BACKGROUND: Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) binds to double-stranded RNA and catalyzes the deamination of adenosine (A) to inosine (I). The functional mechanism of ADAR1 in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to investigate the prognostic significance of ADAR1 in NSCLC and to elucidate its potential role in regulating tumor cell proliferation and migration. METHODS: Data from The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed to assess the correlation between high ADAR1 expression and clinicopathological features as well as prognosis in lung cancer. We performed Western blot (WB), cell proliferation assays, Transwell invasion/migration assays, and nude mouse xenograft modeling to examine the phenotypic changes and molecular mechanisms induced by ADAR1 knockdown. Furthermore, the ADAR1 p150 overexpression model was utilized to validate the proposed mechanism. RESULTS: ADAR1 expression was significantly elevated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared with adjacent non-tumor tissues (LUAD: P=3.70×10-15, LUSC: P=0.016). High ADAR1 expression was associated with poor prognosis (LUAD: P=2.03×10-2, LUSC: P=2.81×10-2) and distant metastasis (P=0.003). Gene Set Enrichment Analysis (GSEA) indicated that elevated ADAR1 was associated with mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation, matrix metalloproteinase-9 (MMP-9) expression, and cell adhesion. ADAR1 and MMP-9 levels showed a strongly positive correlation (P=6.45×10-34) in 10 lung cancer cell lines, highest in H1581. Knockdown of ADAR1 in H1581 cells induced a rounded cellular morphology with reduced pseudopodia. Concomitantly, it suppressed cell proliferation, invasion, migration, and in vivo tumorigenesis. It also suppressed ERK phosphorylation and downregulated cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-FOS), MMP-9, N-cadherin, and Vimentin. Conversely, ADAR1 p150 overexpression in PC9 cells enhanced ERK phosphorylation and increased c-FOS and MMP-9 expression. CONCLUSIONS High ADAR1 expression is closely associated with poor prognosis and distant metastasis in NSCLC patients. Mechanistically, ADAR1 may promote proliferation, invasion, migration, and tumorigenesis in lung cancer cells via the ERK/c-FOS/MMP-9 axis.
Humans ; Lung Neoplasms/physiopathology* ; Adenosine Deaminase/genetics* ; Matrix Metalloproteinase 9/genetics* ; Cell Proliferation ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Cell Movement ; Animals ; Mice ; RNA-Binding Proteins/genetics* ; Female ; Male ; Cell Line, Tumor ; Proto-Oncogene Proteins c-fos/genetics* ; Middle Aged ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; Extracellular Signal-Regulated MAP Kinases/genetics*

Objective:To discuss the effect of temperature-controlled shrinkage polytrimethylene carbonate(PTMC)/polyvinylpyrrolidone(PVP)nanofiber membrane on the biological behavior of mouse fibroblasts and the repairment effect on full-thickness skin defects in the rats,and to clarify the potential mechanism.Methods:The murine L929 fibroblast cells were used in the in vitro experiments and were divided into control group and experimental group(treated with PTMC/PVP nanofiber membranes).The proliferation activities of the cells in two groups were detected by CCK-8 assay;the numbers of live/dead cells in two groups were observed by live/dead cell staining;the morphology of the cells was observed by cytoskeletal staining.A total of 12 six-week-old male SD rats were selected in the in vivo experiment,and were randomly divided into control group and experimental group,and there were six rats in each group.The full-thickness skin defect model was established,and the rats in experimental group were treated with PTMC/PVP nanofiber membranes.The photographs were taken after operation,and the wound healing rates of the cells in two groups were calculated on the 0,3rd,6th,and 12th days.On the 6th and 12th days after operation,the skin samples around the wound of the rats in two groups were taken,and the histopathology of the would skin and adjacent tissue was detected by HE staining;the collagen deposition in wound skin tissue of the rats in two groups was observed by Masson trichrome staining;the numbers of angiogenesis in wound skin tissue of the rats were detected by CD31 immunohistochemical staining.Results:The CCK-8 assay results showed that the proliferation activity of the cells in experimental group showed an increasing trend on the 1st,3st,and 5st days,and there was no significant difference in the proliferation activities of the cells bewteen experimental group and control group(P＞0.05).The live/dead cell staining experiment results showed that compared with control group,the cell density and number of the cells in experimental group had no significant changes,and were predominantly live cells.The cytoskeletal staining results showed that the cells in experimental and control groups appeared spindle-shaped and well-spread.In the in vivo experiments,on the 3rd,6th,and 12th days,compared with control group,the wound healing rates of the cells in experimental group were increased(P＜0.01),and the wound healing rate of the cells was 95.45％on the 12th day,indicating nearly complete healing of the wound.The HE staining showed that on the 12th day,the wound skin structure of the cells in experimental group was more similar to the normal skin,and there was abundant granulation tissue,regular epidermal structure,and new blood vessel formation.The Masson trichrome staining results showed that compared with control group,the collagen deposition in wound tissue of the rats in experimental group was increased.The immunohistochemical staining results showed that the expression of CD31 in wound tissue of the rats in experimental group was increased,indicating the increasing of the number of angiogenesis.Conclusion:The PTMC/PVP thermoresponsive nanofiber membranes exhibit good biocompatibility and can promote the repairment of full-thickness skin defects in the rats;its mechanism may be related to the enhancement of proliferation activity of the basal cells.

Objective:To investigate the concern about pollen broadcasting in Chinese population from multiple dimensions and to understand the information about allergic rhinitis (AR) in China by analyzing related factors.Methods:From March 1 to September 30, 2022, a large-scale multi-center cross-sectional survey was conducted based on the Questionnaire Star platform in 21 Chinese hospitals. A total of 7 056 subjects from 7 regions in China: Northeast, North, East, Central, South, Southwest, and Northwest China were included. Basic characteristics (including social demographic characteristics and disease characteristics of AR patients), concern about pollen broadcasting, the willingness of pollen-induced AR (PiAR) patients to receive pollen broadcasting, and the treatment satisfaction rate of AR patients were collected. The chi-square test, multivariate linear regression model, and Logistic regression analysis were used to analyze the concern about pollen broadcasting in the Chinese population and related factors from multiple dimensions.Results:Among 7 056 subjects, 23.02% were concerned about pollen broadcasting. Among 3 176 self-reported AR and 1 019 PiAR patients, 25.60% and 39.16% were concerned about pollen broadcasting, respectively, which was higher than that of non-AR or non-PiAR subjects ( χ2 value was 21.74 and 175.11, respectively, both P<0.001). Among AR patients, the proportion of spring and autumn allergen-positive patients concerned about pollen broadcasting was higher than that in perennial allergen-positive patients ( χ2 value was 20.90 and 19.51, respectively, both P<0.001). The proportion of AR patients with asthma, sinusitis, allergic conjunctivitis, and cardiovascular and cerebrovascular diseases was higher than those without complications ( χ2 value was 50.83, 21.97, 56.78, 7.62, respectively, all P<0.05). The proportion of AR patients in North China who could find pollen broadcasting locally was 31.01%, significantly higher than those in other regions (all P<0.05). Multivariate linear regression model analysis showed that among PiAR patients, those with higher per capita household income and higher AR disease cognition levels had been concerned about pollen broadcasting in the past, and those complicated with allergic conjunctivitis had stronger intention to receive pollen broadcasting (B value was 0.24, 0.13, 0.66, 0.47, respectively, all P<0.05). The higher the disease cognition level of PiAR patients, the stronger their willingness to actively participate in treatment ( R2=0.72, P<0.001). Only 18.89% of AR patients felt satisfied with the treatment effect. Logistic regression analysis showed that in AR patients, the treatment satisfaction rate was significantly higher among those concerned about pollen broadcasting compared to those who were not ( OR=1.83, P<0.001). Conclusions:Currently, the dissemination of pollen broadcasting in China is hindered by various factors such as disease cognition level. The treatment satisfaction among AR patients remains unsatisfactory.

objective:To prepare a composite photocrosslinked hydrogel containing zeolite imidazole framework-8(ZIF-8),and to evaluate its in vitro cytotoxicity,drug release capability,and antimicrobial propertie.Methods:The ZIF-8 particles were synthesized by hydrothermal method,and the microstructure characteristic was observed under scanning electron microscope(SEM).The particles were mixed with the gelatin methacryloyl(GelMA)with the mass fraction of 0.2%to obtain the composite hydrogel GelMA-Z.The atomic absorption spectroscope was used to detect the cumulative zinc ion(Zn2+)release amounts in GelMA-Z at different time points.The NIH-3T3 cells were co-cultured with GelMA-Z for 1,3,and 7 d;the viabilities of the cells in various groups were detected by CCK-8 assay;the GelMA-Z was co-cultured with Escherichia coli(E.coli)and Staphylococcus aureus(S.aureus)for 6,12,and 24 h and divided into control group,GelMA group,and GelMA-Z group.The bacterial activities of the cells in various groups at different time points were detected by microplate reader;the bacterial formation and the presence of live/dead becterial staining condition were detected by plate antibacterial experiment and live/dead bacterial staining method.Results:The SEM observation results showed that the hydrothermally synthesized ZIF-8 particles had the uniform particle sizes.The atomic absorption spectroscope results showed that Zn2+ in GelMA-Z showed an initial burst phase within 1 d,followed by a slow release,and reached the equilibrium around 7 d.Compared with control group,the viabilities the cells in GelMA group and GelMA-Z group were above 90%on the 1st,3rd,and 7th days,but there was no significant difference(P>0.05).The bacterial activity detection results showed that when co-cultured with bacteria for 6,12,and 24 h,compared with control group and GelMA group,the bacterial activities of the E.coli and S.aureus in GelMA-Z group were decreased(P<0.05).The plate antibacterial experiment results showed that the number of bacterial formation in GelMA-Z group was fewer than those in control group and GelMA group.The live/dead bacterial staining results showed that in GelMA-Z group,there was a large number of red fluorescence stained dead bacteria;in control group and GelMA group,there was a large number of green fluorescence stained live bacteria.Conclusion:The GelMA hydrogel loaded with ZIF-8 particles can achieve the in situ photocrosslinking and possesses good Zn2+ release capability and antimicrobial activity,and it is a novel hydrogel dressing for treatment of the infected wounds.

Objective:To study the impact of the age-adjusted Charlson comorbidity index (ACCI) on the prognosis of patients with hilar cholangiocarcinoma following laparoscopic surgical resection.Methods:Clinical data of 136 patients with hilar cholangiocarcinoma undergoing laparoscopic surgery at Zhengzhou University People's Hospital between January 2013 and January 2018 were retrospectively analyzed, including 81 males and 55 females, aged (63.6±9.8) years. Patients were divided into two groups based on the median ACCI score of 4.0: the high ACCI group (ACCI>4.0, n=49) and low ACCI group (ACCI≤4.0, n=87). The prognosis was compared between the two group. Univariate and multivariate Cox regression analyses were performed to analyze the effect of ACCI on survival after laparoscopic surgery. Results:The 1- and 3-year cumulative survival rates in low ACCI group were 87.4% and 48.3%, respectively, compared to 53.1% and 4.1% in high ACCI group ( χ2=27.97, P<0.001). Univariate Cox regression analysis indicated that ACCI >4.0 was associated with prognosis ( HR=3.73, 95% CI: 2.44-5.68, P<0.001). Multivariate Cox regression analysis also indicated that ACCI >4.0 was associated with an increased risk of postoperative mortality in patients with hilar cholangiocarcinoma ( HR=2.69, 95% CI: 1.65-4.37, P<0.001). Conclusion:The ACCI is a significant risk factor for survival of patients with hilar cholangiocarcinoma following laparoscopic surgery, which could facilitate a precise preoperative assessment of patient status and choice of surgical approach.

Objective:To investigate the influencing factors for microvascular invasion (MVI) in hepatocellular carcinoma based on three-dimensional visualization and the construction of its nomogram model.Methods:The retrospective cohort study method was conducted. The clinico-pathological data of 190 patients with hepatocellular carcinoma who were admitted to Henan University People′s Hospital from May 2018 to May 2021 were collected. There were 148 males and 42 females, aged (58±12)years. The 190 patients were randomly divided into the training set of 133 cases and the validation set of 57 cases by the method of random number table in the ratio of 7:3. The abdominal three-dimensional visualization system was used to characterize the tumor morphology and other imaging features. Observation indicators: (1) analysis of influencing factors for MVI in hepatocellular carcinoma; (2) construction and evaluation of nomogram model of MVI in hepatocellular carcinoma. Measurement data with normal distribution were expressed as Mean± SD, and independent sample t test was used for comparison between groups. Measurement data with skewed distribution were expressed as M( Q1, Q3), and non-parametric rank sum test was used for comparison between groups. Count data were expressed as absolute numbers, and the chi-square test was used for comparison between groups. Corresponding statistical methods were used for univariate analysis. Binary Logistic regression model was used for multivariate analysis. Receiver operator characteristic (ROC) curves were plotted, and the nomogram model was assessed by area under the curve (AUC), calibration curve, and decision curve. Results:(1) Analysis of influencing factors for MVI in hepatocellular carcinoma. Among 190 patients with hepatocellular carcinoma, there were 97 cases of positive MVI (including 63 cases in the training set and 34 cases in the validation set) and 93 cases of negative MVI (including 70 cases in the training set and 23 cases in the validation set). Results of multivariate analysis showed that alpha-fetoprotein, vascular endothelial growth factor, tumor volume, the number of tumors, and tumor morphology were independent factors affecting the MVI of patients with hepatocellular carcinoma ( odds ratio=5.06, 3.62, 1.00, 2.02, 2.59, 95% confidence interval as 1.61-15.90, 1.28-10.20, 1.00-1.01, 1.02-3.98, 1.03-6.52, P<0.05). (2) Construction and evaluation of nomogram model of MVI in hepatocellular carcinoma. The results of multivariate analysis were incorporated to construct a nomogram prediction model for MVI of hepatocellular carcinoma. ROC curves showed that the AUC of the training set of nomogram model was 0.85 (95% confidence interval as 0.79-0.92), the optimal fractional cutoff based on the Jordon′s index was 0.51, the sensitivity was 0.71, and the specificity was 0.84. The above indicators of validation set were 0.92 (95% confidence interval as 0.85-0.99), 0.50, 0.90, and 0.82, respectively. The higher total score of the training set suggested a higher risk of MVI in hepatocellular carcinoma. The calibration curves of both training and validation sets of nomogram model fitted well with the standard curves and have a high degree of calibration. The decision curve showed a high net gain of nomogram model. Conclusions:Alpha-fetoprotein, vascular endothelial growth factor, tumor volume, the number of tumors, and tumor morphology are independent influencing factors for MVI in patients with hepatocellular carcinoma. A nomogram model constructed based on three-dimensional visualized imaging features can predict MVI in hepatocellular carcinoma.

Background and aims:Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma(HCC).However,the tumor-protective functions of growth differentiation factors(GDFs)in HCC are yet to be clarified.In this study,we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo ex-periments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC.Methods:The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues.A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression.Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC.Results:The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in para-tumors(P＜0.001).Kaplan-Meier analysis showed that decreased GDF7 expression in HCC was asso-ciated with worse overall survival(5-year rate:61.8％vs.27.5％,P＜0.001)and increased recurrence risk(P＜0.001).Multivariate Cox regression analysis demonstrated that low GDF7 expression,the presence of microvascular invasion,and elevated alpha-fetoprotein(AFP)levels were independent risk factors for tumor recurrence and poor survival.Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model.GDF7 knockdown promoted migration and invasion via epithelial-mesenchymal transition.Meanwhile,a negative correlation between JunB proto-oncogene(JUNB)and GDF7 was observed in HCC tissues.Modulating JUNB levels altered GDF7 protein expression.Conclusions:GDF7 is a potential biomarker for predicting superior outcomes in patients with HCC.GDF7 amplification is a potential therapeutic option for HCC.

Stem cells have been regarded with promising application potential in tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities. However, their fate is relied on their local microenvironment, or niche. Recent studied have demonstrated that biophysical factors, defined as physical microenvironment in which stem cells located play a vital role in regulating stem cell committed differentiation. In vitro, synthetic physical microenvironments can be used to precisely control a variety of biophysical properties. On this basis, the effect of biophysical properties such as matrix stiffness, matrix topography and mechanical force on the committed differentiation of stem cells was further investigated. This paper summarizes the approach of mechanical models of artificial physical microenvironment and reviews the effects of different biophysical characteristics on stem cell differentiation, in order to provide reference for future research and development in related fields.
Cues ; Stem Cells ; Cell Differentiation ; Regenerative Medicine ; Tissue Engineering

Objective:To analyze the influencing factors of abnormal 15-minute retention rate of indocyanine green (ICG R15) (≥10%) in patients with hepatocellular carcinoma, and to construct a nomogram model, and to evaluate the prediction efficiency of the nomogram model.Methods:The clinical data of 190 patients with hepatocellular carcinoma in Zhengzhou University People's Hospital from December 2017 to June 2022 were retrospectively analyzed, including 148 males and 42 females, aged (57.8±9.9) years. According to ICG R15, the patients were divided into ICG R15 normal group ( n=134, ICG R15<10%) and ICG R15 abnormal group ( n=56, ICG R15≥10%). Univariate and multivariate logistic regression were used to analyze the influencing factors of abnormal ICG R15, and the nomogram model was established. The predictive ability of the model was evaluated by receiver operating characteristic (ROC) curve and C-index, and the model was verified by calibration curve and decision analysis curve. Results:Abnormal ICG R15 group the proportion of liver cirrhosis, albumin ≤35 g/L, hemoglobin ≤110 g/L, platelet count ≤100×10 9/L, prothrombin time >13 s, alanine aminotransferase >40 U/L, aspartate aminotransferase >40 U/L, total bilirubin >34.2 μmol/L, and the largest tumor diameter >5.0 cm, spleen volume >383.1 cm 3, spleen volume to of non-tumor liver volume (SNLR) >0.276 and liver tumor volume >117.2 cm 3 were higher than that of ICG R15 normal group, and the differences were statistically significant (all P<0.05). Logistic regression analysis showed that liver cirrhosis ( OR=3.89, 95% CI: 1.28-11.80, P=0.016), spleen volume >383.1 cm 3( OR=5.17, 95% CI: 1.38-19.38, P=0.015), SNLR >0.276 ( OR=5.54, 95% CI: 1.44-21.26, P=0.013) and total bilirubin >34.2 μmol/L( OR=10.20, 95% CI: 1.88-55.39, P=0.007) increased the risk of abnormal ICG R15. A nomogram model was constructed based on the above risk factors. The C-index of the model was 0.915 (95% CI: 0.872-0.957), and the area under the ROC curve predicted by the nomogram model was 0.915 (95% CI: 0.871-0.958). The calibration curve showed that the correlation index of the abnormal ICG R15 predicted by the nomogram was similar to actual situation. Decision analysis curve showed high returns. Conclusion:Liver cirrhosis, spleen volume >383.1 cm 3, SNLR>0.276 and total bilirubin >34.2 μmol/L were indepentlent risk factors for abnormal ICG R15 in patients with hepatocellur carcinoma. The clinical prediction model of ICG R15 abnormality constructed by nomogram has good prediction efficiency, which can provide a reference for evaluating preoperative liver reserve function of patients with hepatocellular carcinoma.

Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer. In addition to the common mechanisms underlying tumor recurrence, another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis. Transplant oncology is an emerging field that addresses oncological challenges in transplantation. In this context, a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients. Double-negative T cells (DNTs) are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor (TCR) type. Among them, TCRαβ⁺ DNTs are considered to induce immune suppression in immune-mediated diseases, while TCRγδ⁺ DNTs are widely recognized as tumor killers. As a composite cell therapy, healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host. In this work, we summarized the biological characteristics and functions of DNTs in oncology, immunology, and transplantation. Based on the multiple roles of DNTs, we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy (ACT).
Humans ; T-Lymphocytes ; Immunotherapy, Adoptive ; Neoplasm Recurrence, Local ; Transplantation, Homologous ; Cell- and Tissue-Based Therapy