5110 Background: PI3K (phosphatidylinositol-3-kinase) /mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT activating genetic alterations, including mutations in PTEN, PIK3CA, and K-Ras. We evaluated the activity of a dual PI3K/mTOR.inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial cancer cell lines. Methods: We examined anti-tumor effect of RAD001 and NVP-BEZ235 in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA and K-Ras. We also combined these compounds with a MAPK pathway inhibitor in cell lines with K-Rasalterations (mutations or amplification). Results: PTEN mutant cell lines without K-Rasalterations (n=9) were more sensitive to both RAD001 and NVP-BEZ235 than the other cell lines with K-Rasalterations (n=4). NVP-BEZ235 showed lower IC50 values than RAD001 in eight of the nine sensitive cell lines, and G1 arrest was more effectively induced by NVP-BEZ235 than RAD001. We observed in vivo anti-tumor activity of both RAD001 and NVP-BEZ235 at a tolerated dose in nude mice. Combination of NVP-BEZ235 with a MEK inhibitor PD98059 and UO126 synergistically suppressed the proliferation in cells with K-Rasalterations. Conclusions: Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor, such as NVP-BEZ235, is a promising therapeutics in endometrial carcinomas. Our data suggest that presence of PTEN mutations without K-Ras alterations may be a good predictive biomarker to NVP-BEZ235 in certain endometrial carcinomas. Combination of a PI3K/mTOR inhibitor with a MEK inhibitor PD98059 and UO126 might be effective to the tumors with K-Ras alterations.
Polarized one-electron potential (POP) optimization is a powerful and practical method to determine multicenter dipole polarizabilities that can be used for constructing polarizable force fields. The POP optimization is similar to the widely used electrostatic potential (ESP) optimization to determine the partial charges of molecules. However, while the ESP optimization targets the electrostatic potentials on a molecular surface, the POP optimization targets the change of electrostatic potentials on molecular surfaces which are induced by the field of a test charge on the molecular surface. Since only additional one-electron integrals for the test charge are required for the estimation of the surface potentials, the change of electrostatic potentials has been named "polarized one-electron potentials". We show that in the POP optimization, both an explicitly interacting polarizability model and an implicitly interacting polarizability model can be used for the determination of the multicenter polarizabilities. In the explicitly interacting model, intramolecular induced dipole-induced dipole interaction is mutually included in the process of the POP optimization, but the interaction is not included in the implicitly interacting model. In the implicitly interacting polarizability model, a combined model of isotropic atom polarization and anisotropic bond polarization is shown to provide the best fitting results for nucleic acid bases which show large polarization anisotropy. A simple scaling model to the chemical bond has been newly proposed for the explicitly interacting polarizability model. We show that the simple model can be applied to molecular simulations without any damping of exponential type in the intramolecular induced dipole interaction. A detailed procedure for determination of the multicenter dipole polarizability by the POP optimization is also presented.
This paper is concerned with our recent challenge to engineering-arts collaboration, on use of the trident snake robot as a design motif for educational project. Outline of the project is described as well as its resulting works exhibited at the Good Design Expo 2011.
Ten patients with renal failure not on dialysis were subjected to our study to evaluate the effect of 1 alpha (OH)D3 on calcium metabolism and its influence on renal function. The results suggest the possibility that 1 alpha (OH)D3 might be effective in bone disease due to secondary hyperparathyroidism. On the other hand, 1 alpha (OH)D3 depressed creatinine clearance without any increase of Ca, Ca x P product or PRA. 1 alpha (OH)D3 is to be prescribed to patients not on dialysis only with careful attention to the dosage and the duration, and frequent observation of renal function is necessary.
A small hemispherical bulging from the anterior wall of the internal carotid artery (ICA), which we call a blood blister-like aneurysm (BBA), is a treacherous lesion. Treatment of this lesion requires special tactics. We report the course of patients with this lesion treated by endovascular occlusion of the cervical ICA with or without bypass surgery.We describe 3 patients with BBAs who presented with subarachnoid hemorrhage (SAH). In these patients, the initial angiogram soon after SAH showed only a small bulging from the anterior wall of the ICA. This bulge progressed to a saccular appearance within a few weeks. Two patients were treated conservatively, and underwent endovascular occlusion of the cervical ICA in the chronic stage, 1 with and the other without STA-MCA anastomosis. One patient underwent direct surgery on the aneurysm in the acute stage; clipping after wrapping with a strip of gauze was performed. Repeated angiogram showed growth of the aneurysm. Endovascular occlusion of the cervical ICA was subsequently performed. All 3 patients did well and returned to their previous life style.Our experience with these lesions, as well as a review of the literature, suggests that direct clipping often causes laceration of the lesion, and wrapping or clipping after wrapping may fail to prevent growth of the aneurysm. Endovascular occlusion of the cervical ICA with or without bypass surgery, which is less risky than direct surgery, is still useful for this kind of lesion.
The authors report a case of sinus pericranii in a 22-year-old female presenting with severe headache, vomiting, bradycardia, and bradypnea following excessive distention of the tumor. After tumor removal, the symptoms were completely relieved. The symptoms were thought to be due to transient impairment of blood flow in the superior sagittal sinus.
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