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Abstract Background Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have shown remarkable clinical efficacy, they can also induce a paradoxical cancer acceleration, known as hyperprogressive disease (HPD), whose causative mechanisms are still unclear. Methods This study investigated the mechanisms of ICI resistance in an HPD-NSCLC model. Two primary cell cultures were established from samples of a NSCLC patient, before ICI initiation (“baseline”, NSCLC-B) and during HPD (“hyperprogression”, NSCLC-H). The cell lines were phenotypically and molecularly characterized through immunofluorescence, Western Blotting and RNA-Seq analysis. To assess cell plasticity and aggressiveness, cellular growth patterns were evaluated both in vitro and in vivo through 2D and 3D cell growth assays and patient-derived xenografts establishment. In vitro investigations, including the evaluation of cell sensitivity to interferon-gamma (IFN-γ) and cell response to PD-L1 modulation, were conducted to explore the influence of these factors on cell plasticity regulation. Results NSCLC-H exhibited increased expression of specific CD44 isoforms and a more aggressive phenotype, including organoid formation ability, compared to NSCLC-B. Plastic changes in NSCLC-H were well described by a deep transcriptome shift, that also affected IFN-γ–related genes, including PD-L1. IFN-γ–mediated cell growth inhibition was compromised in both 2D-cultured NSCLC-B and NSCLC-H cells. Further, the cytokine induced a partial activation of both type I and type II IFN-pathway mediators, together with a striking increase in NSCLC-B growth in 3D cell culture systems. Finally, low IFN-γ doses and PD-L1 modulation both promoted plastic changes in NSCLC-B, increasing CD44 expression and its ability to produce spheres. Conclusions Our findings identified plasticity as a relevant hallmark of ICI-mediated HPD by demonstrating that ICIs can modulate the IFN-γ and PD-L1 pathways, driving tumor cell plasticity and fueling HPD development.

The genus Clavicornaltica Scherer 1974 consists of very small, soil-dwelling flea beetles in South, Southeast and East Asia. Due to their diminutive size and morphological similarities, very little is known about their ecology and taxonomical diversity. It is likely that further studies will reveal this genus to be much more speciose than the 30 species currently recognised.A new species of Clavicornaltica from Brunei Darussalam is described, C. mataikanensis Otani et al., sp. nov. This is the second species of this genus recorded from Ulu Temburong National Park.

Hypothesis: In recent years, gel polymer electrolytes (quasi-solid state electrolytes) have attracted great attention as a suitable substitute for liquid electrolytes. On the other hand, ionic liquids could dramatically enhance the ionic conductivity of electrolytes. In this work, gel polymer electrolytes based on poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP)/poly(ethylene oxide) (PEO) blends (for application in dye-sensitized solar cells (DSSCs)) and imidazolium-based ionic liquids were prepared. It is supposed that blending these two polymers could reduce the degree of crystallization and increase the porosity of the electrolyte blend to yield a higher electrolyte uptake and ionic conductivity. Methods: Polymer blend electrolytes were prepared in different blend ratios and in the presence of either one of the ionic liquids including BMII or BMIMBF4 through phase inversion method and their properties were investigated by differential scanning calorimetry (DSC), mercury porosimetry, electrolyte uptake, and morphology to optimize the blend ratio. Findings: It was found that the blend ratio of 60/40 (w/w) PVDF-HFP/PEO has the highest porosity and electrolyte uptake. Crystallization investigations by DSC showed that there is a direct relationship between the decrease of crystallinity of two polymers and the increment of electrolyte ionic conductivity. Electrolyte uptake gradually increased with increasing PEO component concentration up to 40 wt%, and reached a maximum of 98.49% and 89.48% for BMIMBF4 and BMII, respectively. Beyond this concentration, a decrease in electrolyte uptake was seen, which is an undesirable feature for the produced samples. In this blend ratio ionic conductivity was measured as 2.07 mS/cm and 1.78 mS/cm for PVDF-HFP/PEO/BMIMBF4 and PVDF-HFP/PEO/BMII electrolytes, respectively.

Background: Technological advancements have been rapidly integrated within the neurosurgical education track since it is a high-risk specialty with little margin for error. Indeed, simulation and virtual reality during training can improve surgical performance and technical skills. Our study aims to investigate the impact of neurosurgical technology-based simulation activities on medical students. Methods and Materials: The “Suturing Mission–The Symposium” was a three-day event held at Humanitas University. Participants had access to live-streamed conferences held by worldwide experts in several fields of neurosurgery and practical simulations of dura mater sutures, microvascular anastomosis, and augmented reality neurosurgical approaches. An anonymous survey was conducted at the beginning and end of the event. Results: 141 medical students with a mean age of 21 participated. After the course, 110 participants (77.5%) showed interest in pursuing a surgical path, with a great prevalence in those who had planned to have a surgical career before the event (88.7% vs. 41.4%, p < 0.001). Participants were also asked about their comfort levels while handling surgical instruments, and a good outcome was reached in 72.7% of participants, with a significant difference between those who had previously attended a suture course (87.8% vs. 66.3%, p = 0.012). Conclusion: Training sessions on surgical simulators were effective in increasing participants’ interest in pursuing a surgical path, improving their understanding of postgraduate orientation, and boosting their confidence with surgical instruments.

City street experiments have proven to possess a capacity to trigger system change in urban mobility. The role that learning plays during this process remains unexplored. Drawing from transition studies and experiential learning theory, this paper focuses on the learning of local government actors involved in street experiments. The paper explores how these actors learn, with whom they learn and what they learn. Two cases of low-traffic neighborhood experiment programs in London reveal how local government actors gain instrumental knowledge concerning the design and implementation of street experiments and how to effectively engage citizens. Transformative knowledge amongst local government actors was observed less, revealing an important consideration for the role experiments play in transitions. Because street experiments reflect the complexity of ‘real-life’ and automatically include participants, they are prone to conflict, which can provide increased opportunities for learning.

With this volume - Conversations with TeMA - the Journal opens a new editorial line specifically dedicated to promoting and disseminating the discussion between worldwide researchers on specific issues concerning the contents, methods and timing of our work. This first experience is dedicated to a deepening, in an interview formula, on the future of spatial planning in Italy both from a regulatory and technical-disciplinary perspective, also concerning what is happening in other countries. In line with the aims we had set, we decided to involve, in this first phase, both colleagues working in Italian universities and those working in foreign universities and research centres. This contribution is by Luca Bertolini, Professor in Urban Planning, University of Amsterdam

A topical medical device, AI500®, constituted of a single-chain polypeptide embedded in hyaluronic acid, was tested and evaluated in patients with reduced knee function due to osteoarthritis and other knee conditions. A total of 35 participants with reduced knee function assessed by the WOMAC Physical Function score were recruited. Four study visits were planned, from the first application at V0 to 1 week follow up at V3. Patient symptomatology was evaluated after 24 h (V1) and after 48 h (V2) through phone contact, and after 1 week from V0, on site (V3). The overall duration of the follow up was one week. An amelioration of 40% in WOMAC Physical Functional scores after 1 week of treatment was recorded, thus achieving the primary endpoint of 20%. Furthermore, a reduction of 29% in Physical Functional scores and of 28% in total WOMAC scores between V0-V2 was registered, together with a decrease of 39% between V0 and V3. The NRS scale showed a 29% and 37% reduction in pain between V0-V1 and V0-V2, respectively. Product safety was confirmed by the very low rate of adverse effects, non-device related, observed in only 2 patients out of 35, resolved spontaneously within 24–48 h. No safety concerns or risks associated with the use of the device were highlighted. There are few the studies on the topical use of HA-based gels for the treatment of knee problems. Compared to invasive intra-articular injections and oral pharmacological therapies used in cases of knee pain, the topical application of AI500® is non-invasive, safe, and appreciated by patients. Good results in terms of functional improvement and symptoms resolution were obtained in less than 1 week.

Despite a growing body of literature, the relationship between transport investment and regional economic development remains elusive. Individual studies highlight certain aspects but neglect others, and yet do not add up to a holistic framework. This paper engages with this gap by developing a holistic conceptual framework based on the synthesis of the literature. A list of variables and relationships were extracted and classified into a broad framework representing common elements of a regional economic system. Then, a causal loop diagram (CLD) was produced as a conceptual model by employing a system dynamics method that captures the interaction of the elements. The conceptual model reveals that the underlying mechanisms of regional economic development represent a complex and dynamic process engaging multiple factors, causalities, and temporal dynamics. Transport investment improves the attractiveness of regions and generates economic activities, reinforcing further investments, thereby fostering regional GDP and urban growth. The conditions of interregional transport infrastructure determine where cities can emerge and grow, and urban transport infrastructure conditions guide how big (population) and wide (area) a city can become. Three additional soft policies (urban transport, urban policies, and institutions and innovation) influence the attractiveness of regions and their economic activities. The time and scales of the policy inputs may produce different outcomes, i.e., city(ies) size and regional GDP, leading to income inequality across regions. We conclude that the generated conceptual model offers a distinct contribution by originally mapping the links between different studies and provides an overarching framework for further explorations.

In response to acute urban mobility and livability challenges, city street experiments have emerged as a way to explore possible solutions for alternative futures. While the added value of these experiments to improve urban living conditions is widely acknowledged, their potential to stimulate larger system change remains unknown. This paper uses the defining characteristics of transition experiments and a multi-level perspective of transitions in order to assess the transitional capacity of city street experiments. We devise an assessment framework to systematically assess six case studies in Amsterdam and Munich, revealing emerging patterns of experimentation within urban mobility systems.

Monitoring of critical civil engineering infrastructures has become a priority for public owners and administrative authorities. Several laws and regulations have been issued on this topic, emphasizing the crucial role of Building Information Modeling (BIM)- based procedures for the design and management of civil infrastructures. This study aims at examining the potential of an interoperable and upgradeable BIM model supplemented by ground-based non-destructive survey data, such as Mobile Laser Scanner (MLS) and Ground-Penetrating Radar (GPR), for the analysis of the potential distresses identified in a transport infrastructure’s pavement. The main goal of the work is to implement an infrastructure management process that aims to reduce the limits associated with the separate observation of these assessments and to provide a more efficient way to store data regarding the status of a linear transport infrastructure, to the advantage of an integrated analysis. As on-site surveys are carried out, preliminary analyses on the condition of the inspected infrastructure are performed by relying on the information provided by Non-Destructive Testing (NDTs) inspections. Subsequently, a digital informative model capable of storing the data obtained by the surveys is generated, integrating both the MLS and GPR information to accurately represent the status of the infrastructure’s pavement in a three-dimensional environment. Data obtained from these instruments were used as the input for the digitalization process, making use of parametric digital elements capable of adapting their configuration to the information provided by the NDT surveys. As more analysis on the surveys’ results is carried out, potential distresses in the deep layers of the pavement are identified, and the information related to these elements is then integrated into the BIM model previously created. The process hereby described allows for an analysis of the three-dimensional configuration of the pavement, along with potential distresses and their location into the road’s superstructure. This digitalization process has shown promising viability for data management aimed at supporting asset managers in various management phases.

The implementation of the digitalization of the linear infrastructure is growing rapidly and new methods for developing BIM-oriented digital models are increasing. The integration of the results obtained from non-destructive surveys carried out along a road infrastructure in a pavement digital model can be a useful method for developing an efficient process from a pavement management systems (PMS) point of view. In fact, several applications to optimize PMS have been thoroughly investigated over the years and several researchers and scientists have investigated significant elements for improving the PMS applied to a transport network, including road infrastructures. This study presents a new, tentative process for implementing into a BIM environment the dataset processed from two surveys carried out in a case study. Moreover, the main reason for this investigation is related to the need for an effective system able to evaluate continuously the pavement conditions and programming maintenance interventions. To date, both the instruments and the methods to detect the pavement configuration have evolved, along with the development of non-destructive technology (NDT) tools such as laser-scanners and ground-penetrating radar. Finally, the main results of the research demonstrate the possibility to provide a digital twin model from the synergistic use of geometric and design information with the results from monitoring conducted on a road infrastructure. The model can be potentially used in future BIM-based PMS applications.

Cement-based materials have been used since the 19th century for different decorative purposes, and a high levels of expertise has often reached in reproducing or restoring even quite elaborated stoneworks. An important example is the application of cement-based decorative materials on the façades of the San Fedele church in Milan. The church, built in the 16th century and characterized by the presence of pinkish-yellowish Angera stone on the façades, was subjected, especially in the 20th century, to several restoration works. Damaged decorative elements of the façades as well as portions of its structural elements were replaced or covered in the last century by “stone imitating render”, made with cementitious materials which imitate the original Angera stone. In this study, several samples of cement-based decorative materials, collected from different elements of the external façades of the Church, were characterized by several analytic techniques (thermogravimetric analysis, X-ray diffraction, scanning electron microscopy and IR analysis), in order to investigate both their microstructure and composition, how the chromatic aspect of the cementitious materials were obtained and their conservation state and to provide useful information for the possible reproduction of materials with comparable appearance to be used in a further restoration project. Results showed that the cement-based materials and decorations were obtained by the application of different layers of renders; in particular, the colour and texture of finishing layer were achieved by blending the binder with fine dolomite particles, probably obtained by grinding the Angera stone. This technique not only allowed an amazing reproduction of the original stone, but also resulted in a durable protection, since the cement-based decorative materials did not show any significant degradation phenomena in the polluted environment of the centre of Milan.

Realising policy solutions needed to achieve ‘sustainable mobility’ is difficult because, for one, they require a strategic capacity for “coordinated action” across multiple actors and organizations. Policy learning and policy transfer have been discussed for decades as a way for policy makers to acquire capacity to effect change. However, the process linking policy learning and transfer to the building of strategic capacity remains a black box. One possible reason for this gap is how learning is conceptualised and measured in contemporary transport policy studies. We turn to conceptual and empirical knowledge from education, organizational development, human resources, environmental sciences, and business strategy and management to expand our understanding of learning processes for strategic capacity building. The purpose of this paper is to tease out relevant implications for transportation planning by (1) building a theoretical and empirical database of learning for capacity building across disciplines; (2) examining how such learning is conceptualised and measured, with particular attention to how the literature links learning and strategic capacity building; and (3) reflecting on the implications for the transportation planning field. Findings demonstrate that learning is an integral part of a larger process (such as ‘innovation’), and mechanisms and conditions of the process drive learning and capacity-building, often accompanying each other. For example, an existing organizational culture that supports learning (condition) demonstrates matured practices of horizontal communication systems and relationship building (mechanisms). We end the paper with a discussion on implications for transportation planning, both in research and practice. Adding to the discourse on policy learning and transfer, we point to policy learning as a potentially valuable pathway for building a strategic capacity to coordinate action.

An assessment of corrosion conditions, aimed at the detection of the most suitable intervention method, of the reinforced concrete elements of Torre Velasca, which, from the late 1950s, characterises the skyline of the city centre of Milan, was carried out. The facades of the Tower are marked by the presence of structural elements coated with thick and dense layers of render and mortar. In-situ and laboratory analyses showed that the high thickness and compactness of the coating played a positive role in preventing the propagation of carbonation and of corrosion. It was estimated that after 50 years most rebars embedded in concrete were either still passive or free from actively-propagating corrosion. Hence it was concluded that most of the original concrete and coating could be preserved without further protection. However, this repair strategy could be compromised by the risk of loss of adhesion of the coating to the underlying concrete, and this crucial aspect should be better investigated in the design of the repair work.

Understanding the relationship between people and their soundscapes in an urban context of innumerable and diverse sensory stimulations is a difficult endeavor. What public space users hear and how they evaluate it in relation to their performed or intended activities can influence users’ engagement with their spaces as well as their assessment of suitability of public space for their needs or expectations. While the interaction between the auditory experience and activity is a topic gaining momentum in soundscape research, capturing the complexity of this relationship in context remains a multifaceted challenge. In this paper, we address this challenge by researching the user-soundscape relationships in relation to users’ activities. Building on previous soundscape studies, we explore the role and interaction of three potentially influencing factors in users’ soundscape evaluations: level of social interaction of users’ activities, familiarity and expectations, and we employ affordance theory to research the ways in which users bring their soundscapes into use. To this end, we employ a mixed methods design, combining quantitative, qualitative and spatial analyses to analyze how users of three public spaces in Amsterdam evaluate their soundscapes in relation to their activities. We documented the use of an urban park in Amsterdam through non-intrusive behavioral mapping to collect spatial data on observable categories of activities, and integrated our observations with on site questionnaires on ranked soundscape evaluations and free responses detailing users’ evaluations, collected at the same time from park users. One of our key findings is that solitary and socially interactive respondents evaluate their soundscapes differently in relation to their activities, with the latter offering higher suitability and lower disruption ratings than the former; this points to qualitatively different auditory experiences, analyzed further based on users’ open-ended justifications for their evaluations. We provide a methodological contribution (adding to existing soundscape evaluation methodologies), an empirical contribution (providing insight on how users explain their soundscape evaluations in relation to their activities) and a policy and design-related contribution, offering additional insight on a transferable methodology and process that practitioners can employ in their work on the built environment to address the multisensory experience of public spaces.

The future of transport, whatever it will be, cannot be consideredseparately from that of cities. But what, where and whenis the city today? The ability to provide opportunities for humaninteraction is the essential reason for cities to exist. In thepre-industrial past this required high-density, compact urbanforms. Modem transport and communication techniques havehowever increasingly offered human beings ways of interactingat a distance. Physical proximity is no longer needed by manytypes of urban activities. As a result, cities have decentralised,as industry first, then residences and services have fled the diseconomiesof high-density agglomerations. For the future,some even predict the advent of an entirely diffuse, 'virtual' city.Actual evidence is at best mixed. Next to ongoing decentralisation,there are also signals that point in the opposite direction,as there are activities that show a tendency to physicallyconcentrate, underscoring a persistent need for physical humaninteraction. These activities include business and financial services,the emerging sectors of culture, entertainment and themedia, but also certain types of residences and of production.As a result, rather than decentralisation or concentration, contemporarycities show a complex combination of decentralisationand concentration.How will these contrasting movements shape the cities ofthe future? Are telecommunication technologies going to radicallyalter current trends? Or will the quest for sustainability dothis? And what will the role of transp01tation- as cause and effect-be? The diffuse urban-regional accessibility warranted bythe car and the inter-metropolitan connections provided by theaeroplane have been essential conditions for the urbanisationpatterns of the recent past. But will the car and the aeroplanealso be the transportation means of the cities of the future?

The effects of the addition of different nanosilica dosages (0.5%, 1%, and 1.5% with respect to cement) on compressive strength and durability properties of concrete with water/binder ratios 0.65, 0.55, and 0.5 were investigated. Water sorptivity, apparent chloride diffusion coefficient, electrical resistivity, and carbonation coefficient of concrete were measured. The results showed that compressive strength significantly improved in case of water/binder = 0.65, while for water/binder = 0.5 no change was found. Increasing nanosilica content, the water sorptivity decreased only for water/binder = 0.55. The addition of 0.5% nanosilica decreased the apparent chloride diffusion coefficient for water/binder = 0.65 and 0.55; however, higher nanosilica dosages did not decrease it with respect to reference value. The resistivity was elevated by 0.5% nanosilica for all water/binder ratios and by 1.5% nanosilica only for water/binder = 0.5. The carbonation coefficient was not notably affected by increasing nanosilica dosages and even adverse effect was observed for water/binder = 0.65. Further information of microstructure was also provided through characterization techniques such as X-ray diffraction, thermal gravimetric analysis, mercury intrusion porosimetry, and scanning electron microscopy. The effectiveness of a certain nanosilica dosage addition into lower strength mixes was more noticeable, while, for the higher strength mix, the effectiveness was less.

Intensification of cities has been a planning aim in many countries over the last decades. A major reason for this is the expectation that urban intensification leads to better accessibility by sustainable transportation modes and therefore contributes to increasing their share. A positive feedback loop exists between the planning of high-capacity transportation networks and intensification of land uses around these transportation networks. Urban intensification policies acknowledge this. However, the integration of transport planning and land-use planning, which one would and should expect as a consequence of this acknowledgement, does not necessarily follow. In the Netherlands, an “implementation gap” in the transport and land-use planning process aimed at urban intensification can be identified, which prevents the positive feedback loop from happening. While similar issues have been identified elsewhere, there is still a lack of knowledge of where in the planning process the implementation gap emerges. This knowledge is essential if the gap is to be closed. To understand this, analysis of various planning documents, interviews, and participant observation are used. The results show that the most critical phases in the planning process are those in which aims need to be translated into actions and actions into performance indicators.