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Abstract Soybean protein is of plant origin and is commonly appropriate for improving the processing characteristics of foods. This study aimed to explore a novel functional ingredient that contained soybean protein isolate (SPI) and blueberry anthocyanins (BANs). The spatial conformation and secondary structure of SPI-BANs complexes were analyzed using circular dichroism and fluorescence spectroscopy, the processing properties were investigated as well as the retention of antioxidant activity during thermal treatments. Results showed that the contents of free sulfhydryl and free amino groups in complexes increased to 3.50 and 1.19 folds than those of SPI, respectively, while the surface hydrophobicity decreased by 74.23%. Compared with SPI, the BANs-modified SPI had a smaller particle size of 29.12 nm and a lower zeta-potential of -8.73 mV and on the other hand, the complexes possessed higher solubility (83.08%) and foaming and emulsifying properties (115.08% and 54.03 m2/g). After fortification with SPI-BANs, the baking loss rate and adhesiveness of chiffon cake were reduced by 10.82% and improved to 0.24 N.mm, respectively. The high antioxidant activities of SPI-BANs under heat led to the cake’s bioactivities largely enhanced by 1.99 ~ 12.71 folds, being 345.19 µg Trolox/g for the DPPH radical scavenging activity. This study developed the functional food ingredients as antioxidants and a substitute for animal-based proteins in bakery products, which was safe and sustainable by using the dietary components from plant resources. Graphical Abstract

Abstract In multicentric studies, data sharing between institutions might negatively impact patient privacy or data security. An alternative is federated analysis by secure multiparty computation. This pilot study demonstrates an architecture and implementation addressing both technical challenges and legal difficulties in the particularly demanding setting of clinical research on cancer patients within the strict European regulation on patient privacy and data protection: 24 patients from LMU University Hospital in Munich, Germany, and 24 patients from Policlinico Universitario Fondazione Agostino Gemelli, Rome, Italy, were treated for adrenal gland metastasis with typically 40 Gy in 3 or 5 fractions of online-adaptive radiotherapy guided by real-time MR. High local control (21% complete remission, 27% partial remission, 40% stable disease) and low toxicity (73% reporting no toxicity) were observed. Median overall survival was 19 months. Federated analysis was found to improve clinical science through privacy-friendly evaluation of patient data in the European health data space.

Abstract Purpose/objective Currently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy. Methods Prospective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the “targeted RT study,” was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0. Results A total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT. Conclusion In conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context. Trial registration number DRKS00026193. Date of registration 12/27/2022 (retrospectively registered).

Abstract We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40–65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.

Abstract The emerging world of 3D food printing is reviewed. Its role in food manufacturing, including benefits and impacts, underemphasized gastrophysical aspects, and limitations are discussed. Foods can be digitally designed and physically prepared using the layer-by-layer deposition of food components, unleashing opportunities to deliver nutritionally personalized food and new food-human interactions. Existing bottlenecks, under-researched gastropsychophysical aspects, and the lack of harmonized standards hindering its use for mass production are mentioned.

Abstract Breast conserving treatment typically involves surgical excision of tumor and adjuvant radiotherapy targeting the breast area or tumor bed. Accurately defining the tumor bed is challenging and lead to irradiation of greater volume of healthy tissues. Preoperative stereotactic body radiotherapy (SBRT) which target tumor may solves that issues. We conducted a systematic literature review to evaluates the early toxicity and cosmetic outcomes of this promising treatment approach. Secondary we reviewed pathological complete response (pCR) rates, late toxicity, patient selection criteria and radiotherapy protocols. We retrieved literature from PubMed, Scopus, Web of Science, Cochrane, ScienceDirect, and ClinicalTrials.gov. The study adhered to the PRISMA 2020 guidelines. Ten prospective clinical trials (7 phase II, 3 phase I), encompassing 188 patients (aged 18–75 years, cT1-T3 cN0-N3 cM0, primarily with ER/PgR-positive, HER2-negative status,), were analyzed. Median follow-up was 15 months (range 3–30). Treatment involved single-fraction SBRT (15-21Gy) in five studies and fractionated (19.5–31.5Gy in 3 fractions) in the rest. Time interval from SBRT to surgery was 9.5 weeks (range 1–28). Acute and late G2 toxicity occurred in 0–17% and 0–19% of patients, respectively, G3 toxicity was rarely observed. The cosmetic outcome was excellent in 85–100%, fair in 0–10% and poor in only 1 patient. pCR varied, showing higher rates (up to 42%) with longer intervals between SBRT and surgery and when combined with neoadjuvant systemic therapy (up to 90%). Preoperative SBRT significantly reduce overall treatment time, enabling to minimalize volumes. Early results indicate excellent cosmetic effects and low toxicity. Graphical abstract

Abstract Background Pathological complete response (pCR) is a well-established prognostic factor in breast cancer treated with neoadjuvant systemic therapy (naST). The determining factors of pCR are known to be intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage as well as type of systemic therapy. The addition of neoadjuvant radiotherapy (naRT) to this paradigm might improve response, freedom from disease, toxicity and cosmetic outcome compared to adjuvant radiotherapy. The factors for pCR and primary tumor regression when neoadjuvant radiation therapy is added to chemotherapy have not been thoroughly described. Methods We performed a retrospective analysis of 341 patients (cT1-cT4/cN0-N+) treated with naRT and naST between 1990 and 2003. Patients underwent naRT to the breast and mostly to the supra-/infraclavicular lymph nodes combined with an electron or brachytherapy boost. NaST was given either sequentially or simultaneously to naRT using different regimens. We used the univariate and multivariate regression analysis to estimate the effect of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) as well as complete primary tumor response (ypT0/Tis; bpCR) in our cohort. Receiver operating characteristic (ROC) analysis was performed to evaluate the interval between radiotherapy (RT) and resection (Rx) as well as radiotherapy dose. Results Out of 341 patients, pCR and pbCR were achieved in 31% and 39%, respectively. pCR rate was influenced by resection type, breast cancer subtype, primary tumor stage and interval from radiation to surgery in the multivariate analysis. Univariate analysis of bpCR showed age, resection type, breast cancer subtype, clinical tumor stage and grading as significant factors. Resection type, subtype and clinical tumor stage remained significant in multivariate analysis. Radiation dose to the tumor and interval from radiation to surgery were not significant factors for pCR. However, when treatment factors were added to the model, a longer interval from radiotherapy to resection was a significant predictor for pCR. Conclusions The factors associated with pCR following naST and naRT are similar to known factors after naST alone. Longer interval to surgery might to be associated with higher pCR rates. Dose escalation beyond 60 Gy did not result in higher response rates.

Abstract Targeted immunotherapy combinations, including the anti-CD38 monoclonal antibody (MoAb) daratumumab, have shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), leading to a considerable increase in progression-free survival. However, a large fraction of patients inevitably relapse. To understand this, we investigated 32 relapsed MM patients treated with daratumumab, lenalidomide, and dexamethasone (Dara-Rd; NCT03848676). We conducted an integrated analysis using whole-genome sequencing (WGS) and flow cytometry in patients with RRMM. WGS before and after treatment pinpointed genomic drivers associated with early progression, including RPL5 loss, APOBEC mutagenesis, and gain of function structural variants involving MYC and chromothripsis. Flow cytometry on 202 blood samples, collected every 3 months until progression for 31 patients, revealed distinct immune changes significantly impacting clinical outcomes. Progressing patients exhibited significant depletion of CD38-positive NK cells, persistence of T-cell exhaustion, and reduced depletion of regulatory T cells over time. These findings underscore the influence of immune composition and daratumumab-induced immune changes in promoting MM resistance. Integrating genomics and flow cytometry unveiled associations between adverse genomic features and immune patterns. Overall, this study sheds light on the intricate interplay between genomic complexity and the immune microenvironment driving resistance to Dara-Rd in patients with RRMM.

Quantifying the effects of external climatic and anthropogenic stressors on aquatic ecosystems is an important task for scientific purposes and management progress in the field of water resources. In this study, we propose an innovative use of biotic communities as real-time indicators, which offers a promising solution to directly quantify the impact of these external stressors on the aquatic ecosystem health. Specifically, we investigated the influence of natural river floods on riverine biotic communities using freshwater mussels (FMs) as reliable biosensors. Using the valvometry technique, we monitored the valve gaping of FMs and analysed both the amplitude and frequency. The valve movement of the FMs was tracked by installing a magnet on one valve and a Hall effect sensor on the other valve. The magnetic field between the magnet and the sensor was recorded using an Arduino board, and its changes over time were normalised to give the opening percentage of the FMs (how open the mussels were). The recorded data were then analysed using continuous wavelet transform (CWT) analysis to study the time-dependent frequency of the signals. The experiments were carried out both in a laboratory flume and in the Paglia River (Italy). The laboratory experiments were conducted with FMs in two configurations: freely moving on the bed and immobilised on vertical rods. Testing of the immobilised configuration was necessary because the same configuration was used in the field in order to prevent FMs from packing against the downstream wall of the protection cage during floods or from breaking their connection wires. These experiments allowed us to verify that immobilised mussels show similar responses to abrupt changes in flow conditions as free mussels. Moreover, immobilised mussels produced more neat and interpretable signals than free-moving mussels due to the reduced number of features resulting from movement constraints. We then analysed the response of 13 immobilised mussels under real river conditions during a flood on 31 March 2022. The FMs in the field showed a rapid and significant change in valve gap frequency as the flood escalated, confirming the general behaviour observed in the laboratory in the presence of an abrupt increase in the flow. These results highlight the effectiveness of using FMs as biosensors for the timely detection of environmental stressors related to natural floods and emphasise the utility of CWT as a powerful signal-processing tool for the analysis of valvometry data. The study proposes the integration of FM valvometry and CWT for the development of operational real-time biological early-warning systems (BEWSs) with the aim of monitoring and protecting aquatic ecosystems. Future research should focus on extending the investigation of the responsiveness of FMs to specific stressors (e.g. turbidity, temperature, and chemicals) and on testing the applications of the proposed BEWSs to quantify the impact of both natural stressors (e.g. heat waves and droughts) and anthropogenic stressors (e.g. hydropeaking, reservoir flushing, and chemical contamination).

Abstract Background Longitudinal assessments of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) during intracranial radiotherapy at magnetic resonance imaging-guided linear accelerators (MR-linacs) could enable early response assessment by tracking tumor diffusivity changes. However, DWI pulse sequences are currently unavailable in clinical practice at low-field MR-linacs. Quantifying the in vivo repeatability of ADC measurements is a crucial step towards clinical implementation of DWI sequences but has not yet been reported on for low-field MR-linacs. This study assessed ADC measurement repeatability in a phantom and in vivo at a 0.35 T MR-linac. Methods Eleven volunteers and a diffusion phantom were imaged on a 0.35 T MR-linac. Two echo-planar imaging DWI sequence variants, emphasizing high spatial resolution (“highRes”) and signal-to-noise ratio (“highSNR”), were investigated. A test–retest study with an intermediate outside-scanner-break was performed to assess repeatability in the phantom and volunteers’ brains. Mean ADCs within phantom vials, cerebrospinal fluid (CSF), and four brain tissue regions were compared to literature values. Absolute relative differences of mean ADCs in pre- and post-break scans were calculated for the diffusion phantom, and repeatability coefficients (RC) and relative RC (relRC) with 95% confidence intervals were determined for each region-of-interest (ROI) in volunteers. Results Both DWI sequence variants demonstrated high repeatability, with absolute relative deviations below 1% for water, dimethyl sulfoxide, and polyethylene glycol in the diffusion phantom. RelRCs were 7% [5%, 12%] (CSF; highRes), 12% [9%, 22%] (CSF; highSNR), 9% [8%, 12%] (brain tissue ROIs; highRes), and 6% [5%, 7%] (brain tissue ROIs; highSNR), respectively. ADCs measured with the highSNR variant were consistent with literature values for volunteers, while smaller mean values were measured for the diffusion phantom. Conversely, the highRes variant underestimated ADCs compared to literature values, indicating systematic deviations. Conclusions High repeatability of ADC measurements in a diffusion phantom and volunteers’ brains were measured at a low-field MR-linac. The highSNR variant outperformed the highRes variant in accuracy and repeatability, at the expense of an approximately doubled voxel volume. The observed high in vivo repeatability confirms the potential utility of DWI at low-field MR-linacs for early treatment response assessment.

Objectives: The chemokine CCL22 is recognized for recruiting immunosuppressive regulatory T-cells (Treg) that contribute to disease progression in various tumor entities helping them to evade the host immune response. Our study aims to identify the expressing cell types and to evaluate the prognostic significance of CCL22 secretion and its association with Treg invasion in endometrial cancer (EC), an immunogenic cancer. Methods: Specimens from 275 patients with EC and 28 healthy controls were screened immunohistochemically for CCL22. Immunofluorescence double-staining for CCL22 and different immune cell markers was performed. In vitro regulation of CCL22-expression was examined in EC cell lines (Ishikawa+, RL95–2) and human PBMCs in coculture settings via qPCR and ELISA. Results: Elevated CCL22 staining in tumor cells and CCL22-positive M1-macrophages in tumordistant areas were significantly associated with increased overall survival (OS). Conversely, high, secretory-appearing staining in the peritumoral and intratumoral stroma correlated with reduced OS. Although the analysis of the in vitro coculture model of epithelial tumor- and immune cells revealed PBMCs as the primary source of CCL22, we could confirm expression of the chemokine also in the EC epithelial cells. Conclusion: Our study suggests that CCL22 in EC is associated with OS, dependent on its location and the cell type producing it. Intracellular upregulation and extracellular secretion must be considered separately when investigating CCL22 expressing cell types in EC. These results may provide evidence for CCL22-mediated Treg recruitment in EC as a potential future therapeutic target.

Background: Extracorporeal photopheresis (ECP) is considered an emerging rescue therapy for patients with chronic lung allograft dysfunction (CLAD). The aim of the study was to set up a web-based data collection tool for lung transplant patients with CLAD undergoing ECP. Methods: The web-based tool was developed using Oracle MySQL and coded in HyperText Markup Language, JavaScript and Cascading Style Sheets and was set up with pre- and post-transplant data of possible interest in CLAD. Results: The software consists of 7 major sections. The validation cohort consisted of 25 lung transplant patients (13 men and 12 women, median age at transplant 51 years). A significant improvement in the rate of decline of forced expiratory volumes in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC after introduction of ECP was observed. Forty-four percent of patients showed a

According to the latest scientific evidence, consumers appreciate hunted wild game meat (HWGM), but its consumption may expose them to some risks. Hunters produce HWGM, even if they may find it hard to identify themselves as food producers since in Western countries, hunting is practiced mostly as a leisure activity. Thus, hunters may underestimate the risk associated with HWGM handling, failing to preserve its safety during the production process. To test this hypothesis, our study aims to explore the presence of optimistic biases (OB) in a sample of Italian hunters. A sample of 408 hunters was asked to indicate their own risk and the perceived risk of their peers causing a foodborne disease to the final consumer, as well as the practices implemented during the phases of HWGM handling and preparation. Moreover, information about HWGM destinations, hunters' knowledge of basic principles of food safety, and risk perceptions of HWGM preparation were collected. Our results show that hunters generally tend to perceive themselves as "better than their peers" in performing actions to preserve HWGM safety, especially if the peers are unfamiliar to the respondent. Furthermore, OB correlates knowledge of basic principles of food safety with risk perceptions of HWGM preparation-related practices. Finally, hunters perceived themselves as "nature lovers" and "hunting enthusiasts" and did not recognize their role as food producers. Therefore, our findings emphasize the importance of improving hunters’ training to preserve public health, addressing the need for more targeted strategies able to enhance hunters’ awareness of their role as food producers.

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1–391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5–142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00–0.69) and the right lacrimal gland (median 0.59, range 0.42–0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021

The type-Silurian Cellon section in the Carnic Alps in Austria underpins much of the current Silurian conodont zonations, forming the basis for the Silurian timescale. However, the Silurian record of the Cellon section lacks radiometric and astrochronological age constraints, making it difficult to gain insights into the processes pacing Silurian (anoxic) events. To attain age constraints and investigate the pacing Silurian (anoxic) events by astronomical cycles, a cyclostratigraphic study was conducted on high-resolution pXRF (CaO, Al2O3, and Fe2O3) and induration records spanning the Ludlow and Pridoli parts of the Cellon section. Astronomical cycles ranging from precession to the 405-kyr eccentricity cycle were first recognised visually in the field and in proxy records. The visual detection of astronomical cycles served as an input for the WaverideR R package, enabling the tracking of the 405-kyr eccentricity period in each proxy’s continous wavelet transform scalograms. These tracked period curves were combined with external age controls through multiple Monte Carlo simulations, generating an (absolute) age model. This age model is used to assign ages and durations and their respective uncertainties to a hiatus in the Ludfordian, conodont zones, lithological units, geochronological units and events, yielding new ages for Silurian stage boundaries (e.g., Gorstian-Ludfordian boundary at 425.92 ± 0.65 Ma, the Ludfordian-Pridoli boundary at 423.03 ± 0.53 Ma, the Silurian-Devonian boundary at 418.86 ± 1.02 Ma), and new durations for the Ludfordian at 2.89 ± 0.35 Myr and Pridoli at 4.24 ± 0.46 Myr. Furthermore, the imprint of astronomical cycles in the Cellon section itself indicates that the Linde, Klev and Silurian-Devonian boundary events all occur after a 2.4-Myr eccentricity node, indicating pacing by astronomical forcing, similar to other Devonian and Cretaceous anoxic events. The Lau event, however, does not appear to coincide with a 2.4-Myr eccentricity node.

Abstract Background Glioblastoma multiforme (GBM) is nowadays the most aggressive tumor affecting brain in adults with a very poor prognosis due to the limited therapies and the systemic cytotoxicity. Among the different new drugs, recently has been reported the in vitro anti-glioma activity of a new cationic platinum(II) complex bearing 8-aminoquinoline as chelating ligand (Pt-8AQ). The purpose of this research work was to confirm the activity of Pt-8AQ on U87-GM spheroid and to investigate the ability of Mesenchymal Stromal Cells (MSCs) to incorporate and release Pt-8AQ in its active form. The MSCs were primed with Pt-8AQ under optimized conditions and the secretome was analyzed for evaluating the cytotoxic activity of Pt-8AQ and the presence of Extracellular Vesicles (Evs). Results The principal results showed that Pt-8AQ incorporated by MSCs was released in the secretome and exerted a significant higher anticancer activity with respect to the free drug. The release of Pt-8AQ did not occur in Evs, as demonstrated for other drugs, but it could be delivered bound to some specific carriers able to enhance its bioavailability and efficacy. Some hypotheses are discussed to explain this surprisingly finding out that, however, it needs more investigations. Conclusions The major conclusions are that cell mediated drug delivery systems could provide a potential approach to facilitate the GBM therapy by intra-tumoral administration of cells loaded with Pt-8AQ, being MSCs able to integrate it into the tumor mass and exert high therapeutic efficacy in situ. The increased efficacy of Pt-8AQ delivered by MSCs even suggests to deeper investigate a possible direct use of MSCs secretome both in situ and/or by systemic administration, being secretome able to pass the blood–brain tumor.

Abstract The Carpathian Mountains have been constantly inhabited by grey wolves and present one of the largest distribution areas in Europe, comprising between 2300 and 2700 individuals in Romania. To date, however, relatively little is known about the Romanian wolf population. We aimed to provide a first assessment of genetic diversity, population structure and wolf-dog hybridisation based on 444 mostly non-invasively collected samples in the Eastern Romanian Carpathians. Pack reconstruction and analysis of population genetic parameters were performed with mitochondrial DNA control-region sequencing and microsatellite genotyping. We found relatively high levels of genetic diversity, which is similar to values found in previous studies on Carpathian wolves from Poland and Slovakia, as well as to the long-lasting Dinaric-Balkan wolf population. We found no significant population structure in our study region, suggesting effective dispersal and admixture. Analysis of wolf-dog hybridisation using a Single Nucleotide Polymorphism panel optimised for hybrid detection revealed low rates of admixture between wolves and domestic dogs. Our results provide evidence for the existence of a genetically viable wolf population in the Romanian Carpathians. The genetic data obtained in this study may serve as valuable baseline information for the elaboration of monitoring standards and management plans for wolves in Romania.

Infantile hemangiomas (IHs) are benign vascular neoplasms of childhood (prevalence 5–10%) due to the abnormal proliferation of endothelial cells. IHs are characterized by a peculiar natural life cycle enclosing three phases: proliferative (≤12 months), involuting (≥13 months), and involuted (up to 4–7 years). The mechanisms underlying this neoplastic disease still remain uncovered. Twenty-seven IH tissue specimens (15 proliferative and 12 involuting) were subjected to hematoxylin and eosin staining and a panel of diagnostic markers by immunohistochemistry. WT1, nestin, CD133, and CD26 were also analyzed. Moreover, CD31pos/CD26pos proliferative hemangioma–derived endothelial cells (Hem-ECs) were freshly isolated, exposed to vildagliptin (a DPP-IV/CD26 inhibitor), and tested for cell survival and proliferation by MTT assay, FACS analysis, and Western blot assay. All IHs displayed positive CD31, GLUT1, WT1, and nestin immunostaining but were negative for D2-40. Increased endothelial cell proliferation in IH samples was documented by ki67 labeling. All endothelia of proliferative IHs were positive for CD26 (100%), while only 10 expressed CD133 (66.6%). Surprisingly, seven involuting IH samples (58.3%) exhibited coexisting proliferative and involuting aspects in the same hemangiomatous lesion. Importantly, proliferative areas were characterized by CD26 immunolabeling, at variance from involuting sites that were always CD26 negative. Finally, in vitro DPP-IV pharmacological inhibition by vildagliptin significantly reduced Hem-ECs proliferation through the modulation of ki67 and induced cell cycle arrest associated with the upregulation of p21 protein expression. Taken together, our findings suggest that CD26 might represent a reliable biomarker to detect proliferative sites and unveil non-regressive IHs after a 12-month life cycle.

In the present study, in order to expand the knowledge on the distribution of parasites of the genus Eustrongylides in never investigated Italian lacustrine areas of Tuscany and Latium, fish specimens from four Tuscan lakes (Bilancino, Chiusi, Montedoglio and San Cipriano) and two Latium lakes (Bolsena and Bracciano) were collected and analyzed. The parasitological analysis, consisting of a visual inspection followed by a chloro-peptic digestion, was performed on 1650 specimens belonging to 17 species: European perch (Perca fluviatilis), Pumpkinseed (Lepomis gibbosus), Pike-perch (Sander lucioperca), Largemouth black bass (Micropterus salmoides), Pike (Esox lucius), Big-scale sand smelt (Atherina boyeri), Tench (Tinca), European Whitefish (Coregonus lavaretus), Channel catfish (Ictalurus punctatus), Chub (Squalius cephalus), Rudd (Scardinius erythrophthalmus), Common bleak (Alburnus alborella), South European roach (Sarmarutilus rubilio), South European nase (Protochondrostoma genei), Italian riffle dace (Telestes muticellus), Goldfish (Carassius auratus), and Freshwater bream (Abramis brama). Eustrongylides spp. larvae were only found in one specimen of European perch caught in Bracciano Lake and purchased from a local fishmonger (P = 3.3%; MI = 1; MA = 0.03). The only isolated Eustrongylides spp. larva was submitted to molecular analysis of the ITS gene region and identified as E. excisus. This finding adds Bracciano Lake to the list of the several Italian lakes in which nematodes belonging to this genus have been reported. Even if the observed prevalence is currently low, the presence of the parasite in this local freshwater fish supply chain requires FBOs to adopt risk management measures to prevent contaminated products from reaching final consumer. Moreover, future investigations will show if the parasite expands in these areas.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Purpose: Due to its close vicinity to critical structures, especially the spinal cord, standards for safety for spine stereotactic body radiotherapy (SBRT) should be high. This study was conducted, to evaluate intrafractional motion during spine SBRT for patients without individualized immobilization (e.g., vacuum cushions) using high accuracy patient monitoring via orthogonal X-ray imaging. Methods: Intrafractional X-ray data were collected from 29 patients receiving 79 fractions of spine SBRT. No individualized immobilization devices were used during the treatment. Intrafractional motion was monitored using the ExacTrac Dynamic (ETD) System (Brainlab AG, Munich, Germany). Deviations were detected in six degrees of freedom (6 DOF). Tolerances for repositioning were 0.7 mm for translational and 0.5° for rotational deviations. Patients were repositioned when the tolerance levels were exceeded. Results: Out of the 925 pairs of stereoscopic X-ray images examined, 138 (15 %) showed at least one deviation exceeding the predefined tolerance values. In all 6 DOF together, a total of 191 deviations out of tolerance were recorded. The frequency of deviations exceeding the tolerance levels varied among patients but occurred in all but one patient. Deviations out of tolerance could be seen in all 6 DOF. Maximum translational deviations were 2.6 mm, 2.3 mm and 2.8 mm in the lateral, longitudinal and vertical direction. Maximum rotational deviations were 1.8°, 2.6° and 1.6° for pitch, roll and yaw, respectively. Translational deviations were more frequent than rotational ones, and frequency and magnitude of deviations showed an inverse correlation. Conclusion: Intrafractional motion detection and patient repositioning during spine SBRT using X-ray imaging via the ETD System can lead to improved safety during the application of high BED in critical locations. When using intrafractional imaging with low thresholds for re-positioning individualized immobilization devices (e.g. vacuum cushions) may be omitted.

Purpose: Stereotactic body radiotherapy (SBRT) is an effective treatment for adrenal gland metastases, but it is technically challenging and there are concerns about toxicity. We performed a multi-institutional pooled retrospective analysis to study clinical outcomes and toxicities after MR-guided SBRT (MRgSBRT) using for adrenal gland metastases. Methods and Materials: Clinical and dosimetric data of patients treated with MRgSBRT on a 0.35 T MR-Linac at 11 institutions between 2016 and 2022 were analyzed. Local control (LC), local progression-free survival (LPFS), distant progression-free survival (DPFS) and overall survival (OS) were estimated using Kaplan-Meier method and log-rank test. Results: A total of 255 patients (269 adrenal metastases) were included. Metastatic pattern was solitary in 25.9 % and oligometastatic in 58.0 % of patients. Median total dose was 45 Gy (range, 16–60 Gy) in a median of 5 fractions, and the median BED10 was 100 Gy (range, 37.5–132.0 Gy). Adaptation was done in 87.4 % of delivered fractions based on the individual clinicians' judgement. The 1- and 2- year LPFS rates were 94.0 % (95 % CI: 90.7–97.3 %) and 88.3 % (95 % CI: 82.4–94.2 %), respectively and only 2 patients (0.8 %) experienced grade 3 + toxicity. No local recurrences were observed after treatment to a total dose of BED10 > 100 Gy, with single fraction or fractional dose of > 10 Gy. Conclusions: This is a large retrospective multi-institutional study to evaluate the treatment outcomes and toxicities with MRgSBRT in over 250 patients, demonstrating the need for frequent adaptation in 87.4 % of delivered fractions to achieve a 1- year LPFS rate of 94 % and less than 1 % rate of grade 3 + toxicity. Outcomes analysis in 269 adrenal lesions revealed improved outcomes with delivery of a BED10 > 100 Gy, use of single fraction SBRT and with fraction doses > 10 Gy, providing benchmarks for future clinical trials.

Background and purpose: To determine the potential prognostic value of proliferation and angiogenesis plasma proteins following CT-guided high dose rate brachytherapy (HDR-BT) of hepatocellular carcinoma (HCC). Materials and methods: For this prospective study, HDR-BT (1 × 15 Gy) was administered to 24 HCC patients. Plasma was obtained and analyzed using an Olink proteomics Target-96 immuno-oncology-panel that included multiple markers of angiogenesis and proliferation. Fold-change (FC) ratios were calculated by comparing baseline and 48 h post HDR-BT paired samples. Patients were classified as responders (n = 12) if they had no local progression within 6 months or systemic progression within 2 years. Non-responders (n = 12) had recurrence within 6 months and/or tumor progression or extrahepatic disease within 2 years. Results: Proliferation marker EGF was significantly elevated in non-responders compared to responders (p = 0.0410) while FGF-2, HGF, and PlGF showed no significant differences. Angiogenesis markers Angiopoietin-1 and PDGF-B were likewise significantly elevated in non-responders compared to responders (p = 0.0171, p = 0.0462, respectively) while Angiopoietin-2, VEGF-A, and VEGFR-2 did not differ significantly. Kaplan-Meier analyses demonstrated significantly shorter time to systemic progression in patients with increased EGF and Angiopoietin-1 (p = 0.0185, both), but not in patients with one of the remaining proteins elevated (all p > 0.1). Pooled analysis for these 9 proteins showed significantly shorter time to systemic progression for FC ≥1.3 and ≥1.5 for at least 3 proteins elevated (p = 0.0415, p = 0.0193, respectively). Conclusion: Increased plasma levels of EGF and Angiopoietin-1 after HDR-BT for HCC are associated with poor response and may therefore function as predictive biomarkers of outcome.

Abstract Introduction The objective was to determine the added value of comprehensive molecular profile by whole‐exome and RNA sequencing (WES/RNA‐Seq) in advanced and refractory cancer patients who had no molecular‐based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array‐based comparative genomic hybridization (aCGH). Materials and Methods In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90‐gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA‐Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA‐Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). Results After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1–10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA‐Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA‐Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA‐Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA‐Seq. Conclusions In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA‐Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

Introduction: Microbial photoinactivation using UV light can be enhanced by the addition of food-grade photosensitizers (PSs), such as curcumin. Micellization of curcumin can improve its stability and antimicrobial activity. The objective of this study was to investigate the potential mechanisms that contribute to the photoinactivation of Escherichia coli O157: H7 and Listeria innocua by curcumin-loaded surfactant solutions produced with Surfynol 465 (S465) or Tween 80 (T80) below, near, and above their critical micelle concentration (CMC).Methods: Stock curcumin-surfactant solutions were produced with S465 or T80 (5 mM sodium citrate buffer, pH 3.5). Mixtures of each bacterial suspension (initial inoculum = 6 LogCFU/mL), 1 µM curcumin, and surfactants were irradiated with UV-A light (λ = 365 nm) for 5 min. Microbial recovery after treatments was assessed by monitoring the growth of the treated E. coli O157: H7 or L. innocua using an oCelloscope™. The growth curves were characterized using a modified logistic model.Results and Discussion: Both gram-positive and gram-negative bacteria showed less and slower recovery when treated with curcumin-S465 (near or at CMC) than curcumin-T80 solutions after irradiation. FLIM micrographs suggested that curcumin was preferentially localized at the cell membrane when S465 was present, as evidenced by its longer lifetimes in samples treated with curcumin-S465 solutions. Washing after treatment resulted in the removal of loosely bound or unbound S465-curcumin micelles; hence, both E. coli O157: H7 and L. innocua recovery was faster. This suggested that curcumin partitioning has a significant role in microbial photoinactivation, possibly due to the production of reactive oxygen species (ROS) closer to/within the membrane. The permeability of the membrane of E. coli O157: H7, as inferred from the Live/Dead cell assay, increased when S465 was present, suggesting that S465 can also facilitate inactivation by disrupting the membrane and by favoring the localization of curcumin adjacent to the cell membrane. Therefore, a synergistic antimicrobial effect is observed when curcumin is present alongside S465 at concentrations below or near its CMC due to the disruption of the cell membrane by S465.

Background: The aim of this prospective observational study was to evaluate the dosimetry benefits, changes in pulmonary function, and clinical outcome of online adaptive MR-guided SBRT. Methods: From 11/2020–07/2022, 45 consecutive patients with 59 lesions underwent multi-fraction SBRT (3–8 fractions) at our institution. Patients were eligible if they had biopsy-proven NSCLC or lung cancer/metastases diagnosed via clinical imaging. Endpoints were local control (LC) and overall survival (OS). We evaluated PTV/GTV dose coverage, organs at risk exposure, and changes in pulmonary function (PF). Acute toxicity was classified per the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: The median PTV was 14.4 cm3 (range: 3.4 – 96.5 cm3). In total 195/215 (91%) plans were reoptimised. In the reoptimised vs. predicted plans, PTV coverage by the prescribed dose increased in 94.6% of all fractions with a median increase in PTV VPD of 5.6% (range: −1.8 – 44.6%, p

Purpose: This systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT). Methods: Following PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies. Results and conclusion: 31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11–0.29) and 0.42 (range 0.18–0.54), respectively. NTCPex was a median of 1.77 (range 1.60–1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66–2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Abstract Purpose/objective Adjuvant whole breast radiotherapy and systemic therapy are part of the current evidence-based treatment protocols for early breast cancer, after breast-conserving surgery. Numerous randomized trials have investigated the therapeutic effects of partial breast irradiation (PBI) compared to whole breast irradiation (WBI), limiting the treated breast tissue. These trials were designed to achieve equal control of the disease with possible reduction in adverse events, improvements in cosmesis and quality of life (QoL). In this meta-analysis, we aimed to investigate the differences between PBI and WBI in side effects and QoL. Material/methods We performed a systematic literature review searching for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was performed using the published event rates and the effect-sizes for available acute and late adverse events. Additionally, we evaluated cosmetic outcomes as well as general and breast-specific QoL using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Results Sixteen studies were identified (n = 19,085 patients). PBI was associated with a lower prevalence in any grade 1 + acute toxicity and grade 2 + skin toxicity (OR = 0.12; 95% CI 0.09–0.18; p

Andrea Ferrari,1 Pablo Berlanga,2 Susanne Andrea Gatz,3 Reineke A Schoot,4 Max M van Noesel,4,5 Shushan Hovsepyan,6 Stefano Chiaravalli,1 Luca Bergamaschi,1 Veronique Minard-Colin,2 Nadege Corradini,7 Rita Alaggio,8 Patrizia Gasparini,9 Bernadette Brennan,10 Michela Casanova,1 Sandro Pasquali,11,12 Daniel Orbach13 1Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; 3Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; 4Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; 5Division Imaging & Cancer, University Medical Center Utrecht, Utrecht, the Netherlands; 6Pediatric Cancer and Blood Disorders Center of Armenia, Yerevan, Armenia; 7Department of Pediatric Hematology and Oncology-IHOPe, Léon Bérard Center, Lyon, France; 8Pathology Department, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy; 9Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 10Pediatric Oncology, Royal Manchester Children’s Hospital, Manchester, UK; 11Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 12Sarcoma Service, Department of Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 13SIREDO Oncology Center(Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, FranceCorrespondence: Andrea Ferrari, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, Milano, MI, 1 20133, Italy, Tel +39 02 23902588, Fax +39 02 23902648, Email andrea.ferrari@istitutotumori.mi.itAbstract: While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients.Keywords: synovial sarcoma, relapse, second line therapy, surgery, new agents, TCR-T cell therapy, children

Volcanoes are known to be important emitters of atmospheric gases and aerosols, which for certain volcanoes can include halogen gases and in particular HBr. HBr emitted in this way can undergo rapid atmospheric oxidation chemistry (known as the bromine explosion) within the volcanic emission plume, leading to the production of bromine oxide (BrO) and ozone depletion. In this work, we present the results of a modelling study of a volcanic eruption from Mt Etna that occurred around Christmas 2018 and lasted 6 d. The aims of this study are to demonstrate and evaluate the ability of the regional 3D chemistry transport model Modèle de Chimie Atmosphérique de Grande Echelle (MOCAGE) to simulate the volcanic halogen chemistry in this case study, to analyse the variability of the chemical processes during the plume transport, and to quantify its impact on the composition of the troposphere at a regional scale over the Mediterranean basin. The comparison of the tropospheric SO2 and BrO columns from 25 to 30 December 2018 from the MOCAGE simulation with the columns derived from the TROPOspheric Monitoring Instrument (TROPOMI) satellite measurements shows a very good agreement for the transport of the plume and a good consistency for the concentrations if considering the uncertainties in the flux estimates and the TROPOMI columns. The analysis of the bromine species' partitioning and of the associated chemical reaction rates provides a detailed picture of the simulated bromine chemistry throughout the diurnal cycle and at different stages of the volcanic plume's evolution. The partitioning of the bromine species is modulated by the time evolution of the emissions during the 6 d of the eruption; by the meteorological conditions; and by the distance of the plume from the vent, which is equivalent to the time since the emission. As the plume travels further from the vent, the halogen source gas HBr becomes depleted, BrO production in the plume becomes less efficient, and ozone depletion (proceeding via the Br+O3 reaction followed by the BrO self-reaction) decreases. The depletion of HBr relative to the other prevalent hydracid HCl leads to a shift in the relative concentrations of the Br− and Cl− ions, which in turn leads to reduced production of Br2 relative to BrCl. The MOCAGE simulations show a regional impact of the volcanic eruption on the oxidants OH and O3 with a reduced burden of both gases that is caused by the chemistry in the volcanic plume. This reduction in atmospheric oxidation capacity results in a reduced CH4 burden. Finally, sensitivity tests on the composition of the emissions carried out in this work show that the production of BrO is higher when the volcanic emissions of sulfate aerosols are increased but occurs very slowly when no sulfate and Br radicals are assumed to be in the emissions. Both sensitivity tests highlight a significant impact on the oxidants in the troposphere at the regional scale of these assumptions. All the results of this modelling study, in particular the rapid formation of BrO, which leads to a significant loss of tropospheric ozone, are consistent with previous studies carried out on the modelling of volcanic halogens.

Organic waste-to-energy (OWtE) technologies are playing a steadily increasing role in the Green Transition, thus becoming a powerful driver in the establishment of an ever more efficient and sustainable circular economy. The advantages of OWtE processes are well known: not only do they reduce the waste volumes sent to landfills or incineration plants, but also and foremost, through the energy they yield (biogenic carbon dioxide, amongst others), they reduce dependance on fossil fuels. This article gives a complete panorama of these technologies, starting from the classical methods and ending with a review of the latest modern novelties. Advantages and disadvantages of each method are highlighted, with particular focus on the formation of by-products and the relevant treatment aimed at preventing environmental pollution. Accordingly, modern techniques for increasing waste-to-energy efficiency and integrating the concept of circular economy and substitutability are analyzed from this perspective. Along with an analysis of modern scientific achievements in this area, practical examples of the implementation of technologies in European countries are given, with an emphasis on the obvious advantages, both economic and environmental.

The cacao fruit is a rich source of polyphenols, including flavonoids and phenolic acids, which possess significant health benefits. The accurate identification and quantification of these bioactive compounds extracted from different parts of the cacao fruit, such as pods, beans, nibs, and cacao shells, require specific treatment conditions and analytical techniques. This review presents a comprehensive comparison of extraction processes and analytical techniques used to identify and quantify polyphenols from various parts of the cacao fruit. Additionally, it highlights the environmental impact of these methods, exploring the challenges and opportunities in selecting and utilizing extraction, analytical, and impact assessment techniques, while considering polyphenols’ yield. The review aims to provide a thorough overview of the current knowledge that can guide future decisions for those seeking to obtain polyphenols from different parts of the cacao fruit.

Endometrial cancer (EC) is a common gynecological cancer worldwide. Treatment has been improved in recent years; however, in advanced stages, therapeutic options are still limited. The expression of galectins is increased in several tumor types and that they are involved in important cell processes. Large studies on endometrial cancer are still pending; Specimens of 225 patients with EC were immunohistochemically stained with antibodies for Gal-8 and Gal-9. Expression was correlated with histopathological variables. The cytosolic expression of both galectins is associated with grading and survival. Cytosolic Galectin-8 expression is a positive prognostic factor for overall survival (OS) and progression-free survival (PFS), while nuclear Gal-8 expression correlates only to OS. The cytosolic presence of Galectin-9 is correlated with a better prognosis regarding OS. Our results suggest that expression of both galectins is associated with OS and PFS in EC. Further studies are needed to understand the underlying molecular mechanisms.

Transition metal dichalcogenides (TMDCs), represented by MX2 (where M = Mo, W and X = S, Se, and Te), and more recently, their moiré superlattices (i.e., formed by superimposing layers of TMDCs with different rotation angles) have attracted considerable interest due to their excellent physical properties and unique nanoscale functionalities. Compared to graphene, the literature indicates that TMDCs offer a competitive advantage in optoelectronic technologies, primarily owing to their compositionally controlled non-zero bandgap. These two-dimensional (2D) nanostructured single or multiple layers exhibit remarkable properties that differ from their bulk counterparts. Moreover, stacking different TMDC monolayers also forms heterostructures and introduces unique quantum effects and extraordinary electronic properties, which is particularly promising for next-generation optoelectronic devices and photo(electro)catalytic applications. Therefore, in this review, we also highlight the new possibilities in the formation of 2D/2D heterostructures of MX2-based materials with moiré patterns and discuss the main critical challenges related to the synthesis and large-scale applications of layered MX2 and MX2-based composites to spur significant advances in emerging optoelectronic and photo(electro)catalytic applications.

In the European Union, salmonellosis is one of the most important zoonoses reported. Poultry meat and egg products are the most common food matrices associated with Salmonella presence. Moreover, wild and domestic animals could represent an important reservoir that could favour the direct and indirect transmission of pathogens to humans. Salmonella spp. can infect carnivorous or omnivorous wild birds that regularly ingest food and water exposed to faecal contamination. Birds kept in captivity can act as reservoirs of Salmonella spp. following ingestion of infected prey or feed. In this paper, we describe the isolation of different Salmonella serovars in several species of raptors hosted in aviaries in an Italian wildlife centre and in the raw chicken necks used as their feed but intended for human consumption. Characterisations of strains were carried out by integrating classical methods and whole genome sequencing analysis. The strains of S. bredeney isolated in poultry meat and birds belonged to the same cluster, with some of them being multidrug-resistant (MDR) and carrying the Col(pHAD28) plasmid-borne qnrB19 (fluoro)quinolone resistance gene, thus confirming the source of infection. Differently, the S. infantis found in feed and raptors were all MDR, carried a plasmid of emerging S. infantis (pESI)-like plasmid and belonged to different clusters, possibly suggesting a long-lasting infection or the presence of additional undetected sources. Due to the high risk of fuelling a reservoir of human pathogens, the control and treatment of feed for captive species are crucial.

Abstract Background and purpose Magnetic resonance imaging guided radiotherapy (MRgRT) offers treatment plan adaptation to the anatomy of the day. In the current MRgRT workflow, this requires the time consuming and repetitive task of manual delineation of organs-at-risk (OARs), which is also prone to inter- and intra-observer variability. Therefore, deep learning autosegmentation (DLAS) is becoming increasingly attractive. No investigation of its application to OARs in thoracic magnetic resonance images (MRIs) from MRgRT has been done so far. This study aimed to fill this gap. Materials and methods 122 planning MRIs from patients treated at a 0.35 T MR-Linac were retrospectively collected. Using an 80/19/23 (training/validation/test) split, individual 3D U-Nets for segmentation of the left lung, right lung, heart, aorta, spinal canal and esophagus were trained. These were compared to the clinically used contours based on Dice similarity coefficient (DSC) and Hausdorff distance (HD). They were also graded on their clinical usability by a radiation oncologist. Results Median DSC was 0.96, 0.96, 0.94, 0.90, 0.88 and 0.78 for left lung, right lung, heart, aorta, spinal canal and esophagus, respectively. Median 95th percentile values of the HD were 3.9, 5.3, 5.8, 3.0, 2.6 and 3.5 mm, respectively. The physician preferred the network generated contours over the clinical contours, deeming 85 out of 129 to not require any correction, 25 immediately usable for treatment planning, 15 requiring minor and 4 requiring major corrections. Conclusions We trained 3D U-Nets on clinical MRI planning data which produced accurate delineations in the thoracic region. DLAS contours were preferred over the clinical contours.

Abstract Background In modern times, horses are utilized not only for labour and transportation purposes but also for recreational activities such as competition and pleasure riding. In these various pursuits, the role of vision plays a crucial role. Electroretinography is the most used test to diagnose diseases of the retinal outer segment. There is a wide variety of devices to perform the electroretinography differing one from each other in the corneal electrode and the light stimulation. The Koijman electrode has been tested in dogs but not in horses. The main purpose of this study was to compare electroretinography parameters from horses sedated with detomidine alone or in combination with butorphanol, during a standardized protocol using the Koijman electrode and RETI-port® system. Seven mares were allocated to the detomidine and detomidine plus butorphanol group in a randomised, controlled, crossover study. Friedman and Willcoxon-signed ranked tests were used to compare the electroretinogram parameters. A Student’s t-test was used to compare differences in the number of artefacts to valid values ratio obtained under both sedation protocols. Results Dark adaptation peaked after 16 min under scotopic conditions in both groups. No significant differences in electroretinogram parameters between groups were observed. During the mixed rod and cone response evaluation under scotopic conditions, all mares made a movement of the head resulting in a high number of artefacts. The detomidine plus butorphanol group showed a non-significant tendency to have fewer artefacts and a longer duration of sedation compared to the detomidine group. Conclusions Detomidine alone or combined with butorphanol may be suitable to use Koijman electrode and the RETI-port® to perform a standardized long protocol in horses with some adaptations.

The rehabilitation of those who have undergone anterior cruciate ligament reconstruction (ACL-R) is a complex process that involves many factors. Physical ability recovery is not the only factor in the return to sport; psychosocial factors such as anxiety, pain response, self-esteem, locus of control, and fear of re-injury also play an important role. A systematic search was conducted on the PubMed, Medline, Cochrane, CINAHL and Embase databases using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). No randomized controlled trials (RCTs) were identified. The Methodological Index for Non-Randomized Studies (MINOR) was used to assess the quality of the identified non-RCT studies. A total of 308 studies were identified, of which 32 met the eligibility criteria. The results of these studies were obtained using the KOOS (ADL, Sport, QoL), ACL, TSK-11, K-SES, questionnaires/interviews, and other scales as instrumental approaches. This systematic review and meta-analysis revealed that psychological factors have a significant influence on the post-anterior cruciate ligament reconstruction outcomes of athletes. Fear of re-injury and pain were the primary factors that limited return to sport, whereas self-efficacy, psychological will, and age were associated with better functional outcomes and were essential for male and young patients. Clinicians should focus on both physical and psychological components to optimize rehabilitation.

Abstract Background and aims Prognostic biomarkers identifying patients with early tumor progression after local ablative therapy remain an unmet clinical need. The aim of this study was to investigate circulating miR-21 and miR-210 levels as prognostic biomarkers of HCC treated by CT-guided high-dose rate brachytherapy (HDR-BT). Materials and Methods 24 consecutive HCC patients (BCLC A and B) treated with CT-guided HDR-BT (1 × 15 Gy) were included in this prospective IRB-approved study. RT-PCR was performed to quantify miR-21 and miR-210 levels in blood samples acquired prior to and 2 d after HDR-BT. Follow-up imaging (contrast-enhanced liver MRI and whole-body CT) was performed in 3 months follow-up intervals. Therapy response was assessed with patients classified as either responders or non-responders (12 each). Responders were defined as having no local or diffuse systemic progression within 6 months and no diffuse systemic progression exceeding 3 nodules/nodule diameter > 3 cm from 6 months to 2 years. Non-responders had recurrence within 6 months and/or tumor progression with > 3 nodules or individual lesion diameter > 3 cm or extrahepatic disease within two years, respectively. Biostatistics included parametric and non-parametric testing (Mann–Whitney-U-test), as well as Kaplan–Meier curve construction. Results The responder group demonstrated significantly decreasing miR-21 values 2 d post therapy compared to non-responders (median miR-21 2−ΔΔCт: responders 0.73 [IQR 0.34], non-responders 1.53 [IQR 1.48]; p = 0.0102). miR-210 did not show any significant difference between responders and non-responders (median miR-210 2−ΔΔCт: responders 0.74 [IQR 0.45], non-responders 0.99 [IQR 1.13]; p = 0.8399). Kaplan–Meier curves demonstrated significantly shorter time to systemic progression for increased miR-21 (p = 0.0095) but not miR-210 (p = 0.7412), with events accumulating > 1 year post therapy in non-responders (median time to systemic progression 397 days). Conclusion Increasing circulating miR-21 levels are associated with poor response and shorter time to systemic progression in HDR-BT-treated HCC. This proof-of-concept study provides a basis for further investigation of miR-21 as a prognostic biomarker and potential stratifier in future clinical trials of interventional oncology therapies. Trial registration: In this monocentric clinical study, we analyzed prospectively acquired data of 24 patients from the “ESTIMATE” patient cohort (Studiennummer: DRKS00010587, Deutsches Register Klinischer Studien). Ethical approval was provided by the ethics committee “Ethikkommission bei der LMU München” (reference number “17-346”) on June 20, 2017 and August 26, 2020.

Abstract Background In certain rare undifferentiated small round cell sarcomas new specific molecular CIC‐DUX4/other partner, BCOR‐CCNB3/other partner, YWHAE fusions, or BCOR‐ITD (internal tandem duplication) were identified. These new “CIC fused” (CIC‐fused/ATXN1::NUTM1) and “BCOR rearranged” (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not well described. Methods Multi‐institutional European retrospective analysis of young patients (0–24 years) with CIC‐fused and BCOR rearranged STS. Results Overall, out of the 60 patients selected, the fusion status was CIC‐fused (n = 29), ATXN1::NUTM1 (n = 2), BCOR::CCNB3 (n = 18), BCOR‐ITD (n = 7), and YWHAE (n = 3), MAML::BCOR STS (n = 1). The main primaries were abdomen‐pelvic (n = 23) and limbs (n = 18). Median age was 14 years (0.9–23.8) and 0.9 (0.1–19.1) for CIC‐fused and BCOR‐rearranged groups, respectively (n = 29; p 5 cm) but only six had lymph node involvement. Patients received mainly chemotherapy (n = 57), local surgery (n = 50), and/or radiotherapy (n = 34). After a median follow‐up of 47.1 months (range, 3.4–230), 33 (52%) patients had an event and 23 patients died. Three‐year event‐free survivals were 44.0% (95% CI 28.7–67.5) and 41.2% (95% CI 25.4–67.0) for CIC and BCOR groups (p = 0.97), respectively. Three‐year overall survivals were 46.3% (95% CI 29.6–72.4) and 67.1% (95% CI 50.4–89.3; p = 0.24), respectively. Conclusions Pediatric patients often present with large tumors and metastatic disease, especially CIC sarcomas. Overall outcome is dismal. New treatment options are needed.

Abstract Toll-like receptor 3 (TLR3) is a pattern recognition receptor mainly known for its role in innate immune response to infection. Indeed, binding of double-stranded RNA (dsRNA) to TLR3 triggers a pro-inflammatory cascade leading to cytokine release and immune cell activation. Its anti-tumoral potential has emerged progressively, associated with a direct impact on tumor cell death induction and with an indirect action on immune system reactivation. Accordingly, TLR3 agonists are currently being tested in clinical trials for several adult cancers. Meanwhile, TLR3 variants have been linked to auto-immune disorders, and as risk factors of viral infection and cancers. However, aside from neuroblastoma, TLR3 role in childhood cancers has not been evaluated. Here, by integrating public transcriptomic data of pediatric tumors, we unveil that high TLR3 expression is largely associated with a better prognosis in childhood sarcomas. Using osteosarcomas and rhabdomyosarcomas as models, we show that TLR3 efficiently drives tumor cell death in vitro and induces tumor regression in vivo. Interestingly, this anti-tumoral effect was lost in cells expressing the homozygous TLR3 L412F polymorphism, which is enriched in a rhabdomyosarcomas cohort. Thus, our results demonstrate the therapeutic potential associated with the targeting of TLR3 in pediatric sarcomas, but also the need to stratify patients eligible for this clinical approach with respect to the TLR3 variants expressed.

Adipose tissue is mainly composed by adipocytes. Moreover, mesenchymal stromal/stem cells (MSCs), macrophages, endothelial cells, and extracellular matrix components are present. The variety of molecules as cytokines and growth factors of its structure very rich in blood vessel makes it also similar to a true endocrine organ that however needs still to be fully investigated. In our study, we used human lipoaspirate to obtain mechanically microfragmented fat (MiFAT) which was washed and then devitalized by freezing–thawing cycles. In our experiments, thawed MiFAT was used to stimulate cultures of MSCs from two different sources (adipose tissue and gingiva papilla) in comparison with a traditional stimulation in vitro obtained by culturing MSCs with adipogenic medium. MSCs stimulated with MiFAT showed a very early production of lipid droplets, after only 3 days, that correlated with an increased expression of adipokines. Furthermore, a significant upregulation of PPAR gamma 1 alpha coactivator (PPARGC1A) was observed with an overexpression of uncoupling protein 1 (UCP1) that suggest a pattern of differentiation compatible with the beige–brown fat.

Electrospun nonwovens of biopolymers are gaining popularity in filtration, coatings, encapsulation, and packaging materials. However, their applications are hindered by limited stability, particularly when loaded with lipids. This research aimed to apply a multiscale approach to gain insights into deteriorative processes, e.g., oxidation, limiting the shelf life of these complex materials, using corn oil-loaded electrospun zein nonwovens as a model system. Oil-doped zein electrospun nonwovens were stored in the dark at 23 °C and 33% relative humidity for 28 days and tested at selected intervals to monitor their morphology and mechanical properties. Lipid oxidation was assessed using the thiobarbituric acid reactive species (TBARS) assay. The photophysical properties of intrinsic, i.e., tyrosine (Tyr), and extrinsic, i.e., boron-dipyrromethene undecanoic acid 581/591 (BODIPY C11), lumiphores were also monitored to evaluate changes in local molecular rigidity, and oxidation, respectively. The protein secondary structure was determined with Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) analysis of the oil-loaded electrospun nonwovens revealed that the diameter of the ribbon-like fiber significantly decreased during storage from 701 ± 23 nm to 620 ± 44 nm. Breakage of the electrospun fibers was observed and correlated with increased brittleness and molecular rigidity of the nonwoven material, reflected by an increase in Tyr emission intensity and phosphorescence lifetime. Changes in tensile strength, brittleness and matrix rigidity also correlated with a zein secondary structure transition from unordered to ordered β-sheets. Raman and luminescence micrographs showed oil migration during storage, thereby increasing lipid oxidation. The correlation between local rigidity and lipid distribution/oxidation suggests that reorganizing protein structures increased material brittleness and displaced encapsulated oils within the electrospun fiber. Understanding deteriorative mechanisms aids in developing innovative strategies to improve the stability of these novel food-grade materials.

Background and purpose: Ultra-hypofractionated online adaptive magnetic resonance-guided radiotherapy (MRgRT) is promising for prostate cancer. However, the impact of online adaptation on target coverage and organ-at-risk (OAR) sparing at the level of accumulated dose has not yet been reported. Using deformable image registration (DIR)-based accumulation, we compared the delivered adapted dose with the simulated non-adapted dose. Materials and methods: Twenty-three prostate cancer patients treated at two clinics with 0.35 T magnetic resonance-guided linear accelerator (MR-linac) following the same treatment protocol (5 × 7.5 Gy with urethral sparing and daily adaptation) were included. The fraction MR images were deformably registered to the planning MR image. Both non-adapted and adapted fraction doses were accumulated with the corresponding vector fields. Two DIR approaches were implemented. PTV* (planning target volume minus urethra+2mm) D95%, CTV* (clinical target volume minus urethra) D98%, and OARs (urethra+2mm, bladder, and rectum) D0.2cc, were evaluated. Statistical significance was inferred from a two-tailed Wilcoxon signed-rank test (p

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8–12-weeks (morphine-sensitive phase; Phase 1) and 16–18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

The identification of patients at high risk of herpes zoster (HZ) requiring a prevention strategy with antiviral prophylaxis and anti-HZ vaccine is a clinically relevant issue in patients with immunological impairment. Absence of trials comparing vaccination to pharmacological prophylaxis or defining their sequential use makes the optimal prevention strategy uncertain. This article presents the results of group discussion among an ad hoc constituted panel of experts aimed to review the literature regarding antiviral prophylaxis and vaccine efficacy and safety in populations with malignant and non-malignant hematological diseases, and submitted to hematopoietic stem cell transplantation. The panel used the consensus methodology and proposed solutions for prevention strategy producing advice for the management of the most relevant unmet clinical needs. Such a comprehensive overview aims to support at the practice of HZ pharmacological and vaccine prevention and informing the design and the need of implementation of new studies in the field.

Background: Leiomyosarcoma (LMS) and liposarcoma (LPS) are ultra-rare sarcomas in pediatric (0–18 years) and young adult (19−30) populations. We aimed to analyze their clinical characteristics at these young ages and to determine whether they should be considered with the same therapeutic strategy in both populations. Methods: National retrospective multicenter study of all young patients (0–30 years) included in the sarcoma database “ConticaBase”, treated for LMS or LPS between 2010 and 2019 via the national NETSARC+ network, with available pathology/biology review. Findings: A total of 218 patients were identified, 34 children (nine LMS, 25 LPS) and 184 young adults (58 LMS, 126 LPS). Myxoid/Round Cell LPS (M/RC-LPS) was the most frequent LPS subtype (72 %). All children had localized LMS and LPS, versus 52/58 and 116/126 respectively in adults. Clinical presentation of LMS and all LPS subtypes was comparable in both populations, except for a preferential limb location of LMS in children. The therapeutic strategy was mainly based on primary surgery in LMS (9/9 children, 52/58 adults) and for LPS (respectively 25/25 and 122/126), exclusively or with adjuvant radiotherapy and systemic treatment. With a median follow-up of 62.4 months (range, 2.5–146), 5-year overall survival was respectively 83 % [95 % CI, 58–100] in children and 73 % [61–88] in young adults for LMS, 100 % [100] vs 92 % [87–99] for M/RC-LPS and 25 % [5–100] vs 60 % [29–100] for pleomorphic LPS. Interpretation: LMS and all LPS subtypes appear to display comparable behavior in children and young adults. The authors propose that the same therapeutic strategy should be considered for both groups.

Purpose: Patients with metastatic rhabdomyosarcoma (MTS RMS) and lung as the only metastatic site have better reported outcomes than other patients with MTS RMS. We analysed patients with lung-only MTS RMS receiving standard treatment within the EpSSG MTS 2008 protocol. Patients and methods: Previously untreated patients aged

Germline predisposing pathogenic variants (GPVs) are present in approximately 8–10 % of children with all cancer types. Very rare tumours (VRTs) represent many different diseases, defined with an annual incidence