Perspectives in the development of hybrid bifunctional antitumour agents

In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents

Complexity-entropy causality plane: a useful approach for distinguishing songs

Nowadays we are often faced with huge databases resulting from the rapid growth of data storage technologies. This is particularly true when dealing with music databases. In this context, it is essential to have techniques and tools able to discriminate properties from these massive sets. In this work, we report on a statistical analysis of more than ten thousand songs aiming to obtain a complexity hierarchy. Our approach is based on the estimation of the permutation entropy combined with an intensive complexity measure, building up the complexity-entropy causality plane. The results obtained indicate that this representation space is very promising to discriminate songs as well as to allow a relative quantitative comparison among songs. Additionally, we believe that the here-reported method may be applied in practical situations since it is simple, robust and has a fast numerical implementation.Comment: Accepted for publication in Physica

Time-Sensitive Networking to Improve the Performance of Distributed Functional Safety Systems Implemented over Wi-Fi

Industry 4.0 has significantly improved the industrial manufacturing scenario in recent years. The Industrial Internet of Things (IIoT) enables the creation of globally interconnected smart factories, where constituent elements seamlessly exchange information. Industry 5.0 has further complemented these achievements, as it focuses on a human-centric approach where humans become part of this network of things, leading to a robust human–machine interaction. In this distributed, dynamic, and highly interconnected environment, functional safety is essential for adequately protecting people and machinery. The increasing availability of wireless networks makes it possible to implement distributed and flexible functional safety systems. However, such networks are known for introducing unwanted delays that can lead to safety performance degradation due to their inherent uncertainty. In this context, the Time-Sensitive Networking (TSN) standards present an attractive prospect for enhancing and ensuring acceptable behaviors. The research presented in this paper deals with the introduction of TSN to implement functional safety protocols for wireless networks. Among the available solutions, we selected Wi-Fi since it is a widespread network, often considered and deployed for industrial applications. The introduction of a reference functional safety protocol is detailed, along with an analysis of how TSN can enhance its behavior by evaluating relevant performance indexes. The evaluation pertains to a standard case study of an industrial warehouse, tested through practical simulations. The results demonstrate that TSN provides notable advantages, but it requires meticulous coordination with the Wi-Fi MAC layer protocol to guarantee improved performance

A Preliminary Study on SVM based Analysis of Underwater Magnetic Signals for Port Protection

People who attend to the problem of underwater port protection usually use sonar based systems. Recently it has been shown that integrating a sonar system with an auxiliary array of magnetic sensors can improve the effectiveness of the intruder detection system. One of the major issues that arise from the integrated magnetic and acoustic system is the interpretation of the magnetic signals coming from the sensors. In this paper a machine learning approach is proposed for the detection of divers or, in general, of underwater magnetic sources. The research proposed here, by means of a windowing of the signals, uses Support Vector Machines for classification, as tool for the detection problem. Empirical results show the effectiveness of the method

Complexity-entropy causality plane: a useful approach for distinguishing songs

Nowadays we are often faced with huge databases resulting from the rapid growth of data storage technologies. This is particularly true when dealing with music databases. In this context, it is essential to have techniques and tools able to discriminate properties from these massive sets. In this work, we report on a statistical analysis of more than ten thousand songs aiming to obtain a complexity hierarchy. Our approach is based on the estimation of the permutation entropy combined with an intensive complexity measure, building up the Complexity-entropy causality plane. The results obtained indicate that this representation space is very promising to discriminate songs as well as to allow a relative quantitative comparison among songs. Additionally, we believe that the here-reported method may be applied in practical situations since it is simple, robust and has a fast numerical implementation.Facultad de Ingenierí

Seeing the sound: a new multimodal imaging device for computer vision

Audio imaging can play a fundamental role in computer vision, in particular in automated surveillance, boosting the accuracy of current systems based on standard optical cameras. We present here a new hybrid device for acousticoptic imaging, whose characteristics are tailored to automated surveillance. In particular, the device allows realtime, high frame rate generation of an acoustic map, overlaid over a standard optical image using a geometric calibration of audio and video streams. We demonstrate the potentialities of the device for target tracking on three challenging setup showing the advantages of using acoustic images against baseline algorithms on image tracking. In particular, the proposed approach is able to overcome, often dramatically, visual tracking with state-of-art algorithms, dealing efficiently with occlusions, abrupt variations in visual appearence and camouflage. These results pave the way to a widespread use of acoustic imaging in application scenarios such as in surveillance and security

Parkin-independent mitophagy controls chemotherapeutic response in cancer cells

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance

Streptozotocin-induced diabetic models in mice and rats

Streptozotocin (STZ) is an antibiotic that causes pancreatic islet β‐cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this article are protocols for producing STZ‐induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116

Tumores de fosa posterior en la infancia

Presentamos 50 niños con tumores de fosa posterior, con una edad promedio de 6 años y 6 meses, que representan 55 % de todos los tumores intracraneanos internados en nuestro servicio. Los procedimientos neurorradiológicos empleados en esta muestra fueron radiografías simples de cráneo en todos, tomografía computada de cerebro en 42 casos, neumoventriculografía en 7, arteriografía vertebral en 4 y neumoencefalografía en 1 caso. El tumor se localizó en tronco encefálico en 10 casos y los otros fueron astrocitomas en 18, meduloblastomas en 12, ependimomas en 5, glioblastoma multiforme en 2, oligodendroglioma en 1, neurinoma del acústico y sarcoma primario de fosa posterior en otro caso. El tratamiento fue quirúrgico, radiante y químico. La cirugía incluyó 40 exéresis tumorales y 17 derivaciones de L. C. R. La radioterapia se aplicó en 33 pacientes, de los cuales en 16 fue craneoespinal, en 15 fue en fosa posterior y en 2 casos el tratamiento radiante fue incompleto. La quimioterapia se empleó en forma complemetaria a la cirugía y la radioterapia sólo en dos casos de glioblastomas de cerebelo; en los otros casos se utilizó cuando había recidiva o metástasis de meduloblastoma. La mortalidad general fue de 40 % y la mortalidad quirúrgica de 9 %. De los 18 astrocitomas, 16 fueron grado I y II grado III-IV. De los 20 pacientes fallecidos, 6 fueron por causa quirúrgicas, 5 por metátasis craneoespinal y 5 por recidiva tumoral. De los 30 pacientes que viven el tumor se localizaba en tronco cerebral en 6, y en los 24 restantes la histología fue astrinomas grado I-II en 15 casos; meduloblastomas, 6; ependimoma, 1; oligodendroglioma, en 1, y 1 caso de glioblastoma multiforme de cerebelo, que en el momento de esta publicación lleva 24 meses de sobrevida