Does high-speed rail affect destination choice for tourism purpose?

There is a growing but controversial literature concerning the link between high-speed rail (HSR) services and the tourism market. The aim of this paper is to identify this link in the case of two theme parks, namely Disneyland Paris and Futuroscope Parks, both served by an HSR station. Two revealed preference surveys were carried out interviewing tourists at both stations, with the objective of investigating the influence of HSRs on their decision to visit these theme parks. The results significantly diverge. In the case of Disneyland, tourists declared that the presence of HSR was fundamental in the choice of the destination; they would not have come without it. On the contrary, in the case of Futuroscope, tourists stated that HSR was not relevant. Indeed they would have come to Futuroscope in any case, also without this service. Moreover, the link between HSR and visiting other places close to these parks is also very different. These two case studies show again that the relationship between HSR and the local economic development in general and tourism in particular is very different according to places. HSR does not always contribute to the tourism market even in the case of a “stay tourism”.Si une littérature abondante se développe concernant le lien entre desserte ferroviaire à grande vitesse et tourisme, les résultats sont très controversés. L’objectif de cet article est d’identifier ce lien dans le cas de deux parcs à thème, Disneyland Paris et le Futuroscope, tous deux desservis par une gare TGV. Deux enquêtes fondées sur les préférences révélées ont été menées auprès de touristes pour tester l’influence de la desserte ferroviaire à grande vitesse sur leur décision de venir dans le parc à thème. Les résultats divergent fortement. Alors que dans le cas de Disneyland, la grande vitesse ferroviaire est importante puisque les touristes ne seraient pas venus sans elle, ce n’est pas le cas du Futuroscope : les touristes seraient venus même sans la desserte. Par ailleurs le lien entre la desserte et le fait de visiter d’autres lieux proches des parcs est aussi très différent. Ces deux cas montrent à nouveau que le lien entre la grande vitesse ferroviaire et le développement économique en général et le tourisme en particulier est très différent selon les lieux : la grande vitesse ne bénéficie pas toujours au tourisme même dans le cas d’un tourisme de destination

Human natural killer cells and other innate lymphoid cells in cancer: Friends or foes?

Innate lymphoid cells (ILC) including NK cells (cytotoxic) and the recently identified "helper" ILC1, ILC2 and ILC3, play an important role in innate defenses against pathogens. Notably, they mirror analogous T cell subsets, regarding the pattern of cytokine produced, while the timing of their intervention is few hours vs days required for T cell-mediated adaptive responses. On the other hand, the effectiveness of ILC in anti-tumor defenses is controversial. The relevance of NK cells in the control of tumor growth and metastasis has been well documented and they have been exploited in the therapy of high risk leukemia in the haploidentical hematopoietic stem cell transplantation setting. In contrast, the actual involvement of helper ILCs remains contradictory. Thus, while certain functional capabilities of ILC1 and ILC3 may favor anti-tumor responses, other functions could rather favor tumor growth, neo-angiogenesis, epithelial-mesenchymal transition and metastasis. In addition, ILC2, by secreting type-2 cytokines, are thought to induce a prevalent pro-tumorigenic effect. Finally, the function of both NK cells and helper ILCs may be inhibited by the tumor microenvironment, thus adding further complexity to the interplay between ILC and tumors

NK cells and ILCs in tumor immunotherapy

Abstract Cells of the innate immunity play an important role in tumor immunotherapy. Thus, NK cells can control tumor growth and metastatic spread. Thanks to their strong cytolytic activity against tumors, different approaches have been developed for exploiting/harnessing their function in patients with leukemia or solid tumors. Pioneering trials were based on the adoptive transfer of autologous NK cell-enriched cell populations that were expanded in vitro and co-infused with IL-2. Although relevant results were obtained in patients with advanced melanoma, the effect was mostly limited to certain metastatic localizations, particularly to the lung. In addition, the severe IL-2-related toxicity and the preferential IL-2-induced expansion of Treg limited this type of approach. This limitation may be overcome by the use of IL-15, particularly of modified IL-15 molecules to improve its half-life and optimize the biological effects. Other approaches to harness NK cell function include stimulation via TLR, the use of bi- and tri-specific NK cell engagers (BiKE and TriKE) linking activating NK receptors (e.g. CD16) to tumor-associated antigens and even incorporating an IL-15 moiety (TriKE). As recently shown, in tumor patients, NK cells may also express inhibitory checkpoints, primarily PD-1. Accordingly, the therapeutic use of checkpoint inhibitors may unleash NK cells against PD-L1+ tumors. This effect may be predominant and crucial in tumors that have lost HLA cl-I expression, thus resulting "invisible" to T lymphocytes. Additional approaches in which NK cells may represent an important tool for cancer therapy, are to exploit the unique properties of the "adaptive" NK cells. These CD57+ NKG2C+ cells, despite their mature stage and a potent cytolytic activity, maintain a strong proliferating capacity. This property revealed to be crucial in hematopoietic stem cell transplantation (HSCT), particularly in the haplo-HSCT setting, to cure high-risk leukemias. T depleted haplo-HSCT (e.g. from one of the parents) allowed to save the life of thousands of patients lacking a HLA-compatible donor. In this setting, NK cells have been shown to play an essential role against leukemia cells and infections. Another major advance is represented by chimeric antigen receptor (CAR)-engineered NK cells. CAR-NK, different from CAR-T cells, may be obtained from allogeneic donors since they do not cause GvHD. Accordingly, they may represent "off-the-shelf" products to promptly treat tumor patients, with affordable costs. Different from NK cells, helper ILC (ILC1, ILC2 and ILC3), the innate counterpart of T helper cell subsets, remain rather ambiguous with respect to their anti-tumor activity. A possible exception is represented by a subset of ILC3: their frequency in peri-tumoral tissues in patients with NSCLC directly correlates with a better prognosis, possibly reflecting their ability to contribute to the organization of tertiary lymphoid structures, an important site of T cell-mediated anti-tumor responses. It is conceivable that innate immunity may significantly contribute to the major advances that immunotherapy has ensured and will continue to ensure to the cure of cancer

Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models

Activated Leukocyte Cell Adhesion Mol. (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a sol. form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addn., ADAM-17 plays a key role in EGFR signalling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previous mol. 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biol. activity of the newly synthesized compds. was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compd. 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compd. maintained good inhibitory properties on sALCAM shedding in several in vitro assays

Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early '90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls' isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes

Fecal Microbiota, Bile Acids, Sterols, and Fatty Acids in Dogs with Chronic Enteropathy Fed a Home-Cooked Diet Supplemented with Coconut Oil

: Medium-chain fatty acids (MCFAs) are considered to be interesting energy sources for dogs affected by chronic enteropathies (CE). This study analyzed the clinical scores, fecal microbiota, and metabolomes of 18 CE dogs fed a home-cooked diet (HCD) supplemented with virgin coconut oil (VCO), a source of MCFA, at 10% of metabolizable energy (HCD + VCO). The dogs were clinically evaluated with the Canine Chronic Enteropathy Activity Index (CCECAI) before and at the end of study. Fecal samples were collected at baseline, after 7 days of HCD, and after 30 days of HCD + VCO, for fecal score (FS) assessment, microbial analysis, and determination of bile acids (BA), sterols, and fatty acids (FA). The dogs responded positively to diet change, as shown by the CCECAI improvement (p = 0.001); HCD reduced fecal fat excretion and HCD + VCO improved FS (p < 0.001), even though an increase in fecal moisture occurred due to HCD (p = 0.001). HCD modified fecal FA (C6:0: +79%, C14:0: +74%, C20:0: +43%, C22:0: +58%, C24:0: +47%, C18:3n-3: +106%, C20:4n-6: +56%, and monounsaturated FA (MUFA): -23%, p < 0.05) and sterol profile (coprostanol: -27%, sitostanol: -86%, p < 0.01). VCO increased (p < 0.05) fecal total saturated FA (SFA: +28%, C14:0: +142%, C16:0 +21%, C22:0 +33%) and selected MCFAs (+162%; C10:0 +183%, C12:0 +600%), while reducing (p < 0.05) total MUFA (-29%), polyunsaturated FA (-26%), campesterol (-56%) and phyto-/zoosterols ratio (0.93:1 vs. 0.36:1). The median dysbiosis index was <0 and, together with fecal BA, was not significantly affected by HCD nor by VCO. The HCD diet increased total fecal bacteria (p = 0.005) and the abundance of Fusobacterium spp. (p = 0.028). This study confirmed that clinical signs, and to a lesser extent fecal microbiota and metabolome, are positively influenced by HCD in CE dogs. Moreover, it has been shown that fecal proportions of MCFA increased when MCFAs were supplemented in those dogs. The present results emphasize the need for future studies to better understand the intestinal absorptive mechanism of MCFA in dogs

Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early ‘90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy

The roles of different forms of IL-15 in human melanoma progression

BackgroundMelanoma is a lethal skin cancer, and the risk of developing it is increased by exposure to ultraviolet (UV) radiation. The production of cytokines such as interleukin-15 (IL-15), induced by the exposure of skin cells to UV rays, could also promote melanoma development. The aim of this study is to investigate the possible role of Interleukin-15/Interleukin-15 Receptor α (IL-15/IL-15Rα) complexes in melanoma development.MethodsThe expression of IL-15/IL-15Rα complexes by melanoma cells was evaluated both ex vivo and in vitro by tissue microarray, PCR, and flow cytometry. The presence of the soluble complex (sIL-15/IL-15Rα) in the plasma of metastatic melanoma patients was detected using an ELISA assay. Subsequently, we investigated the impact of natural killer (NK) cell activation after rIL-2 starvation followed by exposure to the sIL-15/IL-15Rα complex. Finally, by analyzing public datasets, we studied the correlation between IL-15 and IL-15Rα expressions and melanoma stage, NK and T-cell markers, and overall survival (OS).ResultsAnalysis of a melanoma tissue microarray shows a significant increase in the number of IL-15+ tumor cells from the benign nevi to metastatic melanoma stages. Metastatic melanoma cell lines express a phorbol-12-myristate-13-acetate (PMA)-cleavable membrane-bound IL-15 (mbIL-15), whereas cultures from primary melanomas express a PMA-resistant isoform. Further analysis revealed that 26% of metastatic patients present with consistently high plasmatic levels of sIL-15/IL-15Rα. When the recombinant soluble human IL-15/IL-15Rα complex is added to briefly starved rIL-2-expanded NK cells, these cells exhibit strongly reduced proliferation and levels of cytotoxic activity against K-562 and NALM-18 target cells. The analysis of public gene expression datasets revealed that high IL-15 and IL-15Rα intra-tumoral production correlates with the high levels of expression of CD5+ and NKp46+ (T and NK markers) and significantly correlates with a better OS in stages II and III, but not in stage IV.ConclusionsMembrane-bound and secreted IL-15/IL-15Rα complexes are continuously present during progression in melanoma. It is notable that, although IL-15/IL-15Rα initially promoted the production of cytotoxic T and NK cells, at stage IV promotion of the development of anergic and dysfunctional cytotoxic NK cells was observed. In a subgroup of melanoma metastatic patients, the continuous secretion of high amounts of the soluble complex could represent a novel NK cell immune escape mechanism

Engineering Reconnaissance Following the October 2016 Central Italy Earthquakes - Version 2

Between August and November 2016, three major earthquake events occurred in Central Italy. The first event, with M6.1, took place on 24 August 2016, the second (M5.9) on 26 October, and the third (M6.5) on 30 October 2016. Each event was followed by numerous aftershocks. As shown in Figure 1.1, this earthquake sequence occurred in a gap between two earlier damaging events, the 1997 M6.1 Umbria-Marche earthquake to the north-west and the 2009 M6.1 L’Aquila earthquake to the south-east. This gap had been previously recognized as a zone of elevated risk (GdL INGV sul terremoto di Amatrice, 2016). These events occurred along the spine of the Apennine Mountain range on normal faults and had rake angles ranging from -80 to -100 deg, which corresponds to normal faulting. Each of these events produced substantial damage to local towns and villages. The 24 August event caused massive damages to the following villages: Arquata del Tronto, Accumoli, Amatrice, and Pescara del Tronto. In total, there were 299 fatalities (www.ilgiornale.it), generally from collapses of unreinforced masonry dwellings. The October events caused significant new damage in the villages of Visso, Ussita, and Norcia, although they did not produce fatalities, since the area had largely been evacuated. The NSF-funded Geotechnical Extreme Events Reconnaissance (GEER) association, with co-funding from the B. John Garrick Institute for the Risk Sciences at UCLA and the NSF I/UCRC Center for Unmanned Aircraft Systems (C-UAS) at BYU, mobilized a US-based team to the area in two main phases: (1) following the 24 August event, from early September to early October 2016, and (2) following the October events, between the end of November and the beginning of December 2016. The US team worked in close collaboration with Italian researchers organized under the auspices of the Italian Geotechnical Society, the Italian Center for Seismic Microzonation and its Applications, the Consortium ReLUIS, Centre of Competence of Department of Civil Protection and the DIsaster RECovery Team of Politecnico di Torino. The objective of the Italy-US GEER team was to collect and document perishable data that is essential to advance knowledge of earthquake effects, which ultimately leads to improved procedures for characterization and mitigation of seismic risk. The Italy-US GEER team was multi-disciplinary, with expertise in geology, seismology, geomatics, geotechnical engineering, and structural engineering. The composition of the team was largely the same for the two mobilizations, particularly on the Italian side. Our approach was to combine traditional reconnaissance activities of on-ground recording and mapping of field conditions, with advanced imaging and damage detection routines enabled by state-of-the-art geomatics technology. GEER coordinated its reconnaissance activities with those of the Earthquake Engineering Research Institute (EERI), although the EERI mobilization to the October events was delayed and remains pending as of this writing (April 2017). For the August event reconnaissance, EERI focused on emergency response and recovery, in combination with documenting the effectiveness of public policies related to seismic retrofit. As such, GEER had responsibility for documenting structural damage patterns in addition to geotechnical effects. This report is focused on the reconnaissance activities performed following the October 2016 events. More information about the GEER reconnaissance activities and main findings following the 24 August 2016 event, can be found in GEER (2016). The objective of this document is to provide a summary of our findings, with an emphasis of documentation of data. In general, we do not seek to interpret data, but rather to present it as thoroughly as practical. Moreover, we minimize the presentation of background information already given in GEER (2016), so that the focus is on the effects of the October events. As such, this report and GEER (2016) are inseparable companion documents. Similar to reconnaissance activities following the 24 August 2016 event, the GEER team investigated earthquake effects on slopes, villages, and major infrastructure. Figure 1.2 shows the most strongly affected region and locations described subsequently pertaining to: 1. Surface fault rupture; 2. Recorded ground motions; 3. Landslides and rockfalls; 4. Mud volcanoes; 5. Investigated bridge structures; 6. Villages and hamlets for which mapping of building performance was performed