Novamont (Italy)

Abstract Background Nicotinamide phosphoribosyltransferase (NAMPT) is an essential and pleiotropic enzyme expressed in mammalian cells. Its intracellular form (iNAMPT) functions as the rate-limiting enzyme in the NAD+ salvage pathway. Through this activity, iNAMPT regulates cellular metabolism, mitochondrial biogenesis, and adaptive responses to inflammation and oxidative stress. In contrast, extracellular NAMPT (eNAMPT), secreted by multiple cell types including immune cells, acts as a pro-inflammatory cytokine and contributes to several inflammation-driven disorders such as inflammatory bowel disease (IBD). The mechanisms governing eNAMPT secretion and receptor engagement remain incompletely understood; to date, TLR4 is the only receptor that has been identified. Notably, circulating eNAMPT levels are elevated during active disease phases and negatively correlate with responsiveness to anti-TNF therapy (Colombo et al., 2020, 2022).We investigated the mechanistic contribution of eNAMPT to Crohn’s disease (CD) progression using the DNBS-induced colitis model. Methods BALB/c mice received intrarectal DNBS (2 mg for moderate or 3 mg for severe inflammation) and were treated daily with recombinant eNAMPT (50 µg/mouse) to mimic the elevated systemic levels observed in CD patients. Colon, blood, bone marrow were collected for flow cytometry, bulkRNAseq, array, RT-PCR and IHC. Results eNAMPT administration exacerbated disease severity, as evidenced by increased weight loss, colon shortening, and aggravated epithelial and mucosal damage on H&E, Picrosirius Red, and Masson’s Trichrome staining. eNAMPT further enhanced fibroblast activation, collagen deposition, and inflammatory scores. Flow cytometric analyses of the lamina propria revealed increased CD11b+ myeloid infiltration and an immature Ly6G+ granulocytes. phenotype. eNAMPT treatment in moderate colitis promoted a significant expansion of the Lin-c-Kit+ hematopoietic compartment (similar to the DSS model), reaching levels comparable to severe DNBS inflammation. This was accompanied by a selective increase in GMPs indicating skewing toward myelopoiesis. In vitro, NAMPT alone showed minimal pro-myelopoietic activity; however, its combination with IL-6 or G-CSF modestly enhanced colony formation, and a synergistic effect was observed with GM-CSF. Finally, the pathogenic activity of eNAMPT was abolished in TLR4-deficient mice, indicating a TLR4-dependent mechanism. Conclusion Collectively, these findings demonstrate that the cytokine eNAMPT exacerbates Crohn’s disease by acting along the gut–bone marrow axis, promoting HSC proliferation and differentiation toward immature granulocytes that infiltrate the colon and intensify fibrotic remodeling.

Pleural mesothelioma (PM) is a lethal cancer primarily caused by asbestos exposure. Not all exposed individuals develop PM, suggesting the involvement of additional factors. This underscores the need for robust predictive models integrating biomarkers from multi-omic domains to improve risk stratification and early detection. We developed and evaluated polygenic risk scores (PRS) and methylation risk scores (MRS) using a retrospective case-control study (749 participants: 387 PM cases, 362 controls) and a nested case-control European Prospective Investigation into Cancer and Nutrition (EPIC)-Meso study (268 participants: 134 preclinical PM cases, 134 matched controls) within the EPIC cohort. Genome-wide association analyses in the retrospective case-control study identified PM-associated variants. The PRS (1123 SNPs with p < 0.001) in the retrospective training subset stratified disease risk in the test set (ORs 3.46-9.54 across top percentiles) and improved model discrimination (AUC = 0.75 vs. 0.71 in baseline model, p = 0.04). In EPIC-Meso, PRS performance was limited (AUC = 0.52). External validation in the UK-Biobank (UKBB) confirmed a modest but consistent association with PM-risk. A Meta-PRS derived from the UKBB-FinnGen meta-analysis replicated this trend in the full retrospective dataset, showing higher OR across top percentiles (2.5-12.3) and improved discrimination (AUC 0.74 vs. 0.72, p = 0.016). MRS, with 68 differentially methylated CpGs (effect-size >|0.10|, FDR p < 0.05) in the retrospective training set, increased the AUC from 0.66 to 0.85 (p < 0.001) in the test set and from 0.51 to 0.62 in EPIC-Meso. PRS was most predictive in low-exposure groups, while MRS remained robust across exposure levels. Combined PRS-MRS models improved discrimination. Integrating multi-omic biomarkers can enhance PM-risk stratification and support earlier, targeted interventions in high-risk asbestos-exposed groups.

Human fatty acid binding protein-4 (FABP-4), a protein elevated in obesity that promotes colon cancer cell invasiveness and metastasis, may be associated with higher mortality in individuals with colorectal cancer (CRC) and may serve as a mediator of the obesity-mortality association in these individuals. We used a causal diagram to inform covariate selection and applied Cox proportional hazards models to estimate hazard ratios (HRs) for CRC-specific, non-CRC-specific, and all-cause mortality by FABP-4 levels measured in baseline blood samples from 1371 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. Competing risk analyses were adapted for CRC and non-CRC deaths. Mediation analyses were conducted to estimate total effects (TEs), direct effects (DEs), and mediation proportions (MPs) by FABP-4 of pre-diagnostic body mass index (BMI) on mortality. In the fully adjusted model including BMI, higher circulating FABP-4 concentrations were associated with higher CRC mortality (HRQ4vsQ1 = 1.49; 95% CI: 1.11-2.00) and all-cause mortality (HRQ4vsQ1 = 1.49; 95% CI: 1.15-1.93), but not statistically associated with non-CRC mortality (HRQ4vsQ1 = 1.51; 95% CI: 0.82-2.76). The TE and DE per 5 kg/m2 of BMI on all-cause mortality were 1.21; 95% CI: 1.10-1.34, and 1.13; 95% CI: 1.02-1.26, respectively, with a MP of 34.5% (p = .002) by FABP-4. For CRC-specific and non-CRC-specific mortality, MPs by FABP-4 were 33.7% (p = .03) and 36.1% (p = .02), respectively. In conclusion, higher concentrations of FABP-4 were associated with higher CRC-specific and all-cause mortality in individuals with CRC. FABP-4 was a significant partial mediator of the adiposity-mortality relationship in individuals with CRC.

The utilization of agri-food wastes holds significant importance from both environmental and economic standpoints. Whey permeate, a by-product of cheese manufacturing with high lactose content, could be considered a promising substrate for microbial growth to yield value-added products. Whey permeate was therefore investigated as a potential feedstock for the production of polyhydroxyalkanoates (PHAs) by Hydrogenophaga pseudoflava DSM1034. Although the ability of this microorganism to grow and accumulate PHAs on whey permeate has been previously demonstrated, the PHAs yields were notably low. Therefore, a meticulous inoculum optimization was performed, taking into consideration adaptation to lactose-containing substrates, initial bacterial concentration, and growth kinetics. In media containing lactose as a carbon source, the lag phase, exceeding 40 hours in non-optimized conditions, decreased to only 4 hours. In whey permeate, a cell dry weight (CDW) of 5.49 ± 0.08 g/L was obtained. PHAs fraction in CDW and PHAs yield were 52.48 ± 3.14 % of CDW and 0.144 g/g of consumed sugar, respectively. Furthermore, these results were achieved in flask without hydrolysis of lactose contained in the permeate. Moreover, no galactose remained unutilized in the spent broth demonstrating that H. pseudoflava DSM1034 metabolized both sugars contained in lactose. Additionally, in culture media containing mixtures of glucose and galactose, microbial growth was lower compared to growth on comparable amounts of lactose. This study underscores the potential of whey permeate as a valuable resource for the production of PHAs, offering a sustainable solution for the utilization of dairy industry by-products, mitigating its environmental impact and promoting sustainable resource utilization.

Benign thyroid nodules are common in adults, with incidental detection rates reaching 50-60% in women. While most nodules are asymptomatic and require no treatment, some grow and cause compressive symptoms. This study evaluates the economic impact of various treatment modalities for benign thyroid nodules within the Italian healthcare system, comparing total thyroidectomy, hemithyroidectomy, and minimally invasive thermal ablation. The analysis considers both direct healthcare costs and indirect social costs, such as productivity losses, from the perspective of the Italian National Health Service. A literature review and clinician survey were conducted to collect cost data across treatment phases: pre-hospitalization, procedure, and post-operative care. An Activity-Based Costing approach was used to estimate full treatment costs, including medical expenses, staff involvement, material usage, and indirect costs related to work absences. The findings indicate that total thyroidectomy has the highest overall cost (€ 5,185.36), followed by hemithyroidectomy (€ 4,211.92), and thermal ablation (€ 1,560.06). The analysis also highlighted significant cost savings associated with thermal ablation when compared to surgical options, especially in terms of reduced hospital stay and lower indirect costs. Nevertheless, surgical procedures remain the mainstay treatment due to long-term efficacy and well-established clinical guidelines. Thermal ablation represents a cost-effective alternative to surgery for managing benign thyroid nodules. Treatment selection should be individualized, considering clinical factors, patient preferences, and long-term outcomes. These results underscore the importance of updating management guidelines to incorporate economic considerations, promoting optimized care and efficient resource allocation in the healthcare context.