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Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.

Hydrological processes that occur in catchments usually require large space resolution over long periods of time. The advance on numerical methods as well as the increasing power of computation are making possible the physically based simulation of these phenomena. In particular, the 2D shallow water equations can be used to provide distributions of water depth and velocity fields. The necessity of spatial resolution involves the use of a large number of elements hence increasing the computational time when simulating realistic scenarios for a long time period. This work deals with an efficient GPU implementation of the 2D shallow water equations on unstructured meshes analysing the influence of the mesh resolution both on the computational performance and the quality of the results to simulate a rainfall/runoff event. The numerical method to solve them has been developed and compared following three programming approaches: the sequential implementation and its adaptation to the multi-thread and many-core architectures. The particular detail of the influence of the mesh ordering when using unstructured triangular meshes is paid attention in this work to find the best strategy to further reduce the computational time in the context of GPU simulation. The resulting approach is efficient and can become very useful in environmental simulation of hydrological processes.

Abstract Objective Previous studies have demonstrated that emotional stress, changes in lifestyle habits and infections can worsen the clinical course of migraine. We hypothesize that changes in habits and medical care during coronavirus disease 2019 (COVID-19) lockdown might have worsened the clinical course of migraine. Design Retrospective survey study collecting online responses from migraine patients followed-up by neurologists at three tertiary hospitals between June and July 2020. Methods We used a web-based survey that included demographic data, clinical variables related with any headache (frequency) and migraine (subjective worsening, frequency, and intensity), lockdown, and symptoms of post-traumatic stress. Results The response rate of the survey was 239/324 (73.8%). The final analysis included 222 subjects. Among them, 201/222 (90.5%) were women, aged 42.5 ± 12.0 (mean±SD). Subjective improvement of migraine during lockdown was reported in 31/222 participants (14.0%), while worsening in 105/222 (47.3%) and was associated with changes in migraine triggers such as stress related to going outdoors and intake of specific foods or drinks. Intensity of attacks increased in 67/222 patients (30.2%), and it was associated with the subjective worsening, female sex, recent insomnia, and use of acute medication during a headache. An increase in monthly days with any headache was observed in 105/222 patients (47.3%) and was related to symptoms of post-traumatic stress, older age and living with five or more people. Conclusions Approximately half the migraine patients reported worsening of their usual pain during the lockdown. Worse clinical course in migraine patients was related to changes in triggers and the emotional impact of the lockdown.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment. Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.

Green areas and parks are places where people’s quality of life improves, places of recreation and relaxation, in which to carry out various social activities. Among these, the historic gardens represent the union between green areas and historic architecture. Light is considered one of the main factors influencing the perception of such spaces at night; therefore, lighting solutions should be properly balanced. Immersive virtual reality is a tool that allows for lighting design management from different viewpoints. This study investigates how the lighting of a monumental garden affects people’s perception of its architecture at night. With this aim, a detailed 3D model of the western part of Escorial’s monumental complex in Spain was built in DIALux evo 11 and Unreal Engine 4.27 and used to propose six different lighting scenarios. Participants viewed the scenarios through a head-mounted display and provided subjective feedback on the perceived light strength of the environment and architecture. Results highlight that illuminating surrounding areas affects the environment and building perception, as well as the order in which elements capture observer attention. In particular, lit elements between the observer and the façade can reduce façade importance.

Numerical simulation of flows that consider interaction between overland and drainage networks has become a practical tool to prevent and mitigate flood situations in urban environments, especially when dealing with intense storm events, where the limited capacity of the sewer systems can be a trigger for flooding. Additionally, in order to prevent any kind of pollutant dispersion through the drainage network, it is very interesting to have a certain monitorization or control over the quality of the water that flows in both domains. In this sense, the addition of a pollutant transport component to both surface and sewer hydraulic models would benefit the global analysis of the combined water flow. On the other hand, when considering a realistic large domain with complex topography or streets structure, a fine spatial discretization is mandatory. Hence the number of grid cells is usually very large and, therefore, it is necessary to use parallelization techniques for the calculation, the use of Graphic Processing Units (GPU) being one of the most efficient due to the leveraging of thousands of processors within a single device. In this work, an efficient GPU-based 2D shallow water flow solver (RiverFlow2D-GPU) is fully coupled with EPA’s Storm Water Management Model (SWMM). Both models are able to develop a transient water quality analysis taking into account several pollutants. The coupled model, referred to as RiverFlow2D-GPU UD (Urban Drainge) is applied to three real-world cases, covering the most common hydraulic situations in urban hydrology/hydraulics. A UK Environmental Agency test case is used as model validation, showing a good agreement between RiverFlow2D-GPU UD and the rest of the numerical models considered. The efficiency of the model is proven in two more complex domains, leading to a >100x faster simulations compared with the traditional CPU computation.

Bedload sediment transport is an ubiquitous process in natural surface water flows (rivers, dams, coast, etc), but it also plays a key role in catastrophic events such as dyke erosion or dam breach collapse. The bedload transport mechanism can be under equilibrium state, where solid rate and flow carry capacity are balanced, or under non-equilibrium (non-capacity) conditions. Extremely transient surface flows, such as dam/dyke erosive collapses, are systems which always change in space and time, hence absolute equilibrium states in the coupled fluid/solid transport rarely exist. Intuitively, assuming non-equilibrium conditions in transient flows should allow to estimate correctly the bedload transport rates and the bed level evolution. To get insight into this topic, a 2D Finite Volume model for bedload transport based on the non-capacity approach is proposed in this work. This non-equilibrium model considers that the actual bedload sediment discharge can be delayed, spatial and temporally, from the instantaneous solid carry capacity of the flow. Furthermore, the actual solid rate and the adaptation length/time is governed by the temporal evolution of the bedload transport layer and the vertical exchange solid flux. The model is tested for the simulation of overtopping dyke erosion and dambreach opening cases. Numerical results seems to support that considering non-equilibrium conditions for the bedload transport improves the general agreement between the computed results and measured data in both benchmarking cases.

BackgroundCardiac cephalalgia is an unusual condition that occurs during an episode of myocardial ischemia. Information about cardiac cephalalgia is scarce and its characteristics and physiopathology remain unclear. Our aim is to provide a narrative review of clinical characteristics and physiopathology of cardiac cephalalgia and to evaluate the current diagnostic criteria. MethodsA search through PubMed was undertaken for studies on cardiac cephalalgia published until 20th September 2022. We summarized the literature and provide a comprehensive review of the headache characteristics and possible mechanisms. We also evaluated current International Classification of Headache Disorders third edition diagnostic criteria based on prior reported cases. ResultsIn total, 88 cases were found. Headache characteristics were variable. Occipital location and throbbing pain were the most frequently reported. Headache was accompanied in most cases by cardiac symptoms. Criterion B was fulfilled by 98% of cases, criterion C1 by 72%, and criteria C2a and C2b by 37 and 93.2%, respectively. Regarding headache features described in diagnostic criterion C3, ‘moderate to severe intensity’, ‘accompanied by nausea’, ‘not accompanied by photophobia or phonophobia’ and ‘aggravated by exertion’, were reported in 75, 31, 55 and 55% of cases, respectively.ConclusionCardiac cephalalgia characteristics are variable and the headache features described in the diagnostic criterion C3 might not be adequate. Given that cardiac cephalalgia can be the manifestation of a life-threatening condition it is important to increase the knowledge about this entity.

A computational Eulerian–Lagrangian model (ORSA2D_WT) is used for modelling the movement of floating rigid bodies on the water surface. The two-dimensional transport is computed with a dynamic approach, modifying existing formulations for the transport of bodies within fluid flows for the case of floating bodies, by adopting suitable added mass, drag and side coefficients. An original formulation for planar rotation is proposed, which includes the effect of the hydrodynamic torque and a resistance term, named added inertia, based on the difference between the angular velocity of the flow and that of the body. The value of the added inertia coefficient is calibrated against experiments made on purpose, involving the transport of a cylinder in a flume with two side obstacles. The calibrated code is applied to a slightly larger set of experiments for its preliminary evaluation. The outcome of the simulations shows that the streamwise and transversal displacements are well modelled, while some inaccuracies arise when considering the cylinder orientation. The effects of the initial conditions on the cylinders' trajectory and rotation are discussed, showing their influence on the evolution of the rotation angles.