Static and dynamic evaluation of pelvic floor disorders with an open low-field tilting magnet.

AIM: To assess the feasibility of magnetic resonance defaecography (MRD) in pelvic floor disorders using an open tilting magnet with a 0.25 T static field and to compare the results obtained from the same patient both in supine and orthostatic positions. MATERIALS AND METHODS: From May 2010 to November 2011, 49 symptomatic female subjects (mean age 43.5 years) were enrolled. All the patients underwent MRD in the supine and orthostatic positions using three-dimensional (3D) hybrid contrast-enhanced (HYCE) sequences and dynamic gradient echo (GE) T1-weighted sequences. All the patients underwent conventional defaecography (CD) to correlate both results. Two radiologists evaluated the examinations; inter and intra-observer concordance was measured. The results obtained in the two positions were compared between them and with CD. RESULTS: The comparison between CD and MRD found statistically significant differences in the evaluation of anterior and posterior rectocoele during defaecation in both positions and of rectal prolapse under the pubo-coccygeal line (PCL) during evacuation, only in the supine position (versus MRD orthostatic: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.008; versus CD: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.01). The value of intra-observer intra-class correlation coefficient (ICC) ranged from good to excellent; the interobserver ICC from moderate to excellent. CONCLUSION: MRD is feasible with an open low-field tilting magnet, and it is more accurate in the orthostatic position than in the supine position to evaluate pelvic floor disorders

Liquid-Liquid Phase Transition for an Attractive Isotropic Potential with Wide Repulsive Range

Recent experimental and theoretical results have shown the existence of a liquid-liquid phase transition in isotropic systems, such as biological solutions and colloids, whose interaction can be represented via an effective potential with a repulsive soft-core and an attractive part. We investigate how the phase diagram of a schematic general isotropic system, interacting via a soft-core squared attractive potential, changes by varying the parameters of the potential. It has been shown that this potential has a phase diagram with a liquid-liquid phase transition in addition to the standard gas-liquid phase transition and that, for a short-range soft-core, the phase diagram resulting from molecular dynamics simulations can be interpreted through a modified van der Waals equation. Here we consider the case of soft-core ranges comparable with or larger than the hard-core diameter. Because an analysis using molecular dynamics simulations of such systems or potentials is too time-demanding, we adopt an integral equation approach in the hypernetted-chain approximation. Thus we can estimate how the temperature and density of both critical points depend on the potential's parameters for large soft-core ranges. The present results confirm and extend our previous analysis, showing that this potential has two fluid-fluid critical points that are well separated in temperature and in density only if there is a balance between the attractive and repulsive part of the potential. We find that for large soft-core ranges our results satisfy a simple relation between the potential's parameters

Total Syntheses of Amphidinolide H and G

Eureka! The first conquest of the exceptionally potent cytotoxic agent amphidinolide H, which exhibits activity in the picomolar range against human epidermoid cancer cells, was long overdue. The successful route critically hinges upon the scrupulous optimization of the fragment-coupling events (see picture; RCM=ring-closing metathesis) and on the careful adjustment of the peripheral protecting-group pattern

Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of Amphidinolide H2

Nature is a pretty unselective “chemist” when it comes to making the highly cytotoxic amphidinolide macrolides of the B/G/H series. To date, 16 different such compounds have been isolated, all of which could now be approached by a highly convergent and largely catalysis-based route (see figure). This notion is exemplified by the total synthesis of five prototype members of this family. Dinoflagellates of the genus Amphidinium produce a “library” of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making “non-natural” analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille–Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides

Liquid-Liquid Phase Transitions for Soft-Core Attractive Potentials

Using event driven molecular dynamics simulations, we study a three dimensional one-component system of spherical particles interacting via a discontinuous potential combining a repulsive square soft core and an attractive square well. In the case of a narrow attractive well, it has been shown that this potential has two metastable gas-liquid critical points. Here we systematically investigate how the changes of the parameters of this potential affect the phase diagram of the system. We find a broad range of potential parameters for which the system has both a gas-liquid critical point and a liquid-liquid critical point. For the liquid-gas critical point we find that the derivatives of the critical temperature and pressure, with respect to the parameters of the potential, have the same signs: they are positive for increasing width of the attractive well and negative for increasing width and repulsive energy of the soft core. This result resembles the behavior of the liquid-gas critical point for standard liquids. In contrast, for the liquid-liquid critical point the critical pressure decreases as the critical temperature increases. As a consequence, the liquid-liquid critical point exists at positive pressures only in a finite range of parameters. We present a modified van der Waals equation which qualitatively reproduces the behavior of both critical points within some range of parameters, and give us insight on the mechanisms ruling the dependence of the two critical points on the potential's parameters. The soft core potential studied here resembles model potentials used for colloids, proteins, and potentials that have been related to liquid metals, raising an interesting possibility that a liquid-liquid phase transition may be present in some systems where it has not yet been observed.Comment: 29 pages, 15 figure

Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs

Ab Initio Molecular Dynamics Simulation of Liquid Ga_xAs_{1-x} Alloys

We report the results of ab initio molecular dynamics simulations of liquid Ga_xAs_{1-x} alloys at five different concentrations, at a temperature of 1600 K, just above the melting point of GaAs. The liquid is predicted to be metallic at all concentrations between x = 0.2 and x = 0.8, with a weak resistivity maximum near x = 0.5, consistent with the Faber-Ziman expression. The electronic density of states is finite at the Fermi energy for all concentrations; there is, however, a significant pseudogap especially in the As-rich samples. The Ga-rich density of states more closely resembles that of a free-electron metal. The partial structure factors show only a weak indication of chemical short-range order. There is also some residue of the covalent bonding found in the solid, which shows up in the bond-angle distribution functions of the liquid state. Finally, the atomic diffusion coefficients at 1600K are calculated to be 2.1 \times 10^{-4} cm^2/sec for Ga ions in Ga_{0.8}As_{0.2} and 1.7 \times 10^{-4} cm^2/sec for As ions in Ga_{0.2}As_{0.8}.Comment: 29 pages, 10 eps figures, accepted for publication in Phys. Rev.

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases

Ice XII in its second regime of metastability

We present neutron powder diffraction results which give unambiguous evidence for the formation of the recently identified new crystalline ice phase[Lobban et al.,Nature, 391, 268, (1998)], labeled ice XII, at completely different conditions. Ice XII is produced here by compressing hexagonal ice I_h at T = 77, 100, 140 and 160 K up to 1.8 GPa. It can be maintained at ambient pressure in the temperature range 1.5 < T < 135 K. High resolution diffraction is carried out at T = 1.5 K and ambient pressure on ice XII and accurate structural properties are obtained from Rietveld refinement. At T = 140 and 160 K additionally ice III/IX is formed. The increasing amount of ice III/IX with increasing temperature gives an upper limit of T ~ 150 K for the successful formation of ice XII with the presented procedure.Comment: 3 Pages of RevTeX, 3 tables, 3 figures (submitted to Physical Review Letters