On Borders: From Ancient to Postmodern Times

The article deals with the evolution of the concept of borders between human groups and with its slow evolution from the initial no men's land zones to the ideal single-dimension linear borders. In ancient times the first borders were natural, such as mountain ranges or large rivers until, with the development of Geodesy, astronomical borders based on meridians and parallels became a favourite natural base. Actually, Modern States adopted these to fix limits in unknown conquered territories. The postmodern thought led give more importance to cultural borders until, in the most recent times, is becoming rather impossible to fix borders in the virtual cyberspace

Behavioural analysis of interactions between pedestrians and vehicles in street designs with elements of shared space

This paper describes the development and implementation of qualitative behavioural criteria in order to analyse the conduct of pedestrians and vehicles when they are required to interact with each other, with particular interest to street designs with elements of shared space. The new behavioural analysis technique is developed by identifying the fundamental principles that underpin existing traffic analyses, such as traffic conflicts techniques, and adapting those to a qualitative framework that describes the mindset and rationale of road users. The technique is then applied to a case study in London, using video data from periods before and after the redevelopment of the Exhibition Road site from a conventional dual carriageway to a modern design with some elements of shared space. With the main goals being to assess the pedestrians’ confidence and the vehicles’ tolerance/patience when forced to interact with each other, behavioural trends are related to instantaneous characteristics of the vehicle flow (vehicle approach speed and traffic density). The data produced are used to develop and validate qualitative behavioural relationships for pedestrian-vehicle interactions, as well as location-specific conclusions for the Exhibition Road site

Behavioural analysis of vehicle-pedestrian interactions: The case of street designs with elements of shared space

This paper describes the development and implementation of qualitative behavioural criteria in order to analyse the conduct of pedestrians and vehicles when they are required to interact with each other, with particular interest to street designs with elements of shared space. The new behavioural analysis technique is developed by identifying the fundamental principles that underpin existing traffic analyses, such as traffic conflicts techniques, and adapting those to a qualitative framework that describes the mindset and rationale of road users. The technique is then applied to a case study in London, using video data from periods before and after the redevelopment of the Exhibition Road site from a conventional dual carriageway to a modern design with some elements of shared space. With the main goals being to assess the pedestrians’ confidence and the vehicles’ tolerance/patience when forced to interact with each other, behavioural trends are related to instantaneous characteristics of the vehicle flow (vehicle approach speed and traffic density). The data produced are used to develop and validate qualitative behavioural relationships for pedestrian-vehicle interactions, as well as location-specific conclusions for the Exhibition Road site

Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: Rationale, evidence and place in therapy

The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9-14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC

The Role of Cyclo(His-Pro) in Neurodegeneration

Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-B signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function