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

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 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.

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 find the effects of varus degree on the early metabolic changes of the lateral compartment cartilage in knees with medial unicompartmental osteoarthritis by detecting glycosaminoglycan (GAG) in varus knees.Methods From June 2016 to December 2017,twenty middle-aged volunteers without osteoarthritis or coronal deformities were recruited as the control group.Sixty patients diagnosed as medial unicompartmental osteoarthritis were recruited as the osteoarthritis group.The patients were further divided into four groups according to the degrees of varus angle,namely 2°-5° varus group,5°-10° varus group,10°-15° varus group and ＞15° varus group with 15 patients in each group.Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) was performed in all participants.The dGEMRIC indices (T1Gd) representing GAG content were calculated in the weight-bearing femoral cartilage (wbFC),the posterior non-weight-bearing femoral cartilage (pFC),the lateral femoral cartilage (FC,wbFC+pFC) and the tibial cartilage (TC) in the lateral compartment by using Matlab 7.1 and MRIMapper software.Results T1Gd of wbFC,pFC,FC and TC were 400.3±51.5 ms,393.6±57.9 ms,397.5±52.3 ms and 448.6±62.5 ms in the control group,391.8±41.5 ms,407.2±43.8 ms,400.1±37.8 ms and 461.3±41.6 ms in 2°-5° varus group and 386.9±57.1 ms,401.3±73.5 ms,397.7±59.6 ms and 438.9±42.8 ms in 5°-10° varus group.There was no significant difference among the above three groups in T1Gd in any of the analyzed cartilage regions (P＞0.05).In 10°-15° varus group,T1Gd of wbFC,pFC,FC and TC were 380.1±45.5 ms,385.5±76.6 ms,384.0±53.5 ms and 400.2±43.8 ms,respectively.Although T1Gd of wbFC,pFC and FC in 10°-15° varus group were similar with that in the control group,2°-5° varus group and 5°-10° varus (P＞0.05),T1Gd of TC in 10°-15° varus group decreased significantly (P＜0.05).In addition,T1Gd of wbFC,pFC,FC and TC in ＞15° varus groupwere 327.7±54.3 ms,340.1±33.0 ms,334.9±36.0 ms and 363.6±48.6 ms,respectively.T1Gd of all regions of interest in ＞15° varus group were significantly lower than that informer four groups (P＜0.05).Conclusion In medial unicompartmental knee osteoarthritis,there is a relationship between varus degree and GAG content of the lateral compartment cartilage.If varus angle ≤10°,the GAG content of the lateral compartment cartilage was similar with the similar aged subjects without osteoarthritis.If varus angle ＞ 10°,GAG content of the lateral compartment decreases significantly.

Objective To investigate the effect of early screening and intervention on congenital hypothyroid-ism.Methods Thyroid stimulating hormone (TSH),three thyroid stimulating hormone (T3 )and thyroid hormone (T4 )were screened in 72h after birth,and thyroid ultrasound examination.All the patients were treated with the treat-ment of the left -to -thyroid hormone,0 -6 months medication dose 25 -50g/d,6 -12months medication dose 50 -100g/d,1 -3months medication dose 75 -100g/d.Serum TSH was reviewed every three months in the age of 1 years, 2 -3 years old every six months to review the serum TSH.Results The mean value of TSH in children with congeni-tal hypothyroidism was (68.7 ±15.3)mU /L.The mean value of T4 was (42.4 ±13.1)nmol/L.100 cases of chil-dren,including 38 cases of primary congenital hypothyroidism,transient congenital hypothyroidism in 62 cases.Ultra-sound examination showed primary congenital hypothyroidism were developmental abnormalities,and abnormal absence of a total of 18 cases (47.4%),Abnormal blood flow in 15 cases (39.5%);No abnormalities were found in the ultrasound examination of the transient congenital hypothyroidism.Before treatment,TSH in children with congenital hypothyroidism was significantly higher than that in the control group[(68.7 ±15.3)mU /L vs (4.6 ±1.1)mU /L], T4 was significantly lower than the control group[(42.4 ±13.1)nmol/L vs (124.4 ±45.5)nmol/L],the differences
were statistically significant (t =22.867,16.058,all P <0.05);After treatment,the TSH of the children was signifi-cantly decreased[(5.3 ±1.1)mU /L vs (68.7 ±15.3)mU /L],and the T4 was significantly increased[(114.5 ± 35.4)nmol/L vs (42.4 ±13.1)nmol/L],compared with before treatment,the differences were statistically significant (t =41.331,19.101,all P <0.05 ),but compared with the control group,there were no significant differences between TSH and T4 (all P >0.05).After 1 -3 years follow -up observation,children with Gesell development scale test showed that children with adaptability,large movements,fine movements,language and social skills to reach the normal level.Conclusion Early screening and treatment of the patients with congenital hypothyroidism is beneficial to the rehabilitation of the patients with congenital hypothyroidism.