Search

Abstract Compounds targeting non-canonical secondary structures of nucleic acids, known as G-quadruplexes, are highly cytotoxic, both for cancer and healthy cells, because of their action mechanism’s lack of appropriate selectivity. The targeted delivery of cytotoxic molecules to cancer cells is a valuable strategy to expand the repertoire of potential drugs, especially for cancer types for which new therapeutic tools are urgently needed, like glioblastoma. In this work, we conjugated a cyclic arginyl-glycyl-aspartic acid peptide to a naphthalene diimide, previously described as a highly performing stabilizing ligand for DNA G-quadruplexes, to specifically target glioma cells overexpressing RGD-binding integrin receptors. Our results, including confocal microscopy and cell toxicity assays, demonstrated improved efficacy and selective cellular absorption of the new conjugate without affecting the NDI’s ability to interact with the G4 target.

Rosai-Dorfman disease (RDD) is a nonmalignant disease of histiocyte proliferation. RDD usually presents with painless cervical lymphadenopathy, although extranodal involvement can occur. Cardiac involvement was reported in

Abstract We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40–65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.

This study describes the process of co-developing an operational climate forecast service for the viticulture sector. Weather and climate conditions affect grapevine development in cultivars: anticipating the atmospheric variables in the coming weeks and months is thus relevant for effectively managing vineyards, as impacts will be felt in wine production, biodiversity, and a wide range of related aspects. The operational service was co-developed with two types of users: impact modellers, who are the intermediary users incorporating climate forecast outputs in phenological and disease models, and end-users from the wine sector with vineyards in various European locations. For the operational service, sub-seasonal and seasonal climate forecasts were tailored considering their needs. The initial steps of the co-production process identified relevant decisions for which the service was essential and co-defined effective ways to deliver the climate information. Afterwards the climate forecasts outputs were integrated with impact model data. Substantial efforts were directed at the harmonisation of climate services information with the decision-making system of end-users. Because end-users need to navigate, comprehend, and select from various alternative options amidst uncertainty, significant emphasis has been placed on crafting the visual representation of the climate service, incorporating interactive elements, and cognitive considerations, thereby enhancing the overall user experience. Practical implications: Weather and climate conditions affect the development of cultivars: phenological stages, disease risk, or wine quality. This study presents the co-production process for deploying a climate service for vineyard management. The service consists of the near-real-time operational provision of sub-seasonal and seasonal climate forecasts. This service aims to help vineyard managers make decisions by anticipating the climate conditions up to three months in advance for a set of essential climate variables. The service includes the requirements of a set of intermediary users, which are disease risk and phenology researchers who feed their impact models with the provided climate forecasts. To our knowledge, it is the first time that sub-seasonal and seasonal climate forecasts have been integrated into an operational service for vineyard management.The service was developed during the VitiGEOSS project, the primary outcome of which is the VitiGEOSS platform: a single entry-point solution for wine producers aiming to boost vineyard sustainability. Three pilot plots are used for the service development: the Douro region in Portugal, the Catalonia region in Spain, and the Campania region in Italy. The co-production is seen as an iterative, interactive and collaborative process that brings together a plurality of knowledge sources to mutually define problems and develop usable products to address these problems. The process can be divided into three phases: initial co-exploration, co-design and co-development.The co-exploration phase consisted of conducting a benchmark analysis, identifying available services to viticulture and highlighting the gap that the newly developed solution could fill in. In the co-design phase, more intense engagement methods were implemented to communicate the capabilities of climate forecasts and design the product’s visualisation. Finally, the co-evaluation consisted of an ad hoc and ongoing process during the recurring meetings and a final workshop conducted with direct and potential users to obtain feedback on using the platform and potential further developments.As a result, the operational post-processing workflow of the sub-seasonal and seasonal state-of-the-art model outputs was adapted to include users’ requirements. The workflow includes the downscaling of model outputs to increase their spatial resolution, the storage of sub-seasonal climate forecasts at daily frequencies to feed phenological impact models, the provision of past climate simulations to train the impact models, the bias-adjust of climate forecasts to reduce systematic model errors, the assessment of the climate forecasts to aware users on their quality and the deployment of a server to allow access to impact modellers.The variables provided are mean, minimum and maximum temperature, accumulated precipitation and solar radiation. The final co-designed product consists of a graphic of bars. The user can select the location and variable, and the forecasts for the next four weeks or the next three months are displayed for the sub-seasonal and seasonal climate forecasts, respectively. For each week or month, three bars show the tercile probabilities of above-normal, normal or below-normal conditions for the time of the year. The limits of the tercile categories are also displayed, which helps to understand the averaged values of the variable in the selected region and the time of the year calculated with information from the past. The probabilities of extremes, i.e. exceeding (non-exceeding) the percentile 90th (10th), are displayed as extra bars for each week and month in case the prediction is skilful and they are greater than 40%.Last but not least, the results of the skill assessment are shown. This skill assessment consists of calculating a metric for each location, initialisation date and forecast time. When this metric, known as skill score, is positive (negative), the climate model forecast is better (worse) than the climatology (the climatology is a naive forecast which considers all categories equiprobable by definition). If the skill is negative, which means there is no proof of the added value of using the numerical model prediction, the bars are blurred, and the user can still be informed of the tercile category limits.The service has been provided for almost two consecutive years. During this period, we have confirmed the value of some key recommendations from literature when co-producing a climate service. Especially relevant is the need to invest time and resources to conduct a good co-production process by repeating the iterative process. We also tested the idea of providing information in the format of seasonal climate forecast outlooks to end-users before the service was operational. In this way, the climate service process would be ‘slowed down’, by which the use of climate data is incorporated more slowly and allows for place-based knowledge from the resource managers to be included too.One of the most challenging questions is the communication of the probabilistic forecasts product and their quality. The probabilistic nature of climate forecasts is sometimes understood by novice users as the incapacity to provide a deterministic forecast. Similarly, negative skill leads users to interpret the forecast fails. Overall, the perception of the service quality can be low. To avoid this perception, the co-producing process is essential to engage with users and redefine the service if possible.In this work, we have tried different ways to overcome low-quality perception. The users requested access to the climate forecasts for their vineyard plots. For that reason, the downscaling technique was applied to increase the spatial resolution, and the bar plots were designed to show the forecast for a specific location. However, to improve the perception of the forecast quality, the forecast can be contextualised by providing the forecast in the format of a map of the surrounding areas.Despite all these limitations, end-users reported on the extreme importance of climate information. Furthermore, end-users can benefit from getting the climate services integrated with the impact models to take maximum advantage of all services and make timely decisions, but also receiving this information in a clear, parsimonious and direct format that is intuitive and can be easily incorporated into the decision-making processes is key for the sustainability of their farm fields.After the operational provision of the climate forecast service, some implications of our findings have been detected: ● Combined downscaling and contextualisation. Downscaling techniques help to provide more accurate information at the location scale. Nevertheless, the spatial visualization over large regions may help to contextualize the climate forecasts, and that is also beneficial for end-user interpretation of the climate-related information. ● Skill. Efforts to provide more skilful climate forecasts are required, as well as alternative information to be used in situations where skill is lacking (e.g.: past climate information). The skill assessment is crucial to inform users about forecast reliability and accuracy. It enhances user understanding and trust in the service by generating realistic expectations. ● Operationalisation. Reducing the time for data processing or increasing the computational resources will allow the provision of climate forecasts that are closer to the date of production. Users will benefit from earlier access to the information than the current time-lapse. ● Co-production. The co-production process ensures the service is designed based on user needs and feedback which is more likely to be adopted and effectively utilized by users. This process never ends, so, it needs to be applied if future developments or requests are included in the current service. ● Support for sustainability. End-users benefit from the integration of the climate forecast along with phenological and disease risk services. Further explorations to include more climate variables in the service and in the impact models will be beneficial for end-users. For instance, the probabilities of extreme events help vineyard managers prepare for potential adverse conditions, while, safeguarding vineyards against weather impacts through proactive measures. ● Capacity building. By training users about the nature of climate forecasts, they can enhance the preparedness and resilience response to varying climate conditions. New information and products could be co-explored to co-evaluate their utility and usefulness.

IntroductionLung carcinoids (LCs) are a type of neuroendocrine tumor (NET) that originate in the bronchopulmonary tract. LCs account for 20–25% of all NETs and approximately 1–2% of lung cancers. Given the highly vascularized nature of NETs and their tendency to overexpress vascular growth factor receptors (VEGFR), inhibiting angiogenesis appears as a potential therapeutic target in slowing down tumor growth and spread. This study evaluated the long-term antitumor activity and related mechanisms of axitinib (AXI), a VEGFR-targeting drug, in LC cell lines.MethodsThree LC cell lines (NCI-H727, UMC-11 and NCI-H835) were incubated with their respective EC50 AXI concentrations for 6 days. At the end of the incubation, FACS experiments and Western blot analyses were performed to examine changes in the cell cycle and the activation of apoptosis. Microscopy analyses were added to describe the mechanisms of senescence and mitotic catastrophe when present.ResultsThe primary effect of AXI on LC cell lines is to arrest tumor growth through an indirect DNA damage. Notably, AXI triggers this response in diverse manners among the cell lines, such as inducing senescence or mitotic catastrophe. The drug seems to lose its efficacy when the DNA damage is mitigated, as observed in NCI-H835 cells.ConclusionThe ability of AXI to affect cell viability and proliferation in LC tumor cells highlights its potential as a therapeutic agent. The role of DNA damage and the consequent activation of senescence seem to be a prerequisite for AXI to exert its function.

Background & Aims: Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms. Methods: Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model. Results: Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 μm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load. Conclusions: Maternal obesity increases female offspring’s susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition. Impact and implications: The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.

The aim of the article is to conduct a critical analysis on how some historical videogames recreate and reinterpret medieval wars. The historical games analyzed include highly successful video game sagas such as Age of Empires II, and related expansions, and the Total War saga, to which is added the Mod Medieval Kingdoms 1212 A.D. After having analyzed the content, we will proceed to observe how videogames also contribute to mediating our relationship with the Middle Ages through the concept of “medievalism”, that is, that cultural phenomenon that projects in the present time one or more idealized representations of the medieval period, in particular with the sphere of war.

Abstract In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58–97) and 49% (95% CI 31–77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

Abstract This publication is an update of the “Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology” published in 2019, considering the novel, targeted-oriented systemic therapies for atopic dermatitis. The initial recommendations of the current consensus for systemic treatment of patients with atopic dermatitis were based on a recent review of scientific published data and a consensus was reached after voting. The Brazilian Society of Dermatology invited 31 experts from all regions of Brazil and 2 international experts on atopic dermatitis who fully contributed to the process. The methods included an e-Delphi study to avoid bias, a literature search and a final consensus meeting. The authors added novel approved drugs in Brazil and the indication for phototherapy and systemic therapy for AD. The therapeutical response to systemic treatment is hereby reported in a suitable form for clinical practice and is also part of this updated manuscript.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Abstract Background Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. Methods This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3–5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. Discussion Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. Trial registration LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019–004506-10).

The aim of the paper is to explain what is meant by Digital Risk&Governance. For this purpose, it is important to retrace the technological evolution that has affected the last few decades: from branches to Mobile Banking, from the digitalization of transactions to the creation of Fintech, from the first process automations to Artificial Intelligence. This evolutionary journey has not only involved and still involves the birth of new technologies, but also the possibility of seizing new business opportunities and therefore necessarily of facing new types of risk, which are not always intuitive and easy to fully understand and manage. In this context, the role of the Regulator is fundamental not only to make available to companies elements for a correct and complete understanding of Digital/ICT Risk, but also to provide guidelines that allow for the construction of an organizational and governance model suitable for gaining awareness risk and to assess, manage and monitor it. A fundamental role is played by the Digital Operational Resilience Act (DORA), which certainly better defines some aspects that until recently did not find a clear place, but - even more important - which allows these aspects to be included in an organic and holistic framework. Governance and organization are essential in this panorama, the only functions capable of spreading the risk culture necessary to overcome the silo mentality and to establish the cultural paradigm change essential for managing ICT Risk. Given the extension of the perimeter that is generally included under this risk, the paper goes on to underline the most relevant aspects and suggests in a practical way the components on which companies should concentrate in order to implement and make usable an all-round management framework: from the identification of critical functions to the importance of having tools capable of certifying the correctness, completeness and quality of the data. Another high-sounding and closely related theme, which therefore could not fail to be addressed in the paper, is represented by the cyberattack and its impacts on the market. The paper then closes with a theme which, in our opinion, plays an even more stately role than the creation of an overall framework can play: the Digital Strategy, consciously accessible only through a Digital Risk&Governance framework, but which represents the ultimate goal to which companies should aspire.

BackgroundEnterobacterales are often responsible for urinary tract infection (UTI) in kidney transplant recipients. Among these, Escherichia coli or Klebsiella species producing extended-spectrum beta-lactamase (ESBL) are emerging. However, there are only scarce data on frequency and impact of ESBL-UTI on transplant outcomes.MethodsWe investigated frequency and impact of first-year UTI events with ESBL Escherichia coli and/or Klebsiella species in a prospective multicenter cohort consisting of 1,482 kidney transplants performed between 2012 and 2017, focusing only on 389 kidney transplants having at least one UTI with Escherichia coli and/or Klebsiella species. The cohort had a median follow-up of four years.ResultsIn total, 139/825 (17%) first-year UTI events in 69/389 (18%) transplant recipients were caused by ESBL-producing strains. Both UTI phenotypes and proportion among all UTI events over time were not different compared with UTI caused by non-ESBL-producing strains. However, hospitalizations in UTI with ESBL-producing strains were more often observed (39% versus 26%, p = 0.04). Transplant recipients with first-year UTI events with an ESBL-producing strain had more frequently recurrent UTI (33% versus 18%, p = 0.02) but there was no significant difference in one-year kidney function as well as longer-term graft and patient survival between patients with and without ESBL-UTI.ConclusionFirst-year UTI events with ESBL-producing Escherichia coli and/or Klebsiella species are associated with a higher need for hospitalization but do neither impact allograft function nor allograft and patient survival.