Synthesis, Structure, and Dynamics of Chiral Eight-Membered Cyclic Molecules with Thienylene and Cyclopropylene Units Alternately Connected.

A rhodium(II)-catalyzed asymmetric cyclooligomerization of bifunctional monomers possessing triazolyl and vinyl groups at 2,3- and 3,4-positions on the thiophene ring is studied. Structurally interesting cyclic dimers in which thienylene and cyclopropylene units are alternately connected are obtained as the major components. The eight-membered rings in the center are non-planar and adopt a tub-shaped conformation. We also observe the phenomenon of racemization caused by a tub-to-tub ring-flipping, the activation energy of which is determined as 108 kJ mol-1 by electronic circular dichroism spectra measurement.

Chiral Macrocycles Having C3 Symmetry Resulting from Orientation of Thiophene Rings.

An chiral RhII -catalyzed cyclooligomerization reaction of thiophenes having triazolyl and vinyl substituents at the 2- and 4-positions was studied. Structurally interesting cyclic trimers, having chirality that is ascribed only to the orientation of the 2,4-disubstituted thiophene rings, are obtained. The 2,4-disubstitution of the starting thiophene monomer allows production of each of the enantiomers. The observed electronic circular-dichroism spectra are in accord with those simulated by density-functional theory calculations.

Bevacizumab safety in Japanese patients with colorectal cancer.

BACKGROUND: Bevacizumab (Avastin(®)) was approved in Japan in April 2007 for patients with advanced or metastatic colorectal cancer. To address the limited clinical experience in Japanese patients, a post-approval surveillance study was undertaken in bevacizumab-treated patients in Japan. METHODS: Bevacizumab (5 or 10 mg/kg every 2 weeks) was administered with chemotherapy; patients were observed for 26 weeks from initiation of treatment. The primary objective was to investigate the incidence of adverse drug reactions, particularly those of interest for bevacizumab. Univariate and multivariate analyses were performed to identify potential risk factors for adverse drug reactions. RESULTS: In total, 2712 patients were registered and 2696 patients were included in the safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reaction. The incidences of serious adverse drug reactions were low: gastrointestinal perforation occurred in 0.9% of patients, hemorrhage in 1.3%, arterial thromboembolic events in 0.3%, venous thromboembolic events in 1.3% and wound-healing complications in 0.4%. The incidence of bevacizumab-specific adverse drug reactions was not influenced by the bevacizumab dose. Multivariate analyses identified risk factors for the following adverse drug reactions: hypertension (prior/concurrent hypertension); tumor-associated bleeding (performance status, prior/concomitant anticoagulant or nonsteroidal anti-inflammatory drug use); proteinuria (sex, performance status, prior/concurrent diabetes and proteinuria); gastrointestinal perforation (primary tumor in situ, concurrent nonsteroidal anti-inflammatory drug use); venous thromboembolic event (treatment stage, port insertion). CONCLUSIONS: The safety profile of bevacizumab-containing regimens in this Japanese population was comparable with studies performed in Western countries. Bevacizumab is generally well tolerated in Japanese patients with advanced or metastatic colorectal cancer.

[Pulmonary Carcinosarcoma Presenting Hemothorax Caused by Pleural Invasion;Report of a Case].

A 71-year-old man presented with hemothorax with cough, sputa and worsening dyspnea. On chest X-ray and computed tomography(CT), a huge tumor in the right upper lobe with hematoma and small amount of gas suggesting hemopneumothorax was revealed. No apparent lymphadenopathy nor intrapulmonary metastases were observed. The tumor showed a little enhancement on the contrastenhanced CT. Then the resction of the tumor was performed, and the pathological evaluation revealed a carcionosarcoma (adenocarcinoma+osteosarcoma) pT3N0 (stage II B) G4 pl2. Sarcomatoid carcinoma such as carcinosarcoma should be considered as a possible cause of hemothorax in making a diagnosis of hemorrhagic hypovascular huge lung tumor.

Formation and stability of 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide, a stable form of reactive intermediate produced from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in mice.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induced lung tumors in rodents and is likely involved in human lung cancer. 4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (HO-methyl NNK) glucuronide, a glucuronide of the reactive intermediate of NNK, has been identified in rats. The aim of this study is to estimate the role of HO-methyl NNK glucuronide in the tumorigenic effects of NNK. We investigated the urinary excretion and tissue distribution of HO-methyl NNK glucuronide in A/J mice, which are susceptible to NNK carcinogenesis, and C57BL/6J mice, which are resistant to NNK carcinogenesis. The cumulative urinary excretion of the HO-methyl NNK glucuronide in the C57BL/6J mice was more than 20 times higher than in the A/J mouse urine. Tissue concentrations of HO-methyl NNK glucuronide were also higher in the C57BL/6J mice than in the A/J mice. Assessment of the stability of HO-methyl NNK glucuronide in liver homogenates at physiological pH conditions showed that more than 60% of the glucuronide remained until 2 hr of incubation. These results suggested that HO-methyl NNK glucuronide is likely to be a detoxified metabolite and could be one reason for differences in the susceptibility to NNK tumorigenesis between the two strains. Once HO-methyl NNK is formed in tissues, C57BL/6J mice have a high ability to form HO-methyl NNK glucuronide so that HO-methyl NNK, the reactive intermediate formed from NNK, is readily excreted in urine as a stable form.

Pitch discrimination of patterned electric stimulation.

One reason for the poor pitch performance in current cochlear-implant users may be the highly synchronized neural firing in electric hearing that lacks stochastic properties of neural firing in normal acoustic hearing. This study used three different electric stimulation patterns, jittered, probabilistic, and auditory-model-generated pulses, to mimic some aspects of the normal neural firing pattern in acoustic hearing. Pitch discrimination was measured at standard frequencies of 100, 250, 500, and 1000 Hz on three Nucleus-24 cochlear-implant users. To test the utility of the autocorrelation pitch perception model in electric hearing, one, two, and four electrodes were stimulated independently with the same patterned electric stimulation. Results showed no improvement in performance with any experimental pattern compared to the fixed-rate control. Pitch discrimination was actually worsened with the jittered pattern at low frequencies (125 and 250 Hz) than that of the control, suggesting that externally introduced stochastic properties do not improve pitch perception in electric stimulation. The multiple-electrode stimulation did not improve performance but did not degrade performance either. The present results suggest that both "the right time and the right place" may be needed to restore normal pitch perception in cochlear-implant users.