The Natural Compound Fucoidan From New Zealand Undaria Pinnatifida Synergizes With the ERBB Inhibitor Lapatinib Enhancing Melanoma Growth Inhibition

Melanoma remains one of the most aggressive and therapy-resistant cancers. Finding new treatments to improve patient outcomes is an ongoing effort. We previously demonstrated that melanoma relies on the activation of ERBB signaling, specifically of the ERBB3/ERBB2 cascade. Here we show that melanoma tumor growth is inhibited by 60% over controls when treated with lapatinib, a clinically approved inhibitor of ERBB2/EGFR. Importantly, tumor growth is further inhibited to 85% when the natural compound fucoidan from New Zealand U. pinnatifida is integrated into the treatment regimen. Fucoidan not only enhances tumor growth inhibition, it counteracts the morbidity associated with prolonged lapatinib treatment. Fucoidan doubles the cell killing capacity of lapatinib. These effects are associated with a further decrease in AKT and NFκB signaling, two key pathways involved in melanoma cell survival. Importantly, the enhancing cell killing effects of fucoidan can be recapitulated by inhibiting ERBB3 by either a specific shRNA or a novel, selective ERBB3 neutralizing antibody, reiterating the key roles played by this receptor in melanoma. We therefore propose the use of lapatinib or specific ERBB inhibitors, in combination with fucoidan as a new treatment of melanoma that potentiates the effects of the inhibitors while protecting from their potential side effects

Thermal characteristics of springs fed by mountain permafrost in Val di Sole (Eastern Italian Alps)

In alpine areas, spring-water temperature is affected by the presence of permafrost and by changes in the periglacial domain caused by the current atmospheric warming. Our interest in spring-water temperature is related to the possibility of investigating the spatial distribution of alpine permafrost and its changes. In particular, spring-water temperature might be helpful as indicator of permafrost occurrence in areas where it is discontinuous or sporadic, and in general where its distribution is poorly known. The spring-water temperature in late summer is a useful evidence of permafrost, and various authors employed such method as auxiliary permafrost evidence, or as a stand-alone method that can be used for mapping permafrost distribution at the catchment scale. However, little is known on the spatial and temporal variability of water temperature at springs with different permafrost contribution and characteristics. Here we present an analysis of the spatial and temporal variability of spring-water temperature in a 795 km2 catchment located in the Eastern Italian Alps, aimed at investigating the spatial distribution of permafrost and its effect on spring-water temperature. From 2018 to 2021, we measured the late-summer spring-water temperature at 220 springs, 133 of which are located downslope of rock glaciers, 81 downslope of other deposits, and 8 in bedrock. In addition, we installed dataloggers for continuous temperature measurements at 31 springs. Results show that the cold springs are mainly associated with intact rock glaciers but also with rock glaciers classified as relict, especially if they have blocky and sparsely vegetated surface. Accordingly, the latter should be reclassified as pseudo-relict, i.e. they appear to be visually relict but host patchy permafrost, as confirmed by geophysics carried out at selected case studies. These results have important implications for the study and modelling of the hydrological, hydrochemical and ecological response of periglacial environments under ongoing climate change

Brief communication: Mountain permafrost acts as an aquitard during an infiltration experiment monitored with electrical resistivity tomography time-lapse measurements

Frozen layers within the subsurface of rock glaciers are generally assumed to act as aquicludes or aquitards. So far, this behavior has been mainly defined by analyzing the geochemical characteristics of spring waters. In this work, for the first time, we experimentally confirmed this assumption by executing an infiltration test in a rock glacier of the Southern Alps, Italy. Time-lapse electrical resistivity tomography (ERT) technique monitored the infiltration of 800 L of saltwater released on the surface of the rock glacier; 24 h ERT monitoring highlighted that the injected water was not able to infiltrate into the underlying frozen layer.</p

Social Preferences, Skill Segregation and Wage Dynamics

We study the earning structure and the equilibrium asignment of workers to firms in a model in which workers have social preferences, and skills are perfectly substitutable in production. Firms offer long-term contracts, and we allow for frictions in the labour market in the form of mobility costs. The model delivers specific predictions about the nature of worker flows, about the characteristic of workplace skill segregation, and about wage dispersion both within and cross firms. We shows that long-term contracts in the resence of social preferences associate within-firm wage dispersion with novel "internal labour market" features such as gradual promotions, productivity-unrelated wage increases, and downward wage flexibility. These three dynamic features lead to productivity-unrelated wage volatily within firms.Publicad

Quantifying the Loss of Coral from a Bleaching Event Using Underwater Photogrammetry and AI-Assisted Image Segmentation

Detecting the impacts of natural and anthropogenic disturbances that cause declines in organisms or changes in community composition has long been a focus of ecology. However, a tradeoff often exists between the spatial extent over which relevant data can be collected, and the resolution of those data. Recent advances in underwater photogrammetry, as well as computer vision and machine learning tools that employ artificial intelligence (AI), offer potential solutions with which to resolve this tradeoff. Here, we coupled a rigorous photogrammetric survey method with novel AI-assisted image segmentation software in order to quantify the impact of a coral bleaching event on a tropical reef, both at an ecologically meaningful spatial scale and with high spatial resolution. In addition to outlining our workflow, we highlight three key results: (1) dramatic changes in the three-dimensional surface areas of live and dead coral, as well as the ratio of live to dead colonies before and after bleaching; (2) a size-dependent pattern of mortality in bleached corals, where the largest corals were disproportionately affected, and (3) a significantly greater decline in the surface area of live coral, as revealed by our approximation of the 3D shape compared to the more standard planar area (2D) approach. The technique of photogrammetry allows us to turn 2D images into approximate 3D models in a flexible and efficient way. Increasing the resolution, accuracy, spatial extent, and efficiency with which we can quantify effects of disturbances will improve our ability to understand the ecological consequences that cascade from small to large scales, as well as allow more informed decisions to be made regarding the mitigation of undesired impacts

Economies of (Alleged) Deviance: Sex Work and the Sport Mega Event

Based on ethnographic data collected during the 2014 FIFA World Cup and 2016 Olympic Games in Rio de Janeiro, Brazil, thisarticle is interested to examine urban processes which reinvent the changing (sexual) landscape. Focusing on the way (host) citiesshape sex work both imaginatively and physically, we explore the (lived) realities of neoliberal imaginaries that shape urbanspace. Often thought to exist in the urban shadow as an absent-presence in cosmopolitan processes, we demonstrate the manner inwhich sexualized and racialized women creatively resist the political and economic trajectories of neoliberal urbanism that seek toexpropriate land and dispossess certain bodies. In the context of Rio de Janeiro—as in other host cities—this is particularlyevident in the routine encounter between sexual minorities and local law enforcement. Mindful of the literature on state incursioninto social-sexual life, we remain attentive to the everyday strategies through which those deemed sexually deviant and/or victimnavigate local authorities in search of new opportunities for economic salvation in the midst of the sport mega-event

Predictors of atrial fibrillation detection in embolic stroke of undetermined source patients with implantable loop recorder

Background: Covert atrial fibrillation (AF) is a predominant aetiology of embolic stroke of undetermined source (ESUS). Evidence suggested that AF is more frequently detected by implantable loop recorder (ILR) than by conventional monitoring. However, the predictive factors associated with occult AF detected using ILRs are not well established yet. In this study we aim to investigate the predictors of AF detection in patients with ESUS undergoing an ILR. Methods: This observational multi-centre study included consecutive ESUS patients who underwent ILR implantation. The infarcts were divided in deep, cortical infarcts or both. The infarction sites were categorized as anterior and middle cerebral artery, posterior cerebral artery with and without brainstem/cerebellum involvement. Multivariable logistic regression analysis was performed to investigate variables associated with AF detection. Results: Overall, 3,000 patients were initially identified. However, in total, 127 patients who consecutively underwent ILR implantation were included in our analysis. AF was detected in 33 (26%) out of 127 patients. The median follow-up was 411 days. There were no significant differences in clinical characteristics and comorbidities between patients with and without AF detected. AF was detected more often after posterior cerebral artery infarct with brainstem/cerebellum involvement (p < 0.001) whereas less often after infarction in the anterior and middle cerebral artery (p = 0.021). Multivariable regression analysis demonstrated that posterior cerebral artery infarct with brainstem/cerebellum involvement was an independent predictor of AF detection. Conclusion: Our study showed that posterior circulation infarcts with brainstem/cerebellum involvement are associated with AF detection in ESUS patients undergoing ILR. Larger prospective studies are needed to validate our findings

Effectiveness of first and second-line empirical treatment in Italy: Results of the European registry on Helicobacter pylori management.

Background and aims: The optimal management of naïve and not naïve Helicobacter pylori patients remains unclear. Therefore, it is essential to evaluate whether the actual clinical practice mirrors the indications suggested by the guidelines. This study aimed to assess the effectiveness and the safety of the empirical first- and second-line treatments prescribed to patients enroled at Italian centres participating in the European Registry on H. pylori Management (Hp-EuReg). Methods: The Hp-EuReg is an international multicentre prospective non-interventional registry starting in 2013 aiming to evaluate the management of H. pylori infection by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables assessed included demographics, previous eradication attempts, treatment regimen, effectiveness, and tolerance. Results: Overall, 3723 patients from 2013 to February 2021 were included: 2996 and 727 received an empirical first- and second-line treatment, respectively. According to the modified ITT analysis, among the first-line regimens, only the bismuth quadruple therapy with three-in-one-single capsule (BQT-TSC), the concomitant, and the sequential treatment - all lasting 10 days - achieved an eradication rate &gt;90%. Among the second-line regimens, only the 10-day BQT-TSC reported an effectiveness &gt;90%. High-dose PPI twice daily also significantly increased the effectiveness of some therapies. The BQT-TSC was the regimen with the highest incidence of adverse events. Conclusions: Only quadruple therapies lasting at least 10 days achieved over 90% eradication rates among the empirical first- and second-line regimens. It remains unclear whether high-dose PPI twice daily can improve the efficacy of quadruple treatment

Analysis of Clinical Phenotypes through Machine Learning of First-Line H. pylori Treatment in Europe during the Period 2013–2022: Data from the European Registry on H. pylori Management (Hp-EuReg)

The segmentation of patients into homogeneous groups could help to improve eradication therapy effectiveness. Our aim was to determine the most important treatment strategies used in Europe, to evaluate first-line treatment effectiveness according to year and country. Data collection: All first-line empirical treatments registered at AEGREDCap in the European Registry on Helicobacter pylori management (Hp-EuReg) from June 2013 to November 2022. A Boruta method determined the “most important” variables related to treatment effectiveness. Data clustering was performed through multi-correspondence analysis of the resulting six most important variables for every year in the 2013–2022 period. Based on 35,852 patients, the average overall treatment effectiveness increased from 87% in 2013 to 93% in 2022. The lowest effectiveness (80%) was obtained in 2016 in cluster #3 encompassing Slovenia, Lithuania, Latvia, and Russia, treated with 7-day triple therapy with amoxicillin–clarithromycin (92% of cases). The highest effectiveness (95%) was achieved in 2022, mostly in Spain (81%), with the bismuth–quadruple therapy, including the single-capsule (64%) and the concomitant treatment with clarithromycin–amoxicillin–metronidazole/tinidazole (34%) with 10 (69%) and 14 (32%) days. Cluster analysis allowed for the identification of patients in homogeneous treatment groups assessing the effectiveness of different first-line treatments depending on therapy scheme, adherence, country, and prescription year

COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models

The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax—a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)—induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started