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Purpose The cyclic AMP response element–binding protein (CREB) and nerve growth factor (NGF) have been proposed as key modulators of brain health and are involved in synaptic plasticity. The study investigates how combined water-based training affects hippocampal neuron plasticity and memory function in old rats. Methods 16 Wistar male rats 24-month-old were randomly divided into two groups: combined training (n = 8) and control (n = 8). Four sessions were performed per week for 10 weeks, and consisted of resistance and endurance training in water. The control group was placed in a water container during training for 30 minutes to be homogenized in terms of the stress conditions. The.NGF and CREB genes in the hippocampus were evaluated and the working memory was measured using real-time PCR and Y-maze tests. The SPSS 26 software was utilized in which independent t-tests were used to analyze the genes and the Mann-Whitney U test was used to analyze functional memory with a significant level of (P < 0.05). Results The combined training resulted in a significant rise in NGF and CREB gene expression in the hippocampus tissue of elderly rats compared to the control group (P < 0.05); however, there was no notable difference in the Y maze performance test between the two groups (P < 0.05). Conclusions These findings suggest that water-based combined training has beneficial effects on gene expression of NGF and CREB; however, it is necessary to conduct more studies to comprehend the effects of combined training on memory function.

Marine sediments are among the largest carbon reservoirs on the planet and play a key role in the global cycling of organic matter. Bottom fisheries are the most widespread anthropogenic physical disturbance to seabed habitats, prompting NGOs and governments to act on regulating mobile bottom-contacting fishing gear. However, the scientific evidence of the effects of bottom trawling on sediment biogeochemistry is highly diverse and presents contrasting results. Here we present a global harmonized dataset of 71 independent studies that assess the effects of demersal fisheries on sedimentological (i.e. grain size, porosity) and biogeochemical (i.e. organic carbon, phytopigments, nutrient fluxes) properties: the Demersal fishery Impacts on Sedimentary Organic Matter (DISOM) database (Paradis, 2023; https://doi.org/10.3929/ethz-b-000634336). We identify considerable gaps, namely in the geographical extension of the data; coverage of environmental predictors (i.e. seasons); fishing descriptors such as the availability of true controls, quantification of fishing effort, and distribution of fishing gear types; and biogeochemical variables that study the remineralization of organic matter. Future studies should address these data gaps to enhance the comprehensiveness of the dataset. With this harmonized database, we aim to allow researchers to explore the effects of demersal fisheries in variable environmental settings to disentangle the effects of this disturbance and provide efficient management strategies.

Abstract This study aims to assess the predictive capability of cylindrical Tumor Growth Rate (cTGR) in the prediction of early progression of well-differentiated gastro-entero-pancreatic tumours after Radio Ligand Therapy (RLT), compared to the conventional TGR. Fifty-eight patients were included and three CT scans per patient were collected at baseline, during RLT, and follow-up. RLT response, evaluated at follow-up according to RECIST 1.1, was calculated as a percentage variation of lesion diameters over time (continuous values) and as four different RECIST classes. TGR between baseline and interim CT was computed using both conventional (approximating lesion volume to a sphere) and cylindrical (called cTGR, approximating lesion volume to an elliptical cylinder) formulations. Receiver Operating Characteristic (ROC) curves were employed for Progressive Disease class prediction, revealing that cTGR outperformed conventional TGR (area under the ROC equal to 1.00 and 0.92, respectively). Multivariate analysis confirmed the superiority of cTGR in predicting continuous RLT response, with a higher coefficient for cTGR (1.56) compared to the conventional one (1.45). This study serves as a proof of concept, paving the way for future clinical trials to incorporate cTGR as a valuable tool for assessing RLT response.

ABSTRACT Background The identification of actionable molecular targets of pancreatic cancer (PAC) is key to improving patient outcomes. We hypothesized O6‐methylguanine‐DNA methyltransferase (MGMT) silencing may occur in a subset of PAC tumors, with unexplored clinical and molecular correlates. Experimental Design We leveraged sequencing data from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC‐3), and the (Australian Pancreatic Cancer Genome Initiative) PACA‐AU cohorts to characterize MGMT‐silenced PAC. Genomic, transcriptomic, methylation, and clinical data were investigated, and findings were validated in silico using methylation, transcriptomic and drug sensitivity data from Cancer Cell Line Encyclopedia (CCLE) project, and in a real‐world cohort of PAC patients profiled for MGMT status at Istituto Nazionale Tumori of Milan (INT). Results On the basis of Human Methylation 450k data, MGMT silencing was identified in ~6% of PAC cases and was enriched in tumors with non‐ductal histology, with a trend toward longer overall survival. MGMT‐silenced tumors were associated with a lower frequency of KRAS mutations and showed features of immune exclusion. In the INT cohort, MGMT‐silencing was confirmed in ~7% of cases and prevalent in KRAS wild type tumors, with a favorable prognostic impact. In silico analysis suggested a higher sensitivity to alkylating and DNA damaging agents in MGMT‐silenced PAC cell lines. Conclusions MGMT silencing occurs in a small subgroup of PACs and is enriched in KRAS wild type cases, with a favorable prognostic impact. Our findings provide the rationale to explore combinations of alkylating with DNA damaging agents in MGMT‐silenced PAC.

IntroductionThis study explores the efficacy of Autologous Micrografts Technology (AMG) in treating chronic wounds refractory to traditional therapies.MethodsAMGs, derived from adipose tissue or dermis using a mechanical fragmentation process, were applied to patients with post-surgical dehiscence. A comprehensive evaluation of wound healing outcomes, including surface area reduction and complete healing, was conducted over a 90-day follow-up period. Additionally, the study investigated the cellular antioxidant activity of AMG solutions and characterized the exosomes obtained through mechanical disaggregation.ResultsResults indicate significant improvements (p

Abstract The interspecific transmission of pathogens can occur frequently in the environment. Among wild bees, the main spillover cases are caused by pathogens associated with Apis mellifera, whose colonies can act as reservoirs. Due to the limited availability of data in Italy, it is challenging to accurately assess the impact and implications of this phenomenon on the wild bee populations. In this study, a total of 3372 bees were sampled from 11 Italian regions within the BeeNet project, evaluating the prevalence and the abundance of the major honey bee pathogens (DWV, BQCV, ABPV, CBPV, KBV, Nosema ceranae, Ascosphaera apis, Crithidia mellificae, Lotmaria passim, Crithidia bombi). The 68.4% of samples were positive for at least one pathogen. DWV, BQCV, N. ceranae and CBPV showed the highest prevalence and abundance values, confirming them as the most prevalent pathogens spread in the environment. For these pathogens, Andrena, Bombus, Eucera and Seladonia showed the highest mean prevalence and abundance values. Generally, time trends showed a prevalence and abundance decrease from April to July. In order to predict the risk of infection among wild bees, statistical models were developed. A low influence of apiary density on pathogen occurrence was observed, while meteorological conditions and agricultural management showed a greater impact on pathogen persistence in the environment. Social and biological traits of wild bees also contributed to defining a higher risk of infection for bivoltine, communal, mining and oligolectic bees. Out of all the samples tested, 40.5% were co-infected with two or more pathogens. In some cases, individuals were simultaneously infected with up to five different pathogens. It is essential to increase knowledge about the transmission of pathogens among wild bees to understand dynamics, impact and effects on pollinator populations. Implementing concrete plans for the conservation of wild bee species is important to ensure the health of wild and human-managed bees within a One-Health perspective.

We report a case of a 40-year-old female with a solitary plasmacytoma of the right transverse apophysis of C1 who underwent combined transoral ablation using a curved steerable needle and cementoplasty under CBCT and infra-red augmented reality navigation system. An imaging work-up revealed an osteolytic lesion determining partial collapse of the right lateral mass of C1 and involving the vertebral foramen. After a biopsy, that revealed a solid tissue consistent with plasmacytoma, it was decided to proceed with radiation therapy. Subsequent PET-CT restaging scans showed residual tumors treated with a transoral percutaneous approach, combining ablation and cementoplasty. This report evaluates the benefits of this combined procedure and the transoral approach, focusing on the advantages of steerable devices and navigation systems.

Abstract In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58–97) and 49% (95% CI 31–77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

Background: Rectal neuroendocrine tumors (rNENs) are rare, constituting 1–2% of rectal tumors, and are often asymptomatic, leading to challenges in early diagnosis. Current management guidelines recommend endoscopic resection for small lesions and surgical intervention for larger or high-risk tumors. This study aims to retrospectively analyze the pathological characteristics, management, and prognosis of rNEN patients. Methods: Data from the Neuroendocrine Tumor Registry at a tertiary hospital in Milan, Italy from 2005 to 2023 were retrospectively analyzed. Patient demographics, disease characteristics, pathology findings, treatment details, and surveillance data were collected. Statistical analyses included descriptive statistics, multivariable binary logistic regression, and Kaplan–Meier survival analysis. Results: Forty-five patients were included, 53.3% male with a mean age of 57.5 years. Most patients were asymptomatic, with incidental diagnosis during colonoscopy. Endoscopic excision was the primary treatment modality (77.8%), with surgical resection reserved for incomplete or inappropriate endoscopic resections. Disease progression occurred in 13 patients (28.9%), with tumor-related mortality of 22.2%. Kaplan–Meier analysis showed 5- and 10-year survival rates of 68.8% and 59.1%, respectively, with corresponding progression-free survival rates of 72.8% and 54.0%. Tumor stage was significantly associated with disease progression on multivariable analysis (OR = 7.230, p = 0.039). Conclusions: This study highlights the heterogeneous presentation and prognosis of rNENs, with a substantial proportion diagnosed incidentally. Endoscopic management was predominantly utilized, aligning with current guidelines for localized tumors. Tumor stage emerged as a significant predictor of disease progression, emphasizing the importance of accurate staging for optimal management. Further research is warranted to refine management protocols and validate these findings.

Abstract Background Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. Methods This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3–5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. Discussion Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. Trial registration LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019–004506-10).

Abstract Eutrophication affects coastal oceans worldwide, modifies primary production and sediment biogeochemistry and, overall, is progressively compromising marine ecosystems’ integrity. Because of their known bioturbation ability, sea cucumbers are supposed to be candidates for mitigating benthic eutrophication. To provide insights on this, we investigated differences in organic matter quantity and biochemical composition (as proxies of benthic trophic status) of sediments and feces of the sea cucumber Holothuria tubulosa acclimated in mesocosms at temperatures comprised between natural conditions (14–26 °C) and an extreme of 29 °C (representing the highest anomaly under heat waves in the Mediterrranean Sea). Organic matter features differed significantly between sediments characterized by different trophic statuses and the holothuroid’s feces, though with some exceptions. Feces resulted almost always organically enriched when compared with the ambient sediments, though with variable differences in composition in sediments characterized by different initial trophic status. Our results point out that sea cucumbers maintain their bioreactor capacity at all experimental temperatures including the (anomalous) highest one, irrespectively of the available food, suggesting that they could be profitably utilized to mitigate benthic eutrophication also in a warmer Mediterranean Sea.

The ‘immune pattern’ of the esophagogastric junction and gastric cancer (GC) has been related to tumour progression and/or response to therapies. GC can be classified as immunogenic or immune-resistant based on the infiltration of the tumour microenvironment (TME) from different immune cells (ICs), the most significant of which are activated lymphocytes (a-Ly) CD8+ and CD4+. From the amount of a-Ly infiltration in TME, we can identify tumours with high Immunoscore (IS) which correlates with better prognosis in terms of disease-free survival and overall survival (OS). IC activation and consequent immunogenic TME requires high nutrient absorption and synthesis and accumulation of protein, lipid, and nucleotides. However, tumour cells (TCs) promote their own proliferation by stealing micronutrients to ICs, therefore leading to an immunosuppressive TME phenotype. This proof-of-concept protocol aims to assess whether a controlled enteral immune nutrition (EIN) supplementation can revert the TME in favour of ICs over TCs, in both auxotrophic and non-auxotrophic malignancies, witnessed by an increase in IS in surgical specimen over biopsy controls. Secondary endpoints are: (i) tumour regression grade assessment compared to historical data from FLOT4/AIO; (ii) combined proportion score ratio; (iii) relapse-free survival at 3 years and OS; and (iv) quality of life by the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ)-30.