Objective:To explore the efficacy and safety of mitotane in adrenal cortical carcinoma (ACC) at high risk of recurrence.Methods:A prospective observational study was designed from September 2022 to November 2023. ACC patients undergoing surgery with high recurrence risk (positive margin or Ki-67 index >10% or capsule rupture or large size or high-grade ACC) in Peking Union Medical College Hospital were enrolled in this study. All patients started mitotane treatment within 3 months after surgery, with a dose of 1.5 g/d, increased by 0.5 g per week. Once the dose reached 3 g/day, adjustments were made based on blood concentration levels. All patients received mitotane therapy for at least 1 year, and CT was performed every 12 weeks to evaluate the efficacy. The primary endpoint was 1-year progression-free survival (PFS) and safety. The efficacy was analyzed by Kaplan-Meier method for survival, and the occurrence of treatment-related adverse events was summarized.Results:A total of 12 ACC patients at high risk of recurrence were screened, comprising 6 males and 6 females. Tumors were located on the left side in 8 patients, on the right in 3, and bilaterally in 1. Five patients were classified as ENSAT stageⅡ, while 7 were classified as ENSAT stage Ⅲ. The maximum diameter of tumor was (9.07 ± 2.86) cm; the median age at diagnosis was 48 (35, 51) years, and the median Ki-67 index was (28.9 ± 16.1)%. The median time from surgery to initiation of mitotane therapy was 31 (23.0, 43.2) days, and 9 patients had blood drug concentrations of 14-20 mg/L. The median follow-up time was 16.7 (12.4, 25.2) months. At 1 year after mitotane therapy, 10 (83.8%) patients were still in disease-free survival state, with a median mitotane PFS of 27.6 months (95% CI 16.4-not reached). All ACC patients experienced 1-2 grade adverse events after taking mitotane. One patient (8.3%) experienced grade 3 adverse event, including the increasing of alanine aminotransferase and aspartate aminotransferase, as well as anorexia. No grade 4-5 adverse events occurred. The most common adverse events were gastrointestinal symptoms (10 cases), including nausea, vomiting, anorexia, and diarrhea, followed by liver function damage(9 cases) and neurotoxicity(4 cases). Conclusions:Mitotane has shown the prospect of improving the prognosis of ACC patients at high risk of recurrence after surgery. Because of its serious toxic and side effects, it is necessary to monitor its blood concentration to adjust the dosage, and take measures for adverse reactions to ensure the safety of patients.

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.

Osteoporosis and cardiovascular calcification,two major age-related chronic diseases that China is confronting today,pose serious threats to public health.Previous studies have reported overlapping connections in the pathological processes and molecular mechanisms of these two diseases,particularly concerning inflammation,oxidative stress,and dysregulation of mineral metabolism,and that these two diseases tend to share common pathogenic factors.However,research exploring the comorbidity mechanisms of the two diseases remains limited in both depth and scope,largely due to the lack of widely accepted comorbidity animal models.Herein,we analyzed the latest research findings on the comorbidity mechanisms of vascular calcification and osteoporosis,focusing on summarizing the animal disease models currently in extensive use and the relevant evaluation criteria.We aim to provide new references for comorbidity research models and offer scientific evidence for future studies on pathological mechanisms and the development of new therapeutic strategies.

Objective To explore the motor coordination characteristics of the attack leg of the athletes under scoring actions in the front roundhouse kick of competitive taekwondo,and provide a theoretical basis for coaches to formulate precise training strategies in stages and segments so as to enhance the efficiency and success rate of the athletes' movements.Methods Kinematic data and surface electromyography signals were collected from 15 elite Taekwondo athletes during different phases of the front roundhouse kick.The continuous relative phase(CRP)method was used to calculate the joint coordination and variability of continuous relative phase(VCRP),while non-negative matrix factorization and k-means clustering were used to analyze muscle synergy characteristics.Results The coupling of the neural launch phase was dominated by knee-ankle coupling in coronal axis and hip-ankle coupling in sagittal axis.The coupling of the kicking phase was dominated by hip-knee,hip-ankle in coronal axis,and knee-ankle coupling in vertical axis.The coupling of the recovery phase was dominated by hip-knee,hip-ankle coupling in coronal axis,and knee-ankle coupling in sagittal axis.These coupling relationships remained relatively stable around 0 rad.Approximately 80.0％VCRP remained stable across all phases,with minor fluctuations occurring at phase transitions.A total of 4,5,and 4 muscle synergy clusters were identified in neural launch,kicking,recovery phases,respectively.There were significant differences in the mean gap values among phases(P＜0.001).However,there were no significant differences in the mean sparsity values among phases(P＞0.05).Some muscle synergies were shared across phases,while others differentiated to form phase-specific coordination patterns.Conclusions Joint coordination in each phase exhibited 1-3 primary stable patterns with flexibility during transitions.Muscle coordination was dynamically adjusted throughout the motion,and a general muscle synergy pattern functioned consistently across different phases,whereas a differentiated muscle synergy pattern fulfilled the phase-specific functional demands.The neural launch and kicking phases should be focused on during training,with the emphasis on controling over critical points to optimize performance.

Objective:The aim of this study was to explore the risk factors that affect implementation of the innovative technique of single-incision laparoscopic appendectomy (solo-SLA) without assistance in patients with complicated appendicitis, the goal being improving surgical success rates and reducing the incidence of complications.Methods:This was an observational study. Indications for solo-SLA surgery were as follows: (1) computed tomography or ultrasound findings suggestive of acute appendicitis, accompanied by a high white blood cell count and C-reactive protein concentration; (2) disease course exceeding 72 hours, standard anti-infection treatment ineffective, inflammatory reaction not localized, surgery mainly aimed at abscess drainage, and the appendix removed if indicated intraoperatively; (3) acute onset stabilized for more than 3 months after conservative treatment; and (4) recurrent chronic appendicitis. Relative contraindications comprised: (1) cardiopulmonary insufficiency, extremely high risk for general anesthesia for laparoscopic surgery; (2) severe coagulation dysfunction; and (3) imaging findings suggestive of formation of a peri-appendiceal abscess, stable after anti-infection treatment, and a tendency for the inflammatory reaction to localize. We retrospectively collected clinical data of 106 patients with complicated appendicitis who had undergone solo-SLA in the Department of Emergency Surgery, Peking University People's Hospital from February to October 2023. Preoperative computed tomography showed appendiceal fecaliths, blurring of the tissue surrounding fat, intra- and extra-luminal gas and exudate, peri-appendiceal abscess, ascites, and intestinal obstruction by appendicitis. The study cohort comprised 53 male and 53 female patients aged (41.4±17.4) years. The median body mass index was (24.2±3.6) kg/m 2 and median preoperative body temperature (37.3±0.9)℃ Appendicitis had been present for >3 days in 21 of the patients (19.8%) and the maximum diameter of the appendix was (12.4±3.8) mm. The efficacy of the surgery was assessed and logistic regression analysis used to explore the factors affecting the duration of the procedure. The relationship between the maximum diameter of the appendix and duration of surgery was non-linear and was explored using a logistic regression model with restricted cubic spline (RCS). Results:Only one patient required conversion to open surgery; all the other patients successfully completed solo-SLA with a median intraoperative blood loss of 10 (1-100) ml and a surgical time of (65.4±31.7) minutes. Pain scores on postoperative Day 1 and 7 were (3.4±3.2) points and (1.5±1.7) points, respectively. There were no significant postoperative complications .The postoperative hospital stay was (3.5±1.5) days and the interval to resuming normal activities 14 (2-40) days. According to univariate and multivariate analyses, disease course >3 days (OR=5.19, 95%CI: 1.59-16.98, P=0.006) and C-reactive protein >10 mg/L (OR=1.01,95%CI: 1.00-1.02, P=0.003) were independent risk factors for surgical duration >60 minutes, whereas the maximum diameter of the appendix was not independently associated with duration of surgery (OR=1.10, 95%CI: 0.97-1.25, P=0.119). RCS analysis results showed a "U-shaped" association between the maximum diameter of the appendix and duration of surgery, the inflection point of the RCS curve being at a diameter of 10 mm. When the maximum diameter of the appendix was <10 mm, increases in diameter were not associated with longer duration of surgery (OR=1.15,95%CI: 0.55-2.58, P=0.710); whereas when the diameter was ≥10 mm, the maximum diameter of the appendix was associated with increased duration of surgery (OR=1.20, 95% CI: 1.04-1.42, P=0.022). Conclusion:The solo-SLA procedure can be performed to treat complicated appendicitis. A disease course >3 days, C-reactive protein concentration >10 mg/L, and maximum diameter of the appendix ≥10 mm are all associated with greater difficulty of solo-SLA surgery.

ABSTRCT AIM:To verify the effect of polygona-tum polysaccharide(PSP)combined with TGF-β3 in inducing the differentiation of rat tendon-derived stem cells(TDSCs)into chondrocytes by activating the TGF-β3/Smad2 pathway.METHODS:TDSCs were extracted from rat tail tendons using enzyme digestion,purified,passaged,and identified via flow cytometry.TDSCs were treated with different concentrations of PSP,and the optimal growth con-centration was determined using the CCK-8 assay.TDSCs were divided into four groups:PSP,TGF-β3,PSP+TGF-β3,and Control for differentiation induc-tion.Chondrogenic differentiation was evaluated using morphological observations,toluidine blue staining,immunofluorescence staining,and West-ern blot analysis to detect COLⅡ,SOX9,and AGG.Western blot was also used to measure the expres-sion levels of Smad2 and p-Smad2 to evaluate the activation of the TGF-β3/Smad2 pathway after chondrogenic induction.RESULTS:Flow cytometry analysis showed that TDSCs highly expressed CD90 and CD29,while CD11b and CD45 expression was low.The CCK-8 assay indicated that 5 μmol/L PSP was the optimal intervention dose.Toluidine blue staining revealed that the blue staining area in the PSP,PSP+TGF-β3,and TGF-β3 groups was larger compared to the Control group.Immunofluores-cence analysis demonstrated that COLⅡ expression was significantly increased in the PSP,TGF-β3,and PSP+TGF-β3 groups,with the highest expression in the PSP+TGF-β3 group(P＜0.05).Western blot analy-sis showed that the levels of p-Smad2/Smad2,COLⅡ,SOX9,and AGG were elevated in the PSP,TGF-β3,and PSP+TGF-β3 groups,with the highest ex-pression in the PSP+TGF-β3 group(P＜0.05).Compared to the Control group,the TGF-β3 and PSP groups also showed significantly increased expression(P＜0.05).CONCLUSION:PSP promotes the proliferation and chondrogenic differentiation of TDSCs,possibly by activating the TGF-β3/Smad2 pathway.

ABSTRCT AIM:To verify the effect of polygona-tum polysaccharide(PSP)combined with TGF-β3 in inducing the differentiation of rat tendon-derived stem cells(TDSCs)into chondrocytes by activating the TGF-β3/Smad2 pathway.METHODS:TDSCs were extracted from rat tail tendons using enzyme digestion,purified,passaged,and identified via flow cytometry.TDSCs were treated with different concentrations of PSP,and the optimal growth con-centration was determined using the CCK-8 assay.TDSCs were divided into four groups:PSP,TGF-β3,PSP+TGF-β3,and Control for differentiation induc-tion.Chondrogenic differentiation was evaluated using morphological observations,toluidine blue staining,immunofluorescence staining,and West-ern blot analysis to detect COLⅡ,SOX9,and AGG.Western blot was also used to measure the expres-sion levels of Smad2 and p-Smad2 to evaluate the activation of the TGF-β3/Smad2 pathway after chondrogenic induction.RESULTS:Flow cytometry analysis showed that TDSCs highly expressed CD90 and CD29,while CD11b and CD45 expression was low.The CCK-8 assay indicated that 5 μmol/L PSP was the optimal intervention dose.Toluidine blue staining revealed that the blue staining area in the PSP,PSP+TGF-β3,and TGF-β3 groups was larger compared to the Control group.Immunofluores-cence analysis demonstrated that COLⅡ expression was significantly increased in the PSP,TGF-β3,and PSP+TGF-β3 groups,with the highest expression in the PSP+TGF-β3 group(P＜0.05).Western blot analy-sis showed that the levels of p-Smad2/Smad2,COLⅡ,SOX9,and AGG were elevated in the PSP,TGF-β3,and PSP+TGF-β3 groups,with the highest ex-pression in the PSP+TGF-β3 group(P＜0.05).Compared to the Control group,the TGF-β3 and PSP groups also showed significantly increased expression(P＜0.05).CONCLUSION:PSP promotes the proliferation and chondrogenic differentiation of TDSCs,possibly by activating the TGF-β3/Smad2 pathway.

Objective:The aim of this study was to explore the risk factors that affect implementation of the innovative technique of single-incision laparoscopic appendectomy (solo-SLA) without assistance in patients with complicated appendicitis, the goal being improving surgical success rates and reducing the incidence of complications.Methods:This was an observational study. Indications for solo-SLA surgery were as follows: (1) computed tomography or ultrasound findings suggestive of acute appendicitis, accompanied by a high white blood cell count and C-reactive protein concentration; (2) disease course exceeding 72 hours, standard anti-infection treatment ineffective, inflammatory reaction not localized, surgery mainly aimed at abscess drainage, and the appendix removed if indicated intraoperatively; (3) acute onset stabilized for more than 3 months after conservative treatment; and (4) recurrent chronic appendicitis. Relative contraindications comprised: (1) cardiopulmonary insufficiency, extremely high risk for general anesthesia for laparoscopic surgery; (2) severe coagulation dysfunction; and (3) imaging findings suggestive of formation of a peri-appendiceal abscess, stable after anti-infection treatment, and a tendency for the inflammatory reaction to localize. We retrospectively collected clinical data of 106 patients with complicated appendicitis who had undergone solo-SLA in the Department of Emergency Surgery, Peking University People's Hospital from February to October 2023. Preoperative computed tomography showed appendiceal fecaliths, blurring of the tissue surrounding fat, intra- and extra-luminal gas and exudate, peri-appendiceal abscess, ascites, and intestinal obstruction by appendicitis. The study cohort comprised 53 male and 53 female patients aged (41.4±17.4) years. The median body mass index was (24.2±3.6) kg/m 2 and median preoperative body temperature (37.3±0.9)℃ Appendicitis had been present for >3 days in 21 of the patients (19.8%) and the maximum diameter of the appendix was (12.4±3.8) mm. The efficacy of the surgery was assessed and logistic regression analysis used to explore the factors affecting the duration of the procedure. The relationship between the maximum diameter of the appendix and duration of surgery was non-linear and was explored using a logistic regression model with restricted cubic spline (RCS). Results:Only one patient required conversion to open surgery; all the other patients successfully completed solo-SLA with a median intraoperative blood loss of 10 (1-100) ml and a surgical time of (65.4±31.7) minutes. Pain scores on postoperative Day 1 and 7 were (3.4±3.2) points and (1.5±1.7) points, respectively. There were no significant postoperative complications .The postoperative hospital stay was (3.5±1.5) days and the interval to resuming normal activities 14 (2-40) days. According to univariate and multivariate analyses, disease course >3 days (OR=5.19, 95%CI: 1.59-16.98, P=0.006) and C-reactive protein >10 mg/L (OR=1.01,95%CI: 1.00-1.02, P=0.003) were independent risk factors for surgical duration >60 minutes, whereas the maximum diameter of the appendix was not independently associated with duration of surgery (OR=1.10, 95%CI: 0.97-1.25, P=0.119). RCS analysis results showed a "U-shaped" association between the maximum diameter of the appendix and duration of surgery, the inflection point of the RCS curve being at a diameter of 10 mm. When the maximum diameter of the appendix was <10 mm, increases in diameter were not associated with longer duration of surgery (OR=1.15,95%CI: 0.55-2.58, P=0.710); whereas when the diameter was ≥10 mm, the maximum diameter of the appendix was associated with increased duration of surgery (OR=1.20, 95% CI: 1.04-1.42, P=0.022). Conclusion:The solo-SLA procedure can be performed to treat complicated appendicitis. A disease course >3 days, C-reactive protein concentration >10 mg/L, and maximum diameter of the appendix ≥10 mm are all associated with greater difficulty of solo-SLA surgery.

Objective To explore the motor coordination characteristics of the attack leg of the athletes under scoring actions in the front roundhouse kick of competitive taekwondo,and provide a theoretical basis for coaches to formulate precise training strategies in stages and segments so as to enhance the efficiency and success rate of the athletes' movements.Methods Kinematic data and surface electromyography signals were collected from 15 elite Taekwondo athletes during different phases of the front roundhouse kick.The continuous relative phase(CRP)method was used to calculate the joint coordination and variability of continuous relative phase(VCRP),while non-negative matrix factorization and k-means clustering were used to analyze muscle synergy characteristics.Results The coupling of the neural launch phase was dominated by knee-ankle coupling in coronal axis and hip-ankle coupling in sagittal axis.The coupling of the kicking phase was dominated by hip-knee,hip-ankle in coronal axis,and knee-ankle coupling in vertical axis.The coupling of the recovery phase was dominated by hip-knee,hip-ankle coupling in coronal axis,and knee-ankle coupling in sagittal axis.These coupling relationships remained relatively stable around 0 rad.Approximately 80.0％VCRP remained stable across all phases,with minor fluctuations occurring at phase transitions.A total of 4,5,and 4 muscle synergy clusters were identified in neural launch,kicking,recovery phases,respectively.There were significant differences in the mean gap values among phases(P＜0.001).However,there were no significant differences in the mean sparsity values among phases(P＞0.05).Some muscle synergies were shared across phases,while others differentiated to form phase-specific coordination patterns.Conclusions Joint coordination in each phase exhibited 1-3 primary stable patterns with flexibility during transitions.Muscle coordination was dynamically adjusted throughout the motion,and a general muscle synergy pattern functioned consistently across different phases,whereas a differentiated muscle synergy pattern fulfilled the phase-specific functional demands.The neural launch and kicking phases should be focused on during training,with the emphasis on controling over critical points to optimize performance.

Objective:To explore the efficacy and safety of mitotane in adrenal cortical carcinoma (ACC) at high risk of recurrence.Methods:A prospective observational study was designed from September 2022 to November 2023. ACC patients undergoing surgery with high recurrence risk (positive margin or Ki-67 index >10% or capsule rupture or large size or high-grade ACC) in Peking Union Medical College Hospital were enrolled in this study. All patients started mitotane treatment within 3 months after surgery, with a dose of 1.5 g/d, increased by 0.5 g per week. Once the dose reached 3 g/day, adjustments were made based on blood concentration levels. All patients received mitotane therapy for at least 1 year, and CT was performed every 12 weeks to evaluate the efficacy. The primary endpoint was 1-year progression-free survival (PFS) and safety. The efficacy was analyzed by Kaplan-Meier method for survival, and the occurrence of treatment-related adverse events was summarized.Results:A total of 12 ACC patients at high risk of recurrence were screened, comprising 6 males and 6 females. Tumors were located on the left side in 8 patients, on the right in 3, and bilaterally in 1. Five patients were classified as ENSAT stageⅡ, while 7 were classified as ENSAT stage Ⅲ. The maximum diameter of tumor was (9.07 ± 2.86) cm; the median age at diagnosis was 48 (35, 51) years, and the median Ki-67 index was (28.9 ± 16.1)%. The median time from surgery to initiation of mitotane therapy was 31 (23.0, 43.2) days, and 9 patients had blood drug concentrations of 14-20 mg/L. The median follow-up time was 16.7 (12.4, 25.2) months. At 1 year after mitotane therapy, 10 (83.8%) patients were still in disease-free survival state, with a median mitotane PFS of 27.6 months (95% CI 16.4-not reached). All ACC patients experienced 1-2 grade adverse events after taking mitotane. One patient (8.3%) experienced grade 3 adverse event, including the increasing of alanine aminotransferase and aspartate aminotransferase, as well as anorexia. No grade 4-5 adverse events occurred. The most common adverse events were gastrointestinal symptoms (10 cases), including nausea, vomiting, anorexia, and diarrhea, followed by liver function damage(9 cases) and neurotoxicity(4 cases). Conclusions:Mitotane has shown the prospect of improving the prognosis of ACC patients at high risk of recurrence after surgery. Because of its serious toxic and side effects, it is necessary to monitor its blood concentration to adjust the dosage, and take measures for adverse reactions to ensure the safety of patients.