Gender-Specific Cytokine Pathways, Targets, and Biomarkers for the Switch from Health to Adenoma and Colorectal Cancer

Studies focusing on gender have shown that differences exist in how the immune system responds to disease and therapy. Understanding how gender influences immunological mechanisms in health and disease and identifying gender-specific biomarkers could lead to specifically tailored treatment and ultimately improve therapeutic success rates. T helper1 (Th1) and Th2 cytokines (Th1/Th2) have pivotal roles in the homeostasis of Th1 and Th2 cell network functions in the immune response but sex steroids affect Th1/Th2 production in different ways and a natural sexual dimorphism in the immune response has been shown. In order to investigate these differences further, we developed Th-cytokine data-driven models of the immune response and evaluated healthy subject peripheral blood samples. Independent cohorts of colorectal cancer and adenoma patients were also studied for comparison purposes. Our results show that the interferon (IFN)γ production pathway for immune response homeostasis is specific to men whilst the interleukin- (IL-) 6 production pathway for immune response homeostasis is specific to women. The IL-10 pathway for restoring immune system resting homeostasis was common to both but was controlled by the respective gender-specific pathways. These gender pathways could well be used as targets and biomarkers in translational research into developing new clinical strategies

Eco-Friendly Engineered Nanomaterials Coupled with Filtering Fine-Mesh Net as a Promising Tool to Remediate Contaminated Freshwater Sludges: An Ecotoxicity Investigation

The use of eco-friendly engineered nanomaterials represents a recent solution for an effective and safe treatment of contaminated dredging sludge. In this study, an eco-designed engineered material based on cross-linked nanocellulose (CNS) was applied for the first time to decontaminate a real matrix from heavy metals (namely Zn, Ni, Cu, and Fe) and other undesired elements (mainly Ba and As) in a lab-scale study, with the aim to design a safe solution for the remediation of contaminated matrices. Contaminated freshwater sludge was treated with CNS coupled with a filtering fine-mesh net, and the obtained waters were tested for acute and sublethal toxicity. In order to check the safety of the proposed treatment system, toxicity tests were conducted by exposing the bacterium Aliivibrio fischeri and the crustacean Heterocypris incongruens, while subtoxicity biomarkers such as lysosomal membrane stability, genetic, and chromosomal damage assessment were performed on the freshwater bivalve Dreissena polymorpha. Dredging sludge was found to be genotoxic, and such genotoxicity was mitigated by the combined use of CNS and a filtering fine-mesh net. Chemical analyses confirmed the results by highlighting the abetment of target contaminants, indicating the present model as a promising tool in freshwater sludge nanoremediation

Cellular Responses Induced by Zinc in Zebra Mussel Haemocytes. Loss of DNA Integrity as a Cellular Mechanism to Evaluate the Suitability of Nanocellulose-Based Materials in Nanoremediation

: Zinc environmental levels are increasing due to human activities, posing a threat to ecosystems and human health. Therefore, new tools able to remediate Zn contamination in freshwater are highly recommended. Specimens of Dreissena polymorpha (zebra mussel) were exposed for 48 h and 7 days to a wide range of ZnCl2 nominal concentrations (1–10–50–100 mg/L), including those environmentally relevant. Cellulose-based nanosponges (CNS) were also tested to assess their safety and suitability for Zn removal from freshwater. Zebra mussels were exposed to 50 mg/L ZnCl2 alone or incubated with 1.25 g/L of CNS (2 h) and then removed by filtration. The effect of Zn decontamination induced by CNS has been verified by the acute toxicity bioassay Microtox®. DNA primary damage was investigated by the Comet assay; micronuclei frequency and nuclear morphological alterations were assessed by Cytome assay in mussels’ haemocytes. The results confirmed the genotoxic effect of ZnCl2 in zebra mussel haemocytes at 48 h and 7-day exposure time. Zinc concentrations were measured in CNS, suggesting that cellulose-based nanosponges were able to remove Zn(II) by reducing its levels in exposure waters and soft tissues of D. polymorpha in agreement with the observed restoration of genetic damage exerted by zinc exposure alon

Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in italian families with breast/ovarian and pancreatic cancers

The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches

The potential role of thioredoxin 1 and CD30 systems as multiple pathway targets and biomarkers in tumor therapy

Our progress in understanding pathological disease mechanisms has led to the identification of biomarkers that have had a considerable impact on clinical practice. It is hoped that the move from generalized to stratified approaches, with the grouping of patients into clinical/therapeutic subgroups according to specific biomarkers, will lead to increasingly more effective clinical treatments in the near future. This success depends on the identification of biomarkers that reflect disease evolution and can be used to predict disease state and therapy response, or represent themselves a target for treatment. Biomarkers can be identified by studying relationships between serum, tissue, or tumor microenvironment parameters and clinical or therapeutic parameters at onset and during the progression of the disease, using systems biology. Given that multiple pathways, such as those responsible for redox and immune regulation, are deregulated or altered in tumors, the future of tumor therapy could lie in the simultaneous targeting of these pathways using extracellular and intracellular targets and biomarkers. With this aim in mind, we evaluated the role of thioredoxin 1, a key redox regulator, and CD30, a cell membrane receptor, in immune regulation. Our results lead us to suggest that the combined use of these biomarkers provides more detailed information concerning the multiple pathways affected in disease and hence the possibility of more effective treatment

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain

Helicobacter pylori Counteracts the Apoptotic Action of Its VacA Toxin by Injecting the CagA Protein into Gastric Epithelial Cells

Infection with Helicobacter pylori is responsible for gastritis and gastroduodenal ulcers but is also a high risk factor for the development of gastric adenocarcinoma and lymphoma. The most pathogenic H. pylori strains (i.e., the so-called type I strains) associate the CagA virulence protein with an active VacA cytotoxin but the rationale for this association is unknown. CagA, directly injected by the bacterium into colonized epithelium via a type IV secretion system, leads to cellular morphological, anti-apoptotic and proinflammatory effects responsible in the long-term (years or decades) for ulcer and cancer. VacA, via pinocytosis and intracellular trafficking, induces epithelial cell apoptosis and vacuolation. Using human gastric epithelial cells in culture transfected with cDNA encoding for either the wild-type 38 kDa C-terminal signaling domain of CagA or its non-tyrosine-phosphorylatable mutant form, we found that, depending on tyrosine-phosphorylation by host kinases, CagA inhibited VacA-induced apoptosis by two complementary mechanisms. Tyrosine-phosphorylated CagA prevented pinocytosed VacA to reach its target intracellular compartments. Unphosphorylated CagA triggered an anti-apoptotic activity blocking VacA-induced apoptosis at the mitochondrial level without affecting the intracellular trafficking of the toxin. Assaying the level of apoptosis of gastric epithelial cells infected with wild-type CagA+/VacA+ H. pylori or isogenic mutants lacking of either CagA or VacA, we confirmed the results obtained in cells transfected with the CagA C-ter constructions showing that CagA antagonizes VacA-induced apoptosis. VacA toxin plays a role during H. pylori stomach colonization. However, once bacteria have colonized the gastric niche, the apoptotic action of VacA might be detrimental for the survival of H. pylori adherent to the mucosa. CagA association with VacA is thus a novel, highly ingenious microbial strategy to locally protect its ecological niche against a bacterial virulence factor, with however detrimental consequences for the human host

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription