Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-α remains unclear. The objectives of the present study were to examine whether TNF-α inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-Ay mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-α and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-α and TNFR1, in ETN-treated KK-Ay mice were significantly decreased compared with untreated KK-Ay mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-α or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-α-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-α-TNFR2 pathway.
The current study aimed to examine whether the levels of TNF receptors 1 and 2 (TNFR1 and TNFR2) in serum and urine were associated with other markers of kidney injury and renal histological findings, including TNFR expression, in IgA nephropathy (IgAN). The levels of the parameters of interest were measured by immunoassay in 106 biopsy-proven IgAN patients using samples obtained immediately before renal biopsy and in 34 healthy subjects. Renal histological findings were evaluated using immunohistochemistry. The levels of serum TNFRs were higher in IgAN patients than in healthy subjects. The levels of both TNFRs in serum or urine were strongly correlated with each other (r > 0.9). Serum TNFR levels were positively correlated with the urinary protein to creatinine ratio (UPCR) and four markers of tubular damage of interest (N-acetyl-β-D-glucosaminidase [NAG], β2 microglobulin [β2m], liver-type fatty acid-binding protein [L-FABP], and kidney injury molecule-1 [KIM-1]) and negatively correlated with estimated glomerular filtration rate (eGFR). Patients in the highest tertile of serum TNFR levels showed more severe renal interstitial fibrosis than did those in the lowest or second tertiles. The tubulointerstitial TNFR2-, but not TNFR1-, positive area was significantly correlated with the serum levels of TNFRs and eGFR. Stepwise multiple regression analysis revealed that elevated serum TNFR1 or TNFR2 levels were a significant determinant of renal interstitial fibrosis after adjusting for eGFR, UPCR, and other markers of tubular damage. In conclusion, elevated serum TNFR levels were significantly associated with the severity of renal interstitial fibrosis in IgAN patients. However, the source of TNFRs in serum and urine remains unclear.
BackgroundRecurrence patterns in patients who have undergone curative gastrectomy for advanced gastric carcinoma can be classified as peritoneal, hematogenous, or lymphatic. The aim of this study was to clarify differences in risk factors between these different types of recurrence pattern.MethodsPostoperative courses, including sites of recurrence and periods between surgery and recurrence, of patients who had undergone curative gastrectomy for advanced gastric carcinoma (more than pT2 invasion) were surveyed in detail. Clinicopathological factors were examined as potential independent risk factors for each recurrence pattern, based on recurrence-free survival, using multivariate analysis.ResultsMultivariate analysis identified depth of tumor invasion (pT4 vs. pT2/3; hazard ratio (HR), 7.05; P < 0.001), number of lymph node metastases (pN2/3 vs. pN0/1; HR, 4.02; P = 0.001), and histological differentiation (G3/4 vs. G1/2; HR, 2.22; P = 0.041) as independent risk factors for peritoneal metastasis. The number of lymph node metastases (HR, 26.21; P < 0.001) and venous vessel invasion (HR, 5.09; P = 0.001) were identified as independent risk factors for hematogenous metastasis. The number of lymph node metastases (HR, 6.00; P = 0.007) and depth of tumor invasion (HR, 4.70; P = 0.023) were identified as independent risk factors for lymphatic metastasis.ConclusionsThis study clarified differences in risk factors between various patterns of recurrence. Careful examination of risk factors could help prevent oversight of recurrences and improve detection of recurrences during follow-up. The number of lymph node metastases represents an independent risk factor for all three patterns of recurrence; thus, patients with multiple lymph node metastases warrant particular attention.
Cystic lesions of the pancreas can be divided into true cysts, pseudocysts, and cystic neoplasms. Lymphoepithelial cysts (LECs) are a type of true cyst that can mimic pseudocysts and cystic neoplasms. LECs are rare lesions; fewer than 90 cases have been reported in the English language literature. The case of a 60-year-old man with an LEC of the pancreas is reported. He was admitted with upper abdominal discomfort. Computed tomography showed a 64 × 39 mm cystic mass in the retroperitoneum behind the duodenum and inferior caval vein. Magnetic resonance imaging revealed a right-sided mass on T1-weighted imaging, with a clear boundary between the mass and its surroundings, except for the pancreas. The mass had an inhomogeneous intensity on T2-weighted imaging. Within the mass, small floating nodules with low intensity were seen. Endoscopic ultrasound showed many high-echoic nodules and smaller grains scattered everywhere in the mass. Fine needle aspiration and cytologic examination were performed. Characteristic chylaceous fluid was obtained in which anucleate squamous cells were found. There were also a few atypical large cells with irregularly shaped marked nucleoli and degenerative cytoplasm. Cytologic diagnosis was suspicious for malignancy. The lesion was diagnosed as a retroperitoneal cyst, probably of pancreatic origin. Since a neoplastic lesion could not be ruled out, surgery was performed. The lesion was palpable on the dorsal side of the second portion of the duodenum. The mass was completely resected. Macroscopically, the lesion was a multilocular cyst with a thin septal wall. The cyst was filled with cottage cheese-like substance. Microscopically, the cyst wall was composed of stratified squamous epithelium and dense subepithelial lymphatic tissue with developed lymph follicles. The epithelial cells had no atypia. The histopathologic diagnosis was LEC of the pancreas. The patient’s postoperative course was good.
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