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Abstract Whole genome sequencing has transformed rare disease research; however, 50–80% of rare disease patients remain undiagnosed after such testing. Regular reanalysis can identify new diagnoses, especially in newly discovered disease-gene associations, but efficient tools are required to support clinical interpretation. Exomiser, a phenotype-driven variant prioritisation tool, fulfils this role; within the 100,000 Genomes Project (100kGP), diagnoses were identified after reanalysis in 463 (2%) of 24,015 unsolved patients after previous analysis for variants in known disease genes. However, extensive manual interpretation was required. This led us to develop a reanalysis strategy to efficiently reveal candidates from recent disease gene discoveries or newly designated pathogenic/likely pathogenic variants. Optimal settings to highlight new candidates from Exomiser reanalysis were identified with high recall (82%) and precision (88%) when including Exomiser’s automated ACMG/AMP classifier, which correctly converted 92% of variants from unknown significance to pathogenic/likely pathogenic. In conclusion, Exomiser efficiently reinterprets previously unsolved cases.

The article ‘The New European Bauhaus: Beauti­ful-Sustainable-Together in STARHAUS’ aims to ex­plore the principles of the New European Bauhaus (NEB) policy and analyze how these principles are implemented across various European projects, with a specific focus on the STARHAUS project. The New European Bauhaus is an interdisciplinary initiative launched by the European Commission to foster a sustainable and inclusive future by combining aes­thetics, sustainability, and inclusiveness. It seeks to create spaces, products, and services that are envi­ronmentally friendly, inclusive, and accessible while enhancing quality of life.

Objective We aimed to investigate the remission rate and disease duration in idiopathic or post–cardiac injury pericarditis and risk factors for disease duration and anti–interleukin‐1 (IL‐1) agent discontinuation. Methods This was a multicenter, longitudinal, observational study including 370 patients (51.4% female). The remission rate was the proportion of patients who stopped all pericarditis‐related therapies for at least 6 months without recurrences. Results The median follow‐up was 4.9 (interquartile range [IQR] 2.8–8.4) years, and the median age at the end of follow‐up was 49 (IQR 37–60) years. A median of 1.1 (IQR 0.6–1.9) recurrences/year and 0.4 (IQR 0.1–0.9) hospitalizations/year were recorded. The remission rate at follow‐up was 34.0%, 7% per year. Disease duration was shorter for patients in remission (3.1 years, IQR 1.6–6.2 years) than for those still receiving treatment (4 years, IQR 2.2–7.8; P = 0.02). Use of “guidelines‐based therapy” (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.25–2.73; P = 0.02) and colchicine use at first attack (HR 1.51, 95% CI 1.02–2.23; P = 0.038) were protective factors, whereas steroid use was associated with longer disease duration (HR 0.53, 95% CI 0.35–0.81; P = 0.003). Corticosteroids were used in 77.3% of patients, with a median duration of therapy of 1.1 (IQR 0.4–2.6) years. Anakinra was used in 25.9% with a median duration of therapy of 2.4 (IQR 0.9–5.0) years; only 19.8% were able to stop anakinra at the end of observation period. Conclusion This study reports the largest and longest follow‐up in patients with recurrent pericarditis. Guideline adherence from the first attack is associated with a shorter course. The disease was long and impacting in terms of recurrences and hospitalizations, often requiring a long‐term treatment, in particular with anti–IL‐1 agents.

The crosstalk between gut microbiota, intestinal epithelial cells, and innate and adaptive immune system governs the maintenance of the intestinal homeostasis. Any interference in this tight dialogue and in the processes preserving cellular homeostasis (e.g., autophagy) may dysregulate the immune response and impair the clearance of harmful bacteria favoring the dysbiotic alteration of the microbial flora that leads to chronic inflammation. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders, among them the inflammatory bowel disease (IBD). This review discusses the current knowledge on IBD, from the genetic background of high-risk patients to the molecular mechanisms underlying the disease, the contribution of the microbial flora, and the role of autophagy in intestinal epithelia homeostasis. Further, we illustrate the state of art regarding the targeted-nutritional approaches aimed to restore the beneficial crosstalk between an “anti-inflammatory” microbiota and the host. Analysis of the molecular pathogenesis of IBD will help identify genetic and diet-associated risk factors and thus suggest personalized strategies to prevent and manage the disease to improve quality of life with long-term maintenance of the remission phase.

Abstract Physiochemical tissue inducers and mechanical stimulation are both efficient variables in cartilage tissue fabrication and regeneration. In the presence of biomolecules, decellularized extracellular matrix (ECM) may trigger and enhance stem cell proliferation and differentiation. Here, we investigated the controlled release of transforming growth factor beta (TGF-β1) as an active mediator of mesenchymal stromal cells (MSCs) in a biocompatible scaffold and mechanical stimulation for cartilage tissue engineering. ECM-derived hydrogel with TGF-β1-loaded alginate-based microspheres (MSs) was created to promote human MSC chondrogenic development. Ex vivo explants and a complicated multiaxial loading bioreactor replicated the physiological conditions. Hydrogels with/without MSs and TGF-β1 were highly cytocompatible. MSCs in ECM-derived hydrogel containing TGF-β1/MSs showed comparable chondrogenic gene expression levels as those hydrogels with TGF-β1 added in culture media or those without TGF-β1. However, constructs with TGF-β1 directly added within the hydrogel had inferior properties under unloaded conditions. The ECM-derived hydrogel group including TGF-β1/MSs under loading circumstances formed better cartilage matrix in an ex vivo osteochondral defect than control settings. This study demonstrates that controlled local delivery of TGF-β1 using MSs and mechanical loading is essential for neocartilage formation by MSCs and that further optimization is needed to prevent MSC differentiation towards hypertrophy.

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the polarization into the pro-tumoral M2-like TAM phenotype promotes the extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and therapy resistance. Probiotic metabolites can disrupt this crosstalk, possibly reverting the TAM polarization toward a pro-inflammatory anti-tumoral phenotype, thus potentially benefiting the intestinal mucosa and opposing CRC progression. Previously, we showed that Lactiplantibacillus plantarum OC01 metabolites counter interleukin (IL)-6-induced CRC proliferation and migration. Methods: Here, we explore how probiotics affect CRC secretome and how this influences TAM polarization, which then impacts CRC malignancy. Results: The conditioning medium (CM) from CRC cells indeed promoted the polarization of macrophage toward the M2-like phenotype, whereas the CM from CRC pre-treated with L. plantarum OC01 metabolites induced a pro-inflammatory macrophage phenotype, characterized by NLRP3 inflammasome activation and reactive oxygen species (ROS) production, and by decreased expression of the M2 phenotype markers CD206 and CD163. Consistently, the expression of tumor growth factor (TGF)-β, a promoter of M2 macrophage polarization, was reduced in CRC cells treated with L. plantarum OC01. The pro-inflammatory macrophages inhibited CRC proliferation and migration. Conclusions: Overall, our study highlights the potential of metabolites from L. plantarum OC01 to reprogram the metabolism in cancer cells and thus reshape the TME by shifting TAMs toward a more inflammatory and anti-tumoral phenotype, emphasizing the promise of probiotics in advancing novel therapeutic approaches for CRC.

To obtain sustainable food packaging materials, alternatives to traditional ones must be researched. In this work, two different kinds of zeolites, i.e., a natural one, Clinoptilolite, and a synthetic one, Zeolite Na-X, were mixed with thermoplastic polyurethane for the fabrication of composites. Composite films were prepared via a hot mixing stage and then by means of a hot compression molding process. Several TPU/zeolite composites were produced with a filler concentration ranging from 5% to 10%wt. Finally, the obtained films were characterized by Fourier Transform Spectroscopy (FT-IR, ATR), thermal analysis (TGA and DSC), frequency sweep test, scanning electron microscopy (SEM), mechanical tensile test and oxygen permeability test. For both fillers and at all concentrations, the inclusion of zeolites significantly influenced the analyzed properties. In the TPU/zeolite composites, an overall enhancement was observed compared to the neat polymer, attributed to improved processability, superior barrier properties and the potential to create active materials by loading zeolite combined with various chemicals for specific applications. These findings suggest that the resulting composites hold considerable promise for applications in the food packaging sector.

ObjectivesWe analyzed the impact of postoperative necrotizing enterocolitis (NEC) after cardiac surgery in neonatal age on neurodevelopmental (ND) outcome at 1 year of age.MethodsUsing data from the Swiss Neurodevelopmental Outcome Registry for Children with Congenital Heart Disease (ORCHID), we analyzed perioperative variables including postoperative NEC (Bell's stage ≥2) and 1-year ND outcome (Bayley III).ResultsThe included patients (n = 101) had congenital heart disease (CHD), categorized as follows: 77 underwent biventricular repair for CHD with two functional chambers, 22 underwent staged palliation until the Fontan procedure for CHD with single ventricle physiology (n = 22), or 4 underwent single ventricle palliation or biventricular repair for borderline CHD (n = 4). Neonatal cardiopulmonary bypass (CBP) surgery was performed at a median age (IQR) of 8 (6) days. NEC occurred in 16 patients. Intensive care unit (ICU) length of stay (LOS) and the total duration of the hospitalization were longer in children with NEC than those in others (14 with vs. 8 days without NEC, p

Endoscopic ultrasound-guided biliary drainage (EUS-BD) has dramatically spread and improved in the last two decades and is changing the paradigm of drainage in case of malignant biliary obstruction (MBO). EUS-BD can be achieved from different routes, including the common bile duct (choledochoduodenostomy), intrahepatic bile ducts (hepaticogastrostomy), and gallbladder as a rescue (cholecystogastrostomy/cholecystoduodenostomy). EUS-guided hepaticogastrostomy (EUS-HGS) is a valuable option for biliary drainage in MBO when ERCP fails or is not feasible. EUS-HGS has demonstrated high efficacy with a good rate of technical and clinical success. The safety profile is also overall favorable, although severe adverse events may occur in a significant proportion of patients. From a technical perspective, EUS-HGS is considered one of the most demanding procedures in biliopancreatic endoscopy, requiring multiple steps and high technical skills and experience. In this comprehensive review, technical tips and clinical outcomes of EUS-HGS are reviewed according to the latest evidence in the literature.

Aminolysis is widely recognized as a valuable chemical route for depolymerizing polymeric materials containing ester, amide, or urethane functional groups, including polyurethane foams. Bio-based polyurethane foams, pristine and reinforced with 40 wt% of sustainable fillers, were depolymerized in the presence of bio-derived butane-1,4-diamine, BDA. A process comparison was made using fossil-derived ethane-1,2-diamine, EDA, by varying amine/polyurethane ratio (F/A, 1:1 and 1:0.6). The obtained depolymerized systems were analyzed by FTIR and NMR characterizations to understand the effect of both diamines on the degradation pathway. The use of bio-based BDA seemed to be more effective with respect to conventional EDA, owing to its stronger basicity (and thus higher nucleophilicity), corresponding to faster depolymerization rates. BDA-based depolymerized systems were then employed to prepare second-generation bio-based composite polyurethane foams by partial replacement of isocyanate components (20 wt%). The morphological, mechanical, and thermal conductivity properties of the second-generation polyurethane foams were evaluated. The best performances (σ10 %=71 ± 9 kPa, λ = 0.042 ± 0.015 W∙ m-1 ∙K-1) were attained by employing the lowest F/A ratio (1:0.6); this demonstrates their potential application in different sectors such as packaging or construction, fulfilling the paradigm of the circular economy.

Background and aim: Gut microbiota is considered as a complex organ of human body. The interaction between the host and microbiota is dynamic and controlled by a huge number of factors, such as lifestyle, geography, pharmaceuticals, diet, and stress. The breakdown of this relationship could change microbiota composition favoring the onset of several diseases, including cancer. Metabolites released by microbiota bacterial strains have been reported to elicit protective effects on the mucosa that could contrast cancer development and progression. Here, we tested the ability of specific probiotic strain Lactiplantibacillus plantarum OC01-derived metabolites (NCIMB 30624) to contrast the malignant features of colorectal cancer (CRC) cells. Experimental procedure: The study was performed on two cell lines, HCT116 and HT29, cultured in 2D and 3D, and focused on the hallmarks of cell proliferation and migration. Results and conclusion: Probiotic metabolites reduced cell proliferation both in 2D and 3D-spheroid cultures, the latter model mimicking the growth in vivo. The bacterial metabolites also contrasted the pro-growth and pro-migratory activity of inteurleukin-6 (IL-6), an inflammatory cytokine abundantly found in the tumor microenvironment of CRC. These effects were associated with inhibition of the ERK and of the mTOR/p70S6k pathways and with the inhibition of the E−to N-Cadherin switch. In a parallel study, we found that sodium butyrate (a representative of the main probiotic metabolites) induced autophagy and β-Catenin degradation, which is consistent with the growth inhibitory activity. The present data indicate that the metabolites of Lactiplantibacillus plantarum OC01 (NCIMB 30624) elicits anti-tumor effect and support its possible inclusion as adjuvant therapy of CRC for limiting cancer growth and progression.

Abstract Objectives Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer’s disease continuum (AD, n = 2), Parkinson’s disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p

Background and Objectives: Serum alpha-fetoprotein (AFP) is a recognized affordable oncological marker in patients with hepatocellular carcinoma (HCC). However, AFP’s prognostic role has been assessed mainly after specific treatments, and no unanimously recognized cut-offs have been identified. The aim of this study is to investigate the prognostic role of different basal AFP cut-offs on survival and HCC course. Materials and Methods: In this single-center, retrospective study, all patients newly diagnosed with HCC between January 2009 and December 2021 were prospectively enrolled. Only patients suitable for curative HCC treatments were included in the analyses. Patients were stratified according to AFP cut-offs of 20, 200, 400, and 1000 ng/mL, which were correlated with survival outcomes and clinical parameters. Results: A total of 266 patients were analyzed, with a median follow-up time of 41.5 months. Median overall survival (OS) of all cohort was 43 months. At the multivariate Cox-regression analysis, AFP value ≥ 1000 ng/mL correlated with impaired OS (1-year OS: 67% vs. 88%, 5-year OS: 1% vs. 43%; p = 0.005); other risk factors were tumor dimension ≥ 5 cm (HR 1.73; p = 0.002), Child–Pugh class B–C (HR 1.72; p = 0.002), BCLC stage A (vs. 0) (HR 2.4; p = 0.011), and malignant portal vein thrombosis (HR 2.57; p = 0.007). AFP ≥ 1000 ng/mL was also associated with a reduced recurrence-free survival (HR 2.0; p = 0.038), while starting from AFP ≥ 20 ng/mL, a correlation with development of HCC metastases over time (HR 3.5; p = 0.002) was seen. AFP values ≥ 20 ng/mL significantly correlated with tumor size and higher histological grading; starting from AFP values ≥ 400 ng/mL, a significant correlation with Child–Pugh class B–C and female gender was also observed. Conclusions: Basal AFP correlates with relevant outcomes in patients with HCC. It could help identify patients at a higher risk of worse prognosis who might benefit from personalized surveillance and treatment programs. Prospective studies are needed to confirm these results.

Abstract Background Aberrant activation of the MET receptor in cancer is sustained by genetic alterations or, more frequently, by transcriptional upregulations. A fraction of MET-amplified or mutated tumors are sensible to MET targeting agents, but their responsiveness is typically short-lasting, as secondary resistance eventually occurs. Since in the absence of genetic alterations MET is usually not a tumor driver, MET overexpressing tumors are not/poorly responsive to MET targeted therapies. Consequently, the vast majority of tumors exhibiting MET activation still represent an unmet medical need. Methods Here we propose an immunotherapy strategy based on T lymphocytes expressing a Chimeric Antigen Receptor (CAR) targeting MET overexpressing tumors of different histotypes. We engineered two different MET-CAR constructs and tested MET-CAR-T cell cytotoxic activity against different MET overexpressing models, including tumor cell lines, primary cancer cells, organoids, and xenografts in immune-deficient mice. Results We proved that MET-CAR-T exerted a specific cytotoxic activity against MET expressing cells. Cell killing was proportional to the level of MET expressed on the cell surface. While CAR-T cytotoxicity was minimal versus cells carrying MET at physiological levels, essentially sparing normal cells, the activity versus MET overexpressing tumors was robust, significantly controlling tumor cell growth in vitro and in vivo. Notably, MET-CAR-T cells were also able to brake acquired resistance to MET targeting agents in MET amplified cancer cells carrying secondary mutations in downstream signal transducers. Conclusions We set and validated at the pre-clinical level a MET-CAR immunotherapy strategy potentially beneficial for cancers not eligible for MET targeted therapy with inhibitory molecules, including those exhibiting primary or secondary resistance.

Abstract About 15 Tg of plastic are estimated to enter the ocean yearly, with this figure growing exponentially every year. Assessments of floating marine plastic amount to 0.2% of the expected plastic stock, implying that 99.8% is stored in a sink yet to be identified. Marine sediments are believed to be the ultimate sink for oceanic plastic, however, there is currently no global estimate of the plastic load stored there. Here, we synthesize available estimates of micro‐ and mesoplastic stocks in marine sediments and, by integrating stocks across different habitats, we conservatively estimate a load of 170 Tg (25–900 Tg) of nonfibrous plastic globally accumulated in marine sediments from 1950 to 2010, most of which at intermediate depths (200–2000 m). This estimate, despite the uncertainty, is two to three orders of magnitude higher than the floating plastic stock and confirms marine sediments as a major plastic sink.

L’Italia, con la sua posizione strategica dal punto di vista geopolitico ed economico, è da più di trent’anni meta d’immigrazione, pur continuando al contempo a essere paese di emigrazione. Sebbene la Cina del XXI secolo non si collochi tra i primi Paesi quale meta d’emigrazione italiana, nell’ultimo decennio la presenza della popolazione italiana in Cina è in continuo aumento. Il presente contributo si propone di delineare un profilo sociolinguistico degli emigrati italiani in Cina, in cui si vuole mettere in luce non solo la vitalità e la dinamicità delle varietà dell’italiano, ma anche il contatto tra la comunità italiana e le varietà del paese ospitante. L’indagine si concluderà con uno studio di caso basato su un’intervista qualitativa a una coppia genitore-figlio rappresentanti la prima e seconda generazione di emigrati italiani in Cina. L’intervista è finalizzata ad approfondire l’importanza delle varietà dell’italiano nella trasmissione intra-familiare e nella vita quotidiana, e come la lingua possa plasmare il processo di creazione dell’identità personale.” “New” Italians between Italy and China: language and identity of a new italianity Italy, with its strategic position from a geopolitical and economic point of view, has been a destination for immigrants for more than thirty years, while also continuing to be a country of emigration. Although 21st-century China does not rank among the first countries as a destination for Italian emigration, the presence of the Italian community in China has seen a continuous increase in the last decade. This contribution aims at outlining a sociolinguistic profile of Italian emigrants in China, in which we want to highlight not only the vitality and dynamism of the varieties of the Italian language but also the contact between the Italian community and the linguistic varieties of the host country. The contribution will end with a case study based on a qualitative interview with a parent-child pair representing the first and second generation of Italian emigrants in China. The interview aims at investigating the importance that the varieties of Italian have in intra-family transmission and daily life, and how a language can shape personal identity.

Objective: In preclinical research, the use of [18F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [18F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer’s disease (AD). Methods: A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [18F]UCB-H SV2A-PET scan (14.7 ± 1.5 MBq) 0–60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (VT) from an image-derived-input-function (IDIF). [18F]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [18F]FDG and [18F]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [18F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. Results: [18F]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014; cerebellum: p = 0.0018; brainstem: p = 0.0014). Significantly lower SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080; cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042; cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [18F]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the SV2A PET findings. Correlational analyses of [18F]UCB-H and [18F]FDG using Pearson’s correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [18F]FDG and [18F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). Conclusion: [18F]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [18F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.

Abstract Triage is crucial for patient’s management and estimation of the required intensive care unit (ICU) beds is fundamental for health systems during the COVID-19 pandemic. We assessed whether chest computed tomography (CT) of COVID-19 pneumonia has an incremental role in predicting patient’s admission to ICU. We performed volumetric and texture analysis of the areas of the affected lung in CT of 115 outpatients with COVID-19 infection presenting to the emergency room with dyspnea and unresponsive hypoxyemia. Admission blood laboratory including lymphocyte count, serum lactate dehydrogenase, D-dimer and C-reactive protein and the ratio between the arterial partial pressure of oxygen and inspired oxygen were collected. By calculating the areas under the receiver-operating characteristic curves (AUC), we compared the performance of blood laboratory-arterial gas analyses features alone and combined with the CT features in two hybrid models (Hybrid radiological and Hybrid radiomics)for predicting ICU admission. Following a machine learning approach, 63 patients were allocated to the training and 52 to the validation set. Twenty-nine (25%) of patients were admitted to ICU. The Hybrid radiological model comprising the lung %consolidation performed significantly (p = 0.04) better in predicting ICU admission in the validation (AUC = 0.82; 95% confidence interval 0.73–0.97) set than the blood laboratory-arterial gas analyses features alone (AUC = 0.71; 95% confidence interval 0.56–0.86). A risk calculator for ICU admission was derived and is available at: https://github.com/cgplab/covidapp . The volume of the consolidated lung in CT of patients with COVID-19 pneumonia has a mild but significant incremental value in predicting ICU admission.

Diffuse large B-cell lymphoma (DLBCL) is characterized by high molecular and clinical heterogeneity. Autophagy, a lysosome-driven catabolic process devoted to macromolecular turnover, is fundamental in maintaining normal hematopoietic stem cells and progenitors homeostasis, and its dysregulation plays a critical role in the initiation and progression of hematological malignancies. One main regulator of autophagy is BECLIN-1, which may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy. The altered expression of BCL2 and BECN1 correlates with lymphoma outcomes, but whether this is associated with dysregulated cross-talk between autophagy and apoptosis remains to be elucidated. Analysis of the TCGA database revealed that BCL2 and BECN1 mRNA expression were inversely correlated in DLBCL patients. In representative DLBCL cell lines exposed to doxorubicin, the cells highly expressing BCL-2 were resistant, while the ones highly expressing BECLIN-1 were sensitive, and this correlated with low and high autophagy flux, respectively. Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. By interrogating the TCGA DLBCL dataset, we found that BCL2 and BECN1 acted as negative and positive prognostic markers for DLBCL, respectively. The differentially expressed gene analysis in the respective cohorts revealed that BCL2 positively correlated with oncogenic pathways (e.g., glucose transport, HIF1A signaling, JAK-STAT signaling, PI3K-AKT-mTOR pathway) and negatively correlated with autophagy-related transcripts, while BECN1 showed the opposite trend. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy.

Abstract Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren’s syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors’ and patients’ blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT (“neuro-GvHD”). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

Preemptive and therapeutic donor lymphocyte infusions (preDLI and tDLI) are widely used in relapsing and relapsed hematopoietic malignancies after allogeneic stem cell transplantation (alloSCT) to enhance the graft-versus-malignancy effect. However, in advanced myeloid malignancies, long-term survival after preDLI and tDLI remains low, reflecting our inability to master the double-edged sword of alloreactivity, balancing anti-neoplastic activity versus graft-versus-host disease (GvHD). We previously evaluated a quantitative PCR-based high-sensitivity chimerism (hs-chimerism) based on insertion/deletion polymorphisms instead of short tandem repeats, where increasing host chimerism in peripheral blood predicts relapse more than a month before clinical diagnosis, and declining host chimerism signals anti-host alloreactivity. Here we report 32 consecutive patients with advanced myeloid malignancies receiving preDLI or tDLI “navigated” by hs-chimerism (“navigated DLI”). We compared them to a historical cohort of 110 consecutive preDLI or tDLI recipients, prior to implementation of hs-chimerism at our institution (“controls”). Both groups were comparable regarding age, gender, conditioning, donor type, and time to DLI. With longer median follow-up of the navigated DLI group (8.5 versus 5 months), their landmark overall (64%) and disease-free survival (62%) at 2 years from first DLI compared favorably with controls (23% and 21%, respectively). Improved survival of navigated DLI was due to both reduced relapse incidence (38% versus 60%) and non-relapse mortality (17% versus 44%) at 2 years. Early relapse prediction by hs-chimerism allowed a preemptive approach in 28% of navigated DLI versus 7% in controls. Our results confirm hs-chimerism as a highly valuable tool for monitoring and steering immune interventions after alloSCT.

Background: Due to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown. Methods: This is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated. Results: We gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p = 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p = 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p = 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p < 0.001). These benefits were confirmed after correcting for the lead-time bias. Conclusions: Cirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.

Background and aim: Non-coding RNAs control cell functioning through affecting gene expression and translation and their dysregulation is associated with altered cell homeostasis and diseases, including cancer. Nutraceuticals with anti-cancer therapeutic potential have been shown to modulate non-coding RNAs expression that could impact on the expression of genes involved in the malignant phenotype. Experimental procedure: Here, we report on the microarray profiling of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and on the associated biochemical pathways and functional processes potentially modulated in OVCAR-3 ovarian cancer cells exposed for 24 h to Resveratrol (RV), a nutraceutical that has been shown to inhibit carcinogenesis and cancer progression in a variety of human and animal models, both in vitro and in vivo. Diana tools and Gene Ontology (GO) pathway analyses along with Pubmed literature search were employed to identify the cellular processes possibly affected by the dysregulated miRNAs and lncRNAs. Results and conclusion: The present data consistently support the contention that RV could exert anti-neoplastic activity via non-coding RNAs epigenetic modulation of the pathways governing cell homeostasis, cell proliferation, cell death and cell motility.

El objetivo del artículo consiste en analizar las políticas públicas ligadas a las dificultades de acceso al suelo y/o a la vivienda, focalizando la atención en los asentamientos populares de Comodoro Rivadavia (Chubut). En el primer apartado examinamos los instrumentos de gestión urbana existentes: Planes Estratégicos, proyectos de códigos urbanísticos, programas de gestión del suelo, etc. La segunda sección se centra en la legislación que regula el acceso al suelo fiscal en la ciudad, así como nos dedicamos a reflexionar sobre el Estado como propietario de tierras y como productor de espacio construido (para ello, evaluamos la magnitud de los vacíos urbanos al interior del ejido comodorense). Más allá de los instrumentos formales, y ante una realidad urbana muy dinámica dominada por los ritmos del mercado mundial del petróleo, en Comodoro los criterios de excepcionalidad han adquirido notable relevancia en las prácticas estatales encaminadas a “ordenar” la expansión urbana. Así, sostenemos que la planificación urbana históricamente priorizó la extracción y circulación de hidrocarburos. En el tercer apartado se desarrollan las políticas de mejoramiento habitacional implementadas en Comodoro Rivadavia, mientras que el siguiente título gira en torno a ciertas tendencias detectadas con relación a las políticas habitacionales: la incapacidad estatal a la hora de proveer vivienda en una escala acorde con la magnitud de la demanda habitacional; las políticas de viviendas sociales suelen pensar de manera fragmentada al espacio; las entidades intermedias han cobrado un papel central en la implementación de las políticas habitacionales, etc. El último apartado se focaliza en el sistema de créditos hipotecarios: el mismo no ha tenido impacto a la hora de morigerar las necesidades habitacionales de la ciudad.

Con el propósito de cumplir con el objetivo general del dossier, el cual supone analizar el rol del Estado en los procesos de conformación del hábitat popular en tres ciudades patagónicas, enfocándonos en las principales políticas de suelo y de vivienda, consideramos necesario generar un apartado dedicado a caracterizar cada una de las localidades que componen el estudio. De tal modo, el presente texto se organiza en torno a información sobre la ubicación de Comodoro Rivadavia, San Carlos de Bariloche y Cipolletti, la historia y el perfil productivo de estas ciudades, datos demográficos como la tasa de crecimiento poblacional, los flujos migratorios, el nivel de desempleo, pobreza o de necesidades básicas insatisfechas, etc. En tal sentido, destacamos la evolución de las estadísticas ligadas con el déficit habitacional, así como establecemos una primera aproximación sobre la presencia de asentamientos en cada localidad. En la introducción general de la publicación detallamos sobre las estrategias metodológicas implementadas, pero cabe resaltar para esta sección que las mismas se basaron en fuentes como los censos nacionales de población elaborados por el Instituto Nacional de Estadísticas, al igual que en entrevistas a referentes de los gobiernos locales y habitantes de asentamientos populares.

The ITALUNG trial started in 2004 and compared lung cancer (LC) and other-causes mortality in 55–69 years-aged smokers and ex-smokers who were randomized to four annual chest low-dose CT (LDCT) or usual care. ITALUNG showed a lower LC and cardiovascular mortality in the screened subjects after 13 years of follow-up, especially in women, and produced many ancillary studies. They included recruitment results of a population-based mimicking approach, development of software for computer-aided diagnosis (CAD) and lung nodules volumetry, LDCT assessment of pulmonary emphysema and coronary artery calcifications (CAC) and their relevance to long-term mortality, results of a smoking-cessation intervention, assessment of the radiations dose associated with screening LDCT, and the results of biomarkers assays. Moreover, ITALUNG data indicated that screen-detected LCs are mostly already present at baseline LDCT, can present as lung cancer associated with cystic airspaces, and can be multiple. However, several issues of LC screening are still unaddressed. They include the annual vs. biennial pace of LDCT, choice between opportunistic or population-based recruitment. and between uni or multi-centre screening, implementation of CAD-assisted reading, containment of false positive and negative LDCT results, incorporation of emphysema. and CAC quantification in models of personalized LC and mortality risk, validation of ultra-LDCT acquisitions, optimization of the smoking-cessation intervention. and prospective validation of the biomarkers.

Background: Pulmonary function can be impaired as a long-term consequence of SARS-CoV-2 infection. The aim of this study was to evaluate the effect of SARS-CoV-2 infection on pulmonary function, exercise tolerance, and muscle strength in healthy middle-aged military outpatients according during the period of infection. Methods: A cross-sectional study was carried out from March 2020 to November 2022 at the Military Hospital “Celio” (Rome, Italy). If someone had a diagnosis of SARS-CoV-2 infection certified by molecular nasal swab and if they performed pulmonary function tests, diffusion of carbon monoxide (DL’co), a six Minute Walk Test (6MWT), a Handgrip (HG) Test, and a One Minute Sit to Stand Test (1′STST). The included subjects were divided into two groups, A and B, according to the period of infection: A) from March 2020 to August 2021 and B) from September 2021 to October 2022. Results: One hundred fifty-three subjects were included in the study: 79 in Group A and 74 in Group B. Although the values were within the normal range, Group A had smaller FVC, FEV1, and DL’co compared to Group B. Group A also walked a shorter distance at the 6MWT and performed fewer repetitions in the 1′STS test compared to Group B. In both groups, the DL’co (%predicted) correlated with the 6MWT distance (R2 = 0.107, p < 0.001), the number of repetitions of the 1′STST (R2 = 0.086, p = 0.001), and the strength at the HG test (R2 = 0.08, p < 0.001). Conclusions: This study shows that the SARS-CoV-2 infection in healthy middle-aged military outpatients was more severe in the first waves than in the later ones and that, in healthy and physically fit individuals, even a marginal reduction in resting respiratory test values can have a major impact on exercise tolerance and muscles strength. Moreover, it shows that those infected more recently had symptoms related to the upper respiratory tract infection compared to those of the first waves.

Background: Obesity is a chronic disease that impairs quality of life and leads to several comorbidities. When conservative therapies fail, bariatric surgical options such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most effective therapies to induce persistent weight loss. Over the last two decades, bariatric endoscopy has become a valid alternative to surgery in specific settings. Primary bariatric endoscopic therapies: Restrictive gastric procedures, such as intragastric balloons (IGBs) and endoscopic gastroplasty, have been shown to be effective in inducing weight loss compared to diet modifications alone. Endoscopic gastroplasty is usually superior to IGBs in maintaining weight loss in the long-term period, whereas IGBs have an established role as a bridge-to-surgery approach in severely obese patients. IGBs in a minority of patients could be poorly tolerated and require early removal. More recently, novel endoscopic systems have been developed with the combined purpose of inducing weight loss and improving metabolic conditions. Duodenal mucosal resurfacing demonstrated efficacy in this field in its early trials: significant reduction from baseline of HbA1c values and a modest reduction of body weight were observed. Other endoscopic malabsorptive have been developed but need more evidence. For example, a pivotal trial on duodenojejunal bypasses was stopped due to the high rate of severe adverse events (hepatic abscesses). Optimization of these more recent malabsorptive endoscopic procedures could expand the plethora of bariatric patients that could be treated with the intention of improving their metabolic conditions. Revisional bariatric therapies: Weight regain may occur in up to one third of patients after bariatric surgery. Different endoscopic procedures are currently performed after both RYGB and SG in order to modulate post-surgical anatomy. The application of argon plasma coagulation associated with endoscopic full-thickness suturing systems (APC-TORe) and Re-EndoSleeve have shown to be the most effective endoscopic treatments after RYGB and SG, respectively. Both procedures are usually well tolerated and have a very low risk of stricture. However, APC-TORe may sometimes require more than one session to obtain adequate final results. The aim of this review is to explore all the currently available primary and revisional endoscopic bariatric therapies focusing on their efficacy and safety and their potential application in clinical practice.

Abstract Background/aim Autophagy is a macromolecular degradation process playing a pivotal role in the maintenance of stem-like features and in the morpho-functional remodeling of the tissues undergoing differentiation. In this work we investigated the involvement of autophagy in the osteogenic differentiation of mesenchymal stem cells originated from human gingiva (HGMSC). METHODS: To promote the osteogenic differentiation of HGMSCs we employed resveratrol, a nutraceutical known to modulate autophagy and cell differentiation, together with osteoblastic inductive factors. Osteoblastic differentiation and autophagy were monitored through western blotting and immunofluorescence staining of specific markers. Results We show that HGMSCs can differentiate into osteoblasts when cultured in the presence of appropriate factors and that resveratrol accelerates this process by up-regulating autophagy. The prolonged incubation with dexamethasone, β-glycerophosphate and ascorbic acid induced the osteogenic differentiation of HGMSCc with increased expression of autophagy markers. Resveratrol (1 μM) alone elicited a less marked osteogenic differentiation yet it greatly induced autophagy and, when added to the osteogenic differentiation factors, it provoked a synergistic effect. Resveratrol and osteogenic inductive factors synergistically induced the AMPK-BECLIN-1 pro-autophagic pathway in differentiating HGMSCs, that was thereafter downregulated in osteoblastic differentiated cells. Pharmacologic inhibition of BECLIN-1-dependent autophagy precluded the osteogenic differentiation of HGMSCs. Conclusions Autophagy modulation is instrumental for osteoblastic differentiation of HGMSCs. The present findings can be translated into the regenerative cell therapy of maxillary / mandibular bone defects. Graphical abstract

The outbreak of novel coronavirus disease 2019 (COVID-19) has exacted a disproportionate toll on cancer patients. The effects of anticancer treatments and cancer patients’ characteristics shared significant responsibilities for this dismal outcome; however, the underlying immunopathological mechanisms are far from being completely understood. Indeed, despite their different etiologies, SARS-CoV-2 infection and cancer unexpectedly share relevant immunobiological connections. In the pathogenesis and natural history of both conditions, there emerges the centrality of the immune response, orchestrating the timed appearance, functional and dysfunctional roles of multiple effectors in acute and chronic phases. A significant number (more than 600) of observational and interventional studies have explored the interconnections between COVID-19 and cancer, focusing on aspects as diverse as psychological implications and prognostic factors, with more than 4000 manuscripts published so far. In this review, we reported and discussed the dynamic behavior of the main cytokines and immune system signaling pathways involved in acute vs. early, and chronic vs. advanced stages of SARS-CoV-2 infection and cancer. We highlighted the biological similarities and active connections within these dynamic disease scenarios, exploring and speculating on possible therapeutic crossroads from one setting to the other.

L’attività motoria legata al tempo ricreativo nella Scuola dell’Infanzia è stato il tema chiave di questa revisione sistematica che si è posta l’obiettivo di sottolineare la relazione positiva che si instaura tra queste tre componenti. Questo è un argomento che richiede sempre ulteriori aggiornamenti, in quanto il panorama scolastico cambia continuamente aspetto ed evolve nella struttura e negli ideali alla base, ampliando informazioni e azioni. Le nuove ricerche sottolineano la crescente obesità infantile già nei bambini in età prescolare, richiamando nuovamente l’attenzione sull’importanza di fare attività fisica già da questa età. Questa revisione vuole quindi determinare se e quale vantaggio esiste nell’attuare una ricreazione motoria nella Scuola dell’Infanzia. Quanto la ricreazione possa essere da supporto al fine di aumentare il tempo speso in azioni motorie. Si analizzano i concetti di ricreazione con tutte le declinazioni, focalizzandosi su spazi, tempi, attività. Inoltre, in merito alla parte motoria che riguarda lo sviluppo nella fascia dai due ai cinque anni, la relazione tra sviluppo fisico, cognitivo, emotivo e sociale. Sono stati selezionati ventidue tra articoli e protocolli, collocati negli anni tra il 2000 e il 2020. I risultati sono stati analizzati e confrontati per identificare somiglianze e differenze utili per ulteriori e future sperimentazioni.

Aim We aimed to characterise a large population of coronavirus disease 2019 (COVID-19) patients with moderate-to-severe hypoxaemic acute respiratory failure (ARF) receiving continuous positive airway pressure (CPAP) outside the intensive care unit (ICU), and to ascertain whether the duration of CPAP application increased the risk of mortality for patients requiring intubation. Methods In this retrospective, multicentre cohort study, we included adult COVID-19 patients, treated with CPAP outside ICU for hypoxaemic ARF from 1 March to 15 April, 2020. We collected demographic and clinical data, including CPAP therapeutic goal, hospital length of stay and 60-day in-hospital mortality. Results The study included 537 patients with a median (interquartile range (IQR) age of 69 (60–76) years. 391 (73%) were male. According to the pre-defined CPAP therapeutic goal, 397 (74%) patients were included in the full treatment subgroup, and 140 (26%) in the do not intubate (DNI) subgroup. Median (IQR) CPAP duration was 4 (1–8) days, while hospital length of stay was 16 (9–27) days. 60-day in-hospital mortality was 34% (95% CI 0.304–0.384%) overall, and 21% (95% CI 0.169–0.249%) and 73% (95% CI 0.648–0.787%) for full treatment and DNI subgroups, respectively. In the full treatment subgroup, in-hospital mortality was 42% (95% CI 0.345–0.488%) for 180 (45%) CPAP failures requiring intubation, and 2% (95% CI 0.008–0.035%) for the remaining 217 (55%) patients who succeeded. Delaying intubation was associated with increased mortality (hazard ratio 1.093, 95% CI 1.010–1.184). Conclusions We described a large population of COVID-19 patients treated with CPAP outside ICU. Intubation delay represents a risk factor for mortality. Further investigation is needed for early identification of CPAP failures.

Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment.

Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in APC (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and APC, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of CTNNB1 (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene ATG4D. In CRC cells, regardless of the mutational state of APC or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using ad hoc probiotics that stimulate autophagy.

Autoimmune diseases (ADs) are a collection of many complex disorders of unknown aetiology resulting in immune responses to self‐antigens and are thought to result from interactions between genetic and environmental factors. ADs collectively are amongst the most prevalent diseases in the U.S., affecting at least 7% of the population. The diagnosis of ADs is very complex, the standard screening methods provides seeking and recognizing of Antinuclear Antibodies (ANA) by Indirect ImmunoFluorescence (IIF) based on HEp‐2 cells. In this paper an automatic system able to identify and classify the Centromere pattern is presented. The method is based on the grouping of centromeres present on the cells through a clustering K‐means algorithm. The performances were obtained on two public database of IIF images (A.I.D.A. and MIVIA). Our results showed a sensitivity for image of (90 ± 5)% and a Accuracy equal to (98.0 ± 0.5)%. Results demonstrate that the system is able to identify and classify Centromere pattern with accuracy better or comparable with some representative state of the art works. Moreover, it should be noted that for the classification phase the works used for the comparison used an expert‐manual segmentation while, in the present work, the segmentation was obtained automatically.

Abstract Background This study aims to evaluate if invisible orthodontic retainers can affect sleep-time masticatory muscle activity (sMMA) over a short-term period in healthy individuals. Methods Nineteen (N = 19) healthy subjects underwent an in-home evaluation with a portable device for electromyographic (EMG) assessment. The study protocol provided two baseline recording nights, a night off, and then two additional nights with passive customized orthodontic retainers in situ. For each recording night, the sleep bruxism (SB) index (i.e., average number of SB events/hour) and the overall number of masseter muscle contractions were assessed. Comparison between values gathered over the four recording nights was made with a parametric test, based on the null hypothesis that there was no difference between wearing or not wearing the retainers as far as the sMMA variables are concerned. Results Average SB index of the first two nights without the retainers was 3.0 ± 1.5, whilst the average values with the retainers in situ was 3.6 ± 1.9. ANOVA test showed the absence of significant differences between the four nights. Similarly, no differences were shown between the four nights as for the total number of sMMA events. Based on that, the null hypothesis was not rejected. Conclusions Findings suggest the absence of relevant effects of invisible orthodontic retainers on sMMA in healthy individuals during the short-term period.

The Centre for Research on Social Interactions (CRSI) of the University of Neuchâtel emerged as an interdisciplinary (and inter-faculty) collaboration built around the study of social interaction. The CRSI doctoral program, in turn, was created to provide PhD students with theoretical and methodological support in their research endeavours. Within this framework, the Young Researchers Conference of the Centre for Research on Social Interaction (the CRSI-YR Conference) was organised on February 16–17, 2017, as a concrete effort to offer young researchers working on social interaction an opportunity to present their work and to learn from experienced scholars in an environment that fosters dialogue across academic disciplines. [Corrigendum: Kévin Moinier's name is mispelled in this review. We apologize for the error.]

Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.

La conformación urbana de Comodoro Rivadavia en la Patagonia argentina ha sido influida históricamente por la extracción de hidrocarburos, condicionando el acceso al suelo urbano. Esta ciudad responde a una crisis ambiental global que tiene como emergente al riesgo, lo cual quedó reflejado durante las precipitaciones extraordinarias acaecidas en el otoño de 2017. El presente trabajo analiza cómo las dificultades de acceso al suelo son un componente fundamental en la conformación de escenarios de riesgo ambiental. Reconociendo que estos se corresponden con sistemas complejos y en la búsqueda de miradas que confluyan en la ecología política, se pretende vincular estas dificultades con la construcción de la vulnerabilidad. El enfoque metodológico contempló la realización de entrevistas, revisión de fuentes secundarias y el abordaje interdisciplinario. A manera de conclusión, sostenemos que las dificultades de acceso al suelo generadas por la industria petrolera fueron una causa estructural del desastre ambiental.

Maintenance of hematopoietic stem cells and their potential to give rise to progenitors of differentiated lymphoid and myeloid cells are accomplished by a network of regulatory processes. As a part of this network, the heteromeric transcription factor GA-binding protein (GABP) plays a crucial role in self-renewal of murine hematopoietic and leukemic stem cells. Here, we report the consequences of functional impairment of GABP in human hematopoietic and in leukemic stem/progenitor cells. Ectopic overexpression of a dominant-negative acting GABP mutant led to impaired myeloid differentiation of CD34+ hematopoietic stem/progenitor cells obtained from healthy donors. Moreover, drastically reduced clonogenic capacity of leukemic stem/progenitor cells isolated from bone marrow aspirates of chronic myeloid leukemia (CML) patients underlines the importance of GABP on stem/progenitor cell maintenance and confirms the relevance of GABP for human myelopoiesis in healthy and diseased states.

Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53, BRCA1 or BECN1 correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients’ survival has not been validated in a large cohort of ovarian cancer patients. Aim: We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients. Results and conclusion: Compared to EOC with homozygous expression of BECN1 and BRCA1, tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of TP53 status, though it was statistically more significant in the cohort of patients with mutated TP53. Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both BECN1 and BRCA1 could be a strategy to restore chemosensitivity in refractory tumors.

El artículo tiene como objetivo principal indagar en la evolución histórica de la legislación sobre la distribución de la tierra en Comodoro Rivadavia. Para llevar adelante este trabajo es preciso hacer un breve repaso histórico de lo que fue la colonización de la Patagonia y los distintos preceptos que guiaron la distribución de la tierra en esta región. Este trabajo se sitúa específicamente en la ocupación del suelo urbano en la ciudad de Comodoro, usando como fuentes históricas las leyes y ordenanzas que se encargaron de regularla. Las principales conclusiones que aborda el trabajo son el hecho de que en Patagonia, y en el caso específico de Comodoro Rivadavia, primero ha llegado la ocupación y luego la planificación. Esto se sostiene teniendo en cuenta evidencias de asentamientos informales que luego han sido regularizados por la normativa. Las ordenanzas municipales sobre tierras fiscales fueron generalmente hechas a medida de emergencia ante las ocupaciones y el reclamo de la población de establecer prioridades de acceso al suelo urbano. Es la idea de este trabajo poder contribuir a un análisis de éste desde una perspectiva histórica.

Background/Aims: Partially hydrolyzed guar gum (PHGG) relieves symptoms in constipation-predominant irritable bowel syndrome (IBS) and may have prebiotic properties. However, the correlation between the effectiveness of PHGG and patient characteristics has not been examined. We aimed to investigate the effect of PHGG in symptom relief on constipation-predominant IBS according to gender, age, and body mass index (BMI). Patients and Methods: Sixty-eight patients with IBS entered a 2-week run-in period, followed by a 4-week study period with PHGG. Patients completed a daily questionnaire to assess the presence of abdominal pain/discomfort, swelling, and the sensation of incomplete evacuation. The number of evacuations/day, the daily need for laxatives/enemas and stool consistency-form were also evaluated. All patients also underwent a colonic transit time (CTT) evaluation. Results: PHGG administration was associated with a significant improvement in symptom scores, use of laxatives/enemas, stool form/consistency and CTT. At the end of the study period and compared with baseline, the number of evacuations improved in women, patients aged ≥ 45 years and those with BMI ≥ 25 (P < 0.05 for all comparisons); abdominal bloating improved in males (P < 0.05), patients < 45 years (P < 0.01) and those with BMI < 25 (P < 0.05). A decrease in the number of perceived incomplete evacuations/day was reported in patients with a BMI ≥ 25 (P < 0.05). Reductions in laxative/enema use were recorded in females (P < 0.05), patients < 45 years (P < 0.01), and patients with BMI < 25 (P < 0.05). Conclusions: Gender, age, and BMI seem to influence the effect of PHGG supplementation in constipated IBS patients. Further studies are needed to clarify the interaction of such parameters with a fiber-enriched diet.

In this work, we discuss the modelling of transport in Langevin probability density function (PDF) models used to predict turbulent flows [1]. Our focus is on the diffusion limit of these models, i.e. when advection and dissipation are the only active physical processes. In this limit, we show that Langevin PDF models allow for an asymptotic expansion in terms of the ratio of the integral length to the mean gradient length. The main contribution of this expansion yields an evolution of the turbulent kinetic energy equivalent to that given by a k − ε model. In particular, the transport of kinetic energy is given by a gradient diffusion term. Interestingly, the identification between PDF and \hbox{$\overline{k}-\overline{\varepsilon}$} k − ε models raises a number of questions concerning the way turbulent transport is closed in PDF models. In order to validate the asymptotic solution, several numerical simulations are performed, with a Monte Carlo solver and also with a deterministic code.

BACKGROUND: The dry eye sindrome refers to a group of disorders of the tear film due to reduced tear production or excessive tear evaporation that is associated with symptoms of ocular discomfort and may cause disease of the ocular surface. Dry eye syndrome varies in severity, duration and etiology. The cornerstone of dry eye syndrome therapies includes the intraocular gel or ophthalmic solutions instillation, reaching correct artificial lubrication. Molecules that can produce a stable lubricating film are the carbomers. METHODS: In the first step of our work we reviewed the data from literature reporting about carbomers’ characteristics in respect to other lacrimal substitutes. Then, a pharmacoeconomical analysis has been performed on ophtalmic gels derived from carbomers 974P and PVA. RESULTS: Dry eye sindrome, if not adequately treated, determines a deterioration of the patient’s quality of life, other than high secondary costs. CONCLUSION: The high therapeutical index of carbomers 974P and PVA-based gels, in addition to the their limited cost (totally free for Sjögren patients in Italy), suggests that this product is characterized by one of the best benefits-to-costs ratios in the treatment of dry eye sindrome.