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Despite the progressions in COVID-19 understanding, the optimization of patient-specific therapies remains a challenge. Statins, the most widely prescribed lipid-lowering drugs, received considerable attention due to their pleiotropic effects, encompassing lipid metabolism control and immunomodulatory and anti-thrombotic effects. In COVID-19 patients, statins improve clinical outcomes, reducing Intensive Care Unit admission, the onset of ARDS, and in-hospital death. However, the safety of statins in COVID-19 patients has been debated, mainly for statins’ ability to induce the expression of the ACE2 receptor, the main entry route of SARS-CoV-2. Unfortunately, the dynamic of statins’ mechanism in COVID-19 disease and prevention remains elusive. Using different in vitro models expressing different levels of ACE2 receptor, we investigated the role of lipophilic and hydrophilic statins on ACE2 receptor expression and subcellular localization. We demonstrated that the statin-mediated increase of ACE2 receptor expression does not necessarily coincide with its localization in lipid rafts domains, particularly after treatments with the lipophilic atorvastatin that disrupt lipid rafts’ integrity. Through a proteomic array, we analyzed the cytokine patterns demonstrating that statins inhibit the release of cytokines and factors involved in mild to severe COVID-19 cases. The results obtained provide additional information to dissect the mechanism underlying the protective effects of statin use in COVID-19.

Background and Objectives: Uterine sarcomas represents only 3% of all the female genital tract ones. The tumoral stage is the most significant prognostic factor. The role of the bilateral salpingo-oophorectomy (BSO) in the surgical management of FIGO stage IA and IB appears still controversial. This review aims to investigate the impact of bilateral adnexectomy in the treatment of uterine sarcoma. Methods: Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched the PubMed, Scopus, Cochrane, Medline, and Medscape databases in February 2022. We applied no language or geographical restrictions, but we considered only English studies. We included the studies containing data about Recurrence Rate (RR), Disease-free Survival (DFS), and Overall Survival (OS). We used comparative studies for meta-analysis. Results: Seventeen studies fulfilled the inclusion criteria; 2 retrospective observational studies, and 15 retrospective comparative studies, And 14 out of the 15 comparative studies were enrolled in meta-analysis. A total of 3743 patients were analyzed concerning the use of adnexectomy with hysterectomy in patients with uterine sarcoma and compared with those who did not. Meta-analysis highlighted a non-significant worsening of the OS in the BSO group compared to the OP group and showed that adnexectomy does not improve the DFS (BSO OR 1.23 (95% CI 0.81–1.85) p = 0.34; I2 = 24% p = 0.22). Conclusions: Most studies selected for our review showed that adnexectomy does not significantly affect the RR, OS, and PFS in treating FIGO stage I uterine sarcomas. Therefore, even if there is a unanimous consensus about bilateral adnexectomy in menopausal patients, preservation of ovarian tissue may be considered in premenopausal women. Nonetheless, there are not enough cases in the literature to recommend this procedure.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The complex metabolic dysregulation at the base of this syndrome often renders infertility management challenging. Many pharmacological strategies have been applied for the induction of ovulation with a non-negligible rate of severe complications such as ovarian hyperstimulation syndrome and multiple pregnancies. Ovarian drilling (OD) is currently being adopted as a second-line treatment, to be performed in case of medical therapy. Laparoscopic ovarian drilling (LOD), the contemporary version of ovarian wedge resection, is considered effective for gonadotropins in terms of live birth rates, but without the risks of iatrogenic complications in gonadotropin therapy. Its endocrinal effects are longer lasting and, after the accomplishment of this procedure, ovarian responsiveness to successive ovulation induction agents is enhanced. Traditional LOD, however, is burdened by the potential risks of iatrogenic adhesions and decreased ovarian reserve and, therefore, should only be considered in selected cases. To overcome these limits, novel tailored and mini-invasive approaches, which are still waiting for wide acceptance, have been introduced, although their role is still not well-clarified and none of them have provided enough evidence in terms of efficacy and safety.

We report the implementation of our in silico/synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds 1c and 2c showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, 1c and 2c exhibited interesting IC50 values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound 2c induced the cycle arrest in the G0/G1 phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG0/G1 fraction, suggesting an apoptosis/necrosis effect.

Background Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.Methods The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment.Results Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated.Conclusion These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer.Trial registration number This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

Cardiac magnetic resonance imaging (MRI) has revealed fibrosis in embolic stroke of undetermined source (ESUS) patients comparable to levels seen in atrial fibrillation (AFib). We used computational modeling to understand the absence of arrhythmia in ESUS despite the presence of putatively pro-arrhythmic fibrosis. MRI-based atrial models were reconstructed for 45 ESUS and 45 AFib patients. The fibrotic substrate’s arrhythmogenic capacity in each patient was assessed computationally. Reentrant drivers were induced in 24/45 (53%) ESUS and 22/45 (49%) AFib models. Inducible models had more fibrosis (16.7 ± 5.45%) than non-inducible models (11.07 ± 3.61%; p

Hybrid materials based on amorphous titanium or zirconium oxide with specific organic ligands show oxidative activity toward organic pollutants in the dark, owing to the generation and unusual long-term adsorption of superoxide radical anions on their surfaces. Here an overview of perspectives for the development of these materials and their processing towards technological applications is presented, focusing on the TiO2-acetylacetonate system. First, the tuning and optimization of the sol-gel synthesis conditions is discussed, aimed at yielding the desired products, such as chemical gels or stable sols. Then the thermal stability of the hybrid dried gels is assessed, in relation to their ability to form superoxide radicals. Finally, electrospinning is introduced as an efficient and ecofriendly technique to support the xerogel powders embedding them in a porous nanofiber polymer network. The preliminary characterization of the electrospun composite polyvinylpyrrolidone-hybrid TiO2 reveals potentialities for the realization of air filters or antimicrobial gauzes.

The paper aims to analyse Norbert Elias’ legacy in the sociology of sport, marked by the centrality of figurational theory in the tradition of this field of study. The typical features of this approach, also applied to sport analysis, are: the focus on figurations, that is on the networks of interdependence in the structuring of social phenomena; the idea of the processual character of social reality; the idea that social processes are the effect of the interconnection of unintentional actions; the importance of the power differential. On this theoretical basis Elias and his followers explore the relationship between civilization and sportization as fundamental ingredients of the definition of modern society and sports, analyse the role of sport as a site of emotional expression and harmless excitement in a social reality based on the routine control of emotions, seek in the study of hooliganism confirmation of the validity of the basic assumptions of figurational theory. A theory that has produced a wide and fervent debate in the scientific community.

Abstract Introduction: The COVID-19 pandemic has created a high demand on personal protective equipment, including disposable N95 masks. Given the need for mask reuse, we tested the feasibility of vaporized hydrogen peroxide (VHP), ultraviolet light (UV), and ethanol decontamination strategies on N95 mask integrity and the ability to remove the infectious potential of SARS-CoV-2. Methods: Disposable N95 masks, including medical grade (1860, 1870+) and industrial grade (8511) masks, were treated by VHP, UV, and ethanol decontamination. Mask degradation was tested using a quantitative respirator fit testing. Pooled clinical samples of SARS-CoV-2 were applied to mask samples, treated, and then either sent immediately for real-time reverse transcriptase–polymerase chain reaction (RT-PCR) or incubated with Vero E6 cells to assess for virucidal effect. Results: Both ethanol and UV decontamination showed functional degradation to different degrees while VHP treatment showed no significant change after two treatments. We also report a single SARS-CoV-2 virucidal experiment using Vero E6 cell infection in which only ethanol treatment eliminated detectable SARS-CoV-2 RNA. Conclusions: We hope our data will guide further research for evidenced-based decisions for disposable N95 mask reuse and help protect caregivers from SARS-CoV-2 and other pathogens.

The most severe outcome of COVID-19 infection is the development of interstitial pneumonia causing acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), both responsible for the infected patients' mortality. ALI and ARDS are characterized by a leakage of plasma components into the lungs, compromising their ability to expand and optimally engage in gas exchange with blood, resulting in respiratory failure. We have previously reported that zonulin, a protein dictating epithelial and endothelial permeability in several districts, including the airways, is involved in ALI pathogenesis in mouse models, and that its peptide inhibitor Larazotide acetate (also called AT1001) ameliorated ALI and subsequent mortality by decreasing mucosal permeability to fluid and extravasation of neutrophils into the lungs. With the recent crystallographic resolution of the SARS-CoV-2 main protease (Mpro), an enzyme fundamental in the viral lifecycle, bound to peptidomimetic inhibitors N3 and 13b, we were able to perform molecular modeling investigation showing that AT1001 presents structural motifs similar to co-crystallized ligands. Specifically, molecular docking, MM-GBSA-based predictions and molecular dynamics showed that AT1001 docks extremely well in the Mpro catalytic domain through a global turn conformational arrangement without any unfavorable steric hindrance. Finally, we have observed that AT1001 can be superimposed onto the crystallized structures of N3 and 13b, establishing a higher number of interactions and accordingly a tighter binding. In vitro studies confirmed AT1001 anti-Mpro and preliminary investigation indicted an anti-viral activity. Combined, these studies suggest that AT1001, besides its well-demonstrated effect in ameliorating mucosal permeability in ALI/ARDS, may also exert a direct anti-SARS-CoV-2 effect by blocking the Mpro. AT1001 has been used extensively in a variety of animal models of ALI demonstrating robust safety and efficacy; it is currently in phase 3 trials in celiac subjects showing strong safety and efficacy profiles. We therefore propose its use as a specific anti-SARS-CoV-2 multitargeting treatment for the current pandemic.

Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of “early-stage TLS” (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8+ T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS+ tumors were enriched for IgG1 class-switched memory B cells and memory CD4+ T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4+ memory cells, naive B cells and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS+ tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS+ tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. AbbreviationsTLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment.

We find evidence of enrollment increases in both Syracuse and Buffalo following the announcement of a placed-based scholarship program, Say Yes to Education. While the Syracuse increases were accompanied by enrollment declines in surrounding suburban districts, the Buffalo increases coincided with declines in private school enrollments. Buffalo and Rochester also saw enrollment increases relative to trends following the announcement of Say Yes in Syracuse, suggesting that part of the increase in Syracuse might be attributable to factors other than Say Yes. We also find evidence of increases in home prices in Syracuse after the program's announcement, as well as decreases in the surrounding suburbs. We do not find evidence of similar housing price changes in Buffalo.

The development of new bioactive compounds represents one of the main purposes of the drug discovery process. Various tools can be employed to identify new drug candidates against pharmacologically relevant biological targets, and the search for new approaches and methodologies often represents a critical issue. In this context, in silico drug repositioning procedures are required even more in order to re-evaluate compounds that already showed poor biological results against a specific biological target. 3D structure-based pharmacophoric models, usually built for specific targets to accelerate the identification of new promising compounds, can be employed for drug repositioning campaigns as well. In this work, an in-house library of 190 synthesized compounds was re-evaluated using a 3D structure-based pharmacophoric model developed on soluble epoxide hydrolase (sEH). Among the analyzed compounds, a small set of quinazolinedione-based molecules, originally selected from a virtual combinatorial library and showing poor results when preliminarily investigated against heat shock protein 90 (Hsp90), was successfully repositioned against sEH, accounting the related built 3D structure-based pharmacophoric model. The promising results here obtained highlight the reliability of this computational workflow for accelerating the drug discovery/repositioning processes.

Cannabis sativa L. is a plant belonging to the Cannabaceae family, cultivated for its psychoactive cannabinoid (Δ9-THC) concentration or for its fiber and nutrient content in industrial use. Industrial hemp shows a low Δ9-THC level and is a valuable source of phytochemicals, mainly represented by cannabinoids, flavones, terpenes, and alkaloids, with health-promoting effects. In the present study, we investigated the phytochemical composition of leaves of the industrial hemp cultivar Futura 75, a monoecious cultivar commercially used for food preparations or cosmetic purposes. Leaves are generally discarded, and represent waste products. We analyzed the methanol extract of Futura 75 leaves by HPLC and NMR spectroscopy and the essential oil by GC-MS. In addition, in order to compare the chemical constituents, we prepared the water infusion. One new cannabinoid derivative (1) and seven known components, namely, cannabidiol (2), cannabidiolic acid (3), β-cannabispirol (4), β-cannabispirol (5), canniprene (6), cannabiripsol (7), and cannflavin B (8) were identified. The content of CBD was highest in all preparations. In addition, we present the outcomes of a computational study focused on elucidating the role of 2α-hydroxy-Δ3,7-cannabitriol (1), CBD (2), and CBDA (3) in inflammation and thrombogenesis.

During surgical procedures, real-time estimation of the current position of a metal lead within the patient’s body is obtained by radiographic imaging. The inherent opacity of metal objects allows their visualization using X-ray fluoroscopic devices. Although fluoroscopy uses reduced radiation intensities, the overall X-ray dose delivered during prolonged exposure times poses risks to the safety of patients and physicians. This study proposes a potential alternative to real-time visualization of a lead inside the human body. In principle, by making a weak current flow through the lead and measuring the related magnetic field generated outside the body, it is possible to trace the position of the lead. This hypothesis was verified experimentally via two tests: one carried out on a curved copper wire in air and one carried out on a real pacemaker lead in a saline solution. In the second test, a pacemaker lead and a large return electrode were placed in a tank filled with a saline solution that reproduced the mean resistivity of the human torso. In both tests, a current flowed through the lead, which consisted of square pulses with short duration, to avoid any neuro-muscular stimulation effects in a real scenario. A small coil with a ferrite core was moved along a grid of points over a plastic sheet and placed just above the lead to sample the spatial amplitude distribution of the magnetic induction field produced by the lead. For each measurement point, the main coil axis was oriented along the x and y axes of the plane to estimate the related components of the magnetic induction field. The two matrices of measurements along the x and y axes were further processed to obtain an estimate of lead positioning. The preliminary results of this study support the scientific hypothesis since the positions of the leads were accurately estimated. This encourages to deepen the investigation and overcome some limitations of this feasibility study.

Seismocardiography (SCG) is largely regarded as the state-of-the-art technique for continuous, long-term monitoring of cardiac mechanical activity in wearable applications. SCG signals are acquired via small, lightweight accelerometers fixed on the chest. They provide timings of important cardiac events, such as heart valves openings and closures, thus allowing the estimation of cardiac time intervals of clinical relevance. Forcecardiography (FCG) is a novel technique that records the cardiac-induced vibrations of the chest wall by means of specific force sensors, which proved capable of monitoring respiration, heart sounds and infrasonic cardiac vibrations, simultaneously from a single contact point on the chest. A specific infrasonic component captures the heart walls displacements and looks very similar to the Apexcardiogram. This low-frequency component is not visible in SCG recordings, nor it can be extracted by simple filtering. In this study, a feasible way to extract this information from SCG signals is presented. The proposed approach is based on double integration of SCG. Numerical double integration is usually very prone to large errors, therefore a specific numerical procedure was devised. This procedure yields a new displacement signal (DSCG) that features a low-frequency component (LF-DSCG) very similar to that of the FCG (LF-FCG). Experimental tests were carried out using an FCG sensor and an off-the-shelf accelerometer firmly attached to each other and placed onto the precordial region. Simultaneous recordings were acquired from both sensors, together with an electrocardiogram lead (used as a reference). Quantitative morphological comparison confirmed the high similarity between LF-FCG and LF-DSCG (normalized cross-correlation index >0.9). Statistical analyses suggested that LF-DSCG, although achieving a fair sensitivity in heartbeat detection (about 90%), has not a very high consistency within the cardiac cycle, leading to inaccuracies in inter-beat intervals estimation. Future experiments with high-performance accelerometers and improved processing methods are envisioned to investigate the potential enhancement of the accuracy and reliability of the proposed method.

BackgroundBreast cancer represents the most frequent neoplasm diagnosed in women of childbearing age. When the tumour is oestrogen receptor-positive, tamoxifen is among the recommended endocrine treatments. Lactating women are advised not to breastfeed while receiving tamoxifen. However, information about tamoxifen transfer into breast milk is lacking.MethodsWe measured the concentration of tamoxifen and its metabolites by liquid chromatography-tandem mass spectrometry in the milk of a nursing mother that was treated for pregnancy-associated breast cancer diagnosed a few months after delivery. She was advised not to breastfeed her child and she collected milk samples for 23 days while the baby was fed with formula.ResultsTamoxifen concentrations in milk increased reaching a maximum of 214 nM. The two active metabolitesZ-4-hydroxy-tamoxifen and Z-endoxifen, could not be quantified in milk the first days after tamoxifen intake, but increased over time and reached clinically significant levels after day 18.ConclusionThis study demonstrates for the first time in human that tamoxifen and its metabolites transfer into milk. Since tamoxifen has a complete oral bioavailability, a long half-life (>7 days) and may interfere with the normal development of the infant, mothers should not breastfeed during tamoxifen treatment.

Silica-epoxy nanocomposites were prepared via an “in-situ” sol-gel synthesis process and a phosphorus (P) flame-retardant i.e. 6H-dibenz[c,e][1,2]oxaphosphorin,6-[(1-oxido-2,6,7-trioxa-1-phosphabicyclo[2.2.2]oct-4-yl)methoxy]-, 6-oxide (DP) and melamine (Mel) were further added to the matrix to improve its fire performance. The main components of epoxy resin were bisphenol A diglycidyl ether (DGEBA) and isophorone diamine (IPDA) hardener. The addition of DP as well as silica alone into the epoxy system stopped the melt dripping phenomena in the vertical fire test (UL 94), however, the addition of melamine was crucial for achieving the highest fire classification (UL 94-V0 rating). The presence of DP and Mel in the silica-epoxy nanocomposite promoted a large reduction (ranging from 53% up to 80%) in the heat release rate (HRR) and a delay (up to 31%) in the ignition time in the cone calorimetry experiments. Improved fire performance of the epoxy system was attributed to i) a condensed phase activity of silica, DP and melamine to form a protective thermal barrier during combustion and ii) a minor gas phase flame inhibition activity of DOPO component of DP. The mechanical characterization of the epoxy nanocomposites through tensile tests showed that the addition of DP increases the stiffness of the epoxy resin, resulting in a strong increase of Young modulus (up to 32%) and in a slight decrease of fracture strength, elongation at break and toughness. An increased glass transition temperature (up to 8%) of the epoxy system possibly due to hydrogen bonds and polar interactions of DP with the matrix was also observed.

This paper focuses on Social Investment and Social Innovation, two crucial policy strategies within the current reorganization of European Welfare States. The aim is to illuminate the ambivalent dynamics of change, adaptation, and resistance that they unleash in the everyday governance of social services, especially regarding social citizenship and rights. The analysis is based on the empirical investigation of two cases in Italy: the implementation of an anti-poverty measure in Lombardy, a northern region of the country; and a project underway in Milan since 2015 aimed at reconfiguring the balance between supply and demand in care services within the context of a more comprehensive reorganization of local welfare systems. The two cases show different aspects of social services’ governance, in particular concerning the coexistence of increasingly strict control mechanisms with the emphasis placed on principles of sharing and cooperation.

Objectives The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment.Methods The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms.Results Representative outputs and the advantages and disadvantages of mIHC/mIF approaches, such as multiplexed chromogenic IHC, multiplexed immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, and digital spatial profiling are discussed.Conclusions mIHC/mIF technologies are becoming standard tools for biomarker studies and are likely to enter routine clinical practice in the near future. Careful assay optimization and validation will help ensure outputs are robust and comparable across laboratories as well as potentially across mIHC/mIF platforms. Quantitative image analysis of mIHC/mIF output and data management considerations will be addressed in a complementary manuscript from this task force.

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.

IntroductionItaly became the second epicenter of the novel coronavirus disease 2019 (COVID-19) pandemic after China, surpassing by far China's death toll. The disease swept through Lombardy, which remained in lockdown for about two months, starting from the 8th of March. As of that day, the isolation measures taken in Lombardy were extended to the entire country. Here, assuming that effectively there was one case "zero" that introduced the virus to the region, we provide estimates for: (a) the day-zero of the outbreak in Lombardy, Italy; (b) the actual number of asymptomatic infected cases in the total population until March 8; (c) the basic (R0)and the effective reproduction number (Re) based on the estimation of the actual number of infected cases. To demonstrate the efficiency of the model and approach, we also provide a tentative forecast two months ahead of time, i.e. until May 4, the date on which relaxation of the measures commenced, on the basis of the COVID-19 Community Mobility Reports released by Google on March 29.MethodsTo deal with the uncertainty in the number of the actual asymptomatic infected cases in the total population Volpert et al. (2020), we address a modified compartmental Susceptible/ Exposed/ Infectious Asymptomatic/ Infected Symptomatic/ Recovered/ Dead (SEIIRD) model with two compartments of infectious persons: one modelling the cases in the population that are asymptomatic or experience very mild symptoms and another modelling the infected cases with mild to severe symptoms. The parameters of the model corresponding to the recovery period, the time from the onset of symptoms to death and the time from exposure to the time that an individual starts to be infectious, have been set as reported from clinical studies on COVID-19. For the estimation of the day-zero of the outbreak in Lombardy, as well as of the "effective" per-day transmission rate for which no clinical data are available, we have used the proposed SEIIRD simulator to fit the numbers of new daily cases from February 21 to the 8th of March. This was accomplished by solving a mixed-integer optimization problem. Based on the computed parameters, we also provide an estimation of the basic reproduction number R0 and the evolution of the effective reproduction number Re. To examine the efficiency of the model and approach, we ran the simulator to "forecast" the epidemic two months ahead of time, i.e. from March 8 to May 4. For this purpose, we considered the reduction in mobility in Lombardy as released on March 29 by Google COVID-19 Community Mobility Reports, and the effects of social distancing and of the very strict measures taken by the government on March 20 and March 21, 2020.ResultsBased on the proposed methodological procedure, we estimated that the expected day-zero was January 14 (min-max rage: January 5 to January 23, interquartile range: January 11 to January 18). The actual cumulative number of asymptomatic infected cases in the total population in Lombardy on March 8 was of the order of 15 times the confirmed cumulative number of infected cases, while the expected value of the basic reproduction number R0 was found to be 4.53 (min-max range: 4.40- 4.65). On May 4, the date on which relaxation of the measures commenced the effective reproduction number was found to be 0.987 (interquartiles: 0.857, 1.133). The model approximated adequately two months ahead of time the evolution of reported cases of infected until May 4, the day on which the phase I of the relaxation of measures was implemented over all of Italy. Furthermore the model predicted that until May 4, around 20% of the population in Lombardy has recovered (interquartile range: ∼10% to ∼30%).

Human machine interfaces (HMIs) are employed in a broad range of applications, spanning from assistive devices for disability to remote manipulation and gaming controllers. In this study, a new piezoresistive sensors array armband is proposed for hand gesture recognition. The armband encloses only three sensors targeting specific forearm muscles, with the aim to discriminate eight hand movements. Each sensor is made by a force-sensitive resistor (FSR) with a dedicated mechanical coupler and is designed to sense muscle swelling during contraction. The armband is designed to be easily wearable and adjustable for any user and was tested on 10 volunteers. Hand gestures are classified by means of different machine learning algorithms, and classification performances are assessed applying both, the 10-fold and leave-one-out cross-validations. A linear support vector machine provided 96% mean accuracy across all participants. Ultimately, this classifier was implemented on an Arduino platform and allowed successful control for videogames in real-time. The low power consumption together with the high level of accuracy suggests the potential of this device for exergames commonly employed for neuromotor rehabilitation. The reduced number of sensors makes this HMI also suitable for hand-prosthesis control.

Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N6-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of γ-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Salvia miltiorrhiza Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC50 = 1.9 ± 0.4 µM) and 5-LO (IC50 = 7.1 µM), while TIIA showed no relevant inhibition of these targets. This was consistent with their activity to increase mice bleeding time (CRY: 2.44 ± 0.13 min, p ≤ 0.001; TIIA: 2.07 ± 0.17 min p ≤ 0.01) and with the capability to modulate mouse clot retraction (CRY: 0.048 ± 0.011 g, p ≤ 0.01; TIIA: 0.068 ± 0.009 g, p ≤ 0.05). For the first time, our results show that TIIA and, in particular, CRY are able to interact significantly with the key proteins involved not only in the onset of inflammation but also in platelet activity (and hyper-reactivity). Future preclinical and clinical investigations, together with this evidence, could provide the scientific basis to consider these compounds as an alternative therapeutic approach for thrombotic- and thromboembolic-based diseases.

Voluntary hand movements are usually impaired after a cerebral stroke, affecting millions of people per year worldwide. Recently, the use of hand exoskeletons for assistance and motor rehabilitation has become increasingly widespread. This study presents a novel hand exoskeleton, designed to be low cost, wearable, easily adaptable and suitable for home use. Most of the components of the exoskeleton are 3D printed, allowing for easy replication, customization and maintenance at a low cost. A strongly underactuated mechanical system allows one to synergically move the four fingers by means of a single actuator through a rigid transmission, while the thumb is kept in an adduction or abduction position. The exoskeleton’s ability to extend a typical hypertonic paretic hand of stroke patients was firstly tested using the SimScape Multibody simulation environment; this helped in the choice of a proper electric actuator. Force-myography was used instead of the standard electromyography to voluntarily control the exoskeleton with more simplicity. The user can activate the flexion/extension of the exoskeleton by a weak contraction of two antagonist muscles. A symmetrical master–slave motion strategy (i.e., the paretic hand motion is activated by the healthy hand) is also available for patients with severe muscle atrophy. An inexpensive microcontroller board was used to implement the electronic control of the exoskeleton and provide feedback to the user. The entire exoskeleton including batteries can be worn on the patient’s arm. The ability to provide a fluid and safe grip, like that of a healthy hand, was verified through kinematic analyses obtained by processing high-framerate videos. The trajectories described by the phalanges of the natural and the exoskeleton finger were compared by means of cross-correlation coefficients; a similarity of about 80% was found. The time required for both closing and opening of the hand exoskeleton was about 0.9 s. A rigid cylindric handlebar containing a load cell measured an average power grasp force of 94.61 N, enough to assist the user in performing most of the activities of daily living. The exoskeleton can be used as an aid and to promote motor function recovery during patient’s neurorehabilitation therapy.

The fruit of Garcinia mangostana (mangosteen) is known in ancient traditional Asian medicine for its antioxidant, anti-inflammatory, immunomodulatory and anticancer activities. These effects are mainly due to the action of polyphenols known as xanthones, which are contained in the pericarp of the fruit. In recent years, there has been a growing interest from pharmaceutical companies in formulating new topicals based on mangosteen full extracts to prevent skin aging. However, the molecules responsible for these effects and the mechanisms involved have not been investigated so far. Here, the arils and shells of Garcinia mangostana were extracted with chloroform and methanol, and the extracts were further purified to yield 12 xanthone derivatives. Their effects were evaluated using in vitro cultures of human epidermal keratinocytes. After confirming the absence of cytotoxicity, we evaluated the antioxidant potential of these compounds, identifying mangostanin as capable of both protecting and restoring oxidative damage induced by H2O2. We showed how mangostanin, by reducing the generation of intracellular reactive oxygen species (ROS), prevents the activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53, and other cellular pathways underlying cell damage and apoptosis activation. In conclusion, our study is the first to demonstrate that mangostanin is effective in protecting the skin from the action of free radicals, thus preventing skin aging, confirming a potential toward its development in the nutraceutical and cosmeceutical fields.

The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein–protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several tumor cell lines, where it promotes cell survival signaling and apoptosis resistance through the interaction with many protein partners. In addition, its role as a key player of several hallmarks of cancer, such as metastasis, angiogenesis, autophagy activation, and apoptosis inhibition, has been established. Due to its involvement in malignant transformation, BAG3 has emerged as a potential and effective biological target to control multiple cancer-related signaling pathways. Recently, by using a multidisciplinary approach we reported the first synthetic BAG3 modulator interfering with its BAG domain (BD), based on a 2,4-thiazolidinedione scaffold and endowed with significant anti-proliferative activity. Here, a further in silico-driven selection of a 2,4-thiazolidinedione-based compound was performed. Thanks to a straightforward synthesis, relevant binding affinity for the BAG3BD domain, and attractive biological activities, this novel generation of compounds is of great interest for the development of further BAG3 binders, as well as for the elucidation of the biological roles of this protein in tumors. Specifically, we found compound 6 as a new BAG3 modulator with a relevant antiproliferative effect on two different cancer cell lines (IC50: A375 = 19.36 μM; HeLa = 18.67 μM).

Introduction: Endometriosis is a gynecological disease with a severe impact on quality of life. The aim of this study is to assess mental health status in a group of women with endometriosis, investigating their clinical history, pain symptoms and systemic comorbidities. Methods: An observational cross-sectional study was performed on a group of Italian Caucasian women with endometriosis (n = 134). All patients filled the ‘Patient Health Questionnaire’ (PHQ), a self-administered screening tool for mental health disorders. The characteristics of endometriosis, pain symptoms and their severity, the presence and types of comorbid systemic disorders were added into the same survey. Results: According to PHQ algorithms, 59% of patients were affected by at least one psychiatric disorder, with a significant correlation with pain symptoms (p = 0.0026). Patients with severe pain showed a higher incidence of multiple psychiatric disorders (p = 0.026) and somatoform disorder than those with mild pain (p = 0.0009). There was no correlation between the presence of psychiatric disorders and age, BMI, parity, infertility, need for surgery, number of intervention, localization of endometriotic lesions and systemic comorbidities. Discussion: Women with endometriosis showed a high frequency of PHQ results positive for psychiatric disorders, with a significant association with pain severity.

This paper aims to introduce the sociological processes and mechanisms defining the social imaginary of sports hero, who is a sportsperson acquiring a special status by virtues of his/her extraordinary and exemplary skills, achievements and biography. The sports hero inspires long-term identification and he is symbol of a community, of its values, ideas and collective meanings, while his body incorporates socially appreciated and celebrated qualities. In the dramaturgical and ritual dimension of sport, an athlete can become a collective symbol, and, over time, an hero with mythical features. However, it is only through media narratives that a sportsperson can be heroic and mythical. Thus, the social imaginary in the narrative construction of the sports hero as a central role. The stories revitalise myths, archetypes and beliefs displaying human passions, ambitions, contradictions, conflicts and so on.

Abstract Metastatic melanoma represents a challenging clinical situation and, until relatively recently, there was an absence of effective treatment options. However, in 2011, the advanced melanoma treatment landscape was revolutionised with the approval of the anti-cytotoxic T-lymphocyte-associated protein-4 checkpoint inhibitor ipilimumab and the selective BRAF kinase inhibitor vemurafenib, both of which significantly improved overall survival. Since then, availability of new immunotherapies, especially the anti-programmed death-1 checkpoint inhibitors, as well as other targeted therapies, have further improved outcomes for patients with advanced melanoma. Seven years on from the first approval of these novel therapies, evidence for the use of various immune-based and targeted approaches is continuing to increase at a rapid rate. Improved understanding of the tumour microenvironment and tumour immuno-evasion strategies has resulted in different approaches to target and harness the immune response. These new immune-based approaches offer the opportunity for various approaches with distinct modes of action being used in combination with one another, as well as combined with other treatment modalities such as targeted therapy, electrochemotherapy and surgery. The increasing number of treatment options that are now available has resulted in a growing need to identify which patients will derive most benefit from which treatments. Much research is now focused on the identification of biomarkers that can be utilised to help select patients for treatment. These and other recent advances in the management of melanoma were the focus of discussions at the third Melanoma Bridge meeting (30 November–2 December, 2017, Naples, Italy), which is summarised in this report.

N6-Isopentenyladenosine (i6A) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that i6A targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of i6A derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds 2a–m) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds 2, 2a and 2c showed a persistent antiproliferative effect on human CRC lines and compound 2f exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of 2f was related to the ability to inhibit FPPS activity.

The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one apo form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent. Moreover, one complex was simulated for 1 µs to assess the influence of simulation time on the results. A set of MD-derived parameters was computed and compared with molecular docking-derived and experimental data. MM-GBSA and the per-residue interaction energy emerged as the main indicators for the good interaction between the specific binder and the protein counterpart. To assess the performance of the proposed analysis workflow, we tested six molecules featuring different binding affinities for BRD9, obtaining promising outcomes. Further insights were reported to highlight the influence of the starting structure on the molecular dynamics simulations evolution. The data confirmed that a ranking of BRD9 binders using key parameters arising from molecular dynamics is advisable to discard poor ligands before moving on with the synthesis and the biological tests.

Triage is the first interaction between a patient and a nurse/paramedic. This assessment, usually performed at Emergency departments, is a highly dynamic process and there are international grading systems that according to the patient condition initiate the patient journey. Triage requires an initial rapid assessment followed by routine checks of the patients’ vitals, including respiratory rate, temperature, and pulse rate. Ideally, these checks should be performed continuously and remotely to reduce the workload on triage nurses; optimizing tools and monitoring systems can be introduced and include a wearable patient monitoring system that is not at the expense of the patient’s comfort and can be remotely monitored through wireless connectivity. In this study, we assessed the suitability of a small ceramic piezoelectric disk submerged in a skin-safe silicone dome that enhances contact with skin, to detect wirelessly both respiration and cardiac events at several positions on the human body. For the purposes of this evaluation, we fitted the sensor with a respiratory belt as well as a single lead ECG, all acquired simultaneously. To complete Triage parameter collection, we also included a medical-grade contact thermometer. Performances of cardiac and respiratory events detection were assessed. The instantaneous heart and respiratory rates provided by the proposed sensor, the ECG and the respiratory belt were compared via statistical analyses. In all considered sensor positions, very high performances were achieved for the detection of both cardiac and respiratory events, except for the wrist, which provided lower performances for respiratory rates. These promising yet preliminary results suggest the proposed wireless sensor could be used as a wearable, hands-free monitoring device for triage assessment within emergency departments. Further tests are foreseen to assess sensor performances in real operating environments.

Natural products have been the main source of bioactive molecules for centuries. We tested the biological profile of two metabolites extracted from Gentiana lutea L. by means of computational techniques and in vitro assays. The two molecules (loganic acid and gentiopicroside) were tested in silico using an innovative technique, named Inverse Virtual Screening (IVS), to highlight putative partners among a panel of proteins involved in inflammation and cancer events. A positive binding with cyclooxygenase-2 (COX-2), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein emerged from the computational experiments and the outcomes from the promising interaction with COX-2 were confirmed by Western blot, highlighting the reliability of IVS in the field of the natural products.

As a definition, Human–Machine Interface (HMI) enables a person to interact with a device. Starting from elementary equipment, the recent development of novel techniques and unobtrusive devices for biosignals monitoring paved the way for a new class of HMIs, which take such biosignals as inputs to control various applications. The current survey aims to review the large literature of the last two decades regarding biosignal-based HMIs for assistance and rehabilitation to outline state-of-the-art and identify emerging technologies and potential future research trends. PubMed and other databases were surveyed by using specific keywords. The found studies were further screened in three levels (title, abstract, full-text), and eventually, 144 journal papers and 37 conference papers were included. Four macrocategories were considered to classify the different biosignals used for HMI control: biopotential, muscle mechanical motion, body motion, and their combinations (hybrid systems). The HMIs were also classified according to their target application by considering six categories: prosthetic control, robotic control, virtual reality control, gesture recognition, communication, and smart environment control. An ever-growing number of publications has been observed over the last years. Most of the studies (about 67%) pertain to the assistive field, while 20% relate to rehabilitation and 13% to assistance and rehabilitation. A moderate increase can be observed in studies focusing on robotic control, prosthetic control, and gesture recognition in the last decade. In contrast, studies on the other targets experienced only a small increase. Biopotentials are no longer the leading control signals, and the use of muscle mechanical motion signals has experienced a considerable rise, especially in prosthetic control. Hybrid technologies are promising, as they could lead to higher performances. However, they also increase HMIs’ complexity, so their usefulness should be carefully evaluated for the specific application.

Objective: School-based nutrition education can promote the development of skills, such as food label reading, that can contribute to making healthier food choices. The purpose of this study was to assess the reliability of a Russian language version of the previously validated Food Label Literacy for Applied Nutrition Knowledge (FLLANK) questionnaire and also to evaluate the impact of school-based nutrition education programmes on nutrition knowledge and food label-reading skills in Russian adolescents and young adults. Methods: Two nutrition education study programmes were administered to two separate groups of students--at a middle school (n?=?23) and a university (n?=?17). The study programmes consisted of a single 2-hour classroom session and emphasised basic nutrition and food components. The FLLANK questionnaire was administered to both groups of students before and after the intervention to assess change in food label-reading skills. Cronbach's a was calculated for the post-test scores to assess the instrument's internal consistency. Results: Middle school students increased their mean FLLANK scores from 54% to 95% (p?<0.01). University students increased their scores from 46% to 91% (p?<0.01). In the school group only, there was an interaction between time and gender, with boys improving significantly more than girls (p?

Hand prostheses partially restore hand appearance and functionalities. In particular, 3D printers have provided great opportunities by simplifying the manufacturing process and reducing costs. The “Federica” hand is 3D-printed and equipped with a single servomotor, which synergically actuates its five fingers by inextensible tendons; no springs are used for hand opening. A differential mechanical system simultaneously distributes the motor force on each finger in predefined portions. The proportional control of hand closure/opening is achieved by monitoring muscle contraction by means of a thin force sensor, as an alternative to EMG. The electrical current of the servomotor is monitored to provide sensory feedback of the grip force, through a small vibration motor. A simple Arduino board was adopted as the processing unit. A closed-chain, differential mechanism guarantees efficient transfer of mechanical energy and a secure grasp of any object, regardless of its shape and deformability. The force sensor offers some advantages over the EMG: it does not require any electrical contact or signal processing to monitor muscle contraction intensity. The activation speed (about half a second) is high enough to allow the user to grab objects on the fly. The cost of the device is less then 100 USD. The “Federica” hand has proved to be a lightweight, low-cost and extremely efficient prosthesis. It is now available as an open-source project (CAD files and software can be downloaded from a public repository), thus allowing everyone to use the “Federica” hand and customize or improve it.