Search

Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality.

AbstractPeritoneal seeding is frequently detected in patients with gastric cancer. The peritoneal cavity is a compartment in which the immunologic host-tumor interaction can occur. Here, we investigated the gene expression levels of cytokines, and compared these gene expressions with the progression of gastric cancer. Total RNA was extracted from 50 ml of peritoneal washings from 78 patients with gastric cancer and 11 noncancerous patients. The gene expression levels of transforming growth factor-β (TGF-β), interleukin (IL)-2, IL-6 and IL-12 were analyzed by real-time reverse transcription-polymerase chain reaction. The gene expression levels of TGF-β and IL-12 in 16 patients with peritoneal seeding (peritoneal metastasis or free cancer cells) did not differ from those in controls (n = 11) and stage I and II (n = 43) patients. However, the relative gene expression level of IL-2 in patients with peritoneal seeding (0.9) was lower than that in controls (1.4, p = 0.066) and stage I and II patients (1.4, p = 0.036). In contrast, the relative gene expression level of IL-6 in patients with peritoneal seeding (3.3) was higher than that in control (2.4, p = 0.064) and stage I and II patients (2.6, p = 0.065). Low IL-2 gene and high IL-6 gene expressions in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer.Copyright © 2004 S. Karger AG, Basel

The cell surface Fas antigen transducts an apoptotic signal by its crosslinking with Fas ligand or anti-Fas antibody in a variety of human cultured cells. In this study, we examined the expression of Fas antigen and its mediation of apoptosis in six human colorectal carcinoma cell lines. A flow cytometric analysis revealed that LoVo, DLD-1, WiDr and SW837 cell lines showed higher expression levels of Fas antigen, in contrast to lower expression in COLO201 and COLO320DM. Interferon-γ enhanced the expression of Fas antigen in all of the cell lines examined. Both Fas ligand and Fas-associated phosphatase-1 (FAP-1) were expressed only in COLO320DM. Anti-Fas antibody induced apoptosis in LoVo carrying wild-type p53 gene, but not in the other five cell lines carrying mutated p53 gene. The transfection of wild-type p53 gene using an adenovirous vector upregulated P53 protein in WiDr and SW837 cells, both of which showed, however, no increase in apoptotic cells by anti-Fas antibody treatment. These results indicated that (1) Fas antigen was variably expressed, regardless of the p53 gene status and (2) the susceptibility to anti-Fas antibody-mediated apoptosis did not correlate to Fas, Fas ligand or FAP-1 expression levels. Therefore, we conclude that wild-type P53 expression might not necessarily be essential for Fas-mediated apoptosis in human colorectal carcinoma cell lines.

We examined the existence and distribution of apoptotic cells in human gastric mucosa, chronic gastritis, adenomatous dysplasias and carcinomas in 15 surgically removed stomachs in which dysplasia and carcinoma were found simultaneously. Serial sections were cut for immunohistochemistry for p53 oncoprotein and Ki-67 antigen, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling (TUNEL). TUNEL signal-positive apoptotic cells were rare in normal mucosa, while a few apoptotic cells were noted in gastritic mucosa and intestinal metaplasia, intermingled with Ki-67 antigen-positive cells forming a generative cell zone. This suggests the cell-cycle-dependent apoptosis of gastric mucosa. The frequency of apoptotic cells per crypt was higher in incomplete than in complete metaplasia, implying greater underlying DNA damage in the former. TUNEL indices (TI; percentage of TUNEL-positive cells in tumour cells) were slightly higher in adenomatous dysplasias (4.9±2.1) than in carcinoma (3.9±1.1), but there was no no statistical difference. Ki-67 indices (KI; percentage of Ki-67 antigen-positive cells in tumour cells) were significantly (P<0.05) higher in carcinomas than in dysplasias. Thus, gastric adenomatous dysplasias were characterized by relatively higher TI and lower KI, which might reflect a more static growth potential. The expression of p53 oncoprotein in cancer cells is thought to be an apoptosis-suppressing event, although its precise role remains to be elucidated. Overall, these results indicate that apoptosis plays a crucial part in the morphogenesis of gastritic mucosa including intestinal metaplasia, and that the process is correlated both with tumourigenesis and with proliferative activity.

We examined chemosensitivity to 5-fluorouracil (5-FU) in four human gastric cancer cell lines, by analyzing the expression of p53 and its related genes. Treatment with 1mM 5-FU induced variable degrees of apoptosis in the cultured cells. The apoptotic indices 72 h after treatment were approximately 14% in MKN-74 (wild-type p53 gene), 12% in MKN-45 (wild-type), 3% in MKN-28 (mutated) and 0.5% in KATO-III cells (deleted), respectively. On the other hand, 50 μM 5-FU had little effect on the induction of apoptosis in MKN-74 cells, the value being approximately 2% after 72 h. Induction of P53 expression was noted 3 h after initiating the treatment, followed by the induction of P21/Waf1 after 6 h in both MKN-74 and MKN-45 cells. The same expression mode was noted in MKN-74 treated with 50 μM 5-FU. Conversely, the level of P53 expression was constant in MKN-28 cells and absent in KATO-III cells, in which P21/Waf1 had never been induced. The Bax/Bcl-2 expression ratio was gradually elevated for up to 72 h in MKN-74 and MKN-45 cells treated with 1mM 5-FU; in contrast, it was unchanged in MKN-28 and KATO-III cells, and MKN-74 treated with 50 μM 5-FU. These results might indicate that (1) 1mM 5-FU induces apoptosis in cultured gastric cancer cells carrying the wild-type p53 gene, but not those carrying the mutated type or a gene deletion, and (2) the elevated Bax/Bcl-2 expression ratio plays a more crucial role than the higher expression of P21/Waf1 in the induction of p53- gene dependent apoptosis.