BACKGROUND: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. METHODS: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. RESULTS: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05). CONCLUSIONS The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; China ; Prognosis ; Transcription Factors

Objective To evaluate the effect of preoperative metabolic syndrome on early function of renal allografts in allogeneic kidney transplant recipients.Methods Clinical data of 117 kidney transplant recipients were retrospectively analyzed.According to the renal allograft function,they were divided into the delayed graft function(DGF)group(n=29)and non-DGF group(n=88).Relevant risk factors of DGF in recipients undergoing allogeneic kidney transplantation were assessed by univariate and multivariate regression analyses.The effect of preoperative metabolic syndrome on early function of renal allografts was analyzed.Results Among 117 kidney transplant recipients,47 cases were complicated with preoperative metabolic syndrome,and 29 cases developed postoperative DGF.In the DGF group,83％of the recipients were complicated with preoperative metabolic syndrome,higher than 74％in the non-DGF group(P＜0.05).Univariate analysis showed that the body mass index(BMI)and terminal serum creatinine(Scr)level of the donors,and BMI,blood glucose level,triglyceride level and the proportion of preoperative metabolic syndrome of the recipients in the DGF group were higher than those in the non-DGF group(all P＜0.05).Multivariate logistic regression analysis revealed that high Scr levels of the donors,high hemoglobin levels of the recipients and preoperative metabolic syndrome of the recipients were the independent risk factors for DGF after kidney transplantation(all P＜0.05).Conclusions Preoperative metabolic syndrome is an independent risk factor for DGF in allogeneic kidney transplant recipients.Corresponding measures should be taken to lower the incidence of DGF and other metabolic complications.

Objective: To evaluate the effectiveness of recombinant Mycobacterium tuberculosis fusion protein skin test (EC-ST) in screening for latent tuberculosis infection (LTBI) among HIV/AIDS patients, so as to provide insights into the applicability of EC-ST in LTBI screening among HIV/AIDS patients. Methods: From April to June 2023, HIV/AIDS patients under management and treatment in Yangzhou City, Jiangsu Province, were selected as study subjects. Basic information was collected through questionnaire surveys. LTBI was screened by EC-ST and interferon-gamma release assay (IGRA). Taking IGRA results as the diagnostic standard, the positive rate, sensitivity, specificity and consistency rate of EC-ST, and the impact of CD4+T lymphocyte (CD4) counts on the screening effect of EC-ST were analyzed. Results: A total of 523 HIV/AIDS patients were screened, including 458 males (87.57%) and 65 females (12.43%). The median age was 48.00 (interquartile range, 21.00) years. The positive rate of EC-ST was 7.27% and the positive rate of IGRA was 7.46%, with no statistically significant difference (P>0.05). The consistency rate of the two methods was 94.84%, and the Kappa value of 0.621 (95%CI: 0.489-0.752, P<0.05). The sensitivity of EC-ST was 64.10% and the specificity was 97.31%. Comparing the groups with CD4 counts <500 and ≥500 cells/μL, the consistency rates of the two methods were 95.32% and 94.44%, and the Kappa values were 0.568 and 0.650, respectively (both P<0.05). There were no statistically significant differences in the positive rates, sensitivity, and specificity of EC-ST (all P>0.05). Comparing the groups with CD4 counts <200 and ≥200 cells/μL, the consistency rates of the two methods were 96.55% and 94.62%, and the Kappa values were 0.648 and 0.619, respectively (both P<0.05). There were no statistically significant differences in the positive rates, sensitivity, and specificity of EC-ST (all P>0.05). Conclusion The effectiveness of EC-ST in screening for LTBI among HIV/AIDS patients is consistent with that of IGRA and is not affected by CD4 counts.

Objective:To evaluate the efficacy of modified corporeal rotation technique in the treatment of congenital penile downward curvature.Methods:A retrospective analysis was conducted on the clinical data of 32 patients with congenital penile curvature who underwent surgical procedure in Beijing Hospital from June 2021 to December 2022. The patients' age was (25.3±5.4) years old, preoperative erect penile length was (14.0±1.4) cm, preoperative erect penile circumference was (12.3±0.6) cm, preoperative erect penile downward curvature angle was (41.8±9.3)°, and preoperative International Index of Erectile Function(IIEF-5) score was (19.6±2.8). All 32 cases underwent modified corporeal rotation technique with local anesthesia, while the surgical instruments and suturing techniques employed in this study aimed to minimize damage to the penile neurovascular bundle by utilizing plastic surgery instruments and magnifier. Additionally, the use of inverted horizontal mattress sutures, with knots embedded within the tissue, was implemented to reduce their impact on postoperative patient satisfaction. Surgical time, preoperative and immediate postoperative penile length, circumference, and curvature angle were recorded. Follow-ups were conducted at 1, 3, and 6 months postoperatively, and IIEF-5 scores, postoperative penile sensation scores, and surgery-related complications (wound pain, infection, poor incision healing, etc.)were recorded.Results:The immediate postoperative erect penile length was (13.9±1.4) cm, with no statistically significant difference compared to preoperative length( P=0.127).The immediate postoperative erect penile curvature angle was (2.1±1.1) °, with a statistically significant difference compared to preoperative angle, ( P<0.01). IIEF-5 scores at 1, 3, and 6 months postoperatively were (20.4±1.7), (22.0±1.0), and (22.3±0.8) respectively, compared with preoperative scores, the differences were statistically significant ( P<0.001). The proportions of patients with fully restored glans sensation at 1, 3, and 6 months postoperatively were 0, 31.2% (10/32), and 68.8% (22/32), respectively, with sensation scores of (1.1±0.8), (3.2±0.6), and (3.7±0.5). Three patients (9.0%) experienced poor ventral wound healing postoperatively, but fully recovered after regular wound dressing. Conclusions:The modified corporeal rotation technique effectively corrects congenital penile downward curvature without significant loss of penile length, no adverse effects on erectile function or neurological damage were found, presenting high surgical safety and clinical value.

Background::We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model.Methods::In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups ( n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. Results::After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. Conclusions::MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Objective To investigate the accuracy and feasibility of shear wave elastography(SWE)combined with superb microvascular imaging(SMI)for the differential diagnosis of benign and malignant thyroid nodules.Methods A total of 190 patients with thyroid nodu-les detected in the Ultrasound Department of our hospital from January 2021 to December 2022 who underwent ultrasound-guided fine-needle aspiration biopsy or exhibited postoperative histopathological improvement were selected as the study subjects.Among them,a total of 224 thyroid nodules(74 benign and 150 malignant nodules)were detected,all of whom underwent thyroid ultrasonography,SWE,and SMI.The parameters related to the Young's modulus of the tissue as well as the condition of fine blood flow and perforating vessels were calculated.Using histopathological results as the gold standard to construct receiver operating characteristic(ROC)curves,observe the effectiveness of SWE combined with SMI in the differential diagnosis of thyroid nodules,and compare the efficacy of different examination methods in the diagnosis of thyroid nodules.Results There were significant differences in the internal composition,echo,margin,cal-cification,and aspect ratio between the benign and malignant thyroid nodules(all P<0.05);however,there was no significant difference in the average diameter of the benign and malignant nodules(P>0.05).There were statistically significant differences in maximum elas-ticity,mean elasticity,elasticity ratio,microvascular score,peak shear wave velocity,and average shear wave velocity between the benign and malignant thyroid nodules(all P<0.05).The ROC curve showed that the area under the curve of the maximum elastic value was the highest,while the optimal diagnostic threshold was 29.52 kPa.The optimal diagnostic threshold for the microvascular flow score was 2.3 points.In terms of diagnostic efficacy,SWE combined with SMI showed the highest sensitivity(94.67%)and specificity(94.59%).Conclusion SWE combined with SMI can further improve the diagnostic efficiency of benign and malignant thyroid nodules and achieve quantitative evaluation and dynamic observation of lesions,which has application and promotion value.

BACKGROUND: Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA. METHODS: This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1:1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0-10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events. RESULTS: Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147-0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00-22.50] vs . 16.00 [11.00-27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs . 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain. CONCLUSIONS This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.
Humans ; Female ; Middle Aged ; Aged ; Osteoarthritis, Knee/drug therapy* ; Flurbiprofen/therapeutic use* ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use* ; Pain/drug therapy* ; Treatment Outcome ; Double-Blind Method

Danshen, the dried roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza), is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tanshinones, the bioactive compounds from Danshen, exhibit a wide spectrum of pharmacological properties, suggesting their potential for future therapeutic applications. Tanshinone biosynthesis is a complex process involving at least six P450 enzymes that have been identified and characterized, most of which belong to the CYP76 and CYP71 families. In this study, CYP81C16, a member of the CYP71 clan, was identified in S. miltiorrhiza. An in vitro assay revealed that it could catalyze the hydroxylation of four para-quinone-type tanshinones, namely neocryptotanshinone, deoxyneocryptotanshinone, and danshenxinkuns A and B. SmCYP81C16 emerged as a potential broad-spectrum oxidase targeting the C-18 position of para-quinone-type tanshinones with an impressive relative conversion rate exceeding 90%. Kinetic evaluations andin vivo assays underscored its highest affinity towards neocryptotanshinone among the tested substrates. The overexpression of SmCYP81C16 promoted the accumulation of (iso)tanshinone in hairy root lines. The characterization of SmCYP81C16 in this study accentuates its potential as a pivotal tool in the biotechnological production of tanshinones, either through microbial or plant metabolic engineering.
Humans ; Salvia miltiorrhiza/metabolism* ; Biosynthetic Pathways ; Quinones/metabolism* ; Plant Roots/metabolism* ; Gene Expression Regulation, Plant

Objective:To explore the association of bone resorption marker β carboxyterminal peptide of collagen Ⅰ (β-CTX) with hypercalcemia in patients with Graves′ disease (GD).Methods:287 patients with GD who were hospitalized in the endocrinology department of Fuyang People′s Hospital from January 2021 to December 2021 were divided into control group ( n=251) and hypercalcemia group ( n=36) according to the corrected blood calcium level. The clinical data and serum β-CTX level of the two groups were compared. Logistic regression model was used to analyze the risk factors of hypercalcemia in GD patients. Pearson correlation was used to analyze the correlation between serum β-CTX level and other indexes. Results:Of the 287 GD patients, 36 were diagnosed as hypercalcemia, and the incidence of hypercalcemia was 12.54%. The levels of free triiodothyronine (FT3), free thyroxine (FT4), blood phosphorus (P) and β-CTX in hypercalcemia group were higher than those in control group, and the total parathyroid hormone (iPTH) in hypercalcemia group were lower than those in control group (all P<0.05). Multivariate Logistic regression analysis showed that FT3 ( OR=1.283, 95% CI: 1.049-1.570, P<0.05), iPTH ( OR=0.924, 95% CI: 0.863-0.989, P<0.05), β-CTX ( OR=2.488, 95% CI: 1.193-5.189, P<0.05) were the influencing factors for hypercalcemia in GD patients. Pearson correlation analysis showed that β-CTX was positively correlated with FT3, FT4, blood calcium, P, alkaline phosphatase (ALP), total procollagen type I amino end terminal peptide (PINP), N-bone-gamma-carboxyglutamic-acid-containing proteins (N-MID) and 25(OH)D, and negatively correlated with iPTH (all P<0.05). Conclusions:β-CTX is highly expressed in the serum of GD patients with hypercalcemia, which is a risk factor for the occurrence of hypercalcemia in GD patients.

Humans ; Asthma/drug therapy* ; Biological Therapy