Multicenter study on atypical femoral fractures in patients with bone metastases taking bone- modifying agents.

Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation.

Photodetachment spectroscopy of fluorenone radical anions microsolvated with methanol: rationalizing the anomalous solvatochromic behavior due to hydrogen bonding.

The attribution of the extraordinary blue shift for the intramolecular charge-transfer absorption band of fluorenone radical anion solvated in protic media was investigated by means of photodetachment spectroscopy of the gas-phase anions microsolvated with methanol, in conjunction with quantum chemical calculations based on density functional theory. Sequential shifts of the vertical detachment energy as a function of the cluster size are consistent with theoretical predictions, where up to two methanol molecules can directly attach to the carbonyl group. In the photodetachment excitation spectra as alternatives to the photoabsorption spectra, with increasing cluster size, a new absorption band grows in the higher-energy region, which coincides with the blue-shifted band in protic media. Spectral simulations using time-dependent density functional theory with the CAM-B3LYP functional reproduced the feature of the phenomenon. Analyses on the electronic configuration elucidated that the extraordinarily blue shifts originate from energy-level repulsion due to solvation-induced resonant coupling with another electronic state. The orbital transition for the counterpart state corresponds to the first absorption band of the neutral fluorenone molecule, which has small oscillator strength from the ground state. It was found that correction of long-range electron exchange correlation is important for the spectral simulation involving the electronic-state coupling.

Size-dependent metamorphosis of electron binding motif in cluster anions of primary amide molecules.

Electron binding motifs in cluster anions of primary amides, (acetamide)(n)(-) and (propionamide)(n)(-), were studied with photoelectron spectroscopy. For both the amides, two band series due to distinct isomeric species in the multipole-bound states were found in the low electron binding energy region (<~0.4 eV) of the photoelectron spectra at the excitation wavelength of 1064 nm. In the case of acetamide, the isomer of higher band peak energies is predominant for 6≤ n ≤ 8, but it vanishes completely for n ≥ 9 to be replaced with the lower energy isomer. The same spectral behavior was seen for propionamide exhibiting an exception at n = 7. The isomers appearing in the lower and higher energy sides were attributed to the straight and folded forms of ladder-like hydrogen bond network structures, respectively, on the basis of density functional calculations. In the folded forms, the excess electron is held in the space between two terminal amide molecules of the ladder-like networks. Referring to calculations of potential energy curves with respect to the folding coordinate of the ladder-like networks, it is inferred that the major isomer alternation between n = 8 and 9 originates from an increase of stiffness of the molecular ladders depending on the cluster sizes. In photoelectron spectra at the 355 nm excitation, the valence anion state having a band peak around 2.5 eV was observed to emerge with threshold sizes of n = 13 and 9 for acetamide and propionamide, respectively. Static and dynamical effects of alkyl groups on the electron binding motifs are discussed in comparison with the previous study on formamide cluster anions.

Interpreting the physical background of empirical solvent polarity via photodetachment spectroscopy of microsolvated aromatic ketyl anions.

The physical background of empirical solvent polarity is explored in regard to trends in solute-solvent intermolecular potential energy functions. Aromatic ketyl anions, benzophenone, and 9-fluorenone radical anions, are chosen for a model solute molecule showing solvatochromic behavior similar to betaine-30 dye, which provides the most established solvent polarity scale, E(T)(30). Common features among the ketyl anions and betaine-30 were examined with quantum chemical calculations for the electronic states and solvation structure. Vertical photodetachment and photoabsorption energies were determined for the ketyl anions microsolvated with a single solvent molecule by measuring photoelectron spectra as well as photodetachment excitation spectra for several aprotic and protic solvents. The spectroscopic data were analyzed through quantum chemical calculations based on density functional theory, and their relationship with the characteristics of intermolecular potential energies was considered. As a result, the typical solvent polarity parameter can be interpreted to reflect essentially the gradient of a potential energy function (namely, the strength of force) between a negative charge and the solvent molecules in the attractive region. A large polarity for protic solvents is attributed to an effective interaction of a proton-like hydrogen atom with the negative charge in a short-range.

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor alpha1 (Runx2/Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.