Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Objective To investigate the expression and clinical significance of PHH 3 and β-catenin in non-small cell lung cancer ( NSCLC) .Methods 78 cases of NSCLC tissue removed from June 2013 to June 2017 in Rizhao Central Hospital were collected .The expression of PHH3 and β-catenin protein in NSCLC and 30 cases of normal lung tissues were detected by immunohistochemical MaxVision method .The relationship between the expres-sion of PHH3 andβ-catenin protein was analyzed .The relationship between the expression of PHH 3,β-catenin and the clinicopathological features of NSCLC was analyzed .Results The positive rate of PHH3 in NSCLC tissues ( 57/78,73.1％) was significantly higher than that in normal lung tissues (2/30,6.7％)(χ2 =38.553,P<0.05).The expression level of PHH3 was significantly correlated with tumor differentiation (χ2 =5.248,P<0.05),lymph node metastasis(χ2 =7.747,P<0.05),but it was not related to the age (χ2 =0.209,P>0.05),gender(χ2 =0.033,P>0.05) and pathological type (χ2 =0.190,P>0.05).The positive rate of β-catenin in NSCLC tissues (54/78, 69.2％) was significantly higher than that in normal lung tissues (3/30,10.0％) (χ2 =30.499,P <0.05).The expression level of β-catenin was significantly correlated with tumor differentiation (χ2 =4.934,P<0.05),lymph node metastasis(χ2 =8.098,P<0.05),but it was not related to the age (χ2 =0.006,P>0.05),gender(χ2 =0.595,P>0.05) and pathological type (χ2 =0.071,P>0.05).The expression of PHH3 was positively correlated withβ-catenin(r=0.597,P<0.05).Kaplan-Meier analysis showed that PHH3 and β-catenin expression was negatively correlated with prognosis .Conclusion The overexpression of PHH3 and β-catenin in NSCLC may be related to the development ,invasion and metastasis of NSCLC ,which is expected to be an indicator of NSCLC ,and to predict invasion and metastasis .

Objective To assess the value of SPECT/CT lung perfusion imaging (SPECT/CT-LPI) in evaluation of the regional lung function and the correlation between lung perfusion defects (LPD) and the clinical findings in NSCLC patients.Methods A total of 48 NSCLC patients (43 males,5 females;average age 61.06 years) who underwent pulmonary function tests (PFT),CT and 99Tcm-MAA SPECT/CT-LPI from December 2006 to March 2013,were retrospectively studied.LPD were divided into four grades:grade 0 (no lung perfusion defect was identified),grade 1 (the area of lung perfusion defect (LPDA) was similar to the size of local tumor),grade 2 (the LPDA was larger than local tumor and extends to 1 pulmonary lobe),grade 3 (the LPDA exceeded 1 pulmonary lobe).x2 test,one-way analysis of variance and Logistic regression analysis were used to analyze the correlation of the lung perfusion function and clinical findings.Results LPD were found in 44 patients (91.67％,44/48),including 18 with grade 1,15 with grade 2,11 with grade 3.The abnormal results of PFT were found in 16 patients (33.33％,16/ 48).The abnormal findings by SPECT/CT-LPI were more than that by PFT (x2=34.844,P＜0.01).The rates of LPD with grade ≥ 2 were significant different between patients with central lung cancer and those with peripheral lung cancer (x2 =8.392,P＜0.01),and between hilar lymph nodes positive group and negative group (x2=10.801,P＜0.01).The degree of LPD was related to tumor location (1 was assigned for central lung cancer,2 was assigned for peripheral lung cancer),tumor size (1 was assigned for maximum diameter ≤3.0 cm,2 was assigned for ＞3.0 cm and ≤5.0 cm,3 was assigned for ＞5.0 cm) and hilar lymph node (1 was assigned for with metastasis,0 was assigned for no metastasis) (Wald=8.176,5.352,10.100,all P＜0.05).Conclusions Compared with PFT,SPECT/CT-LPI has a more significant value in assessment of the regional lung function in NSCLC patients.Tumor location,tumor size and metastasis of hilar lymph nodes may be helpful for LPD grading.SPECT-LPI may be beneficial for patients with central lung cancer,large tumor and hilar lymph nodes metastasis.

Objective To discuss the spatial-temporal distribution and epidemic trends of autumn-winter type scrub typhus in Shandong province,and provide scientific evidence for further study for the prevention and control of the disease.Methods The scrub typhus surveillance data during 2006-2014 were collected from Shandong Disease Reporting Information System.The data was analyzed by using software ArcGIS 9.3 (ESRI Inc.,Redlands,CA,USA),GeoDa 0.9.5-i and SatScan 9.1.1.The Moran' s I,log-likelihood ratio (LLR),relative risk (RR) were calculated and the incidence choropleth maps,local indicators of spatial autocorrelation cluster maps and space scaning cluster maps were drawn.Results A total of 4 453 scrub typhus cases were reported during 2006-2014,and the annual incidence increased with year.Among the 17 prefectures (municipality) in Shandong,13 were affected by scrub typhus.The global Moran' s I index was 0.501 5 (P＜0.01).The differences in local Moran' s I index among 16 prefectures were significant (P＜0.01).The "high-high" clustering areas were mainly Wulian county,Lanshan district and Juxian county of Rizhao,Xintai county of Tai' an,Gangcheng and Laicheng districts of Laiwu,Yiyuan county of Zibo and Mengyin county of Linyi.Spatial scan analysis showed that an eastward moving trend of high-risk clusters and two new high-risk clusters were found in Zaozhuang in 2014.The centers of the most likely clusters were in the south central mountainous areas during 2006-2010 and in 2012,eastem hilly areas in 2011,2013 and 2014,and the size of the clusters expanded in 2008,2011,2013 and 2014.One spatial-temporal cluster was detected from October 1,2014 to November 30,2014,the center of the cluster was in Rizhao and the radius was 222.34 kilometers.Conclusion A positive spatial correlation and spatial agglomerations were found in the distribution of autumn-winter type scrub typhus in Shandong.Since 2006,the epidemic area of the disease has expanded and the number of high-risk areas has increased.Moreover,the eastward moving and periodically expanding trends of high-risk clusters were detected.

Objective To explore the spatial and temporal characteristics of human brucellosis in Shandong province and to provide scientific basis for the development of related regional public health strategies.Methods 1 802 diagnosed cases of human brucellosis patients were selected based on the data that was collected by Diseases Reporting Information System between year 2004 and 2012 in Shandong province.Methods on spatial thematic mapping,spatial autocorrelation analysis,spatial clustering analysis,and temporal clustering analysis were applied to describe the temporal and spatial distribution on human brucellosis cases.Results The incidence rate of human brucellosis increased from 0.038 2/100 000 (35 cases) to 0.620 5/100 000 (598 cases),with annual average incidence rate as 0.211 1/100 000 and the incidence was evidently increased.The value of M (0.375 3) showed that this disease was seasonal,with the epidemic months between March and June,accounting for 56.27％ (1 014/1 802).The Global Moran' s I index was 0.198 901 (P=0.000 120),showing that there was a positive correlation between space and the incidence of brucellosis.The incidence rates in 2006,2007,2009 and 2012 and the space distribution appeared a positive correlation (P＜0.05) in Shandong province.The local Moran's I index showed that there were 8 “High-High” (HH) clustering areas,which were proved to have statistical significance (P＜0.05).Local indicators of spatial association (LISA) revealed that southwest and north districts of Shandong were highly clustered districts of brucellosis and the areas paralleled to the areas that having higher incidence rates.There were two spatial clustering areas in this study,one as the center of Juanchen with radiation radius at 33.83 km whose RR was 9.78 (P＜0.05) and the other was the center of Binchen with radiation radius at 62.78 km with RR as 4.99 (P＜0.05).All the 8 HH counties (districts) were included in the two cluster regions.Conclusion Incidence of human brucellosis showed an obvious increase in Shandong during year 2004-2012.Months with epidemics were between March and June.The incidence of brucellosis in counties (districts) was non-randomly distributed.A positive spatial correlation and the feature of clusters was noticed.

Objective To compare 18 F-FDG PET/CT and electronic endoscopy for measuring the length of esophageal squamous cell carcinoma (ESCC) and to evaluate the optimal SUV threshold for contour determination of the size of the lesion.Methods Twenty-four patients (19 males and 5 females,median age:59 years) with histologically confirmed ESCC were enrolled.Three patients had stage Ⅱ,14 had stage Ⅲ and 7 had stage Ⅳ diseases.PET studies were performed before treatment.The length of ESCC was measured on FDG PET imaging using different SUV thresholds of 2.0 (L2.0),2.5 (L2.5),3.0 (L3.0),3.5 (L3.5),and 35％(L35),40％(L40),45％(L45),50％(L50),55％(L55) of SUVmax.The length of ESCC on PET imaging was compared with the length of gross tumor in vivo measured by electronic endoscopy (Lst) to determine the optimal threshold of SUV using paired t test.Pearson correlation analysis was used to assess the correlation.Results The SUVmax of primary tumor was 14.51±5.72 and the Lst was (5.27± 2.45) cm.The length was in a descending order of L2.0,L2.5,Lst,L3.0,L3.5,L35,L40,L45,L50 and L55 when using different criteria.There were significant differences between the Lst and the lengths measured on PET except those by L2.5 and L3.0((5.65±2.69) cm,(5.11±2.51) cm; t=-1.74 and 0.76,both P＞0.05).The lengths measured on PET by all criteria were significandy correlated with the Lst,respectively,with the better r values by L3.5(0.935),L2.5(0.920) and L3.0(0.919) (all P＜0.01).When SUVm~＜15,there were no significant differences between the Lst ((4.82±2.14) cm) and L2.5((4.95±2.76) cm),L3.0((4.45±2.50) cm) and L35((4.42±1.85) cm),respectively (t=-0.439,1.299,2.011,all P＞0.05).The best correlation (r=0.953,P＜0.05) was between Lst and Lz5.When SUVmax ≥ 15,there was no significant difference between Lst ((5.67±2.64) cm) and L3.0((6.11±2.61) cm; t=-0.897,P＞0.05; r=0.791,P＜ 0.05).Conclusions For better correlation of ESCC lesion size,it is suggested that the optimal threshold of SUV for contouring is 2.5 for tumor SUVmax＜15,and 3.0 for tumor SUVmax ≥ 15.A larger sampling size is needed for further confirmation or modification.

Objective To evaluate the treatment efficacy and treatment-related toxicity of late course accelerated hyperfractionated radiotherapy (LCAHRT) combined with cisplatin-based chemotherapy (CHT) for locally advanced esophageal squamous cell carcinoma (ESCC).Methods A total of 46 patients with histologically confirmed ESCC,11 in the stage Ⅱa,3 in the stage Ⅱb,and 32 in the stage Ⅲ,underwent conventional fractioned radiation of 40 Gy in 20 fractions on the primary and metastatic lymph nodes,and high-risk lymph node drainage regions,and then the primary and metastatic lymph nodes were irradiated as boost with an additional dose of 19.6 Gy in 14 fractions (1.4 Gy twice a day),and the total prescribed dose was 59.6 Gy in 34 fractions.Two cycles of CHT were administered concurrently during the radiotherapy.The 1-,3-,and 5-year overall survival (OS) rates and local control rates (LCRs) were evaluated by Kaplan-Meier method,and treatment-related toxicity was analyzed based on the RTOG and CTCAE criteria 3.0.Results All patients received the whole course of treatment.The median followup time was 34.4 months (6-67 months).The overall response rate was 91.3％ (42/46).The median OS was 38.5 months (95％ CI 29.6-47.4 months).The 1-,3-,and 5-year OS rates and LCRs were 78.6％,49.4％,and 39.9％,and 84.3％,68.2％,and 61.4％ respectively.The incidence of ≥ G3 radiationinduced esophagitis was 23.9％.Three kinds of serious (≥G3) hematologic toxicities were recorded,including leucopenia (26.1％),thrombocytopenia (13.0％),and anemia (10.9％).Esophagotracheal fistula was recorded in 2 patients (4.3％).Conclusion LCAHRT plus CTH can be favorable for the patients with locally advanced ESCC,however,the treatment-related toxicities may be serious.

Objective To assess the efficacy and the adverse effects of improved late course accelerated hyperfractionated radiotherapy (LCAHRT) combined with cisplatin-based chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC).Methods 68 Patients with pathologically confirmed ESCC were enrolled.Conventional fractionation was implemented to 40 Gy/20 fractions,followed by LCAHRT delivered 2 fractions of 1.4 Gy with an interval of 6-8 hours per day to 14 fractions,thus the total dose was 59.6 Gy.Two cycles of cisplatin-based chemotherapy were administered concurrently,followed by two more cycles.The short-term efficacy of treatment,overall survival for 1-,3-,5-year,and treatment-related toxicity were evaluated.Results All patients successfully completed LCAHRT and the overall response rate was 91.6％ (62/68).The overall survival rate of 1-,3-,and 5-year was 75.5％,46.5％,22.7％,respectively.The incidence of radiation esophagitis (grade 3 or greater) was 26.4％,and no patients developed grade 3 or worse radiation pneumonitis.The radiation-induced skin injury were most of grade 0 or 1.Grade 3 of leucopenia and neutropenia were observed in 29.4％ and 7.4％ of patients,respectively,and grade 4 were both in 2.9％.During long-term follow-up,no esophageal stenosis and severe pulmonary fibrosis was developed except for two cases(2.9％)of esophageal mediastinal fistula.Conclusion Late course accelerated hyperfractionated radiotherapy combined with chemotherapy yields promising long-term survival,with lower treatment-related toxicity for patients of locally advanced esophageal squamous cell carcinoma.

Objective To analyze the clinical and dosimetric risk factors for acute radiation esophagitis (ARE) in non-small cell lung cancer (NSCLC) patients treated with three-dimensional conformal radiotherapy (3D-CRT),and to find significant risk factors for clinical therapy.Methods A total of 102 NSCLC patients treated with 3D-CRT were retrospectively analyzed.ARE was scored according to the Radiation Therapy Oncology Group (RTOG) criteria with grade 2 or worse.Patients were divided into non-concurrent chemoradiotherapy group and concurrent chemoradiotherapy group.The clinical and dosimetric factors associated with grade 2 or worse ARE were analyzed using univariate logistic regression,multivariate logistic analysis and receiver operating characteristic ( ROC ) curve.Results There were no grade 4 or5 ARE observed in the 102 patients.Nineteen developed grade 2,15 developed grade 3.In nonconcurrent chemoradiotherapy group,multivariate analysis showed that V55 was the only risk factor of grade 2/3 ARE.For ROC curve analysis,the cut-off point of V55 was 16.0 while the area under ROC curve was 0.870 ( 95 ％ CI:0.782 - 0.957,P ＜ 0.05 ).In concurrent chemoradiotherapy group,multivariate analysis showed that V35 and chemotherapy regimens during radiotherapy were risk factors of grade 2/3 ARE.The cut-off point of V35 was 23.75 while the area under ROC curve was 0.782 (95％ CI:0.636 -0.927,P ＜0.05).Vinorelbine and cisplatin regimen showed low incidence of ARE contrast with gemcitabine/docetaxel and cisplatin regimens (33.3％ and 66.7％ ).Conclusions V55 is the only statistically significant risk factor associated with grade 2 or worse ARE for patients who don't accepted concurrent chemotherapy.V35 and chemotherapy regimens during radiotherapy are statistically significant risk factors associated with grade 2 or worse ARE for patients who accept concurrent chemotherapy.Vinorelbine and cisplatin regimen during radiotherapy shows low incidence of ARE.

The present study investigated different types of eoexpression of brain derived neumtmphic factor(BDNF),nerve growth factor(NGF)and neutmphin-3(NT-3)mRNA and/or proteins in the left sixth lumbar dorsal root ganglion(DRG)of cats and discuss themechanism of coexpression in order to provide foundation for elucidating the relationship between the expression of neurotrophic factors andspinal cord plasticity.The eats used in this study were normal animals without any interventional treatment.They were subjected to renloveof the left L6 DRG and their DRG were processed for immunohistechemistry and in situ hybridization double staining to observe whetherthere are coexpression of mRNA and proteins of BDNF,NGF and NT-3.The results showed that the pmteios and mRNA of BDNF,NGFand NT-3 were all expressed in the DRG of cats,but the types of coexpression of mRNA and proteins were different and diverse amongthese three neumtrophic factors.The results of immunohiatochemistry showed that BDNF immunoreactivities were mainly observed in thecytoplasm and nucleus,and the staining of nucleus was weaker than that of cytoplasm;NGF immunoreactivities were mainly observed innucleus while NT-3 mainly in cytoplasm.The results of in situ hybridization showed that BDNF and NGF positive signals mostly distributedin the cytoplasm,NT-3 positive signals were observed in both the cytoplasm and nucleus.Our results suggest that the proteins and mRNAof BDNF,NGF and NT-3 have different types of coexpression which indicate they may have autocrine and/or paracrine mechanism contrib-uting to the plasticity of spinal cord in the left L6 DRG of cats.