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High-performance liquid chromatography (HPLC) is the most common analytical method practiced in various fields and used for analysis of almost all drug compounds in the pharmaceutical industries. During drug development, an evaluation of potential drug interaction with cytochrome P450 (CYP) is essential. A “cocktail” approach is often used in drug development to evaluate the effect of a drug candidate on multiple CYP enzymes in a single experiment. So far, simultaneous analysis of multiple CYP substrates, which have greatly different structure and physicochemical properties, has required organic solvents and mobile phase gradient methods. However, despite the recent emphasis on environmental protection, analytical methods that use only aqueous solvents without the use of organic solvents for separation have not been studied well. This study sought to develop the simultaneous analysis of multiple CYP substrates by using poly( N -isopropylacrylamide) (PNIPAAm)-based temperature-responsive chromatography with only aqueous solvents and isocratic methods. Good separation of multiple CYP substrates was achieved without using organic solvents and any gradient methods by temperature-responsive chromatography utilizing a P(NIPAAm- co - n -butyl methacrylate (BMA))- and P(NIPAAm- co - N -acryloyl L-tryptophan methyl ester (L-Trp-OMe))-grafted silica column. Overall, PNIPAAm-based temperature-responsive chromatography represents a remarkably simple, versatile, and environmentally friendly bioanalytical method for CYP substrates and their metabolites.

The precipitation of intermetallic phases and the associated hardening by artificial aging treatments at elevated temperatures above 400 °C were systematically investigated in the commercially available AC2B alloy with a nominal composition of Al–6Si–3Cu (mass%). The natural age hardening of the artificially aged samples at various temperatures was also examined. A slight increase in hardness (approximately 5 HV) of the AC2B alloy was observed at an elevated temperature of 480 °C. The hardness change is attributed to the precipitation of metastable phases associated with the α-Al15(Fe, Mn)3Si2 phase containing a large amount of impurity elements (Fe and Mn). At a lower temperature of 400 °C, a slight artificial-age hardening appeared. Subsequently, the hardness decreased moderately. This phenomenon was attributed to the precipitation of stable θ-Al2Cu and Q-Al4Cu2Mg8Si6 phases and their coarsening after a long duration. The precipitation sequence was rationalized by thermodynamic calculations for the Al–Si–Cu–Fe–Mn–Mg system. The natural age-hardening behavior significantly varied depending on the prior artificial aging temperatures ranging from 400 °C to 500 °C. The natural age-hardening was found to strongly depend on the solute contents of Cu and Si in the Al matrix. This study provides fundamental insights into controlling the strength level of commercial Al–Si–Cu cast alloys with impurity elements using the cooling process after solution treatment at elevated temperatures above 400 °C.

The cellulose oligomers with different degrees of polymerization (DP), 7, 11, 18, 24, 26, 40 and 52, were prepared by hydrolysis of microcrystalline cellulose with phosphoric acid. These oligomers including the starting microcrystalline cellulose (DP 124) were converted to tris(3,5-dimethylphenylcarbamate) (CDMPC) derivatives by the reaction with an excess of 3,5-dimethylphenyl isocyanate to be used as the chiral stationary phase (CSP) in high-performance liquid chromatography (HPLC). The structures of the CDMPC derivatives were investigated by infrared spectroscopy (IR), 1H-NMR, circular dichroism (CD) and size exclusion chromatography (SEC), and the DPs of the derivatives estimated by SEC agreed with those estimated by 1H-NMR. After coating the derivatives on silica gel, their chiral recognition abilities were evaluated using eight racemates under a normal phase condition with a hexane-2-propanol (99/1) mixture as an eluent. The chiral recognition abilities of 7- and 11-mers, particularly the former, were lower than those of the higher oligomers from DP 18 to 52, which had rather similar abilities to that of 124-mer, although the abilities depended on the racemates. DP 18 seems to be sufficient for CDMPC to exhibit chiral recognition similar to that of the CDMPC with larger DPs.

Introduction As the ligamentum flavum (LF) covers most of the posterolateral part of the lumbar spinal canal, its thickening can be attributed to the development of lumbar canal encroachment. Nevertheless, there have been few reports describing the natural history of the LF. Method To investigate the natural history and to subsequently clarify the pathogenesis of LF thickening, we conducted a transverse radiological study of the LF at the lumbar spine using magnetic resonance images. Patients: One hundred and sixty-two patients complaining of low back pain and/or leg pain were evaluated ( n  = 162; mean age 52.1 years). The thickness of LF was measured at L2–3, L3–4, L4–5 and L5–S levels ( n  = 648). The relationships among thickness, age, and spinal level were examined. Patients One hundred and sixty-two patients complaining of low back pain and/or leg pain were evaluated ( n  = 162; mean age 52.1 years). The thickness of LF was measured at L2–3, L3–4, L4–5 and L5–S levels ( n  = 648). The relationships among thickness, age, and spinal level were examined. Results The following results were obtained. (1) LF thickness increased with age; however, the increments at L4–5 and L3–4 were larger than one at L2–3 and L5–S1. (2) At L4–5, LF was over 3.0 mm thick in patients in the 20–29 age bracket, and in many of them it was more than 3.5 mm thick. (3) All patients with a thickened LF at L2–3 (>3.0 mm) had very thick LFs at all spinal levels. (4) In elderly patients, there was no correlation between the thickness of LF and the decrease of the disc height. In this study, we concluded that thickening of LF at L4–5 had already started in patients in the 30–39 age bracket and that thickening of the LF was not the buckling of the LF into the spinal canal with disc degeneration. The thickness of LF at L2–3 may serve as an indicator of lumbar spinal canal stenosis at multiple levels.

In this study, we examined the role of c-kit receptor (KIT) signal transduction on the proliferation and invasion of colorectal cancer cells. We found that c-kit was expressed in 2 colorectal cancer cell lines as determined by RT-PCR, Western blot, and flow cytometry. In KIT-positive lines, KIT was activated by stem cell factor (SCF). SCF enhanced cellular proliferation of positive lines as demonstrated by the WST-1 proliferation assay. Furthermore, SCF enhanced the invasive ability of KIT-positive cell lines. SCF stimulation upregulated p44/42 mitogen-activated protein kinase (MAPK) and Akt as shown by Western blot. We examined the roles played by p44/42 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways in proliferation and invasion. PI3K/Akt activity strongly correlated with proliferation and invasion and p44/42 MAPK was correlated with only invasion. In conclusion, the SCF-enhanced proliferation and invasion of KIT-positive colorectal cancer cells is achieved mainly through the PI3K/Akt pathway.

Pancreatic cancer frequently invades and migrates along neural tissue. Although the exact mechanisms are unknown, perineural invasion negatively impacts prognosis for pancreatic cancer patients. Matrix metalloproteinases (MMPs) are overexpressed in pancreatic cancer and are associated with poor prognosis. We hypothesized that nerve growth factor (NGF) released from neural tissue increases the invasive properties of pancreatic cancer cells. In the present study we investigated the effect of NGF on the expression and activity of MMP-2 in human pancreatic cancer cells. NGF dose dependently increased MMP-2 protein in the culture medium and stimulated MMP-2 gelatinolytic activity. This effect was mediated by specific binding of NGF to its receptor trk A, which was detected on all pancreatic cancer cells, with subsequent activation of the p44/42 MAPK signaling pathway. The NGF-induced increase in MMP-2 expression and activity lead to an enhanced invasion in vitro. These findings support the hypothesis that neurotrophic factors, e.g., NGF, are critically involved in mediating perineural invasion of pancreatic cancer.

We describe a case of a solid variant of serous cystadenoma of the pancreas. The preoperative examination results led to a diagnosis of a nonfunctional pancreatic islet cell tumour, and the patient underwent a pylorus-preserving pancreaticoduodenectomy. The tumour was diagnosed as a solid variant of serous cystadenoma by histopathological examination. Solid variant of serous cystadenoma of the pancreas is difficult to diagnose preoperatively. More cases must be accumulated and investigated to obtain clues for accurate diagnosis.

Background/Aims: The plasma concentration of catecholamines and their metabolites generated by catechol-O-methyl transferase (COMT) were measured and their correlation with the progress of renal dysfunction was investigated in two distinctive animal models: a 5/6 nephrectomized Sprague-Dawley rat model and a 1/2 nephrectomized diabetic fatty Zucker rat model. Methods: A highly sensitive, high-performance liquid chromatography-peroxyoxalate chemiluminescence reaction detection was employed to obtain values for the ratio [NMN]/([NE] + [NMN]), where [NE] represents the plasma concentration of norepinephrine and [NMN] represents the plasma concentration of normetanephrine. Results: The [NMN]/([NE] + [NMN]) ratio correlated with both the increase in blood urea nitrogen concentration and the decrease in creatinine clearance. Conclusion: The [NMN]/([NE] + [NMN]) ratio represents a quantitative indicator of the progress of renal dysfunction in the animal models. Regulation of COMT activity seemed to relate with the progress of renal dysfunction. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Receptors mediating prostanoid‐induced contractions of longitudinal sections of gastric fundus and ileum were characterized by using tissues obtained from mice deficient in each type and subtype of prostanoid receptors. The fundus and ileum from mice deficient in either EP3 (EP3−/− mice), EP1 (EP1−/− mice) and FP (FP−/− mice) all showed decreased contraction to PGE2 compared to the tissues from wild‐type mice, whereas contraction of the fundus slightly increased in EP4−/− mice. 17‐phenyl‐PGE2 also showed decreased contraction of the fundus from EP3−/−, EP1−/− and FP−/− mice. Sulprostone showed decreased contraction of the fundus from EP3−/− and FP−/− mice, and decreased contraction of the ileum to this compound was seen in tissues from EP3−/−, EP1−/− and FP−/− mice. In DP−/− mice, sulprostone showed increased contraction. DI‐004 and AE‐248 caused the small but concentration‐dependent contraction of both tissues, and these contractions were abolished in tissues obtained from EP1−/− and EP3−/− mice, respectively, but not affected in other mice. Contractions of both fundus and ileum to PGF2α was absent at lower concentrations (10−9 to 10−7 M), and suppressed at higher concentrations (10−6 to 10−5 M) of the agonist in the FP−/− mice. Suppression of the contractions at the higher PGF2α concentrations was also seen in the fundus from EP3−/−, EP1−/− and TP−/− mice and in the ileum from EP3−/− and TP−/− mice. Contraction of the fundus to PGD2 was significantly enhanced in DP−/− mice, and contractions of the fundus and ileum to this PG decreased in FP−/− and EP3−/− mice. Contractions of both tissues to I‐BOP was absent at 10−9 to 10−7 M and much suppressed at higher concentrations in TP−/− mice. Slight suppression to this agonist was also observed in the tissues from EP3−/− mice. PGI2 induced small relaxation of both tissues from wild‐type mice. These relaxation reactions were much potentiated in EP3−/− mice. On the other hand, significant contraction to PGI2 was observed in both tissues obtained from IP−/− mice. These results show that contractions of the fundus and ileum induced by each prostanoid agonist are mediated by actions of this agonist on multiple types of prostanoid receptors and in some cases modified by its action on relaxant receptors. British Journal of Pharmacology (2000) 131, 745–755; doi:10.1038/sj.bjp.0703627