Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group

Annals of Surgical Oncology - Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly...     

Glyoxal-induced formation of advanced glycation end-products in type 1 collagen decreases both its strength and flexibility in vitro

The high plasma glucose induced in glucose metabolism disorders leads to the non-enzymatic glucose-dependent modification (glycation) of type 1 collagen, which is an essential component of bone tissue. The glycation of proteins induces the formation of advanced glycation end-products, such as carboxymethyl arginine, which is preferentially generated in glycated collagen. However, the effect of advanced glycation end-product formation on the characteristics of type 1 collagen remains unclear due to the lack of suitable in vitro experimental systems analyzing type 1 collagen. Here, we show that the glycation of type 1 collagen can be analyzed in vitro using a goldfish-scale bone model. Our study using these scales provides evidence that the advanced glycation end-product formation in type 1 collagen induced by glyoxal, the carboxymethyl arginine inducer, facilitates the crosslinking of type 1 collagen, decreasing both its strength and flexibility.     

Usefulness of intravenous myocardial contrast echocardiography in rats

OBJECTIVES: Few intravenous myocardial contrast echocardiography trials have evaluated myocardial perfusion in small animals. The feasibility of using intravenous myocardial contrast echocardiography to assess the ischemic area in rats was investigated. METHODS: Fourteen open chest Wister male rats were examined. Intravenous myocardial contrast echocardiography was performed by fundamental and intermittent mode using a high frequency (5-12 MHz) transducer (SONOS 5500) with injection of NC100100 (20% dilution) into the femoral vein. The mechanical index was set to 1.6. Baseline-subtracted video intensity (256 level) was measured in the anterior, posterior, septal and lateral walls of the left ventricle. The left anterior descending artery was ligated in 16 rats. The area at risk was evaluated by myocardial contrast echocardiography and compared to the area of defect by Evans Blue staining. RESULTS: All wall segments were clearly opacified (anterior 63.8 +/- 24.7, posterior 27.0 +/- 11.0, septal 44.5 +/- 11.6, lateral 52.3 +/- 19.1), although the baseline-subtracted video intensity of the posterior wall was low. The area at risk was clearly observed, and there was a good correlation with the nonperfused area by Evans Blue staining (y = 1.13x-3.54, r = 0.98). CONCLUSIONS: Intravenous myocardial contrast echocardiography can detect the perfusion defect even in rats using a high frequency transducer and suitable setup of equipment.     

Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells

Aggregation of high-affinity IgE receptor FcepsilonRI induces sequential activation of nonreceptor-type protein-tyrosine kinases and subsequent tyrosine phosphorylation of cellular proteins, leading to degranulation in mast cells. A hematopoietic cell-specific adaptor protein, 3BP2, that was originally identified as an Abl SH3-binding protein was rapidly tyrosine phosphorylated by the aggregation of FcepsilonRI on rat basophilic leukemia RBL-2H3 cells. Tyrosine phosphorylation of 3BP2 did not depend on calcium influx from external sources. To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells. Overexpression of 3BP2-SH2 domain resulted in a suppression of antigen-induced degranulation as assessed by beta-hexosaminidase release. Even though overall tyrosine phosphorylation of cellular protein was not altered, antigen-mediated tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma) and calcium mobilization were significantly suppressed in the cells overexpressing the 3BP2-SH2 domain. Furthermore, antigen stimulation induced the association of 3BP2-SH2 domain with LAT and other signaling molecule complexes in the RBL-2H3 cells. FcepsilonRI-mediated phosphorylation of JNK and ERK was not affected by the overexpression of 3BP2-SH2 domain. These data indicate that 3BP2 functions to positively regulate the FcepsilonRI-mediated tyrosine phosphorylation of PLC-gamma and thereby the signals leading to degranulation.     

Do eicosapentaenoic acid supplements attenuate age-related increases in arterial stiffness in patients with dyslipidemia?: A preliminary study.

The present study was conducted to examine the effect of eicosapentaenoic acid supplements on pulse wave velocity (PWV) in patients with dyslipidemia as a prospective open-labeled study. Eicosapentaenoic acid supplements (1,800 mg/day) were prescribed to 40 patients, and diet therapy in consultation with a nutritionist was conducted in 44 patients as a control group. These interventions were continued for 12 months, and PWV and blood examinations were performed at the start and end of these interventions. PWV increased in the control group but not in the eicosapentaenoic acid group. After adjustment for age, gender, the initial PWV, and the changes in mean blood pressure during the study period, a general linear model univariate analysis post hoc comparison demonstrated that the change in PWV during the period of study was significantly larger in the control group (42 +/- 20 cm/s) than in the eicosapentaenoic acid group (-9 +/- 19 cm/s) (p<0.05). Thus, this preliminary study suggested that eicosapentaenoic acid supplements attenuate age-related increases in arterial stiffness in patients with dyslipidemia. A further study with a larger number of subjects is proposed to confirm this beneficial effect of eicosapentaenoic acid supplements on arterial stiffness.     

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.