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Systemic sclerosis (SSc) is an immune disorder characterized by diffuse fibrosis and vascular abnormalities of the affected organs. Although the etiopathology of this disease is largely unknown, endothelial damage and oxidative stress appear implicated in its initiation and maintenance. Here, we show for the first time that circulating factors present in SSc sera increased reactive oxygen species (ROS) production, collagen synthesis, and proliferation of human pulmonary microvascular endothelial cells (HPMECs). The observed phenomena were also associated with endothelial to mesenchymal transition (EndMT) as indicated by decreased von Willebrand factor (vWF) expression and increased alpha-smooth muscle actin, respectively, an endothelial and mesenchymal marker. SSc-induced fibroproliferative effects were prevented by HPMECs exposition to the NADPH oxidase inhibitor diphenyleneiodonium, demonstrating ROS’s causative role and suggesting their cellular origin. Sera from SSc patients showed significant changes in the expression of a set of fibrosis/EndMT-associated microRNAs (miRNA), including miR-21, miR-92a, miR-24, miR-27b, miR-125b, miR-29c, and miR-181b, which resulted significantly upregulated as compared to healthy donors sera. However, miR29b resulted downregulated in SSc sera, whereas no significant differences were found in the expression of miR-29a in the two experimental groups of samples. Taking together our data indicate NADPH oxidase-induced EndMT as a potential mechanism of SSc-associated fibrosis, suggesting fibrosis-associated miRNAs as potentially responsible for initiating and sustaining the vascular alterations observed in this pathological condition.

Gallstone ileus is a dramatic complication of gallstone disease, uncommon but not exceptional in a busy emergency department. It represents a cause of mechanical intestinal obstruction, which predominantly occurs in elderly and frail patients; this contributes to the high morbidity and mortality rates associated with this condition. The modern radiologist is frequently asked to determine the cause of bowel obstruction and should be aware of the most pictorial features of this unusual disease. Broadly speaking, abdominal radiography and ultrasonography alone are limited in detecting the cause of bowel obstruction, but the sensitivity for the preoperative diagnosis of gallstone ileus may be improved by combining the findings obtained by both techniques. Computed tomography is the modality of choice for the diagnosis of this disease: it may accurately describe the number, size, and location of migrated gallstones and the exact site of bowel obstruction, providing a detailed preoperative planning. Magnetic resonance imaging may be used in selected cases for an exquisite anatomic definition of the fistulous communication.

Abstract Background The growing understanding of cancer biology and the establishment of new treatment modalities has not yielded the expected results in terms of survival for Laryngeal Squamous Cell Cancer (LSCC). Early diagnosis, as well as prompt identification of patients with high risk of relapse would ensure greater chance of therapeutic success. However, this goal remains a challenge due to the absence of specific biomarkers for this neoplasm. Methods Serum samples from 45 LSCC patients and 23 healthy donors were collected for miRNA expression profiling by TaqMan Array analysis. Additional 20 patients and 42 healthy volunteers were included for the validation set, reaching an equal number of clinical samples for each group. The potential diagnostic ability of the such identified three-miRNA signature was confirmed by ROC analysis. Moreover, each miRNA was analyzed for the possible correlation with HNSCC patients’ survival and TNM status by online databases Kaplan–Meier (KM) plotter and OncomiR. In silico analysis of common candidate targets and their network relevance to predict shared biological functions was finally performed by PANTHER and GeneMANIA software. Results We characterized serum miRNA profile of LSCC patients identifying a novel molecular signature, including miR-223, miR-93 and miR-532, as circulating marker endowed with high selectivity and specificity. The oncogenic effect and the prognostic significance of each miRNA was investigated by bioinformatic analysis, denoting significant correlation with OS. To analyse the molecular basis underlying the pro-tumorigenic role of the signature, we focused on the simultaneously regulated gene targets—IL6ST, GTDC1, MAP1B, CPEB3, PRKACB, NFIB, PURB, ATP2B1, ZNF148, PSD3, TBC1D15, PURA, KLF12—found by prediction tools and deepened for their functional role by pathway enrichment analysis. The results showed the involvement of 7 different biological processes, among which inflammation, proliferation, migration, apoptosis and angiogenesis. Conclusions In conclusion, we have identified a possible miRNA signature for early LSCC diagnosis and we assumed that miR-93, miR-223 and miR-532 could orchestrate the regulation of multiple cancer-related processes. These findings encourage the possibility to deepen the molecular mechanisms underlying their oncogenic role, for the desirable development of novel therapeutic opportunities based on the use of short single-stranded oligonucleotides acting as non-coding RNA antagonists in cancer.

Introducing the symposium “The Interpretation of Cultures at Fifty,” editors Andrea Cossu and Matteo Bortolini reflect on the dynamics of the iconicization of texts and the paradoxical quality of so-called “classics”: their being present while being rewritten and forgotten. A brief illustration of the papers by the contributors to the symposium — Joan W. Scott, Anne Taylor and Jeffrey C. Alexander, Ann Swidler and Ronald Jepperson, Simon Susen, and Monika Krause — completes the introduction.

Abstract Background Exosomes are nanosized vesicles released from all cells into surrounding biofluids, including cancer cells, and represent a very promising direction in terms of minimally invasive approaches to early disease detection. They carry tumor-specific biological contents such as DNA, RNA, proteins, lipids, and sugars, as well as surface molecules that are able to pinpoint the cellular source. By the above criteria, exosomes may be stratified according to the presence of tissue and disease-specific signatures and, due to their stability in such biofluids as plasma and serum, they represent an indispensable source of vital clinical insights from liquid biopsies, even at the earliest stages of cancer. Therefore, our work aimed to isolate and characterize LCa patients’ derived exosomes from serum by Flow Cytometry in order to define a specific epitope signature exploitable for early diagnosis. Methods Circulating exosomes were collected from serum collected from 30 LCa patients and 20 healthy volunteers by the use of antibody affinity method exploiting CD63 specific surface marker. Membrane epitopes were then characterized by Flow cytometry multiplex analysis and compared between LCa Patients and Healthy donors. Clinical data were also matched to obtain statistical correlation. Results A distinct overexpression of CD1c, CD2, CD3, CD4, CD11c, CD14, CD20, CD44, CD56, CD105, CD146, and CD209 was identified in LCa patients compared to healthy controls, correlating positively with tumor presence. Conversely, CD24, CD31, and CD40, though not overexpressed in tumor samples, showed a significant correlation with nodal involvement in LCa patients (p < 0.01). Conclusion This approach could allow us to set up a cost-effective and less invasive liquid biopsy protocol from a simple blood collection in order to early diagnose LCa and improve patients’ outcomes and quality of life. Graphical Abstract

Abstract Alumina ceramics were reinforced with different amounts of stabilized-tetragonal zirconia nanoparticles, 3Y-TZP, and their properties were evaluated aiming for future applications in orthopedic medicine. Different amounts of 3Y-TZP (3 to 15 wt%) were mixed with Al2O3 powder, using high-energy milling (400 rpm-24 h). Samples were uniaxially compacted and sintered at 1600 °C-2 h. The samples were characterized by their relative density, microstructure, and crystalline phases. Furthermore, Vickers hardness, fracture toughness, and bending strength were determined. After the high-energy milling process, a considerable amount of monoclinic (m) ZrO2 was detected in the powder mixtures, besides the α-Al2O3 and tetragonal (t) ZrO2 phases. After sintering the samples presented relative densities greater than 98.5%, regardless of the amount of the Y-TZP additions used. Furthermore, the monoclinic phase was reconverted into the tetragonal phase during sintering. The Vickers hardness varied between 1750 and 1690 HV, depending on the amount of Y-TZP added. Bending strength and fracture toughness were also sensitive to the addition of Y-TZP, with values increasing from 351.5 to 701.7 MPa and KIC from 3.5 to 5.6 MPa.m1/2, indicating that the t-ZrO2 grains enable the activation of the transformation toughening mechanisms such as t→m phase transformation and residual stress. The biological responses of the composites, evaluated by their cytotoxicity and chemical solubility, accredit the materials developed for future in vitro and in vivo studies aimed at application as biomaterials.

Abstract Background Preliminary studies suggest that moderate ARDS and acute renal failure might benefit from extracorporeal CO2 removal (ECCO2R) coupled with CRRT. However, evidence is limited and potential for this coupled treatment may need to be explored. The aim of the present study was to evaluate whether a protective driving pressure was obtained applying low-flow ECCO2-R plus CRRT in patients affected by moderate ARDS with COVID-19 compared to an historical group without COVID-19. Methods A case-control study has been conducted comparing a group of consecutive moderate ARDS patients presenting AKI and affected by COVID-19, who needed low-flow ECCO2-R plus CRRT to achieve an ultra-protective ventilatory strategy, with historical group without COVID-19 that matched for clinical presentation and underwent the same ultra-protective treatment. VT was set at 6 mL/kg predicted body weight then ECCO2R was assessed to facilitate ultra-protective low VT ventilation to preserve safe Pplat and low driving pressure. Results ECCO2R+CRRT reduced the driving pressure from 17 (14-18) to 11.5 (10-15) cmH2O (p

In monotocous mammals, most individuals experience the birth of a younger sibling. This period may induce losses in maternal care and can be physiologically, energetically and emotionally challenging for the older sibling, yet has rarely been studied in wild primates. We used behavioural data collected from a natural population of mandrills to investigate changes in maternal care and mother–juvenile relationship throughout the transition to siblinghood (TTS), by comparing juveniles who recently experienced the birth of a younger sibling, to juveniles who did not. We found that the TTS was associated with an abrupt cessation of the weaning process for the juvenile, and to a decrease in maternal affiliation. Juveniles’ reactions were sex-specific, as males associated less with their mother, while females tended to groom their mother more often after the birth of their sibling. Despite the substantial loss of maternal care, juveniles did not show an increase in conflict or anxiety-related behaviours. This study contributes to explain why short interbirth intervals often pose a risk to juveniles’ survival in monotocous primates. Our results contrast existing studies and further highlight the importance of examining the TTS in species and populations with various life histories and ecologies.

Echinococcus granulosus sensu lato is a zoonotic agent with a life cycle consisting of definitive hosts (dogs and wild carnivores), and intermediate hosts (usually ungulates). Other animals and humans may accidentally ingest eggs and contract cystic echinococcosis, acting as aberrant hosts. A 3-year-old neutered female cat was brought to a veterinary practice in Sassari (Italy) with abdominal distension. Ultrasound showed multiple intraperitoneal vesicles, which on laparotomy were found to be metacestodes of E. granulosus. Videos of the extraction of cysts are provided. Phylogenetic analysis based on a fragment of the cytochrome oxidase subunit 1 (cox1) mitochondrial gene identified the isolate as E. granulosus sensu stricto genotype G1, the most common genotype circulating in Europe and the Mediterranean basin. This is the first case report of cystic echinococcosis in domestic cats from Italy.

The early detection of neurodevelopmental disorders in newborns is of utmost importance in clinical practice. Recently, to predict the neurodevelopment scores in preterms, Artificial Intelligence (AI) methods have been proposed mainly based on Electroencephalographic (EEG) or heart rate variability (HRV) analysis. In this work, HRV measures of preterm newborns with and without Sepsis are computed and used as input features of AI regression models. The study assesses the reliability of such features in predicting BAYLEY-III scores obtained during the clinical follow-up at 6- and 12-months. Forty-eight preterms (gestational age $27.8{\pm }1.8$ weeks) were involved, 27 of which were diagnosed with Sepsis. HRV analysis was performed on ECG signals recorded at the corrected term age. BAYLEY-III score prediction was implemented, considering HRV features as input predictors of ensemble regression models. Models were validated using the Leave-One-Subject-Out (LOSO) framework. Encouraging results were achieved, with a Mean Absolute Error (MAE) < 5 points for the Sepsis group in the BAYLEY-III cognitive and language scales at 6- and 12-months. Preliminary results suggested that the autonomic nervous system development may be linked to central nervous system maturation. HRV features, and AI regression models could predict alterations that affect the correct neurodevelopment of newborns.

Abstract No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Abstract Background Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia. Methods A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms. Results Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival. Conclusions The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.

The COVID-19 pandemic accelerated research and innovation across numerous fields of medicine. It emphasized how disease concepts must reflect dynamic and heterogeneous interrelationships between physical characteristics, genetics, co-morbidities, environmental exposures, and socioeconomic determinants of health throughout life. This article explores how scientists and other stakeholders must collaborate in novel, interdisciplinary ways at these new frontiers of medicine, focusing on communicable diseases, precision/personalized medicine, systems medicine, and data science. The pandemic highlighted the critical protective role of vaccines against current and emerging threats. Radical efficiency gains in vaccine development (through mRNA technologies, public and private investment, and regulatory measures) must be leveraged in the future together with continued innovation in the area of monoclonal antibodies, novel antimicrobials, and multisectoral, international action against communicable diseases. Inter-individual heterogeneity in the pathophysiology of COVID-19 prompted the development of targeted therapeutics. Beyond COVID-19, medicine will become increasingly personalized via advanced omics-based technologies and systems biology—for example targeting the role of the gut microbiome and specific mechanisms underlying immunoinflammatory diseases and genetic conditions. Modeling proved critical to strengthening risk assessment and supporting COVID-19 decision-making. Advanced computational analytics and artificial intelligence (AI) may help integrate epidemic modeling, clinical features, genomics, immune factors, microbiome data, and other anthropometric measures into a “systems medicine” approach. The pandemic also accelerated digital medicine, giving telehealth and digital therapeutics critical roles in health system resilience and patient care. New research methods employed during COVID-19, including decentralized trials, could benefit evidence generation and decision-making more widely. In conclusion, the future of medicine will be shaped by interdisciplinary multistakeholder collaborations that address complex molecular, clinical, and social interrelationships, fostering precision medicine while improving public health. Open science, innovative partnerships, and patient-centricity will be key to success.

For decades, lead-acid batteries have been supplying power to electrical systems through redox reactions involving Pb and PbO2. However, the energy supply capacity is inherently constrained by low energy density and challenges associated with charge/discharge cycles. Studies have indicated that additions of C to the composition of the active mass improve the electrochemical properties of batteries. This work aims to produce, characterize the microstructure and evaluate the electrochemical properties of Pb-Carbon composites, comparing different types of C (graphite, graphene and xerogel). The samples were produced through powder metallurgy, pressed at 550 MPa and sintered at 320°C-48 h. The microstructure was characterized by XRD, SEM/EDS, and Vickers microhardness. Electrochemical analyses were evaluated through OCP, polarization, and cyclic voltammetry (CV) measurements in a solution of 4.91 mol•L-1 of H2SO4. Microstructural characterizations revealed dispersions of C particles in the Pb matrix and an increase in the microhardness of the composites. Electrochemical analyses showed an increase in polarization resistance and a reduction in the corrosion rate compared to Pb. CV curves, demonstrated that C particles enhanced electrical conductivity for the formation of PbSO4 and PbO2, allowing greater absorption of electrical overpotentials when compared to Pb, thereby improving charge/discharge cycles in positive grids.

3D trench silicon pixel sensors, recently developed by the TimeSPOT collaboration, have shown excellent performance in terms of spatial resolution, timing precision and detection efficiency. The combination of these three features make them one of the best candidate for inner tracking detectors operating in high luminosity hadron colliders experiments. This article presents systematic characterisations of these devices made with minimum ionising particles on irradiated sensors with neutrons up to 2.5 ⋅ 1016 1 MeV neq cm−2. The results show that 3D trench pixels have extremely high resistance to radiation. The measured time resolution and the detection efficiency of irradiated sensors match those of non-irradiated ones if a slightly higher bias voltage, few tens of Volts, is applied to the pixels. As of today, 3D trench pixels are the only sensors capable of achieving 10 ps time resolution after being irradiated at extremely high fluences, extending by far the capabilities of future tracking systems of HEP experiments operating under extreme conditions.