Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.
Humans ; Oral Submucous Fibrosis/immunology* ; Extracellular Matrix/metabolism* ; Myofibroblasts

ObjectiveTo analyze the expression level of triggering receptor expressed on myeloid cells-1 （TREM-1） in serum and ascites of patients with cirrhotic ascites， and to investigate its correlation with clinical features and inflammatory markers and its role in the diagnosis of infection and prognostic evaluation. MethodsA total of 110 patients with cirrhotic ascites who were hospitalized in The Fifth Hospital of Shijiazhuang from January 2019 to December 2020 were enrolled， and according to the presence or absence of intra-abdominal infection， they were divided into infection group with 72 patients and non-infection group with 38 patients. The patients with infection were further divided into improvement group with 38 patients and non-improvement group with 34 patients. Clinical data and laboratory markers were collected from all patients. Serum and ascites samples were collected， and ELISA was used to measure the level of TREM-1. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between multiple groups； the chi-square test was used for comparison of categorical data between two groups. A Spearman correlation analysis was used to investigate the correlation between indicators. A multivariate Logistic regression analysis was used to identify the influencing factors for the prognosis of patients with cirrhotic ascites and infection. The receiver operating characteristic （ROC） curve was used to evaluate the diagnostic and prognostic efficacy of each indicator， and the Delong test was used for comparison of the area under the ROC curve （AUC）. ResultsThe level of TREM-1 in ascites was significantly positively correlated with that in serum （r=0.50， P<0.001）. Compared with the improvement group， the non-improvement group had a significantly higher level of TREM-1 in ascites （Z=-2.391， P=0.017） and serum （Z=-2.544， P=0.011）， and compared with the non-infection group， the infection group had a significantly higher level of TREM-1 in ascites （Z=-3.420， P<0.001）， while there was no significant difference in the level of TREM-1 in serum between the two groups （P>0.05）. The level of TREM-1 in serum and ascites were significantly positively correlated with C-reactive protein （CRP）， procalcitonin （PCT）， white blood cell count， and neutrophil-lymphocyte ratio （r=0.288， 0.344， 0.530， 0.510， 0.534， 0.454， 0.330， and 0.404， all P<0.05）. The ROC curve analysis showed that when PCT， CRP， and serum or ascitic TREM-1 were used in combination for the diagnosis of cirrhotic ascites with infection， the AUCs were 0.715 and 0.740， respectively. The multivariate Logistic regression analysis showed that CRP （odds ratio ［OR］=1.019， 95% confidence interval ［CI］： 1.001‍ ‍—‍ ‍1.038， P=0.043） and serum TREM-1 （OR=1.002， 95%CI： 1.000‍ ‍—‍ ‍1.003， P=0.016） were independent risk factors for the prognosis of patients with cirrhotic ascites and infection， and the combination of these two indicators had an AUC of 0.728 in predicting poor prognosis. ConclusionThe level of TREM-1 is closely associated with the severity of infection and prognosis in patients with cirrhotic ascites， and combined measurement of TREM-1 and CRP/PCT can improve the diagnostic accuracy of infection and provide support for prognostic evaluation.

Objective:To explore the binding characteristics of N, N-diethyl-2-(2-(4-(2- 18F-fluoroethoxy)phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl)acetamide ( 18F-DPA-714) and ( R)- N-sec-butyl- N-methyl-4-(3-( 18F-trifluoromethyl)phenyl)quinazoline-2-carboxamide ( 18F-TFQC) to the single nucleotide polymorphisms of the 18×10 3 translocator protein (TSPO), and to evaluate the imaging efficacy and feasibility of those 2 molecular probes in neuroinflammation rat models. Methods:To test the selectivity of 18F-DPA-714 and 18F-TFQC for TSPO polymorphisms, the wild-type (high-affinity binding, HAB) and mutant (low-affinity binding, LAB) sequences of the human TSPO gene were transfected into 293T cells respectively. A competitive inhibition assay was carried out with N-methyl- N-(1-methylpropyl)-1-(2-chlorophenyl)-3-isoquinoline carboxamide (PK11195) as an inhibitor to determine the binding affinities of 2 probes to TSPO polymorphisms. Rat neuroinflammation models ( n=6) were established using lipopolysaccharide. Three days after modeling, small animal PET/CT imaging was performed using 18F-DPA-714 and 18F-TFQC, respectively, to observe and compare the uptake of the tracers, and the ratio of SUV mean of the right striatum to SUV mean of the left striatum (SUVR) was calculated. After the imaging, the expression and distribution of microglia and TSPO were detected by tissue immunofluorescence. Repeated-measures analysis of variance was used to analyze the SUVR data of different groups. Results:The inhibition constants ( Ki) of 18F-TFQC on 293T-LAB and 293T-HAB cells were 23.51 and 14.60 nmol/L, respectively, with a Ki LAB/ Ki HAB ratio of 1.61, indicating low sensitivity to TSPO single nucleotide polymorphisms. The Ki of 18F-DPA-714 for binding to 293T-LAB and 293T-HAB cells were 45.23 and 6.47 nmol/L, respectively, with a Ki LAB/ Ki HAB ratio of 6.99. Small animal PET/CT imaging demonstrated that specifically uptake of both probes could be found in neuroinflammatory lesions. The overall SUVR of 18F-DPA-714 in the lesions within 60minutes was slightly higher than that of 18F-TFQC, but no significant difference was observed ( F values: inter-group 0.40, time effect 0.30, cross-effect 0.03; all P>0.05). Conclusions:Compared with 18F-DPA-714, 18F-TFQC is less sensitive to TSPO gene polymorphisms, thus being more suitable for clinical application and promotion. It holds promise for the early identification of neuroinflammation and the efficacy monitoring of anti-inflammatory drug treatments.

Objective:To identify factors associated with depressive symptoms in maintenance hemodialysis patients and to examine the relationship between these symptoms and mortality.Methods:Between January and December 2019, patients who received maintenance hemodialysis in the Blood Purification Center of the Second Affiliated Hospital of Nanjing Medical University were enrolled in a prospective cohort study. Depressive symptoms were assessed using the internationally validated patient health questionnaire-8 (PHQ-8). Sleep quality and anxiety were measured with the Pittsburgh sleep quality index (PSQI) and the generalized anxiety disorder-7 (GAD-7) scale, respectively. Follow-up continued until December 31, 2022, with all-cause mortality as the primary outcome. Ordinal logistic regression was used to identify independent predictors of depression severity. Cox proportional hazards models evaluated the association between depressive symptoms and mortality.Results:A total of 532 maintenance hemodialysis (MHD) patients completed the study. Among them, 177 (33.3%) exhibited depressive symptoms. Compared with patients without depression, those with mild or moderate-to-severe depression were older [median age: 58 (50, 66) vs. 60 (55, 65) vs. 55 (46, 64)], more likely to smoke [35.9% (51/142) vs. 40.0% (14/35) vs.26.2% (93/355)], had poorer sleep quality [PSQI: 9 (6, 13) vs. 12 (9, 17) vs. 5 (3, 9)], and higher anxiety levels [GAD-7: 1 (0, 3) vs. 3 (1, 6) vs. 0 (0, 1)], the differences among the three groups were statistically significant (all P<0.05). Ordinal logistic regression identified smoking status, history of diabetes or cardiovascular disease, hemoglobin level, PSQI score, and GAD-7 score as independent predictors of depression severity ( OR=1.60, 1.80, 1.81, 0.98, 3.67, 8.67; all P<0.05). After a median follow-up of 40 (35, 44) months, 109 patients died, including 66 (60.6%) from cardio-cerebrovascular causes and 24 (22.0%) from infections. Kaplan-Meier analysis revealed significantly lower cumulative survival in the depression group compared to the non-depression group ( P<0.001). Cox regression analysis demonstrated that depressive symptoms remained independently associated with all-cause mortality after adjusting for confounders ( HR=1.06, 95% CI 1.00-1.13, P=0.048), with an even stronger association observed for patients with PHQ-8 scores≥2.9 ( HR=1.10, 95% CI 1.03-1.16, P=0.005). However, the associations between depression and cardio-cerebrovascular mortality ( P=0.111) or infection-related mortality ( P=0.509) were not statistically significant. Conclusions:Depressive symptoms are prevalent among maintenance hemodialysis patients and are independently associated with increased all-cause mortality. Smoking, comorbid diabetes or cardiovascular disease, low hemoglobin level, poor sleep quality, and anxiety are risk factors contributing to depression. Maintenance hemodialysis patients with PHQ-8 scores≥3 should be considered at heightened risk for mortality.

Objective To analyze the influencing factors of the success of clinical pregnancy in secondary infertility patients undergoing in vitro fertilization-embryo transfer(IVF-ET)and construct a nomogram prediction model.Methods A retrospective analysis was conducted on the clinical data of 235 patients with secondary infertility who underwent IVF-ET at Urumqi Maternal and Child Health Hospital from January 2020 to December 2023.They were divided into successful pregnancy group(n=109)and failed pregnancy group(n=1 26)based on whether clinical pregnancy was successful.The general information,ovulation induction data and embryo data of two groups of patients were compared.Multivariate Logistic regression analysis was used to screen out statistically significant indicators,and based on this,a nomogram prediction model was constructed.The receiver operating characteristic curve,calibration curve and decision analysis curve were drawn to verify the discrimination,accuracy and clinical practicability of the model.Results The results of multivariate Logistic regression analysis showed that the female's age,overweight and obesity were all risk factors for clinical pregnancy failure,while anti-Müllerian hormone(AMH)and the total amount of gonadotropins(Gn)were protective factor for clinical pregnancy outcomes.On this basis,a nomogram prediction model was successfully constructed,which has a medium degree of discrimination,good accuracy and clinical practicability.Conclusion For secondary infertility patients undergoing IVF-ET,the female's age,overweight and obesity,AMH,and the total amount of Gn have certain influences on clinical pregnancy.The clinical pregnancy outcome can be predicted through the constructed nomogram prediction model.

Objective To analyze the expression level of triggering receptor expressed on myeloid cells-1(TREM-1)in serum and ascites of patients with cirrhotic ascites,and to investigate its correlation with clinical features and inflammatory markers and its role in the diagnosis of infection and prognostic evaluation.Methods A total of 110 patients with cirrhotic ascites who were hospitalized in The Fifth Hospital of Shijiazhuang from January 2019 to December 2020 were enrolled,and according to the presence or absence of intra-abdominal infection,they were divided into infection group with 72 patients and non-infection group with 38 patients.The patients with infection were further divided into improvement group with 38 patients and non-improvement group with 34 patients.Clinical data and laboratory markers were collected from all patients.Serum and ascites samples were collected,and ELISA was used to measure the level of TREM-1.The independent-samples t test was used for comparison of normally distributed continuous data between two groups;the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups,and the Kruskal-Wallis H test was used for comparison between multiple groups;the chi-square test was used for comparison of categorical data between two groups.A Spearman correlation analysis was used to investigate the correlation between indicators.A multivariate Logistic regression analysis was used to identify the influencing factors for the prognosis of patients with cirrhotic ascites and infection.The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic and prognostic efficacy of each indicator,and the Delong test was used for comparison of the area under the ROC curve(AUC).Results The level of TREM-1 in ascites was significantly positively correlated with that in serum(r=0.50,P<0.001).Compared with the improvement group,the non-improvement group had a significantly higher level of TREM-1 in ascites(Z=-2.391,P=0.017)and serum(Z=-2.544,P=0.011),and compared with the non-infection group,the infection group had a significantly higher level of TREM-1 in ascites(Z=-3.420,P<0.001),while there was no significant difference in the level of TREM-1 in serum between the two groups(P>0.05).The level of TREM-1 in serum and ascites were significantly positively correlated with C-reactive protein(CRP),procalcitonin(PCT),white blood cell count,and neutrophil-lymphocyte ratio(r=0.288,0.344,0.530,0.510,0.534,0.454,0.330,and 0.404,all P<0.05).The ROC curve analysis showed that when PCT,CRP,and serum or ascitic TREM-1 were used in combination for the diagnosis of cirrhotic ascites with infection,the AUCs were 0.715 and 0.740,respectively.The multivariate Logistic regression analysis showed that CRP(odds ratio[OR]=1.019,95%confidence interval[CI]:1.001-1.038,P=0.043)and serum TREM-1(OR=1.002,95%CI:1.000-1.003,P=0.016)were independent risk factors for the prognosis of patients with cirrhotic ascites and infection,and the combination of these two indicators had an AUC of 0.728 in predicting poor prognosis.Conclusion The level of TREM-1 is closely associated with the severity of infection and prognosis in patients with cirrhotic ascites,and combined measurement of TREM-1 and CRP/PCT can improve the diagnostic accuracy of infection and provide support for prognostic evaluation.

Objective:To explore the binding characteristics of N, N-diethyl-2-(2-(4-(2- 18F-fluoroethoxy)phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl)acetamide ( 18F-DPA-714) and ( R)- N-sec-butyl- N-methyl-4-(3-( 18F-trifluoromethyl)phenyl)quinazoline-2-carboxamide ( 18F-TFQC) to the single nucleotide polymorphisms of the 18×10 3 translocator protein (TSPO), and to evaluate the imaging efficacy and feasibility of those 2 molecular probes in neuroinflammation rat models. Methods:To test the selectivity of 18F-DPA-714 and 18F-TFQC for TSPO polymorphisms, the wild-type (high-affinity binding, HAB) and mutant (low-affinity binding, LAB) sequences of the human TSPO gene were transfected into 293T cells respectively. A competitive inhibition assay was carried out with N-methyl- N-(1-methylpropyl)-1-(2-chlorophenyl)-3-isoquinoline carboxamide (PK11195) as an inhibitor to determine the binding affinities of 2 probes to TSPO polymorphisms. Rat neuroinflammation models ( n=6) were established using lipopolysaccharide. Three days after modeling, small animal PET/CT imaging was performed using 18F-DPA-714 and 18F-TFQC, respectively, to observe and compare the uptake of the tracers, and the ratio of SUV mean of the right striatum to SUV mean of the left striatum (SUVR) was calculated. After the imaging, the expression and distribution of microglia and TSPO were detected by tissue immunofluorescence. Repeated-measures analysis of variance was used to analyze the SUVR data of different groups. Results:The inhibition constants ( Ki) of 18F-TFQC on 293T-LAB and 293T-HAB cells were 23.51 and 14.60 nmol/L, respectively, with a Ki LAB/ Ki HAB ratio of 1.61, indicating low sensitivity to TSPO single nucleotide polymorphisms. The Ki of 18F-DPA-714 for binding to 293T-LAB and 293T-HAB cells were 45.23 and 6.47 nmol/L, respectively, with a Ki LAB/ Ki HAB ratio of 6.99. Small animal PET/CT imaging demonstrated that specifically uptake of both probes could be found in neuroinflammatory lesions. The overall SUVR of 18F-DPA-714 in the lesions within 60minutes was slightly higher than that of 18F-TFQC, but no significant difference was observed ( F values: inter-group 0.40, time effect 0.30, cross-effect 0.03; all P>0.05). Conclusions:Compared with 18F-DPA-714, 18F-TFQC is less sensitive to TSPO gene polymorphisms, thus being more suitable for clinical application and promotion. It holds promise for the early identification of neuroinflammation and the efficacy monitoring of anti-inflammatory drug treatments.

Objective:To identify factors associated with depressive symptoms in maintenance hemodialysis patients and to examine the relationship between these symptoms and mortality.Methods:Between January and December 2019, patients who received maintenance hemodialysis in the Blood Purification Center of the Second Affiliated Hospital of Nanjing Medical University were enrolled in a prospective cohort study. Depressive symptoms were assessed using the internationally validated patient health questionnaire-8 (PHQ-8). Sleep quality and anxiety were measured with the Pittsburgh sleep quality index (PSQI) and the generalized anxiety disorder-7 (GAD-7) scale, respectively. Follow-up continued until December 31, 2022, with all-cause mortality as the primary outcome. Ordinal logistic regression was used to identify independent predictors of depression severity. Cox proportional hazards models evaluated the association between depressive symptoms and mortality.Results:A total of 532 maintenance hemodialysis (MHD) patients completed the study. Among them, 177 (33.3%) exhibited depressive symptoms. Compared with patients without depression, those with mild or moderate-to-severe depression were older [median age: 58 (50, 66) vs. 60 (55, 65) vs. 55 (46, 64)], more likely to smoke [35.9% (51/142) vs. 40.0% (14/35) vs.26.2% (93/355)], had poorer sleep quality [PSQI: 9 (6, 13) vs. 12 (9, 17) vs. 5 (3, 9)], and higher anxiety levels [GAD-7: 1 (0, 3) vs. 3 (1, 6) vs. 0 (0, 1)], the differences among the three groups were statistically significant (all P<0.05). Ordinal logistic regression identified smoking status, history of diabetes or cardiovascular disease, hemoglobin level, PSQI score, and GAD-7 score as independent predictors of depression severity ( OR=1.60, 1.80, 1.81, 0.98, 3.67, 8.67; all P<0.05). After a median follow-up of 40 (35, 44) months, 109 patients died, including 66 (60.6%) from cardio-cerebrovascular causes and 24 (22.0%) from infections. Kaplan-Meier analysis revealed significantly lower cumulative survival in the depression group compared to the non-depression group ( P<0.001). Cox regression analysis demonstrated that depressive symptoms remained independently associated with all-cause mortality after adjusting for confounders ( HR=1.06, 95% CI 1.00-1.13, P=0.048), with an even stronger association observed for patients with PHQ-8 scores≥2.9 ( HR=1.10, 95% CI 1.03-1.16, P=0.005). However, the associations between depression and cardio-cerebrovascular mortality ( P=0.111) or infection-related mortality ( P=0.509) were not statistically significant. Conclusions:Depressive symptoms are prevalent among maintenance hemodialysis patients and are independently associated with increased all-cause mortality. Smoking, comorbid diabetes or cardiovascular disease, low hemoglobin level, poor sleep quality, and anxiety are risk factors contributing to depression. Maintenance hemodialysis patients with PHQ-8 scores≥3 should be considered at heightened risk for mortality.

Based on the theory of circulation of qi,a theoretical model of the circulation of phase fire in the human body was con-structed.It is proposed that cancer toxicity is the key factor that triggers the disorder of phase fire and hinders the circulation of phase fire.The disorder of phase fire and poor circulation are important pathogenesis of the occurrence and development of cancer toxicity.With the principle of strengthening healthy qi and eliminating evil qi,the Wenzi Jiedu method is used to treat tumors,which plays an important role in warming and nourishing,regulating yin and yang,and eliminating cancer toxicity.The combination of war-ming,nourishing and detoxification can promote the return of the phase fire and make the human body's generation and transformation active,providing a new treatment idea for TCM diagnosis and treatment of tumors with mainly cold poison or mixed cold and heat.

Objective To analyze the influencing factors of the success of clinical pregnancy in secondary infertility patients undergoing in vitro fertilization-embryo transfer(IVF-ET)and construct a nomogram prediction model.Methods A retrospective analysis was conducted on the clinical data of 235 patients with secondary infertility who underwent IVF-ET at Urumqi Maternal and Child Health Hospital from January 2020 to December 2023.They were divided into successful pregnancy group(n=109)and failed pregnancy group(n=1 26)based on whether clinical pregnancy was successful.The general information,ovulation induction data and embryo data of two groups of patients were compared.Multivariate Logistic regression analysis was used to screen out statistically significant indicators,and based on this,a nomogram prediction model was constructed.The receiver operating characteristic curve,calibration curve and decision analysis curve were drawn to verify the discrimination,accuracy and clinical practicability of the model.Results The results of multivariate Logistic regression analysis showed that the female's age,overweight and obesity were all risk factors for clinical pregnancy failure,while anti-Müllerian hormone(AMH)and the total amount of gonadotropins(Gn)were protective factor for clinical pregnancy outcomes.On this basis,a nomogram prediction model was successfully constructed,which has a medium degree of discrimination,good accuracy and clinical practicability.Conclusion For secondary infertility patients undergoing IVF-ET,the female's age,overweight and obesity,AMH,and the total amount of Gn have certain influences on clinical pregnancy.The clinical pregnancy outcome can be predicted through the constructed nomogram prediction model.