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Pancreatic adenocarcinoma (PDAC) is an incurable cancer without adequate tumor markers. Our previous study has showed a better diagnostic performance of Protein Induced by Vitamin K Absence II (PIVKA-II) compared to currently used PDAC biomarkers. To corroborate our previous data with a larger sample size and to assess a possible role of PIVKA-II in predicting surgical success. Additionally, to further evaluate the hypothesis of a direct PIVKA-II production by PDAC cells, we examined PIVKA-II tissue expression in a case of PDAC using immunofluorescence. We enrolled 76 newly diagnosed PDAC patients and selected 11 patients to determine PIVKA-II levels also after surgical resection. An immunofluorescence (IF) study of PIVKA-II tissue expression was carried out in one of them. PIVKA-II serum values were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Belgium). PIVKA-II serum levels were above the cut-off at baseline in 71 patients (94%) with a median value of 464 mAU/Ml (range 27-40783 mAU/mL); the sensitivity and specificity were 78.67% and 90.67% respectively. Patients with pre-operative PIVKA-II positivity showed a significant decrease (P < 0.015) of median PIVKA-II serum concentrations after surgery: 820 (91-40783) mAU/mL at diagnosis vs 123 (31-4666) mAU/mL post-operatively. IF assay on PDAC sections demonstrated PIVKA-II expression in cancer cells. These data are the first showing a decreased PIVKA-II serum levels after surgery in PDAC patients and reporting PIVKA-II expression in PDAC tissue. Further studies are needed to confirm these findings and to determine PIVKA-II usefulness in diagnosing and monitoring PDAC patients.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25–35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1–42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.

In the context of growing infections, plant-derived natural compounds play a crucial role in the search for new antimicrobial agents, as they offer a diverse array of bioactive molecules. Similarly, nanomaterials, particularly those based on zinc oxide, hold great potential for biomedical applications due to their unique properties. This study evaluates the antimicrobial efficacy of a formulation combining propolis, pollen, and ZnO nanorods (PrPoZnO). SEM and FTIR analysis confirmed ZnO nanorod integration within the propolis-pollen matrix. Antimicrobial testing revealed significant inhibitory effects on Staphylococcus aureus and Pseudomonas aeruginosa , with viability reduction of up to 85% and biofilm inhibition of 50% and 40%, respectively. The PrPoZnO mixture also reduced Candida albicans growth by 90%, inhibited biofilm formation by 60%, and suppressed the yeast-to-hyphae transition, a key virulence factor. Furthermore, the biocompatibility testing of the PrPoZnO mixture in several cell lines demonstrated no cytotoxic effects at the higher concentration, suggesting its potential for safe biomedical applications. In terms of mechanism, PrPoZnO modulated oxidative stress responses, decreasing ROS levels in bacteria while inducing ROS production in C. albicans , suggesting that ZnO nanorods are the key player to induce mechanical damage of microbes. These findings underscore the potential of PrPoZnO as an innovative and biocompatible compound, supporting its suitability for further clinical investigation.

Background/Objectives: The primary objective of the present study was to investigate early global development in children after one year of cochlear implant (CI) use. The secondary objective was to investigate the role of variables such as age at CI activation, gender, and parental schooling in early global development in children with a CI. Methods: The study sample included 24 subjects. All children were affected by severe-to-profound congenital bilateral sensorineural hearing loss (HL). The HL was diagnosed between 1 and 23 months of age (median 3 months) and participants underwent cochlear implant activation at 9–25 months (median 14 months). Participants were evaluated before CI surgery and after one year of CI use using the Italian version of the Griffiths III scales. Results: The general developmental quotient remained stable, as did the developmental quotients on scales A, C, D, and E. However, the development quotients on scale B, corresponding to the domain of “language and communication,” underwent a significant increase (p value < 0.05). There was a statistically significant negative effect of “age at CI activation” on both DQ at scale B (t − 3.457) and GDQ (t − 42.069). Maternal schooling had a significant positive effect on GDQ and DQ for scales A to D (p. value < 0.05). Conclusions: After one year of CI use, a significant improvement in the early global development of children was found in the language and communication domain. The age at CI activation and the level of the mother’s education were found to be related to early global development.

The prognosis for patients with head and neck cancer (HNC) is usually poor, highlighting the need for new therapeutic strategies. To this end, this study aims to evaluate the antitumor efficacy of a combined treatment with low doses of different molecular targeted drugs, i.e. Y15, a FAK inhibitor, Afatinib (AFA) an ErbB inhibitor and TP-0903, an Axl inhibitor, on HNC. Human cell lines from salivary gland, tongue and pharynx HNC, cultured in 2D and 3D (spheroids) conditions, were used to evaluate the antitumor effects of Y15, AFA and TP-0903, alone or in combination. Cell survival, death and migration were evaluated. Western blotting and immunofluorescence analysis were performed to investigate the expression and activation of proteins involved in signal transduction and epithelial to mesenchymal transition. The combined treatment with low doses of Y15, AFA and TP-0903, was more effective than the individual and dual drug treatments in reducing survival, increasing cell death and reducing migration of HNC cells. The three inhibitors in combination had a synergistic effect in reducing survival of HNC cell lines in both 2D and 3D conditions. Moreover, as compared to the individual inhibitors and their pairwise combinations, the triple drug combination was the only able to simultaneously downregulate Axl, FAK, and N-cadherin while upregulating E-cadherin expression levels. The results reported herein provide compelling preliminary evidence supporting the combined use of Y15, AFA and TP-0903 as a novel therapeutic strategy for HNCs. Clinical trial number Not applicable.

Microglia, the innate immune cells of the CNS, respond to brain injury by activating and modifying their morphology. Our study arises from the great interest that has been focused on blueberry (BB) for the antioxidant and pharmacological properties displayed by its components. We analyzed the influence of hydroalcoholic BB extract in resting or lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. BB exerted a protective effect against LPS-induced cytotoxicity, as indicated by cell viability. BB was also able to influence the actin cytoskeleton organization, to recover the control phenotype after LPS insult, and also to reduce LPS-driven migration. We evaluated the activity of Rho and Rac1 GTPases, which regulate both actin cytoskeletal organization and migratory capacity. LPS caused an increase in Rac1 activity, which was counteracted by BB extract. Furthermore, we demonstrated that, in the presence of BB, mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α decreased, as did the immunofluorescence signal of iNOS, whereas that of Arg-1 was increased. Taken together, our results show that, during the inflammatory response, BB extract shifts the M1 polarization towards the M2 phenotype through an actin cytoskeletal rearrangement. Based on that, we might consider BB as a nutraceutical with anti-inflammatory activities.

Background Malignant mesothelioma (MM) is a rare tumor with a dismal prognosis. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients’ survival. Bortezomib (Bor) is a specific and reversible inhibitor of the chymotrypsin-like activity of the 20S core of the proteasome, currently approved for the treatment of multiple myeloma and mantle cell lymphoma. On the other hand, Bor appears to have limited clinical effects on solid tumors, because of its low penetration and accumulation into tumor tissues following intravenous administration. These limitations could be overcome in MM through intracavitary delivery, with the advantage of increasing local drug concentration and decreasing systemic toxicity. Methods In this study, we investigated the effects of Bor on cell survival, cell cycle distribution and modulation of apoptotic and pro-survival pathways in human MM cell lines of different histotypes cultured in vitro. Further, using a mouse MM cell line that reproducibly forms ascites when intraperitoneally injected in syngeneic C57BL/6 mice, we investigated the effects of intraperitoneal Bor administration in vivo on both tumor growth and the modulation of the tumor immune microenvironment. Results We demonstrate that Bor inhibited MM cell growth and induced apoptosis. Further, Bor activated the Unfolded Protein Response, which however appeared to participate in lowering cells’ sensitivity to the drug’s cytotoxic effects. Bor also affected the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors, including ERK1/2 and AKT. In vivo, Bor was able to suppress MM growth and extend mice survival. The Bor-mediated delay of tumor progression was sustained by increased activation of T lymphocytes recruited to the tumor microenvironment. Conclusions The results presented herein support the use of Bor in MM and advocate future studies aimed at defining the therapeutic potential of Bor and Bor-based combination regimens for this treatment-resistant, aggressive tumor.

Lactic acid bacteria (LAB) share several beneficial effects on human organisms, such as bioactive metabolites’ release, pathogens’ competition and immune stimulation. This study aimed at determining the probiotic potential of autochthonous lactic acid bacteria isolated from carrots. In particular, the work reported the characterization at the species level of four LAB strains deriving from carrots harvested in Fucino highland, Abruzzo (Italy). Ribosomal 16S DNA analysis allowed identification of three strains belonging to Leuconostoc mesenteroides and a Weissella soli strain. In vitro and in vivo assays were performed to investigate the probiotic potential of the different isolates. Among them, L. mesenteroides C2 and L. mesenteroides C7 showed high survival percentages under in vitro simulated gastro-intestinal conditions, antibiotic susceptibly and the ability to inhibit in vitro growth against Salmonella enterica serovar Typhimurium, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus pathogens. In parallel, the simple model Caenorhabditis elegans was used for in vivo screenings. L. mesenteroides C2 and L. mesenteroides C7 strains significantly induced pro-longevity effects, protection from pathogens’ infection and innate immunity stimulation. Overall, these results showed that some autochthonous LAB from vegetables such as carrots have functional features to be considered as novel probiotic candidates.

Calcium silicate-based cements have reached excellent levels of performance in endodontics, providing predictable and successful results. To better assess the properties of these bioactive materials, the present study aimed to compare the biocompatibility and antibiofilm properties of ProRoot MTA and Biodentine. Human osteogenic sarcoma (Saos-2) cells were cultured on ProRoot MTA and Biodentine samples or in the presence of both cement extracts. Cell viability assay, measurement of reactive oxygen species (ROS), immunofluorescence analysis, as well as morphological evaluations were conducted. Moreover, Streptococcus mutans was used to assess the biofilm forming ability on ProRoot MTA and Biodentine disks. Finally, both cements were applied in vivo to treat immature permanent teeth affected by reversible pulpitis. Results: Cell viability assay demonstrated that Saos-2 cells had a dose- and time-dependent cytotoxicity to both analyzed cements, although cells exposed to ProRoot MTA showed a better cell vitality than those exposed to Biodentine (p < 0.001). Both cements demonstrated ROS production while this was greater in the case of Biodentine than ProRoot MTA (p < 0.001). Immunofluorescence images of the cytoskeleton and focal adhesions showed no differences in Saos-2 cells grown in the presence of ProRoot MTA eluate; whereas in the Biodentine groups, cells showed a morphology and focal adhesions more similar to that of the control sample, as the eluate concentration decreased. Morphological analysis revealed that Saos-2 cells were more flattened and exhibited better spreading when attached to ProRoot MTA disks than to Biodentine ones. The antibiofilm properties showed a time-dependent powerful inhibition of S. mutans superficial colonization and an antibiofilm effect of both cements. Clinically, complete root formation of the treated elements was achieved using the two studied cements, showing stable results over time. ProRoot MTA and Biodentine was demonstrated to be biocompatible and to possess antibiofilm properties. Their clinical application in vital pulp therapy provided successful outcomes after 2 years of follow-up.

Cancer cells need to become motile in order to escape the primary tumor and move to distant areas to form metastasis. They move as single cells or as a group, following different stimuli, including growth factors. Among them, insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) and their receptors have been implicated in the development and progression of human breast carcinoma. In this report, we provide evidence that the tyrosine kinase Src is responsible for migration promoted by both IGF-1 and EGF in MDA-MB-231 and MCF7 cells, although with a different effect. Moreover, both IGF-1 and EGF induce reorganization of actin cytoskeleton in lamellipodia and membrane ruffles in a time- and Src-dependent manner. Furthermore, we analyzed the tyrosine phosphorylation status of the actin-binding protein cortactin upon growth factor stimulation, showing that even the activation of cortactin is time- and Src-dependent. In addition, immunofluorescence analysis with anti-paxillin antibody reveals that, after treatment with growth factors, tyrosine phosphorylated cortactin is localized on the plasma membrane in correspondence of focal adhesions. Collectively, our findings suggest a crucial role for Src-mediated activation of cortactin in cell migration, reorganization of actin cytoskeleton and phosphotyrosine cortactin localization to the focal adhesions in human breast cancer cell lines upon both IGF-1 and EGF stimulation.