Isoquercetin activates the ERK1/2-Nrf2 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro.

Isoquercetin has exhibited a wide range of therapeutic properties, including antioxidant, anti-inflammatory and anti-allergic activities. The aim of the present study was to investigate the effect of isoquercetin on rats with 2 h middle cerebral artery occlusion (MCAO) and evaluate the neuroprotective effect of isoquercetin on a primary culture of rat hippocampal neuronal cells subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R). In vivo, the rats treated with isoquercetin exhibited a lower degree of neurological dysfunction and smaller infarct volume than the vehicle-treated rats. In vitro, it was found that isoquercetin prevented the OGD/R-induced increase in apoptosis, lactate dehydrogenase release and reduction in cell viability. Additionally, isoquercetin induced the upregulation of nuclear factor erythroid 2-related factor 2 gene and protein expression, and increased extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation. This indicates that the ERK1/2 pathway may contribute to the neuroprotective effect of isoquercetin against OGD/R-induced oxidative damage in rat hippocampal neurons. These findings suggest the potential importance of isoquercetin in the treatment of ischemia/reperfusion-related brain injury and associated diseases.

A truncated splice variant of human lysyl oxidase-like 2 promotes migration and invasion in esophageal squamous cell carcinoma.

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family, which plays an important role in extracellular matrix protein biosynthesis and tumor progression. In the present study, we identified a novel splice variant, LOXL2Δ72, which encodes a peptide having the same N- and C-termini as wild-type LOXL2 (LOXL2WT), but lacks 72 nucleotides encoding 24 amino acids. LOXL2Δ72 had dramatically reduced enzymatic activity, and was no longer secreted. However, LOXL2Δ72 promoted greater cell migration and invasion than LOXL2WT. Furthermore, a dual luciferase reporter assay indicated that LOXL2Δ72 activates distinct signal transduction pathways compared to LOXL2WT, consistent with cDNA microarray data showing different expression levels of cell migration- and invasion-related genes induced following over-expression of each LOXL2 isoform. In particular, LOXL2Δ72 distinctly promoted esophageal squamous cell carcinoma (ESCC) cell migration via up-regulating the C-C motif chemokine ligand 28 (CCL28). Our results suggest that the new LOXL2 splice variant contributes to tumor progression by novel molecular mechanisms different from LOXL2WT.

Comparison of Therapeutic Effect of Recombinant Tissue Plasminogen Activator by Treatment Time after Onset of Acute Ischemic Stroke.

We aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) administered at different time windows within the first 6 hours after onset of acute ischemic stroke (AIS). A retrospective analysis was performed of data collected from 194 patients who received rt-PA thrombolysis within 4.5 hours after AIS onset and from 29 patients who received rt-PA thrombolysis between 4.5-6 hours after AIS onset. The National Institutes of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P < 0.05) at 24 hours and 7 days after onset. There was no statistical difference in the modified Rankin score or mortality at day 90 after treatment between the two groups (P > 0.05). In conclusion, AIS patients who received rt-PA treatment between 4.5-6 hours after onset were similar in therapeutic efficacy to those who received rt-PA within 4.5 hours after onset. Our results suggest that intravenous thrombolytic therapy for AIS within 4.5-6 hours after onset is effective and safe.

Autoantibody Signatures Combined with Epstein-Barr Virus Capsid Antigen-IgA as a Biomarker Panel for the Detection of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is prevalent in Southern China and Southeast Asia, and autoantibody signatures may improve early detection of NPC. In this study, serum levels of autoantibodies against a panel of six tumor-associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, Prx VI, and Bmi-1) and Epstein-Barr virus capsid antigen-IgA (VCA-IgA) were tested by enzyme-linked immunosorbent assay in a training set (220 NPC patients and 150 controls) and validated in a validation set (90 NPC patients and 68 controls). We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy. ROC curves showed that use of these 6 autoantibody assays provided an area under curve (AUC) of 0.855 [95% confidence interval (CI), 0.818-0.892], 68.2% sensitivity, and 90.0% specificity in the training set and an AUC of 0.873 (95% CI, 0.821-0.925), 62.2% sensitivity, and 91.2% specificity in the validation set. Moreover, the autoantibody panel maintained diagnostic accuracy for VCA-IgA-negative NPC patients [0.854 (0.809-0.899), 67.8%, and 90.0% in the training set; 0.879 (0.815-0.942), 67.4%, and 91.2% in the validation set]. Importantly, combination of the autoantibody panel and VCA-IgA improved diagnostic accuracy for NPC versus controls compared with the autoantibody panel alone [0.911 (0.881-0.940), 81.4%, and 90.0% in the training set; 0.919 (0.878-0.959), 78.9%, and 91.2% in the validation set), as well as for early-stage NPC (0.944 (0.894-0.994), 87.9%, and 94.0% in the training set; 0.922 (0.808-1.000), 80.0%, and 92.6% in the validation set]. These results reveal autoantibody signatures in an optimized panel that could improve the identification of VCA-IgA-negative NPC patients, may aid screening and diagnosis of NPC, especially when combined with VCA-IgA.

miR-200b suppresses invasiveness and modulates the cytoskeletal and adhesive machinery in esophageal squamous cell carcinoma cells via targeting Kindlin-2.

To further our understanding of the pathobiology of esophageal squamous cell carcinoma (ESCC), we previously performed microRNA profiling that revealed downregulation of miR-200b in ESCC. Using quantitative real-time PCR applied to 88 patient samples, we confirmed that ESCC tumors expressed significantly lower levels of miR-200b compared with the respective adjacent benign tissues (P = 0.003). Importantly, downregulation of miR-200b significantly correlated with shortened survival (P = 0.025), lymph node metastasis (P = 0.002) and advanced clinical stage (P = 0.020) in ESCC patients. Quantitative mass spectrometry identified 57 putative miR-200b targets, including Kindlin-2, previously implicated in the regulation of tumor invasiveness and actin cytoskeleton in other cell types. Enforced expression of miR-200b mimic in ESCC cells led to a decrease of Kindlin-2 expression, whereas transfection of miR-200b inhibitor induced Kindlin-2 expression. Furthermore, transfection of miR-200b mimic or knockdown of Kindlin-2 in ESCC cells decreased cell protrusion and focal adhesion (FA) formation, reduced cell spreading and invasiveness/migration. Enforced expression of Kindlin-2 largely abrogated the inhibitory effects of miR-200b on ESCC cell invasiveness. Mechanistic studies revealed that Rho-family guanosine triphosphatases and FA kinase mediated the biological effects of the miR-200b-Kindlin-2 axis in ESCC cells. To conclude, loss of miR-200b, a frequent biochemical defect in ESCC, correlates with aggressive clinical features. The tumor suppressor effects of miR-200b may be due to its suppression of Kindlin-2, a novel target of miR-200b that modulates actin cytoskeleton, FA formation and the migratory/invasiveness properties of ESCC.

Efficacy and safety of a modified intravenous recombinant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke.

BACKGROUND: Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA; 0.90 mg/kg, with a maximum dose of 90 mg) has been recommended as the standard management for acute ischemic stroke (AIS) thrombolysis. However, the dose of IV rtPA in Asia remains controversial. METHODS: This study was designed to verify the safety and efficacy of IV rtPA treatment for AIS with a lower dosage (0.90 mg/kg, with a maximum dose of 50 mg). Patients were divided into 3 dosage groups according to body weight (BW): group 1, <55 kg for 0.90 mg/kg; group 2, 55 to 67 kg for 0.75 to 0.90 mg/kg; and group 3, >67 kg for <0.75 mg/kg. The following data were collected: patient demographics, vascular risk factors, neuroimaging results, time of rtPA administration, National Institutes of Health Stroke Scale score before treatment and at 24 hours, and a modified Rankin Scale (mRS) score at 3 months. RESULTS: Eighty-three AIS patients who were of Han Chinese descent were included in the study. The baseline characteristics of the 3 dosage groups were well matched. In group 1 (BW <55 kg for 0.90 mg/kg; n = 19), 57.1% had a favorable outcome at 3 months, compared with 61.2% of patients in group 2 (BW 55-67 kg for 0.75-0.90 mg/kg; n = 33) and 51.5% in group 3 (BW >67 kg for <0.75 mg/kg; n = 31; P = .362). There were no significantly statistical differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. CONCLUSIONS: This IV rtPA regimen (0.90 mg/kg, with a maximum dose of 50 mg) not only shows sufficient favorable outcome in clinical practice in Chinese patients with AIS but also good health economic savings. This regimen could be suitable for many developing countries.

Clinical experience in diagnosis and treatment of malignant gastrointestinal stromal tumors.

This study investigated the clinical pathologic character of malignant gastrointestinal stromal tumors (MGIST), their treatment with surgery, and evaluated the efficacy of imatinib postoperation. A total of 68 MGIST patients were enrolled. Of these, 27 patients underwent imatinib auxiliary therapy (treatment group) and 41 underwent imatinib therapy (control group). The therapeutic effects on the two groups were compared using χ(2) test analysis after follow-up of two years. The expressions of CD117, CD34, S100, Vimentin, and alpha smooth-muscle actin (SMA) were detected by immunohistochemistry methods. Of the 68 cases, 28 showed potential MGIST, whereas 40 had MGIST. Haemorrhagia or necrosis, abundant cell, manifest heteromorphism, and caryocinesia were observed in varying degrees. The positive rates of CD117, CD34, Vimentin, S100, and SMA were 89.7% (61/62), 88.2% (60/62), 73.5% (50/62), 41.1% (28/62) and 25.0% (17/62), respectively. The recurrence rate in the treatment group was significantly lower than that in the control group (p < 0.01). We concluded that CD117 and CD34 may be the most valuable markers in the diagnosis of MGIST, and the diagnosis of MGIST depends on the pathology. Surgery is a far better approach in the treatment of such patients, and imatinib is the more efficient target drug in preventing recurrence and metastasis.

A meta-analysis of chemotherapy regimen fluorouracil/leucovorin/oxaliplatin compared with fluorouracil/leucovorin in treating advanced colorectal cancer.

BACKGROUND: We performed a meta-analysis to evaluate the efficacy and safety of Fluorouracil (FU)/Leucovorin (LV)/Oxaliplatin compared to FU/LV in treating advanced colorectal cancer. METHODS: Two independent researchers identified and extracted all relevant literature using MEDLINE and the Cochrane Library Database. The regimens included arm A (FU/LV) and arm B (FU/LV/Oxaliplatin) with no other chemotherapy agent. RESULTS: Five randomized controlled trials (RCTs) fulfilled the requirements. All RCTs showed superiority of FU/LV/Oxaliplatin to FU/LV when measuring RR (response rate) and PFS (progression-free survival); no significant improvement in OS (overall survival) was observed. This meta-analysis shows a better RR for the FU/LV/Oxaliplatin group (OR 4.02, 95% CI 2.37-6.82, p<0.00001). The incidence of grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, neurological toxicity, toxicity-related dose modification and discontinuation was higher in the FU/LV/Oxaliplatin group, while the incidence of anemia, nausea and diarrhea was not different. CONCLUSION: FU/LV/Oxaliplatin offers better efficacy (RR and PFS) than FU/LV in the treatment of advanced colorectal cancer. The incidence of grade 3/4 toxicities, i.e. neutropenia, thrombocytopenia, vomiting, neurological toxicity, is significantly higher in the FU/LV/Oxaliplatin than in the FU/LV group but these are manageable or reversible.

Full laparoscopic incisional hernia repair using a 2-port route technique.

BACKGROUND AND AIMS: The incidence of incisional hernia repair is increasing each year throughout the world. We created a full laparoscopic herniorrhaphy by means of an easy, reliable, and minimally invasive (two trocars) intraperitoneal onlay technique, using different sizes of a DualMesh (W. L. Gore & Associates; Flagstaff, AZ) with the soft side against the adherence material. METHODS: A group of patients with an incisional hernia and other ventral hernias underwent a laparoscopic herniorrhaphy using this technique. By combining simple extra- and endocorporeal manipulation, a mesh, prior to being inserted into peritoneal cavity through a trocar port was completed with four sutures between the corner of the mesh and the abdominal wall, so that when pulling the strands outside the abdomen, the furled intraperitoneal mesh being unfurled flat, was lifted from and overlapped the hernial defect at the top of the abdomen spontaneously and exactly. The mesh was anchored by nonabsorbable surtures and endo-Helical Fasteners. The sutures were either tied and the knots buried subcutaneously, or were eventually removed. RESULTS: It is by employing only two trocars applying this technique to a complete full laparoscopic intraperitoneal onlay of different sizes of a DualMesh incisional and ventral hernia repair. The mesh overlapped all hernial margins nicely and was anchored firmly. Postoperative courses were uneventful, without any complications. During the longest follow-up period of 2 years and 1 month, there was no recurrent evidence of the hernia in this group. CONCLUSIONS: This technique, which applies to almost every laparoscopic ventral hernia repair procedure for use against an adherence mesh, can help to carry out an ideal, easy, and quick orientation and intraperitoneal anchoring of the mesh.

[Clinical analysis of 60 cases with malignant gastrointestinal stromal tumors].

OBJECTIVE: To investigate the clinicopathological characteristics, and treatment of malignant gastrointestinal stromal tumors (MGIST). METHODS: Immunohistochemistry was used to detect CD117, CD34, S100, vimentin and SMA expressions. The postoperative curative effect was compared between the patients with or without imatinib treatment. RESULTS: Radical resection was performed in 60 cases. Twenty-two tumors with a mean diameter of 5.3 cm were potentially malignant, and 38 tumor with a mean diameter of 9.2 cm were malignant. Microscopical examination revealed haemorrhagia or necrosis, abundant tumor cells, heteromorphism and caryocinesia of the tumors. 54 Cases were CD117 positive, 53 cases CD34 positive, 48 cases vimentin positive, 27 cases S100 positiveì16 cases SMA positive. The two-year recurrence rate was 80.5% in the patients without postoperative imatinib treatment, significantly higher than 21.1% in the patients with postoperative imatinib treatment(P< 0.05). CONCLUSIONS: CD117 and CD34 markers are most valuable diagnostic indexes of MGIST, but its final diagnosis depends on pathology. Postoperative imatinib treatment is most effective to control recurrence and metastasis.

Hand-assisted laparoscopic surgery of abdominal large visceral organs.

AIM: To design a hand-assisted laparoscopic approach in an attempt to provide an option for laparoscopic resection of abdominal large viscera. METHODS: A 5-6 cm incision (for HandPort) and 2 trocars were employed. The main vessel of the target organ was taken as a "core", and all tissues around the core were taken as peripheral structures. The peripheral structures were dissected first, and the core vessels were treated last. Twenty-six patients underwent laparoscopic deroofing of the hepatic huge cysts, resection of the segments lying at the outer edge of the liver (segments 2 to 6), splenectomy, hemicolectomy, ileocecectomy and subtotal gastrectomy with HandPort device, harmonic scalpel, or Ligasure. RESULTS: The duration of the procedure was within 2 h. Blood loss amounted to 8-120 mL. The conversion rate was 3.8% (1/26). All patients had uneventful postoperative courses with less pain, earlier oral intake, and faster recovery, compared with conventional surgery. CONCLUSION: This method combines the advantages of both open and laparoscopic techniques, achieving better hemostasis effect, shortening the operative time, and is beneficial to the patients.