Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats. Prorenin has a prosegment of 43 amino acid residues that are attached to the N terminus of mature (active) renin, and the prosegment folds into the active site cleft of mature renin to prevent catalytically productive interaction with angiotensinogen. When a prorenin-binding protein interacts with the "handle region" of the prorenin prosegment, the prorenin molecule undergoes a conformational change to an enzymatically active state. 1 This phenomenon is called nonproteolytic activation, and recent studies found that such binding proteins include the (pro)renin/renin receptor. 2,3 We recently found that nonproteolytic activation of prorenin plays a pivotal role in the activation of the renal renin-angiotensin system (RAS) and the development of nephropathy in diabetic rats and that the (pro)renin receptor blocker (PRRB; formerly handle region decoy peptide) clearly prevented the development of nephropathy and suppressed an increase of renal angiotensins. 3 However, whether nonproteolytically activated prorenin is also involved in the progression of nephropathy that had already developed in diabetic rats remained undetermined.This study was designed to determine whether PRRB is able to inhibit the progression of nephropathy after its development in diabetic rats. Prorenin prosegment has a tetrameric segment termed "gate region" (GR; S 7 FGR 10 ) that is not accessible by its

BackgroundHomeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis.MethodsWe examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens.ResultsHOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system.ConclusionsHOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.

Compared with surgical intervention, SEMS could provide feasible palliation for patients with bowel obstructions and unresectable CRC, because of their acceptable morbidity rates and better patient prognoses.

Isolated para-aortic lymph node (PLN) recurrence from colorectal cancer (CRC) is rare, with no currently validated treatments. Few reports have described the successful resection of isolated PLN involvement from CRC following chemotherapy. We report the case of a 63-year-old man who underwent sigmoidectomy for sigmoid colon cancer at our hospital. Pathological examination demonstrated advanced sigmoid colon cancer with metastatic involvement in both of the tested PLNs. Palliative chemotherapy was initiated four weeks after surgical resection, with administration of the FOLFIRI regimen. Four years after the operation, computed tomography (CT) revealed an enlarged PLN below the left renal vein. As PLN enlarged to 15 mm in the minor axis on a CT scan in 2014 after receiving a total of 156 courses of the FOLFIRI regimen, we considered the enlarged PLN to represent an isolated metastasis. Accordingly, lymph node resection was performed with microscopically negative margins. The patient maintained a good quality of life without any side effects throughout the whole course of his treatment and remains disease-free at 24 months without chemotherapy after resection of the isolated PLN. Curative resection following chemotherapy may improve survival of carefully selected advanced CRC patients with locoregional recurrence, such as isolated PLN involvement.

BackgroundA cavenous hemangioma of the appendix (CHA) is rare. The clinical pathophysiology and adequate management of a CHA have not been sufficiently explained since reports on CHA are scarce.Case presentationA 56-year-old woman presented with chronic right lower quadrant pain. Abdominal contrast-enhanced computed tomography revealed a thickened appendix (1.5 cm in diameter) and some focal calcifications in the appendiceal wall. No acute inflammatory signs were visible around the appendix. For diagnosis and treatment, we performed a laparoscopic surgery. Intraoperative findings included purple granular lesions that were spread diffusely along the surface of the appendix. Since these lesions were spread to the terminal ileum, laparoscopic ileocecal resection was performed. Upon macroscopic inspection, purple-colored, raspberry-like lesions were found diffusely on the serosal surface of the appendix. No lesions were found on the mucosal surface. Hematoxylin and eosin staining indicated the presence of blood-filled sinus-like spaces largely in the subserosal layer. Immunohistochemistry analysis indicated that CD34-positive cells lined these spaces. Given these findings, we diagnosed the patient with a diffuse cavernous vascular malformation of the appendix.ConclusionsCHA is difficult to diagnose. A laparoscopic approach may be useful for both the diagnosis and treatment of the disease.