A scanning tunneling microscope has been built, which can resolve atomic arrangements of conductors and semiconductors in ultra high vacuum below Torr. Its background and operational principles are reviewed and the guide lines in building the scanning tunneling microscope are shown. The results of measurements for highly oriented pyrolytic graphite and Si(111) surface are presented.
Abstract CKD-516 is a potent anticancer agent that inhibits microtubule assembly and disrupts tumor vasculature (VDA). CKD-516 is an amino acid prodrug of S516 releasing S516 in vivo. Previously we reported the discovery and its antitumor efficacy of CKD-516 as well as various in vitro studies (Abstract 5561, 2009 AACR). As a continuation of the investigation, a detailed ADME evaluation of CKD-516 in both rats and dogs and its potential as an oral agent is described in this report. Following intravenous administration to rats and dogs, CKD-516 rapidly became the active metabolite S516 in plasma and the half-lives of S516 were 1.5 hrs in rats, and 8 hrs in dogs. Protein binding was high with an unbound fraction less than or equal to 20% in all species tested. In distribution studies in rats dosed intravenously, S516 was mainly distributed in thymus, lung and stomach and had a short half-life less than 2 hrs in all tissues tested. In rats, the excretion of CKD-516 in urine, bile and feces amounted to 0.22%, 8.22% and 4.92%, respectively. S516 was found to have comparable metabolic stabilities both in dog and human liver microsomes where there was no difference between male and female microsomes. However, the rate of metabolism in rats from male and female liver microsomes were markedly different. In general, S516 is expected to have low drug-drug interaction with IC50 values of >10 μM against most CYP450 enzymes but had a moderate inhibition against CYP450 1A2 and 2C8. The intestinal absorption of CKD-516 was predicted to be moderate to high as the apparent permeabilities (×106 cm/sec) of CKD-516 and its active metabolite S516 in Caco-2 permeability assay were 15.1 and 35.4, respectively. Thus, CKD-516 was found to have an acceptable oral bioavailability in rats, supporting its potential efficacy as an oral agent. In vivo antitumor experiments were performed in the HCT116 human tumor xenograft model. When the established tumor reached the size of 150 mm3, CKD-516 was administered to mice orally. Groups of animals were received CKD-516 with doses of 10 mg/kg or 20 mg/kg (Q4d × 5). The treated group showed a tumor growth suppression (IR = 50∼60%). Drug related toxicity and body weight decrease were not detected at doses tested. In summary, a complete ADME characterization of CKD-516, a novel tubulin polymerization inhibitor and VDA, both in vitro and in vivo was described. Moreover, CKD-516 was found to have a good potential as an oral agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4425.
Abstract Histone deacetylases (HDAC) inhibition is now well established as a new approach for solid and hematological tumor therapy. Studies with different HDAC inhibitors showed broad activity toward cancer cells, i.e. activation of proapoptotic pathway and inhibition of antiapoptotic pathway, induction of cell differentiation, antiangiogenic activity and synergism with other cancer therapeutics. Several HDAC inhibitors have demonstrated therapeutic benefits and are under clinical investigations as mono- or combi-therapy in various cancer cell lines such as cutaneous T-cell lymphoma (CTCL) with SAHA launched in 2006. Highly water-soluble CKD-581 is a potent and novel pan HDAC inhibitor developed in our institute. In this study, we analyzed first the in vitro growth inhibitory effect of CKD-581 on various cancer cells by MTT assay and inhibition of HDAC enzymes as well as its antitumor efficacy in human colon, prostate, and lung xenograft models. In addition, western blotting analysis for acH3, acH4 and p21 (WAF-1/CIP-1) and fluorescence-activated cell sorting analysis were performed to verify the associated molecular mechanisms involved in CKD-581 mediated cell death and cell cycle progression. CKD-581 showed strong cytotoxicity against several cancer cell lines including HCT-116, PC-3, A549 and H460 with IC50 values ranging from 10 nM to 100 nM. Its cytotoxicity was closely related with potent inhibitory activity against human HDAC1 and HDAC6 enzymes at single nMs. In various cancer cell lines, CKD-581 induced acetylation of histone and expression of tumor suppressor proteins involved in apoptosis pathway. CKD-581 significantly inhibited the in vivo growth of human tumor xenografts (HCT-116, PC-3, A549 and H460) in nude mice in a dose-dependent manner. Treatment of CKD-581 (60, 80, 100 mg/kg, b.i.wk, i.p.) caused 50-70% reduction in the mean tumor volume compared with controls. It is of note to observe that CKD-581 was highly efficacious when orally administered to nude mice bearing HCT 116. To correlate the pharmacodynamics with pharmacokinetics of CKD-581 in nude mice (HCT-116), we analyzed the kinetics of histone acetylation in tumors and plasma drug exposure at the end of 3 weeks of treatment (80 mg/kg, b.i.wk, i.p.), where Tmax of CKD-581 in tumor and in plasma were 4 h and 0.25 h after dosing, respectively and AUClast in tumor was 2.6 times higher than that of in plasma. CKD-581 is a potent HDAC inhibitor and showed a strong cytotoxicity against many cancer cell lines, demonstrated through the various in vitro and in vivo studies. Moreover, significant antitumor efficacy was shown in nude mice bearing several human tumors. Its potency together with excellent pharmacokinetic properties warrants further clinical investigations of CKD-581. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5435.
Several of the latest GAN-based vocoders show remarkable achievements, outperforming autoregressive and flow-based competitors in both qualitative and quantitative measures while synthesizing orders of magnitude faster. In this work, we hypothesize that the common factor underlying their success is the multi-resolution discriminating framework, not the minute details in architecture, loss function, or training strategy. We experimentally test the hypothesis by evaluating six different generators paired with one shared multi-resolution discriminating framework. For all evaluative measures with respect to text-to-speech syntheses and for all perceptual metrics, their performances are not distinguishable from one another, which supports our hypothesis.
The atomic structure of monatomic steps on Si(001) is investigated with scanning tunneling microscopy. On the upper terrace of the ${S}_{B}$ step the existence of kinks induces a local $p(2\ifmmode\times\else\texttimes\fi{}2)$ structure with the direction to the center of the step. The structure of the ${S}_{B}$ step is correlated to that of the ${S}_{A}$ step through the kinks and is determined by the boundary conditions imposed by the ${S}_{A}$ step. The atomic structure of the steps is also correlated with the zigzag buckling along the dimer row of the lower terrace through the subsurface interaction. The formation of various structures observed near the steps is explained by the simple geometric rule based on the bonding characteristics.
We propose a novel architecture and improved training objectives for non-parallel voice conversion. Our proposed CycleGAN-based model performs a shape-preserving transformation directly on a high frequency-resolution magnitude spectrogram, converting its style (i.e. speaker identity) while preserving the speech content. Throughout the entire conversion process, the model does not resort to compressed intermediate representations of any sort (e.g. mel spectrogram, low resolution spectrogram, decomposed network feature). We propose an efficient axial residual block architecture to support this expensive procedure and various modifications to the CycleGAN losses to stabilize the training process. We demonstrate via experiments that our proposed model outperforms Scyclone and shows a comparable or better performance to that of CycleGAN-VC2 even without employing a neural vocoder.
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