Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents.

This study reports that a selective COX-2 inhibitor JTE-522inhibits both in vitro and in vivo growth of human lung cancer cells as a single agent. Furthermore, the adjunct use of JTE-522 is shown to significantly enhance treatment efficacy of conventional anticancer drugs not only in vitro but also in vivo without causing any noticeable side effects. Indeed, IC(50)s of various anticancer agents in vitro were reduced by up to 70%, whereas the combination therapy of JTE-522 with docetaxel and vinorelbine inhibited tumor growth in vivo by 65 and 55%, respectively. Taken together, these findings suggest that the use of a selective COX-2 inhibitor in the treatment of lung cancer may be promising, especially because of its enhancement of the treatment efficacy of conventional anticancer agents without compromising quality of life.     

Release of interleukin-6 by alveolar macrophages in patients with sarcoidosis]

The supernatants from cultures of alveolar macrophages from 12 patients with sarcoidosis and 7 control subjects were assayed for interleukin-6 (IL-6) using an ELISA system. IL-6 was detectable without a stimulant in supernatants from all subjects with sarcoidosis and controls. However, the supernatants from 4 of 12 untreated patients with sarcoidosis contained significantly greater amounts of IL-6. When macrophages were stimulated by Propionibacterium acnes (P. acnes), the mean level of IL-6 in the supernatant of patients with sarcoidosis was 5.18 +/- 1.46 ng/ml, which was significantly higher than in controls (3.34 +/- 0.39) (p less than 0.05). Furthermore, in patients with sarcoidosis, the mean level of IL-6 in the supernatant was significantly correlated with the percentage of lymphocytes in bronchoalveolar lavage fluid (p less than 0.05), the level of interleukin-1 released by alveolar macrophages stimulated by P. acnes (p less than 0.05), and the phagocytic index of alveolar macrophages (p less than 0.05). The large amount of IL-6 in the supernatant after stimulation by LPS was measured in patients with sarcoidosis (24.49 +/- 13.36) and in controls (12.4 +/- 8.53), and there was no significant difference between patients with sarcoidosis and controls. Small amounts of IL-6 were detectable in bronchoalveolar fluid from only 2 of 26 patients with sarcoidosis; however, it was detected in none of 15 controls. It is suggested that the enhancement of IL-6 release by alveolar macrophages has a role in the activation of immune effector cells at sites of sarcoidosis.     

Thyroid carcinoma and acute lymphoblastic leukemia in childhood

A 12-year-old boy with T-cell ALL was found to have occult papillary thyroid carcinoma at autopsy. This patient was treated with chemotherapy but no radiotherapy was utilized. Family history was not contributory. Because of short latent period (14 months) and no history of radiotherapy, an intrinsic factor might have played a major role in developing this second malignancy. Currently 11 solid tumors have been reported as second malignant neoplasms after ALL in childhood. Four (including this case) of 11 were thyroid carcinoma. Two of them did not receive any radiotherapy. Special interrelation between ALL and thyroid carcinoma may be considered. And this interrelation should be taken into account in following the patients with ALL in the future.     

Suppression of puerperal lactation by metergoline

Suppression of puerperal lactation by a potent serotonin antagonist, metergoline was studied in 33 puerperal women, i.e., abortion after sixteen weeks of gestation 6, premature labor 13, labor at term 13, and hydatiform mole 1. The drug was administered orally at a dose of 4 mg bid for 5 days to 26 subjects, starting within one week from delivery (group A). The remaining 7 subjects received 4 mg of metergoline bid for 7 days after more than 2 weeks from delivery (group B). Lactation was either rapidly suppressed or prevented in 22 out of the 26 subjects in group A and in all subjects in group B. After the therapy was stopped, rebound phenomena were observed in 4 subjects in group A and in 2 subjects in group B, but a further 5-7 days' treatment with metergoline produced satisfactory results. The mean plasma prolactin levels, studied in 10 subjects in group A at hourly intervals after the first metergoline dose, decreased significantly one hour later (p less than 0.05) and reached the nadir level, 19.9 +/- 2.6% of the mean basal value, 4 hours later. The daily plasma prolactin levels in 9 subjects were significantly lower than those of the control group during metergoline treatment (p less than 0.001). No side effects of metergoline medication were observed. Metergoline for a short course of administration is very effective in the suppression of puerperal lactation. In case of the suppression of lactation after the second week of puerperium, 10-14 days of metergoline treatment is recommended to avoid the rebound phenomena.     

Gene testing of hereditary cancer on comprehensive gene medical examination support system

It has been estimated that genetic factors or a combination of genetic and environmental factors play a role in the development of 10-15% of all cancers. A genetic cause of hereditary cancer has been identified in more than 40 diseases till now. For preventing this cancer, gene testing is essential because it has no definite clinical marker as in hereditary non-polyposis colorectal cancer: HNPCC. Much more experience must be accumulated in this testing at the clinical base in order to increase specificity and sensitivity while safeguarding ethical, legal and social issues (ELSI). Recently, the Personal Information Protection Law was enforced. Gene inspection involving hereditary cancer should be carried out under a comprehensive gene medical examination organization. It is important for the family doctor, medical specialist, and gene inspection person in charge to cooperate closely with one another, and this will be a subject of future study.     

UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination

p73 protein level is kept extremely low in mammalian cultured cells and its stability may be regulated by not only the ubiquitin/proteasome-dependent proteolysis but also through other unidentified mechanisms. Here, we found for the first time that p73 is physically as well as functionally associated with the U-box-type E3/E4 ubiquitin ligase UFD2a. The immunoprecipitation experiments demonstrated that this interaction is mediated by the COOH-terminal region of p73alpha containing SAM domain. During the cisplatin-induced apoptosis in SH-SY5Y neuroblastoma cells, p73alpha accumulated at a protein level, whereas the endogenous UFD2a was significantly reduced in response to cisplatin. Ectopic expression of UFD2a decreased the half-life of p73alpha in association with a significant inhibition of the p73alpha-mediated transactivation as well as proapoptotic activity. Downregulation of endogenous UFD2a by antisense strategy resulted in a remarkable accumulation of p73alpha. Unexpectedly, UFD2a-mediated degradation of p73alpha was sensitive to the proteasomal inhibitor, however, UFD2a did not affect the ubiquitination levels of p73alpha. Taken together, our present findings imply that UFD2a might promote the proteasomal turnover of p73 in a ubiquitination-independent manner, and also suggest that UFD2a might play an important role in the regulation of cisplatin-induced apoptosis mediated by p73.     

Loss of p21WAF1/CIP1 expression in invasive fronts of oral tongue squamous cell carcinomas is correlated with tumor progression and poor prognosis

The clinicopathological significance of cell-cycle proteins has remained unclear in oral tongue squamous cell carcinomas (OTSCC). In the current study, we evaluated several cell-cycle proteins in relation to clinicopathological parameters and disease outcome for OTSCC. A total of 123 previously untreated patients with OTSCC, who underwent surgical treatment, were enrolled. Tumor specimens were examined for expression of p21, p27, p16, p53, and p63 using immunohistochemistry, with reference to clinicopathological factors and disease outcome. It is noteworthy that differences in p21 immunoreactivity were evident between the shallow region and invasive front of tumors within the same specimens. Loss of p21 expression in invasive fronts was found to be associated with clinicopathological factors of tumor progression and poor prognosis. p21 expression in invasive fronts is a significant indicator for impact on survival. Moreover, p21 is one of the important factors that regulate the progression of malignant cells in OTSCC.