ObjectiveTo investigate the potential mechanism of Danggui Buxuetang （DBT） in the treatment of vascular dementia （VAD）. MethodsSixty male SD rats were randomly assigned to the sham-operated group， model group， DBT low-， medium-， and high-dose groups， and the donepezil group. Except for the sham-operated group， rats in all other groups underwent bilateral common carotid artery ligation. After successful modeling， DBT was administered at doses of 9.2， 18.4， 36.8 g·kg^-1 for the low-， medium-， and high-dose groups， respectively， while the donepezil group received 3 mg·kg^-1 donepezil solution by gavage once daily. After 4 consecutive weeks of drug treatment， rats underwent the Morris water maze test， novel object recognition test， Nissl staining to observe hippocampal neurons， and immunofluorescence staining to detect the expression of neuronal nuclear protein （NeuN） in the hippocampus. Western blot was used to assess the expression of PTEN-induced kinase 1 （PINK1）， Parkin， microtubule-associated protein 1 light chain 3Ⅱ （LC3Ⅱ）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Transmission electron microscopy was used to observe hippocampal neuronal ultrastructure. Real-time PCR was used to detect the expression of NADPH oxidase subunits p22^phox and p47^phox in hippocampal tissues. The levels of malondialdehyde （MDA）， glutathione （GSH）， superoxide dismutase （SOD）， and total antioxidant capacity were measured to evaluate oxidative stress levels. ResultsIn the Morris water maze test， escape latency changed significantly over time in all groups except the model group. Compared with the sham-operated group， the model group showed significantly prolonged escape latency （P<0.01）. Compared with the model group， rats in the DBT groups and the donepezil group exhibited significantly shorter escape latency （P<0.05， P<0.01）. The number of crossings over the original platform was significantly reduced in the model group compared with the sham-operated group （P<0.01）， whereas rats in the DBT and donepezil groups showed significantly increased platform crossings compared with the model group （P<0.05， P<0.01）. Compared with the sham-operated group， exploration time of new objects was significantly reduced in the model group （P<0.01）. Compared with the model group， exploration time of new objects increased significantly in the medium- and high-dose DBT groups and the donepezil group （P<0.05， P<0.01）， while no significant change was observed in the low-dose DBT group. Compared with the high-dose DBT group， rats in the donepezil group had significantly prolonged escape latency and reduced platform crossings and new-object exploration time （P<0.05）. Nissl staining showed decreased density of healthy neurons in the CA1 and CA3 regions of the hippocampus in the model group， with loss of Nissl bodies and nuclear atrophy or disappearance. In the high-dose DBT group， neuronal density in CA1 and CA3 increased， with neurons arranged closely and displaying normal morphology. Immunofluorescence showed that compared with the sham-operated group， the hippocampal NeuN⁺ cell count in the VAD model group was significantly decreased（P<0.01）， compared with the VAD model group， the hippocampal NeuN⁺ cell count in the high-dose DBT group was significantly increased（P<0.01）. Compared with the sham-operated group， the expression of PINK1， Parkin， LC3Ⅱ， and Bax proteins was significantly increased（P<0.01）， while the expression of Bcl-2 was significantly decreased in the VAD model group（P<0.01）. Compared with the VAD model group， the high-dose DBT group showed significantly decreased expression of PINK1， Parkin， LC3Ⅱ， and Bax proteins（P<0.01）and significantly upregulated Bcl-2 expression（P<0.01）. The medium-dose DBT group exhibited significantly reduced expression of Parkin， LC3Ⅱ， and Bax proteins（P<0.05，P<0.01） and significantly increased Bcl-2 expression（P<0.01）， while no statistically significant differences were observed in the low-dose DBT group. Transmission electron microscopy showed mitochondrial pyknosis， thickened cristae， increased electron density， and the presence of mitochondrial autophagy in the model group. In contrast， hippocampal neurons in the high-dose DBT group contained abundant mitochondria with intact morphology， clear cristae， and uniform matrix. Compared with the sham-operated group， total antioxidant capacity， SOD activity， and GSH levels were significantly decreased， while MDA levels were significantly increased in the model group （P<0.01）. Compared with the model group， total antioxidant capacity and antioxidant levels （SOD， GSH） increased significantly， and MDA decreased significantly in the medium- and high-dose DBT groups （P<0.01）， while no significant changes were observed in the low-dose DBT group. Compared with the sham-operated group， mRNA expression of p22^phox and p47^phox was significantly increased in the model group （P<0.01）. Compared with the model group， expression of p22^phox and p47^phox was significantly decreased in the DBT groups （P<0.05， P<0.01）. ConclusionDBT may exert neuroprotective effects by regulating PINK1/Parkin-mediated mitochondrial autophagy， thereby improving learning and memory abilities and treating VAD.

Ocular adnexal lymphoma is a common orbital malignant tumor.The incidence of ocular adnexal lymphoma is in-creasing rapidly each year,and the clinical manifestations and imaging characteristics of the disease are not specific.Therefore,the diagnosis of the disease relies on pathological tissue analysis.Accurate diagnosis of ocular adnexal lymphoma relies on mor-phology,immunohistochemistry,molecular and cytogenetics.With in-depth research on the disease,it has been found that the clinical prognosis of this tumor is characterized by high recurrence.This article mainly explains the correlation between high dis-ease recurrence rate and histopathological characteristics.

BACKGROUND: This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines, named Scientific, Transparent and Applicable Rankings tool (STAR), and test its reliability, validity, and usability. METHODS: This study set up a multidisciplinary working group including guideline methodologists, statisticians, journal editors, clinicians, and other experts. Scoping review, Delphi methods, and hierarchical analysis were used to develop the STAR tool. We evaluated the instrument's intrinsic and interrater reliability, content and criterion validity, and usability. RESULTS: STAR contained 39 items grouped into 11 domains. The mean intrinsic reliability of the domains, indicated by Cronbach's α coefficient, was 0.588 (95% confidence interval [CI]: 0.414, 0.762). Interrater reliability as assessed with Cohen's kappa coefficient was 0.774 (95% CI: 0.740, 0.807) for methodological evaluators and 0.618 (95% CI: 0.587, 0.648) for clinical evaluators. The overall content validity index was 0.905. Pearson's r correlation for criterion validity was 0.885 (95% CI: 0.804, 0.932). The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min. CONCLUSION The instrument performed well in terms of reliability, validity, and efficiency, and can be used for comprehensively evaluating and ranking guidelines.
Reproducibility of Results ; Surveys and Questionnaires ; Practice Guidelines as Topic ; Humans

Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3

Purpose: The purpose of the current study was to explore the functions and potential mechanism of miR-451a in breast cancer (BC). Methods: Quantitative reverse transcription real-time polymerase chain reaction was used to analyze the expression of miR-451a in human normal mammary cells (MCF-10A) and BC cells. Colony formation assay, terminal-deoxynucleoitidyl transferase mediated nick end labeling assay and transwell assays were conducted to validate the effect of miR-451a on proliferation, apoptosis, migration and invasion of BC cells, respectively. RNA pull-down, RNA immunoprecipitation and luciferase reporter assays were applied to investigate the upstream and downstream mechanisms of miR-451a in BC cells. Results: MiR-451a was expressed at a low level in BC cells. Overexpression of miR-451a repressed BC cells proliferation, migration and invasion. Moreover, long non-coding RNA AC092127.1 acted as a sponge of miR-451a to enhance the expression level of AE binding protein 2 (AEBP2) that was demonstrated to be the target gene of miR-451a in BC cells. Finally, rescue experiments validated that miR-451a and AEBP2 involved in AC092127.1-mediated BC cell growth, migration and invasion. Conclusion In a word, AC092127.1/miR-451a/AEBP2 axis contributes to BC cell growth, migration and invasion. Our results may help to find novel potential targets for BC treatment.

Purpose: The purpose of the current study was to explore the functions and potential mechanism of miR-451a in breast cancer (BC). Methods: Quantitative reverse transcription real-time polymerase chain reaction was used to analyze the expression of miR-451a in human normal mammary cells (MCF-10A) and BC cells. Colony formation assay, terminal-deoxynucleoitidyl transferase mediated nick end labeling assay and transwell assays were conducted to validate the effect of miR-451a on proliferation, apoptosis, migration and invasion of BC cells, respectively. RNA pull-down, RNA immunoprecipitation and luciferase reporter assays were applied to investigate the upstream and downstream mechanisms of miR-451a in BC cells. Results: MiR-451a was expressed at a low level in BC cells. Overexpression of miR-451a repressed BC cells proliferation, migration and invasion. Moreover, long non-coding RNA AC092127.1 acted as a sponge of miR-451a to enhance the expression level of AE binding protein 2 (AEBP2) that was demonstrated to be the target gene of miR-451a in BC cells. Finally, rescue experiments validated that miR-451a and AEBP2 involved in AC092127.1-mediated BC cell growth, migration and invasion. Conclusion In a word, AC092127.1/miR-451a/AEBP2 axis contributes to BC cell growth, migration and invasion. Our results may help to find novel potential targets for BC treatment.

PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy. However, many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune activation. The combination of checkpoint blockers has been proposed to increase the response rates. Besides, antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems. In this study, we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3. As a result, C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR (MHC-II). Additionally, C25 could significantly stimulate CD8 T cell activation in human PBMCs. The results also demonstrated that C25 could inhibit tumor growth of CT26, B16 and B16-OVA bearing mice, and the infiltration of CD8 T cells was significantly increased while FOXP3 Tregs significantly decreased in the tumor site. Furthermore, the secretion of IFN- by CD8 T cells in spleen, draining lymph nodes and especially in the tumors was promoted. Simultaneously, we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide, and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects CD8 T cells but not direct killing. In conclusion, cyclic peptide C25 provides a rationale for targeting the immune checkpoint, by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity, and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.

Objective:To analyze the characteristics of malaria epidemic situation before and after malaria elimination in Qiandongnan Prefecture, and to provide the basis for establishment of effective strategies and measures to consolidate the achievements of malaria prevention and control.Methods:The data of malaria cases in 16 counties (cities) of Qiandongnan Prefecture from 2005 to 2018 were collected, and descriptive epidemiological method was used to analyze the infection rate of Plasmodium among local residents and floating population before (2005-2011) and after (2012-2018) elimination of malaria, and the characteristics of population distribution, seasonal distribution, species of Plasmodium and types of malaria vectors were analyzed. Results:Before elimination of malaria, total of 1 412 cases of malaria were reported, among those cases, 1 361 cases were local cases, accounting for 96.39% of the total cases. After elimination of malaria, total of 17 cases were reported, all of them were imported cases. After comparison of malaria cases before and after the elimination, the proportion of people aged from 18 to 60 was 70.54% (996/1 412) before the elimination, all 17 imported cases were 18-60 years old after the elimination, and the proportion of children/students decreased from 24.65% (348/1 412) before the elimination to 0 after the elimination. The peak incidence of malaria cases before the elimination was from June to October, and cases occurred every month. After the elimination, the imported cases were sporadic. Plasmodium vivax was the main species of Plasmodium before the elimination (98.58%, 1 392/1 412), and Plasmodium falciparum was mainly imported after the elimination (70.59%, 12/17). Before and after the elimination, Anopheles sinensis, the malaria vector, was the dominant population, but no distribution of Anopheles minimus and Anopheles anthropophagus was found after 2015. Conclusions:After the elimination of malaria in Qiandongnan Prefecture, there is a risk of local malaria cases caused by imported cases. It is suggested that local authorities should focus on the treatment of suspected malaria cases and vector surveillance of overseas returnees in the future.

Objective? To explore status quo of rumination in primary liver cancer (PLC) patients receiving chemotherapy after surgery and its influencing factors. Methods? Totally 165 PLC patients receiving surgery in a ClassⅢ Grade A hospital in Heilongjiang Province from October 2016 to December 2017 were selected by convenient sampling and investigated with the general information questionnaire, Rumination Rating Scale (RRS) and Social Support Rating Scale (SSRS). Totally 165 questionnaires were distributed, and 158 valid questionnaires were collected. Results? The RSS score of the 158 PLC patients totaled (62.29±14.46), including (33.43±7.32) for symptom rumination, (15.03±4.01) for forced thinking, and (13.83±3.66) for reflection. Multiple regression analysis showed that educational background, presence of comorbidities, frequency of chemotherapy, chemotherapy protocol and social support were the factors affecting the patients' rumination (P＜ 0.05). Conclusions? Rumination is prevalent in PLC patients, which stands at a medium and severe level. Clinicians need to formulate targeted protocols based on the patients' specific conditions, improve their social support, and regulate their mode of rumination.

Objective To investigate the effect of pyrin domain 3 (NLRP3) inflammasome in the process of contrast induced human kidney cell apoptosis.Methods Human kidney 2 (HK-2) cells were cultured in DMEM-F12 medium with 5％ FBS.Cells were divided into control group,Contrast group (O group),NLRP3-siRNA+Iohexol group (si-NLRP3+O group),ASC-siRNA+Iohexol group (si-ASC+O group),and mannitol group (M group).Different concentrations of hypotonic contrast agent were added to HK-2 cell culture plates for 24,48 and 72 h.Flow cytometry was used to detect apoptosis.NLRP3 and ASC mRNA expressions were detected by RT-PCR.The expressions of NLRP3,ASC,caspase-8/cleaved caspase-8,Bcl-2/Bax,caspase-1/cleaved caspase-1,and caspase-3/cleaved caspase-3 protein were detected by Western blot.The levels of interleukin (IL) 1β and IL-18 in supernatant were detected by ELISA.Results Compared with the control group,the rate of apoptotic cells,as well as the expressions of NLRP3,ASC and cleaved caspase-1 proteins were increased in HK-2 cells of contrast group.The expressions of NLRP3 and ASC mRNA in the contrast group also increased,so did IL-1β and IL-18 levels (all P＜0.05),suggesting that NLRP3 inflammasome in HK-2 cells was activated by contrast.Compared with the control group,the expressions of cleaved caspase-8,Bax and cleaved caspase-3 protein were increased,and the expression of anti-apoptotic protein Bcl-2 was decreased (all P ＜ 0.05).Compared with the contrast group,the rate of apoptotic cells in the si-NLRP3 + contrast group and si-ASC + contrast group was significantly decreased;the expression of cleaved caspase-1 was decreased;the expressions of Bax and cleaved caspase-3 were decreased,and Bcl-2 level was increased.The expressions of IL-1β and IL-18 in the supernatant of cells were decreased (all P ＜ 0.05).Conclusion Contrast agent can activate the NLRP3 pathway in HK-2 cells and induce apoptosis,which could be reduced by blocking the NLRP3 pathway.