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Objective: To evaluate the oncologic outcome of patients with hypermetabolic tumors resected by segmentectomy or lobectomy. Methods: This was a retrospective analysis of all consecutive patients with peripheral clinical stage IA1-2 non–small cell lung cancer (January 2017-June 2023) who underwent resection by segmentectomy or lobectomy in a single center. A hypermetabolic tumor was defined as a tumor with a positron emission tomography (PET) maximum standardized uptake value >2.5. Propensity score case-matching analysis was used to generate 2 balanced groups of patients with hypermetabolic tumors operated by segmentectomy or lobectomy. Four-year overall survival (OS), event-free survival (EFS), and cancer-specific survival were compared between the matched groups. Results: A total of 164 segmentectomies and 234 lobectomies were analyzed. There were 91 (55%) hypermetabolic tumors in the segmentectomy group versus 178 in the lobectomy group (76%), P

Abstract Lower limb amputation is a medical intervention which causes motor disability and may compromise quality of life. Several factors determine patients’ health outcomes, including an appropriate prosthetic provision and an effective rehabilitation program, necessitating a thorough quantitative observation through different data sources. In this context, the role of interoperability becomes essential, facilitating the reuse of real-world data through the provision of structured and easily accessible databases. This study introduces a comprehensive 10-year dataset encompassing clinical features, mobility measurements, and prosthetic knees of 1006 trans-femoral amputees during 1962 hospital stays for rehabilitation. The dataset is made available in both comma-separated values (CSV) format and HL7 Fast Healthcare Interoperability Resources (FHIR)-based representation, ensuring broad utility and compatibility for researchers and healthcare practitioners. This initiative contributes to advancing community understanding of post-amputation rehabilitation and underscores the significance of interoperability in promoting seamless data sharing for meaningful insights into healthcare outcomes.

Climate change has the potential to fundamentally transform landscapes on global scale. Leveraging advanced predictive modeling to enhance water resource management within the Alto Paranapanema Basin (Brazil), holds the potential to proactively anticipate challenges and alleviate the impacts and conflicts arising from this phenomenon. This is particularly important in a region boasting over 1,600 centerpivot irrigation systems. This study employs the Soil Moisture Accounting Procedure, a physical model, to simulate long-term climate datasets and flows. Future climate scenarios, rooted in the Representative Concentration Pathways, are developed through the downscaling of Global Climate Models. The findings reveal a temporal shift in rainfall patterns, characterized by a reduction during the wet season of up to 40% compared to the average historical rainfall, and an increase throughout the dry season up to 40% compared to the same historical, estimated by the Eta -BESM model. These changes present challenges regarding to water availability, hydroelectric generation, and agricultural. By fostering collaboration among different governmental entities responsible for the managements of basins and harnessing the potential of predictive models, this research advocates for the adoption of proactive strategies in management of water resources. These strategies are imperative to effectively counteract the far-reaching effects of climate change. HIGHLIGHTS Impacts of climate change, with four Regional Climate Models and two Representative Concentration Pathways, in rainfall and river flow utilizing Soil Moisture Accounting Procedure as an analytical tool.; Watershed has a major impact on society around the river and downstream.; River flow changes could disrupt energy and water for those communities.;

Abstract Background Oligo-progression or further recurrence is an open issue in the multi-integrated management of oligometastatic disease (OMD). Re-irradiation with stereotactic body radiotherapy (re-SBRT) technique could represent a valuable treatment option to improve OMD clinical outcomes. MRI-guided allows real-time visualization of the target volumes and online adaptive radiotherapy (oART). The aim of this retrospective study is to evaluate the efficacy and toxicity profile of MRI-guided repeated SBRT (MRIg-reSBRT) in the OMD setting and propose a re-SBRT classification. Methods We retrospectively analyzed patients (pts) with recurrent liver metastases or abdominal metastatic lesions between 1 and 5 centimeters from liver candidate to MRIg-reSBRT showing geometric overlap between the different SBRT courses and assessing whether they were in field (type 1) or not (type 2). Results Eighteen pts completed MRIg-reSBRT course for 25 metastatic hepatic/perihepatic lesions from July 2019 to January 2020. A total of 20 SBRT courses: 15 Type 1 re-SBRT (75%) and 5 Type 2 re-SBRT (25%) was delivered. Mean interval between the first SBRT and MRIg-reSBRT was 8,6 months. Mean prescribed dose for the first treatment was 43 Gy (range 24–50 Gy, mean BEDα/β10=93), while 41 Gy (range 16–50 Gy, mean BEDα/β10=92) for MRIg-reSBRT. Average liver dose was 3,9 Gy (range 1–10 Gy) and 3,7 Gy (range 1,6–8 Gy) for the first SBRT and MRIg-reSBRT, respectively. No acute or late toxicities were reported at a median follow-up of 10,7 months. The 1-year OS and PFS was 73,08% and 50%, respectively. Overall Clinical Benefit was 54%. Conclusions MRIg-reSBRT could be considered an effective and safe option in the multi-integrated treatment of OMD.

Abstract In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.

Automatic morphological characterization of river systems is important because it provides valuable information on river behavior, helps quantify fluvial changes, improves model accuracy, and supports the management and restoration of river systems. In recent years, scientific interest in the development and use of automated tools for the geomorphological characterization of rivers has increased. The objective of this study was to characterize in a semi-automated way the River Styles of the Duqueco River in south-central Chile. To achieve this objective, an experimental complement within QGIS called South Rivers Toolbox (SRT) was developed. This toolbox allows users to characterize and classify River Styles based on hydromorphological metrics extracted at segment scale, implementing a semi-automatic approach that no longer relies on subjective expert judgment. As a result of the analysis, 43 Rivers Styles have been classified and characterized using the SRT. The upper zone is characterized by being mostly confined, single-channel, with a bed dominated by boulders and blocks, this section of the river is highly affected by hydropower generation plants; the middle zone is confined and single-channel, with a change in the granulometry more dominated by boulders. The lower zone is more diverse in styles, unconfined, with a high presence of geomorphic units that give way to multichannel styles and transition zones. Using the SRT program it is possible to retrospectively analyze the evolution of the river, identifying sections sensitive to geomorphological modification, which is very useful to synoptically evaluate the flood risk, given that, traditionally, for this type of studies only hydraulic modeling is implemented at a river section scale, often with total lack of knowledge of how the river functions and evolves.

Abstract The crosstalk between the chromaffin and adrenocortical cells is essential for the endocrine activity of the adrenal glands. This interaction is also likely important for tumorigenesis and progression of adrenocortical cancer and pheochromocytoma. We developed a unique in vitro 3D model of the whole adrenal gland called Adrenoid consisting in adrenocortical carcinoma H295R and pheochromocytoma MTT cell lines. Adrenoids showed a round compact morphology with a growth rate significantly higher compared to MTT-spheroids. Confocal analysis of differential fluorescence staining of H295R and MTT cells demonstrated that H295R organized into small clusters inside Adrenoids dispersed in a core of MTT cells. Transmission electron microscopy confirmed the strict cell–cell interaction occurring between H295R and MTT cells in Adrenoids, which displayed ultrastructural features of more functional cells compared to the single cell type monolayer cultures. Adrenoid maintenance of the dual endocrine activity was demonstrated by the expression not only of cortical and chromaffin markers (steroidogenic factor 1, and chromogranin) but also by protein detection of the main enzymes involved in steroidogenesis (steroidogenic acute regulatory protein, and CYP11B1) and in catecholamine production (tyrosine hydroxylase and phenylethanolamine N-methyltransferase). Mass spectrometry detection of steroid hormones and liquid chromatography measurement of catecholamines confirmed Adrenoid functional activity. In conclusion, Adrenoids represent an innovative in vitro 3D-model that mimics the spatial and functional complexity of the adrenal gland, thus being a useful tool to investigate the crosstalk between the two endocrine components in the pathophysiology of this endocrine organ.

Background: Programmed death-ligand 1 (PD-L1) expression serves as a predictive biomarker for response to immune checkpoint inhibitors (ICIs) in metastatic gastroesophageal adenocarcinoma (mGEA). The peritoneum is one of the most common metastatic sites and is associated with a poor prognosis and apparently lower clinical efficacy of ICIs. Patients and methods: We investigated the heterogeneity of PD-L1 expression in mGEA by examining its concordance between primary tumors and matched peritoneal metastases (PMs), and before and after systemic treatment. PD-L1 expression was assessed using combined positive score (CPS) by immunohistochemistry with VENTANA PD-L1 (SP263) assays on formalin-fixed paraffin-embedded tumor tissues. Results were reported using CPS cut-offs of 1 and 5. Results: Twenty-two primary tumor and matched PM specimens from patients with mGEA were analyzed. The concordance of PD-L1 CPS was 54.5% with a CPS cut-off of 1 and 72.7% with a CPS cut-off of 5, highlighting spatial heterogeneity. Notably, none of the PD-L1-positive primary tumor samples tested positive in the matched PM specimens using the CPS ≥5 cut-off. Potential temporal heterogeneity of PD-L1 expression related to chemo(immuno)therapy administration was also observed, with a 55.6% concordance rate using the CPS ≥5 cut-off. Conclusions: PD-L1 expression in PMs from mGEA is characterized by both spatial and potentially temporal heterogeneity, with the variability being more pronounced at lower CPS cut-off values. This variability complicates its role as a predictive biomarker for ICI outcomes. The high intrapatient discordance rate in PD-L1 CPS expression between positive primary tumor samples and matched PM specimens suggests that peritoneal specimens should not be used as the only source for PD-L1 assessment if representative tissue from other disease sites is available.

Some studies showed a “rejuvenating” effect of exposing aging tissues to a young environment. In mouse heterochronic parabiosis experiments, in response to young organisms, old animals lived longer than isochrony old age-matched conjoint animals. Comparable “rejuvenating” effects were obtained by injecting young plasma in old mice. This raised great hopes of slowing down the senescence process in humans by the injection of young plasma, as well as to prevent or cure age-related diseases. Some clinical trials are currently being performed or were recently completed. However, these studies are small and of limited duration, and we still lack convincing evidence to support the effectiveness of young plasma injection. It is urgent to perform additional investigations, including the development of an assay to measure the cell proliferation induction capability of different human plasmas, before one can seriously think of a large-scale treatment of humans. We adopted a simple method to measure the potential of different plasmas in supporting cell line proliferation, regardless of the co-presence of a platelet lysate. By comparing plasmas from young and old subjects, we observed a decreased activity in plasmas from old individuals. The young plasma effect may be attributed to specific proteins and growth factors more abundant in younger individuals that could decrease with age. Alternatively, or at the same time, the reduced cell proliferation support could be due to inhibitors present in the old plasma. Studying the different protein content of young and old plasmas was out of the scope of this article. Such differences should be adequately investigated by proteomics using many samples. However, a preliminary study of the different protein content of young and old plasmas was part of the assay validation using a commercially available cytokine array for parallel determination of the relative levels of 105 selected human proteins. We could show the existence of specific differences between young and old plasmas and that plasmas from old individuals presented a higher concentration of “inflammatory” proteins.

Ewing Sarcomas (EWS, OMIM#612219) presents a major challenge in pediatric oncology due to its aggressive nature and poor prognosis, particularly in metastatic cases. Genetic fusions involving the EWSR1 gene and ETS family transcription factors are common in EWS, though other rarer fusions have also been identified. Current standard techniques like immunohistochemistry have failed to fully characterize the immune tumor microenvironment of EWS, hindering insights into tumor development and treatment strategies. Recent efforts apply gene expression datasets to quantify tumor-infiltrating immune cells in EWS. Similar deconvolution techniques can be also applied to DNA methylation (DNAm) arrays, which are much more stable compared to RNA-based methods. This study aims to characterize immune cell infiltration in EWS using DNAm array data. We collected 32 EWS samples from 32 consecutive patients referred to Bambino Gesù Children’s Hospital. DNAm analysis was performed by EPIC arrays; data loading, normalization, deconvolution and survival analysis were then performed in R programming environment. We observed a higher content of dendritic cells and longer overall survival in samples with EWSR1::FLI1 translocation compared to samples with rarer fusions. Moreover, T-memory lymphocytes and monocytes emerged as a significant predictor of overall survival. This study underscores the potential of DNAm arrays in providing robust insights into EWS immune profiles, offering a promising avenue for future research. Further investigations with larger cohorts are warranted to validate these findings and explore additional immune cell types influencing EWS outcomes.

ABSTRACT When the premise is the best final use of wood, evaluation of anatomical variables is recommended, bearing in mind that they are correlated with the properties of this material. The present study aimed to evaluate the correlation between anatomy and the physical properties of wood from Parapiptadenia rigida (Benth.) Brenan, Peltophorum dubium (Spreng.) Taub., Eucalyptus grandis W. Hill × Eucalyptus urophylla S.T. Blake (hybrid) and Schizolobium parahyba (Vell.) Blake, from an agroforestry system. For this purpose, five trees of each species, aged 9 years old, were selected, and samples were collected from the diameter at 1.30 m height from the ground for analysis of the anatomical characteristics and physical properties of the wood. Anatomical variables, with the exception of fiber length and cell wall thickness, correlated with the physical properties of wood and influenced their values. The higher the cell wall fraction (0.79), vessel frequency (0.44) and ray frequency (0.92), the greater the basic density of the wood. The greater the fiber diameter (0.94), lumen diameter (0.88), vessel diameter (0.88), ray height (0.86) and ray width (0.84), the higher the moisture content of the wood.

ABSTRACT: This study was conducted with the aim of analyzing the implications of removing the parameters from the mathematical model on the results of path analysis, with oats grown in different years and agricultural scenarios (with and without fungicide). For this, two field trials were conducted in southern Brazil, in five years of growth. The experimental design used in trial I (with fungicide application) was randomized complete blocks (RCB), in a 22 × 4 bifactorial arrangement, characterized by twenty-two oat cultivars and four fungicide applications. For trial II (without fungicide application) the RCB design was used, and the treatments were characterized by twenty-two oat cultivars, with three replications. The traits measured were panicle length, panicle mass, number of spikelets, number of grains, grain mass, and grain yield. For each year, data group, and scenario, the correlation coefficients between the explanatory variables and grain yield were calculated. The diagnosis of multicollinearity indicated violation of the statistical assumption, so it was necessary to proceed with a path analysis under multicollinearity (ridge). The removal of parameters from the mathematical model caused changes in the linear relationships between the oat yield traits, with the maintenance of the linear correlation coefficients in 3.30% and 20% of the situations, for the scenarios with and without fungicide application, respectively. Regarding the path coefficients, it was observed that the direct effects were maintained in 3.30% and 30% and indirect effects in 7.33% and 24.67% of the situations, for the scenarios with and without fungicide application, respectively.

Vulvar lichen sclerosus is a chronic inflammatory condition characterized by the thinning and atrophy of the skin and mucosa surrounding the vulva and anus. This study evaluates the efficacy of a treatment protocol utilizing blue-diode laser photobiomodulation in managing vulval lichen sclerosus symptoms in a cohort of 12 female patients. The treatment protocol consisted of laser sessions for 3 times a week for 2 weeks, and follow-up sessions over a 16-week period. Objective and subjective parameters were assessed before treatment, at the end of treatment, and at 4-month follow-up visits. Results demonstrated significant reductions in subjective symptoms such as itching and pain, as well as improvements in objective signs including erythema and fissures. No side effects were observed, indicating the safety and tolerability of laser treatment. These findings suggest that photobiomodulation can be an effective therapeutic option for patients with vulval lichen sclerosus, with future research aimed at refining treatment protocols and evaluating its long-term benefits.

Introduction: Organ motion (OM) and volumetric changes pose challenges in radiotherapy (RT) for locally advanced cervical cancer (LACC). Magnetic Resonance-guided Radiotherapy (MRgRT) combines improved MRI contrast with adaptive RT plans for daily anatomical changes. Our goal was to analyze cervico-uterine structure (CUS) changes during RT to develop strategies for managing OM. Materials and methods: LACC patients received chemoradiation by MRIdian system with a simultaneous integrated boost (SIB) protocol. Prescription doses of 55–50.6 Gy at PTV1 and 45–39.6 Gy at PTV2 were given in 22 and 25 fractions. Daily MRI scans were co-registered with planning scans and CUS changes were assessed.Six PTVs were created by adding 0.5, 0.7, 1, 1.3, 1.5, and 2 cm margins to the CUS, based on the simulation MRI. Adequate margins were determined to include 95 % of the CUSs throughout the entire treatment in 95 % of patients. Results: Analysis of 15 LACC patients and 372 MR scans showed a 31 % median CUS volume decrease. Asymmetric margins of 2 cm cranially, 0.5 cm caudally, 1.5 cm posteriorly, 2 cm anteriorly, and 1.5 cm on both sides were optimal for PTV, adapting to CUS variations. Post-14th fraction, smaller margins of 0.7 cm cranially, 0.5 cm caudally, 1.3 cm posteriorly, 1.3 cm anteriorly, and 1.3 cm on both sides sufficed. Conclusion: CUS mobility varies during RT, suggesting reduced PTV margins after the third week. MRgRT with adaptive strategies optimizes dose delivery, emphasizing the importance of streamlined IGRT with reduced PTV margins using a tailored MRgRT workflow with hybrid MRI-guided systems.

Abstract Self-propelled particles such as bacteria or algae swimming through a fluid are non-equilibrium systems where particle motility breaks microscopic detailed balance, often resulting in large-scale collective motion. Previous theoretical work has identified long-ranged hydrodynamic interactions as the driver of collective motion in unbounded suspensions of rear-actuated (“pusher”) microswimmers. In contrast, most experimental studies of collective motion in microswimmer suspensions have been carried out in restricted geometries where both the swimmers’ motion and their long-range flow fields become altered due to the proximity of a boundary. Here, we study numerically a minimal model of microswimmers in such a restricted geometry, where the particles move in the midplane between two no-slip walls. For pushers, we demonstrate collective motion with short-ranged order, in contrast with the long-ranged flows observed in unbounded systems. For front-actuated (“puller”) microswimmers, we discover a long-wavelength density instability resulting in the formation of dense microswimmer clusters. Both types of collective motion are fundamentally different from their previously studied counterparts in unbounded domains. Our results show that this difference is dictated by the geometrical restriction of the swimmers’ motion, while hydrodynamic screening due to the presence of a wall is subdominant in determining the suspension’s collective state.

Abstract Extracellular vesicles (EVs) are lipid-bilayered particles, containing various biomolecules, including nucleic acids, lipids, and proteins, released by cells from all the domains of life and performing multiple communication functions. Evidence suggests that the interaction between host immune cells and fungal EVs induces modulation of the immune system. Most of the studies on fungal EVs have been conducted in the context of fungal infections; therefore, there is a knowledge gap in what concerns the production of EVs by yeasts in other contexts rather than infection and that may affect human health. In this work, we characterized EVs obtained by Saccharomyces cerevisiae and Pichia fermentans strains isolated from a fermented milk product with probiotic properties. The immunomodulation abilities of EVs produced by these strains have been studied in vitro through immune assays after internalization from human monocyte-derived dendritic cells. Results showed a significant reduction in antigen presentation activity of dendritic cells treated with the fermented milk EVs. The small RNA fraction of EVs contained mainly yeast mRNA sequences, with a few molecular functions enriched in strains of two different species isolated from the fermented milk. Our results suggest that one of the mechanisms behind the anti-inflammatory properties of probiotic foods could be mediated by the interactions of human immune cells with yeast EVs.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) account for 3–10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance. Results We studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions. By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort. Conclusion DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a ‘hybrid’ category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

The full potential of the Internet of Musical Things (IoMusT) paradigm can be fully unleashed only in the presence of widespread, reliable wireless connectivity, allowing musicians to connect their smart instruments (almost) anywhere they are. For this reason, we propose a realistic, end-to-end communication architecture for a IoMusT system based on public fifth-generation (5G) mobile networks that considers a networked music performance use case, and we introduce a model for the resulting system. We define high-level service requirements and key performance indicators for the network’s connect-compute architecture. We evaluate our solution via system-level simulations using the well-known 5G-LENA/ns3 and Simu5G/OMNeT++ frameworks. We found that operating 6 or more IoMusT devices over a fourth-generation (4G) network results in a worst-case latency well over 20 ms for more than 90% of the packet transmissions, while losing more than 10% of packets. On the other hand, operating the same number of devices over a 5G network reduces the latency significantly. After testing our findings both in single-cell and in multi-cell scenarios, assuming a transient in the upgrade of mobile network infrastructures from 4G to 5G, we consider a E-UTRA-NR dual connectivity (EN-DC) scenario, where a 5G base station serves a subset of the users of a 4G cell. Furthermore, we conducted a user study where musicians were asked to assess their playing experience during simulated 4G- and 5G-based networked music performances. The results of the simulations and of the user study consistently indicate that the use of 5G technology improves performance significantly, and advocate the need for a 5G framework to fully support the IoMusT.

Abstract Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

Abstract The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the “CNS tumor with EP300:BCOR(L1) fusion” methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD.

Background: Heart failure (HF) is a chronic disease with a steadily increasing prevalence, high mortality, and social and economic costs. Furthermore, every hospitalization for acute HF is associated with worsening prognosis and reduced life expectancy. In order to prevent hospitalizations, it would be useful to have instruments that can predict them well in advance. Methods: We performed a review on remote monitoring of heart failure through implantable devices. Results: Precise multi-parameter algorithms, available for ICD and CRT-D patients, have been created, which also use artificial intelligence and are able to predict a new heart failure event more than 30 days in advance. There are also implantable pulmonary artery devices that can predict hospitalizations and reduce the impact of heart failure. The proper organization of transmission and alert management is crucial for clinical success in using these tools. Conclusions: The full implementation of remote monitoring of implantable devices, and in particular, the use of new algorithms for the prediction of acute heart failure episodes, represents a huge challenge but also a huge opportunity.

In Structural Silicone Glazing (SSG) when applied to unitised curtain wall systems typical practice incorporates a pair of dead load plates intended to carry the glass self-weight and so avoid subjecting structural silicone to permanent shear. However in reality, due to the fabrication sequence and system behaviour some loads can occur which will be resisted permanently by the structural silicone. In a hung and sworded system (H&S), designers typically assume that slab deflection, or inter-story drift will cause a unitised panel to lift off from one support and so change the load path within it. To conform with this new load path, shear deformation will occur in the SSG joints. The deformation in the SSG joint will be permanent unless the supporting main structure returns to its original position. The structural performance of SSG joints subjected to permanent shear deformation in combination with short term loads is not adequately covered by any guidance. The aim of this paper is to provide a better understanding of the effect of the permanent shear deformation on SSG joints. Experimental tensile and shear testing has been carried out by Sika on H-specimens (Sikasil® SG-500) while imposing prescribed levels of shear deformation in combination with different accelerated aging conditions. The testing procedure, results and main conclusions are explained and summarised.

ABSTRACT Lippia alba (Mill.), popularly known bushy matgrass, is considered an aromatic and medicinal plant with physiotherapeutic characteristics, leading to its use in the chemical and pharmaceutical industries. Therefore, the study aimed to evaluate the chemical composition and yield of the essential oil of Lippia alba (Mill.) after the occurrence of frost in southern Brazil. The study was carried out in an experimental area located at the Federal University of Santa Maria, Frederico Westphalen Campus, in July 2014. The essential oil was extracted using the hydrodistillation technique for three hours after the start of boiling. The chemical composition of Lippia alba (Mill.) essential oil was identified through chromatographic analysis. The chemical composition of Lippia alba (Mill.) essential oil was not altered by frost. As for the yield, it was 0.311% before the frost and 0.363% after the frost.

A fundamental goal of modern-day astrophysics is to understand the connection between supermassive black hole (SMBH) growth and galaxy evolution. Merging galaxies offer one of the most dramatic channels for galaxy evolution known, capable of driving inflows of gas into galactic nuclei, potentially fueling both star formation and central SMBH activity. Dual active galactic nuclei (dual AGNs) in late-stage mergers with nuclear pair separations 10 keV) studies offer a relatively contamination-free tool for probing the dense obscuring environments predicted to surround the majority of dual AGN in late-stage mergers. To date, only a handful of the brightest and closest systems have been studied at these energies due to the demanding instrumental requirements involved. We demonstrate the unique capabilities of HEX-P to spatially resolve the soft and - for the first time - hard X-ray counterparts of closely-separated (∼2″−5″) dual AGNs in the local Universe. By incorporating physically-motivated obscuration models, we reproduce realistic broadband X-ray spectra expected for deeply embedded accreting SMBHs. Hard X-ray spatially resolved observations of dual AGNs—accessible only to HEX-P—will hence transform our understanding of dual AGN in the nearby Universe.

Ever since the discovery of the first active galactic nuclei (AGN), substantial observational and theoretical effort has been invested into understanding how massive black holes have evolved across cosmic time. Circum-nuclear obscuration is now established as a crucial component, with almost every AGN observed known to display signatures of some level of obscuration in their X-ray spectra. However, despite more than six decades of effort, substantial open questions remain: how does the accretion power impact the structure of the circum-nuclear obscurer? What are the dynamical properties of the obscurer? Can dense circum-nuclear obscuration exist around intrinsically weak AGN? How many intermediate mass black holes occupy the centers of dwarf galaxies? In this paper, we showcase a number of next-generation prospects attainable with the High-Energy X-ray Probe (HEX-P1) to contribute toward solving these questions in the 2030s. The uniquely broad (0.2–80 keV) and strictly simultaneous X-ray passband of HEX-P makes it ideally suited for studying the temporal co-evolution between the central engine and circum-nuclear obscurer. Improved sensitivities and reduced background will enable the development of spectroscopic models complemented by current and future multi-wavelength observations. We show that the angular resolution of HEX-P both below and above 10 keV will enable the discovery and confirmation of accreting massive black holes at both low accretion power and low black hole masses even when concealed by thick obscuration. In combination with other next-generation observations of the dusty hearts of nearby galaxies, HEX-P will be pivotal in paving the way toward a complete picture of black hole growth and galaxy co-evolution.

Abstract Background The THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial’s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence. Methods Stage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale. Results From March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463). Conclusions MRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial’s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.