Nalbuphine attenuates morphine-induced scratching by inhibiting PKCß-dependent microglial activation and p38 phosphorylation in male mice.

Morphine-induced scratching (MIS) is a common adverse effect associated with the use of morphine as analgesia after surgery. However, the treatment of MIS is less than satisfactory due to its unclear mechanism, which needs to be enunciated. We found that intrathecal (i.t.) injections of morphine significantly enhanced scratching behavior in C57BL/6J male mice as well as increased the expressions of protein kinase C ß (PKCß), phosphorylated p38 mitogen-activated protein kinases (MAPK), and ionized calcium-binding adapter molecule 1 (Iba1) within spinal cord dorsal horn. Conversely, using the kappa opioid receptor antagonist nalbuphine significantly attenuated scratching behavior, reduced PKCß expression and p38 phosphorylation, and decreased spinal dorsal horn microglial activation, while PKCδ and KOR expression elevated. Spinal PKCß silencing mitigated MIS and microglial activation. Still, knockdown of PKCδ reversed the inhibitory effect of nalbuphine on MIS and microglial activation, indicating that PKCδ is indispensable for the antipruritic effects of nalbuphine. In contrast, PKCß is crucial for inducing microglial activation in MIS in male mice. Our findings show a distinct itch cascade of morphine, PKCß/p38MAPK, and microglial activation, but an anti-MIS pathway of nalbuphine, PKCδ/KOR, and neuron activation.

Development of nomograms to predict therapeutic response and prognosis of non-small cell lung cancer patients treated with anti-PD-1 antibody.

BACKGROUND: Anti-programmed death-1 (PD-1) antibody changed the treatment of non-small cell lung cancer (NSCLC), however, reliable predictive markers were lacking. We aimed to explore factors associated with response and survival, and develop predictive models. METHODS: This multicenter retrospective study included a training cohort (n = 92) and validation cohort (n = 111) with NSCLC patients received anti-PD-1 antibody monotherapy in eight Chinese hospitals, and a control cohort (n = 124) with NSCLC patients received chemotherapy. Logistic and Cox models were used to identify factors associated with response and survival respectively. Nomograms were developed based on significant factors, and evaluated by Concordance-index (C-index), area under the curve (AUC) and calibration curve. RESULT: In training cohort, smoking history (P = 0.027) and higher absolute lymphocyte count (P = 0.038) were associated with response. Female (P < 0.001), age ≥ 65 years (P = 0.004) and higher lactate dehydrogenase (LDH, P < 0.001) were associated with shorter progression-free survival (PFS). Higher LDH (P < 0.001) and derived neutrophil-to-lymphocyte ratio (P = 0.035) were associated with poorer overall survival (OS). While these factors were nonsignificant in chemotherapy cohort. Three nomograms to predict response at 6-week after treatment, PFS and OS at 6-, 12- and 18-months were developed, and validated in validation cohort. The C-indices of each nomogram in both cohorts were as follow (training vs validation): 0.706 vs 0.701; 0.728 vs 0.701; 0.741 vs 0.709; respectively. AUC showed a good discriminative ability. Calibration curves demonstrated a consistence between actual results and predictions. CONCLUSION: We developed predictive nomograms based on easily available factors to help clinicians early assess response and prognosis for NSCLC patients received anti-PD-1 antibody.

Combining serum calcitonin, carcinoembryonic antigen, and neuron-specific enolase to predict lateral lymph node metastasis in medullary thyroid carcinoma.

BACKGROUND: This study aimed to investigate the clinical application of combined detection of serum calcitonin (Ctn), carcinoembryonic antigen (CEA), and neuron-specific enolase (NSE) in predicting lateral lymph node metastasis (LLNM) in medullary thyroid carcinoma (MTC). METHODS: Seventy-four consecutive patients with MTC were enrolled. The relationship between serum Ctn, CEA, and NSE and LLNM was retrospectively analyzed by univariate analysis and logistic regression analysis. Furthermore, the clinical application of serum Ctn, CEA, and NSE combined detection in prediction of LLNM in MTC was also evaluated. RESULTS: The rate of LLNM in this study was 48.64% (36/74).The expression levels of serum Ctn, CEA, and NSE in MTC with LLNM were significantly higher than those without LLNM (all P < .01). The area under the curve (AUC) predicted by serum Ctn, CEA, and NSE for LLNM in MTC patients was 0.867, 0.831, and 0.726, respectively, and the AUC of serum Ctn, CEA, and NSE combined detection was up to 0.890, higher than using a single biomarker. The sensitivity and specificity of serum Ctn, CEA, and NSE combined detection in prediction of LLNM were 88.89% and 81.57%, respectively. CONCLUSIONS: The concentrations of serum Ctn, CEA, and NSE are closely related to LLNM in MTC, and the combined detection of all three biomarkers has a higher clinical value in the evaluation of MTC patients with LLNM. With more perspective study in the future, it would be an indicator of influencing personalized surgical strategy for different MTC patients.

The HosA Histone Deacetylase Regulates Aflatoxin Biosynthesis Through Direct Regulation of Aflatoxin Cluster Genes.

Histone deacetylases (HDACs) always function as corepressors and sometimes as coactivators in the regulation of fungal development and secondary metabolite production. However, the mechanism through which HDACs play positive roles in secondary metabolite production is still unknown. Here, classical HDAC enzymes were identified and analyzed in Aspergillus flavus, a fungus that produces one of the most carcinogenic secondary metabolites, aflatoxin B1 (AFB1). Characterization of the HDACs revealed that a class I family HDAC, HosA, played crucial roles in growth, reproduction, the oxidative stress response, AFB1 biosynthesis, and pathogenicity. To a lesser extent, a class II family HDAC, HdaA, was also involved in sclerotia formation and AFB1 biosynthesis. An in vitro analysis of HosA revealed that its HDAC activity was considerably diminished at nanomolar concentrations of trichostatin A. Notably, chromatin immunoprecipitation experiments indicated that HosA bound directly to AFB1 biosynthesis cluster genes to regulate their expression. Finally, we found that a transcriptional regulator, SinA, interacts with HosA to regulate fungal development and AFB1 biosynthesis. Overall, our results reveal a novel mechanism by which classical HDACs mediate the induction of secondary metabolite genes in fungi.

Diagnostic roles of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein, and cancer antigen 125 for ovarian cancer.

OBJECTIVE: To compare the diagnostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP) level, and cancer antigen 125 (CA125) level for ovarian cancer (OC). METHODS: Data of 72 patients with OC, 50 patients with benign ovarian disease, and 46 healthy controls were retrospectively analyzed, and receiver operating characteristic analysis was performed. RESULTS: The platelet count was higher in patients with a tumor diameter of ≥10 vs. <10 cm. The absolute lymphocyte count was significantly higher in patients with stage I/II OC than in those with multiple and stage III/IV OC. The absolute monocyte count, NLR, MLR, and CA125 were significantly higher in patients with multiple and stage III/IV OC than in those with single and stage I/II OC. The NLR, PLR, MLR, fibrinogen, D-dimer, CRP, and CA125 were useful for distinguishing between the OC and healthy control groups. CONCLUSIONS: Our analysis showed that the following combinations have practical diagnostic value in OC: NLR + PLR + MLR + CA125, NLR + PLR + MLR + CA125 + CRP, NLR + MLR +PLR + CA125 + CRP + fibrinogen, and NLR + MLR + PLR + CA125 + CRP + fibrinogen + D-dimer.

Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer.

OBJECTIVE: To investigate the prevalence and characteristics of gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Medical records of 197 patients with histologically proven NSCLC received gemcitabine-based chemotherapy from June 2011 to June 2013 in our hospital were collected. The relative risk factors were identified and evaluated by univariate and multivariate analyses. RESULTS: The incidence of gemcitabine-based chemotherapy-induced thrombocytopenia in these NSCLC patients was 85.8%. Between thrombocytopenia and nonthrombocytopenia patients, in patients with thrombocytopenia and thrombocytopenia, we found Stage III/IV patients got more probabilities for thrombocytopenia (P < 0.01). In addition, patients who received gemcitabine and cisplatin (GP) regimen resulted in more thrombocytopenia than gemcitabine and carboplatin (GC) and other regimens (P < 0.001). In addition, majority of the thrombocytopenia patients presented thrombocytopenia in their first cycle (P < 0.001). Whereas, other potential risk factors such as age, gender, performance status value, diabetes mellitus or not, and other underlying disease (hypertension and hepatopathy) were not showed such significance in this study. Further, the multivariate analysis revealed that stage (odds ratio [OR] 7.113, P < 0.01) and chemotherapy cycles (OR 0.543, P < 0.01) were also statistically significant independent risk factors for gemcitabine-based chemotherapy-induced thrombocytopenia. CONCLUSION: This study shows that thrombocytopenia is common in Chinese NSCLC patients receiving gemcitabine-based regimens. Chemotherapy cycles and stage might be the important factors influencing the occurrence of gemcitabine-based regimens-induced thrombocytopenia.

Effects of low-level organic selenium on lead-induced alterations in neural cell adhesion molecules.

Low-level lead (Pb) exposure has been reported to impair the formation and consolidation of learning and memory by inhibiting the expression of neural cell adhesion molecules (NCAMs) and altering the temporal profile of its polysialylation state. In this study, we investigated whether administration of low-level organic selenium (selenomethionine, Se) at different time points could affect Pb-induced changes of NCAMs in female Wistar rats. Here we reported that the exposure of Se (60µg/kg body weight/day) at different time points significantly alleviated Pb-induced reductions in the mRNA and protein levels of NCAMs, and increases in the mRNA levels of two polysialyltransferases (St8sia II, Stx; St8sia IV, Pst) as well as the sialyltransferase activity (p<0.05). The concentrations of Pb in blood and hippocampi of Wistar rats treated with the combination of Se and Pb were significantly lower than those treated with Pb alone (p<0.05). Our results suggest that low-level organic Se can not only prevent but also reverse Pb-induced alterations in the expression and polysialylated state of NCAMs as well as the concentration of Pb in rat blood and hippocampus.

Low-level lead exposure attenuates the expression of three major isoforms of neural cell adhesion molecule.

Toxic lead (Pb) exposure poses serious risks to human health, especially to children at developmental stages, even at low exposure levels. Neural cell adhesion molecule (NCAM) is considered to be a potential early target in the neurotoxicity of Pb due to its role in cell adhesion, neuronal migration, synaptic plasticity, and learning and memory. However, the effect of low-level Pb exposure on the specific expression of NCAM isoforms has not been reported. In the present study, we found that Pb could concentration-dependently (1-100 nM) inhibit the expression of three major NCAM isoforms (NCAM-180, -140, and -120) in primary cultured hippocampal neurons. Furthermore, it was verified that levels of all three major isoforms of NCAM were reduced by Pb exposure in human embryonic kidney (HEK)-293 cells transiently transfected with NCAM-120, -140, or -180 isoform cDNA constructs. In addition, low-level Pb exposure delayed the neurite outgrowth and reduced the survival rate of cultured hippocampal neurons at different time-points. Together, our results demonstrate that developmental low-level Pb exposure can attenuate the expression of all three major NCAM isoforms, which may contribute to the observed Pb-mediated neurotoxicity.