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 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.

The waste water-based epidemiology is an important technique to fight against drug abuse by analyzing the concentration of illicit drugs in urban sewage, which can monitor the abuse of drugs.An SPE-UPLC-MS/MS method was developed for the analysis of 12 common drugs and their metabolites involving amphetamine and morphine.It was shown that the best result was achieved when hydrochloric acid/ acetonitrile (5∶95) was added to acidify the sample during the concentration process, guaranteeing the anti-across contamination of the analysis of organic nitrogen basic trace components, and improve the stability, specificity, and accuracy of the method.The optimized method meets the analytical requirements of complex sewage samples, and has been successfully applied to the assessment of urban drug abuse through sewage analysis.

Objective:To evaluate the effectiveness and safety of intravitreal injection of different doses of aflibercept for polypoidal choroidal vasculopathy (PCV) with serous pigment epithelial detachment (PED) resistant to ranibizumab.Methods:A non-randomized controlled clinical study was conducted.Seventy-three eyes of 73 patients with PCV and serous PED resistant to ranibizumab were enrolled at the First Affiliated Hospital of Zhengzhou University from January 2019 to December 2020.All patients were treated by intravitreal injection of 2 mg or 4 mg aflibercept according to patients' willingness.2 mg aflibercept or 4 mg aflibercept was intravitreally injected monthly for three consecutive months following pro re nata (PRN) regimen in 2 mg aflibercept group (38 eyes) and 4 mg aflibercept group (35 eyes), respectively.PED height and central macular thickness (CMT) were measured by optical coherence tomography, and the best corrected visual acuity (BCVA) was examined with a visual acuity chart and converted to logarithm of the minimum angle of resolution (LogMAR) unit before injection and 1 month, 2, 3, 6 months from the first injection.Intraocular pressure and treatment-related adverse events were recorded.This study adhered to the Declaration of Helsinki and was approved by an Ethics Committee of The First Affiliated Hospital of Zhengzhou University (No.2021-KY-1252).Written informed consent was obtained from each patient prior to entering study cohort.Results:Thirty-three patients (86.84%) in 2 mg aflibercept group and 30 patients (85.71%) in 4 mg aflibercept group finished the treatment and follow-up, respectively. The PED, BCVA and CMT before treatment and at the end of follow-up were (379.24±95.50) and (280.09±120.50)μm, 0.68±0.27 and 0.51±0.19, (393.96±100.81) and (291.70±44.09)μm in 2 mg aflibercept group, respectively, showing statistically significant differences (all at P<0.05).The PED, BCVA and CMT before treatment and at the end of follow-up were (393.07±93.76) and (278.63±145.07)μm, 0.66±0.31 and 0.48±0.22, (377.43±79.61) and (284.67±84.88)μm in 4 mg aflibercept group, respectively, with statistically significant differences (all at P<0.05).The CMT value in 4 mg aflibercept group was significantly lower than that in the 2 mg aflibercept group in one month after injection ( P<0.05).No severe ocular and systemic adverse events were found during the follow-up, such as retinal detachment, endophthalmitis, cataract, and persistent high intraocular pressure. Conclusions:Both 2 mg and 4 mg aflibercept can effectively treat ranibizumab-resistant PCV with serous PED, and improve the anatomical structure of retina and BCVA.4 mg aflibercept can accelerate the recovery of PED and CMT.

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.

In this study,we developed a novel on-line solid phase extraction (SPE)-ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS)-based analytical method for simulta-neously quantifying 12 illicit drugs and metabolites (methamphetamine,amphetamine,morphine,co-deine,6-monoacetylmorphine,benzoylecgonine,3,4-methylenedioxymethamphetamine,3,4-methylenedioxyamphetamine,cocaine,ketamine,norketamine,and methcathinone) and cotinine(COT) in wastewater samples.The analysis was performed by loading 2 mL of the sample onto an Oasis hydrophilic-lipophilic balance cartridge and using a cleanup step (5％ methanol) to eliminate interference with a total run time of 13 min.The isotope-labeled internal standard method was used to quantify the target substances and correct for unavoidable losses and matrix effects during the on-line SPE process.Typical analytical characteristics used for method validation were sensitivity,linearity,precision,repeatability,recovery,and matrix effects.The limit of detection (LOD) and limit of quantification (LOQ)of each target were set at 0.20 ng/L and 0.50 ng/L,respectively.The linearity was between 0.5 ng/L and 250 ng/L,except for that of COT.The intra-and inter-day precisions were ＜10.45％ and 25.64％,respec-tively,and the relative recovery ranged from 83.74％ to 162.26％.The method was used to analyze various wastewater samples from 33 cities in China,and the results were compared with the experimental re-suits of identical samples analyzed using off-line SPE.The difference rate was between 19.91％and-20.44％,and the error range could be considered acceptable.These findings showed that on-line SPE is a suitable alternative to off-line SPE for the analysis of illicit drugs in samples.

Objective: To evaluate the effect of locoregional risk factors of esophageal cancer on the recurrence of gross tumor volume (GTV) in patients with N₀ esophageal squamous cell carcinoma after radical intensity-modulated radiotherapy (IMRT) and to evaluate its effect on the 10-year survival of patients. Methods: Clinical data of 374 patients with clinical N₀ esophageal squamous cell carcinoma who underwent radical IMRT in the Fourth Hospital of Hebei Medical University from 2005 to 2010 were retrospectively analyzed. Involved-field irradiation was performed in 284 patients and selective lymph node irradiation was given in 90 patients. Concurrent radiochemotherapy was conducted in 69l patients and sequential radiochemotherapy was performed in 38 patients. The survival analysis was carried out by Kaplan-Meier method. The prognosis analysis was performed by multivariate Cox’s regression model. Results: A total of 143 patients (38.2%) had recurrence in GTV. The maximum transverse diameter (GTV-D), GTV volume (GTV-V) and GTV volume/length (GTV-V/L) of GTV patients were significantly longer than those without recurrence in GTV (P=0.008, 0.043, 0.001). ROC curve analysis showed that the optimal diagnostic thresholds for GTV-D, GTV-L, GTV-V and GTV-V/L for GTV recurrence were 3.5 cm, 5.5 cm, 24.0 cm³ and 4.6 cm², respectively (P=0.000, 0.003, 0.000 and 0.000), and the ratio of recurrence within GTV in the patient group was significantly greater than that in the smaller group (P=0.000, 0.002, 0.001 and 0.000). GTV-L and GTV-V/L were the independent risk factors of recurrence in GTV (P=0.021 and 0.009). The 3-, 5-and 10-year survival rates of all patients in the whole group were 42.9%, 23.2% and 7.9%, respectively. Multivariate analysis demonstrated that age, T stage, concurrent radiochemotherapy, GTV-D and GTV-V/L were the independent risk factors of survival (P=0.027, 0.000, 0.018, 0.009 and 0.034). The main cause of death in patients with a survival time of more than 5 years was still associated with cancer. Conclusions The locoregional risk factors of esophageal cancer exert significant effect on the recurrence of GTV in patients with N₀ esophageal squamous cell carcinoma undergoing radical radiochemotherapy, which can be utilized as the predicting markers. Both GTV-D and GTV-V/L are significantly correlated the 10-year survival of patients.