Objective:To preliminarily investigate the safety and efficacy of programmed death-1(PD-1)inhibitor combined with cord blood-derived natural killer cells(NK cells)in the treatment of advanced malignant solid tumors in an exploratory clinical trial.Methods:Three patients with advanced solid tumors treated at the Second Affiliated Hospital of Xi'an Medical University from December 2019 to December 2021 were enrolled.According to tumor type and CSCO guidelines,patients received multiple treatment cycles(21 days per cycle)consisting of standard chemotherapy,targeted therapy,or bevacizumab combined with PD-1 inhibitor.Umbilical cord blood-derived NK cells(8×107 cells per infusion)were infused at appropriate intervals during the treatment course.Target lesion size,tumor markers,levels of 12 peripheral blood cytokines,and lymphocyte subsets were assessed in each treatment cycle.Adverse events were also monitored throughout the treatment.Results:Following the treatment with PD-1 inhibitor combined with cord blood NK cells,2 patients achieved stable disease(SD,per RECIST 1.1 criteria),with durations of 118 days and 92 days,respectively.After NK cell infusion,patient#1 exhibited a marked decrease in the tumor marker CA199 to normal range and sustained for three follow-up periods;patient#2 showed significant reductions in tumor markers CA199,CA242,and CA724.Conclusion:The combination of NK cells with chemotherapy and PD-1 inhibitor demonstrates potential therapeutic efficacy for solid tumors.No severe immune-related adverse reactions were observed in the three patients enrolled in this study.

OBJECTIVE: The objective of our study was to evaluate the vaccine effectiveness (VE) of the pentavalent rotavirus vaccine (RV5) among < 5-year-old children in three provinces of China during 2020-2024 via a propensity score-matched test-negative case-control study. METHODS: Electronic health records and immunization information systems were used to obtain data on acute gastroenteritis (AGE) cases tested for rotavirus (RV) infection. RV-positive cases were propensity score matched with RV-negative controls for age, visit month, and province. RESULTS: The study included 27,472 children with AGE aged 8 weeks to 4 years at the time of AGE diagnosis; 7.98% (2,192) were RV-positive. The VE (95% confidence interval, CI) of 1-2 and 3 doses of RV5 against any medically attended RV infection (inpatient or outpatient) was 57.6% (39.8%, 70.2%) and 67.2% (60.3%, 72.9%), respectively. Among children who received the 3rd dose before turning 5 months of age, 3-dose VE decreased from 70.4% (53.9%, 81.1%) (< 5 months since the 3rd dose) to 63.0% (49.1%, 73.0%) (≥ 1 year since the 3rd dose). The three-dose VE rate was 69.4% (41.3%, 84.0%) for RVGE hospitalization and 57.5% (38.9%, 70.5%) for outpatient-only medically attended RVGE. CONCLUSION Three-dose RV5 VE against rotavirus gastroenteritis (RVGE) in children aged < 5 years was higher than 1-2-dose VE. Three-dose VE decreased with time since the 3rd dose in children who received the 3rd dose before turning five months of age, but remained above 60% for at least one year. VE was higher for RVGE hospitalizations than for medically attended outpatient visits.
Humans ; Rotavirus Vaccines/immunology* ; China/epidemiology* ; Case-Control Studies ; Child, Preschool ; Infant ; Rotavirus Infections/epidemiology* ; Male ; Propensity Score ; Female ; Vaccine Efficacy ; Gastroenteritis/virology* ; Vaccines, Attenuated ; Rotavirus

With the increasing demand for dynamic,real-time and rapid qualitative analysis of chemical composition in areas such as emergency response and space exploration,chip-scale mass spectrometers have attracted significant attention.These devices are expected to drive the integration of mass spectrometry with micro/nano-fabrication and intelligent sensing technologies,fostering profound innovation and breakthroughs in analytical chemistry.As an excellent mass analyzer,the ion trap exhibits numerous advantages,and its miniaturization creates favorable conditions for the high-density integration of miniature mass spectrometers.However,the reduction in ion storage capacity may compromise its sensitivity and dynamic range,rendering the study of ion unidirectional ejection in highly miniaturized ion traps of significant practical importance.In this work,a research was conducted on achieving efficient ion unidirectional ejection while maintaining high mass resolution in the extremely miniature hyperbolic linear ion trap(M-HLIT)with a field radius of 1 mm,and an electric field compensation method was proposed,which combined asymmetric electrode stretching and unbalanced RF voltage to achieve high-precision optimization of the electric field composition.Simulations showed that in an ideal structure,this method achieved 100％unidirectional ejection efficiency with the mass resolution of 518,significantly outperforming traditional asymmetric structure method(365)and unbalanced voltage method(321).Following the introduction of ion ejection slots,further optimization through bidirectional stretching and electrical parameters improved the resolution to 790 while maintaining a unidirectional ejection efficiency of 93％.This method eliminated the requirement for additional excitation voltage,offering an ideal solution for the miniature mass analyzer with high detection performance of chip-level mass spectrometers.

OBJECTIVE: To investigate the effect of TBL1XR1 mutation on cell biological characteristics of diffuse large B-cell lymphoma (DLBCL). METHODS: The TBL1XR1 overexpression vector was constructed and DNA sequencing was performed to determine the mutation status. The effect of TBL1XR1 mutation on apoptosis of DLBCL cell line was detected by flow cytometry and TUNEL fluorescence assay; CCK-8 assay was used to detect the effect of TBL1XR1 mutation on cell proliferation; Transwell assay was used to detect the effect of TBL1XR1 mutation on cell migration and invasion; Western blot was used to detect the effect of TBL1XR1 mutation on the expression level of epithelial-mesenchymal transition (EMT) related proteins. RESULTS: The TBL1XR1 overexpression plasmid was successfully constructed. The in vitro experimental results showed that TBL1XR1 mutation had no significant effect on apoptosis of DLBCL cells. Compared with the control group, TBL1XR1 mutation enhanced cell proliferation, migration and invasion of DLBCL cells. TBL1XR1 gene mutation significantly increased the expression of N-cadherin protein, while the expression of E-cadherin protein decreased. CONCLUSION TBL1XR1 mutation plays a role in promoting tumor cell proliferation, migration and invasion in DLBCL. TBL1XR1 could be considered as a potential target for DLBCL therapy in future research.
Humans ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Cell Proliferation ; Mutation ; Receptors, Cytoplasmic and Nuclear/genetics* ; Apoptosis ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Cell Movement ; Repressor Proteins/genetics* ; Nuclear Proteins/genetics* ; Cadherins/metabolism*

Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

OBJECTIVE: Based on metabonomics technology of high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) and hydrogen nuclear magnetic resonance spectroscopy (¹H NMR), the pharmacokinetic characteristics and therapeutic mechanism of Rhei Radix et Rhizoma (RhRR, Dahuang in Chinese), Eupolyphaga Steleophaga (EuS, Tubiechong in Chinese) combined with RhRR acting on acute liver injury were explored. METHODS: Models of acute liver injury were established, and the pharmacokinetic methods of five components of RhRR-EuS in rats were found by HPLC-MS/MS. The liver tissues of different groups of mice were analyzed by ¹H NMR spectroscopy combined with multivariate statistical analysis to investigate the metabolomics of RhRR-EuS and RhRR. RESULTS: Pharmacokinetic results showed there were different levels of bimodal phenomenon in different groups, and the absorption of free anthraquinone in RhRR increased after compatibility with EuS. In addition, the pathological state of acute liver injury in rats can selectively promote the absorption of emodin, chrysophanol, physcion and aloe emodin. Through 15 differential metabolites in the liver tissue of acute liver injury mice, it was revealed that RhRR-EuS and RhRR could protect the liver injury by regulating the metabolism of glutamine and glutamic acid, alanine, aspartic acid and glutamic acid, and phosphoinositide. However, the regulation of RhRR was weaker than that of RhRR-EuS. CONCLUSION For the first time, we studied the pharmacokinetics and metabolomics differences of RhRR-EuS and RhRR in rats and mice with acute liver injury, in order to provide theoretical reference for clinical treatment of liver disease by DHZCP.

Objective:To investigate the relative expression level and clinical significance of LINC00475 in serum of patients with multiple myeloma(MM).Methods:The expression of LINC00475 in serum of 108 MM patients and five MM cell lines including RPMI 8226,NCI-H929,U266,OPM2 and CAG were detected by real-time fluorescence quantitative PCR.The diagnostic value of LINC00475 in MM was evaluated by receiver operating characteristic(ROC)curve analysis.The correlation of LINC00475 with patients'characteristics was analyzed.Results:Compared with control groups,the expression of LINC00475 was up-regulated in serum of MM patients and MM cell lines(all P＜0.05).ROC curve analysis showed that the optimal cut-off value of LINC00475 was 262.4,the area under curve(AUC)was 0.924(95％CI:0.884-0.964),and sensitivity and specificity was 83.3％and 91.7％,respectively,which indicated that LINC00475 had good evaluation value in MM patients.Compared with low-LINC00475 expression group,patients in high-LINC00475 expression group had higher levels of β2-microglobulin(β2-MG)and Cystatin C(Cys-C)but lower albumin(ALB)(all P＜0.05).Compared with MM patients with International Staging System(ISS)stage I,the expression level of LINC00475 was significantly higher in patients with stage Ⅱ and Ⅲ(both P＜0.05).Conclusion:LINC00475 is helpful to distinguish MM patients from healthy adults,which is correlated with the prognostic indicators such as β2-MG,ALB,and ISS stage.

Objective Viral encephalitis is an infectious disease severely affecting human health.It is caused by a wide variety of viral pathogens,including herpes viruses,flaviviruses,enteroviruses,and other viruses.The laboratory diagnosis of viral encephalitis is a worldwide challenge.Recently,high-throughput sequencing technology has provided new tools for diagnosing central nervous system infections.Thus,In this study,we established a multipathogen detection platform for viral encephalitis based on amplicon sequencing. Methods We designed nine pairs of specific polymerase chain reaction(PCR)primers for the 12 viruses by reviewing the relevant literature.The detection ability of the primers was verified by software simulation and the detection of known positive samples.Amplicon sequencing was used to validate the samples,and consistency was compared with Sanger sequencing. Results The results showed that the target sequences of various pathogens were obtained at a coverage depth level greater than 20×,and the sequence lengths were consistent with the sizes of the predicted amplicons.The sequences were verified using the National Center for Biotechnology Information BLAST,and all results were consistent with the results of Sanger sequencing. Conclusion Amplicon-based high-throughput sequencing technology is feasible as a supplementary method for the pathogenic detection of viral encephalitis.It is also a useful tool for the high-volume screening of clinical samples.

Objective To investigate the mechanism by which mycobacterial antigen 85B (Ag85B) inhibits autophagy and promotes apoptosis in Hodgkin lymphoma (HL) cells. Methods The clinical data and pathological tissue slides were retrospectively collected from 80 HL children and 30 children with reactive lymphadenopathy (control group) treated at the First Affiliated Hospital of Xinjiang Medical University. Immunohistochemical analysis was performed to assess the expression of microtubule-associated protein 1 light chain 3 (LC3),sequestosome 1 (P62/SQSTM1),and Beclin-1 in the pathological tissues of HL and control groups. Human Hodgkin lymphoma cells (HDLM-2) were divided into the HDLM-2 group and the HDLM-2+Ag85B groups (with Ag85B concentrations of 0.5,1,2,and 4 μg/mL). The CCK8 method was used to measure HDLM-2 cell proliferation;qRT-PCR was employed to detect the expression of LC3,P62,Beclin-1,Akt,and mTOR mRNA in cells. An apoptosis kit was used to detect cell apoptosis. Results The positive expression of LC3 and Beclin-1 in the HL group were higher than those in the control group (P<0.05),while the positive expression of P62 was lower than that in the control group (P<0.05). In stages Ⅲ-Ⅳ compared to stages Ⅰ-Ⅱ,the positive expression of LC3 and Beclin-1 increased,while the positive expression of P62 decreased (P<0.05). Cell experiment results showed that the HDLM-2+Ag85B group had suppressed cell proliferation compared to the HDLM-2 group,with decreased mRNA expression of LC3 and Beclin-1,and increased mRNA expression of P62,PI3K,Akt,and mTOR,leading to increased cell apoptosis. Notably,when Ag85B was at a concentration of 2 μg/mL,it had the strongest effect on HDLM-2 cells after 24 hours (P<0.05). Conclusions Autophagy is enhanced in children with HL and increases with disease stage. Ag85B can inhibit the proliferation and autophagy of HL tumor cells and promote apoptosis,possibly related to the activation of the PI3K/Akt/mTOR pathway.