AIM: To investigate the effects of agkis-trodon halys venom anti-tumor component (AHVAC-) on the biological behavior of gastric cancer MKN-28 cells. METHODS: Gastric cancer MKN-28 cells were treated with the experimental concentrations (5, 10, 15 μg/mL) of AHAVC- for 24 h. Cell proliferation and toxicity assay (cell counting kit-8, CCK-8) was used to detect the inhibition rates of the cells in different concentrations of AHVAC-. The migration ability of the cells was evaluated by wound-healing and Transwell assay. The apoptosis were observed by laser confocal microscopy with annexin V-mCherry/DAPI double staining, and the apoptosis rates were analyzed by flow cytometry with annexin V-FITC/PI double fluorescence staining. The protein level of Caspease-3 was determined by Western blot. RESULTS: Compared with normal control group, the results of AHVAC- concentration groups showed that with the increase of AHVAC- concentration, the proliferative activity of MN-28 cells decreased gradually (P<0.01), the cell migration ability decreased gradually (P<0.01), and the cell apoptosis rate increased (P<0.05). The expression of apoptosis-related protein Caspease-3 was up-regulated (P<0.01). CONCLUSION: AHVAC- inhibits proliferation and migration of gastric cancer MSN-28 cells and induces apoptosis.

Objective:To investigate the effect of decarbromodiphenyl ether(BDE-209)exposure on the migration ability of triple-negative breast cancer(TNBC)cells and to explore the underlying mechanism.Methods:Human TNBC MDA-MB-231 cells were divided into blank control group and BDE-209 exposure groups(treated with 0.02,0.20,2.00,20.00 and 200.00 ng/mL BDE-209 in high glucose DMEM).Extracellular vehicles(EVs)secreted by MDA-MB-231 cells were isolated by differential ultracentrifugation.Transmission electron microscopy(SEM),nanoparticle tracking analysis(NTA)and Western blotting were performed to characterize the EVs.The effect of the EVs induced by BDE-209 exposure(EVs-BDE-209)on the migration and invasion of MDA-MB-231 cells was detected by wound-healing assay and Transwell test.qRT-PCR was used to measure the miR-221 level in EVs-BDE-209.The expression of MMP9 in MDA-MB-231 cells was determined by Western blotting.Results:Compared with the blank control,BDE-209 exposure increased the tumor cell-derived EVs in dose-dependent manner.The MDA-MB-231 cells co-cultured with EVs released by 200.00 ng/mL BDE-209 exposure showed an 86%increase in cell migration rate,a 1.32-fold higher number of membrane-penetrating cells,a 2.71-fold higher expression level of miR-221,and a 1.62-fold higher expression level of MMP9 compared with the blank control group(all P<0.05).While transfection with anti-miR-221 antibody to decrease miR-221 level in EVs significantly reversed the increased invasion ability of the MDA-MB-231 cells treated with EVs-BDE-209.Conclusion:BDE-209 exposure may promote metastasis potential of MDA-MB-231 cells via EVs-BDE-209 transmitted miR-221.

Objective:To evaluate the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with secondary acute myeloid leukemia (sAML) .Methods:In this multicenter, retrospective clinical study, adult patients aged ≥18 years who underwent allo-HSCT for sAML at four centers of the Zhejiang Hematopoietic Stem Cell Transplantation Collaborative Group from January 2014 to November 2022 were included, and the efficacy and prognostic factors of allo-HSCT were analyzed.Results:A total of 95 patients were enrolled; 66 (69.5%) had myelodysplastic syndrome-acute myeloid leukemia (MDS-AML) , 4 (4.2%) had MDS/MPN-AML, and 25 (26.3%) had therapy-related AML (tAML) . The 3-year CIR, LFS, and overall survival (OS) rates were 18.6% (95% CI 10.2%-27.0%) , 70.6% (95% CI 60.8%-80.4%) , and 73.3% (95% CI 63.9%-82.7%) , respectively. The 3-year CIRs of the M-AML group (including MDS-AML and MDS/MPN-AML) and the tAML group were 20.0% and 16.4%, respectively ( P=0.430) . The 3-year LFSs were 68.3% and 75.4%, respectively ( P=0.176) . The 3-year OS rates were 69.7% and 75.4%, respectively ( P=0.233) . The 3-year CIRs of the groups with and without TP53 mutations were 60.0% and 13.7%, respectively ( P=0.003) ; the 3-year LFSs were 20.0% and 76.5%, respectively ( P=0.002) ; and the 3-year OS rates were 40.0% and 77.6%, respectively ( P=0.002) . According to European LeukmiaNet 2022 (ELN2022) risk stratification, the 3-year CIRs of patients in the low-, intermediate-, and high-risk groups were 8.3%, 17.8%, and 22.6%, respectively ( P=0.639) . The three-year LFSs were 91.7%, 69.5%, and 65.6%, respectively ( P=0.268) . The 3-year OS rates were 91.7%, 71.4%, and 70.1%, respectively ( P=0.314) . Multivariate analysis revealed that advanced disease at allo-HSCT and TP53 mutations were independent risk factors for CIR, LFS, and OS. Conclusion:There was no significant difference in the prognosis of patients who underwent allo-HSCT among the MDS-AML, MDS/MPN-AML, and tAML groups. Advanced disease at transplantation and TP53 mutations were poor prognostic factors. ELN2022 risk stratification had limited value for predicting the prognosis of patients with sAML following allo-HSCT.

Hepatocellular carcinoma (HCC) has an insidious onset, and most patients are in the advanced stage when attending the hospital and thus lose the opportunity for radical surgical resection, which results in the poor prognosis of patients. With the development of clinical treatment, the treatment of advanced HCC has gradually transitioned from the relatively single and limited treatment options in the past to the new model of comprehensive treatment. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has become widely used in clinical practice. At present, a number of clinical studies have been conducted for immunotherapy combined with local and targeted antitumor therapy, and in particular, ICIs combined with targeted therapy have become a research hotspot in the field of HCC treatment. This article reviews the research advances in immunotherapy for the treatment of HCC.

Objective:To study the distribution and antibiotics resistance of the main pathogens of neonatal purulent meningitis in different regions of China.Methods:A retrospective descriptive clinical epidemiological study was conducted in children with neonatal purulent meningitis which admitted to 18 tertiary hospitals in different regions of China between January 2015 to December 2019. The test results of blood and cerebrospinal fluid, and drug sensitivity test results of the main pathogens were collected. The distributions of pathogenic bacteria in children with neonatal purulent meningitis in preterm and term infants, early and late onset infants, in Zhejiang Province and other regions outside Zhejiang Province, and in Wenzhou region and other regions of Zhejiang Province were analyzed. The chi-square test was used for statistical analysis.Results:A total of 210 neonatal purulent meningitis cases were collected. The common pathogens were Escherichia coli ( E. coli)(41.4%(87/210)) and Streptococcus agalactiae ( S. agalactiae)(27.1%(57/210)). The proportion of Gram-negative bacteria in preterm infants (77.6%(45/58)) with neonatal purulent meningitis was higher than that in term infants (47.4%(72/152)), and the difference was statistically significant ( χ2=15.54, P=0.001). There were no significant differences in the constituent ratios of E. coli (36.5%(31/85) vs 44.8%(56/125)) and S. agalactiae (24.7%(21/85) vs 28.8%(36/125)) between early onset and late onset cases (both P>0.05). The most common pathogen was E. coli in different regions, with 46.7%(64/137) in Zhejiang Province and 31.5%(23/73) in other regions outside Zhejiang Province. In Zhejiang Province, S. agalactiae was detected in 49 out of 137 cases (35.8%), which was significantly higher than other regions outside Zhejiang Province (11.0%(8/73)). The proportions of Klebsiella pneumoniae, and coagulase-negative Staphylococcus in other regions outside Zhejiang Province (17.8%(13/73) and 16.4%(12/73)) were both higher than those in Zhejiang Province (2.9%(4/137) and 5.1%(7/137)). The differences were all statistically significant ( χ2=14.82, 12.26 and 7.43, respectively, all P<0.05). The proportion of Gram-positive bacteria in Wenzhou City (60.8%(31/51)) was higher than that in other regions in Zhejiang Province (38.4%(33/86)), and the difference was statistically significant ( χ2=6.46, P=0.011). E. coli was sensitive to meropenem (0/45), and 74.4%(32/43) of them were resistant to ampicillin. E. coli had different degrees of resistance to other common cephalosporins, among which, cefotaxime had the highest resistance rate of 41.8%(23/55), followed by ceftriaxone (32.4%(23/71)). S. agalactiae was sensitive to penicillin, vancomycin and linezolid. Conclusions:The composition ratios of pathogenic bacteria of neonatal purulent meningitis are different in different regions of China. The most common pathogen is E. coli, which is sensitive to meropenem, while it has different degrees of resistance to other common cephalosporins, especially to cefotaxime.

Objective:To calculate the relative biological effectiveness (RBE) value of the released low-energy electrons in gadolinium neutron capture therapy ( 157GdNCT) based on microdosimetry. Methods:The Monte Carlo (MC) code Geant4-DNA package was used to simulate the energy deposition distribution and microdosimetry parameters of low-energy electrons released during gadolinium neutron capture treatment in different sensitive target volumes and physical models on track structures. On this basis, RBE value was obtained based on the microdosimetry kinetic model (MKM).Results:The low-energy electron RBE value was highly variable in different sensitive target volumes and decreases with increasing sensitive target volumes. With 6-nm-diameter sensitive target as reference, RBE value was 1.77 for 6-nm diameter, 1.53 for 10 nm diameter with percentage difference 13%, and 1.40 for 15-nm diameter with percentage difference of 21%, respectively. The effect of different Geant4-DNA physical models on the RBE of low-energy electrons was small. Using the RBE value of 1.53 for physical model option2 as reference, the RBE values of option6 and option7 were 1.49 and 1.52, respectively, with the percentage differences of 2.6% and 0.6%, respectively.Conclusions:The RBE values of low energy electrons released by 157GdNCT in different sensitive target volumes and physical models were calculated by MKM to be 1.40-1.77.

Objective:To evaluate the feasibility of delineating subvolume target in radiotherapy for brain tumors using Gd-based contrast clearance difference.Methods:Twenty-six patients with malignant brain tumors were scanned with MRI. The first and second acquisitions of standard T 2-weighted images (T 2WI) and T 1-weighted images (T 1WI) were performed at 5 min and 60 min after injection of contrast agent. Delayed contrast extravasation (DCEM) MRI computed by Brainlab comprised regions of contrast agent clearance representing active tumors and regions of contrast accumulation representing non-tumor tissues. Based on T 2WI images, 14 patients with liquefaction necrosis were divided into group A, and 12 patients without liquefaction necrosis into group B, respectively. Then, gross target volume (GTV) was delineated on T 1WI images. Based on the GTV, active tumor (GTV tumor) and non-tumor regions (GTV non-tumor) were delineated on T 1WI-DCEM fusion images, while liquefaction necrosis (GTV liquefaction) and non-liquefaction (GTV non-liquefaction) were delineated on T 1-T 2WI fusion images. Finally, the differences between different subvolumes were compared by paired t-test. Results:In group A, the GTV non-liquefaction and GTV liquefaction were (13.65±18.15) cm 3 and (6.30±7.57) cm 3. The GTV tumor was (10.40±13.52) cm 3 and the GTV non-tumor was (9.55±14.57) cm 3. The GTV non-liquefaction was significantly increased by 16.3% on average compared with the GTV tumor ( P<0.05). The GTV non-tumor was significantly increased by 16.3% on average compared with the GTV liquefaction ( P<0.05). In group B, The GTV non-tumor was significantly reduced by 68.8% on average compared with the GTV tumor ( P<0.05). Conclusions:Compared with T 2WI, DCEM has advantages in identifying the liquefaction area and can clearly differentiate the subvolume of active tumors from non-liquefaction necrosis. DCEM provides evidence for guiding the delineation of subvolume in primary and metastatic brain tumors.

Objective:To evaluate the feasibility of magnetic resonance (MR) perfusion imaging for sub-region segmentation of brain metastases (BMs), and to provide reference for individualized radiotherapy based on blood flow perfusion heterogeneity in BMs patients.Methods:96 BMs patients were selected, including 55 patients with necrosis and 41 without necrosis. Each patient was scanned with CT simulation and MR simulation before radiotherapy. MIM Maestro 6.8.8 software was used to delineate the gross tumor volume (GTV) and necrosis GTV (GTV N) from enhanced T 1W images and T 2 Propeller images, respectively, and the solid GTV (GTV S) was obtained by the subtraction of the two. Then, the cerebral blood flow map of three dimensional arterial spin labeling (3D-ASL) was employed to determine the high perfused GTV (GTV H) and low perfused GTV (GTV L). The volume and proportion of sub-regions were counted and compared between two groups and the correlation of each sub-region was analyzed. Results:The volume of GTV in the necrosis and non-necrosis groups was 19.56 and 7.34 cm 3, respectively. Besides, the AUC of the ROC between GTV volume and necrosis was 0.749. In the necrosis group, the ratio of GTV N, GTV S, GTV H and GTV L to GTV was 20.47%, 79.53%, 33.03% and 46.50%, respectively (all P<0.05). Among them, the r value between GTV S and GTV was 0.963, 0.849 for GTV L and GTV, and 0.840 for GTV L and GTV S, significantly higher than 0.683 for GTV H and GTV and 0.764 for GTV H and GTV S (all P<0.05). In the non-necrosis group, the ratio of GTV H to GTV was higher than that in the necrosis group (58.95% vs. 33.03%, P<0.05). In addition, the ratio of GTV L to GTV was slightly lower than that in the necrosis group (41.05% vs. 46.50%, P>0.05). The r value between GTV H and GTV was 0.776, significantly higher than 0.574 between GTV L and GTV ( P<0.05). Conclusion:MR-3D-ASL can quantitatively analyze the heterogeneous blood perfusion of BMs, which could guide the sub-region segmentation and local dose escalation of tumors.

Background: Endoscopic submucosal dissection (ESD) has become the preferred treatment of early colorectal cancer. PDCD4 and autophagy have important clinical significance in the pathogenesis of colorectal cancer. Aims: To explore the expressions and significance of apoptosis factor PDCD4 and autophagy factors LC3Ⅱ and p62 in colorectal cancer. Methods: Fifty-four early colorectal adenocarcinoma patients treated by ESD from Jan. 2015 to Nov. 2020 at Binzhou Medical University Hospital were collected. The expressions of PDCD4, LC3Ⅱ and p62 were detected by immunohistochemistry, and the correlations with clinicopathological factors were analyzed. The differential expression of PDCD4 in pan-cancer was analyzed by bioinformatics analysis. Results: Expression of PDCD4 was associated with the long-diameter of paracancer adenoma (P<0.05), and expressions of LC3Ⅱ and p62 were associated with the long-diameters of adenocarcinoma and paracancer adenoma (P<0.05). The positive expression of PDCD4 in P-NIMM was located in the nucleus, while the positive expression in adenocarcinoma was located in cytoplasm. The nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-NIMM than in P-LGIN, P-HGIN and adenocarcinoma (P<0.05), and the nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-LGIN, P-HGIN than in adenocarcinoma (P<0.05). The positive expression rates of LC3Ⅱ and p62 were significantly higher in adenocarcinoma than in P-NIMM and P-LGIN (P<0.05). In P-LGIN, P-HGIN and adenocarcinoma, the expression of PDCD4 was negatively correlated with the expressions of LC3Ⅱ and p62 (P<0.05). The bioinformatics analysis showed that expression of PDCD4 was significantly reduced in a variety of malignant tumors including colorectal cancer (P<0.05). Conclusions: The inhibition of apoptosis and activation of autophagy may promote the occurrence of colorectal cancer, and its mechanism may be related to the intracellular transposition of PDCD4 that inhibits cell apoptosis and enhances autophagy, and activating cellular autophagy may further accelerate the degradation of PDCD4 and thus reducing its cancer inhibiting effect.

Objective:To analyze the spatial-temporal distribution characteristics of gonorrhea in Fujian province from 2010 to 2019, and to provide scientific evidence for developing prevention and control strategies.Methods:Data on gonorrhea cases reported in counties and districts in Fujian province from 2010 to 2019 were collected from the National Notifiable Disease Report System of the Chinese Center for Disease Control and Prevention. OpenGeoda 1.12 software was used for global and local spatial autocorrelation analysis with Moran′s I as the statistic, and SaTScan 9.6 software was used for spatial-temporal cluster analysis to explore high-risk areas.Results:A total of 56 053 cases of gonorrhea were reported in Fujian province from 2010 to 2019. The reported incidence of gonorrhea slightly increased from 2010 to 2013, decreased from 2013 to 2014, and markedly increased from 2014 to 2018 with an average annual increase rate of 8.36%. However, the reported incidence sharply dropped again in 2019. Global autocorrelation analysis showed that the global Moran′s I index ranged from 0.48 to 0.65 between 2010 and 2019 (all P < 0.05), and there was global spatial autocorrelation of gonorrhea cases in counties and districts in Fujian province. Local autocorrelation analysis showed that the main spatial clustering patterns of gonorrhea cases in Fujian province were high-high, low-low and high-low clusters. In recent years, high-high clustering areas had shown an expanding trend, and were mainly distributed in Siming and Huli districts in Xiamen city, as well as in Licheng and Fengze districts, Jinjiang, Shishi and Nan′an county-level cities in Quanzhou city. Spatial-temporal clustering analysis revealed that the first-level spatial-temporal clustering areas were counties and districts in Xiamen city, as well as central urban areas, Jinjiang, Shishi and Nan′an county-level cities in Quanzhou city from January 2015 to December 2019. Conclusions:There was a spatial and temporal clustering of gonorrhea cases in Fujian province. High-high clustering areas were mainly distributed in the economically developed areas along the southeast coast of Fujian province, and had shown a gradually expanding trend in recent years. Counties and districts in Xiamen city, central urban areas and their surrounding county-level cities in Quanzhou city should be regarded as key areas for gonorrhea prevention and control.