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Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment. [ABSTRACT FROM AUTHOR]

Background: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur.Methods: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery.Results: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups.Conclusions: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway induces innate immunity by activating the production of inflammatory cytokines and type I interferons. Recently, studies revealed that self-DNA from by-products of chromosome instability and tumors could activate the cGAS-STING pathway, and subsequently promote or inhibit tumor development. However, the prognostic value and correlations with immune infiltrates of the cGAS-STING pathway in hepatocellular carcinoma (HCC) have not been clarified. In the present study, we used theMolecular Signatures Database, Oncomine, UALCAN, Human Protein Atlas, Kaplan-Meier plotter, LinkedOmics, and Tumor Immune Estimation Resource databases. Overexpression of XRCC5, IRF3, TRIM21, STAT6, DDX41, TBK1, XRCC6, TREX1, PRKDC, and TMEM173 was markedly correlated with clinical stages and pathological grades in HCC. Moreover, higher mRNA expression of XRCC5, XRCC6, and PRKDC was significantly related with shorter overall survival. However, higher mRNA expression of IFI16, STAT6, NLRC3, and TMEM173 was associated with favorable overall survival. Our results suggested that the kinase targets of the cGAS-STING pathway included the SRC family of tyrosine kinases (LCK and LYN), phosphoinositide 3-kinase-related protein kinase (PIKK) family kinases (ATM and ATR), and mitogen-activated protein kinase 1 (MAPK1). Furthermore, we identified significant correlations among the expression of cGAS-STING pathway and infiltration of B cells, CD4+T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC. The expression of the cGAS-STING pathway also exhibited strong relationships with diverse immune marker sets in HCC. These findings suggest that cGAS-STING pathway members may be used as prognostic biomarkers and immunotherapeutic targets HCC patients. [ABSTRACT FROM AUTHOR]

Background: A totally implantable venous access device (TIVAD) provides reliable, long-term vascular access and improves patients’ quality of life. The wide use of TIVADs is associated with important complications. A meta-analysis was undertaken to compare the internal jugular vein (IJV) with the subclavian vein (SCV) as the percutaneous access site for TIVAD to determine whether IJV has any advantages. Methods: All randomized controlled trials (RCTs) and cohort studies assessing the two access sites, IJV and SCV, were retrieved from PubMed, Web of Science, Embase, and OVID EMB Reviews from their inception to December 2015. Random-effects models were used in all analyses. The endpoints evaluated included TIVAD-related infections, catheterrelated thrombotic complications, and major mechanical complications. Results: Twelve studies including 3905 patients published between 2008 and 2015, were included. Our metaanalysis showed that incidences of TIVAD-related infections (odds ratio [OR] 0.71, 95 % confidence interval [CI] 0.48-1.04, P = 0.081) and catheter-related thrombotic complications (OR 0.76, 95 % CI 0.38-1.51, P = 0.433) were not significantly different between the two groups. However, compared with SCV, IJV was associated with reduced risks of total major mechanical complications (OR 0.38, 95 % CI 0.24-0.61, P < 0.001). More specifically, catheter dislocation (OR 0.43, 95 % CI 0.22-0.84, P = 0.013) and malfunction (OR 0.42, 95 % CI 0.28-0.62, P<0.001) were more prevalent in the SCV than in the IJV group; however, the risk of catheter fracture (OR 0.47, 95 % CI 0.21-1.05, P = 0.065) were not significantly different between the two groups. Sensitivity analyses using fixed-effects models showed a decreased risk of catheter fracture in the IJV group. Conclusion: The IJV seems to be a safer alternative to the SCV with lower risks of total major mechanical complications, catheter dislocation, and malfunction. However, a large-scale and well-designed RCT comparing the complications of each access site is warranted before the IJV site can be unequivocally recommended as a first choice for percutaneous implantation of a TIVAD. [ABSTRACT FROM AUTHOR]

Previous studies have shown that ulinastatin, an effective inhibitor of the inflammatory response in clinical applications, can attenuate hyperalgesia in rodents. However, the underlying mechanism remains unclear. In the present study, we first examined the change in the calcineurin level, which plays an important role in regulating cytokine release in the nervous system, following lumbar 5 ventral root transection in the rat. Furthermore, we determined whether intraperitoneal (i.p.) injection of ulinastatin attenuated pain behavior via inhibition of the calcineurin-mediated inflammatory response induced by lumbar 5 ventral root transection. The results showed that the paw withdrawal threshold and paw withdrawal latency were significantly decreased following lumbar 5 ventral root transection compared to the sham group. Neuropathic pain induced by lumbar 5 ventral root transection significantly decreased the expression of calcineurin in the DRG, and calcineurin was mostly located with NF-200-positive cells, IB4-positive cells, and CGRP-positive cells and less with GFAP-positive satellite cells. Furthermore, intrathecal (i.t.) injection of exogenous calcineurin attenuated the pain behavior induced by lumbar 5 ventral root transection. Importantly, intraperitoneal injection of ulinastatin alleviated the pain behavior and calcineurin downregulation induced by lumbar 5 ventral root transection. Lastly, the cytokine IL-10 was significantly decreased following lumbar 5 ventral root transection, and application of calcineurin (intrathecal) or ulinastatin (intraperitoneal) inhibited the IL-10 downregulation induced by lumbar 5 ventral root transection. These results suggested that ulinastatin, by acting on the CN/IL-10 pathway, might be a novel and effective drug for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Background Previous studies have shown that preoperative anemia is correlated with the prognoses of various solid tumors. This study was performed to determine the effect of preoperative anemia on relapse and survival in patients with breast cancer. Methods A total of 2960 patients with breast cancer who underwent surgery between 2002 and 2008 at the Sun Yat-sen University Cancer Center (Guangzhou, PR China) were evaluated in a retrospective analysis. A total of 2123 qualified patients were divided into an anemic group [hemoglobin (Hb) ≥ 12.0 g/dL, N = 535)] and a nonanemic group (Hb = 12.0 g/dL, N = 1588). The effects of anemia on local relapse-free survival (LRFS), lymph node metastasis- free survival (LNMFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Independent prognostic factors were identified in the final multivariate Cox proportional hazards regression model. Results Among the 2123 women who qualified for the analysis, 535 (25.2%) had a Hb level ≤ 12.0 g/dL. The Kaplan--Meier curves showed that anemic patients had worse LRFS, LNMFS, DMFS, RFS, and OS than nonanemic patients, even in the same clinical stage of breast cancer. Cox proportional hazards regression model indicated that preoperative anemia was an independent prognostic factor of LRFS, LNMFS, DMFS, RFS, and OS for patients with breast cancer. Conclusions Preoperative anemia was independently associated with poor prognosis of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that preoperative anemia is correlated with the prognoses of various solid tumors. This study was performed to determine the effect of preoperative anemia on relapse and survival in patients with breast cancer. Methods: A total of 2960 patients with breast cancer who underwent surgery between 2002 and 2008 at the Sun Yat-sen University Cancer Center (Guangzhou, PR China) were evaluated in a retrospective analysis. A total of 2123 qualified patients were divided into an anemic group [hemoglobin (Hb) < 12.0 g/dL, N = 535)] and a nonanemic group (Hb ≥ 12.0 g/dL, N = 1588). The effects of anemia on local relapse-free survival (LRFS), lymph node metastasis-free survival (LNMFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Independent prognostic factors were identified in the final multivariate Cox proportional hazards regression model. Results: Among the 2123 women who qualified for the analysis, 535 (25.2%) had a Hb level < 12.0 g/dL. The Kaplan- Meier curves showed that anemic patients had worse LRFS, LNMFS, DMFS, RFS, and OS than nonanemic patients, even in the same clinical stage of breast cancer. Cox proportional hazards regression model indicated that preoperative anemia was an independent prognostic factor of LRFS, LNMFS, DMFS, RFS, and OS for patients with breast cancer. Conclusions: Preoperative anemia was independently associated with poor prognosis of patients with breast cancer. [ABSTRACT FROM AUTHOR]

The aims of this study were to evaluate the anti-inflammatory and analgesic effects of bufalin, a major component of "Chan-su." We used a carrageenan-induced paw edema model to assess the anti-inflammatory activity of this compound, and Western blot analysis detected NF-κB signaling during this effect. The antinociceptive activities were evaluated by acetic acid-induced writhing, formalin, and hot-plate tests; open-field test investigated effects on the central nervous system. Our data showed that bufalin (0.3 and 0.6mg/kg, i.p.) potently decreased carrageenan-induced paw edema. Bufalin down regulated the expression levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) during these treatments. Further studies demonstrated that bufalin significantly inhibited the activation ofNF-κB signaling. Bufalin also reduced acetic acid-induced writhing and the licking time in the formalin test and increased hot-plate reaction latencies. Naloxone pretreatment (2mg/kg, i.p.) in the early phases of the formalin test and hot-plate test significantly attenuated the bufalininduced antinociception effects, which suggests the involvement of the opioid system. A reduction in locomotion was not observed in the open-field test after bufalin administration. Taken together, bufalin treatment resulted in in vivo anti-inflammatory and analgesic effects, and bufalin may be a novel, potential drug for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]