Cancers of unknown primary site (CUPs) as a model of metastatic process.

Cancers of unknown primary site (CUPs) are a rare group of metastatic tumours, with a frequency of 3-5%, with an overall survival of 6-10 month. The identification of tumour primary site is usually reached by a combination of diagnostic investigations and immunohistochemical testing of the tumour tissue. In CUP patients, these investigations are inconclusive. Since international guidelines for treatment are based on primary site indication, CUP treatment requires a blind approach. As a consequence, CUPs are usually empiric treated with poorly effective. In this study, we applied a set of microRNAs using EvaGreen-based Droplet Digital PCR in a retrospective and prospective collection of formalin-fixed paraffin-embedded tissue samples. We assessed miRNA expression of 155 samples including primary tumours (N=94), metastases of known origin (N=10) and metastases of unknown origin (N=50). Then, we applied the shrunken centroids predictive algorithm to obtain the CUP’s site(s)-of-origin. The molecular test was successfully applied to all CUP samples and provided a site-of-origin identification for all samples, potentially within a one-week time frame from sample inclusion. In the second part of the study we derived two CUP cell lines, and corresponding patient-derived xenografts (PDXs). CUP cell lines and PDXs underwent histological, molecular, and genomic characterization confirming the features of the original tumour. Tissues-of-origin prediction was obtained from the tumour microRNA expression profile and confirmed by single cell RNA sequencing. Genomic testing analysis identified FGFR2 amplification in both models. Drug-screening assays were performed to test the activity of FGFR2-targeting drug and the combination treatment with the MEK inhibitor trametinib, which proved to be synergic and exceptionally active, both in vitro and in vivo. In conclusion, our study demonstrated that miRNA expression profiling could be employed as diagnostic test. Then we successfully derived two CUP models from patients, used for therapy tests, bringing personalized therapy closer to CUP patients.

Addressing challenges in heterogeneous embedded systems programming: security and performance

Embedded systems are increasingly integral to daily life, improving and facilitating the efficiency of modern Cyber-Physical Systems which provide access to sensor data, and actuators. As modern architectures become increasingly complex and heterogeneous, their optimization becomes a challenging task. Additionally, ensuring platform security is important to avoid harm to individuals and assets. This study primarily addresses challenges in contemporary Embedded Systems, focusing on platform optimization and security enforcement. The initial section of this study delves into the application of machine learning methods to efficiently determine the optimal number of cores for a parallel RISC-V cluster to minimize energy consumption using static source code analysis. Results demonstrate that automated platform configuration is not only viable but also that there is a moderate performance trade-off when relying solely on static features. The second part focuses on addressing the problem of heterogeneous device mapping, which involves assigning tasks to the most suitable computational device in a heterogeneous platform for optimal runtime. The contribution of this section lies in the introduction of novel pre-processing techniques, along with a training framework called Siamese Networks, that enhances the classification performance of DeepLLVM, an advanced approach for task mapping. Importantly, these proposed approaches are independent from the specific deep-learning model used. Finally, this research work focuses on addressing issues concerning the binary exploitation of software running in modern Embedded Systems. It proposes an architecture to implement Control-Flow Integrity in embedded platforms with a Root-of-Trust, aiming to enhance security guarantees with limited hardware modifications. The approach involves enhancing the architecture of a modern RISC-V platform for autonomous vehicles by implementing a side-channel communication mechanism that relays control-flow changes executed by the process running on the host core to the Root-of-Trust. This approach has limited impact on performance and it is effective in enhancing the security of embedded platforms.

Design, construction and evaluation of a simple pressurized solvent extraction system

This work describes the construction and testing of a simple pressurized solvent extraction (PSE) system. A mixture of acetone:water (80:20), 80 ºC and 103.5 bar, was used to extract two herbicides (Diuron and Bromacil) from a sample of polluted soil, followed by identification and quantification by high-performance liquid chromatography coupled with diode array detector (HPLC-DAD). The system was also used to extract soybean oil (70 ºC and 69 bar) using pentane. The extracted oil was weighed and characterized through the fatty acid methyl ester analysis (myristic (< 0.3%), palmitic (16.3%), stearic (2.8%), oleic (24.5%), linoleic (46.3%), linolenic (9.6%), araquidic (0.3%), gadoleic (< 0.3%), and behenic (0.3%) acids) using high-resolution gas chromatography with flame ionization detection (HRGC-FID). PSE results were compared with those obtained using classical procedures: Soxhlet extraction for the soybean oil and solid-liquid extraction followed by solid-phase extraction (SLE-SPE) for the herbicides. The results showed: 21.25 ± 0.36% (m/m) of oil in the soybeans using the PSE system and 21.55 ± 0.65% (m/m) using the soxhlet extraction system; extraction efficiency (recovery) of herbicides Diuron and Bromacil of 88.7 ± 4.5% and 106.6 ± 8.1%, respectively, using the PSE system, and 96.8 ± 1.0% and 94.2 ± 3.9%, respectively, with the SLP-SPE system; limit of detection (LOD) and limit of quantification (LOQ) for Diuron of 0.012 mg kg-1 and 0.040 mg kg-1, respectively; LOD and LOQ for Bromacil of 0.025 mg kg-1 and 0.083 mg kg-1, respectively. The linearity used ranged from 0.04 to 1.50 mg L-1 for Diuron and from 0.08 to 1.50 mg L-1 for Bromacil. In conclusion, using the PSE system, due to high pressure and temperature, it is possible to make efficient, fast extractions with reduced solvent consumption in an inert atmosphere, which prevents sample and analyte decomposition.

Tamoxifen Is Effective in the Treatment of Leishmania amazonensis Infections in Mice

Background: Chemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America. Methodology/Principal Findings: BALB/c mice were infected with L. amazonensis promastigotes. Five weeks post-infection, treatment with 15 daily intraperitoneal injections of 20 mg/kg tamoxifen was administered. Lesion and ulcer sizes were recorded and parasite burden quantified by limiting dilution. A significant decrease in lesion size and ulcer development was noted in mice treated with tamoxifen as compared to control untreated animals. Parasite burden in the inoculation site at the end of treatment was reduced from 10(8.5 +/- 0.7) in control untreated animals to 10(5.0 +/- 0.0) in tamoxifen-treated mice. Parasite load was also reduced in the draining lymph nodes. The reduction in parasite number was sustained: 6 weeks after the end of treatment, 10(15.5 +/- 0.5) parasites were quantified from untreated animals, as opposed to 10(5.1 +/- 0.1) parasites detected in treated mice. Conclusions/Significance: Treatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction in the number of parasites in treated animals supports the proposal of further testing of this drug in other models of leishmaniasis.

Biaxial strain-induced suppression of spinodal decomposition in GaMnAs and GaCrAs

The thermodynamic properties of the magnetic semiconductors GaMnAs and GaCrAs are studied under biaxial strain. The calculations are based on the projector augmented wave method combined with the generalized quasichemical approach to treat the disorder and composition effects. Considering the influence of biaxial strain, we find a tendency to the suppression of binodal decomposition mainly for GaMnAs under compressive strain. For a substrate with a lattice constant 5% smaller than the one of GaAs, for GaMnAs, the solubility limit increases up to 40%. Thus, the strain can be a useful tool for tailoring magnetic semiconductors to the formation or not of embedded nanoclusters. (C) 2010 American Institute of Physics. [doi:10.1063/1.3448025]

Exploring the emission intensities of ICP OES aided by chemometrics in the geographical discrimination of mineral waters

A rapid method for classification of mineral waters is proposed. The discrimination power was evaluated by a novel combination of chemometric data analysis and qualitative multi-elemental fingerprints of mineral water samples acquired from different regions of the Brazilian territory. The classification of mineral waters was assessed using only the wavelength emission intensities obtained by inductively coupled plasma optical emission spectrometry (ICP OES), monitoring different lines of Al, B, Ba, Ca, Cl, Cu, Co, Cr, Fe, K, Mg, Mn, Na, Ni, P, Pb, S, Sb, Si, Sr, Ti, V, and Zn, and Be, Dy, Gd, In, La, Sc and Y as internal standards. Data acquisition was done under robust (RC) and non-robust (NRC) conditions. Also, the combination of signal intensities of two or more emission lines for each element were evaluated instead of the individual lines. The performance of two classification-k-nearest neighbor (kNN) and soft independent modeling of class analogy (SIMCA)-and preprocessing algorithms, autoscaling and Pareto scaling, were evaluated for the ability to differentiate between the various samples in each approach tested (combination of robust or non-robust conditions with use of individual lines or sum of the intensities of emission lines). It was shown that qualitative ICP OES fingerprinting in combination with multivariate analysis is a promising analytical tool that has potential to become a recognized procedure for rapid authenticity and adulteration testing of mineral water samples or other material whose physicochemical properties (or origin) are directly related to mineral content.

Co-electrodeposition and characterization of Cu-Si(3)N(4) composite coatings

Smooth copper coatings containing well-distributed silicon nitride particles were obtained by co-electrodeposition in acidic sulfate bath. The cathodic current density did not show significant influence on incorporated particle volume fraction, whereas the increase of particle concentration in the bath led to its decrease. The increase of stirring rate increased the amount of embedded particles. The microhardness of the composite layers was higher than that of pure copper deposits obtained under the same conditions due to dispersion-strengthening and copper matrix grain refinement and increased with the increase of incorporated particle volume fraction. The microhardness of composites also increased with the increase of current density due to copper matrix grain refining. The composite coatings presented higher strength but lower ductility than pure copper layers. Pure copper and composite coatings showed the same corrosion resistance in 0.5 wt.% H(2)SO(4) solution at room temperature. (C) 2011 Elsevier B.V. All rights reserved.

Short-term experimental data of drying shrinkage of ground granulated blast-furnace slag cement concrete

This paper presents results of laboratory testing of unrestrained drying shrinkage during a period of 154 days of different concrete mixtures from the Brazilian production line that utilize ground granulated blast-furnace slag in their compositions. Three concrete mixtures with water/cement ratio of 0.78(M1), 0.41(M2), and 0.37(M3) were studied. The obtained experimental data were compared with the analytical results from prediction models available in the literature: the ACI 209 model (ACI), the B3 model (B3), the Eurocode 2 model (EC2), the GL 2000 model (GL), and the Brazilian NBR 6118 model (NBR), and an analysis of the efficacy of these models was conducted utilizing these experimental data. In addition, the development of the mechanical properties (compressive strength and modulus of elasticity) of the studied concrete mixtures was also measured in the laboratory until 126 days. From this study, it could be concluded that the ACI and the GL were the models that most approximated the experimental drying shrinkage data measured during the analyzed period of time.

Fretting fatigue in overhead conductors: Rig design and failure analysis of a Grosbeak aluminium cable steel reinforced conductor

The performance optimisation of overhead conductors depends on the systematic investigation of the fretting fatigue mechanisms in the conductor/clamping system. As a consequence, a fretting fatigue rig was designed and a limited range of fatigue tests was carried out at the middle high cycle fatigue regime in order to access an exploratory S-N curve for a Grosbeak conductor, which was mounted on a mono-articulated aluminium clamping system. Subsequent to these preliminary fatigue tests, the components of the conductor/clamping system, such as ACSR conductor, upper and lower clamps, bolt and nuts, were subjected to a failure analysis procedure in order to investigate the metallurgical free variables interfering on the fatigue test results, aiming at the optimisation of the testing reproducibility. The results indicated that the rupture of the planar fracture surfaces observed in the external At strands of the conductor tested under lower bending amplitude (0.9 mm) occurred by fatigue cracking (I mm deep), followed by shear overload. The V-type fracture surfaces observed in some At strands of the conductor tested under higher bending amplitude (1.3 mm) were also produced by fatigue cracking (approximately 400 mu m deep), followed by shear overload. Shear overload fracture (45 degrees fracture surface) was also observed on the remaining At wires of the conductor tested under higher bending amplitude (1.3 mm). Additionally, the upper and lower Al-cast clamps presented microstructure-sensitive cracking, which was folowed by particle detachment and formation of abrasive debris on the clamp/conductor tribo-interface, promoting even further the fretting mechanism. The detrimental formation of abrasive debris might be inhibited by the selection of a more suitable class of as-cast At alloy for the production of clamps. Finally, the bolt/nut system showed intense degradation of the carbon steel nut (fabricated in ferritic-pearlitic carbon steel, featuring machined threads with 190 HV), with intense plastic deformation and loss of material. Proper selection of both the bolt and nut materials and the finishing processing might prevent the loss in the clamping pressure during the fretting testing. It is important to control the specification of these components (clamps, bolt and nuts) prior to the start of large scale fretting fatigue testing of the overhead conductors in order to increase the reproducibility of this assessment. (c) 2008 Elsevier Ltd. All rights reserved.

Failure assessments of corroded pipelines with axial defects using stress-based criteria: Numerical studies and verification analyses

Conventional procedures used to assess the integrity of corroded piping systems with axial defects generally employ simplified failure criteria based upon a plastic collapse failure mechanism incorporating the tensile properties of the pipe material. These methods establish acceptance criteria for defects based on limited experimental data for low strength structural steels which do not necessarily address specific requirements for the high grade steels currently used. For these cases, failure assessments may be overly conservative or provide significant scatter in their predictions, which lead to unnecessary repair or replacement of in-service pipelines. Motivated by these observations, this study examines the applicability of a stress-based criterion based upon plastic instability analysis to predict the failure pressure of corroded pipelines with axial defects. A central focus is to gain additional insight into effects of defect geometry and material properties on the attainment of a local limit load to support the development of stress-based burst strength criteria. The work provides an extensive body of results which lend further support to adopt failure criteria for corroded pipelines based upon ligament instability analyses. A verification study conducted on burst testing of large-diameter pipe specimens with different defect length shows the effectiveness of a stress-based criterion using local ligament instability in burst pressure predictions, even though the adopted burst criterion exhibits a potential dependence on defect geometry and possibly on material`s strain hardening capacity. Overall, the results presented here suggests that use of stress-based criteria based upon plastic instability analysis of the defect ligament is a valid engineering tool for integrity assessments of pipelines with axial corroded defects. (C) 2008 Elsevier Ltd. All rights reserved.

Numerical modeling of ductile crack extension in high pressure pipelines with longitudinal flaws

This study examines the applicability of a micromechanics approach based upon the computational cell methodology incorporating the Gurson-Tvergaard (GT) model and the CTOA criterion to describe ductile crack extension of longitudinal crack-like defects in high pressure pipeline steels. A central focus is to gain additional insight into the effectiveness and limitations of both approaches to describe crack growth response and to predict the burst pressure for the tested cracked pipes. A verification study conducted on burst testing of large-diameter, precracked pipe specimens with varying crack depth to thickness ratio (a/t) shows the potential predictive capability of the cell approach even though both the CT model and the CTOA criterion appear to depend on defect geometry. Overall, the results presented here lend additional support for further developments in the cell methodology as a valid engineering tool for integrity assessments of pipelines with axial defects. (C) 2011 Elsevier Ltd. All rights reserved,

Effects of mechanical properties, residual stress and indenter tip geometry on instrumented indentation data in thin films

In this work, an axisymmetric two-dimensional finite element model was developed to simulate instrumented indentation testing of thin ceramic films deposited onto hard steel substrates. The level of film residual stress (sigma(r)), the film elastic modulus (E) and the film work hardening exponent (n) were varied to analyze their effects on indentation data. These numerical results were used to analyze experimental data that were obtained with titanium nitride coated specimens, in which the substrate bias applied during deposition was modified to obtain films with different levels of sigma(r). Good qualitative correlation was obtained when numerical and experimental results were compared, as long as all film properties are considered in the analyses, and not only sigma(r). The numerical analyses were also used to further understand the effect of sigma(r) on the mechanical properties calculated based on instrumented indentation data. In this case, the hardness values obtained based on real or calculated contact areas are similar only when sink-in occurs, i.e. with high n or high ratio VIE, where Y is the yield strength of the film. In an additional analysis, four ratios (R/h(max)) between indenter tip radius and maximum penetration depth were simulated to analyze the combined effects of R and sigma(r) on the indentation load-displacement curves. In this case, or did not significantly affect the load curve exponent, which was affected only by the indenter tip radius. On the other hand, the proportional curvature coefficient was significantly affected by sigma(r) and n. (C) 2010 Elsevier B.V. All rights reserved.

Characterization of the microtube emitters used in a novel micro-sprinkler

The microtube is a simple and cheap emitter that was widely used throughout the world in the early days of drip irrigation. Its length can be adjusted according to the pressure distribution along the lateral line and the discharge from the microtube can be adjusted by its length. This not only counters the pressure loss due to pipe friction but also makes it suitable for undulating and hilly conditions, where pressure in the lateral line varies considerably according to the differences in elevation. This is the major problem facing the designer, i.e., emitter flow changes as the acting pressure head changes. In this study, a novel micro-sprinkler system is proposed that uses microtube as the emitter and where the length of the microtube can be varied in response to pressure changes along the lateral to give uniformity of emitter discharges. The objective of this work is to develop and validate empirical and semi-theoretical equations for the emitter hydraulics. Laboratory testing of two microtube emitters of different diameter over a range of pressures and discharges was used in the development of the equations relating pressure and discharge, and pressure and length for these emitters. The equations proposed will be used in the design of the micro-sprinkler system, to determine the length of microtube required to give the nominal discharge for any given pressure. The semi-theoretical approach underlined the importance of accurate measurements of the microtube diameter and the uncertainty in the estimation of the friction factor for these tubes.

Development and In Vitro Evaluation of Propranolol Hydrochloride Controlled Release Tablets Using HPMC as Matrix Former

The purpose of this paper was to produce controlled-release matrices with 120 mg of propranolol hydrochloride (PHCl) employing hydroxypropyl methylcellulose (HPMC, Methocel (R) K100) as the gel forming barrier. Although this class of polymers has been commonly used for direct compression, with the intent of use reduced polymer concentrations to achieve controlled drug release, in this study tablets were produced by the wet granulation process. HPMC percentages ranged from 15-34 % and both soluble and non soluble diluents were tested in the 10 proposed tablet compositions. Dissolution testing of matrices was performed over a 12 h period in 1.2 pH medium (the first 2 h) and in pH 6.8 (10 h). Dissolution kinetic analysis was performed by applying Zero-order, First-order and Higuchi models with the aim of elucidating the drug release mechanism. All physical-chemical characteristics such as average weight, friability, hardness, diameter, height, and drug content were in accordance to the pharmacopeial specifications. Taking into account that PHCl is a very soluble drug, low concentrations (15 %) of HPMC were sufficient to reduce the drug release and to promote controlled release of PHCl, presenting good dissolution efficiencies, between 50 % and 63 %. The Higuchi model has presented the best fit to the 15 % HPMC formulations, indicating that the main release mechanism was diffusion. It could be concluded that the application of the wet granulation method reduced matrices erosion and promoted controlled release of the drug at low HPMC percentages.

Field prevalence of Wolbachia in the mosquito vector Aedes albopictus

The endosymbiotic bacteria in the genus Wolbachia have been proposed as a potential candidate to deliver pathogen-blocking genes into natural populations of medically important insects. The successful application of Wolbachia in insect vector control depends on the ability of the agent to successfully invade and maintain itself at high frequency under field conditions. Here, we evaluated the prevalence of Wolbachia infections in a field population of the Wolbachia-superinfected mosquito Aedes albopictus. A field prevalence of 100% (n = 1,016) was found in a single population in eastern Thailand via polymerase chain reaction (PCR) testing of Wolbachia both from individual parent females and their corresponding F1 offspring. This is the first report of accurate Wolbachia prevalence in a field population of an insect disease vector. The prevalence of superinfection was estimated to be 99.41%. All single-infected individual mosquitoes (n = 6) were found to harbor group A Wolbachia. For this particular population, none was found to be single-infected with group B Wolbachia. Our results also show that PCR testing of field materials alone without checking F1 offspring overestimated the natural prevalence of single infection. Thus, the confirmation of infection status by means of F1 offspring was critical to the accurate estimates of Wolbachia prevalence under field conditions.