Upregulation of thymidine phosphorylase in rectal cancer tissues by mitomycin C

BACKGROUND AND OBJECTIVES: We have investigated the regulation by mitomycin C (MMC) of thymidine phosphorylase (dThdPase) and dihydropyrimidine dehydrogenase (DPD), which enhances or reduces the efficacy of capecitabine and its metabolite 5'-deoxy-5-fluorouridine (5'-DFUR), in rectal cancer tissues. MATERIALS AND METHODS: In 31 patients with a rectal cancer, tumor biopsies were performed before and after pre-operative venous administration of 4 mg/m2, 6 mg/m2, or 10 mg/m2 of MMC. The dThdPase and DPD levels in the biopsy and surgical specimens were measured using ELISA, and immunostaining for dThdPase was performed. RESULTS: The fitting multiple linear regression models indicated that the dThdPase levels increased after MMC administration, in particular in the patients with a pre-treatment dThdPase level less than 56.2 U/mg protein (median value). The time course analysis indicated that the increase in the dThdPase level by 4 mg/m2 of MMC administration continued for 3 weeks. The dThdPase/DPD ratio was increased after MMC administration in patients with a pre-treatment dThdPase/DPD ratio less than 1.79 (median value). MMC enhanced the expression of dThdPase protein both in the tumor cells and in the stromal cells. The disease free-survival rate in the Dukes B or C patients with a high dThdPase/DPD ratio in surgical specimen who received 5'-DFUR based adjuvant chemotherapy tended to be higher than that in those with a low dThdPase/DPD ratio. CONCLUSION: MMC may upregulate the dThdPase level and the dThdPase/DPD ratio in rectal cancer tissues. Combined use of MMC with capecitabine or 5'-DFUR may offer a more effective colorectal cancer therapy.     

Effect of Prostaglandin E1 on Ischemia–Reperfusion Injury During Abdominal Aortic Aneurysm Surgery

Objective Abdominal aortic aneurysm (AAA) surgery subjects the lower extremities to ischemia and reperfusion. Although it is not extensive or prolonged, ischemia of the lower extremities during aortic cross-clamping is gradually and steadily induced. We studied the effects of prostaglandin E₁ (PGE₁) on ischemia–reperfusion injury of the lower extremities during AAA repair. Methods During AAA surgery, two near-infrared spectroscopy probes were positioned on each calf muscle to monitor oxygen metabolism in the lower extremities. We also measured lactate concentration in both iliac veins. Results Near-infrared spectroscopy signals responded sensitively to aortic cross-clamping and declamping. Lactate increased time-dependently during aortic cross-clamping. The continuous venous administration of PGE₁ (20 ng/kg per minute) inhibited the accumulation of lactate during aortic cross-clamping. Declamping of the first iliac artery resulted in a further but transient increase in ipsilateral venous lactate, which may be one component in the mechanism of declamping shock. Prostaglandin E₁ eliminated the transient increase in ipsilateral lactate. The administration of PGE₁ inhibited the contralateral accumulation of lactate after first declamping, and the lactate level decreased gradually before the second declamping. Conclusions Prostaglandin E₁ seems to have a protective effect against ischemia–reperfusion injury of the lower extremities during AAA surgery.     

Long-Term Survival After Resection of Metachronous Bilateral Adrenal Metastases of Mucinous Gastric Carcinoma: Report of a Case

We report a case of metachronous bilateral adrenal metastases from mucinous adenocarcinoma of the stomach. A 68-year-old man who had undergone surgery for advanced gastric cancer 5 months earlier had a follow-up computed tomography (CT) scan, which showed a right adrenal tumor. We performed a right adrenalectomy, and histopathological examination revealed a mucinous adenocarcinoma with features consistent with those of gastric cancer. A routine follow-up CT scan done 41 months after the right adrenalectomy showed a left adrenal mass. Chemotherapy had no apparent effect, and left adrenalectomy was performed 65 months after the right adrenalectomy. Histopathological examination also revealed a metastasis from gastric cancer. The patient was alive without recurrence 40 months after the left adrenalectomy. This case suggests that resection of adrenal metastasis from gastric cancer is an effective treatment option that may prolong survival in selected patients.     

Differential expression of the intermediate filament protein nestin during renal development and its localization in adult podocytes

Nestin, an intermediate filament protein, is widely used as stem cell marker. Nestin has been shown to interact with other cytoskeleton proteins, suggesting a role in regulating cellular cytoskeletal structure. These studies examined renal nestin localization and developmental expression in mice. In developing kidney, anti-nestin antibody revealed strong immunoreactivity in vascular cleft of the S-shaped body and vascular tuft of capillary loop-stage glomerulus. The nestin-positive structures also were labeled by endothelial cell markers FLK1 and CD31 in immature glomeruli. Nestin was not detected in epithelial cells of immature glomeruli. In contrast, in mature glomerular, nestin immunoreactivity was observed only outside laminin-positive glomerular basement membrane, and co-localized with nephrin, consistent with podocyte nestin expression. In adult kidney, podocytes were the only cells that exhibited persistent nestin expression. Nestin was not detected in ureteric bud and its derivatives throughout renal development. Cell lineage studies, using a nestin promoter-driven Cre mouse and a ROSA26 reporter mouse, showed a strong beta-galactosidase activity in intermediate mesoderm in an embryonic day 10 embryo and all of the structures except those that were derived from ureteric bud in embryonic kidney through adult kidney. These studies show that nestin is expressed in progenitors of glomerular endothelial cells and renal progenitors that are derived from metanephric mesenchyme. In the adult kidney, nestin expression is restricted to differentiated podocytes, suggesting that nestin could play an important role in maintaining the structural integrity of the podocytes.     

Irinotecan as a new agent for urachal cancer

The urachal carcinoma, in a 64-year-old male with multiple lung metastases, had shown the resistance to several anti-neoplastic agents including cisplatinum, methotrexate, 5-FU, doxorubicin, epirubicin, and mitomycin C. Because the tumor was adenocarcinoma producing mucin and serum carcinoembryonic antigen (CEA) increased, which resembled colorectal carcinoma, we administrated Irinotecan, which was very effective as the CEA decreased from 98.3 to 38.7 ng/ml and the pulmonary metastatic lesions were reduced by 60%. To our knowledge, this is the first case with urachal carcinoma in which Irinotecan was effective.     

Glomerular changes in the KK-Ay/Ta mouse: a possible model for human type 2 diabetic nephropathy

BACKGROUND: In type 2 diabetic nephropathy, there is no animal model which has been completely matched with humans. Advanced glycation end products (AGE) and transforming growth factor-beta (TGF-beta) are closely related to hyperglycaemia and their pathobiochemistry could explain diabetic nephropathy. The objective of the present study was to evaluate the KK-A(y)/Ta mouse as a suitable model for type 2 diabetic nephropathy including pathological changes and immunohistochemical analyses of AGE and TGF-beta, compared with the non-diabetic BALB/cA mouse. METHODS: The urinary albumin/creatinine ratio (ACR), body weight (BW), fasting and casual blood glucose, blood haemoglobin A(1c) (HbA(1c)), creatinine clearance (Ccr) and blood pressure were measured for phenotypic characterisation. The pathological changes of glomeruli were evaluated by light microscopy, immunofluorescence and electron microscopy. AGE and TGF-beta accumulation were evaluated by immunoperoxidase staining. RESULTS: The mean levels of ACR, casual blood glucose, blood HbA(1c) and Ccr in KK-A(y)/Ta mice were higher than those in age-matched non-diabetic BALB/cA mice after 12 weeks of age. There were no significant changes in the levels of systemic blood pressure among all groups. The pathological changes of glomeruli in KK-A(y)/Ta mice were consistent with those in the early stage of human diabetic nephropathy. AGE and TGF-beta protein appeared to be localised in the glomerular mesangial matrices. CONCLUSION: It appears that KK-A(y)/Ta mice, especially in terms of histopathological findings, are a suitable animal model for the early stage of type 2 diabetic nephropathy.     

Effects of basic fibroblast growth factor on experimental diabetic neuropathy in rats

Basic fibroblast growth factor (bFGF) stimulates angiogenesis and induces neural cell regeneration. We investigated the effects of bFGF on diabetic neuropathy in streptozotocin-induced diabetic rats. Diabetic rats were treated with human recombinant bFGF as follows: 1) intravenous administration, 2) intramuscular injection into thigh and soleus muscles with cross-linked gelatin hydrogel (CGH), and 3) intramuscular injection with saline. Ten or 30 days later, the motor nerve conduction velocity (MNCV) of the sciatic-tibial and caudal nerves, sensitivity to mechanical stimuli, sciatic nerve blood flow (SNBF), and retinal blood flow (RBF) were measured. Delayed MNCV in the sciatic-tibial and caudal nerves, hypoalgesia, and reduced SNBF in diabetic rats were all ameliorated by intravenous administration of bFGF after 10, but not 30, days. Intramuscular injection of bFGF with CGH also improved sciatic-tibial MNCV, hypoalgesia, and SNBF after 10 and 30 days, but caudal MNCV was not improved. However, intramuscular injection of bFGF with saline had no significant effects. bFGF did not significantly alter RBF in either normal or diabetic rats. These observations suggest that bFGF could have therapeutic value for diabetic neuropathy and that CGH could play important roles as a carrier of bFGF.