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The Cava Madre of Candoglia represents an important underground rock cavern in the northwest of Italy, both for historical reasons and for the material that is extracted there: the marble for the continuous reconstruction and renovation works of the Milan Cathedral. Over time, the cavern reached considerable dimensions, and the existing state of stress (considerable horizontal stresses) required the creation of impressive structures to contrast and support the side walls. A complex and effective monitoring system guarantees the continuous control of the cavern. To improve the reliability of the geomechanical characterization and, therefore, of the numerical model that allows the analysis of the stress and strain behavior of the cavern, a back-analysis was developed. This allowed us to “calibrate” the two geomechanical parameters on which there was the greatest uncertainty: the elastic modulus of the marble at the scale of the problem and the lateral thrust coefficient at rest (k0). Finally, the numerical model made the results of the back-analysis more effective, allowing us to verify the support and contrast structures of the walls and to proceed with a careful definition of the project relating to future mining works for the continuation of the exploitation of the existing marble bench.

To increase the sustainability of trout farming, the industry requires alternatives to fish-based meals that do not compromise animal health and growth performances. To develop new feeds, detailed knowledge of intestinal morphology and physiology is required. We performed histological, histochemical, immunohistochemical and morphometric analysis at typical time points of in vivo feeding trials (50, 150 and 500 g). Only minor changes occurred during growth whereas differences characterized two compartments, not linearly distributed along the intestine. The first included the pyloric caeca, the basal part of the complex folds and the villi of the distal intestine. This was characterized by a significantly smaller number of goblet cells with smaller mucus vacuoles, higher proliferation and higher apoptotic rate but a smaller extension of fully differentiated epithelial cells and by the presence of numerous pinocytotic vacuolization. The second compartment was formed by the proximal intestine and the apical part of the posterior intestine complex folds. Here we observed more abundant goblet cells with bigger vacuoles, low proliferation rate, few round apoptotic cells, a more extended area of fully differentiated cells and no pinocytotic vacuoles. Our results suggest that rainbow trout intestine is physiologically arranged to mingle digestive and absorptive functions along its length.

The Cava Madre of Candoglia is a centuries-old mining cavern of significant historical-architectural interest because it is the site from which the marble is extracted for the renovation of the external structure of the Milan Cathedral. This activity is continuous and therefore requires the guarantee of the supply of the same marble that was used for the construction of the Cathedral. Over the time, block extraction and handling techniques have changed and evolved, ensuring their effectiveness and safety. Today diamond wire is used to detach the bank and to cut the blocks. The movement takes place using trucks capable of traveling along the access road to the quarry and transporting the blocks to the processing laboratories. Some geomechanical aspects play a fundamental role: a careful characterization of the rock materials (marble vein and embedding rocks) in the laboratory and on site, a reliable numerical modeling capable of representing the evolution of the stresses and deformations in the rock and in the present support and reinforcement structures, continuous geomechanical monitoring to control the state of stresses and deformations that actually develop in the rocks and support structures.

An eight-week experiment was carried out to evaluate the effects of different protein sources (fish and haemoglobin meal, soybean meal and torula yeast), in practical diets, on growth, body composition and gut morphology of fingerling grey mullet (Mugil cephalus). Weight gain (%), SGR, FCR, N retention, PER, PGR, FDR and carcass composition of fish were not significantly affected by the dietary protein source. Fish fed the torula yeast based diet showed reduction in growth performance. Histological examinations performed on the alimentary tract of the fish showed a normal structural pattern in the experimental groups, as fundamental histological and histochemical aspects were similar if compared to the control group. The lower growth performance observed in fish fed a torula yeast based diet may be tentatively correlated with the presence of some detrimental morpho-functional aspects in the gut of these fish if compared to fish fed the other diets. Further studies are necessary to confirm this hypothesis.[PUBLICATION ABSTRACT]

Background In advanced urothelial carcinoma (UC), the prognostic impact of metastatic site and burden during avelumab maintenance therapy remains poorly defined. Methods We performed a sub-analysis of the Italian multicenter retrospective–prospective observational study Meet-URO 25, including patients with advanced UC who received avelumab maintenance after disease control with first-line platinum-based chemotherapy. We assessed the association between metastatic site and number of metastatic sites at the start of avelumab and clinical outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results A total of 243 patients were included. Lymph nodes (79.0%), lungs (32.1%), and bones (27.2%) were the most common metastatic sites. The median number of metastatic sites at the start of avelumab maintenance was 1. ORR and disease control rate (DCR) were higher in patients with nodal-only disease (ORR 28.9%, DCR 69.4%) and significantly lower in those with bone metastases (ORR 9.8%, DCR 50.8%). Median PFS and OS were 7.4 and 24.1 months, respectively, in the overall cohort. Bone metastases were associated with markedly shorter PFS (3.7 vs. 8.2 months; HR 1.92, p  < 0.001) and OS (11.3 vs. 27.6 months; HR 2.44, p  < 0.001), especially when present as a single metastatic site. Increasing number of metastatic sites was also associated with poorer outcomes (OS: 35.5 months with one site vs. 11.9 months with ≥ 3 sites; p  < 0.001). Conclusions In this real-world cohort, both metastatic site and burden strongly influenced response and survival of avelumab. Bone metastases were independently associated with poor prognosis, while nodal-only disease identified a favorable subgroup. These findings support risk-based treatment stratification in the maintenance setting.

Background Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a therapy approved for cystic fibrosis (CF) that has given improved clinical outcomes in patients carrying the F508del mutation. There are few published data regarding ETI’s effects on patients’ quality of life (QoL). This study aims to (fill the data gap in current literature by assessing) evaluate the long-term effects of ETI on QoL. Methodology A prospective observational study was conducted with thirty-seven severe patients that received ETI for compassionate use (group A), 184 received it for on-label use (group B). All carried one F508del mutation. Patients were assessed using the CFQ-R (Cystic Fibrosis Questionnaire-Revised). The evaluation time-points were pre-treatment (T0), and after 12 (T1) and 24 months (T2); group A was also assessed after 36 months (T3). Twenty-five patients completed 3 years of treatment and 65 patients completed 2 years of treatment, in groups A and B respectively. Results At T1, median values for almost all areas of CFQ-R statistically significant increased in group A, particularly Physical Functioning (+ 25.0), Respiratory (+ 22.2) and Health Perception (+ 22.2).The Social Functioning area statistically significant increased at T2 (+ 5.6). At T3, these improvements remained stable. At T1, all areas of CFQ-R statistically significant increased in group B, particularly the Health Perception (+ 22,2) heading. At T2, these improvements remained stable. For both groups, the changes identified at the last follow-up showed no major differences by gender, age or genetic status. Conclusions Treatment with ETI significantly improved patients’ QoL in both groups at 12–24 months, these improvements remaining stable in patients tested at 36 months.

Avelumab maintenance therapy is an established therapeutic approach for patients with advanced urothelial carcinoma (UC) whose disease has not progressed after first-line platinum-based chemotherapy. However, evidence on its effectiveness and safety in elderly patients remains limited. This multicenter retro-prospective Italian study included 251 patients with advanced UC who received avelumab maintenance between 2021 and 2023. Outcomes were compared between patients aged ≥75 and <75 years. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Among 96 elderly and 155 younger patients, median PFS was 7.2 months (95% CI, 4.9-17.5) and 6.7 months (95% CI, 4.9-9.3), respectively (p = 0.547), while median OS was 28.1 months (95% CI, 17.3-42.1) versus 18.5 months (95% CI, 12.0-38.6) (p = 0.238). Immune-related adverse events were infrequent and generally comparable across age groups. In multivariable analyses, lung metastases independently predicted worse OS in elderly patients, whereas bone metastases and concomitant corticosteroid therapy were adverse prognostic factors in younger patients. Avelumab maintenance demonstrated similar efficacy and safety in elderly and younger patients, supporting its use regardless of age. In the evolving therapeutic landscape of advanced UC, this treatment strategy remains a relevant and practical option, particularly for elderly or comorbid patients who may not be candidates for more intensive first-line combinations.

Ali Gharavi, Rick Lifton and colleagues report a genome-wide association study for IgA nephropathy, a major cause of kidney failure. They identify five susceptibility loci. We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance ( P values for association between 1.59 × 10 −26 and 4.84 × 10 −9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

Ali Gharavi and colleagues report a genome-wide association analysis of IgA nephropathy in over 20,000 individuals of European and East Asian ancestry. They identify genome-wide significant signals at three new loci near VAV3 , CARD9 and ITGAM - ITGAX and correlations between genetic risk and pathogen diversity. We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM - ITGAX , VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA . We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host–intestinal pathogen interactions in shaping the genetic landscape of IgAN.

The formation of neutrophil extracellular traps (NETs) is a strategy utilized by neutrophils for capturing infective agents. Extracellular traps consist in a physical net made of DNA and intracellular proteins externalized from neutrophils, where bacteria and viruses are entrapped and killed by proteolysis. A complex series of events contributes to achieving NET formation: signaling from infectious triggers comes first, followed by decondensation of chromatin and extrusion of the nucleosome components (DNA, histones) from the nucleus and, after cell membrane breakdown, outside the cell. NETs are composed of either DNA or nucleosome proteins and hundreds of cytoplasm proteins, a part of which undergo post-translational modification during the steps leading to NETs. There is a thin balance between the production and the removal of circulating NETs from blood where digestion of DNA by circulating DNases 1 and IL3 has a critical role. A delay in NET removal may have consequences for autoimmunity. Recent studies have shown that circulating NET levels are increased in systemic lupus erythematosus (SLE) for a functional block of NET removal mediated by anti-DNase antibodies or, in rare cases, by DNase IL3 mutations. In SLE, the persistence in circulation of NETs signifies elevated concentrations of either free DNA/nucleosome components and oxidized proteins that, in some cases, are recognized as non-self and presented to B-cells by Toll-like receptor 9 (TLR9). In this way, it is activated as an immunologic response, leading to the formation of IgG2 auto-antibody. Monitoring serum NET levels represents a potential new way to herald the development of renal lesions and has clinical implications. Modulating the balance between NET formation and removal is one of the objectives of basic research that are aimed to design new drugs for SLE. Clinical Trial Registration Number: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).