p125, a mammalian Sec23p-interacting protein, exhibits sequence homology with bovine testis phosphatidic acid-preferring phospholipase A 1 . In this study, we identified and characterized a new homologue of p125, KIAA0725p. KIAA0725p exhibited remarkable sequence similarity with p125 throughout the entire sequence determined but lacked an N-terminal proline-rich, Sec23p-interacting region. In vitro binding analysis showed that KIAA0725p does not bind to Sec23p. KIAA0725p possessed phospholipase A 1 activity preferentially for phosphatidic acid. We examined the effects of overexpression of KIAA0725p on the morphology of organelles. Overexpression of KIAA0725p, like that of p125, caused dispersion of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus. Different from the case of p125, overexpression of KIAA0725p resulted in dispersion of tethering proteins located in the Golgi region and caused aggregation of the endoplasmic reticulum. Our results indicate that KIAA0725p is a new member of the phosphatidic acid-preferring phospholipase A 1 protein family and suggest that the cellular function of KIAA0725p is different from that of p125.
Objectives: To assess the effects of tocilizumab on pregnancy outcomes in Japanese patients with rheumatic disease.
Methods: Data from Chugai’s tocilizumab safety database (April 2005 to October 2014) were retrospectively analyzed to identify pregnancy outcomes in patients exposed to tocilizumab.
Results: Data were available for 61 pregnancies exposed to tocilizumab, and outcomes were reported for 50 of those pregnancies. In 36 births, no congenital anomalies were identified; however, six neonatal abnormalities were reported: five cases of low birth weight (<2500 g) and one case of neonatal asphyxia. Of 36 births, tocilizumab was resumed during lactation in two patients, with no subsequent adverse events reported in newborns. The spontaneous abortion rate was 18.0% (9 of 50 pregnancies), which is comparable to the rate in the general population. The five terminated pregnancies included one case of caudal regression syndrome.
Conclusions: The present retrospective study of 61 pregnancies exposed to tocilizumab at conception indicated no increased rates of spontaneous abortion or congenital abnormalities in patients with rheumatic disease. However, further study is necessary to confirm the benefit-risk profile of tocilizumab treatment during pregnancy.
We previously reported that mouse NIH 3T3 cells transformed by transfection of activated human c-Ha-ras become apparently normal upon treatment with the antibiotic azatyrosine. The revertant cells maintain their normal phenotype during prolonged culture in the absence of azatyrosine, although activated p21 is still expressed. The normal phenotype induced by azatyrosine could be due to activation of expression of some cellular gene(s) in the cells that results in suppression of ras function. To identify the genes with increased expression in the revertant cells, we adopted differential screening of recombinants from a phage cDNA library made from mRNA of the revertant cells, hybridized with 32P-labeled cDNAs made from mRNAs of the rs-transformed NIH 3T3 cells and the revertant cells. Two clones thus isolated were found to be almost identical to the ras recision gene (rrg), the clones were found to contain a sequence corresponding to that of the murine retrovirus-like intracisternal A particle. We speculate that azatyrosine activates several cellular genes in the ras-transformed cells and that some of these genes, including prg, act cooperatively to counteract ras function, resulting in reversion of the ras-transformed cells to the normal phenotype.Mouse NIH 3T3 cells that have been transformed by insertion of activated c-Ha-ras, c-Ki-ras, N-ras, c-raf, or c-erbB-2 (neu) can be converted to an apparently normal phenotype by incubation for 6 days in culture medium containing the antibiotic azatyrosine [L-P-(5-hydroxy-2-pyridyl)alanine] (ref. 1 and unpublished results). The apparently normal flat revertant cells show contact inhibition, cannot proliferate in soft agar, and scarcely form tumors in nude mice, although the activated oncogenes inserted are still expressed in the revertant cells. The reversion induced by azatyrosine is permanent, and the phenotype of the revertant cells does not change during prolonged culture in the absence of azatyrosine. Since the reversion efficiency is quite high (more than 85% of the cells showed reversion, and the other 15% were killed on treatment with azatyrosine), it is likely that an epigenetic change takes place in the revertant cells, and the gene(s) specifically expressed in the revertant cells counteracts ras, raf, or erbB-2 function, acting as a tumor-suppressor gene. To determine which genes are activated in the revertant cells, we prepared a AgtlO cDNA library from the revertant cells and screened it by differential hybridization with 32p-labeled cDNAs from the original ras-transformed NIH 3T3 cells and the revertant cells. Among 30 clones thus isolated, two were found to be nearly identical with the ras recision gene (rrg), § which was isolated as a tumor-suppressor gene by Contente et al. (2) and subsequently identified as the gene for lysyl oxidase (3). The other clones thus far identified were those of collagen type III and rhoB. They were not expressed in normal NIH 3T3 cells or in ras-transformed NIH 3T3 cells. Approximately half the 30 clones were found t...
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