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Objectives The antitumour effect of bacillus Calmette-Guerin (BCG) still remains relatively undefined. Most investigations on its mechanism of action have focused on mononuclear cells; little consideration has been given to granulocytes. We analysed urine of patients with bladder cancer during 8 wk of intravesical BCG prophylaxis. The number of polymorphonuclear neutrophils (PMNs) and urothelial cells (UCs) was evaluated. We examined the in vitro response of the T24 UC line to human PMNs after BCG treatment. Methods Seventeen patients were enrolled in the study. Cytologic analyses were performed on urine samples collected before each BCG instillation and after 2h from the first voided urine after BCG instillation. Elastase activity was determined on these samples to evaluate PMN activation. PMN-induced damage was measured on the T24 cell line treated with BCG. Results After BCG treatment, a large number of PMNs transmigrated through the urothelium and PMNs adherent to detached UCs were found. One patient, who did not respond with significant PMN transmigration, experienced recurrent disease. The number of eosinophils that transmigrated was low, with the exception of three patients with recurrent disease. In vitro, PMNs adhered to BCG-primed T24 cells and damaged the monolayer. Conclusions The results agree with recent evidence that PMNs may play an important role in the antitumour action of BCG during the BCG induction period. This role is probably nonspecific because both normal UCs in vivo and tumour cells in vitro appeared to be injured. As suggested by results obtained from a limited number of patients, a high number of eosinophils in the urine may indicate therapy failure.

Iron is a fundamental nutrient utilized by living cells to support several key cellular processes. Despite its paramount role to sustain cell survival, excess of labile iron availability can inflict severe cell damage via reactive oxygen species generation which, in turn, can promote neoplastic transformation. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tensions herein present. Moreover, cigarette smoke as well as air pollution particulate can function as vehicles of iron supply, leading to an iron dysregulation condition shown to be crucial in the pathogenesis of several respiratory diseases including lung cancer. Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases emerged to contribute to cellular iron homeostasis by favouring its export. Although HEPH can affect the concentration of intracellular iron labile pool, its expression in lung cancer and its influence on prognosis have not been investigated.In this study we explored the expression pattern and prognostic value of HEPH in the most prevalent histotypes of lung cancers including lung adenocarcinoma and lung squamous cell carcinoma across in silico analyses using UALCAN, Gepia and Kaplan-Meier plotter bioninformatics. We took advantage of TIMER to assess the correlation between HEPH and tumour infiltrating immune and non-immune cells. Then we performed immunohistochemical analysis to dissect the presence of HEPH either in “healthy” and tumor lung tissues. Overall, our data suggest a positive correlation between higher level of HEPH expression with a favorable prognosis in both cancer histotypes.

Copyright © 2021 Agostinis, Zorzet, Balduit, Zito, Mangogna, Macor, Romano, Toffoli, Belmonte, Morello, Martorana, Borelli, Ricci, Kishore and Bulla. The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts. Ministry of Health: Project code: ENDO-2020-23670288 “Pathogenesis of endometriosis: the role of genes, inflammation and environment”; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy (RC20/16, RC23/18; 5MILLE15D; PORFESR 2014/2020 FVG (“TiCheP” project).

Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an "asbestos-resistant exposed population". A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC "genetic signature" may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.

Summary Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver‐specific responses caused by a diet switch to a medium‐fat (MF) diet in 24‐month‐old lifelong, CR‐exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine‐week‐old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitum MF feeding (CR‐MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long‐term exposure to the CR regimen, mice in the CR‐MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR‐improved survival was observed in the diet switch group. The liver transcriptomic profile of CR‐MF mice largely shifted to a profile similar to the MF‐fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR‐MF‐exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm- aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

Background and aims: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity pro- grams in prediabetic subjects. Methods and results: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic sub- jects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treat- ment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in sub- jects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR ac- tivity). Plasma N-glycans were also favourably modified by metformin compared to placebo. Conclusion: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials.gov Identifier: NCT01765946 e January 2013.

Background: Glycosylation, i.e the enzymatic addition of oligosaccharides (or glycans) to proteins and lipids, known as glycosylation, is one of the most common co-/posttranslational modifications of proteins. Many important biological roles of glycoproteins are modulated by N-linked oligosaccharides. As glucose levels can affect the pathways leading to glycosylation of proteins, we investigated whether metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), pathological conditions characterized by altered glucose levels, are associated with specific modifications in serum N-glycome. Methods: We enrolled in the study 562 patients with Type 2 Diabetes Mellitus (T2DM) (mean age 65.6 +/- 8.2 years) and 599 healthy control subjects (CTRs) (mean age, 58.5 +/- 12.4 years). N-glycome was evaluated in serum glycoproteins. Results: We found significant changes in N-glycan composition in the sera of T2DM patients. In particular, alpha(1,6)-linked arm monogalactosylated, core-fucosylated diantennary N-glycans (NG1(6)A2F) were significantly reduced in T2DM compared with CTR subjects. Importantly, they were equally reduced in diabetic patients with and without complications (P