Nanomedicine applied to translational oncology: A future perspective on cancer treatment.

The high global incidence of cancer is associated with high rates of mortality and morbidity worldwide. By taking advantage of the properties of matter at the nanoscale, nanomedicine promises to develop innovative drugs with greater efficacy and less side effects than standard therapies. Here, we discuss both clinically available anti-cancer nanomedicines and those en route to future clinical application. The properties, therapeutic value, advantages and limitations of these nanomedicine products are highlighted, with a focus on their increased performance versus conventional molecular anticancer therapies. The main regulatory challenges toward the translation of innovative, clinically effective nanotherapeutics are discussed, with a view to improving current approaches to the clinical management of cancer. Ultimately, it becomes clear that the critical steps for clinical translation of nanotherapeutics require further interdisciplinary and international effort, where the whole stakeholder community is involved from bench to bedside. From the Clinical Editor: Cancer is a leading cause of mortality worldwide and finding a cure remains the holy-grail for many researchers and clinicians. The advance in nanotechnology has enabled novel strategies to develop in terms of cancer diagnosis and therapy. In this concise review article, the authors described current capabilities in this field and outlined comparisons with existing drugs. The difficulties in bringing new drugs to the clinics were also discussed.

Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.

In autoimmune type 1 diabetes, pathogenic T lymphocytes are associated with the specific destruction of insulin-producing beta-islet cells. Identification of the autoantigens involved in triggering this process is a central question. Here we examined T cells from pancreatic draining lymph nodes, the site of islet-cell-specific self-antigen presentation. We cloned single T cells in a non-biased manner from pancreatic draining lymph nodes of subjects with type 1 diabetes and from non-diabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from control subjects. The oligoclonally expanded T cells from diabetic subjects with DR4, a susceptibility allele for type 1 diabetes, recognized the insulin A 1-15 epitope restricted by DR4. These results identify insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes.

Nuclear phospholipase C beta1 and cellular differentiation.

Phosphoinositides (PI) are the most extensively studied lipids involved in cell signaling pathways. The bulk of PI is found in membranes where they are substrates for enzymes, such as kinases, phosphatases and phospholipases, which respond to the activation by cell-surface receptors. The outcome of the majority of signaling pathways involving lipid second messengers results in nuclear responses finally driving the cell into differentiation, proliferation or apoptosis. Some of these pathways are well established, such as that of PI-specific phospholipase C (PI-PLC), which cleaves phosphatidylinositol-4,5-bisphosphate (PIP2) into the two second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). Two independent cycles of PI are present inside the cell. One is localized at the plasma membrane, while the most recently discovered PI cycle is found inside the nuclear compartment. The regulation of the nuclear PI pool is totally independent from the plasma membrane counterpart, suggesting that the nucleus constitutes a functionally distinct compartment of inositol lipids metabolism. In this report we will focus on the signal transduction-related metabolism of nuclear PI and review the most convincing evidence that the PI cycle is involved in differentiation programs in several cell systems.

Effects of metal(loid)-based nanomaterials on essential element homeostasis: the central role of nanometallomics for nanotoxicology.

The growing use of engineered nanomaterials in both commercial products and biomedical applications leads to increasing exposure for production line workers, consumers and patients. Therefore, the understanding of biological effects induced by nanomaterials is crucial for their safety assessment. An important group of nanomaterials is represented by metal(loid)-based nanoparticles, because of their unique physico-chemical properties. Metal(loid)-based nanoparticles themselves, the related ion release, and their nanometallomes, can potentially interact with essential elements causing dys-homeostasis and adverse biological effects. In this work, we describe the effects of metal(loid)-based nanoparticles on essential element homeostasis. In particular, we consider the most used and promising metal(loid)-based nanoparticles, highlighting that the new emerging concept of nanometallomics is important to disclose the impact of these nanoparticles on human health and the related long-term effects.

Antibacterial activity of silver nanoparticles: sensitivity of different Salmonella serovars.

Salmonella spp. is one of the main causes of foodborne illnesses in humans worldwide. Consequently, great interest exists in reducing its impact on human health by lowering its prevalence in the food chain. Antimicrobial formulations in the form of nanoparticles exert bactericidal action due to their enhanced reactivity resultant from their high surface/volume ratio. Silver nanoparticles (AgNPs) are known to be highly toxic to Gram-negative and Gram-positive microorganisms, including multidrug resistant bacteria. However, few data concerning their success against different Salmonella serovars are available. Aims of the present study were to test the antimicrobial effectiveness of AgNPs, against Salmonella Enteritidis, Hadar, and Senftenberg, and to investigate the causes of their different survival abilities from a molecular point of view. Results showed an immediate, time-limited and serovar-dependent reduction of bacterial viability. In the case of S. Senftenberg, the reduction in numbers was observed for up to 4 h of incubation in the presence of 200 mg/l of AgNPs; on the contrary, S. Enteritidis and S. Hadar resulted to be inhibited for up to 48 h. Reverse transcription and polymerase chain reaction experiments demonstrated the constitutive expression of the plasmidic silver resistance determinant (SilB) by S. Senftenberg, thus suggesting the importance of a cautious use of AgNPs.

Toxicity of antimony trioxide nanoparticles on human hematopoietic progenitor cells and comparison to cell lines.

Nanoparticles (NPs) are materials with one dimension in the range of 1-100 nm. The toxicity of NPs remains widely unknown and still poses concerns, due to the peculiar characteristics of materials in the nano-size range. We analyze the toxicity of seven NPs ((Fe2O3, Fe3O4, Sb2O3, Au, TiO2, Co, and Ag) on primary cultures of human hematopoietic progenitor cells from the bone marrow of healthy donors with CFU assays, and show that antimony oxide (Sb2O3) NPs and cobalt (Co) NPs have a toxic effect, while the other NPs have no effect at the tested concentrations (5, 25 and 100 microg/ml). While Co NPs suspension is toxic to both erythroid and granulocytic-monocytic precursors, Sb2O3 NPs at 5 microg/ml are specifically toxic to erythroid colony development, suggesting a highly selective type of toxicity. With liquid culture assays we show that Sb2O3 NPs impair the proliferation of erythroid progenitors, while no toxic effect is observed when Sb2O3 NPs are added during erythroid differentiation. CFU assays and liquid culture assays on seven human cell lines of hematopoietic origin (K562, HL-60, CEM, CEM-R, Thp-1, Jurkat, and Molt-4) show that, contrary to what observed on primary cultures of bone marrow progenitors, Sb2O3 NPs have no toxic effect on proliferation of any of the cell lines, raising concerns about the use of immortalized cell lines for nanotoxicology tests.

Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells.

CD4+ T helper 1 (TH1) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate TH1 immunity and may be able to influence a range of inflammatory conditions.

Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein.

Autoantibodies to myelin oligodendrocyte glycoprotein (MOG) can induce demyelination and oligodendrocyte loss in models of multiple sclerosis (MS). Whether anti-MOG Abs play a similar role in patients with MS or inflammatory CNS diseases by epitope spreading is unclear. We have therefore examined whether autoantibodies that bind properly folded MOG protein are present in the CNS parenchyma of MS patients. IgG was purified from CNS tissue of 14 postmortem cases of MS and 8 control cases, including cases of encephalitis. Binding was assessed using two independent assays, a fluorescence-based solid-phase assay and a solution-phase RIA. MOG autoantibodies were identified in IgG purified from CNS tissue by solid-phase immunoassay in 7 of 14 cases with MS and 1 case of subacute sclerosing panencephalitis, but not in IgG from noninflamed control tissue. This finding was confirmed with a solution-phase RIA, which measures higher affinity autoantibodies. These data demonstrate that autoantibodies recognizing MOG are present in substantially higher concentrations in the CNS parenchyma compared with cerebrospinal fluid and serum in subjects with MS, indicating that local production/accumulation is an important aspect of autoantibody-mediated pathology in demyelinating CNS diseases. Moreover, chronic inflammatory CNS disease may induce autoantibodies by virtue of epitope spreading.