Potential role of the PD-L1 expression and tumor-infiltrating lymphocytes on neuroblastoma

Pediatric Surgery International - The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway has garnered much attention for its roles in clinical oncology. The aim of this study was...     

The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model

Cancer Chemotherapy and Pharmacology - Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of...     

Temporal Delta Wave and Ischemic Lesions on MRI

Abstract: The present study was designed to determine the clinical significance of a temporal low-voltage irregular delta wave (TLID) on EEG. Among 808 EEG records examined during one year at our hospital, the TLID was commonly detected in patients with clinically diagnosed ischemic brain diseases such as multiple infarction. Subsequently, a relation of the TLID to ischemic lesions on MRI was examined in 50 elderly depressive patients. It was found that there was a close correlation between the occurrence of the TLID and small ischemic lesions on MRI (p<0.001). These results suggest that the TLID is a valuable indicator of minor ischemic changes of the brain.     

Intestinal epithelial culture under an air‐liquid interface: a tool for studying human and mouse esophagi

This study investigated whether an intestinal epithelial culture method can be applied to mouse and human esophageal cultures. The esophagi harvested from 1‐day‐old mice and adult humans were maintained in collagen gels. A commercially available culture medium for human embryonic stem cells was used for the human esophageal culture. We discovered that the intestinal epithelial culture method can be successfully applied to both mouse and human esophageal cultures. The long‐term cultured esophageal organoids were rod‐like luminal structures lined with myofibroblasts. We discovered that regeneration of the esophageal mucosal surface can be almost completely achieved in vitro, and the advantage of this method is that organoid cultures may be generated using host‐derived fibroblasts as a niche. This method is a promising tool for mouse and human research in intestinal biology, carcinogenesis, and regenerative medicine.     

A case of tracheo-bronchial stenosis after extended end-to-end aortic arch anastomosis for interrupted aortic arch treated with suspension of the ascending artery and pulmonary artery

A 9-day-old boy had pulmonary artery banding and extended end-to-end aortic arch anastomosis for ventricular septal defect (VSD) and type A interrupted aortic arch. Severe dyspnea gradually developed. At 3 months of age, intracardiac repair of VSD was performed. Weaning from the ventilator was difficult. Endoscopic examination and chest CT revealed stenosis of the right and left main bronchi and compression of tracheal bifurcation and the right and left main bronchi by the ascending aorta and pulmonary artery. Suspension of the ascending aorta and pulmonary artery was performed 15 days after VSD closure. Nine days after this procedure, the patient was weaned from respirator. Postoperative course was uneventful. Bronchial stenosis may be caused from extended end-to-end aortic arch anastomosis.     

Immune responses of graft mesenteric lymph node in small bowel transplantation

BACKGROUND: The high proportions of lymphoid tissues are thought to be one of the underlying factors inducing severe allograft rejection following small bowel transplantation. Mesenteric lymph nodes (MLN) contained in the intestinal graft are not only a source of donor-derived professional antigen-presenting cells, but also offer a field for immune interaction between donor and host cells. We investigated immune responses in graft MLNs with or without FK506 to develop a novel strategy to control small bowel allograft rejection. MATERIALS AND METHODS: Heterotopic small bowel transplantations were performed from Brown Norway donors to Lewis recipients. Changes in population of lymphocytes, expressions of costimulatory molecules, apoptosis, and cytokine profiles in graft MLNs were evaluated. RESULTS: The increase in apoptotic cells and cytokine responses relating to rejection in the graft MLNs developed prior to those in graft jejunum. While donor lymphocytes in graft MLNs were rapidly replaced to host-derived lymphocytes independent of FK treatment, increase in CD8(+) T cells in host population was seen only in recipients without FK506 treatment. The expressions of B7 molecules on donor cells in graft MLNs were significantly lower in the recipients with FK treatment. CONCLUSIONS: Immune responses in graft MLNs have significant impact on the outcome of the small bowel allograft. Apoptosis of graft MLN cells was well correlated with and ahead of progression of acute rejection. Modulation of costimulatory molecules on donor-derived MLN cells in the allograft and specific suppression of host CD8(+) T cells are possible ways to control severe rejection after allogeneic small bowel transplantation.     

Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer

BACKGROUND: Ribonucleotide reductase M2 subunit (RRM2) overexpression enhances tumor chemoresistance and cellular invasiveness. We hypothesized that the RNA interference (RNAi) induced by retrovirally delivered small interfering RNA (siRNA) would sensitize pancreatic adenocarcinoma cells to gemcitabine and attenuate their invasive potential. METHODS: Stable suppression of RRM2 expression in PANC1, MIAPaCa2, BxPC3, and Capan2 cells was induced by exposure to a novel replication-deficient retrovirus, engineered to express RRM2-specific siRNA (psiRRM2), and confirmed by Western blot analysis. Single-base mismatch vector (psiControl) served as control. Ribonucleotide reductase activity was quantified, and gemcitabine 50% inhibitory concentrations were calculated. TUNEL staining and caspase profiling were performed after gemcitabine exposure. Cellular invasiveness was quantified in a Matrigel Boyden chamber. NF-kappaB activity and matrix metalloproteinase-9 (MMP-9) expression and activity were measured. RESULTS: RRM2 expression was stably and specifically suppressed in psiRRM2, but not psiControl transfectants. psiRRM2 transfectants exhibited lower 50% inhibitory concentrations, increased gemcitabine-induced apoptosis, and greater caspase-3 activation, relative to psiControl transfectants. Invasiveness was attenuated in psiRRM2 transfectants, as was NF-kappaB activity, MMP-9 expression, and MMP-9 activity, relative to psiControl transfectants. CONCLUSIONS: RRM2 gene silencing attenuates pancreatic adenocarcinoma cellular invasiveness and gemcitabine chemoresistance. Retroviral siRNA delivery can efficiently induce stable RNAi, allowing dissection of gene function and potentially representing a new therapeutic modality.     

Dual role of vascular endothelial growth factor in hepatic ischemia-reperfusion injury

BACKGROUND: Vascular endothelial growth factor (VEGF), a major angiogenic factor, mediates a variety of disease conditions through promotion of angiogenesis. It also plays a critical role as a potent proinflammatory cytokine in a variety of physiologic and pathologic immune responses. In the present study, we evaluated the expression of VEGF in hepatic warm ischemia-reperfusion (I/R) injury and examined the effect of recombinant human (rh)VEGF administration in an established murine model. METHOD: The expression of VEGF in the liver was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry during I/R injury using 70% partial hepatic ischemia model. The effect of rhVEGF administration on I/R injury was evaluated by measuring liver function and histology. In addition, local inducible nitric oxide synthase (iNOS) and endothelial NO synthase expressions were examined to address the underlying mechanisms. RESULTS: The local expression of VEGF was significantly up-regulated at 2 hours after reperfusion after 60 minutes of ischemia compared with that in the naive liver. VEGF was expressed predominantly in CD11b+ cells infiltrating into the ischemic liver. The administration of rhVEGF had a significant protective effect on ischemic injury in the liver. This effect was associated with the up-regulation of iNOS expression in the rhVEGF-treated liver. CONCLUSION: We demonstrate a dual role of VEGF in hepatic warm I/R injury. Although endogenous VEGF is expressed and functional to initiate hepatic I/R injury, exogenous rhVEGF has a beneficial effect on the ischemic liver. These data may provide new insights into the role of VEGF as well as pathophysiology of hepatic I/R injury.     

Perimembrane Aurora-A Expression is a Significant Prognostic Factor in Correlation with Proliferative Activity in Non-Small-Cell Lung Cancer (NSCLC)

Purpose Aurora-A, also known as STK15/BTAK, is a member of the protein serine/threonine kinase family, and experimental studies have revealed that Aurora-A plays critical roles in cell mitosis and in carcinogenesis. However, no clinical studies on Aurora-A expression in non-small-cell lung cancer (NSCLC) have been reported. Thus, the present study was conducted to assess the clinical significance of Aurora-A status. Experimental Design A total of 189 consecutive patients with resected pathologic (p-)stage I-IIIA, NSCLC were retrospectively reviewed, and immunohistochemical staining was used to detect Aurora-A expression. Results Aurora-A expression was negative in 31 patients (16.4%); among Aurora-A positive patients, 124 patients showed pure diffuse cytoplasmic Aurora-A expression and the other 34 patients showed perimembrane Aurora-A expression. Perimembrane Aurora-A tumors showed the highest proliferative index (PI) (mean PIs for negative, diffuse cytoplasmic, and perimembrane tumors: 49.2, 41.7, and 63.5, respectively; P < .001). Five-year survival rates of Aurora-A negative, diffuse cytoplasmic, and perimembrane patients were 67.8%, 66.7%, and 47.6%, respectively, showing the poorest postoperative survival in perimembrane patients (P = .033). Subset analyses revealed that perimembrane Aurora-A expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. A multivariate analysis confirmed that perimembrane Aurora-A expression was an independent and significant factor to predict a poor prognosis. Conclusions Perimembrane Aurora-A status was a significant factor to predict a poor prognosis in correlation with enhanced proliferative activity in NSCLC.