A noise-robust data assimilation method for crystal structure determination using powder diffraction intensity.

Crystal structure prediction for a given chemical composition has long been a challenge in condensed-matter science. We have recently shown that experimental powder x-ray diffraction (XRD) data are helpful in a crystal structure search using simulated annealing, even when they are insufficient for structure determination by themselves [Tsujimoto et al., Phys. Rev. Mater. 2, 053801 (2018)]. In the method, the XRD data are assimilated into the simulation by adding a penalty function to the physical potential energy, where a crystallinity-type penalty function, defined by the difference between experimental and simulated diffraction angles was used. To improve the success rate and noise robustness, we introduce a correlation-coefficient-type penalty function adaptable to XRD data with significant experimental noise. We apply the new penalty function to SiO2 coesite and ɛ-Zn(OH)2 to determine its effectiveness in the data assimilation method.

[Serum HER-2 determination using a centauer HER-2/neu kit (CLIA method) in metastatic breast cancer].

Employing CLIA and EIA methods simultaneously, we determined serum HER-2/neu levels a total of 92 times in 51 patients with metastatic breast cancer(MBC)and 3 patients with non-recurrent breast cancer, and compared the levels measured by both methods with the level of IHC-staining for HER-2 and the clinical course. Among 20 patients with IHC HER-2/3+ MBC (including FISH+MBC), 14(70%)showed high levels by the CLIA method (>cut-off value of 15.2 ng/mL), whereas only 4(20%)revealed high levels by the EIA method(>cut-off value of 6.5 ng/mL). None of the patients with CR or non-recurrent breast cancer exhibited high levels by either method. Some IHC HER-2(-) patients also frequently showed high levels by the CLIA method. The EIA method not only revealed low-level sensitivity, but also was subject to interference(abnormally low levels)due to trastuzumab administration. The results obtained by the CLIA method were in agreement with the clinical course. In 93 MBC patients(except CR patients)whose serum HER-2 levels were determined by the CLIA method, the initial HER-2 levels were compared with the CEA and CA15-3 levels. Of the 32 IHC HER-2/3+ patients, 25, 13, and 12 were noted to have high serum levels of HER-2, CEA, and CA15-3, respectively. These results indicate that the serum HER-2 level as assessed by the CLIA method is the most sensitive marker of HER-2-positive MBC.

E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase-IV inhibitor.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, which is a novel imidazopyridazinone-derived DPP-IV inhibitor. E3024 inhibited recombinant human and mouse DPP-IV with IC50 values of approximately 100 nM. E3024 inhibited DPP-IV in human, mouse, rat and canine plasma with IC50 values of 140 to 400 nM. In contrast, E3024 did not inhibit DPP-8 or DPP-9 activity. Kinetic analysis indicated that E3024 is a competitive DPP-IV inhibitor. In Zucker fa/fa rats, E3024 (1 mg/kg) reduced glucose excursion after glucose load, with increases in plasma insulin and active glucagon-like peptide-1 levels. In fasted rats, this compound did not cause hypoglycemia. In a rat 4-week toxicological study, no notable changes were found at doses up to 750 mg/kg. The present preclinical studies indicate that E3024 is a novel selective DPP-IV inhibitor with anti-diabetic effects and a good safety profile.

Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes.

The adenosine receptor subtype mediating glucose production by glycogenolysis and gluconeogenesis was studied in primary cultured rat hepatocytes. Adenosine and adenosine agonists caused cyclic AMP accumulation in rat hepatocytes. The order of potency was 5'-N-ethylcarboxamidoadenosine (NECA)>R(-)-N(6)-(2-phenylisopropyl)adenosine (RPIA)>adenosine>2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Furthermore, adenosine agonists stimulated glycogenolysis and gluconeogenesis. The order of potency was NECA>RPIA>CGS21680. The rank order of potency is typical for adenosine A(2B) receptors. Glycogenolysis stimulated by NECA was fully inhibited by nonselective adenosine antagonists, 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943). However, the adenosine A(2A) receptor-selective antagonist, 8-(3-chlorostyryl)caffeine (CSC), and the adenosine A(1) receptor-selective antagonist, (+)-(R)-[(E)-3-(2-phenylpyrazolo[1,5-alpha]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453), had a low inhibitory potency. A strong correlation was found between the inhibitory effect of adenosine antagonists on NECA-induced glucose production and that on intracellular cyclic AMP generation in rat hepatocytes. Our results suggest that adenosine stimulates cyclic AMP formation and regulates glycogenolysis and gluconeogenesis, most likely through the adenosine A(2B) receptor subtype in rat hepatocytes.