Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Humans ; Paxillin/metabolism* ; Protein-Lysine 6-Oxidase/metabolism* ; Carcinoma, Squamous Cell/pathology* ; Epithelial-Mesenchymal Transition ; Integrin alpha2beta1/metabolism* ; Mouth Neoplasms/pathology* ; Collagen/metabolism* ; Fibroblasts ; Extracellular Vesicles/metabolism* ; Cell Line, Tumor ; Tumor Microenvironment

Objective:To analyze the prognosis and influencing factors of different radiotherapy modes in patients with brain metastases from non-small cell lung cancer (NSCLC), and to explore the best benefit population with radiotherapy boost under different prognostic scores.Methods:634 patients with brain metastasis from NSCLC admitted to the Fourth Hospital of Hebei Medical University from 2013 to 2015 were analyzed retrospectively. According to different radiotherapy modes, they were divided into three groups: no radiotherapy group ( n=330), whole-brain radiotherapy group (WBRT)( n=127) and whole-brain radiotherapy combined with boost group (WBRT+ boost)( n=177). The intracranial progression-free survival (iPFS) and overall survival (OS) were calculated by Kaplan-Meier method. The multivariate prognostic factors were analyzed by the Cox models. Results:The median iPFS and OS of all patients were 6.9 months and 9.0 months, respectively. In the no radiotherapy, WBRT and WBRT+ boost groups, the 1-year iPFS was 15.1%, 16.3% and 40.2%( P=0.002), and the 1-year OS was 33.7%, 38.2% and 48.1%( P<0.001), respectively. Multivariate survival analysis demonstrated that different radiotherapy modes were the independent factors affecting iPFS and OS. Subgroup analysis revealed that for patients with 1-3 brain metastases, the 1-year OS and iPFS in the WBRT+ boost group were better than those of WBRT alone ( P=0.026, P=0.044) when GPA score was 2.5-4.0; the 1-year OS and iPFSin the WBRT+ boost group were better than those of WBRT alone ( P=0.036, P=0.049) when there was no targeted therapy; for patients with ≥4 brain metastases, the 1-year iPFS in the WBRT+ boost group was better than that of WBRT alone ( P=0.019, P=0.012) when GPA score was 2.5-4.0 and there was no targeted therapy. When the GPA score was 0-2 or there was targeted therapy, the 1-year OS and iPFS in the WBRT+ boost group were better than those of WBRT alone, but the difference was not statistically significant (all P>0.05). Conclusions:Radiotherapy can significantly improve the iPFS and OS of NSCLC patients with brain metastases. When the number of brain metastases is 1-3, GPA score is 2.5-4.0 or no targeted therapy, boost may improve the iPFS and OS; when the number of brain metastases is more than 4, GPA score is 2.5-4.0 or no targeted therapy, boost may only bring iPFS benefit; when GPA score is 0-2 or targeted therapy, boost may not benefit significantly.

BACKGROUND: Hypertension is associated with stroke-related mortality. However, the long-term association of blood pressure (BP) and the risk of stroke-related mortality and the influence path of BP on stroke-related death remain unknown. The current study aimed to estimate the long-term causal associations between BP and stroke-related mortality and the potential mediating and moderated mediating model of the associations. METHODS: This is a 45-year follow-up cohort study and a total of 1696 subjects were enrolled in 1976 and 1081 participants died by the latest follow-up in 2020. COX proportional hazard model was used to explore the associations of stroke-related death with baseline systolic blood pressure (SBP)/diastolic blood pressure (DBP) categories and BP changes from 1976 to 1994. The mediating and moderated mediating effects were performed to detect the possible influencing path from BP to stroke-related deaths. E value was calculated in the sensitivity analysis. RESULTS: Among 1696 participants, the average age was 44.38 ± 6.10 years, and 1124 were men (66.3%). After a 45-year follow-up, a total of 201 (11.9%) stroke-related deaths occurred. After the adjustment, the COX proportional hazard model showed that among the participants with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg in 1976, the risk of stroke-related death increased by 217.5% (hazard ratio [HR] = 3.175, 95% confidence interval [CI]: 2.297-4.388), and the adjusted HRs were higher in male participants. Among the participants with hypertension in 1976 and 1994, the risk of stroke-related death increased by 110.4% (HR = 2.104, 95% CI: 1.632-2.713), and the adjusted HRs of the BP changes were higher in male participants. Body mass index (BMI) significantly mediated the association of SBP and stroke-related deaths and this mediating effect was moderated by gender. CONCLUSIONS In a 45-year follow-up, high BP and persistent hypertension are associated with stroke-related death, and these associations were even more pronounced in male participants. The paths of association are mediated by BMI and moderated by gender.
Adult ; Blood Pressure/physiology* ; China/epidemiology* ; Follow-Up Studies ; Humans ; Hypertension ; Male ; Middle Aged ; Risk Factors ; Stroke

Objective:To analyze the prognosis and influencing factors of patients with brain metastases from non-small cell lung cancer (NSCLC) treated with different doses of whole brain radiotherapy (WBRT).Methods:A total of 244 NSCLC patients with brain metastases who underwent WBRT in the Fourth Hospital of Hebei Medical University from 2013 to 2015 were analyzed retrospectively. According to different doses of WBRT (EQD 2Gy), they were divided into the 30-39 Gy group ( n= 104) and ≥40 Gy group ( n= 140). The intracranial progression-free survival (iPFS) and overall survival (OS) were compared betweentwo groups. According to the number of brain metastases, GPA score, KPS score, chemotherapy and targeted therapy, the prognosis of different doses of WBRT was further analyzed. Results:The median iPFS and OS of all patients were 6.9 months and 11.8 months, respectively. Univariate survival analysis: the 1-year iPFS and 1-year OS between two groups were 22.5% and 25.4%( P=0.430) and 41.1% and 46.4%( P=0.068), respectively. Multivariate survival analysis: different doses of WBRT were not associated with the improvement of iPFS and OS; independent factors influencing iPFS included local boost, gender, number of brain metastases, chemotherapy and targeted therapy; independent factors influencing OS included gender, number of brain metastases, chemotherapy and targeted therapy. Subgroup analysis: in patients with KPS≥90, the 1-year iPFS and OS of patients with WBRT ≥ 40 Gy were seemingly better than those of their counterparts with 30-39 Gy, but the difference was statistically significant only in OS ( P=0.047), the difference was not statistically significant in iPFS ( P=0.068); in patients with chemotherapy, the 1-year iPFS and OS of patients with WBRT≥40 Gy were better than those of their counterparts with 30-39 Gy ( P=0.017, P=0.012); in patients with targeted therapy, the 1-year iPFS and OS in the WBRT≥40 Gy group were better than those in the 30-39 Gy group ( P=0.012, P=0.045). Conclusions:The 30-39 Gy may be the appropriate dose of WBRT for NSCLC patients with brain metastases. WBRT≥40 Gy does not bring more benefits. WBRT≥40 Gy may benefit NSCLC patients with brain metastases with high KPS score or active systemic therapy.

Objective:To investigate basic characteristics of diabetes prevalence and associated factors in centenarians in Hainan province of China.Methods:All the subjects were from China Hainan Centenarian Cohort Study. A total of 1 002 centenarians were included in the final analysis, who were divided into three groups: diabetes group, impaired fasting glucose (IFG) group, and normal glucose group according to the guideline.Results:The average age of centenarians was (102.77±2.55) years, and the proportion of females was 82.0%. There were 95 centenarians who suffered from diabetes, and the prevalence rate was 9.5%. There were 81 centenarians who had IFG, and the prevalence rate was 8.1%. The mean fasting plasma glucose (FPG) level of centenarians was (5.12±1.44) mmol/L, while 43.5% of centenarians had FPG levels ranging from 4.00 to 5.00 mmol/L and 22.1% of centenarians had the FPG levels ranging from 5.00 to 6.00 mmol/L. Increased triglyceride level and abdominal obesity might be associated with the risk for diabetes.Conclusion:The glycometabolism in centenarians in Hainan was better than that in other age groups, and no gender specific difference was observed.

Objective:To explore the blood pressure levels and the influencing factors of hypertension among Hainan centenarians, and provide basic data for the further blood pressure related studies of the centenarian population.Methods:The baseline data were from China Hainan Centenarian Cohort Study (CHCCS). This cross-sectional data, based on the community population, was a complete sample study of centenarians, including questionnaire survey, physical examination and physiological index detection. A total of 1 002 centenarians were recruited to describe the blood pressure level. According to the guidelines for the prevention and treatment of hypertension in Chinese adults in 2018, the prevalence of hypertension was analyzed.Results:The median levels of systolic blood pressure, diastolic pressure and pulse pressure were 152.0, 76.0 and 76.5 mmHg, respectively. Blood pressure level was higher in females than in males. The prevalence of hypertension was 71.9%, mainly in isolated systolic hypertension with the prevalence of 60.1%. The results of multivariate analysis showed that the risk of hypertension in women was higher than that in men ( OR=1.624, 95% CI: 1.155-2.283), and the risk of hypertension in the northern ( OR=0.625, 95% CI: 0.434-0.901) and central areas ( OR=0.586, 95% CI: 0.346-0.993) was lower than that of the Eastern. Conclusion:The prevalence of hypertension, mainly in isolated systolic hypertension, showing gender and regional distribution differences.

Objective:To explore the prevalence of lipid profile and the influencing factors of dyslipidemia in centenarians in Hainan province, and provide basic data for the study of the lipid profile in centenarians.Methods:The data of this study were from the baseline data of China Hainan Centenarian Cohort Study from June 2014 to December 2016. A total of 1 002 centenarians were recruited. According to the guidelines for the prevention and treatment of dyslipidemia in Chinese adults in 2016, the prevalence of lipid profile were described and the prevalence of dyslipidemia with different clinical classifications were compared, and the main influencing factors were analyzed.Results:The median levels of TC, TG, LDL-C and HDL-C were 4.60 mmol/L, 1.05 mmol/L, 2.77 mmol/L and 1.41 mmol/L, respectively, in centenarians in Hainan. Blood lipid profile level was higher in females than in males. With the increase of BMI, TC, TG and LDL-C increased significantly, while HDL-C decreased significantly. The total prevalence of dyslipidemia was 19.1%. Smoking, BMI and area distribution were the main influencing factors of dyslipidemia.Conclusion:The prevalence of dyslipidemia in centenarians in Hainan was at a low level compared with other countries, and the blood lipid profile level was higher in females than in males.

Objective:To analyze the association of waist circumference, BMI, waist-hip ratio, waist-height ratio, calf circumference and waist-calf circumference ratio (WCR) with depression risk in centenarians in Hainan province.Methods:A total of 1 002 centenarians in Hainan were selected by cluster sampling. GDS-15 was used to investigate the depression. Multivariate linear regression and logistic regression analyses were conducted to evaluate the correlation between anthropometric indicators and depression risk. Restricted cubic spline was used to analyze and visualize the linear relationship.Results:After adjusting demographic characteristics (gender, age, ethnic group, marital status, educational level and type of residence) and lifestyle (smoking and drinking), the standard β of BMI, WC, WHR, WHtR, calf circumference and WCR associated with GDS-15 were -0.069, -0.032,0.009, -0.009, -0.099 and 0.060, respectively, and the P values of BMI and calf circumference were <0.05. With the increase of calf circumference, the risk of depression decreased, OR value was 0.94 (95% CI:0.90-0.98), and after adjustment, the results were still significant. Classified variable analysis indicated with the decrease of calf circumference and the increase of WCR, the risk of depression increased gradually, the trend P values were 0.038 and 0.042, respectively. Conclusion:Central obesity (waist circumference and WCR) and periphery obesity (calf circumference) have differed effects on depression in centenarians, and increased calf circumference is a protective factor for depression in female centenarians, attention should be paid to the mental health of the elderly women with lower calf circumference.

Objective:To explore the current status and influencing factors of self-management of depression in community residents, so as to provide clues and basis for promoting the mental health of community residents.Methods:From June to August 2020, the residents of a community in Jining city in Shandong Province were selected as the survey objects, and 458 permanent residents were selected by simple random sampling method. The self-designed general data questionnaire, Depression Self-management Scale, General Self-Efficacy Scale (GSES) , Simple Coping Style Questionnaire (SCSQ) and Social Support Rating Scale (SSRS) were used to conduct cross-sectional survey, and structural equation was used to analyze the influencing factors of depression self-management of community residents. A total of 458 questionnaires were sent out and 443 were effectively received, with the effective recovery rate of 96.72%.Results:The depression self-management score of 443 community residents was (32.72±5.72) , GSES score was (23.47±5.12) , score of positive coping in SCSQ (2.07±0.51) , score of negative coping in SCSQ was (1.14±0.43) and total score of SSRS (32.89±3.43) . The structural equation model showed that the total effects of self-efficacy, positive coping, negative coping and social support on self-management of depression in community residents were respectively 0.45, 0.42, -0.52 and 0.37 ( P<0.05) . Conclusions:The depression self-management level of community residents is directly or indirectly affected by self-efficacy, coping styles and social support. When conducting mental health publicity and education in the community, it should be based on improving the self-efficacy of residents, coping styles and the level of social support to choose effective methods and content of publicity and education to promote the improvement of the self-management level of individual depression.

Objective To investigate the effect of olmesartan medoxomil on osteoprotegerin and serum inflammatory factor expression in atherosclerosis model rat.Methods From 2015 April in Jiangsu Institute of schistosomiasis control,24 Sprague-Dawley rats were randomly divided into the following three groups:the control group was fed with standard food,the model group was fed with high fat diet based on standard food(normal food +2％ cholesterol +5％ goat fat +0.2％ acid +7×105 IU/(kg·d) Vitamin D3),and the olmesartan group was given 3 mg/(kg·d) olmesartan gavage daily on the basis of high fat diet.On the fourth week of experiment the level of serum high sensitivity C reactive protein and serum lipids include total cholesterol,low density lipoprotein,high density lipoprotein and triglyceride were detected.The structure and changes of aortic pathology was observed.The expression of osteoprotegerinin in aortic was detected by immunohistochemistry staining and Western blot.Results Within the model group,the level of serum lipid and high-sensitivity C reactive protein increased significantly,endometrial thickness,intima-to-media thickness ratio and osteoprotegerin expression in aorta was significantly higher than that of normal group,the difference was statistically significant(P<0.05).The serum high density lipoprotein increased significantly,the level of other serum lipids and high sensitive C reaction protein decreased significantly,endometrial thickness,intima-to-media thickness ratio and osteoprotegerin expression in aorta of the olmesartan treated rats were significantly lower than those of model animals,the difference was statistically significant(P<0.05).Conclusion Olmesartan may suppress the development of atherosclerosis in model rats by decreasing the expression of osteoprotegerin and the level of serum inflammatory cytokines.