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Pairwise comparisons between alternatives are a well-established tool to decompose decision problems into smaller and more easily tractable sub-problems. However, due to our limited rationality, the subjective preferences expressed by decision makers over pairs of alternatives can hardly ever be consistent. Therefore, several inconsistency indices have been proposed in the literature to quantify the extent of the deviation from complete consistency. Only recently, a set of properties has been proposed to define a family of functions representing inconsistency indices. The scope of this paper is twofold. Firstly, it expands the set of properties by adding and justifying a new one. Secondly, it continues the study of inconsistency indices to check whether or not they satisfy the above mentioned properties. Out of the four indices considered in this paper, in their present form, two fail to satisfy some properties. An adjusted version of one index is proposed so that it fulfills them.

Directional amplification, in which signals are selectively amplified depending on their propagation direction, has attracted much attention as key resource for applications, including quantum information processing. Recently, several, physically very different, directional amplifiers have been proposed and realized in the lab. In this work, we present a unifying framework based on topology to understand non-reciprocity and directional amplification in driven-dissipative cavity arrays. Specifically, we unveil a one-to-one correspondence between a non-zero topological invariant defined on the spectrum of the dynamic matrix and regimes of directional amplification, in which the end-to-end gain grows exponentially with the number of cavities. We compute analytically the scattering matrix, the gain and reverse gain, showing their explicit dependence on the value of the topological invariant. Parameter regimes achieving directional amplification can be elegantly obtained from a topological ‘phase diagram’, which provides a guiding principle for the design of both phase-preserving and phase-sensitive multimode directional amplifiers. In information processing applications, directional amplifiers are key components which can be realized in very different systems. Here, the authors present a theoretical framework based on the introduction of a topological invariant that helps to understand directional amplification in coupled cavity arrays.

Pairwise comparisons are a well-known method for the representation of the subjective preferences of a decision maker. Evaluating their inconsistency has been a widely studied and discussed topic and several indices have been proposed in the literature to perform this task. As an acceptable level of consistency is closely related to the reliability of preferences, a suitable choice of an inconsistency index is a crucial phase in decision-making processes. The use of different methods for measuring consistency must be carefully evaluated, as it can affect the decision outcome in practical applications. In this paper, we present five axioms aimed at characterizing inconsistency indices. In addition, we prove that some of the indices proposed in the literature satisfy these axioms, whereas others do not, and therefore, in our view, they may fail to correctly evaluate inconsistency.

The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research. Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed. Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer. Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.

Renal cell carcinomas with t(6;11) chromosome translocation has been classically characterized by the rearrangement of the TFEB gene, located on chromosome 6, and MALAT1 gene, located on chromosome 11. Recently, a few other genes have been described as fusion partners in TFEB rearranged renal cell carcinomas. Although most of TFEB rearranged renal cell carcinomas have an indolent behavior, in the rare cases of advanced metastatic disease targeted therapy and predictive markers remain lacking. In the present study, we collected 13 TFEB rearranged renal cell carcinomas, confirmed by FISH, analyzing their morphology and exploring the novel gene partners. Looking for predictive markers, we have also performed PDL1 immunohistochemical analysis by using four different assays (E1L3N, 22C3, SP142, and SP263). MALAT1 gene rearrangement has been found in ten tumors, five cases showing classical biphasic morphology with “rosettes”, five cases without “rosettes” mimicking other renal cell carcinomas or epithelioid angiomyolipoma/pure epithelioid PEComa. We identified two different partner genes, ACTB and NEAT1, the latter previously unreported and occurring in a tumor with an unusual solid and cystic appearance. In both cases, the “rosettes” were absent. In one case no gene partner was identified. Overall, in 12 of 13 TFEB-rearranged renal cell carcinomas staining for PDL1 SP263 was observed, whereas the other antibodies were less reliable or more difficult to interpret. In conclusion, we described the third case of ACTB-TFEB rearranged renal cell carcinoma and a novel NEAT1-TFEB rearranged renal cell carcinoma, both without the distinctive biphasic morphology typical of t(6;11) renal cell carcinoma. Finally, PDL1 SP263 was constantly expressed in TFEB rearranged renal cell carcinoma with possible clinical benefit which requires further investigations.

The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell carcinoma harboring TFEB gene fusion. At the beginning, they were recognized in childhood; nevertheless, it has been demonstrated that these neoplasms can occur in adults as well. In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement. Recently, many other genes have been identified, and a wide spectrum of morphologies has been described. For this reason, the diagnosis may be challenging based on the histology, and the differential diagnosis includes the most common renal cell neoplasms and pure epithelioid PEComa/epithelioid angiomyolipoma of the kidney. During the last decades, many efforts have been made to identify immunohistochemical markers to reach the right diagnosis. To date, staining for PAX8, cathepsin K, and melanogenesis markers are the most useful identifiers. However, the diagnosis requires the demonstration of the chromosomal rearrangement, and fluorescent in situ hybridization (FISH) is considered the gold standard. The outcome of Xp11 translocation renal cell carcinoma is highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Despite most instances of t(6;11) renal cell carcinoma having an indolent clinical course, a few published cases demonstrate aggressive behavior. Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma. Those tumors appear to be associated with a more aggressive clinical course. For the aggressive cases of MiT family translocation carcinoma, the optimal therapy remains to be determined; however, new target therapies seem to be promising, and the search for predictive markers is mandatory.

Eosinophilic, solid and cystic (ESC) renal cell carcinoma (RCC) is characterized by a solid and cystic architecture with cells showing abundant eosinophilic cytoplasm with hobnail arrangement and a cytokeratin 7-negative/cytokeratin 20-positive immunophenotype. Recent studies have suggested that bi-allelic events affecting TSC genes might play an important role for such tumors. However, only indirect evidence of the clonal origin of TSC mutation has been gathered so far. Therefore, in this paper we aimed to perform multi-regional tumor sampling molecular analysis in four ESC RCC cases that had been completely embedded, three sporadic and one occurring in a patient with tuberous sclerosis complex (TSC). Histologically, the 4 cases showed cystic and solid architecture and cells with abundant eosinophilic cytoplasm with cytoplasmic stippling and round to oval nuclei. Immunohistochemistry showed at least focal expression of cytokeratin 20 in all tissue samples and negative cytokeratin 7, as well as diffuse positivity for S100A1 and at least focal expression of cathepsin K in three out of four cases. The sporadic cases showed the same somatic TSC1 mutations in all tissue samples analyzed, while the TSC-associated case showed the same TSC1 alteration in both normal tissue and all tumor samples analyzed, proving the germline nature of the alteration. In conclusion, our data demonstrate that clonal TSC loss is a key event in ESC RCC and support considering ESC RCC as an entity given its distinct morphologic, immunophenotypical and molecular characteristics.

The expression of programmed death-ligand 1 (PD-L1) is an established prerequisite for the administration of checkpoint inhibitor therapy and is of prognostic value in several cancer types. Data concerning the potential effect of PD-L1 on the prognosis of thyroid carcinoma are limited. Therefore, this study aimed to provide a systematic review of the published data on this topic. The literature was reviewed to gather and quantify evidence on the prognostic role of PD-L1 in follicular epithelial derived thyroid carcinomas and determine its association with clinicopathological parameters. A meta-analysis was performed using the DerSimonian-Laird random-effects model. The quality of studies was evaluated with the Newcastle-Ottawa Scale and a modified GRADE approach used to rate the quality of evidence. Out of 445 papers, 18 were included and 15 provided adequate data for meta-analysis. The quality of evidence ranged from low to high. PD-L1 expression was significantly associated with a reduced disease-free survival (DFS) (RR 1.63, CI 1.04–2.56, p = 0.03, I2 68%, τ2 0.19 and HR 1.90, CI 1.33–2.70, p< 0.001, I2 0%, τ2 0.00); however, no association was found with the overall survival (OS). Furthermore, a significant association was found with respect to underlying chronic lymphocytic thyroiditis and BRAFV600E mutation status in papillary thyroid carcinomas. In the subgroup analysis, the association of PD-L1 and DFS remained strong in papillary thyroid carcinoma when compared with dedifferentiated thyroid carcinomas (anaplastic and poorly differentiated thyroid carcinomas) that failed to demonstrate a significant association with respect to PD-L1. These findings underscore the role of PD-L1 immunohistochemistry as a potential prognostic biomarker of disease recurrence in patients with papillary thyroid carcinoma.

The presence of pesticides in aquatic ecosystems has become an increasing concern. Contamination of ground and surface water results from substances escaping wastewater treatment plants (WWTP) and leaching from soil. Pesticides pose a significant threat to the aquatic environment, as even trace concentrations can damage the central nervous systems (CNS) of animals and humans. Rotenone (ROT), an electron transport chain inhibitor, causes selective dopaminergic (DA) degeneration, while deltamethrin (DM), a widely used type II pyrethroid insecticide, is known for its neurotoxic effect. We assessed the impact of chronic exposure to ROT (2 µg/L, 4 weeks) and DM (1 and 2.5 µg/L, 15 days) on the central nervous system of adult zebrafish. TUNEL assay analysis ( n  = 15 in total) revealed both pesticides triggered cell death in different brain regions of fish, including areas involved in sensory, motor, and cognitive processes. DM additionally affected regions associated with complex behaviors such as learning, memory, and decision-making. Immunohistological analyses ( n  = 12 in total) showed loss of DA neurons in the areas involved in the motor control of animals exposed to both pesticides. These neurotoxic effects were further supported by behavioral changes ( n  = 38 in total) in the Novel Tank Test (NTT), indicating alterations in movement and anxiety-like behavior. Our findings confirm that chronic sub-threshold exposure to chemicals present in environmental waters causes significant damage to cerebral tissue, leading to apoptosis and behavioral alterations.

The new concept of Urban Air Mobility (UAM) and the emergent unmanned aerial vehicles are receiving more and more attention by several stakeholders for implementing new transport solutions. However, there are several issues to solve in order to implement successful UAM systems. Particularly, setting a suitable framework is central for including this new transportation system into the existing ones—both ground and aerial systems. Regulation and definition of aerial networks, but also the characterization of ground facilities (vertiports) to allow passengers and freight to access the services are among the most relevant issues to be discussed. To identify UAM transportation networks, suitably connected with ground transportation services, digital twin models could be adopted to support the modelling and simulation of existing—and expected—scenarios with constantly updated data for identifying solutions addressing the design and management of transport systems. In this perspective, a digital twin model applied to an existing urban context—the city of Bologna, in northern Italy—is presented in combination with a novel air transport network that includes the third dimension. The 3D Urban Air Network tries to satisfy the principle of linking origin/destination points by ensuring safe aerial paths and suitable aerial vehicle separations. It involves innovative dynamic links powered by a heuristic cost function. This work provides the initial framework to explore the integration of UAM services into realistic contexts, by avoiding the costs associated with flight simulations in reality. Moreover, it can be used for holistic analyses of UAM systems.