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 investigate the clinicopathological characteristics of early gastric cancer with mixed histological staging, and to analyze the prognostic effect of endoscopic submucosal dissection (ESD) for early gastric cancer.Methods:Clinical data of early gastric cancer patients treated with ESD in Gansu Wuwei Cancer Hospital from January 2011 to March 2020 were collected, and clinicopathological characteristics of patients with mixed-type early gastric cancer were analyzed by descriptive statistical methods. The clinical effects and influencing factors of ESD on early gastric cancer were analyzed by logistic regression. Kaplan-Meier was used to estimate the survival rate, and log-rank test was used to compare the survival rate.Results:A total of 269 patients (280 lesions) were included in this study, including 216 males (80.30%) and 53 females (19.70%), with age of 60.43±8.01 years. There were 25 lesions (8.93%) of mixed early gastric cancer, 248 lesions (88.57%) of differentiated early gastric cancer, and 7 lesions (2.50%) of undifferentiated early gastric cancer. Compared with differentiated and undifferentiated early gastric cancer, the lesion site of mixed early gastric cancer was mainly located in the upper 1/3 of the stomach [64.00% (16/25), 40.73% (101/248) VS 0.00% (0/7), χ2=10.211, P=0.006], the proportion of the lesion size ≤2 cm was relatively small [52.00% (13/25), 80.65% (200/248) VS 85.71% (6/7), χ2=11.173, P=0.004], and the proportion of infiltration depth in the mucosa was lower [52.00% (13/25), 85.48% (212/248) VS 57.14% (4/7), χ2=20.019, P<0.001], the proportion of positive vertical resection margin was relatively high [20.00% (5/25), 2.82% (7/248) VS 0.00% (0/7), χ2=16.657, P<0.001], the proportion of vascular invasion was higher than that of differentiated carcinoma but lower than that of undifferentiated carcinoma [36.00% (9/25), 2.42% (6/248) VS 42.86% (3/7), χ2=58.413, P<0.001], the complete resection rate was lower [76.00% (19/25), 93.15% (231/248) VS 100.00% (7/7), χ2=9.497, P=0.009], the curative resection rate was lower than that of differentiated early gastric cancer, but higher than that of undifferentiated early gastric cancer [48.00% (12/25), 89.52% (222/248) VS 42.86% (3/7), χ2=39.757, P<0.001], and the proportion of eCura grade C2 was higher than that of differentiated cancer, but lower than that of undifferentiated cancer [48.00% (12/25), 5.65% (14/248) VS 57.14% (4/7), χ2=58.766, P<0.001]. The results of multivariate analysis showed that the larger lesions ( P=0.004, OR=0.539, 95% CI: 0.354-0.822) was the risk factor for curative resection. In terms of infiltration depth, mucosal ( P=0.001, OR=51.799, 95% CI: 5.535-84.768) and submucosal 1 ( P<0.001, OR=29.301, 95% CI: 24.694-73.972) were protective factors for curative resection compared with submucosal 2. In terms of differentiation degree, compared with mixed type, differentiated type ( P=0.024, OR=3.947, 95% CI: 1.195-13.032) was the protective factor for curative resection, while undifferentiated type ( P=0.443, OR=0.424, 95% CI: 0.048-3.788) showed no difference between curative resection and mixed type. During the follow-up, 7 patients died. The overall survival time was 114.42±0.97 months, and the 5-year survival rate was 97.10%. There was no significant difference in the survival rate of early gastric cancer patients with different degrees of differentiation ( χ2=0.434, P=0.805). The survival rate of early gastric cancer patients with or without curative resection was significantly different ( χ2=4.081, P=0.043). Conclusion:Mixed early gastric cancer patients show high margin positive rate, vascular infiltration, and less curative resection than differentiated early gastric cancer. Therefore, the process of treating mixed early gastric cancer should be more rigorous. The long-term survival prognosis of early gastric cancer after ESD treatment is promising.

Objective To present and discuss beam characteristics of the first Mevion S250i gantry-mounted accelerator pencil beam scanning proton therapy system in China.Methods The output dose was measured using a parallel-plate ionization chamber.The integrated depth dose was measured with a large-radius Bragg peak ionization chamber,covering 19 energy levels ranging from 227 MeV to 28 MeV,to analyze the proton beam characteristics.The spots in the air were measured with Phoenix flat panel detector on the beam central axis,and the precision of the delivery position was verified by measuring the multi-spot beam map.The interleaf leakage and penumbra reduction of adaptive aperture were measured to characterize its performance.Results The proton system was calibrated for a maximum energy of 227 MeV,with a(10×10)cm2uniform field delivering 1 Gy dose at a depth of 5 cm underwater.The system effectively modulated the proton beam range to the patient's surface,maintaining a constant 80%-80%Bragg peak width of 8.6 mm at all energy levels.The spot size of the highest energy beam at the isocenter was about 4 mm in the air,and the spot delivery position error was less than 1 mm.The interleaf leakage rate of the adaptive aperture for the highest energy beam was below 1.5%,and the penumbra was significantly reduced.Conclusion Mevion S250i proton therapy system demonstrates unique design and beam characteristics,which is reflected in the Bragg peak shape,spot size variation with energy,and penumbra sharpening of adaptive aperture;and these differences should be considered in treatment planning system modeling and planning for precision treatment.

The incidence of osteoporotic thoracolumbar vertebral fracture (OTLVF) in the elderly is gradually increasing. The kyphotic deformity caused by various factors has become an important characteristic of OTLVF and has received increasing attention. Its clinical manifestations include pain, delayed nerve damage, sagittal imbalance, etc. Currently, the definition and diagnosis of OTLVF with kyphotic deformity in the elderly are still unclear. Although there are many treatment options, they are controversial. Existing guidelines or consensuses pay little attention to this type of fracture with kyphotic deformity. To this end, the Lumbar Education Working Group of the Spine Branch of the Chinese Medicine Education Association and Editorial Committee of Chinese Journal of Trauma organized the experts in the relevant fields to jointly develop Clinical guidelines for the diagnosis and treatment of osteoporotic thoracolumbar vertebral fractures with kyphotic deformity in the elderly ( version 2024), based on evidence-based medical advancements and the principles of scientificity, practicality, and advanced nature, which provided 18 recommendations to standardize the clinical diagnosis and treatment.

Objective:To measure and assess relevant radiation doses at the radiotherapy site of the first domestic single-vault proton therapy system.Methods:The radiation levels of the therapy system during and after beam irradiation were measured, and annual effective doses were assessed for personnel at the site.Results:During beam irradiation, the highest radiation dose was detected at the shielded door of the equipment floor, with a gamma radiation level of 2.140 μSv/h and a neutron radiation level of 0.850 μSv/h. Neutron radiation disappeared immediately once the beams stopped. In contrast, the radiation activated originated mostly from gamma rays. A longer time after beams stopped was associated with lower induced radiation intensity at the same location. Furthermore, a farther distance from the irradiated object corresponded to lower induced radiation intensity at the same time. The assessment result reveal that the annual effective doses to the personnel were at the safe level, with physicists exposed to the highest dose of 2.138 mSv.Conclusions:The radiation level at the studied proton therapy site meets the safety requirement, and the treatment can be performed safely at this site.

BACKGROUND: The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the genomic alterations (GAs) of the SWI/SNF complex are observed in several cancer types, correlating with multiple biological features of tumor cells. However, their role in liver metastasis of non-small cell lung cancer (NSCLC) remains unclear. Our study aims to investigate the role and potential mechanisms underlying NSCLC liver metastasis induced by the GAs of SWI/SNF complex. METHODS: The GAs of SWI/SNF complex in NSCLC cell lines (H1299, H23 and H460) were identified by whole-exome sequencing (WES). ARID1A knockout H1299 cell was constructed with the CRISPR/Cas9 technology. The mouse model of liver metastasis from NSCLC was established to simulate lung cancer liver metastasis and observe the metastasis rate under different gene mutation conditions. RNA sequencing and Western blot were conducted for differential gene expression analysis. Immunohistochemistry (IHC) analysis was used to assess protein expression levels of SWI/SNF-regulated target molecules in mouse liver metastases. RESULTS: WES analysis revealed intracellular gene mutations. The animal experiments demonstrated a correlation between the GAs of SWI/SNF complex and a higher liver metastasis rate in immunodeficient mice. Transcriptome sequencing and Western blot analysis showed upregulated expression of ALDH1A1 and APOBEC3B in SWI/SNF-mut cells, particularly in ARID1A-deficient H460 and H1299 sgARID1A cells. IHC staining of mouse liver metastases further demonstrated elevated expression of ALDH1A1 in the H460 and H1299 sgARID1A group. CONCLUSIONS This study underscores the critical role of the GAs of SWI/SNF complex, such as ARID1A and SMARCA4, in promoting liver metastasis of lung cancer cells. The GAs of SWI/SNF complex may promote liver-specific metastasis by upregulating ALDH1A1 and APOBEC3B expression, providing novel insights into the molecular mechanisms underlying lung cancer liver metastasis.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Liver Neoplasms/genetics*

Objective:To explore the driving mechanisms of doctors′ collaborative willingness and behavior in the tiered diagnosis and treatment system, in order to provide reference for promoting the construction of the tiered diagnosis and treatment system.Methods:Based on the harmonious management theory, a theoretical framework for the driving mechanisms of doctors′ collaborative behavior in the tiered diagnosis and treatment system was developed. Through random sampling, a questionnaire survey was conducted among doctors from 40 medical institutions in five prefecture-level cities in Zhejiang province between April and May 2022. The t-test, variance analysis, and non-parametric tests were employed to analyze the differences in collaborative willingness and behavior among doctors based on various demographic characteristics. The structural equation model and stratified linear regression were used to assess the impact of collaborative factors (professional environment and work expectations) and harmonious factors (perception of policy support and perception of management mechanism) on doctors′ collaboration willingness and behavior. Results:A total of 1 959 doctors participated in the survey. Doctors′ collaborative behavior scored 2.13±1.12, indicating a slightly below-average level, whereas their willingness to collaborate scored 3.88±0.79, falling between neutral and somewhat willing. Significant differences in collaborative behavior scores were observed based on the medical institution′s ranking, age, years of experience, monthly average income, and professional titles ( P<0.05). Both collaborative and harmonious factors directly influenced the doctors′ willingness to collaborate, with standardized path coefficients of 0.428 and 0.139, respectively. Similarly, these factors directly impacted their collaborative behavior, with standardized path coefficients of 0.104 and 0.366. The perceptions of policy support and management mechanisms demonstrated a significant positive moderating effect on the relationship between doctors′ collaborative willingness and behavior, with effect values of 0.047 and 0.043 respectively ( P<0.05). Conclusions:The collaborative and harmonious elements serve as positive drivers for collaboration among doctors in the tiered diagnosis and treatment system at both the cognitive and behavioral levels. Enhancing and optimizing policy support and management mechanisms can facilitate the transition from intention to actual collaborative actions among doctors from different levels of medical institutions.

Objective:To investigate the clinical and pathological features and improve the acknowledgement of intraductal tubulopapillary neoplasm (ITPN) of pancreas.Methods:Six cases with ITPN in the Shandong Provincial Hospital Affiliated to Shandong First Medical University combined with 40 cases from PubMed and CNKI were retrospectively analyzed. There were 25 males and 21 females, aged (58.6±16.0) years. The clinical manifestations, pathological features, treatment and so on were analyzed.Results:All cases were treated with surgery. The main clinical symptoms were upper abdominal pain and discomfort (23 cases, 50.0%), followed by jaundice (9 cases, 19.6%). Seven cases (15.2%) had no clinical symptoms. Three cases (6.5%) had low back discomfort, chills and other rare symptoms, and 4 cases (8.7%) had no clinical symptoms mentioned in the literature. Tumors of 27 cases (58.7%) located in the head of the pancreas, 9 cases (19.6%) in the body and tail, 4 cases (8.7%) in the whole pancreas, 3 cases (6.5%) in the body, 2 cases (4.3%) in ampulla and 1 case (2.2%) in head and body. Most of the tumors located in the main pancreatic duct. Microscopically, back-to-back tubular glands were densely arranged, parts of them with papillary structure, with obvious cell atypia and many mitoses. Twenty-two cases (47.8%) of ITPN were completely confined to the pancreatic duct, and 24 cases (52.2%) were with associated invasive carcinoma. Tumor cells were positive for cytokeratin 7 and mucin 1, but negative for cytokeratin 20, synaptophysin, chromogranin and trypsin. Mucin 2, mucin 5AC and mucin 6 were negative in most cases. Ki-67 ranged from 10% to 70%.Conclusion:Pancreatic ITPNs were mostly located in the pancreatic head, confined to the main pancreatic duct, and were mostly manifested as pain and discomfort in the upper abdomen. Surgery was the main treatment. Tumors cells of ITPN were arranged in tubular and papillary, with severe epithelial atypia and special immunophenotype, parts of cases accompanied with associated invasive carcinoma.

【Objective】 To screen the risk factors of severe postpartum hemorrhage that can be found at 32 weeks of pregnancy through univariate and multivariate analysis and establish the risk prediction diagram. 【Methods】 A retrospective analysis was performed on pregnant women who gave birth and received blood transfusion in Women's Hospital of Nanjing Medical University from 2019 to 2021. According to the blood transfusion volume during and after operation, the patients were divided into low/moderate transfusion group (transfusion volume <2 000 mL) and massive-transfusion group (transfusion volume ≥2 000 mL), and the basic information of puerperal, single high risk factor, measures of operation and use of blood preparations were recorded. The differences of physiological and pathological factors between the low/moderate transfusion group and the massive transfusion group were analyzed by univariate analysis. Multivariate analysis and nomogram were performed on the statistically significant factors to calculate the consumption of blood components and hemostatic measures in the massive transfusion group. 【Results】 There were significant differences in age, number of pregnancies, advanced age at first delivery, history of abortion, scar uterus, pernicious placenta previa, placenta accreta, eclampsia/pre-eclampsia and acquired coagulopathy between the low/moderate transfusion group (n=930) and the massive transfusion group (n=108) (P<0.05), among which the number of pregnancies, advanced age for the first delivery, pernicious placenta previa, placenta accreta, and eclampsia/pre-eclampsia were independent risk factors for severe postpartum hemorrhage at 32 weeks of gestation. The scores of risk factors for massive blood transfusion from high to low were placenta accreta, primiparity at advanced age, eclampsia/pre-eclampsia, pernicious placenta previa, number of pregnancies≥4 and scar uterus. 【Conclusion】 The possibility of severe postpartum hemorrhage can be accurately evaluated in the third trimester (around 32 weeks) by univariate analysis, multivariate analysis and nomogram drawing. Among the puerpera underwent blood transfusion, the risk factors for massive hemorrhage included pregnancies ≥4 times, primiparity at advanced age, pernicious placenta previa, placenta accreta, and eclampsia/pre-eclampsia. The model based on these factors has a good prediction effect on massive hemorrhage.

BACKGROUND: The treatment mode of lung cancer is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for patients with EGFR mutant in non-small cell lung cancer (NSCLC). At the same time programmed death receptor 1 (PD-1) and its programmed death receptor ligand 1 (PD-L1) inhibitors therapy as the representative immune checkpoint inhibitors (ICIs) has a significant effect in the treatment of lung cancer. The aim of this study was to investigate the correlation between the expression of PD-1 and PD-L1 in NSCLC and clinicopathologic feature, EGFR gene mutation. METHODS: The protein expression of PD-1 and PD-L1 was detected by immunohistochemistry from 127 patients with NSCLC and EGFR gene mutation was detected by quantitative polymerase chain reaction (qPCR) to analyze its relation with clinicopathologic feature. Also, the correlation between protein expression of PD-1 and PD-L1 and EGFR mutation. RESULTS: The PD-1 positive expression in NSCLC tumor cells and tumor infiltrating immune cells is 53.5% (68/127), PD-L1 is 57.5% (73/127). The PD-1 and PD-L1 expression significantly higher in well-differentiated and moderately-differentiated carcinoma than poorly differentiated carcinoma, I+II than III+IV in clinical staging (P<0.05). The EGFR mutation rate was 46.5% (59/127), correlate with female, without smoking history, adenocarcinoma and well-differentiated and moderately-differentiated patients respectively higher than male, smoking history, squamous carcinoma and poorly differentiated patients (P<0.05). The protein expression of PD-L1 and PD-1 had the consistency in NSCLC patients (kappa=0.107,5, P=0.487). There was a negative correlation between the EGFR mutation and PD-1 and PD-L1 expression (Φ=-0.209, Φ=-0.221, P<0.05). Follow-up of NSCLC patients, the median total survival in under the age of 65, adenocarcinoma, well-differentiated and moderately-differentiated, with PD-L1 expression patients respectively higher than over the age of 65, squamous carcinoma, poorly differentiated, without PD-L1 expression patients (P<0.05). The median survival of hypo expression patients of PD-L1 significantly higher than hyper expression patient (P=0.04). CONCLUSIONS According to the Chinese Expert Consensus on Standards of PD-L1 immunohistochemistry testing for NSCLC, we tested the PD-L1 expression in NSCLC and then the dominant population of anti-PD-1/PD-L1 treatment was screened out. Patients with EGFR mutation were also detected and EGFR mutation was negatively correlated with the expression of PD-1 and PD-L1 as well. On the basis of PD-L1 expression and EGFR mutation status, it may benefit NSCLC patients from individualized treatment. Meanwhile, patients who were under the age of 65, adenocarcinoma, well-differentiated and moderately-differentiated, hypo expression of PD-L1 have a relatively good prognosis, to provide reference for the prognosis evaluation of NSCLC.