Incidental diagnosis of bladder cancer in a national observational study in spain.

INTRODUCTION: Bladder cancer (BC) is a common malignancy in Spain. The aims of this study were: to identify the proportion of patients diagnosed with BC incidentally or after symptomatic presentation in a contemporary period in Spain; to compare demographic, clinical, and pathologic characteristics between these groups. METHODS: This was a retrospective analysis of a multi-centre observational study of 26 hospitals in the Spanish National Health System of all BCs newly diagnosed in 2011. The study represented 21.5% of the Spanish population and hospitals were selected in proportion to Spain's regions to ensure a representative sample. Patients were categorized by whether the cancer was diagnosed incidentally or after symptomatic presentation and baseline demographic, pathologic, and clinical characteristics were analyzed. RESULTS: 2472 were newly diagnosed with BC at the 26 participating Spanish hospitals with 308 (12.5%) of cases diagnosed incidentally and 2164 (87.5%) diagnosed after symptomatic presentation. No differences were observed between patients diagnosed incidentally vs. symptomatically in terms of demographics or measured co-morbidities. Compared to symptomatically diagnosed bladder tumours, those diagnosed incidentally were more likely to have a papillary appearance, to be significantly smaller, and less likely to have positive/suspicious cytology. Additionally, incidentally diagnosed bladder tumours were less likely to be muscle-invasive (11.7% vs. 25.0%, p < 0.01) nor aggressive at pathology, with 33.6% Grade 3 compared to 50.1%, (p < 0.01). CONCLUSIONS: We identified a significant percentage (12.5%) of new bladder cancer diagnosis made incidentally in a representative sample of the Spanish population. These tumours exhibited less aggressive pathologic characteristics than their symptomatic counterparts.

Is Tumor Budding a New Predictor for Early Cystectomy in pT1 High-Grade Bladder Cancer?

Background & Objectives: We aimed to evaluate the risk of progression in high-grade T1 (HGT1) tumors using tumor budding (TB) and other standard clinical and histological features. TB is defined as an isolated cancer cell or a cluster composed of fewer than 5 cells scattered in the stroma and is usually used as a strong predictor of lymph node metastasis in T1 colorectal cancer. METHODS: This is an observational longitudinal cohort study involving 168 consecutive patients with HGT1 between 2013 and 2016. Cox regression was performed to analyze the relationship between the clinical and histological features and progression. All slides were blindly assessed by 2 genitourinary pathologists. Budding was determined to be positive when the number of buds was equal to or greater than 6. RESULTS: The median age was 75 years; 152 (90.5%) patients were men, and 49 (29.2%) were positive for TB. At a median follow-up time of 35 months, 33 patients (19.6%) showed progression. Progression was observed in 32.7% of the patients positive for TB and in only 14.3% of those who were negative (p = 0.006). TB was significantly associated with the endoscopic tumor pattern (TP) (papillary/solid) and lymphovascular invasion (LVI). Univariate analysis showed that TB, carcinoma in situ (CIS), TP, LVI, sub-staging, and BCG induction predict progression. The multivariate analysis showed that TB (p = 0.032, hazard ratio 2.1), CIS, TP, and lack of BCG induction were significant for progression. CONCLUSIONS: TB is a new and significant pathological variable for predicting progression in HGT1 tumors and can be easily introduced in clinical practice. Its inclusion in the TNM system should be carefully considered, as it may aid early cystectomy decisions.

Polymer-coated superparamagnetic iron oxide nanoparticles as T2 contrast agent for MRI and their uptake in liver.

AIM: To study the efficiency of multifunctional polymer-based superparamagnetic iron oxide nanoparticles (bioferrofluids) as a T2 magnetic resonance contrast agent and their uptake and toxicity in liver. MATERIALS & METHODS: Mice were intravenously injected with bioferrofluids and Endorem®. The magnetic resonance efficiency, uptake and in vivo toxicity were investigated by means of magnetic resonance imaging (MRI) and histological techniques. RESULTS: Bioferrofluids are a good T2 contrast agent with a higher r2/r1 ratio than Endorem. Bioferrofluids have a shorter blood circulation time and persist in liver for longer time period compared with Endorem. Both bioferrofluids and Endorem do not generate any noticeable histological lesions in liver over a period of 60 days post-injection. CONCLUSION: Our bioferrofluids are powerful diagnostic tool without any observed toxicity over a period of 60 days post-injection.

Functional insights into the cellular response triggered by a bile-acid platinum compound conjugated to biocompatible ferric nanoparticles using quantitative proteomic approaches.

At present, bioferrofluids are employed as powerful multifunctional tools for biomedical applications such as drug delivery, among others. The present study explores the cellular response evoked when bile-acid platinum derivatives are conjugated with bioferrofluids by testing the biological activity in osteosarcoma (MG-63) and T-cell leukemia (Jurkat) cells. The aim of this work is to evaluate the biocompatibility of a bile-acid platinum derivative conjugated with multi-functional polymer coated bioferrofluids by observing the effects on the protein expression profiles and in intracellular pathways of nanoparticle-stimulated cells. To this end, a mass spectrometry-based approach termed SILAC has been applied to determine in a high-throughput manner the key proteins involved in the cellular response process (including specific quantitatively identified proteins related to the vesicular transport, cellular structure, cell cycle, biosynthetic process, apoptosis and regulation of the cell cycle). Finally, biocompatibility was evaluated and validated by conventional strategies also (such as flow cytometry, MTT, etc.).

Studies on a "Disappearing Polymorph": Thermal and Magnetic Characterization of α-p-NCC6F4CNSSN•.

The α-and ß-phases of the thiazyl radical p-NCC6F4CNSSN• (1) can be selectively prepared by careful control of the sublimation conditions, with the α-phase crystallizing preferentially when the substrate temperature is maintained below -10 °C, whereas the ß-phase is isolated when the substrate temperature is maintained at or above ambient temperature. Differential scanning calorimatry studies reveal that the α-phase converts to the ß-phase upon warming over the range 111-117 °C (ΔH = +4 kJ·mol-1) via a melt-recrystallization process, with the ß-phase itself melting at 167-170 °C (ΔHfus = 27 kJ·mol-1). IR and Raman spectroscopy can be used to clearly discriminate between 1α and 1ß. The α-phase shows a broad maximum in the magnetic susceptibility around 8 K that, coupled with a broad maximum in the heat capacity, is indicative of short-range order. Some field dependence of the susceptibility below 3 K is observed, but the lack of features in the ac susceptibility, M vs H plots, or heat capacity mitigates against long-range order in 1α.

Cell compatibility of a maghemite/polymer biomedical nanoplatform.

We are reporting the cytocompatibility and cellular fate of an iron oxide/polymer nanoplatform (IONP) in its most basic formulation, using both mesenchymal (vascular smooth muscle cells, VSMC), and epithelial (opossum kidney, OK) cells. The cytotoxicity and cell internalization of the nanoplatform has been evaluated in relation to time of exposure and concentration of different components. A series of samples with different iron oxide nanoparticle, sizes, hydrodynamic sizes and iron/polymer ratio have been examined. In all cases cytotoxicity is low, and it is mostly determined by the internalization rate, being higher in VSMC than in OK cells. The mean lethal dose has a very narrow threshold, and necrosis is the only cell death type. IONP uptake shows little incidence on oxidative stress, and inflammasome activation is only observed with the smaller IONP at high concentration. The internalization rate in VSMC is determined by the polymer concentration exclusively. In OK cells, internalization rate seems to increase with decreasing hydrodynamic size. Internalization occurs through clathrin-dependent endocytosis, as it is prevented by potassium depletion and chlorpromazine. IONP are directed and accumulated in lysosomes. Under IONP overload, lysosomal dysfunction would cause cell death using concentrations that are hardly achieved in vivo.

Joining time-resolved thermometry and magnetic-induced heating in a single nanoparticle unveils intriguing thermal properties.

Whereas efficient and sensitive nanoheaters and nanothermometers are demanding tools in modern bio- and nanomedicine, joining both features in a single nanoparticle still remains a real challenge, despite the recent progress achieved, most of it within the last year. Here we demonstrate a successful realization of this challenge. The heating is magnetically induced, the temperature readout is optical, and the ratiometric thermometric probes are dual-emissive Eu(3+)/Tb(3+) lanthanide complexes. The low thermometer heat capacitance (0.021·K(-1)) and heater/thermometer resistance (1 K·W(-1)), the high temperature sensitivity (5.8%·K(-1) at 296 K) and uncertainty (0.5 K), the physiological working temperature range (295-315 K), the readout reproducibility (>99.5%), and the fast time response (0.250 s) make the heater/thermometer nanoplatform proposed here unique. Cells were incubated with the nanoparticles, and fluorescence microscopy permits the mapping of the intracellular local temperature using the pixel-by-pixel ratio of the Eu(3+)/Tb(3+) intensities. Time-resolved thermometry under an ac magnetic field evidences the failure of using macroscopic thermal parameters to describe heat diffusion at the nanoscale.

In the dawn of magnets made from molecules.

I discuss here the contribution from J. S. Miller and co-workers concerning the discovery of ferromagnetism in an organometallic compound. The important peculiarities around this discovery, that the moments from p-electrons participate in magnetic ordering, strongly contributed to open the area of molecule-based magnetic materials as a new area of research.

A discrete neutral transition-metal citrate cubane with an M4O4 core; coordinative versatility of the [M(II)4(citrate)4]8⁻ fragment.

The neutral cluster [Mn(II)8(citrate)4(H2O)18] is formed by the [M4(citrate)4](8-) fragment, with an Mn4O4 cubane core, which bonds four peripheral aquomanganese units--two [Mn(H2O)4](2+) and two [Mn(H2O)5](2+)--through a total of six metal-ligand bonds, giving a discrete neutral compound. The compound presents a unique coordination mode in which the citrate cubane acts as a chelate to each of the two peripheral [Mn(H2O)4](2+) (tetra-aquo) units. A detailed analysis of the central and peripheral geometries is given in terms of the tetrahedral distortions of key structural features. A reversible dehydration-rehydration process has been observed in a polycrystalline sample of the complex, whose structure lacks pores or channels.

Enhanced cytotoxic activity of bile acid cisplatin derivatives by conjugation with gold nanoparticles.

This article explores the potential cytotoxic activity of bile-acid cisplatin derivatives like bisursodeoxycholate(ethylenediamine)platinum(II), PtU2, when conjugated with gold nanoparticles, being a promising alternative to cisplatin in the treatment of cancer due to their lower toxicity. For our purpose we analyzed the intracellular delivery ability of these compounds after conjugation with 20-nm gold nanoparticles (PtU2-AuNPs) in the MG63 (osteosarcoma) cell line. Same platinum uptake after incubation with PtU2 and PtU2-AuNPs-derivatives is associated with a higher cytotoxic activity in case of the platinum-gold nanoparticle conjugate, the overall IC50 of PtU2 being reduced more than 10 fold for these new conjugates. When conjugated with gold nanoparticles, this bile-acid derivative is more efficient than the platinum compound alone in terms of their cytotoxic activity.

Hemostasis disorders caused by polymer coated iron oxide nanoparticles.

BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIONs) are inorganic nanomaterials gaining strong clinical interest due to their increasing number of biological and medical applications. The stabilization of SPIONs in a biocompatible stable suspension (bioferrofluid) is generally achieved by an adequate polymeric coating. As many applications using these materials are intended for clinical use through intravenous injection, it is of outmost importance to evaluate their hemostatic behaviour. OBJECTIVES: The aim of this work is to evaluate the hemocompatibility of selected polymer coated bioferrofluids and of their separated components by observing the effects of the bioferrofluid on: the coagulation process--by measuring the prothrombin time (PT) and activated partial thromboplastin time (aPTT)--, the complete blood count (CBC)--Erythrocytes, Leucocytes, Platelets, Hemoglobin and hematocrit--and the hemolysis. METHODS: A SPIONs/bioferrofluid model consisting of a magnetic core of iron oxide nanoparticles embedded within poly(4-vinyl pyridine) (P4VP) and all coated with polyethylene glycol (PEG) has been selected. RESULTS AND CONCLUSIONS: By increasing the concentration of the bioferrofluids an inhibitory effect on the intrinsic pathway of blood coagulation is observed, as indicated by significant increase in aPTT in vitro while PT values stay normal. The effect of the coating components on the inhibition of blood coagulation process shows that PEG has no effect on the process while the P4VP-g-PEG copolymer coating has a strong anticoagulant effect indicating that P4VP is at the origin of such effects. The studied bioferrofluids have no effect on the CBC neither they show in vitro hemolytic effect on blood.

Ratiometric highly sensitive luminescent nanothermometers working in the room temperature range. Applications to heat propagation in nanofluids.

There is an increasing demand for accurate, non-invasive and self-reference temperature measurements as technology progresses into the nanoscale. This is particularly so in micro- and nanofluidics where the comprehension of heat transfer and thermal conductivity mechanisms can play a crucial role in areas as diverse as energy transfer and cell physiology. Here we present two luminescent ratiometric nanothermometers based on a magnetic core coated with an organosilica shell co-doped with Eu(3+) and Tb(3+) chelates. The design of the hybrid host and chelate ligands permits the working of the nanothermometers in a nanofluid at 293-320 K with an emission quantum yield of 0.38 ± 0.04, a maximum relative sensitivity of 1.5% K(-1) at 293 K and a spatio-temporal resolution (constrained by the experimental setup) of 64 × 10(-6) m/150 × 10(-3) s (to move out of 0.4 K--the temperature uncertainty). The heat propagation velocity in the nanofluid, (2.2 ± 0.1) × 10(-3) m s(-1), was determined at 294 K using the nanothermometers' Eu(3+)/Tb(3+) steady-state spectra. There is no precedent of such an experimental measurement in a thermographic nanofluid, where the propagation velocity is measured from the same nanoparticles used to measure the temperature.

Magnetically responsive dry fluids.

Ferrofluids and dry magnetic particles are two separate classes of magnetic materials with specific niche applications, mainly due to their distinct viscosity and interparticle distances. For practical applications, the stability of these two properties is highly desirable but hard to achieve. Conceptually, a possible solution to this problem would be encapsulating the magnetic particles but keeping them free to rotate inside a capsule with constant interparticle distances and thus shielded from changes in the viscosity of the surrounding media. Here we present an example of such materials by the encapsulation of magnetic ferrofluids into highly hydrophobic silica, leading to the formation of dry ferrofluids, i.e., a material behaving macroscopically as a dry powder but locally as a ferrofluid where magnetic nanoparticles are free to rotate in the liquid.

Synthesis of cobalt aluminate nanopigments by a non-aqueous sol-gel route.

Here we report the chemical synthesis of cobalt aluminum oxide (CoAl2O4) nanoparticles by a non-aqueous sol-gel route. The one-pot procedure is carried out at mild temperatures (in the 150 to 300 °C range), and consists of the reaction between cobalt acetate and aluminium isopropoxide in benzyl alcohol. The resulting CoAl2O4 nanoparticles show an unusually low average size, between 2.5 and 6.2 nm, which can be controlled by the synthesis temperature. The colorimetric properties of the nanoparticles are also determined by the synthesis temperature and the characteristic blue color of CoAl2O4 pigments is achieved in samples prepared at T ≥ 200 °C. The nanoparticles are antiferromagnetically ordered below ∼27 K with an uncompensated configuration. The uncompensated moment shows the typical features of strongly interacting superparamagnetic nanoparticles and spin-glass systems.

Organic-Inorganic Eu(3+)/Tb(3+) codoped hybrid films for temperature mapping in integrated circuits.

The continuous decrease on the geometric size of electronic devices and integrated circuits generates higher local power densities and localized heating problems that cannot be characterized by conventional thermographic techniques. Here, a self-referencing intensity-based molecular thermometer involving a di-ureasil organic-inorganic hybrid thin film co-doped with Eu(3+) and Tb(3+) tris (ß-diketonate) chelates is used to obtain the temperature map of a FR4 printed wiring board with spatio-temporal resolutions of 0.42 µm/4.8 ms.

Thermometry at the nanoscale.

Non-invasive precise thermometers working at the nanoscale with high spatial resolution, where the conventional methods are ineffective, have emerged over the last couple of years as a very active field of research. This has been strongly stimulated by the numerous challenging requests arising from nanotechnology and biomedicine. This critical review offers a general overview of recent examples of luminescent and non-luminescent thermometers working at nanometric scale. Luminescent thermometers encompass organic dyes, QDs and Ln(3+)ions as thermal probes, as well as more complex thermometric systems formed by polymer and organic-inorganic hybrid matrices encapsulating these emitting centres. Non-luminescent thermometers comprise of scanning thermal microscopy, nanolithography thermometry, carbon nanotube thermometry and biomaterials thermometry. Emphasis has been put on ratiometric examples reporting spatial resolution lower than 1 micron, as, for instance, intracellular thermometers based on organic dyes, thermoresponsive polymers, mesoporous silica NPs, QDs, and Ln(3+)-based up-converting NPs and ß-diketonate complexes. Finally, we discuss the challenges and opportunities in the development for highly sensitive ratiometric thermometers operating at the physiological temperature range with submicron spatial resolution.

Metal-free highly luminescent silica nanoparticles.

Stable, cost-effective, brightly luminescent, and metal-free organosilica nanoparticles (NPs) were prepared using the Stöber method without any thermal treatment above 318 K. The white-light photoluminescence results from a convolution of the emission originated in the NH(2) groups of the organosilane and oxygen defects in the silica network. The time-resolved emission spectra are red-shifted, relative to those acquired in the steady-state regime, pointing out that the NPs emission is governed by donor-acceptor (D-A) recombination mechanisms. Moreover, the increase of the corresponding lifetime values with the monitored wavelength further supports that the emission is governed by a recombination mechanism typical of a D-A pair attributed to an exceptionally broad inhomogeneous distribution of the emitting centers peculiar to silica-based NPs. These NPs exhibit the highest emission quantum yield value (0.15 ± 0.02) reported so far for organosilica biolabels without activator metals. Moreover, the emission spectra and the quantum yield values are quite stable over time showing no significant aging effects after exposure to the ambient environment for more than 1 year, stressing the potential of these NPs as metal-free biolabels.

A square two-dimensional polymer of cobalt citrate cubanes.

The structure of the title complex, poly[dicaesium(I) hexaaquacobalt(II) [octaaquatetra-µ-citrato-hexacobalt(II)] dodecahydrate], {Cs(2)[Co(H(2)O)(6)][Co(6)(C(6)H(4)O(7))(4)(H(2)O)(8)]·12H(2)O}(n), at 100 (1) K is formed by layers of a square two-dimensional polymer composed of Co(II) citrate cubanes bridged by magnetically active six-coordinate Co(II) cations. The polymer has plane symmetry p4mm in the c-axis projection. The cubanes reside on sites of crystallographic symmetry 4, while the bridging Co(II) centres lie on twofold axes. The basic polymeric unit has a charge of 4-, balanced by two Cs(+) and a [Co(H(2)O)(6)](2+) (symmetry -4) cation, which lie in channels between the polymeric layers. Unligated water molecules, of which there are 12 per cubane, enter into an extended intralayer and layer-bridging hydrogen-bond pattern, which can be described in detail even though not all of the H atoms of the water molecules were located.

Magnetic and relaxation properties of multifunctional polymer-based nanostructured bioferrofluids as MRI contrast agents.

A series of maghemite/polymer composite ferrofluids with variable magnetic core size, which show a good efficiency as MRI contrast agents, are presented. These ferrofluids are biocompatible and can be proposed as possible platforms for multifunctional biomedical applications, as they contain anchoring groups for biofunctionalization, can incorporate fluorescent dyes, and have shown low cellular toxicity. The magnetic properties of the ferrofluids have been determined by means of magnetization and ac susceptibility measurements as a function of temperature and frequency. The NMR dispersion profiles show that the low frequency behavior of the longitudinal relaxivity r(1) is well described by the heuristic model of (1)H nuclear relaxation induced by superparamagnetic nanoparticles proposed by Roch and co-workers. The contrast efficiency parameter, i.e., the nuclear transverse relaxivity r(2), for samples with d > 10 nm assumes values comparable with or better than the ones of commercial samples, the best results obtained in particles with the biggest magnetic core, d = 15 nm. The contrast efficiency results are confirmed by in vitro MRI experiments at ν = 8.5 MHz, thus allowing us to propose a set of optimal microstructural parameters for multifunctional ferrofluids to be used in MRI medical diagnosis.