NMDA Receptor Modulates Spinal Iron Accumulation Via Activating DMT1(-)IRE in Remifentanil-Induced Hyperalgesia

N-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca²⁺ and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca²⁺ and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca²⁺ influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca²⁺ influx, contributing to remifentanil-induced hyperalgesia.PerspectiveRemifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.     

Pattern of lymph node metastases and its implication in radiotherapeutic clinical target volume in patients with non-small-cell lung cancer: a study of 2062 cases

Objective:

To study the pattern of lymph node metastasis (LNM) of non-small-cell lung cancer (NSCLC) and to clarify which node level should be included while undergoing radiotherapy (RT).

Methods:

A total of 2062 patients with NSCLC patients who had undergone thoracotomy were retrospectively examined. The clinicopathological factors related to LNM were analysed.

Results:

The LNM rates (the number of node-positive patients/the total number of patients) in patients with primary tumours in different lobes (left upper lobe, left lower lobe, right upper lobe, right middle lobe and right lower lobe) were 53.25%, 53.87%, 53.77%, 64.67% and 61.58%, respectively. We have found that in all of the clinicopathological factors, including sex, age, tumour location, histological type, maximum diameter, T stage, degree of differentiation and tumour growth pattern, only maximum diameter (p = 0.336) and histological type (p = 0.360) did not have significant correlation with LNM rate. All of the above factors except tumour growth pattern (p = 0.239) and maximum diameter (p = 0.613) were significantly associated with lymph node ratio [LNR, ratio between metastatic and examined lymph nodes (LNs)] in linear regression.

Conclusion:

For patients with NSCLC, LNM rate and LNR can be recommended as applicable parameters for LN involvement. Multiple clinicopathological factors should be considered comprehensively to design the clinical target volume for RT of NSCLC.

Advances in knowledge:

This article can provide evidence to radio-oncologists how to choose range of lymph nodal clinical target volume when they are treating inoperable patients with NSCLC patients by analysing data of patients after surgery.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Nitric oxide donor,NOC7, reveals dose dependently and cGMP pathway independently biphasic effects on contractile force of isolated rat heart after global ischemia

Purpose: Our purpose was to investigate whether the 3-(2-hydroxy-1-methyl-2-nitroso-hydrazino)-N-methyl-1-propanamine (NOC7), an ideal NO donor was dose dependently and cGMP-independent in restored cardiac function after global ischemia in an isolated rat heart model. Methods: Langendorff preparations of an isolated rat heart model were established. Isolated rat hearts (n = 40) were randomly divided into 5 groups (ischemic control group, NOC7 groups and NOC7+NS2028 groups). All groups were subjected to 35 min global ischemia, followed by 30 min reperfusion with Krebs-Henseleit bicarbonate buffer (KHB), and NOC7, NOC7+NS2028 at 2 and 200 μM, respectively. Left ventricular developed pressure (LVDP), the maximum and the minimal rate of rise in LVP (±dP/dt), and coronary flows were measured continuously. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels were measured in myocardium homogenate, using enzyme immunoassay (EIA). Results: 30 min of global ischemia increased LVDP to 121.9±11.5% at 35 min of reperfusion of 2 μM NOC7 group and 2 μM NOC7 associated with NS2028 group from the ischemic control group (P < 0.05). While in 200 μM NOC7 group and 200 μM NOC7 associated with NS2028 group, the LVDP value only slightly reduced, resulting in a value of only 45.3±10.4% and 35.3±6.0% of baseline (P > 0.05). Conclusion: NOC7 has biphasic effect on isolated rat heart after ischemia and reperfusion myocardial contractility. This biphasic effect shows neither concentration-dependent nor the cGMP-dependent characteristics.     

Hypomethylation of DNA-binding inhibitor 4 serves as a potential biomarker in distinguishing acquired tamoxifen-refractory breast cancer

Objective: To explore the methylation status of DNA-binding inhibitor 4 (ID4) in tamoxifen-refractory (TR) breast cancer. Methods: From January 2012 to December 2014, breast cancer patients managed by radical mastectomy previously and receiving tamoxifen treatment for at least 12 months were enrolled. According to the response to tamoxifen, patients were divided into TR group and tamoxifen-sensitive (TS) group. Genomic DNA was isolated from fasting venous blood, and methylight technique was applied to determine the methylation status of ID4. Results: 43 patients with TS breast cancer and 31 patients with TR breast cancer were enrolled. No significant difference between groups was observed in term of patients’ characteristics, such as age (P=0.693), progesterone receptor (P=0.970), menopausal status (P=0.784) and histological type (P=0.537), while the stage of cancer in TR group was significantly higher than TS group (P<0.001). Compared to TS group, PMR of ID4 was significantly higher in TR group (P=0.002). ROC curve analysis indicated that ID4 yielded an AUC of 0.716 with 77.4% sensitivity and 62.79% specificity in distinguishing TR breast cancer at the cut point of 3.8%. The PMR cut point of ID4 was set at 6.8% in survival analysis, log-rank test indicated the risk of disease progression was comparable between patients with ID4 hypermethylation or hypomethylation (P=0.287). Conclusion: ID4 hypomethylation is present in TR breast cancer, and it may serve as a potential biomarker in distinguishing TR breast cancer. However, the results need further validation in larger studies.     

Comparative prognostic value of low-density lipoprotein cholesterol and C-reactive protein in patients with stable coronary artery disease treated with percutaneous coronary intervention and chronic statin therapy

BackgroundThe comparative prognostic value of low density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI) and statin therapy is poorly investigated.MethodsThe study included 7595 patients with stable CAD treated with PCI. Based on a cut-off of 100 mg/dl for LDL-C and 3 mg/L for CRP, patients were divided into 4 groups: patients with LDL-C ≤ 100 mg/dl and CRP ≤ 3 mg/L (n = 2795); patients with LDL-C > 100 mg/dl and CRP ≤ 3 mg/L (n = 2091); patients with LDL-C ≤ 100 mg/dl and CRP > 3 mg/L (n = 1296); and patients with LDL-C > 100 mg/dl and CRP > 3 mg/L (n = 1413). Statins at discharge were prescribed in all patients. The primary outcome was 1-year all-cause mortality.ResultsOne-year mortality was 2.1% (160 deaths): 1.2% (33 deaths) among patients with LDL-C ≤ 100 mg/dl and CRP ≤ 3 mg/L, 1.4% (28 deaths) among patients with LDL-C > 100 mg/dl and CRP ≤ 3 mg/L, 4.8% (60 deaths) among patients with LDL-C ≤ 100 mg/dl and CRP > 3 mg/L and 2.9% (39 deaths) among patients with LDL-C > 100 mg/dl and CRP > 3 mg/L (P < 0.001). After adjustment, CRP (hazard ratio [HR] = 1.64, 95% confidence interval [CI] 1.33–2.02, for 1 standard deviation increase in the logarithmic scale) but not LDL-C (HR = 1.03 [0.90–1.17], for 30 mg/dl increase) showed an independent association with 1-year mortality. CRP (P = 0.045) but not LDL-C (P = 0.294) increased the discriminatory power of multivariable model for prediction of mortality.ConclusionIn patients with stable CAD treated with PCI and statin therapy, CRP but not LDL-C was independently associated with increased risk of 1-year mortality.