Interactions between Magnetic Nanowires and Living Cells : Uptake, Toxicity and Degradation

We report on the uptake, toxicity and degradation of magnetic nanowires by NIH/3T3 mouse fibroblasts. Magnetic nanowires of diameters 200 nm and lengths comprised between 1 {\mu}m and 40 {\mu}m are fabricated by controlled assembly of iron oxide ({\gamma}-Fe2O3) nanoparticles. Using optical and electron microscopy, we show that after 24 h incubation the wires are internalized by the cells and located either in membrane-bound compartments or dispersed in the cytosol. Using fluorescence microscopy, the membrane-bound compartments were identified as late endosomal/lysosomal endosomes labeled with lysosomal associated membrane protein (Lamp1). Toxicity assays evaluating the mitochondrial activity, cell proliferation and production of reactive oxygen species show that the wires do not display acute short-term (< 100 h) toxicity towards the cells. Interestingly, the cells are able to degrade the wires and to transform them into smaller aggregates, even in short time periods (days). This degradation is likely to occur as a consequence of the internal structure of the wires, which is that of a non-covalently bound aggregate. We anticipate that this degradation should prevent long-term asbestos-like toxicity effects related to high aspect ratio morphologies and that these wires represent a promising class of nanomaterials for cell manipulation and microrheology.Comment: 21 pages 12 figure

Nanomaterials versus ambient ultrafine particles: an opportunity to exchange toxicology knowledge

BACKGROUND: A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite clear parallels in their physicochemical properties and biological actions in in vitro models. OBJECTIVES: NMs are available with a range of physicochemical characteristics, which allows a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NMs, and the study of NMs provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP. METHODS: A workshop of experts systematically analyzed the available information and identified 19 key lessons that can facilitate knowledge exchange between these discipline areas. DISCUSSION: Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas in which additional research prioritization would facilitate both research fields simultaneously. CONCLUSION: There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa.info:eu-repo/semantics/publishedVersio

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&amp;Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings

Advancing tools to promote health equity across European Union regions : The EURO-HEALTHY project

Population health measurements are recognised as appropriate tools to support public health monitoring. Yet, there is still a lack of tools that offer a basis for policy appraisal and for foreseeing impacts on health equity. In the context of persistent regional inequalities, it is critical to ascertain which regions are performing best, which factors might shape future health outcomes and where there is room for improvement. Under the EURO-HEALTHY project, tools combining the technical elements of multi-criteria value models and the social elements of participatory processes were developed to measure health in multiple dimensions and to inform policies. The flagship tool is the Population Health Index (PHI), a multidimensional measure that evaluates health from the lens of equity in health determinants and health outcomes, further divided into sub-indices. Foresight tools for policy analysis were also developed, namely: (1) scenarios of future patterns of population health in Europe in 2030, combining group elicitation with the Extreme-World method and (2) a multi-criteria evaluation framework informing policy appraisal (case study of Lisbon). Finally, a WebGIS was built to map and communicate the results to wider audiences. The Population Health Index was applied to all European Union (EU) regions, indicating which regions are lagging behind and where investments are most needed to close the health gap. Three scenarios for 2030 were produced - (1) the 'Failing Europe' scenario (worst case/increasing inequalities), (2) the 'Sustainable Prosperity' scenario (best case/decreasing inequalities) and (3) the 'Being Stuck' scenario (the EU and Member States maintain the status quo). Finally, the policy appraisal exercise conducted in Lisbon illustrates which policies have higher potential to improve health and how their feasibility can change according to different scenarios. The article makes a theoretical and practical contribution to the field of population health. Theoretically, it contributes to the conceptualisation of health in a broader sense by advancing a model able to integrate multiple aspects of health, including health outcomes and multisectoral determinants. Empirically, the model and tools are closely tied to what is measurable when using the EU context but offering opportunities to be upscaled to other settings

A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1–7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML)

3015 Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients. Allogeneic SCT is a curative approach for AML. In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts. To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated. We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60–80 years with non promyelocytic AML in first CR following induction and 1–6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme. Pharmacokinetic (PK) and circulating cytokines (MIP1β, TNF) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: To date, inclusion has been completed until 1mg/kg cohort. Data of the first 15 patients (end of 0.3 mg/kg cohort) are available. No dose limiting toxicity has been observed. Side effects that could be related to drug administration were mild and transient. The first dose level resulted in a transient KIR occupancy ranging from 20 to 50%. PK values were then in line with modelling data, resulting at 0.3 mg/kg in a Cmax= 6350 ± 504 ng/mL, &gt;80% KIR saturation for one week, and desaturation in the following week. As expected for an IgG4, NK cell numbers were unaffected by the treatment. Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet. Conclusions: Anti-KIR treatment is safe and well tolerated to date. At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed. [Table: see text] </jats:p

Novel monoclonal antibody that enhances natural killer (NK) cell cytotoxicity against multiple myeloma (MM): Preclinical data and interim phase I clinical trial results

3032 Background: MM is increasing in incidence and remains incurable. NK cells have modest killing activity against MM cells in part because of inhibitory signals from HLA class 1 antigens which act via the KIR receptors on NK cells. A novel anti-KIR blocking antibody (1–7F9 named IPH 2101) enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro and appears safe in an ongoing phase 1 clinical trial. Methods: NK cells from healthy controls or patients were pre-treated with IPH 2101 or IgG4 isotype control and co-cultured with MM cell lines or autologous MM tumor targets. NK cell production of interferon-gamma (IFN-γ) or granzyme B (GrB) were measured by ELISPOT. An open-label, single-agent, phase 1 dose escalation study of IPH 2101 is being conducted in patients with relapsed/refractory MM. KIR binding, pharmacokinetics, pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: At an effector to target (E:T) ratio of 1:1, IPH 2101 significantly enhances NK cell IFN-γ release against MM targets (mean 33 spots/well ± 12, SEM vs. 11 ± 0.3, p = 0.005). At an E:T ratio of 10:1, IPH 2101 enhances NK cell cytotoxicity, by GrB release, of patient NK cells against autologous MM tumor cells (mean 111 spots/well ± 14, SEM vs 56 ± 10, p = 0.002). By Western blot, IPH 2101 may reduce levels of src, a kinase known to be involved in inhibitory KIR signaling. Dose escalation in the phase 1 study has been completed from 0.0003 mg/kg to 0.075 mg/kg in 14 evaluable patients. At the highest dose tested, KIR occupancy has been detected at a mean 95% ± 1.4 at 2 hours post dose, lasting up to 56% ± 18 during 2 weeks post dose. At this dose level, PK data show good correspondence with previous modeling activity. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the ongoing clinical trial, the antibody appears safe and well tolerated at the doses tested. This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. [Table: see text] </jats:p

Cellules épithéliales : témoins passifs ou participants actifs de la défense de l'hôte ? Modèle d'épithélium respiratoire infecté par Aspergillus fumigatus

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