Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis.

OBJECTIVES: Human six-transmembrane epithelial antigen of prostate 4 (STEAP4) is one of the STEAP family as a homologue of mouse tumour necrosis factor-α-induced adipose-related protein (TIARP). Recently, we reported that the TIARP gene expression was remarkably increased in spleen and joints of glucose-6-phosphate isomerise (GPI)-induced arthritis model, suggesting pivotal association to arthritis. The aim of the present study was to assess the expression, localisation and function of STEAP4 in peripheral blood of patients with rheumatoid arthritis (RA). METHODS: Peripheral blood was obtained from seven patients with RA, the surface expression of STEAP4 was detected by flow cytometry. The number of neutrophils was compared with the expression of STEAP4 mRNA derived from peripheral blood of patients with RA. Neutrophils were introduced by HL60 with retinoic acid, and were transfected with GFP-STEAP4 plasmid DNA, then the migration of neutrophil-like HL60 was determined by transwell assay. In addition, the fluctuation of STEAP4 mRNA was analysed before and after treatment with infliximab in 40 patients with RA. RESULTS: STEAP4 was expressed on monocytes and neutrophils in peripheral blood in RA. The number of neutrophils and expression of STEAP4 mRNA was positively correlated. Migration of neutrophil-like HL60 was down-regulated by over-expression of STEAP4. Expression of STEAP4 Mrna was significantly decreased after infliximab treatment in patients with RA, especially in good responders. CONCLUSIONS: STEAP4 is expressed on monocytes and neutrophils in peripheral blood, regulates cell migration, is down-regulated by TNF antagonist, and might be a possible predictor of response to TNF antagonist.

B cells play a crucial role as antigen-presenting cells and collaborate with inflammatory cytokines in glucose-6-phosphate isomerase-induced arthritis.

Anti-glucose-6-phosphate isomerase (GPI) antibodies from K/BxN mice directly induce arthritis; however, the transfer of these antibodies from mice with GPI-induced arthritis does not induce arthritis. CD4(+) T cells play an important role in the induction and effector phase in this model; however, the roles of B cells and immunoglobulins (Igs) have not been elucidated. We investigated the roles of B cells and Igs in GPI-induced arthritis by using adoptive transfer system into SCID mice. Transfer of splenocytes of male DBA/1 mice immunized with GPI into SCID mice induced arthritis on day 6 in the latter, in association with the production of anti-GPI antibodies. Co-localization of C3 and IgG on the articular surface was identified in arthritic SCID mice. Inoculation of IgG (or anti-GPI antibodies) and CD19(+)-depleted splenocytes from arthritic DBA/1 mice induced arthritis in SCID mice, but not CD19(+)-depleted or CD4(+)-depleted splenocytes from DBA/1 mice. In vitro analysis of cytokine production by splenocytes from DBA/1 arthritic mice demonstrated production of large amounts of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 in an antigen-specific manner (P < 0.01), and production was dominated by CD19(+)-depleted than CD4(+)-depleted splenocytes (P < 0.05). Addition of IgG from DBA/1 arthritic mice to the culture enhanced TNF-alpha but not IL-6 production, and this effect was blocked by anti-Fcgamma receptor antibody. In vivo analysis of neutralization with TNF-alpha protected arthritis completely in SCID mice. Our results highlight the important role of B cells in GPI-induced arthritis as autoantibody producers, and these autoantibodies can trigger joint inflammation in orchestration with inflammatory cytokines, especially TNF-alpha.

The effect of Lazaroid U-74389G on extended liver resection with ischemia in dogs.

BACKGROUND: In liver surgery, total clamping of the portal triad (Pringle's procedure) is commonly used, and it sometimes causes liver failure. This study was designed to evaluate the effect of Lazaroid U-74389G (LAZ-G), which inhibits iron-dependent lipid peroxidation, on ischemia-reperfusion injury during liver resection in dogs. METHODS: The experiment animals were divided into 2 groups. The control group was subjected to 60 minutes of warm ischemia by partial inflow occlusion. The LAZ-G-treated group received LAZ-G before ischemia and then underwent liver ischemia. After reperfusion, the nonischemic lobes were resected, and the remnant liver function was evaluated. RESULTS: The LAZ-G-treated group showed a significantly improved animal survival rate. Biochemical analysis and morphologic evaluation by electron microscopy suggest that LAZ-G pretreatment protects both hepatic parenchymal cells and sinusoidal endothelial cells from ischemia-reperfusion injury. Expression of IL-1 beta messenger RNA in hepatic venous blood was measured by a reverse transcriptase-polymerase chain reaction; it was shown to be inhibited in the LAZ-G-treated group after reperfusion. This suggests that LAZ-G decreases the activation of proinflammatory cytokine expression. CONCLUSIONS: Lazaroid U-74389G ameliorates ischemia-reperfusion injury caused by Pringle's procedure during extensive liver resection. This agent may therefore be clinically applicable for extended liver surgery involving vascular isolation.

Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs.

BACKGROUND: FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model. STUDY DESIGN: The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction. RESULTS: Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group. CONCLUSIONS: FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.

Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs.

BACKGROUND: Nitric oxide attenuates ischemia-reperfusion injury by maintaining organ circulation through its actions as a vasoregulator, an inhibitor of platelet aggregation, and an attenuator of leukocyte adhesion. Otherwise, the harmful effects of enhanced nitric oxide production induced by inducible nitric oxide synthase mediate ischemia-reperfusion injury. FK409 has been characterized as a spontaneous nitric oxide donor. The aim of this study was to evaluate the effects of FK409 on extended liver resection with ischemia using a canine model. STUDY DESIGN: Adult mongrel dogs were subjected to 60 minutes of warm ischemia by partial inflow occlusion. After reperfusion the nonischemic lobes were resected and the remnant liver function was evaluated. The dogs were divided into two groups: the control group (n = 7) and the FK409 group (n = 6), which was given FK409 through the portal vein. RESULTS: The hepatic tissue blood flow, serum liver enzymes levels, and serum endothelin-1 level after reperfusion were significantly better in the FK409 group than in the control group. Electron microscopy demonstrated that endothelial cells and Ito cells were well-preserved in the FK409 group. The 3-day survival rate was statistically better in the FK409 group (67%) than in the control group (14%). CONCLUSIONS: FK409 appears to have protective effects during extended liver resection with ischemia.

A case of esophageal sarcomatoid carcinoma with molecular evidence of a monoclonal origin.

A case of polypoid tumor of the esophagus consisting of a sarcomatous tumor partly covered with superficial squamous cell carcinoma is described. The sarcomatous component consisted of anaplastic spindle and pleomorphic tumor cells that mimicked malignant fibrous histiocytoma (MFH). Both the sarcomatous and carcinomatous components were positive for p53 immunohistochemically. Further molecular analysis revealed that the two components had the same somatic mutation in the p53 gene. These results suggest a monoclonal origin of this biphasic tumor.

Effect of lazaroid U-74389G on pulmonary ischemia-reperfusion injury in dogs.

Lipid peroxidation induced by oxygen free radicals is a contributing factor in ischemia-reperfusion injury. Lazaroid U-74389G (LAZ-G) is a group of new synthetic 21-aminosteroids and inhibits irondependent lipid peroxidation. We investigated the effects of LAZ-G on pulmonary ischemia-reperfusion injury in dogs. Twenty dogs were divided into three groups. In the LAZ-G group (n = 6), LAZ-G was administered 15 min before ischemia. In the St group (n = 5), methylprednisolone was injected 15 min before ischemia and 15 min before reperfusion. In the control group (n = 9), the vehicle of Lazaroid was injected 15 min before ischemia. Warm ischemia was induced for 3 h by clamping the pulmonary artery and veins. Arterial oxygen saturation (SaO2), cardiac output (CO), left pulmonary vascular resistance (L-PVR), and blood levels of interleukin-1beta mRNA were measured. The lung specimen was harvested for histologic study and polymorphonuclear neutrophils (PMNs) counting. SaO2 levels at 30 min and 2 h after reperfusion were significantly higher in the LAZ-G group than in the control group. After 30 min of reperfusion, CO was significantly better in the LAZ-G group than in the St and control groups, and the L-PVR level was significantly lower in the LAZ-G group than in the control group. Survival rates were significantly better in the LAZ-G group than in the control group. Histological damages and PMNs infiltration were more severe in the control group than in the LAZ-G group. Interleukin-1beta mRNA levels were lower in the LAZ-G group than in the control group. Lazaroid U-74389G appears to generate a protective effect against ischemia-reperfusion injury of the lung.

[A case of recurrent breast cancer responding to combination therapy with mitoxantrone (MIT), 5'-deoxy-5-fluorouridine (5'-DFUR) and medroxyprogesterone acetate (MPA)].

The patient was a 50-year-old woman who had undergone left standard radical mastectomy who had undergone left standard radical mastectomy on June 1, 1986. She showed multiple liver metastases with elevation of CEA level in July, 1991, and 5'-DFUR plus MPA combination therapy was started. The daily dosages were: 800 mg/body and 1,200 mg/body, respectively. After intra-arterial infusion of pirarubicin and Lipiodol, bilateral oophorectomy was performed and an implantable reservoir for intra-arterial infusion chemotherapy was implanted via the proper hepatic artery. Then she was treated by arterial-infusion of mitoxantrone 10mg/body intermittently every two weeks. The metastatic foci responded to this therapy and her CEA level decreased.