasibility in atmospheric pressure, 3D Micro-PIXE seems especially suited for investigations in the field of cultural heritage.     

The Chick Chorioallantoic Membrane Model: A New In Vivo Tool to Evaluate Breast Cancer Stem Cell Activity

The high plasticity of cancer stem-like cells (CSCs) allows them to differentiate and proliferate, specifically when xenotransplanted subcutaneously into immunocompromised mice. CSCs are highly tumorigenic, even when inoculated in small numbers. Thus, in vivo limiting dilution assays (LDA) in mice are the current gold standard method to evaluate CSC enrichment and activity. The chick embryo chorioallantoic membrane (CAM) is a low cost, naturally immune-incompetent and reproducible model widely used to evaluate the spontaneous growth of human tumor cells. Here, we established a CAM-LDA assay able to rapidly reproduce tumor specificities—in particular, the ability of the small population of CSCs to form tumors. We used a panel of organotropic metastatic breast cancer cells, which show an enrichment in a stem cell gene signature, enhanced CD44⁺/CD24^−/low cell surface expression and increased mammosphere-forming efficiency (MFE). The size of CAM-xenografted tumors correlate with the number of inoculated cancer cells, following mice xenograft growth pattern. CAM and mice tumors are histologically comparable, displaying both breast CSC markers CD44 and CD49f. Therefore, we propose a new tool for studying CSC prevalence and function—the chick CAM-LDA—a model with easy handling, accessibility, rapid growth and the absence of ethical and regulatory constraints.     

P16 and HPV Genotype Significance in HPV-Associated Cervical Cancer—A Large Cohort of Two Tertiary Referral Centers

The expression of p16 is a good surrogate of human papillomavirus (HPV) infection in HPV-associated cancers. The significance of p16 expression, HPV genotype and genera in the outcome of patients with HPV-associated cervical cancer (CC) is unclear. Our aim is to ascertain the prognostic significance of these factors. Data from 348 patients (median age: 47.5 years old) with CC, diagnosed in two referral centers, were retrospectively collected. Advanced disease (FIGO2018 IB2-IV) was present in 68% of patients. A single HPV genotype was identified in 82.8% of patients. The most common HPVs were HPV16 (69%) and HPV18 (14%). HPV genera reflected this distribution. HPV16 tumors presented at an earlier stage. P16 was negative in 18 cases (5.2%), 83.3% of which were squamous cell carcinomas. These cases occurred in older patients who tended to have advanced disease. In the univariate analysis, HPV16 (HR: 0.58; p = 0.0198), α-9 genera (HR: 0.37; p = 0.0106) and p16 overexpression (HR: 0.54; p = 0.032) were associated with better survival. HPV16 (HR: 0.63; p = 0.0174) and α-9 genera (HR: 0.57; p = 0.0286) were associated with less relapse. In the multivariate analysis, only the International Federation of Gynecology and Obstetrics (FIGO) stage retained an independent prognostic value. HPV16, α-9 genera and p16 overexpression were associated with better survival, although not as independent prognostic factors. Patients with p16-negative HPV-associated CC were older, presented with advanced disease and had worse prognosis.     

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGlo^TM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.     

Coaxial Alginate Hydrogels: From Self-Assembled 3D Cellular Constructs to Long-Term Storage

Alginate as a versatile naturally occurring biomaterial has found widespread use in the biomedical field due to its unique features such as biocompatibility and biodegradability. The ability of its semipermeable hydrogels to provide a favourable microenvironment for clinically relevant cells made alginate encapsulation a leading technology for immunoisolation, 3D culture, cryopreservation as well as cell and drug delivery. The aim of this work is the evaluation of structural properties and swelling behaviour of the core-shell capsules for the encapsulation of multipotent stromal cells (MSCs), their 3D culture and cryopreservation using slow freezing. The cells were encapsulated in core-shell capsules using coaxial electrospraying, cultured for 35 days and cryopreserved. Cell viability, metabolic activity and cell–cell interactions were analysed. Cryopreservation of MSCs-laden core-shell capsules was performed according to parameters pre-selected on cell-free capsules. The results suggest that core-shell capsules produced from the low viscosity high-G alginate are superior to high-M ones in terms of stability during in vitro culture, as well as to solid beads in terms of promoting formation of viable self-assembled cellular structures and maintenance of MSCs functionality on a long-term basis. The application of 0.3 M sucrose demonstrated a beneficial effect on the integrity of capsules and viability of formed 3D cell assemblies, as compared to 10% dimethyl sulfoxide (DMSO) alone. The proposed workflow from the preparation of core-shell capsules with self-assembled cellular structures to the cryopreservation appears to be a promising strategy for their off-the-shelf availability.     

Characterization of Oleogels Based on Waxes and Their Hydrolyzates

In this paper, the structuring of liquid oils, also known as oleogelation, is systematically investigated for the first time using a quasi-quaternary mixing system approach. Native waxes with different quantities of wax esters (WE), n-alkanes (hydrocarbons (HC)), fatty acids (FA), and fatty alcohols (FaOH) are applied in mixtures with hydrolyzed waxes to systematically change the composition. Hydrolyzed waxes contain high levels of FA and FaOH. The model systems are investigated on microscopic level (brightfield light microscopy (BFM), cryogenic scanning electron microscopy (cryo-SEM)) as well as on their macroscopic properties (rheology, gel hardness) and calorimetric behavior (differential scanning calorimetry (DSC)). It is found that sunflower wax (SFW)-based gels (12% structurant) become less hard on any admixture. Beeswax (BW)-based gels show significant increases in hardness when 25% and 50% (w/w) hydrolyzate are admixed. This could be related to stepwise crystallization. Further analysis reveals that the dissolution/melting behavior of the wax ester mixtures can be surprisingly well described as ideal solubility of a single pseudocomponent. The approach to unravel the individual contributions of the different species present in waxes is successful and marks a first step to better understand the systematic of wax functionality as oleogelators. Practical Application: The substitution of hardstock fats in structured oil phases is of interest for two reasons. The improved nutritional profile oleogels offer are beneficial for public health while the elimination of palm oil based ingredients appears to be a general public desire. Among the technical solutions for non-TAG oil structuring waxes are very promising. This is primarily due to their availability, prior consumption, potentially low cost for functionality. Currently waxes are technically and scientifically wrongly treated as single components. In order to better utilize the potential of waxes and design future sourcing strategies it is necessary to understand the wax functionality at a compositional/molecular level. This contribution marks the first step into this direction by considering classes of molecules with respect to their contribution to functionality. This understanding is considered as a key for future compositional design.     

In search of trustworthy information: a qualitative study of the search behavior of people with dyslexia in Norway

Universal Access in the Information Society - Access to trustworthy information is a premise for participation in a democratic society. However, locating useful and valid information may not be a...