Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood. This condition compromises mucosal barrier integrity particularly in the gut and oral cavity. However, the mechanisms underlying this association remain unclear. This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions. Hypoxia upregulated methyltransferase-like protein 4 (METTL4) expression in platelets, resulting in N⁶-methyladenine modification of mitochondrial DNA (mtDNA). This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation, leading to cytosolic mtDNA accumulation. Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets. This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis. Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology. Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.
DNA, Mitochondrial/metabolism* ; Mouth Mucosa/pathology* ; Hypoxia/immunology* ; Methyltransferases/metabolism* ; Blood Platelets/metabolism* ; Animals ; Periodontitis/immunology* ; Humans ; Platelet Activation ; Mice

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin’s lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

Objective:To provide the risk stratification method of hepatoblastoma (HB) suitable for implementation in China and explore the new treatment method for high-risk HB patients.Methods:A total of 100 cases of children and adolescents under 18 years old with newly diagnosed HB in Sun Yat-sen University Cancer Center and Sun Yat-sen University First Affiliated Hospital from September 2014 to September 2018 were included. According to the clinical stage, AFP level, pathological subtype and other factors, patients were stratified into four groups: extremely low-, low-, intermediate- and high-risk. The patients at very low risk were treated with surgery only and followed-up. The patients at very low risk were treated with C5V(Cisplatin+ 5-Fluroracil+ Vincristine) regimen for 4 courses. The patients at intermediate risk were treated with C5VD(Cisplatin+ 5-Fluroracil+ Vincristine+ Doxorubicin)regimen before and after surgery for 6-8 courses. The patients at high risk were treated with C5VD and IIV (ifoshamide+ irinotecan+ vincristine) alternately before and after surgery for 8 courses.Results:One hundred patients were stratified into extremely low-risk, low-risk, medium-risk and high-risk groups for 2, 10, 51 and 37 cases, respectively. Eighty three cases had evaluable lesions before chemotherapy. Among them, 65 patients achieved partial remission, stable disease and progressive disease were observed in 10, and 8 cases, respectively, with a response rate of 78.3%. During a median follow-up of 20 months, 30 patients experienced tumor relapse or progression, and 27 of them died. The 2-years progression-free survival (PFS) and overall survival (OS) rates were 69.2% and 72.0%, respectively. The 2-years PFS rates of patients with extremely low risk, low risk, medium risk and high risk were 100%, 88.9%, 75.3% and 43.2%, respectively. The 2-years OS rates were 100%, 100%, 81.0% and 44.8%, respectively.Conclusions:The novel HB risk classification is simple and feasible. With active comprehensive treatment, patients at extremely low-, low- and medium-risk have excellent outcomes. The survival rate of high-risk HB patients remains to be improved, and new treatment strategies need to be explored.

Objective:To analyze the influence of obesity status on the development of cardiometabolic disorders in school-age children.Methods:Information about children's body weight, body height and cardiovascular risk factors were collected in baseline survey in 2017 and follow-up survey in 2019. The school-age children were divided into four groups based on their baseline and follow-up obesity status, i.e. sustained non-obesity group, restored obesity group, newly classified obesity group, and persistent obesity group. Analysis of covariance was used to compare the difference of change in levels of cardiometabolic factors among the four groups. The multivariate logistic regression model was used to analyze the relationship between obesity status and the incidence risk of cardiometabolic disorders.Results:The present study included 11 379 school-age children (boys accounting for 49.6%). During the 2 years, the incidence of obesity was 3.2% (95% CI: 2.9%-3.5%) with the restoration ratio of obesity of 4.4% (95% CI: 4.0%-4.8%). Compared with the sustained non-obesity group, increases in SBP, DBP, TG, LDL-C and non-HDL-C were much higher in newly classified obesity group and persistent obesity group, but lower in restored obesity groups except for DBP (all P<0.05). In addition, the incidence risk of hypertension, high glucose, dyslipidemia and cardiometabolic disorders (≥2 risks) were much higher in newly classified and persistent obese children than in sustained non-obese children. No difference was found in incidence risks of most cardiovascular disorders between restored obese children and sustained non-obese children, except for hypertension and cardiometabolic risks. Conclusion:Both newly classified obesity and persistent obesity increased the incidence risks for multi cardiovascular disorders, while these risks could be reduced when non-obese status restore.

Objective:To provide the risk stratification method of hepatoblastoma (HB) suitable for implementation in China and explore the new treatment method for high-risk HB patients.Methods:A total of 100 cases of children and adolescents under 18 years old with newly diagnosed HB in Sun Yat-sen University Cancer Center and Sun Yat-sen University First Affiliated Hospital from September 2014 to September 2018 were included. According to the clinical stage, AFP level, pathological subtype and other factors, patients were stratified into four groups: extremely low-, low-, intermediate- and high-risk. The patients at very low risk were treated with surgery only and followed-up. The patients at very low risk were treated with C5V(Cisplatin+ 5-Fluroracil+ Vincristine) regimen for 4 courses. The patients at intermediate risk were treated with C5VD(Cisplatin+ 5-Fluroracil+ Vincristine+ Doxorubicin)regimen before and after surgery for 6-8 courses. The patients at high risk were treated with C5VD and IIV (ifoshamide+ irinotecan+ vincristine) alternately before and after surgery for 8 courses.Results:One hundred patients were stratified into extremely low-risk, low-risk, medium-risk and high-risk groups for 2, 10, 51 and 37 cases, respectively. Eighty three cases had evaluable lesions before chemotherapy. Among them, 65 patients achieved partial remission, stable disease and progressive disease were observed in 10, and 8 cases, respectively, with a response rate of 78.3%. During a median follow-up of 20 months, 30 patients experienced tumor relapse or progression, and 27 of them died. The 2-years progression-free survival (PFS) and overall survival (OS) rates were 69.2% and 72.0%, respectively. The 2-years PFS rates of patients with extremely low risk, low risk, medium risk and high risk were 100%, 88.9%, 75.3% and 43.2%, respectively. The 2-years OS rates were 100%, 100%, 81.0% and 44.8%, respectively.Conclusions:The novel HB risk classification is simple and feasible. With active comprehensive treatment, patients at extremely low-, low- and medium-risk have excellent outcomes. The survival rate of high-risk HB patients remains to be improved, and new treatment strategies need to be explored.

Objective:To summarize the efficiency and long-term outcomes of limited-stage Hodgkin lymphoma in children and adolescents with ABVD therapy and determined whether omitting radiotherapy for a low-risk patient enabled the achievement of complete response (CR) after chemotherapy.Methods:We retrospectively analyzed data from 13 y (2004-2016) from patients aged ≤18 y with limited-stage HL admitted to the Sun Yat-sen University Cancer Center. Patients received treatment with ABVD chemotherapy alone or ABVD chemotherapy followed by low-dose involved field radiotherapy.Results:Total 85 subjects were eligible for study inclusion; the median age was 12 (3-18) y; 66 (77.6%) were men, 80 (94.1%) had stage-II disease, 56 (65.9%) were at low-risk, and the median follow-up duration was 72 (8-196) months; 12 relapsed, 2 had secondary neoplasm, and 2 died. The 5-year event free survival (EFS) was (85.6±3.8) %, and the overall survival (OS) was 100%. The 5-year EFS and OS was (89.1±4.2) % and 100%, respectively, for the low-risk cohort and (79.3±7.5) % and 100%, respectively for the intermediate-risk cohort. Among the 39 low-risk patients who achieved CR after chemotherapy, 15 received treatment with chemotherapy followed by LD-IFRT. In the exploratory subset analysis, the low-risk cohort who achieved CR after chemotherapy, the 5-year EFS for comparing ABVD alone with chemotherapy followed by LD-IFRT was (87.0±7.0) % versus 100% ( P=0.506) , and the OS was 100% for both the groups. Conclusions:Our retrospective analysis showed excellent survival of limited-stage HL patients with ABVD therapy. For patients who achieving CR after chemotherapy with low-risk HL, received chemotherapy followed by LD-IFRT does not improve 5-year OS and EFS. The use of risk- and response-based stratification may facilitate the development of effective and less toxic protocols.

Objective: To understand the association between body fat distribution and calcaneal bone mineral density (BMD) in children and adolescents aged 6-16 years in Beijing. Methods: Children and adolescents were selected in 30 schools (8 primary schools, 21 middle schools and one 12-year education school) from Dongcheng, Tongzhou, Fangshan and Miyun districts of Beijing by using a stratified cluster sampling method from November 2017 to January 2018. A total of 15 030 students in grade 1 to 4 of primary school, grade 1 of junior and senior middle school were enrolled after excluding subjects who were not able to participate into this study due to trauma or other uncomfortable physical conditions or with missing key values or with diabetes and kidney diseases. Questionnaire survey, body composition and calcaneus bone mineral density were conducted. The relation of fat mass percentage (FMP), trunk to total fat ratio (TrTFR), trunk to limb fat ratio (TrLFR), limb to total fat ratio (LTFR) and viscera to total fat ratio (VTFR) with calcaneus BMD were assessed using the multivariate linear regression models after adjusting for possible confounding effects. The central fat distribution types were divided into 4 groups including type 1: both trunk fat and visceral fat greater than the sex-and age-specific internal P₇₅; type 2: barely trunk fat greater than P₇₅; type 3: barely visceral fat greater than P₇₅; type 4: both trunk fat and visceral fat greater than P₇₅. The central fat distribution types were included into the model in the form of dummy variables to analyze its relationship with calcaneal BMD. The sex-and age-specific z-scores of fat distribution indicators and BMD were calculated. Results: A total of 15 030 participants aged (11.4±3.3) years (50.2% boys) were involved in the analysis. In both genders, after adjusting for age, height, lean mass index, smoking, drinking, physical activity, milk intake, vitamin D and calcium supplementation, FMP, TrTFR, TrLFR and VTFR were negatively correlated with calcaneal BMD (all P value<0.05), while LTFR was positively associated with calcaneal BMD (all P values<0.05). Compared to the central fat distribution type 1, the regression coefficients (95% CI) of type 2, 3 and 4 were -0.253 (-0.418, -0.087), -0.385 (-0.567, -0.204) and -0.428 (-0.487, -0.369) in boys, respectively; the regression coefficients (95% CI) of type 3 and 4 were -0.158 (-0.301, -0.015) and -0.226 (-0.290, -0.163), respectively. Conclusion Body fat distribution and central fat distribution in children and adolescents were correlated with calcaneus bone mineral density.

Objective: To investigate the association between blood lipid and calcaneus bone mineral density (BMD) in children and adolescents aged 6-16 years in Beijing. Methods: Children and adolescents were selected in 30 schools (8 primary schools, 21 middle schools and one 12-year education school) from Dongcheng, Tongzhou, Fangshan and Miyun districts of Beijing by using a stratified cluster sampling method from November 2017 to January 2018. A total of 14 303 students in grade 1 to 4 of primary school, grade 1 of junior and senior middle school were enrolled after excluding subjects who were not able to participate into this study due to trauma or other uncomfortable physical conditions or with missing key values or with diabetes and kidney diseases. Questionnaire survey, blood lipid and calcaneus BMD were conducted. Multivariate linear regression was applied to quantify the association between calcaneal BMD as a dependent variable and blood lipid level as an independent variable after adjusting for the potential confounding factors. Furthermore, quantile regression was used to analyze the association between blood lipid level and different percentiles (P₂₅, P₅₀ and P₇₅) of ultrasonic velocity values of bone mineral density, and parallel test was conducted for regression coefficients of different percentiles. Results: A total of 14 303 participants aged (11.4±3.3) years (49.9% boys) were involved in the analysis. The mean age of 14 303 participants was (11.0±3.3) years. 7 142 boys accounted for 49.9%. The mean±SD of calcaneal BMD, total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) were (1 540.9±33.8) m/s, (3.90±0.76), (2.18±0.62), and (1.40±0.32) mmol/L, respectively. The P₅0 (P₂₅, P₇₅) of triglyceride (TG) was 0.69 (0.49-0.94) mmol/L. After the adjustment of age, height, smoking, drinking, vitamin D and calcium supplementation, dairy intake, physical activity, FMI, and MMI, a significantly inverse association (P<0.05) between TG level and calcaneus BMD was observed in both genders, which the regression coefficients (95%CI) in boys and girls were -0.064 (-0.085, -0.044) and -0.073 (-0.094, -0.053), respectively. Conclusion The level of BMD was associated with TG in boys and girls. Therefore, it is important to prevent children from hypertriglyceridemia for the bone health promotion.

OBJECTIVE: To explore the effect of small interfering RNA (siRNA)-mediated CEP55 gene silencing on the proliferation of mouse spermatogonia. METHODS: Six patients with azoospermia diagnosed to have maturation arrest (3 cases) or normal spermatogenesis (3 cases) based on testicular biopsy between January 1 and December 31, 2017 in our center were examined for differential proteins in the testicular tissue using isobaric tags for relative and absolute quantitation (iTRAQ), and CEP55 was found to differentially expressed between the two groups of patients. We constructed a CEP55 siRNA for transfection in mouse spermatogonia and examined the inhibitory effects on CEP55 expressions using Western blotting and qPCR. The effect of CEP55 gene silencing on the proliferation of mouse spermatogonia was evaluated with CCK8 assay. RESULTS: In the testicular tissues from the 6 patients with azoospermia, iTRAQ combined with LC/MS/MS analysis identified over two hundred differentially expressed proteins, among which CEP55 showed the most significant differential expression between the patients with maturation arrest and those with normal spermatogenesis. The cell transfection experiment showed that compared with the cells transfected with the vehicle or the negative control sequence, the mouse spermatogonia transfected with CEP55 siRNA showed significantly lowered expressions of CEP55 mRNA and protein ( < 0.05) and significantly decreased proliferation rate as shown by CCK8 assay ( < 0.05). CONCLUSIONS CEP55 may play a key role in spermatogenesis and may serve as a potential therapeutic target for non-obstructive azoospermia with maturation arrest.
Animals ; Azoospermia ; congenital ; genetics ; Cell Cycle Proteins ; genetics ; Gene Silencing ; Humans ; Male ; Mice ; Nuclear Proteins ; genetics ; Spermatogenesis ; Spermatogonia ; Tandem Mass Spectrometry ; Transfection

Objective To understand the association between body fat distribution and calcaneal bone mineral density (BMD) in children and adolescents aged 6-16 years in Beijing. Methods Children and adolescents were selected in 30 schools (8 primary schools, 21 middle schools and one 12?year education school) from Dongcheng, Tongzhou, Fangshan and Miyun districts of Beijing by using a stratified cluster sampling method from November 2017 to January 2018. A total of 15 030 students in grade 1 to 4 of primary school, grade 1 of junior and senior middle school were enrolled after excluding subjects who were not able to participate into this study due to trauma or other uncomfortable physical conditions or with missing key values or with diabetes and kidney diseases. Questionnaire survey, body composition and calcaneus bone mineral density were conducted. The relation of fat mass percentage (FMP), trunk to total fat ratio (TrTFR), trunk to limb fat ratio (TrLFR), limb to total fat ratio (LTFR) and viscera to total fat ratio (VTFR) with calcaneus BMD were assessed using the multivariate linear regression models after adjusting for possible confounding effects. The central fat distribution types were divided into 4 groups including type 1: both trunk fat and visceral fat greater than the sex?and age?specific internal P75; type 2: barely trunk fat greater than P75; type 3: barely visceral fat greater than P75; type 4: both trunk fat and visceral fat greater than P75. The central fat distribution types were included into the model in the form of dummy variables to analyze its relationship with calcaneal BMD. The sex?and age?specific z?scores of fat distribution indicators and BMD were calculated. Results A total of 15 030 participants aged (11.4 ± 3.3) years (50.2% boys) were involved in the analysis. In both genders, after adjusting for age, height, lean mass index, smoking, drinking, physical activity, milk intake, vitamin D and calcium supplementation, FMP, TrTFR, TrLFR and VTFR were negatively correlated with calcaneal BMD (all P value<0.05), while LTFR was positively associated with calcaneal BMD (all P values<0.05). Compared to the central fat distribution type 1, the regression coefficients (95% CI ) of type 2, 3 and 4 were-0.253 (-0.418,-0.087),-0.385 (-0.567,-0.204) and-0.428 (-0.487, -0.369) in boys, respectively; the regression coefficients (95% CI) of type 3 and 4 were -0.158 (-0.301,-0.015) and-0.226 (-0.290,-0.163), respectively. Conclusion Body fat distribution and central fat distribution in children and adolescents were correlated with calcaneus bone mineral density.