Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To investigate the prognostic value of Onodera's prognostic nutrition index (PNI) before treatment in patients with cervical and upper thoracic esophageal squamous cell carcinoma (CUTESCC) undergoing definitive chemoradiotherapy (dCRT) and its predictive value in the occurrence of ≥ grade 2 radiation esophagitis (RE).Methods:The data of 163 CUTESCC patients eligible for inclusion criteria admitted to the Fourth Hospital of Hebei Medical University from January 2012 to December 2017 were retrospectively analyzed. The receiver operating characteristic (ROC) curve was used to calculate the best cut-off value of PNI for predicting the prognosis of patients. The prognosis of patients was analyzed by univariate and Cox multivariate analyses. Logistics binary regression model was adopted to analyze the risk factors of ≥ grade 2 RE in univariate and multivariate analyses. The significant factors in logistic multivariate analysis were used to construct nomogram for predicting ≥ grade 2 RE.Results:The optimal cut-off value of PNI was 48.57 [area under the curve (AUC): 0.653, P<0.001]. The median overall survival (OS) and progression-free survival (PFS) were 26.1 and 19.4 months, respectively. The OS ( χ2=6.900, P=0.009) and PFS ( χ2=9.902, P=0.003) of patients in the PNI ≥ 48.57 group ( n=47) were significantly better than those in the PNI < 48.57 group ( n=116). Cox multivariate analysis showed that cTNM stage and PNI were the independent predictors of OS ( HR=1.513, 95% CI: 1.193-1.920, P=0.001; HR=1.807, 95% CI: 1.164-2.807, P=0.008) and PFS ( HR=1.595, 95% CI: 1.247-2.039, P<0.001; HR=2.260, 95% CI: 1.439-3.550, P<0.001). Short-term efficacy was another independent index affecting PFS ( HR=2.072, 95% CI: 1.072-4.003, P=0.030). Logistic multivariate analysis showed that the maximum transverse diameter of the lesion ( OR=3.026, 95% CI: 1.266-7.229, P=0.013), gross tumor volume (GTV) ( OR=3.456, 95% CI: 1.373-8.699, P=0.008), prescription dose ( OR=3.124, 95% CI: 1.346-7.246, P=0.009) and PNI ( OR=2.072, 95% CI: 1.072-4.003, P=0.030) were the independent factors affecting the occurrence of ≥ grade 2 RE. These four indicators were included in the nomogram model, and ROC curve analysis showed that the model could properly predict the occurrence of ≥ grade 2 RE (AUC=0.686, 95% CI: 0.585-0.787). The calibration curve indicated that the actually observed values were in good agreement with the predicted RE. Decision curve analysis (DCA) demonstrated satisfactory nomogram positive net returns in most threshold probabilities. Conclusions:PNI before treatment is an independent prognostic factor for patients with CUTESCC who received definitive chemoradiotherapy. The maximum transverse diameter of the lesion, GTV, prescription dose and PNI are the risk factors for ≥ grade 2 RE in this cohort. Establishing a prediction model including these factors has greater predictive value.

Objective:To evaluate the efficacy and prognostic factors of radiotherapy combined with immunotherapy as the first-line treatment for patients with locally advanced or metastatic esophageal squamous cell carcinoma (LA/M ESCC).Methods:A single-center, retrospective analysis was conducted for the recent efficacy, survival, prognostic factors, post-treatment failure modes, and treatment-related adverse reactions of 57 LA/M ESCC patients eligible for enrollment.Results:The entire group of patients had 1-, 2-, and 3-year overall survival (OS) of 86.0%, 57.5%, and 53.9%, respectively and 1-, 2-, and 3-year progression-free survival (PFS) of 61.4%, 31.0%, and 31.0%, respectively. The median OS was not reached, and the median PFS was 15.0 (95% CI: 10.77-19.23) months. These patients had an overall response rate (ORR) of 80.7% (46/57) and a disease control rate (DCR) of 94.7% (54/57). As indicated by the result of the multivariate analysis, the independent prognostic factors affecting the OS of the patients included their age, clinical stage, number of immunotherapy cycles, and recent efficacy ( HR = 0.25, 2.58, 0.35, 4.05, P < 0.05), and the independent factors influencing the PFS of the patients included their clinical stage and recent efficacy ( HR = 2.27, 1.97, P < 0.05). There were no statistically significant differences in the effects of irradiation ranges and the combination modes of immunologic drugs and chemoradiotherapy on both OS and PFS of the patients ( P > 0.05). A total of 32 patients suffered post-treatment failure. After the second treatment, they had 1- and 2-year OS of 55.7% and 25.3%, respectively, with median OS of 14.0 (95% CI: 5.17-22.83) months. A total of 26 cases experienced treatment-associated adverse reactions of grades 2 or higher during and after treatment. Conclusions:The combination of radiotherapy and immunotherapy is effective and safe as the first-line treatment for LA/M ESCC patients. The post-treatment failure modes still include local recurrence and distant metastasis. Therefore, such combination merits further investigation.

Objective:To investigate the recurrence-free survival (RFS) and influencing factors of intensity-modulated radiotherapy±chemotherapy (IMRT±C) for the upper thoracic esophageal cancer.Methods:The medical records of 168 patients with cervical and upper thoracic esophageal cancer who met the inclusion criteria from January 2011 to December 2015 were retrospectively analyzed. The RFS was calculated by the Kaplan-Meier method. Multivariate prognostic analysis was performed by Cox models. The recurrence factors were identified by the Logistics model. Results:The 1-, 3-, and 5-year RFS rates were 67.8%, 38.0%, and 20.4%, respectively, and the median RFS was 21.9 months. The locoregional recurrence rate was 47.6%(80/168). The recurrence sites were local esophagus ( n=63), regional lymph nodes ( n=7), and local esophagus+ regional lymph node recurrence ( n=10). Multivariate analysis showed that hoarseness, cTstaging, combined with chemotherapy, 95%PTV 1 exposure dose and GTV average exposure dose were the influencing factors of RFS ( P=0.029, <0.001, 0.031, 0.038, 0.020). Logistics model showed that cTstaging, cNstaging, short-term efficacy, irradiationmethod, GTV maximum transverse diameter and PTV average exposure dose were the influencing factors of recurrence ( P=0.046, 0.022, 0.001, <0.001, 0.012, 0.001). Conclusions:Patients with cervical and upper thoracic esophageal cancer treated with radical IMRT combined with/without chemotherapy have a higher locoregional recurrence rate, and the recurrence rate is mainly the esophagus. The independent factors that affect RFS are different from the risk factors of recurrence.

Objective:To analyze the therapeutic effects and prognosis after radiotherapy (chemotherapy) of patients with postoperative recurrent esophageal cancer.Methods:This study analyzed 501 patients with postoperative recurrent esophageal cancer who were treated in the Radiotherapy Department of the Fourth Hospital of Hebei Medical University and met enrollment conditions. Among them, 274 patients received concurrent chemotherapy and radiotherapy. The analyses in this study focused on the survival after the retreatment, postoperative recurrence patterns, prognosis of retreatment, and prognostic factors affecting the retreatment. Meanwhile, statistical analysis was conducted using the software SPSS Statistics 19.0.Results:The time of postoperative recurrence was 0.3-87.4 months, with a median number of 11.6 months. The median survival time was 12.1 months after the retreatment. Among all the patients, 344 patients suffered from only local recurrence, while the remaining 157 patients experienced distant metastasis. According to multivariate analysis result, independent prognostic factors included gender, pN stage, lymph node positive logarithmic ratio (LODDS), the number of chemotherapy cycles, time of recurrence, and distant metastasis ( P < 0.05). Meanwhile, prognostic factors affecting the 344 patients with only local recurrence included the time of recurrence, the number of chemotherapy cycles, and prescription dose ( χ2=22.605, 13.957, 10.446; P< 0.05). The remaining 157 patients suffered from distant metastasis. The 1-, 3-, and 5-year survival rates of them were 43.3%, 9.1%, and 5.5%, respectively, and those of the patients with only local recurrence were 53.6%, 22.6%, and 16.4%, respectively. The differences were statistically significant (χ 2=10.786, P< 0.05). Conclusions:Radiotherapy (chemotherapy) is safe and effective for the treatment of recurrent esophageal cancer. However, it features poor prognosis for male patients with a late pN stage, a high LODDS, the number of chemotherapy cycles ≤ 2, the time of recurrence≤ 24 months, and distant metastasis.

Objective:To evaluate the effects of different irradiation doses on postoperative local recurrence in patients with esophageal cancer after radio (chemo) therapy.Methods:Clinical data of 331 esophageal cancer patients presenting with postoperative local recurrence admitted to our hospital from 2009 to 2014 were collected. The recurrence site, the effects of different radiotherapy doses on the prognosis of patients and the independent prognostic factors were retrospectively analyzed. The survival rate was calculated by Kaplan-Meier method. Univariate prognostic analysis was performed by log-rank test. Multivariate prognostic analysis was conducted by Cox proportional hazard regression model.Results:The 1-, 3-and 5-year overall survival rates were 54.3%, 23.2% and 16.6%, respectively. The median overall survival was 13.4 months (95% CI: 11.7-15.0). The median survival of patients with radiotherapy doses< 60 Gy and ≥60 Gy was 10.8 and 13.9 months ( P=0.013). Stratified analysis showed that patients with age< 60 years, no smoking history, no drinking history, no family history, upper thoracic segment, left thoracotomy, N 0 staging, log odds of positive lymph nodes (LODDS)< 0.030, recurrence time ≥ 13.1 months and recurrence site ≥ 2 had better prognosis when receiving radiotherapy dose ≥ 60 Gy ( P=0.038, 0.033, 0.001, 0.003, 0.018, 0.010, 0.041, 0.039, 0.043 and 0.007). Moreover, the short-term clinical efficacy of patients treated with ≥60 Gy dose was significantly better than that of those with<60 Gy dose ( P<0.001), which did not increase the incidence of ≥grade 2 radiation-induced gastritis ( P=0.977) or radiation-induced pneumonitis ( P=0.444). Cox multivariate analysis showed that the LODDS size, prescription dose and short-term efficacy were the independent factors affecting clinical prognosis of patients ( P=0.006, 0.008 and<0.001). Conclusions:The recommended dose for esophageal cancer patients with local recurrence after radiotherapy (chemotherapy) is greater than or equal to 60 Gy. The results of this study need to be confirmed by prospective studies with a large sample size.

Objective:To explore the benefit groups of patients with locoregional recurrence of esophageal thoracic squamous cell carcinoma who received radiotherapy or chemoradiotherapy with different patterns of irradiation.Methods:Clinical data of 344 esophageal thoracic squamous cell carcinoma patients with postoperative recurrence who received intensity conformal radiotherapy or concurrent chemoradiotherapy in the Fourth Hospital of Hebei Medical University from 2009 to 2014 were retrospectively analyzed. The distribution of recurrence sites and prognostic factors were analyzed. A stratified analysis was carried out on the benefit groups of patients receiving the elective nodal irradiation (ENI) and involved field irradiation (IFI).Results:276 cases (80.2%) recurred at a single site and 68 cases (19.8%) recurred at more than two sites. The follow-up rate was 96.2%. The 1-, 3-and 5-year overall survival rates were 53.6%, 22.6% and 16.4%, respectively, with a median of 12.8 months (95% CI: 11.3-14.3 months). The 1-, 3-and 5-year local recurrence-free survival rates were 46.5%, 16.9% and 12.0%, respectively, with a median of 11.0 months (95% CI: 9.6-12.4 months). The 1-, 3-and 5-year progression-free survival rates were 39.8%, 11.3% and 6.7%, respectively, with a median of 7.9 months (95% CI: 5.8-10.0 months). Multivariate analysis showed that gender, the log odds of metastatic lymph nodes (LODDS) and the number of chemotherapy cycles were the independent prognostic factors ( P=0.003, <0.001, <0.001). Subgroup univariate analysis demonstrated that patients with an esophageal lesion length<5.0 cm, N 0 stage, the number of surgically-dissected lymph nodes of ≤9, the number of postoperative positive lymph node metastasis site of 0, and LODDS≤0.030 obtained benefits from ENI ( P=0.032, 0.012, 0.001, 0.012 and 0.014). Patients with the number of surgically-dissected lymph nodes of ≥16 achieved benefits from IFI ( P=0.035). Conclusions:Radiotherapy is an effective treatment mode for patients with local recurrence after esophageal cancer surgery. For patients with preoperative esophagography showing shorter esophageal lesions, earlier postoperative pathological N stage, lower LODDS score, and fewer surgically-dissected lymph nodes probably obtain more benefits from ENI than IFI. However, patients with more surgically-dissected lymph nodes may obtain more benefit from IFI compared with ENI.

Fentanyl and fentanyl-related substances are a series of synthetic and powerful anesthetics represented by fentanyl. In recent years,the abuse and trafficking of these substances in many countries around the world are serious which poses a great threat to people"s health and social stability. This paper focuses on the abuse,pharmacological and toxicological action,detection methods and control of fentanyl and fentanyl-related substances and aims to enhance people"s understanding of their basic properties,current research and control so as to provide references for future research.

Objective:To investigate the prognosis and failure mode of patients with esophageal squamous cell carcinoma receiving selective lymph node irradiation (ENI).Methods:A total of 179 eligible patients with esophageal squamous cell carcinoma were retrospectively analyzed. The prognostic value of tumor-related factors, the influencing factors of short-term curative effect and prognosis of patients, and the single and multi factor indexes of affecting the overall survival rate (OS), progression free survival rate (PFS) and recurrence of patients were analyzed.SPSS 19.0 software was used for statistical analysis.Results:The 1, 3- and 5-year OS of the whole group were 77.1%, 40.1% and 26.0%, respectively, and 1-, 3- and 5-year PFS were 62.6%, 30.6%, and 20.3%, respectively. Multivariate analysis showed that hoarseness, cN stage, cTNM stage, GTV-transverse diameter (GTV-D) and GTV-volume/length (GTV-V/L) were independent factors affecting OS ( P<0.05). The sonar, cTNM staging, and short-term efficacy were independent factors affecting PFS ( P<0.05). Recurrence occurred in 75 patients (41.9%) in the whole group, and 61 patients (34.1%) had distant metastases. Among them, 9 patients (10.6%) had both recurrence and distant metastasis. Of the 75 patients with recurrence, 64(85.3%) had simple esophageal recurrence, 4(5.3%) had lymph node recurrence, and 7 (9.3%) had both. Recurrence occurred in 18 of the 63 patients who achieved CR after treatment. Only 2 patients had lymph node recurrence. Logistic multivariate analysis showed that the surrounding tissue/organ invasion, GTV-D and short-term were independent factors affecting the recurrence rate ( P<0.05). Conclusions:ENI is feasible in patients with esophageal squamous cell carcinoma, and the main mode of failure is esophageal recurrence. Pre-treatment sonar, larger GTV-D and GTV-V/L, more advanced clinical stage and poorer short-term efficacy are indicators of poor prognosis, while the peripheral tissue involvement, GTV-D and short-term efficacy are the independent factors that influence failure.

Objective:To analyze the effect of positive lymph node log ratio (LODDS) on the prognosis of postoperative patients with esophageal cancer, and analyze the effect of LODDS on the evaluation of the efficacy of patients receiving different postoperative adjuvant treatment.Methods:A total of 1 546 patients with esophageal cancer treated in the Fourth Hospital of Hebei Medical University were retrospectively analyzed. The effect of LODDS on the prognosis of patients was retrospectively analyzed. The significance of LODDS in choosing different treatment options for patients after operation was further analyzed.Results:The 1-, 3- and 5-year survival rates were 87.5%, 61.7% and 52.2%, respectively. The result of area under curve(ROC)curve analysis show that -1.354 1 is the best cut-off point for LODDS. Multivariate analysis showed that gender, age, lesion location, degree of adhesion, adjuvant therapy, pTNM stage and LODDS were the independent factors affecting the patients ( P<0.05). After propensity-matched analysis(PSM)analysis, there were 205 patients in each group. Multivariate analysis showed that gender, degree of adhesion, adjuvant therapy, pTNM stage and LODDS were independent prognostic factors ( P<0.05). The result of stratified analysis showed that patients with small LODDS values had better prognosis (OS) in patients undergoing postoperative adjuvant therapy than patients in the surgery alone ( χ2=81.470, 5.182, P<0.05), but postoperative chemotherapy (POCT) and postoperative radiotherapy and chemotherapy (POCRT) had no significant difference in the OS of patients ( P>0.05). However, in the larger LODDS group, the OS of patients in the POCRT group was significantly better than the other two groups ( χ2=4.151, 24.020, P<0.05), and there was also a significant difference between the POCT and POCRT groups ( χ2=8.728, P<0.05). Conclusions:LODDS is an independent prognostic factor for postoperative patients with esophageal squamous cell carcinoma and can guide the choice of postoperative adjuvant therapy to a certain extent. This conclusion needs further clinical research to confirm.