The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

Gallbladder cancer has an insidious onset,and most of the cases are in advanced stage at the time of diagnosis,with unfavorable prognosis. Radical surgery is the only potential curative method for gallbladder cancer at present,but radical surgery of advanced gallbladder cancer is difficult and the postoperative recurrence rate is high. Neoadjuvant therapy and conversion therapeutic modalities are of great significance to improve the rate of radical resection of advanced gallbladder cancer and reducing the risk of postoperative recurrence. The application and research of minimally invasive approach surgery in gallbladder cancer are increasing; organoid technology provides a new platform for precise and individualized treatment and new drug development, and the application of artificial intelligence combined with big data shows great potential in tumor diagnosis, surgical assistance and prognosis evaluation. Although these techniques provide more means to improve the therapeutic effect of advanced gallbladder cancer, there are still challenges in clinical practice and more high-quality clinical studies.

Gallbladder cancer has an insidious onset,and most of the cases are in advanced stage at the time of diagnosis,with unfavorable prognosis. Radical surgery is the only potential curative method for gallbladder cancer at present,but radical surgery of advanced gallbladder cancer is difficult and the postoperative recurrence rate is high. Neoadjuvant therapy and conversion therapeutic modalities are of great significance to improve the rate of radical resection of advanced gallbladder cancer and reducing the risk of postoperative recurrence. The application and research of minimally invasive approach surgery in gallbladder cancer are increasing; organoid technology provides a new platform for precise and individualized treatment and new drug development, and the application of artificial intelligence combined with big data shows great potential in tumor diagnosis, surgical assistance and prognosis evaluation. Although these techniques provide more means to improve the therapeutic effect of advanced gallbladder cancer, there are still challenges in clinical practice and more high-quality clinical studies.

Objective:To explore the relationship between hemoglobin variability (Hb-var) and risk of all-cause death and cardiovascular death in patients with peritoneal dialysis (PD), and to provide basis for reducing the risk of death in PD patients.Methods:It was a multicenter retrospective cohort study. The clinical data of regular PD patients from Nanfang Hospital of Southern Medical University, Shunde Hospital of Southern Medical University, Foshan First People's Hospital and Ganzhou People's Hospital from July 1, 2008 to December 31, 2019 were collected. Hb-var was calculated based on hemoglobin at baseline before PD and in the first year after PD. The patients were divided into low Hb-var group, moderate Hb-var group and high Hb-var group according to the tertiles of first year Hb-var, and the differences of baseline clinical data among three groups were compared. Follow-up endpoints included death, transfer to hemodialysis, transfer to kidney transplantation, transfer to other centers, loss of follow-up, or on December 31, 2021. Cox regression analysis model was used to analyze the association of the first-year Hb-var with all-cause death and cardiovascular death. Fine-Gray competitive risk regression model was used to evaluate the impact of competitive events on mortality risk.Results:A total of 1 562 patients with PD were included in the study, aged (47.6±13.8) years old, with 821 males (52.6%) and baseline hemoglobin of 81 (69, 94) g/L. Hb-var in the first year of PD was 26.6 (16.7, 40.3) g/L. There were statistically significant differences in age, body mass index, serum albumin, hemoglobin, serum creatinine, serum calcium, serum phosphorus, intact parathyroid hormone and the proportion of renin-angiotensin system inhibitors among low Hb-var group (<20.0 g/L), moderate Hb-var group (20.0-35.5 g/L) and high Hb-var group (≥35.5 g/L, all P<0.05). The follow-up time was 33 (19, 51) months, and 208 patients (13.3%) died, among which 111 patients (53.4%) died of cardiovascular death. Multivariate Cox regression analysis showed that the higher Hb-var in the first year, the lower the risk of all-cause death ( HR=0.98, 95% CI 0.97-0.99, P=0.018) and cardiovascular death ( HR=0.98, 95% CI 0.97-0.99, P=0.041) in PD patients. Compared with low Hb-var group, the risk of all-cause death ( HR=0.56, 95% CI 0.37-0.82, P=0.003) and cardiovascular death ( HR=0.54, 95% CI 0.31-0.95, P=0.032) was lowest in the high Hb-var group. The competitive risk regression model analysis showed that Hb-var in the first year was still negatively correlated with the risk of all-cause death ( HR=0.98, 95% CI 0.97-0.99, P=0.041) and cardiovascular death ( HR=0.98, 95% CI 0.97-0.99, P=0.039). Conclusion:High Hb-var in the first year is associated with low risk of all-cause death and cardiovascular death in PD patients with severe anemia at baseline.

Objective:To explore the therapeutic efficacy and toxicity of oral Etoposide chemotherapy in children with disseminated medulloblastoma (MB) after the standard treatment plan.Methods:The clinical data of 86 children with disseminated MB admitted in the Department of Pediatrics, Beijing Shijitan Hospital of Capital Medical University from January 2016 to May 2020 were analyzed retrospectively.The median age of children was 8.8 (3.0-16.7) years old.Among them, 33 children treated with maintenance chemotherapy via oral Etoposide were included in the chemotherapy group, and 53 children without oral maintenance chemotherapy were included in the non-chemotherapy group.The gender distribution, surgical resection range, pathological type, molecular classification, postoperative mutism, M-stage and survival[progression-free survival (PFS) and overall survival (OS)] of the 2 groups were compared.The main adverse events of oral Etoposide chemotherapy were recorded. Chi- square test is used for data comparison, Kaplan-Meier method was used to plot the survival curve of disseminated MB patients, followed by the Log- rank test. Results:There were no significant differences in gender, surgical resection range, pathological type, molecular typing, postoperative mutism and M-stage between the 2 groups (all P>0.05). Of 86 patients, the median PFS and OS were 3.0 (0.2-6.3) years, and 3.6 (0.5-6.3) years, respectively.Twenty five cases (29.1%) relapsed, 13 cases (15.1%) died.The 3-year[(65.8±6.8)% vs.(82.0±7.3)%] and 5-year PFS[(56.8±7.7)% vs.(82.0±7.3)%] in non-chemotherapy group were significantly lower than those of chemotherapy group ( P=0.037). The 3-year[(81.6±5.6)% vs.100.0%] and 5-year OS[(71.2±7.7)% vs.(92.3±7.4)%] in non-chemotherapy group were significantly lower than those of chemotherapy group ( P=0.025). Among the children with the SHH subtype, the PFS of children with oral Etoposide maintenance chemotherapy after a regular treatment was significantly higher than that without oral maintenance chemotherapy (100.0% vs.57.1%)( P=0.021). The major adverse events of oral Etoposide were myelosuppression and gastrointestinal symptoms, which were mostly relieved after a symptomatic treatment.Treatment-related deaths were not reported. Conclusions:The prognosis of disseminated MB in children is relatively poor.Oral Etoposide for maintenance therapy after a standard treatment is beneficial in reducing relapse and improving the 5-year survival, which is well tolerated.

OBJECTIVE To isolate and identify the chemical compounds of the n-butanol fraction of the pods of Macleaya microcarpa, and to predict the targets and pathways for its treatment of Alzheimer's disease by network pharmacology. METHODS Silica gel, Sephadex LH-20 column chromatography and ODS preparative liquid chromatography were used to separate and purify the n-butanol extract of the pods of Macleaya microcarpa, and the structure of the compounds were identified by NMR spectroscopic. The targets of active compounds were obtained using SwissTargetPrediction and Targetnet database. Alzheimer's disease-related target were obtained by Genecard, OMIM and TTD database. The two were imported into Venny online tool to select the effect targets of the active compounds for Alzheimer's disease treatment. The interaction network map of “drug-component-target-disease” was constructed by Cytoscape 3.9.1 software. The String database was used to build the protein protein interaction network analysis. KEGG and GO pathway enrichment analysis were performed with Metascape database, and molecular docking was studied with AutoDockTools 1.5.7 software. RESULTS Five phenolic glycosides were isolated from the n-butanol fraction of the pods of Macleaya microcarpa. Ten key targets such as TNF, PTGS2 and APP, and 10 important pathways such as Pathways in cancer, Serotonergic synapse and Alzheimer's disease were screened by network pharmacology, and molecular docking showed that the active ingredients had good binding ability to the key targets. CONCLUSION Compounds 3-5 are isolated from Macleaya microcarpa for the first time, and compound 5 is isolated from Papaveraceae for the first time. The mechanism of Macleaya microcarpa in the treatment Alzheimer's disease may affect on key targets such as TNF, PTGS2, APP, ABCB1, and influence signaling pathway such as the APP/Aβ/NMDAR, so as to reduce inflammatory factors, inhibit inflammatory responses and reduce Aβ deposition in the brain.

Objective:Summarizing the clinical characteristics of extraneural metastasis in childhood medulloblastoma.Methods:A total of 616 cases with medulloblastoma treated in Beijing Shijitan Hospital from April 2010 to April 2019 were analyzed retrospectively, among which 11 cases developed extraneural metastasis.The age of onset, location and time of extraneural metastasis, pathological and molecular typing, treatment and prognosis were descriptively analyzed.The differences of blood biochemical indexes between medulloblastoma cases with and without extraneural metastasis were statistically analyzed by t test. Results:As of February 2020, the median follow-up period was 16 months (ranging from 3 to 69 months). Eleven cases, including 8 males and 3 females, were diagnosed with extraneural metastasis, with the incidence being about 1.8%.The median age of medulloblastoma was 6 years (2-10 years), and the median age at presentation of extraneural metastasis was 7 years (2-12 years). Extraneural metastasis occurred from 0.5 months to 38.0 months after the operation, and the affected location includes bone (6 cases), bone marrow (3 cases), lung (3 cases), pelvis (2 cases) and abdominal cavity (1 case). In these patients, the range of lactic dehydrogenase (LDH) was (2 298.00±1 570.70) U/L and neuron-specific enolase (NSE) was (201.00±68.34) μg/L, which were significantly higher than those in patients without extraneural metastasis [(249.50±46.28) U/L and (22.80±7.12) μg/L, all P<0.05]. Partial patients were treated with chemotherapy, while the majority of them were treated with palliative treatment in the terminal stage, with the survival period mostly less than 10 months. Conclusions:Although there is a low incidence of extraneural metastasis in medulloblastoma pediatric patients, the prognosis of these patients with extraneural metastasis is poor and most of them would die within one year.The most common sites include bone, followed by bone marrow and lungs, which may be related to the spread of cerebrospinal fluid and the increased levels of LDH and NSE.

Objective:To explore the effect of neutrophil-lymphocyte ratio (NLR) at the initial visit on the survival of children with newly diagnosed medulloblastoma (MB).Methods:This was a case-control study involving 61 children with newly diagnosed MB at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University from August 2018 to January 2020 .The blood cell counts, lymphocyte subsets and immunoglobulin in the periphe-ral blood were measured to calculate NLR at the initial visit.Based on the cut-off value determined by receiver opera-ting characteristic (ROC) curve, patients were divided into high NLR group (≥ 2.07, n=21) and low NLR group (<2.07, n=40). The progression-free survival (PFS) and overall survival (OS) between 2 groups were analyzed by the Kaplan-Meier method, followed by Log- rank test.The correlation between NLR at the initial visit with clinical characteristics, lymphocyte subsets and immunoglobulin of children with newly diagnosed MB was analyzed.Differences between groups were compared by the Chi- square test, Mann- Whitney U test and independent sample t test. Results:The survival analysis showed that the relapse rate (38.1% vs.10.0%, χ2=6.879, P=0.016) and mortality rate (19.0% vs.0, χ2=8.154, P=0.011) were significantly higher in high NLR group than those of low NLR group.PFS (12 months vs.19 months, χ2=9.775, P=0.002) and OS (19 months vs.20 months, χ2=8.432, P=0.004) were significantly shorter in high NLR group than those of low NLR group.No significant differences in clinical characteristics were detected between groups (all P>0.05). Compared with low NLR group, the percentage of T lymphocyte[(67.93±6.37)% vs.(73.38±8.08)%, t=2.886, df=48.865, P=0.006], T helper cells (Th)[(30.86±5.53)% vs.(34.29±7.44)%, t=2.037, df=51.981, P=0.047], and T suppressor cells (Ts)[(27.39±5.50)% vs.(30.84±6.58)%, t=2.164, df=47.581, P=0.035] were significantly lower in high NLR group.Spearman correlation analysis showed a negative correlation between NLR and T lymphocyte count ( r=-0.303, P=0.018), and Ts lymphocyte count ( r=-0.260, P=0.043). Conclusions:Children with newly diagnosed MB expressing a high level of NLR had a poor prognosis, which may be associated with T lymphocyte and Ts lymphocyte.

Alzheimer′s disease is a progressive neurodegenerative disease that requires medication to improve patient symptoms, but there is an individual difference in the efficacy. In this paper, the correlation between single nucleotide polymorphism and the drug efficacy of Alzheimer′s disease (AD) in the past 20 years was searched through the databases of China National Knowledge Infrastructure, VIP Database, Wanfang Database, Pubmed, Springer Link and Cochrane Library with key words of Alzheimer′s disease, drug efficacy, single nucleotide polymorphism. The correlation between AD drug efficacy difference and gene single nucleotide polymorphism was reviewed, including ABCA1, ApoE, ChAT, CHRNA7, IL-6, A2M, CYP2D6, BChE, 5HT2a, PON-1 and ESR1 genes, so as to provide a reference basis for clinicians to select drugs in the treatment of AD.

Objective To analyze the infiltration abundance of macrophage M2 in breast cancer tissues and explore the correlation between VSIG4 and macrophage M2 and the potential mechanism of regulating the invasion and migration of breast cancer patients. Methods We downloaded the RNA-seq data of TCGA-BRCA and assessed the infiltration abundance of immune cells in the samples by CIBERSORT, and established a prognostic risk prediction model. Then, we analyzed the effect of macrophage M2 and VSIG4 on the prognosis of breast cancer patients. In addition, we analyzed the signaling pathway associated with VSIG4 by gene set enrichment analysis and predicted its upstream regulation of miRNA. Results The infiltration abundance of macrophage M2, age, PR status and pathological stage were involved in the establishment of risk prediction model, and the model had a good prediction performance (AUC=0.816). High infiltration of macrophage M2 (HR=1.35, P < 0.05) and high expression of VSIG4 (HR=1.4, P=0.039) suggested poor prognosis of breast cancer patients. VSIG4 could be regulated by upstream miR-29a-3p and significantly correlated with Toll-like receptor, cell adhesion, production and release of cytokine. Conclusion VSIG4 is significantly associated with breast cancer patients' prognosis and infiltration of macrophage M2, regulated by the upstream miR-29a-3p and promotes the invasion and migration of breast cancer cells. It can be used as a potential prognostic marker for breast cancer.