How the Analysis of the Pathogenetic Variants of DDR Genes Will Change the Management of Prostate Cancer Patients

Herein, we analyze answers achieved, open questions, and future perspectives regarding the analysis of the pathogenetic variants (PV) of DNA damage response (and repair) (DDR) genes in prostate cancer (PC) patients. The incidence of PVs in homologous recombination repair (HRR) genes among men with metastatic PC varied between 11% and 33%, which was significantly higher than that in non-metastatic PC, and BRCA2 mutations were more frequent when compared to other DDR genes. The determination of the somatic or germline PVs of BRCA2 was able to define a tailored therapy using PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) progression after first-line therapy, with significant improvements in the radiologic progression-free survival (rPFS) and overall survival (OS) rates. We propose testing all metastatic PC patients for somatic and germline HRR mutations. Somatic determination on the primary site or on historic paraffin preparations with a temporal distance of no longer than 5 years should be preferred over metastatic site biopsies. The prognostic use of DDR PVs will also be used in selected high-risk cases with non-metastatic stages to better arrange controls and therapeutic primary options. We anticipate that the use of poly-ADP-ribose polymerase (PARP) inhibitors in hormone-sensitive prostate cancer (HSPC) and in combination with androgen receptor signaling inhibitors (ARSI) will be new strategies.     

An application of non-homogeneous Poisson point processes to the reliability analysis of service water pumps

The purpose of this paper is to present an application of the non-homogeneous Poisson point process to the study of the rates of occurrence of failures (ROCOF) when they are time dependent, and the times between failures are neither independent nor identically distributed. The application concerns the analysis of the reliability of service water pumps of a typical PWR nuclear power plant. These pumps are repairable components, in general. Standard statistical techniques, such as the maximum likelihood parameter estimation and linear regression analysis are applied. As a conclusion, the non-homogeneous Poisson process is an adequate tool for analyzing time-dependent ROCOFs for repairable component failure data. It can be used for surveying aging mechanisms during the operation life of repairable systems and also for the assessment of maintenance policies effectiveness.     

Integration of TETRA with Satellite Networks: A Contribution to the IMT-A Vision

The paper addresses the integration architecture (I-concept) between a terrestrial technology—TETRA (TErrestrial Trunked Radio)—and satellite systems. This approach, that enhances and harmonises the features of both technologies, could provide an interesting contribution to the effectiveness of the International Mobile Telecommunications-Advanced (IMT-A) and, hence, to the 4G vision. TETRA can represent an interesting building block of an integrated network devoted to both civil and military scenarios; it meets the “suitable technological capability” requirement for integration, because it represents a consolidated terrestrial technology that can be trusted, hence focusing the integration effort on the definition, design and implementation of proper interfaces. System architectures are here proposed referring to short, medium term and long term scenarios.

Inhibitory effect of the essential oil of Curcuma longa L. and curcumin on aflatoxin production by Aspergillus flavus Link

Aflatoxins are highly toxic, mutagenic, teratogenic and carcinogenic mycotoxins. Consumption of aflatoxin-contaminated food and commodities poses serious hazards to the health of humans and animals. Turmeric, Curcuma longa L., is a native plant of Southeast Asia and has antimicrobial, antioxidant and antifungal properties. This paper reports the antiaflatoxigenic activities of the essential oil of C. longa and curcumin. The medium tests were prepared with the oil of C. longa, and the curcumin standard at concentrations varied from 0.01% to 5.0%. All doses of the essential oil of the plant and the curcumin standard interfered with mycotoxin production. Both the essential oil and curcumin significantly inhibited the production of aflatoxins; the 0.5% level had a greater than 96% inhibitory effect. The levels of aflatoxin B₁ (AFB₁) production were 1.0 and 42.7 μg/mL, respectively, for the samples treated with the essential oil of C. longa L. and curcumin at a concentration of 0.5%.     

Giving Drugs a Second Chance: Antibacterial and Antibiofilm Effects of Ciclopirox and Ribavirin against Cystic Fibrosis Pseudomonas aeruginosa Strains

Drug repurposing is an attractive strategy for developing new antibacterial molecules. Herein, we evaluated the in vitro antibacterial, antibiofilm, and antivirulence activities of eight FDA-approved “non-antibiotic” drugs, comparatively to tobramycin, against selected Pseudomonas aeruginosa strains from cystic fibrosis patients. MIC and MBC values were measured by broth microdilution method. Time–kill kinetics was studied by the macro dilution method, and synergy studies were performed by checkerboard microdilution assay. The activity against preformed biofilms was measured by crystal violet and viable cell count assays. The effects on gene expression were studied by real-time quantitative PCR, while the cytotoxic potential was evaluated against IB3-1 bronchial CF cells. Ciclopirox, 5-fluorouracil, and actinomycin D showed the best activity against P. aeruginosa planktonic cells and therefore underwent further evaluation. Time–kill assays indicated actinomycin D and ciclopirox, contrarily to 5-fluorouracil and tobramycin, have the potential for bacterial eradication, although with strain-dependent efficacy. Ciclopirox was the most effective against the viability of the preformed biofilm. A similar activity was observed for other drugs, although they stimulate extracellular polymeric substance production. Ribavirin showed a specific antibiofilm effect, not dependent on bacterial killing. Exposure to drugs and tobramycin generally caused hyperexpression of the virulence traits tested, except for actinomycin D, which downregulated the expression of alkaline protease and alginate polymerization. Ciclopirox and actinomycin D revealed high cytotoxic potential. Ciclopirox and ribavirin might provide chemical scaffolds for anti-P. aeruginosa drugs. Further studies are warranted to decrease ciclopirox cytotoxicity and evaluate the in vivo protective effects.     

Changes in Astroglial K+ upon Brief Periods of Energy Deprivation in the Mouse Neocortex

Malfunction of astrocytic K⁺ regulation contributes to the breakdown of extracellular K⁺ homeostasis during ischemia and spreading depolarization events. Studying astroglial K⁺ changes is, however, hampered by a lack of suitable techniques. Here, we combined results from fluorescence imaging, ion-selective microelectrodes, and patch-clamp recordings in murine neocortical slices with the calculation of astrocytic [K⁺]. Brief chemical ischemia caused a reversible ATP reduction and a transient depolarization of astrocytes. Moreover, astrocytic [Na⁺] increased by 24 mM and extracellular [Na⁺] decreased. Extracellular [K⁺] increased, followed by an undershoot during recovery. Feeding these data into the Goldman–Hodgkin–Katz equation revealed a baseline astroglial [K⁺] of 146 mM, an initial K⁺ loss by 43 mM upon chemical ischemia, and a transient K⁺ overshoot of 16 mM during recovery. It also disclosed a biphasic mismatch in astrocytic Na⁺/K⁺ balance, which was initially ameliorated, but later aggravated by accompanying changes in pH and bicarbonate, respectively. Altogether, our study predicts a loss of K⁺ from astrocytes upon chemical ischemia followed by a net gain. The overshooting K⁺ uptake will promote low extracellular K⁺ during recovery, likely exerting a neuroprotective effect. The resulting late cation/anion imbalance requires additional efflux of cations and/or influx of anions, the latter eventually driving delayed astrocyte swelling.     

Piecewise linear second moment statistical simulation of ICs affected by non‐linear statistical effects

This paper presents a methodology for statistical simulation of non‐linear integrated circuits affected by device mismatch. This simulation technique is aimed at helping designers maximize yield, since it can be orders of magnitude faster than other readily available methods, e.g. Monte Carlo. Statistical analysis is performed by modeling the electrical effects of tolerances by means of stochastic current or voltage sources, which depend on both device geometry and position across the die. They alter the behavior of both linear and non‐linear components according to stochastic device models, which reflect the statistical properties of circuit devices up to the second order (i.e. covariance functions). DC, AC, and transient analyses are performed by means of the stochastic modified nodal analysis, using a piecewise linear stochastic technique with respect to the stochastic sources, around a few automatically selected points. Several experimental results on significant circuits, encompassing both the analog and the digital domains, prove the effectiveness of the proposed method. Copyright © 2009 John Wiley & Sons, Ltd.     

An efficient implementation of PRNGs based on the digital sawtooth map

In this paper, the sawtooth map digitally implemented is analysed to evaluate its suitability for pseudo‐random binary numbers generation. Period and statistical properties of the sequences generated by the digital map are evaluated versus arithmetic precision, approximation strategy and characteristic parameter of the map. In general, the digital implementation of the sawtooth map requires the use of a multiplier, which is quite expensive in terms of gate count. However, results show that values of design parameters that lead to adequate statistical features and to a relatively high period also allow for significantly reducing the complexity required in the implementation. To better evaluate performance of the digital sawtooth map as a pseudo‐random number generator, it is compared to a linear feedback shift register with the same number of flip‐flops, which is well known for its output sequences with a long period, appealing statistical quality, and for a reduced gate count. Performance comparison and implementation on a programmable logic device show that the digital sawtooth map is suitable for pseudo‐random number generation, also requiring a relatively small amount of hardware. Copyright © 2004 John Wiley & Sons, Ltd.     

The relative influence of packaging,labelling, branding and sensory attributes on liking and purchase intent: Consumers differ in their responsiveness

The relative impact of several extrinsic attributes on informed hedonic liking and purchase intent for wine is measured by combining a blind hedonic test with an informed tasting of the same wine packaged in different product concepts. This study separated the relative effect of various attributes and also considers differences between consumers in their responsiveness to various product cues.Five-hundred and twenty-one regular wine consumers participated in a central location test in three German cities in 2005. Respondents first rated hedonic liking of a white wine in a blind condition, then evaluated elements of product concepts differing in four extrinsic attributes, region of origin, grape variety, brand and packaging style, before indicating their liking and purchase intent in an informed condition.Overall, label style and brand evaluation were the strongest drivers for informed liking followed by liking in the blind condition. Purchase intent was influenced directly only by informed liking and price evaluation; the effect of the extrinsic and intrinsic cues is mediated through informed liking. A latent class regression resulted in three consumer segments that differ in the responsiveness of their informed liking to the different product characteristics. Younger inexperienced consumers utilised a mix of various cues, wine experienced consumers based their evaluation mainly on grape variety and blind hedonic liking, and older frequent wine consumers were influenced most strongly by brand and packaging. These findings provide insights into the relative impact of product packaging, branding and labelling on overall product liking and indicate strong differences in how consumers respond to different product characteristics.     

Qualitative evaluation of tortellini meat filling by histology and image analysis

The aim of this study was to identify the presence of different animal tissues in tortellini meat‐filling with special emphasis on the percentage of skeletal muscle. Industrially packed and refrigerated tortellini filling from four different Italian commercial brands were examined and compared. From each brand, five different batches were sampled at intervals of 1 month. From each batch, four fillings were randomly sampled and coded to allow a blind examination. Histological sections were examined to identify the presence of various animal tissues. The presence of large fragments of skeletal muscle in specimens were assessed and semiquantitatively ranked. To evaluate the percentage area of skeletal muscle in the samples, a computerised image analysis system was used. Animal tissues were well preserved in all examined samples. The filling quality was quantified by histology and image analysis evaluating: skeletal muscle density, size of skeletal muscle fragments, and uniformity of batches. In addition to the effective enforcement of food labelling law and the protection of consumers, histology and image analysis are reliable tools to identify small amounts of various animal tissues in a processed meat product.