Elective neck irradiation in the management of esthesioneuroblastoma: a systematic review and meta-analysis.

BACKGROUND: There is no consensus about the optimal management of the neck in clinically node negative esthesioneuroblastoma (ENB). The aim of this study is to assess the impact of elective neck irradiation (ENI) in terms of regional disease control and survival. METHODS: The study was performed according to the PRISMA guidelines searching on Scopus, PubMed/MEDLINE, and Google Scholar databases. The primary outcome was the regional recurrence rate (RRR), that was reported as odds ratio (OR) and 95% confidence interval (CI). Secondary outcomes were the overall survival (OS), and the distant-metastases free survival (DMFS), that were reported as logarithm of the hazard ratios (logHRs) and 95% confidence intervals (CIs). RESULTS: A total of 489 clinically node negative patients were included from 9 retrospective studies. ENI significantly reduced the risk of regional recurrence compared to no treatment. No difference was measured between ENI and observation, according to both OS and DMFS. No stratified analysis could be performed based on Kadish stage and Hyams grade. CONCLUSIONS: ENI should be recommended to improve the regional disease control. No advantage was measured in terms of survival or distant metastases with a low quality of evidence. Further prospective studies should be designed to understand if ENI could be avoided in early stage and low-grade tumors.

Symmetry and dynamics of FHF- anion in vacuum, in CD2Cl2 and in CCl4. Ab initio MD study of fluctuating solvent-solute hydrogen and halogen bonds.

FHF- anion is a classic example of a central-symmetric strongly hydrogen bonded system that has been intensively investigated both experimentally and theoretically. In this paper we focus on solvent effects on symmetry, structure and dynamics of the anion. The FHF- anion is studied in vacuum, dissolved in CH2Cl2 and dissolved in CCl4 by ab initio molecular dynamics simulations. We show that CH2Cl2 molecules form CHF hydrogen bonds with lone pairs of fluorine atoms, while CCl4 molecules form halogen bonds. These specific non-covalent solvent-solute interactions are cooperatively coupled to the FHF- hydrogen bonds. The fluctuation of solvent molecules' positions is the driving force changing the FHF- hydrogen bond geometry. Most of the time, the anion is solvated asymmetrically, which leads to the asymmetric bridging particle position, though the time-averaged D∞h symmetry is retained. Interestingly, this transient asymmetrization of FHF- is more pronounced in CCl4, than in CH2Cl2. We show that the 1H and 19F NMR chemicals shifts react sensitively to the changes of anion's geometry and the limiting chemical shifts of free solvated FH and F- are strongly solvent-dependent.

Polar solvent fluctuations drive proton transfer in hydrogen bonded complexes of carboxylic acid with pyridines: NMR, IR and ab initio MD study.

We study a series of intermolecular hydrogen-bonded 1 : 1 complexes formed by chloroacetic acid with 19 substituted pyridines and one aliphatic amine dissolved in CD2Cl2 at low temperature by 1H and 13C NMR and FTIR spectroscopy. The hydrogen bond geometries in these complexes vary from molecular (O-HN) to zwitterionic (O-H-N+) ones, while NMR spectra show the formation of short strong hydrogen bonds in intermediate cases. Analysis of C[double bond, length as m-dash]O stretching and asymmetric CO2- stretching bands in FTIR spectra reveal the presence of proton tautomerism. On the basis of these data, we construct the overall proton transfer pathway. In addition to that, we also study by use of ab initio molecular dynamics the complex formed by chloroacetic acid with 2-methylpyridine, surrounded by 71 CD2Cl2 molecules, revealing a dual-maximum distribution of hydrogen bond geometries in solution. The analysis of the calculated trajectory shows that the proton jumps between molecular and zwitterionic forms are indeed driven by dipole-dipole solvent-solute interactions, but the primary cause of the jumps is the formation/breaking of weak CHO bonds from solvent molecules to oxygen atoms of the carboxylate group.

The structure and IR signatures of the arginine-glutamate salt bridge. Insights from the classical MD simulations.

Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)-glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded ß-sheet structure. The 1 µs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898-915 (2011)]. These structures are stabilized by the short (+)N-H⋯O(-) bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB-ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm(-1). It is caused by the asymmetric stretching vibrations of the (+)N-H⋯O(-) fragment. Result of the present paper suggests that infrared spectroscopy in the 2000-2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is usually not considered in spectroscopic studies of peptides and proteins.

Bulk chemical shifts in hydrogen-bonded systems from first-principles calculations and solid-state-NMR.

We present an analysis of bulk (1)H NMR chemical shifts for a series of biochemically relevant molecular crystals in analogy to the well-known solvent NMR chemical shifts. The term bulk shifts denotes the change in NMR frequency of a gas-phase molecule when it undergoes crystallization. We compute NMR parameters from first-principles electronic structure calculations under full periodic boundary conditions and for isolated molecules and compare them to the corresponding experimental fast magic-angle spinning solid-state NMR spectra. The agreement between computed and experimental lines is generally very good. The main phenomena responsible for bulk shifts are packing effects (hydrogen bonding and pi-stacking) in the condensed phase. By using these NMR bulk shifts in well-ordered crystalline model systems composed of biologically relevant molecules, we can understand the individual spectroscopic signatures of packing effects. These local structural driving forces, hydrogen bonding, pi-stacking, and related phenomena, stand as a model for the forces that govern the assembly of much more complex supramolecular aggregates. We show to which accuracy condensed-phase ab initio calculations can predict structure and structure-property relationships for noncovalent interactions in complex supramolecular systems.

Nuclear Velocity Perturbation Theory of Vibrational Circular Dichroism.

We report the first implementation of vibrational circular dichroism (VCD) within density functional theory (DFT) using the nuclear velocity perturbation (NVP) theory. In order to support VCD calculations in large-scale systems such as solvated (bio)molecules and supramolecular assemblies, we have chosen a plane-wave electronic structure code (CPMD). This implementation allows the incorporation of fully anharmonic effects in VCD spectra on the basis of ab initio molecular dynamics simulations. On the conceptual level, we compare our NVP results for rigid molecules with an existing implementation based on the magnetic field perturbation (MFP) technique using a Gaussian basis set and find an excellent agreement. Regarding numerical aspects, we analyze our results for their correct origin dependence and gauge invariance of the physical observables. The correlation with experimental data is very satisfactory, with certain deviations mainly due to the level of electronic structure theory used.

Eigensystem Representation of the Electronic Susceptibility Tensor for Intermolecular Interactions within Density Functional Theory.

We present an efficient implementation of the electronic susceptibility tensor within density functional theory. The susceptibility is represented by means of its eigensystem, which is computed using an iterative Lanczos diagonalization technique for the susceptibility tensor within density functional perturbation theory. We show that a representation in a finite basis of eigenstates is sufficiently accurate to compute the linear response of the electronic density to external potentials. Once the eigensystem representation is computed, the actual response computation can be done at very low computational cost. The method is applied to the water molecule in a dipole field as a benchmark system. The results illustrate the potential of the approach for the first-principles calculation of supramolecular interactions in complex disordered systems in the condensed phase.

Diffusion in binary gas mixtures studied by NMR of hyperpolarized gases and molecular dynamics simulations.

The dependence of the individual mean square displacement of rare gases in binary mixtures is studied by a combined experimental and theoretical approach. We show that the diffusion constant can be varied in a considerable range by changing the molar fractions of the mixtures. On the experimental side, NMR diffusion measurements are done on hyperpolarized 3He and 129Xe, mixed with several inert buffer gases, in the presence of a magnetic field gradient. The results are compared to diffusion coefficients obtained from atomistic molecular dynamics simulations based on Lennard-Jones type potentials of the corresponding gas mixtures, and to appropriate analytical expressions, yielding very good mutual agreement. This study is the first quantitative validation of the effects of the mutual interactions between gas particles on the individual diffusion properties. It is shown that the dependency of gas phase diffusion properties on the local chemical environment may not be neglected, e.g. in diffusion-controlled chemical reactions.

Anomalous temperature dependence of nuclear quadrupole interactions in strongly hydrogen-bonded systems from first principles.

We present an analysis of the effect of finite temperatures on the deuteron nuclear quadrupole coupling constants in a strongly hydrogen-bonded molecular crystal by means of first-principles Car-Parrinello molecular-dynamics simulations. Our findings agree well with experiments and provide a microscopic explanation of the anomalous increase of the quadrupole coupling in this class of systems. We show that a simple model based on the anharmonicity of the hydrogen bond potential fails to describe the temperature dependence of the couplings even qualitatively. Instead, the inclusion of fluctuations and disorder in terms of atomic motion of the surrounding molecules turns out to be important to obtain the correct magnitude of the temperature effect.

Accurate total energies without self-consistency.

We present a new way of calculating approximate but accurate total energies within the framework of density functional theory. Our technique is based on an expansion of the energy functional to second order and does not require self-consistent iterations of the total density. The functional can be minimized by using the same techniques as developed for variational density functional perturbation theory. The method is ideally suited to systems composed of weakly interacting fragments, but it can also be applied to semiconductors and insulators. We show the versatility of our approach in a variety of examples exhibiting different types of chemical bonding.

Ab initio molecular dynamics-based assignment of the protonation state of pepstatin A/HIV-1 protease cleavage site.

A recent 13C NMR experiment (Smith et al. Nature Struct. Biol. 1996, 3, 946-950) on the Asp 25-Asp25' dyad in pepstatin A/HIV-1 protease measured two separate resonance lines, which were interpreted as being a singly protonated dyad. We address this issue by performing ab initio molecular dynamics calculations on models for this site accompanied by calculations of 13C NMR chemical shifts and isotopic shifts. We find that already on the picosecond time-scale the model proposed by Smith et al. is not stable and evolves toward a different monoprotonated form whose NMR pattern differs from the experimental one. We suggest, instead, a different protonation state in which both aspartic groups are protonated. Despite the symmetric protonation state, the calculated 13C NMR properties are in good agreement with the experiment. We rationalize this result using a simple valence bond model, which explains the chemical inequality of the two C sites. The model calculations, together with our calculations on the complex, allow also the rationalization of 13C NMR properties on other HIV-1 PR/inhibitor complexes. Both putative binding of the substrate to the free enzyme, which has the dyad singly protonated (Piana, S.; Carloni, P. Proteins: Struct., Funct., Genet. 2000, 39, 26-36), and pepstatin A binding to the diprotonated form are consistent with the inverse solvent isotope effect on the onset of inhibition of pepsin by pepstatin and the kinetic iso-mechanism proposed for aspartic proteases (Cho, T.-K.; Rebholz, K.; Northrop, D.B. Biochemistry 1994, 33, 9637-9642).