Diagnostic yield of repeat screening colonoscopy ten years after an adenoma-negative index screening endoscopy.

In Germany, colonoscopy was introduced as a screening instrument about 20 years ago. Ten years after an adenoma-negative index endoscopy, a second screening colonoscopy can be performed in younger persons, but this approach is based on limited evidence. We therefore prospectively analyzed the diagnostic yield of second screening colonoscopies in clinical routine.Ten years following adenoma-negative screening endoscopy a second screening colonoscopy was performed in 401 persons (210 women and 191 men); mean age was 70 years. A total of 244 benign neoplastic lesions were removed in 135 persons (34%). Eight persons had three or more small tubular adenomas removed; 19 persons had at least one tubular adenoma measuring ≥ 10 mm; 14 persons had adenomas with villous characteristics; 19 persons had serrated adenomas; one person had an adenoma with high grade dysplasia. Thus 61 persons (33 men and 28 women) were classified as bearing a significant risk for the development of colorectal cancer (15%). An additional patient had a low-risk malignant polyp removed endoscopically.We conclude that a significant number of small and advanced adenomas can be identified in a second screening colonoscopy ten years after an adenoma-negative index screening endoscopy, but malignant lesions are rare. Whether or not removal of the benign lesions in a second screening colonoscopy will reduce incidence and mortality of colorectal carcinoma remains to be seen in this elderly group.

Zirconium Oxycarbide: A Highly Stable Catalyst Material for Electrochemical Energy Conversion.

Metal carbides and oxycarbides have recently gained considerable interest due to their (electro)catalytic properties that differ from those of transition metals and that have potential to outperform them as well. The stability of zirconium oxycarbide nanopowders (ZrO0.31 C0.69 ), synthesized via a hybrid solid-liquid route, is investigated in different gas atmospheres from room temperature to 800 °C by using in-situ X-ray diffraction and in-situ electrical impedance spectroscopy. To feature the properties of a structurally stable Zr oxycarbide with high oxygen content, a stoichiometry of ZrO0.31 C0.69 has been selected. ZrO0.31 C0.69 is stable in reducing gases with only minor amounts of tetragonal ZrO2 being formed at high temperatures, whereas it decomposes in CO2 and O2 gas atmosphere. From online differential electrochemical mass spectrometry measurements, the hydrogen evolution reaction (HER) onset potential is determined at -0.4 VRHE . CO2 formation is detected at potentials as positive as 1.9 VRHE as ZrO0.31 C0.69 decomposition product, and oxygen is anodically formed at 2.5 VRHE , which shows the high electrochemical stability of this material in acidic electrolyte. This peopwery makes the material suited for electrocatalytic reactions at anodic potentials, such as CO and alcohol oxidation reactions, in general.

Mimicking the Chemistry of Natural Eumelanin Synthesis: The KE Sequence in Polypeptides and in Proteins Allows for a Specific Control of Nanosized Functional Polydopamine Formation.

The oxidation of dopamine and of other catecholamines leads to the formation of conformal films on the surface of all known materials and to the formation of a precipitate in solution. In some cases, it has been shown that the addition of additives in the dopamine solution, like certain surfactants or polymers, polyelectrolytes, and certain proteins, allows to get polydopamine nanoparticles of controlled size and the concomitant decrease, in an additive/dopamine dependent manner, in film formation on the surface of the reaction beaker. However, the mechanism behind this controlled oxidation and self-assembly of catecholamines is not known. In this article, it is shown that a specific diad of amino acids in proteins, namely KE, allows for specific control in the oxidation-self-assembly of dopamine to obtain polydopamine@protein core-shell nanoparticles which are biocompatible. The interactions between dopamine and the adjacent KE amino acids potentially responsible for the size control of polydopamine aggregates was investigated by molecular dynamics simulations. The obtained core-shell nanoparticles display the biological activity of the protein used to control the self-assembly of PDA. The photon to heat conversion ability of PDA is conserved in the PDA@protein particles.

Role of sulphuric acid, ammonia and galactic cosmic rays in atmospheric aerosol nucleation.

Atmospheric aerosols exert an important influence on climate through their effects on stratiform cloud albedo and lifetime and the invigoration of convective storms. Model calculations suggest that almost half of the global cloud condensation nuclei in the atmospheric boundary layer may originate from the nucleation of aerosols from trace condensable vapours, although the sensitivity of the number of cloud condensation nuclei to changes of nucleation rate may be small. Despite extensive research, fundamental questions remain about the nucleation rate of sulphuric acid particles and the mechanisms responsible, including the roles of galactic cosmic rays and other chemical species such as ammonia. Here we present the first results from the CLOUD experiment at CERN. We find that atmospherically relevant ammonia mixing ratios of 100 parts per trillion by volume, or less, increase the nucleation rate of sulphuric acid particles more than 100-1,000-fold. Time-resolved molecular measurements reveal that nucleation proceeds by a base-stabilization mechanism involving the stepwise accretion of ammonia molecules. Ions increase the nucleation rate by an additional factor of between two and more than ten at ground-level galactic-cosmic-ray intensities, provided that the nucleation rate lies below the limiting ion-pair production rate. We find that ion-induced binary nucleation of H(2)SO(4)-H(2)O can occur in the mid-troposphere but is negligible in the boundary layer. However, even with the large enhancements in rate due to ammonia and ions, atmospheric concentrations of ammonia and sulphuric acid are insufficient to account for observed boundary-layer nucleation.

Upper limits to the reaction rate coefficients of C(n)(-) and C(n)H(-) (n = 2, 4, 6) with molecular hydrogen.

In the interstellar medium (ISM) ion­molecule reactions play a key role in forming complex molecules. Since 2006, after the radioastronomical discovery of the first of by now six interstellar anions, interest has grown in understanding the formation and destruction pathways of negative ions in the ISM. Experiments have focused on reactions and photodetachment of the identified negatively charged ions. Hints were found that the reactions of CnH(­) with H2 may proceed with a low (<10(­13) cm(3) s(­1)), but finite rate [Eichelberger, B.; et al. Astrophys. J. 2007, 667, 1283]. Because of the high abundance of molecular hydrogen in the ISM, a precise knowledge of the reaction rate is needed for a better understanding of the low-temperature chemistry in the ISM. A suitable tool to analyze rare reactions is the 22-pole radiofrequency ion trap. Here, we report on reaction rates for Cn(­) and CnH(­) (n = 2, 4, 6) with buffer gas temperatures of H2 at 12 and 300 K. Our experiments show the absence of these reactions with an upper limit to the rate coefficients between 4 × 10(­16) and 5 × 10(­15) cm(3) s(­1), except for the case of C2(­), which does react with a finite rate with H2 at low temperatures. For the cases of C2H(­) and C4H(­), the experimental results were confirmed with quantum chemical calculations. In addition, the possible influence of a residual reactivity on the abundance of C4H(­) and C6H(­) in the ISM were estimated on the basis of a gas-phase chemical model based on the KIDA database. We found that the simulated ion abundances are already unaffected if reaction rate coefficients with H2 were below 10(­14) cm(3) s(­1).

Mesoporous Silica Nanoparticles as pH-Responsive Carrier for the Immune-Activating Drug Resiquimod Enhance the Local Immune Response in Mice.

Nanoparticle-based delivery systems for cancer immunotherapies aim to improve the safety and efficacy of these treatments through local delivery to specialized antigen-presenting cells (APCs). Multifunctional mesoporous silica nanoparticles (MSNs), with their large surface areas, their tunable particle and pore sizes, and their spatially controlled functionalization, represent a safe and versatile carrier system. In this study, we demonstrate the potential of MSNs as a pH-responsive drug carrier system for the anticancer immune-stimulant R848 (resiquimod), a synthetic Toll-like receptor 7 and 8 agonist. Equipped with a biotin-avidin cap, the tailor-made nanoparticles showed efficient stimuli-responsive release of their R848 cargo in an environmental pH of 5.5 or below. We showed that the MSNs loaded with R848 were rapidly taken up by APCs into the acidic environment of the lysosome and that they potently activated the immune cells. Upon subcutaneous injection into mice, the particles accumulated in migratory dendritic cells (DCs) in the draining lymph nodes, where they strongly enhanced the activation of the DCs. Furthermore, simultaneous delivery of the model antigen OVA and the adjuvant R848 by MSNs resulted in an augmented antigen-specific T-cell response. The MSNs significantly improved the pharmacokinetic profile of R848 in mice, as the half-life of the drug was increased 6-fold, and at the same time, the systemic exposure was reduced. In summary, we demonstrate that MSNs represent a promising tool for targeted delivery of the immune modulator R848 to APCs and hold considerable potential as a carrier for cancer vaccines.

Spectro-electrochemical setup for in situ and operando mechanistic studies on metal oxide electrode surfaces.

This work shows a combined setup of Diffuse Reflectance FT-IR Spectroscopy (DRIFTS) and electrochemical characterization by AC and DC methods for in situ and operando investigations of surface species during CO2 electrolysis on metal oxide electrodes and their correlation with electrochemical activity. A high-temperature reaction chamber enables conducting DRIFTS and electrochemical experiments simultaneously at temperatures up to 1000 °C in both reductive and oxidative reaction atmospheres and under anodic and cathodic polarization conditions. A dedicated gas- and electrical feedthrough solution is presented, which is the key element required for recording electrochemical AC and DC characteristics using an electrochemical cell, which is simultaneously studied by DRIFTS experiments under realistic operation conditions. Selected results, obtained on a gadolinium doped ceria model solid oxide electrolysis cell upon different polarization states, demonstrate the basic functionality and capabilities of the setup and show how the simultaneous DRIFT-spectroscopic and electrochemical investigation of the surface and bulk chemistry on electrode materials leads to increased insight in the population of potential intermediates during CO2 electrolysis. With infrared spectroscopy and impedance spectroscopy as common and complementary spectroscopic methods in material science, the setup is considered to exhibit a huge potential in a wide field of fundamental and applied mechanistic research.

From Bioinspired Glue to Medicine: Polydopamine as a Biomedical Material.

Biological structures have emerged through millennia of evolution, and nature has fine-tuned the material properties in order to optimise the structure-function relationship. Following this paradigm, polydopamine (PDA), which was found to be crucial for the adhesion of mussels to wet surfaces, was hence initially introduced as a coating substance to increase the chemical reactivity and surface adhesion properties. Structurally, polydopamine is very similar to melanin, which is a pigment of human skin responsible for the protection of underlying skin layers by efficiently absorbing light with potentially harmful wavelengths. Recent findings have shown the subsequent release of the energy (in the form of heat) upon light excitation, presenting it as an ideal candidate for photothermal applications. Thus, polydopamine can both be used to (i) coat nanoparticle surfaces and to (ii) form capsules and ultra-small (nano)particles/nanocomposites while retaining bulk characteristics (i.e., biocompatibility, stability under UV irradiation, heat conversion, and activity during photoacoustic imaging). Due to the aforementioned properties, polydopamine-based materials have since been tested in adhesive and in energy-related as well as in a range of medical applications such as for tumour ablation, imaging, and drug delivery. In this review, we focus upon how different forms of the material can be synthesised and the use of polydopamine in biological and biomedical applications.

Cytotoxicity of Mn-based photoCORMs of ethynyl-α-diimine ligands against different cancer cell lines: The key role of CO-depleted metal fragments.

A series of tricarbonyl manganese complexes bearing 4-ethynyl-2,2'-bipyridine and 5-ethynyl-1,10-phenanthroline α-diimine ligands were synthetized, characterized and conjugated to vitamin B12, previously used as a vector for drug delivery, to take advantage of its water solubility and specificity toward cancer cells. The compounds act as photoactivatable carbon monoxide-releasing molecules rapidly liberating on average ca. 2.3 equivalents of CO upon photo-irradiation. Complexes and conjugates were tested for their anticancer effects, both in the dark and following photo-activation, against breast cancer MCF-7, lung carcinoma A549 and colon adenocarcinoma HT29 cell lines as well as immortalized human bronchial epithelial cells 16HBE14o- as the non-carcinogenic control. Our results indicate that the light-induced cytotoxicity these molecules can be attributed to both their released CO and to their CO-depleted metal fragments including liberated ligands.

Hybrid synthesis of zirconium oxycarbide nanopowders with defined and controlled composition.

A combined synthesis strategy involving a carbothermal reduction and gelation approach with glycine as gelating agent was used to obtain Zr-based (oxy)carbide materials with defined and controlled composition. A comparatively low temperature approach (1500 °C) allows exploration of the ZrC-ZrO2 phase diagram and reproducibly leads to zirconium (oxy)carbide phases with different C/Zr ratios, as confirmed by combined X-ray diffraction (XRD) and transmission electron microscopy (TEM) data. The latter also indicates a chemically very homogeneous distribution of oxygen and carbon throughout the sample bulk, a prerequisite for further characterization of its intrinsic physico-chemical properties. Due to the general variability of the synthesis procedure - variation of metal precursor, amount of gelating agent and carbon precursor source - it is expected that the method can be easily adapted and transferred to other metal - oxycarbide materials.

Biodistribution, Clearance, and Long-Term Fate of Clinically Relevant Nanomaterials.

Realization of the immense potential of nanomaterials for biomedical applications will require a thorough understanding of how they interact with cells, tissues, and organs. There is evidence that, depending on their physicochemical properties and subsequent interactions, nanomaterials are indeed taken up by cells. However, the subsequent release and/or intracellular degradation of the materials, transfer to other cells, and/or translocation across tissue barriers are still poorly understood. The involvement of these cellular clearance mechanisms strongly influences the long-term fate of used nanomaterials, especially if one also considers repeated exposure. Several nanomaterials, such as liposomes and iron oxide, gold, or silica nanoparticles, are already approved by the American Food and Drug Administration for clinical trials; however, there is still a huge gap of knowledge concerning their fate in the body. Herein, clinically relevant nanomaterials, their possible modes of exposure, as well as the biological barriers they must overcome to be effective are reviewed. Furthermore, the biodistribution and kinetics of nanomaterials and their modes of clearance are discussed, knowledge of the long-term fates of a selection of nanomaterials is summarized, and the critical points that must be considered for future research are addressed.

Polydopamine/Transferrin Hybrid Nanoparticles for Targeted Cell-Killing.

Polydopamine can form biocompatible particles that convert light into heat. Recently, a protocol has been optimized to synthesize polydopamine/protein hybrid nanoparticles that retain the biological function of proteins, and combine it with the stimuli-induced heat generation of polydopamine. We have utilized this novel system to form polydopamine particles, containing transferrin (PDA/Tf). Mouse melanoma cells, which strongly express the transferrin receptor, were exposed to PDA/Tf nanoparticles (NPs) and, subsequently, were irradiated with a UV laser. The cell death rate was monitored in real-time. When irradiated, the melanoma cells exposed to PDA/Tf NPs underwent apoptosis, faster than the control cells, pointing towards the ability of PDA/Tf to mediate UV-light-induced cell death. The system was also validated in an organotypic, 3D-printed tumor spheroid model, comprising mouse melanoma cells, and the exposure and subsequent irradiation with UV-light, yielded similar results to the 2D cell culture. The process of apoptosis was found to be targeted and mediated by the lysosomal membrane permeabilization. Therefore, the herein presented polydopamine/protein NPs constitute a versatile and stable system for cancer cell-targeting and photothermal apoptosis induction.

Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via transcobalamin-mediated uptake.

Herein we report the synthesis of new water-soluble vitamin B12 prodrugs bearing metal complexes at the ß-upper side of the cobalt center. A total of three derivatives with the general design {Co-C[triple bond, length as m-dash]C-bpy-M}, where M represents a cytotoxic metal complex, were prepared and tested for their cytotoxicity against MCF-7 breast cancer cells. The choice of the metal was oriented on the eminent Pt and promising Ru and Re species to demonstrate the general applicability of the approach. The recognition of the derivatives by transcobalamin was demonstrated by competitive displacement assays using rhodamine labeled B12. This compound further served to prepare a dual luminescent probe by orthogonal synthesis with M = ((HCCbpy)Ru(bpy)2)Cl2 and to perform in vitro assays. Cellular imaging experiments allowed us to observe the different compartmentalization of both dyes and thus prove that the species follow the natural cobalamin uptake as well as the self-triggered release of the ß-upper complex.

Cellular Shuttles: Monocytes/Macrophages Exhibit Transendothelial Transport of Nanoparticles under Physiological Flow.

A major hurdle in the development of biomedical nanoparticles (NP) is understanding how they interact with complex biological systems and navigate biological barriers to arrive at pathological targets. It is becoming increasingly evident that merely controlling particle physicochemical properties may not be sufficient to mediate particle biodistribution in dynamic environments. Thus, researchers are increasingly turning toward more complex but likewise more physiological in vitro systems to study particle--cell/particle-system interactions. An emerging paradigm is to utilize naturally migratory cells to act as so-called "Trojan horses" or cellular shuttles. We report here the use of monocytes/macrophages to transport NP across a confluent endothelial cell layer using a microfluidic in vitro model. With a custom-built flow chamber, we showed that physiological shear stress, when compared to low flow or static conditions, increased NP uptake by macrophages. We further provided a mathematical explanation for the effect of flow on NP uptake, namely that the physical exposure times of NP to cells is dictated by shear stress (i.e., flow rate) and results in increased particle uptake under flow. This study was extended to a multicellular, hydrodynamic in vitro model. Because monocytes are cells that naturally translocate across biological barriers, we utilized a monocyte/macrophage cell line as cellular NP transporters across an endothelial layer. In this exploratory study, we showed that monocyte/macrophage cells adhere to an endothelial layer and dynamically interact with the endothelial cells. The monocytes/macrophages took up NP and diapedesed across the endothelial layer with NP accumulating within the cellular uropod. These data illustrate that monocytes/macrophages may therefore act as active shuttles to deliver particles across endothelial barriers.