BACKGROUND: Treatment with chimeric antigen receptor-T (CAR-T) cells has shown promising effectiveness in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), although the process of preparing for this therapy usually takes a long time. We have recently created CD19 Fast-CAR-T (F-CAR-T) cells, which can be produced within a single day. The objective of this study was to evaluate and contrast the effectiveness and safety of CD19 F-CAR-T cells with those of CD19 conventional CAR-T cells in the management of R/R B-ALL. METHODS: A multicenter, retrospective analysis of the clinical data of 44 patients with R/R B-ALL was conducted. Overall, 23 patients were administered with innovative CD19 F-CAR-T cells (F-CAR-T group), whereas 21 patients were given CD19 conventional CAR-T cells (C-CAR-T group). We compared the rates of complete remission (CR), minimal residual disease (MRD)-negative CR, leukemia-free survival (LFS), overall survival (OS), and the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between the two groups. RESULTS: Compared with the C-CAR-T group, the F-CAR-T group had significantly higher CR and MRD-negative rates (95.7% and 91.3%, respectively; 71.4% and 66.7%, respectively; P = 0.036 and P = 0.044). No significant differences were observed in the 1-year or 2-year LFS or OS rates between the two groups: the 1-year and 2-year LFS for the F-CAR-T group vs.C-CAR-T group were 47.8% and 43.5% vs. 38.1% and 23.8% (P = 0.384 and P = 0.216), while the 1-year and 2-year OS rates were 65.2% and 56.5% vs. 52.4% and 47.6% (P = 0.395 and P = 0.540). Additionally, among CR patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T-cell therapy, there were no significant differences in the 1-year or 2-year LFS or OS rates: 57.1% and 50.0% vs. 47.8% and 34.8% (P = 0.506 and P = 0.356), 64.3% and 57.1% vs. 65.2% and 56.5% (P = 0.985 and P = 0.883), respectively. The incidence of CRS was greater in the F-CAR-T group (91.3%) than in the C-CAR-T group (66.7%) (P = 0.044). The incidence of ICANS was also greater in the F-CAR-T group (30.4%) than in the C-CAR-T group (9.5%) (P = 0.085), but no treatment-related deaths occurred in the two groups. CONCLUSION Compared with C-CAR-T-cell therapy, F-CAR-T-cell therapy has a superior remission rate but also leads to a tolerably increased incidence of CRS/ICANS. Further research is needed to explore the function of allo-HSCT as an intermediary therapy after CAR-T-cell therapy.

Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength, leading to increased fragility. Buqi-Tongluo (BQTL) decoction, a traditional Chinese medicine (TCM) prescription, has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis. To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments. We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages (BMMs) at various concentrations. TRAcP experiments were conducted to examine BQTL's impact on osteoclast differentiation. RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation. Finally, in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings. This study revealed that BQTL suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity. The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity, primarily through attenuation of the MAPK, NF-κB, and Calcineurin signaling pathways. BQTL's inhibitory capacity was further examined in vivo using an ovariectomized (OVX) rat model, demonstrating a strong protective effect against bone loss. BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
Animals ; NFATC Transcription Factors/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Ovariectomy ; Osteoclasts/metabolism* ; Female ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; NF-kappa B/genetics* ; Osteoporosis/genetics* ; Signal Transduction/drug effects* ; Bone Resorption/genetics* ; Cell Differentiation/drug effects* ; Humans ; RANK Ligand/metabolism* ; Mitogen-Activated Protein Kinases/genetics* ; Transcription Factors

Five previously undescribed diterpenoids, named succipenoids D‒H (1‒5), along with four undescribed lignans, named succignans A‒D (6‒9), were isolated from the dichloromethane extract of Chinese medicinal succinum. Compounds 1‒5 were characterized as nor-abietane diterpenoids, while compounds 6‒9 were identified as lignans polymerized from two groups of phenylpropanoid units. The structures of these novel compounds, including their absolute configurations, were determined through spectroscopic and computational methods. Biological assessments of renal fibrosis demonstrated that compounds 6 and 7 effectively reduce the expression of proteins associated with renal fibrosis, including α-smooth muscle actin (α-SMA), collagen I, and fibronectin in transforming growth factor-β1 (TGF-β1) induced normal rat kidney proximal tubular epithelial cells (NRK-52e).
Animals ; Rats ; Lignans/isolation & purification* ; Diterpenes/isolation & purification* ; Fibrosis/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Molecular Structure ; Cell Line ; Kidney Diseases/pathology* ; Transforming Growth Factor beta1/genetics* ; Kidney/metabolism* ; Actins/genetics* ; Fibronectins/genetics* ; Collagen Type I/genetics* ; Epithelial Cells/metabolism*

Objective To employ the mesh meta analysis to compare the effectiveness and safety of short-term reaching-standard treatment in the patients with moderate to severe atopic dermatitis among the different biologics.Methods The randomized controlled trials (RCT) were retrieved from the databases of CNKI,Chinese Biomedical Literature Database,Wanfang,VIP,PubMed,Cochrane Library and Embase data-bases.The retrieval time was from the database establishment to August,2023.The related literatures on the biologics for treating moderate to severe atopic dermatitis were collected.The literatures were screened by the inclusion and exclusion standards,the literature quality was evaluated and the data were extracted.Then the mesh meta analysis was performed by using RevMan 5.3 and Stata 16.0 softwares.Results A total of 754 ar-ticles were retrieved,and 11 articles were finally included,involving in 14 RCT with a total sample number of 5528 cases.There were 4 intervention methods,including placebo and 3 kinds of drugs.The drugs were Dupi-lumab,Lebrikizumab and Tralokinumab.The results showed that for each of effectiveness indicator,different medication regimens had different performance,after comprehensively meeting the treatment criteria,Dupri-uliumab was superior to Lebrikizumab,and Lebrikizumab was superior to Tralokinumab.There was no statis-tical difference in adverse reactions between the three drugs and placebo (P>0.05).Conclusion Dupilumab is currently the most effective biologic agent for short-term target treatment,capable of reducing inflamma-tion and improving skin symptoms.Future studies should further evaluate its long-term efficacy and safety to guide clinical application.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM. METHODS: Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells. RESULTS: In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow (P = 0.013), lower percentages of CAR-T cells in the peripheral blood at peak (P = 0.037), and higher percentages of CD8+ T cells (P = 0.034). Furthermore, there is a substantial correlation between high ctDNA level (>143 ng/mL) and shorter progression-free survival (PFS) (P = 0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143 ng/mL), MM-driven high-risk mutations (including IGLL5 [P = 0.004], IRF4 [P = 0.024], and CREBBP [P = 0.041]), number of multisite mutations, and resistance-related mutation (ERBB4, P = 0.040) were independent risk factors for PFS. CONCLUSION: Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy. REGISTERATION Chinese Clinical Trial Registry (ChiCTR2100046474) and National Clinical Trial (NCT04670055, NCT05430945).

Objective:To investigate the effect of miR-200c-3p on the proliferation and apoptosis of nephroblastoma SK-NEP-1 cell and its mechanism.Methods:From January 2015 to August 2019, nephroblastoma tissue and peritumoral tissue of 30 patients in Shenzhen Children′s hospital were collected.The experimental group of mimic negative control, miR-200c-3p and miR-200c-3p inhibitor was set up.The expression of miR-200c-3p in 30 paired nephroblastoma tissues and adjacent kidney tissues were detected by real-time fluorescence quantitative PCR.The differential expression of miR-200c-3p was also detected in SK-NEP-1 and 293FT cell lines.The effects of miR-200c and miR-200c-3p inhibitor on the proliferation, cell cycle distribution and apoptosis of SK-NEP-1 cells were detected by cell counting kit-8(CCK-8)and flow cytometry assays, respectively.Xenograft tumors were generated by peri-renal adipose tissue injection to assess the effect of miR-200c-3p on tumor growth in vivo.The pathological morphology of xenograft tumors was observed by HE staining.The proliferation index of Ki-67 were detected by immunohistochemistry.Western blot method was used to detect the B-cell lymphoma 2(Bcl-2), Bcl-2 related X protein (Bax) and cleaved cysteinyl aspartate specific proteinase-3(Caspase-3)expression level on xenograft tumors. Results:The expression level of miR-200c-3p in nephroblastoma(0.420±0.587)was significantly lower than that in matched normal kidney(1.500±0.504)( t=8.613, P<0.001). The expression level of miR-200c-3p in SK-NEP-1 cells (0.363±0.006) was significantly lower than that in human embryonic kidney 293FT cells (0.807±0.186) ( t=4.136, P<0.05). The group and time interaction results of CCK-8 proved that miR-200c-3p could inhibit the proliferation of SK-NEP-1 cells( F=16.81, P<0.001). The flow cytometer test of cell cycle and apoptosis showed that miR-200c-3p could block in G0/G1 and S phase( t=-7.770, P<0.01; t=11.501, P<0.001). Moreover, it increased the early apoptosis rate and decreased the late apoptosis rate ( t=-22.270, P<0.001; t=4.612, P<0.01). A orthotopic transplantation assay was employed to evaluate the effect of miR-200c-3p and miR-200c-3p inhibitor on the proliferation of SK-NEP-1 cells.The final volume of tumor miR-200c-3p group [(0.419±0.16) cm 3]was significantly lower than those in the control group [(2.469±0.914) cm 3, t=0.507, P<0.001]. However, the miR-200c-3p inhibitor group had no significant difference [(1.627±0.189) cm 3; t=2.209, P=0.052]. miR-200c-3p overexpression upregulated expression levels of apoptotic proteins cleaved Caspase-3 and Bax ( t=-47.000, -82.730, all P<0.001), but downregulated the expression level of anti-apoptotic protein Bcl-2( t=53.740, P<0.001). Conclusions:The overexpression of miR-200c-3p can inhibit the proliferation, promote the apoptosis of the SK-NEP-1 cells and partially inhibited tumorigenicity of nude mouse acted as a tumor suppressor gene.

[Abstract] Objective: To explore the pathogenosis and prognostic markers for non-smoking female lung cancer patients with bioinfor‐ matics analysis and functional prediction of potential lung cancer associated genes in female non-smokers. Methods: Data for nonsmoking female patients with lung cancer were downloaded from the Gene Expression Omnibus (GEO) database and the differentially expressed genes (DEGs) were identified using GEO2R. DAVID online data base was used to perform gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG), and STRING online software was used to perform protein-protein interaction (PPI) analysis; then the plug-in (M-CODE) was used to screen the key DEGs; finally, GEPIA and Kaplan-Meier plotter were used to perform function prediction and prognosis analysis of key DEGs. Results: A total of 160 DEGs were screened, including 54 up-regulated and 106 down-regulated genes; GO enrichment analysis showed that these DEGs were mainly related to neovascularization, single cell adhesion, positive regulation of GTPase activity and signal transduction (all P<0.05). KEGG pathway analysis revealed that DEGs were mainly involved in cell adhesion molecules (CAMs), leukocyte transendothelial migration, tight junction and endocytosis (all P<0.05); PPI network analysis revealed 8 key DEGs, including TIE1, PECAM1, CLDN5, VEGFD, ICAM2, ESAM, EMCN and ROBO4. Conclusion: TIE1, CLDN5, ICAM2, ESAM, VEGFD and ROBO4 may be the research targets of the pathogenesis of non-smoking female lung cancer patients. PECAM1 and EMCN may be the new bio-markers to predict the progression and prognosis of nonsmoking female lung cancer patients.

AIM:To observe the expression of nuclear factor-kappa B ( NF-κB) , N-methyl-D-aspartic acid re-ceptor 2B (NR2B) and inducible nitric oxide synthase (iNOS) in the spinal cord in a rat model of chronic constriction in-jury (CCI) of the sciatic nerve.METHODS:Fifty-six adult male Sprague-Dawley rats weighing 180~220 g were random-ly divided into sham group (n=8) and CCI group (n=48).The mechanical withdrawal threshold (MWT) and paw with-drawal latency (PWL) of the hind paws were measured 1 d before CCI and 1 d, 4 d, 7 d, 14 d and 21 d after surgery.The L4~L6 segment of the spinal cord was taken for determining the expression of NF-κB, NR2B and iNOS by RT-PCR and Western blotting.RESULTS:At 1 d, 4 d, 7 d, 14 d and 21 d after surgery, the MWT and PWL in CCI group were obviously lower than those in sham group .The expression of NF-κB, NR2B and iNOS at mRNA and protein levels in-creased significantly.Positive correlations were found between the mRNA expression of NF-κB and iNOS (r=0.842, P<0.05), and between the mRNA expression of NR2B and iNOS (r=0.833, P<0.05).CONCLUSION:The generation and maintenance of hyperalgesia in sciatic nerve injury rats may attribute to the activation of NF -κB and NR2B and concom-itant increase in iNOS .

Objective To observe the expression of Toll-like receptor(TLR) on peripheral blood dendritic cells(DC) in children with Henoch-Schtinlein purpura(HSP),and to investigate the pathogenesis of the abnormal expression of TLR in children with HSP.Methods Twenty hospitalized children with HSP in the Affiliated Hospital of Qingdao University Medical College from Dec.2011 to Jul.2012 were enrolled in the study(HSP group).Twenty agemetched healthy children were selected as a healthy control group.Peripheral venous blood was sampled under aseptic condition,peripheral blood mononuclear cells (PBMC) were isolated from density gradient centrifugation,and DC were generated by recombinat human granulocyte-macrophage colony-stimulating factor(GM-CSF),interleukin-4(IL-4) and tumor necrosis factor-α(TNF-α) in vitro.Expressions of CD83,CD86 and TLR2,TLR3,TLR4 in peripheral blood DC were examined by fluorescent activated cell sorter (FACS).Results 1.No significant distinction was found in the expression of the C Ds3 on peripheral blood DC between HSP group and healthy control group(t =0.80,P ＞ 0.05) ;in HSP group had remarkably increased expression of the CD86 on peripheral blood DC than that of the healthy control group (t =9.56,P ＜ 0.01).2.Expression rates of TLR2,TLR3,TLR4 on peripheral blood DC in the HSP group were higher than those in the healthy control group(t =1 1.79,13.29,9.45,all P ＜ 0.01).3.Expression rates of TLR2,TLR3 and TLR4 in HSP group had positive correlation with expression rates of CD86 (r =0.84,P ＜ 0.01 ; r =0.53,P ＜ 0.05 ; r =0.66,P ＜ 0.05).Conclusions Expressions of TLR2,TLR3 and TLR4 on peripheral blood DC significantly increased and were positively correlated with expression of CD86.This implies that TLR and co-stimulatory molecules might participate in the pathogenesis of HSP by mediating signal transduction,leading to abnormity of cytokines,then inducing Th1/Th2 immune imbalance by showing the advantage of Th2 function.