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Background Infliximab is effective in inflammatory bowel disease through several mechanisms, possibly acting at the mucosal level. Aim To assess the role of infliximab on intestinal mucosa and whether it contributes to mucosal healing. Methods Human colonic mucosal biopsies were incubated with or without infliximab. Cultured biopsies were evaluated for histological staining, CD68, CD3, E-cadherin and phospho-extracellular signal-regulated kinases (ERK) expression, and apoptosis. A scratch assay and MTT assay were performed with Caco2 cells in the presence of infliximab and/or tumour necrosis factor (TNF)-α or treated with supernatants obtained from human peripheral blood mononuclear cells or human intestinal fibroblasts treated with TNF-α and infliximab alone or in association. Results Infliximab-treated biopsies displayed a better histological appearance, reduced inflammation with an increase of E-cadherin, phospho-ERK and apoptosis. Supernatants showed lower TNF-α, IL-17, IL-6 and IL-8 concentration, with an increase in fibroblast-growth-factor. Motility at scratch assay and proliferation at MTT assay of Caco2 cells displayed differential modulation by TNF-α and infliximab, directly or through supernatants of human intestinal fibroblasts and human peripheral blood mononuclear cells exposed to them. Conclusion Infliximab contributes to the mucosal healing process by acting directly at an intestinal mucosal level; infliximab indirectly affects epithelial cell migration and proliferation by acting on both fibroblasts and leukocytes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Infliximab is effective in human and murine IBD, but its pharmacodynamic is still poorly known. The aim of this study was to assess the affinity of infliximab to murine TNF-α, its role in murine colitis when administered intra-rectally and its levels in the blood, gut mucosa and stool of healthy and sick mice. Methods: An ELISA kit was built in order to assess the affinity of infliximab to human or murine-TNF-α. Human IgG were used as controls. DSS model of colitis on C57BL/6 mice was used to assess clinical efficacy of infliximab administered intravenously or by enema. Stool, serum and colon samples were collected to assess infliximab levels and histology for Rachmilewitz score. Results: Infliximab showed a good affinity both for human-TNF-α and murine-TNF-α. In DSS colitic mice infliximab ameliorated the severity of colitis, regardless of the administration route. In comparison with colitic mice, healthy mice displayed higher serum and mucosal infliximab levels, while detectable levels of infliximab were found in faeces, particularly in colitic mice. Conclusion: Our data support murine models to study infliximab pharmacokinetics and dynamics. Measurable levels of infliximab can be found at different concentrations in blood, intestinal mucosa and stool from healthy and sick mice, thus infliximab pharmacokinetics could have a major impact in human IBD. [Copyright &y& Elsevier]

Abstract: Silybin is the major flavonolignan of silymarin and it displays a plethora of biological effects, generally ascribed to its antioxidant properties. Herein we shall describe an efficient synthetic strategy to obtain a variety of new and more water-soluble silybin and 2,3-dehydrosilybin (DHS) derivatives in which the 23-hydroxyl group was converted to a sulfate, phosphodiester, or amine group, using a solution-phase approach. Furthermore a new and efficient method for the preparation of DHS from silybin was developed and optimised. The antioxidant properties of the new compounds were evaluated in a cellular model in vivo and they displayed an antioxidant activity comparable to or higher than silybin and DHS, being able to prevent H2O2-induced generation of intracellular reactive oxygen species (ROS). Most of the derivatives also displayed a better hydrophilicity while retaining the biological activities of silybin and they might broaden the in vivo applications of this class of natural compounds. [Copyright &y& Elsevier]

In this study, new biocompatible, nanostructured materials made of titanium alloys have been developed, manufactured and studied in terms of their biocompatibility. The major feature of such materials is to comprise structures with zero dimensionality (groups of atoms “clusters”), monodimensioned multilayers and nanophasic solid or three-dimensional nanocrystalls. Moreover, they theoretically have no limitations in chemical composition. Various samples with different compositions have been proposed, with varying parameters in their manufacturing process. A composition was found to appear more suitable for the specific demands for such applications of these materials. Moreover, cytotoxicity tests (both for direct and indirect contact) have been performed and the ability of osteogenic cells to attach, grow and differentiate on these materials has been analyzed “in vitro.” The results show that even small granulometric variations of few nanometers can influence the biocompatibility of these materials in terms of their cytotoxicity and in terms of osteogenic cells attachment and growth. These data are important because they probably reflect the behavior of osteoblast cells and relate to bone remodeling “in vivo.” [Copyright &y& Elsevier]

Background & Aims Mesenchymal stem cells (MSCs) are pluripotent cells that can promote expansion of immune regulatory cells and might be developed for the treatment of immune disorders, including inflammatory bowel diseases. MSCs were reported to reduce colitis in mice; we investigated whether MSC localization to the intestine and production of paracrine factors, including tumor necrosis factor–induced protein 6 (TSG6), were required for these effects. Methods MSCs were isolated from bone marrow (BM-MSCs) of 4- to 6-week-old C57BL/6, C57BL/6–green fluorescent protein, or Balb/c Tsg6 -/- male mice. Colitis was induced by ad libitum administration of dextran sulfate sodium for 10 days; after 5 days the mice were given intraperitoneal injections of BM-MSCs or saline (controls). Blood samples and intestinal tissues were collected 24, 48, 96, and 120 hours later; histologic and flow cytometry analyses were performed. Results Injection of BM-MSCs reduced colitis in mice, increasing body weight and reducing markers of intestinal inflammation, compared with control mice. However, fewer than 1% of MSCs reached the inflamed colon. Most of the BM-MSCs formed aggregates in the peritoneal cavity. The aggregates contained macrophages and B and T cells, and produced immune-regulatory molecules including FOXP3, interleukin (IL)10, transforming growth factor-β, arginase type II, chemokine (C-C motif) ligand 22 (CCL22), heme oxygenase-1, and TSG6. Serum from mice given BM-MSCs, compared with mice given saline, had increased levels of TSG6. Injection of TSG6 reduced the severity of colitis in mice, along with the numbers of CD45+ cells, neutrophils and metalloproteinase activity in the mucosa, while increasing the percentage of Foxp3CD45+ cells. TSG6 injection also promoted the expansion of regulatory macrophages that expressed IL10 and inducible nitric oxide synthase, and reduced serum levels of interferon-γ, IL6, and tumor necrosis factor. Tsg6 -/- MSCs did not suppress the mucosal inflammatory response in mice with colitis. Conclusions BM-MSCs injected into mice with colitis do not localize to the intestine but instead form aggregates in the peritoneum where they produce immunoregulatory molecules, including TSG6, that reduce intestinal inflammation. TSG6 is sufficient to reduce intestinal inflammation in mice with colitis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second most common cause of cancer death, leading to almost 1 million deaths per year. Despite constant progress in surgical and therapeutic protocols, the 5-year survival rate of advanced CRC patients remains extremely poor. Colorectal Cancer Stem Cells (CRC-CSCs) are endowed with unique stemness-related properties responsible for resistance, relapse and metastasis. The development of novel therapeutics able to tackle CSCs while avoiding undesired toxicity is a major need for cancer treatment. Natural products are a large reservoir of unexplored compounds with possible anticancer bioactivity, sustainability, and safety. The family of meroterpenoids derived from sponges share interesting bioactive properties. Bioassay-guided fractionation of a meroterpenoids extract led to the isolation of three compounds, all cytotoxic against several cancer cell lines: Metachromins U, V and W. In this study, we evaluated the anticancer potential of the most active one, Metachromins V (MV), on patient-derived CRC-CSCs. MV strongly impairs CSCs-viability regardless their mutational background and the cytotoxic effect is maintained on therapy-resistant metastatic CSCs. MV affects cell cycle progression, inducing a block in G2 phase in all the cell lines tested and more pronouncedly in CRC-CSCs. Moreover, MV triggers an important reorganization of the cytoskeleton and a strong reduction of Rho GTPases expression, impairing CRC-CSCs motility and invasion ability. By Proteomic analysis identified a potential molecular target of MV: CCAR1, that regulates apoptosis under chemotherapy treatments and affect β-catenin pathway. Further studies will be needed to confirm and validate these data in in vivo experimental models • The development of novel therapeutics able to tackle CSCs is a major need for cancer treatment. • The family of meroterpenoids derived from sponges share interesting bioactive properties. • Metachromins V has anticancer potential on patient-derived CRC-CSCs. • A potential molecular target of Methacromins V has been identified: CCAR1, that regulates apoptosis under chemotherapy. [ABSTRACT FROM AUTHOR]

Our group has previously shown that corticotropin releasing factor (CRF) inhibits proliferation of human endocrine-related cancer cell lines via the activation of CRF type-1 receptors (CRF-R1). Tumors originating from the nervous system also express CRF receptors but their role on neoplastic cell proliferation was poorly investigated. Here we investigated the effect of CRF receptor stimulation on nervous system-derived cancer cells, using the SK-N-SH (N) human neuroblastoma cell line as an experimental model. We found that SK-N-SH (N) cells express functionally active CRF-R1, whose activation by CRF and the cognate peptide urocortin (UCN) is associated to reduced cell proliferation and motility, as well as neuronal-like differentiation. UCN did not interfere with cell viability and cell-cycle arrest. Those effects seem to be mediated by a mechanism involving the activation of cAMP/PKA/CREB pathway and the subsequent downstream increase in p27 Kip1 and underphosphorylated retinoblastoma protein levels, as well as reduced c-Myc mRNA accumulation. [ABSTRACT FROM AUTHOR]

Highlights: [•] Post vaccination cytokines levels were lower in HIV+ patients than healthy subjects. [•] This was confirmed in a multivariate analysis adjusting for potential confounders. [•] No difference in humoral response between HIV-infected and healthy subjects. [•] Efficacy of immune response related to HIV-RNA, CD4 and CD8 count. [ABSTRACT FROM AUTHOR]

Abstract: Environmental concentration of the platinum group elements is increased in the last years due to their use in automobile catalytic converters. Limited data are available on the effects of such elements at a cellular level and on their toxicity, especially for rhodium and iridium which have been more recently introduced in use. The toxic effects of rhodium and iridium salts were analyzed on a normal diploid rat fibroblast cell line in vitro. Both salts halted cell growth in a dose- and time-dependent fashion by inhibiting cell cycle progression, inducing apoptosis and modulating the expression of cell cycle regulatory proteins. In fact, they both caused an accumulation of cells in the G2/M phase of the cell cycle and affected the expression levels of pRb, cyclins D1 and E, p21Waf1 and p27Kip1. DNA strand breaks, as assessed by comet test, and an increase in the intracellular levels of reactive oxygen species also occurred in exposed cell cultures. These findings suggest a potential toxicity of both iridium and rhodium salts and emphasize the need for further studies to understand their effects at a cellular level to enable a better assessment of their toxic effects and to identify ways for their modulation and/or prevention. [Copyright &y& Elsevier]

Mathematical modeling constitutes an emerging area of oncological research aiming to predict spatial and temporal evolution of tumors, by describing many different phenomena which occur at different scales. Among these, modeling at the macroscopic scale has a great potential of application, when diagnostic imaging evaluation is used to identify the metabolic tumor volume undergoing proliferation. With breast carcinoma one of the most common cancer occurrences, the personal involvement for the patient and the cost for the national health system vary considerably with the adopted treatment. When a neoadjuvant (volume reducing) drug therapy is a direct option, the choice of drug may dictate the physical burden and the surgical strategy for subsequent lumpectomy/mastectomy. This paper employs a mass transfer modeling approach in order to gain deeper insight into breast carcinoma proliferation and therapy at the tissue scale. The aim is to develop a predictive, quantitative method for each given patient. Model flexibility is demonstrated, to facilitate model replication for large patient cohorts. The proposed procedure may serve as a basis for a decision support system for surgeons and towards personalized treatment optimization of breast tumors. [ABSTRACT FROM AUTHOR]

Mathematical modeling constitutes an emerging area of oncological research aiming to predict spatial and temporal evolution of tumors, by describing many different phenomena, which occur at different scales. Among these, modeling at the macroscopic scale has an interesting potential of application, when applied in a framework where actual diagnostic imaging is used to identify the metabolic tumor volume undergoing proliferation. Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. The most common form of Non-Hodgkin lymphoma among adults, DLBCL can arise in any part of the body and may play a very aggressive malignancy. This paper aims to enforce a mass transfer modeling approach in order to gain deeper insight into the dynamics of tumor growth at the tissue scale and to develop a predictive, quantitative method for each patient at hand. A cohort of 18 patients has been successfully enrolled to validate the model. Results confirm that tumor proliferation, at the macroscopic scale, scores many nonlinear features, and show that the proposed model could be used by oncologists as a decision support tool towards personalized treatment optimization of solid tumors. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine malignancy, with well-differentiated subtypes characterized by an excellent prognosis due to their optimal sensitivity to standard therapies whereas poorly differentiated and anaplastic tumours by chemo/radio-resistance and unfavourable outcome. Heat Shock Proteins (HSPs) are molecular chaperones overexpressed in thyroid malignancies and involved in crucial functions responsible for thyroid carcinogenesis, as protection from apoptosis, drug resistance and cell migration. Thus, HSPs inhibitors have been proposed as novel therapeutic agents in thyroid cancer to revert molecular mechanisms of tumour progression. In this review, we report an overview on the biological role of HSPs, and specifically HSP90s, in thyroid cancer and their potential involvement as biomarkers. We discuss the rationale to evaluate HSPs inhibitors as innovative anticancer agents in specific subtypes of thyroid cancer characterized by poor response to therapies with the objective to target single family chaperones to reduce, simultaneously, the expression/stability of multiple client proteins. Potential therapeutic targets of HSPs inhibitors in the management of the poorly differentiated and anaplastic thyroid cancer. Image 1 • HSPs upregulation in thyroid cancer (TC) drives tumour dedifferentiation. • Molecular panels including HSPs may discriminate malignant from benign nodules. • HSPs targeting is a potential therapeutic strategy in TCs with poor prognosis. [ABSTRACT FROM AUTHOR]