Antitumor Effects of Vitamin D Analogs on Hamster and Mouse Melanoma Cell Lines in Relation to Melanin Pigmentation

Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)₂D₃) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)₂D₃ and 25(OH)D₃), and novel relatively non-calcemic ones (20(OH)D₃, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti-melanoma treatment. Novel Vitamin D analogs with a short side-chain and lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin D analogs, and altered expression of key genes involved in Vitamin D signaling, which was opposite to the effect on heavily pigmented cells. Interestingly, melanogenesis inhibited ligand-induced Vitamin D receptor translocation and ligand-induced expression of VDR and CYP24A1 genes. These findings indicate that melanogenesis can affect the anti-melanoma activity of Vitamin D analogs in a complex manner.     

Study of a BGO calorimeter using electron and hadron beams from 1 to 50 GeV

A calorimeter of 25 bismuth germanate (BGO) crystals equipped with silicon photodiode readout has been tested at the CERN SPS in the energy range 1–50 GeV. The response for electrons has been shown to be linear in this energy range and the rms resolution obtained ( ) is approximately 1%, for E > 4 GeV. The electron/pion separation was found to be better than 1:500 in the energy range 1–20 GeV. Data on lateral and longitudinal shower development were compared with the results of a Monte Carlo simulation using the SLAC-EGS program and found to be in good agreement.     

Evolution of weakly non-linear shallow water waves generated by a moving boundary

Summary In this study we describe the evolution of weakly non-linear shallow water waves in a rectangular channel of 16 m length which aregenerated by a moving boundary. We present a detailed comparison of computaticnal and observational waveheight-time series and thus verify the theoretical model as presented by Villeneuve and Savage [27].Three different types of wave generating devices were used: pistons with vertical and inclined frontal faces, submerged boxes and a rotating plate. Waveheight-time series are recorded at eight different positions along the channel by electrical resistivity gauges, and velocity profiles are determined at certain selective cross sections. Data of many wave experiments are presented in nondimensional form. This representation reveals that the initial wave forms depend upon a Froude number of the motion of the wave generator, the slope angle of the wedge-type pistons and on the dimensionless displaced volume. Evolving waveheight-time series that are recorded at the various gauges are compared with those obtained from computations by use of equations which generalize the Boussinesq equations to include time variations of the boundaries.The method of inverse scattering is applied both, experimental and numerical waveheight-time series are prescribed as initial data. Results are tested relative to two different observers one fixed in time the other fixed in space. Deviations are shown to be small in all cases.     

A monotone multigrid solver for two body contact problems in biomechanics

The purpose of the paper is to apply monotone multigrid methods to static and dynamic biomechanical contact problems. In space, a finite element method involving a mortar discretization of the contact conditions is used. In time, a new contact-stabilized Newmark scheme is presented. Numerical experiments for a two body Hertzian contact problem and a biomechanical application are reported. This work was supported by the DFG Research Center Matheon.     

A functional programming approach to the specification and verification of concurrent systems

Networks of communicating processes can be viewed as networks of stream transformers and programmed in a lazy functional language. Thus the correctness of concurrent systems can be reduced to the correctness of functional programs. In this paper such correctness is proved formally in the-calculus extended with recursion equations for functional programs. The-calculus is chosen since it allows the definition of properties by least fixed points (induction) as well as by greatest fixed points (coinduction), and since greatest fixed points are useful for formalising properties, such as fairness, of infinitely proceeding programs. Moreover, non-deterministic processes are represented as incompletely specified deterministic processes, that is, as properties of stream transformers. This method is illustrated by proving the correctness of the alternating bit protocol.     

Target Score—A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms.     

Polarity as a criterion in protein design

Hypothetical proteins can be tested computationally by determiningwhether or not the designed sequence-structure pair has thecharacteristics of a typical globular protein. We have developedsuch a test by deriving quantities with approximately constantvalue for all globular proteins, based on empirical analysisof the exposed and buried surfaces of 128 structurally knownproteins. The characteristic quantities that best appear tosegregate badly designed or deliberately misfolded proteinsfrom their properly folded natural relatives are the polar fractionof side chains on the protein surface and, independently, inthe protein interior. Three of the seven hypothetical structurestested here can be rejected as having too many polar side-chaingroups in the interior or too few on the protein surface. Inaddition, a recently designed nutritional protein is identifiedas being very much unlike globular proteins. These database-derivedcharacteristic quantities are useful in screening designed proteinsprior to experiment and may be useful in screening experimentallydetermined (X-ray, NMR) protein structures for possible errors.     

Scales to measure parents and caretakers satisfaction with the food and nutrition component of Child care Centers

Two Likert-type scales for measuring parents' and caretakers' level of satisfaction with the food and nutrition services offered at childcare multi-centers in a peri-urban community in Caracas, were developed and validated. An intentional sample of 20 parents and caretakers were interviewed within the naturalistic-constructivist perspective, to capture their perceptions of distinct aspects of the food and nutrition components of the program. Categories emerged from the interviews that served to construct the items for two scales that measure level of satisfaction of parents and caretakers with the food and nutrition aspects of the program. To validate the scales, they were applied to 73 parents and 32 caretakers. Factor and multiple components analysis showed that overall, the scales explained 61% and 69% of the variation in level of satisfaction of parents and caretakers respectively. Confiability measured with Alpha Cronbach coefficient was 0.74 and 0.77 for parents' and caretakers' scales respectively. These results reveal scales that have content validity and good reliability. Besides, the scales detect specific aspects of the food and nutrition service that should be reinforced or modified, to make the Child-care Centers program more effective and efficient. External validation of the scales is recommended, since they provide an instrument capable of capturing useful information for monitoring and evaluating the Child-care Centers program nation-wide, from the perspective of program managers and parents of program users.