Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective To construct reference ranges of cardiac size and morphologic parameters in low-risk fetuses at 28-39 gestational weeks using two-dimensional speckle tracking technique.Methods A prospective collection of 453 low-risk singleton pregnancies with echocardiography at Obstetrics and Gynecology Hospital,Fudan University was used to assess the size(length,width,and area)and morphology(sphericity index,i.e.,the ratio of length to width)of the fetal four-chamber view and two ventricles using two-dimensional speckle tracking technique.Repeated inter-and intra-observer agreement of measurements was assessed using the intraclass correlation coefficients(ICCs).Statistical analysis of cardiac measurement parameters was performed to establish reference ranges of values for cardiac size and morphology in low-risk fetuses.Results The inter-and intra-group ICCs for reproducibility tests of fetal cardiac parameters measurements were 0.691 to 0.980.Fetal four-chamber view and ventricular size increased with gestational week(all P<0.001),the end-diastolic length of the left ventricle was larger than that of the right ventricle,and the end-diastolic diameter was smaller than that of the right ventricle(both P<0.001),while there was no significant difference in the end-diastolic area of the two ventricles(P= 0.050).The spherical index of four-chamber view did not correlate with gestational week(P=0.811).The sphericity index of the basal and intermediate segments of the left ventricle was greater than that of the right ventricle,and the sphericity index of the apical segment was less than that of the right ventricle,the differences were statistically significant(all P<0.01).Conclusion The two-dimensional speckle tracking technique for measuring fetal cardiac parameters has good reproducibility.The reference ranges for cardiac size and morphology in low-risk fetuses developed in this study will be useful for prenatal evaluation of cardiac remodeling.

Objective To observe the effects of grain-sized moxibustion on Th1 cell/Th2 cell(Th1/Th2)balance and transcription factors T-box transcription factor(T-bet)and GATA binding protein 3(GATA3)in immunosuppressive mice induced by chemotherapy.Methods According to the random number table method,32 SPF male CD-1(ICR)mice were randomly divided into the normal group,model group,levamisole hydrochloride group,and grain-sized moxibustion group,with eight mice per group.Except for the normal group,the immunosuppressive model was established by intraperitoneal injection of cyclophosphamide(80 mg/kg,once daily for three consecutive days).Mice in the levamisole hydrochloride group were given levamisole hydrochloride solution(10 mg/kg)by gavage.Mice in the grain-sized moxibustion group was given grain-sized moxibustion at"Guanyuan"(CV4),bilateral"Zusanli"(ST36),and bilateral"Sanyinjiao"(SP6),with three Zhuang at each acupoint for approximately 30 s each.The intervention was administered once daily for seven consecutive days.The general condition of mice was observed.The spleen mass and spleen index were detected.The pathological changes of spleen tissue were observed by HE staining.The protein and mRNA expressions of T-bet,GATA3,interferon-γ(IFN-γ),and interleukin(IL)-4 in spleen tissue of mice were detected by Western blotting and real-time PCR.The contents of IFN-γ,IL-2,and IL-4 in serum of mice were detected by enzyme-linked immunosorbent assay.Results Compared with the normal group,the mice in the model group were slow in response,unstable in gait;the spleen weight and spleen index were increased(P<0.05);the structure of spleen tissue was disordered,the mRNA and protein expressions of T-bet and IFN-γ in spleen tissue were decreased,and the mRNA and protein expressions of GATA3 and IL-4 were increased(P<0.05);the contents of IFN-γ and IL-2 in serum were decreased,and the content of IL-4 was increased(P<0.05).Compared with the model group,the general condition of mice in the levamisole hydrochloride group and the grain-sized moxibustion group was improved,the structure of spleen tissue was improved,the mRNA and protein expressions of T-bet and IFN-γ in spleen tissue were decreased,and the mRNA and protein expressions of GATA3 and IL-4 were increased(P<0.05);the contents of IFN-γ and IL-2 in serum were decreased,and the content of IL-4 was increased(P<0.05).Conclusion Grain-sized moxibustion can significantly improve the immunosuppressive symptoms induced by chemotherapy.The mechanism may be through regulating the expressions of transcription factors T-bet and GATA3,regulating Th1/Th2 balance,and thus restoring the immune balance.

Objective:To compare the clinical efficacy of ultrasound-guided spinal nerve block (SNB) and paraverteral nerve block (PVB) in treating postherpetic neuralgia.Methods:A total of 52 patients with postherpetic neuralgia who visited the Pain Clinic of the Xiangya Hospital, Central South University from February 2020 to December 2022 were selected and randomly divided into an ultrasound-guided SNB group and a PVB group using a random number table method, with 26 patients in each group. Patients in the SNB group received ultrasound-guided spinal nerve block therapy; The PVB group received ultrasound-guided paraverteral nerve block treatment. Visual Analog Scale (VAS) scores, 36-Item Short Form Survey (SF-36) scores, and total effective rate were observed in two groups of patients before treatment, 2 weeks after treatment, 1 month after treatment, 3 months after treatment, and 6 months after treatment. Complications during treatment were also observed.Results:The total effective rates of SNB group patients at 1, 3, and 6 months after treatment were significantly higher than those of PVB group (all P<0.05). After treatment, the VAS scores of both groups of patients at each time point were significantly reduced compared to before treatment (all P<0.05); The VAS scores of patients in the SNB group were lower than those in the PVB group at 1, 3, and 6 months after treatment, but the difference was not statistically significant (all P>0.05). There was no statistically significant difference in Physical Component Summary (PCS) and Mental Component Summary (MCS) scores between SNB and PVB groups before nerve block treatment (all P>0.05). The MCS and PCS scores of the two groups of patients were significantly higher than before treatment at 2 weeks, 1 month, 3 months, and 6 months after treatment (all P<0.05). The MCS scores of the SNB group were significantly higher than those of the PVB group at 2 weeks, 1 month, 3 months, and 6 months after treatment (all P<0.05), but there was no statistically significant difference in PCS scores between the two groups (all P>0.05). Both groups of patients did not experience any serious complications related to the treatment in this study during the follow-up period. Conclusions:Both ultrasound-guided spinal nerve block and paraverteral nerve block can safely and effectively treat postherpetic neuralgia. The clinical effect of ultrasound-guided spinal nerve block in treating postherpetic neuralgia is better than that of paraverteral nerve block.

Objective: To analyze the impact of parental sports concept and behavior on physical activity in preschool children, so as to provide a foundation for future guidance on fostering childrens physical activity within the family context. Methods: From November to December 2020, a clustered convenience sampling method was employed to conduct surveys, and a total of 283 children were selectal from one kindergarten each in Beijing, Shenyang, and Xian. Participating children wore ActiGraph GT9X accelerometers continuously for one week to collect data on different intensity levels of physical activity. Physical Activity afterschool Questionnaire for Preschooler (P-PAQ) was utilized to assess parental sports concept and behavior. The gender differences in physical activity level and physical activity compliance rate were analyzed by using ttest, Mann-Whitney U test, and Chisquare test; and the relationship between parental exercise concepts and behaviors and physical activity of preschool children was analyzed using Spearman rank correlation analysis and multiple linear regression analysis. Results: Parental sports concept was significantly positively correlated with average daily moderatetovigorous physical activity (MVPA) and total physical activity (TPA) in children (r=0.12-0.16, P<0.05). Parental sports behavior was significantly positively correlated with childrens average daily TPA (r=0.25, P<0.05). Multiple linear regression revealed that parental sports concept was positively correlated with average daily MVPA and TPA in both boys and girls (B=0.65-0.83), while parental sports behavior only was positively correlated with boys average daily MVPA and TPA (B=0.24-0.25)(P<0.05). Conclusions Parental sports concept and behavior can impact physical activity levels in preschool children, exhibiting gender differences. Future guidance on physical activity in family upbringing should consider both parental sports concept and behavior, and pay attention to the influence of childrens gender.

Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Objective To compare the clinical outcomes of using elastic intramedullary nail and plate to fix fibular frac-ture.Methods The 60 patients with tibiofibular fractures admitted from January 2015 to December 2022 were divided into two groups:intramedullary nail group and plate group,30 cases each,intramedullary nail group was treated with elastic in-tramedullary nail fixation group,plate group was treated with steel plate and screw fixation group.Intramedullary nail group,there were 18 males and 12 females,aged from 22 to 75 years old with an average of(39.4±9.8)years old,including 24 cases of traffic accidents injury,6 cases of falling injury,23 cases of closed fractures,7 cases of open fractures.Steel plate group,there were 15 males and 15 females,aged from 24 to 78 years old with an average of(38.6±10.2)years old.The 22 cases were injured by traffic accident,8 cases were injured by falling.The 24 cases were closed fractures and 6 cases were open fractures.The operation time,intraoperative bleeding,American Orthopedic Foot and Ankle Society(AOFAS)ankle and hind foot scores,clinical healing time of fibula and the incidence of wound complications were compared between the two groups.Re-sults The patients in both groups were followed up for 6 to 21 months,with an average of(14.0±2.8)months.Compared with plate group,intramedullary nail group had shorter operative time,less bleeding,shorter clinical healing time of fibula,and low-er infection rate of incision,and the difference was statistically significant(P＜0.05).There were 2 cases of delayed healing in intramedullary nail group,1 case of nonunion in plate group,and 2 cases of delayed healing in plate group,and there was no statistically significant difference between the two groups(P＞0.05).In the last follow-up,according to the AOFAS scoring standard,the ankle function in intramedullary nail group was excellent in 17 cases,good in 12 cases,fair in 1 case,with an av-erage of(88.33±4.57)points,while in plate group,excellent in 16 cases,good in 10 cases,fair in 4 cases,with an average of(87.00±4.14)points;There was no statistical difference between the two groups(P＞0.05).Conclusion Elastic intramedullary nail has the advantages of short operation time,less intraoperative bleeding,short fracture healing time and less incision com-plications in the treatment of fibular fracture,which is worthy of clinical application.

Objective:To investigate respiratory virus infection in children with septic shock in pediatric care units (PICU) in China and its influence on clinical outcomes.Methods:The clinical data of children with septic shock in children′s PICU from January 2018 to December 2019 in 10 Chinese hospitals were retrospectively collected. They were divided into the pre-COVID-19 and post-COVID-19 groups according to the onset of disease, and the characteristics and composition of respiratory virus in the 2 groups were compared. Matching age, malignant underlying diseases, bacteria, fungi and other viruses, a new database was generated using 1∶1 propensity score matching method. The children were divided into the respiratory virus group and non-respiratory virus group according to the presence or absence of respiratory virus infection; their clinical characteristics, diagnosis, and treatment were compared by t-test, rank sum test and Chi-square test. The correlation between respiratory virus infection and the clinical outcomes was analyzed by logistic regression. Results:A total of 1 247 children with septic shock were included in the study, of them 748 were male; the age was 37 (11, 105) months. In the pre-and post-COVID-19 groups, there were 530 and 717 cases of septic shock, respectively; the positive rate of respiratory virus was 14.9% (79 cases) and 9.8% (70 cases); the seasonal distribution of septic shock was 28.9% (153/530) and 25.9% (185/717) in autumn, and 30.3% (161/530) and 28.3% (203/717) in winter, respectively, and the corresponding positive rates of respiratory viruses were 19.6% (30/153) and 15.7% (29/185) in autumn, and 21.1% (34/161) and 15.3% (31/203) in winter, respectively. The positive rates of influenza virus and adenovirus in the post-COVID-19 group were lower than those in the pre-COVID-19 group (2.1% (15/717) vs. 7.5% (40/530), and 0.7% (5/717) vs. 3.2% (17/530), χ2=21.51 and 11.08, respectively; all P<0.05). Rhinovirus virus were higher than those in the pre-Covid-19 group (1.7% (12/717) vs. 0.2% (1/530), χ2=6.51, P=0.011). After propensity score matching, there were 147 cases in both the respiratory virus group and the non-respiratory virus group. Rate of respiratory failure, acute respiratory distress, rate of disseminated coagulation dysfunction, and immunoglobulin usage of the respiratory virus group were higher than those of non-respiratory virus group (77.6% (114/147) vs. 59.2% (87/147), 17.7% (26/147) vs. 4.1% (6/147), 15.6% (25/147) vs. 4.1% (7/147), and 35.4% (52/147) vs. 21.4% (32/147); χ2=11.07, 14.02, 11.06 and 6.67, all P<0.05); and PICU hospitalization of the former was longer than that of the later (7 (3, 16) vs. 3 (1, 7)d, Z=5.01, P<0.001). Univariate logistic regression analysis showed that the presence of respiratory viral infection was associated with respiratory failure, disseminated coagulation dysfunction, the use of mechanical ventilation, and the use of immunoglobulin and anti-respiratory viral drugs ( OR=2.42, 0.22, 0.25, 0.56 and 1.12, all P<0.05). Conclusions:The composition of respiratory virus infection in children with septic shock is different between pre and post-COVID-19. Respiratory viral infection is associated with organ dysfunction in children with septic shock. Decreasing respiratory viral infection through respiratory protection may improve the clinical outcome of these children.

Objective:To investigate the clinical features, pathogen composition, and prognosis of septic shock in pediatric intensive care units (PICU) in China.Methods:A multicenter retrospective cohort study. A retrospective analysis was conducted on the clinical data of children with septic shock from 10 hospitals in China between January 2018 and December 2021. The clinical features, pathogen composition, and outcomes were collected. Patients were categorized into malignant tumor and non-malignant tumor groups, as well as survival and mortality groups. T test, Mann Whitney U test or Chi square test were used respectively for comparing clinical characteristics and prognosis between 2 groups. Multiple Logistic regression was used to identify risk factors for mortality. Results:A total of 1 247 children with septic shock were included, with 748 males (59.9%) and the age of 3.1 (0.9, 8.8) years. The in-patient mortality rate was 23.2% (289 cases). The overall pathogen positive rate was 68.2% (851 cases), with 1 229 pathogens identified. Bacterial accounted for 61.4% (754 strains) and virus for 24.8% (305 strains). Among all bacterium, Gram negative bacteria constituted 64.2% (484 strains), with Pseudomonas aeruginosa and Enterobacter being the most common; Gram positive bacteria comprised 35.8% (270 strains), primarily Streptococcus and Staphylococcus species. Influenza virus (86 strains (28.2%)), Epstein-Barr virus (53 strains (17.4%)), and respiratory syncytial virus (46 strains (17.1%)) were the top three viruses. Children with malignant tumors were older and had higher pediatric risk of mortality (PRISM) Ⅲ score, paediatric sequential organ failure assessment (pSOFA) score (7.9 (4.3, 11.8) vs. 2.3 (0.8, 7.5) years old, 22 (16, 26) vs. 16 (10, 24) points, 10 (5, 14) vs. 8 (4, 12) points, Z=11.32, 0.87, 4.00, all P<0.05), and higher pathogen positive rate, and in-hospital mortality (77.7% (240/309) vs. 65.1% (611/938), 29.7% (92/309) vs. 21.0% (197/938), χ2=16.84, 10.04, both P<0.05) compared to the non-tumor group. In the death group, the score of PRISM Ⅲ, pSOFA (16 (22, 29) vs. 14 (10, 20) points, 8 (12, 15) vs. 6 (3, 9) points, Z=4.92, 11.88, both P<0.05) were all higher, and presence of neoplastic disease, positive rate of pathogen and proportion of invasive mechanical ventilation in death group were also all higher than those in survival group (29.7% (87/289) vs. 23.2% (222/958), 77.8% (225/289) vs. 65.4% (626/958), 73.7% (213/289) vs. 50.6% (485/958), χ2=5.72, 16.03, 49.98, all P<0.05). Multiple Logistic regression showed that PRISM Ⅲ, pSOFA, and malignant tumor were the independent risk factors for mortality ( OR=1.04, 1.09, 0.67, 95% CI 1.01-1.05, 1.04-1.12, 0.47-0.94, all P<0.05). Conclusions:Bacterial infection are predominant in pediatric septic shock, but viral infection are also significant. Children with malignancies are more severe and resource consumptive. The overall mortality rate for pediatric septic shock remains high, and mortality are associated with malignant tumor, PRISM Ⅲ and pSOFA scores.

Curettage is the main treatment method for oral maxillofacial cystic lesions,but simple curettage may easily damage surrounding structures such as adjacent teeth and nerves,leading to incomplete removal of the cyst and large jaw defects.The curettage assisted by endoscopy can provide a good surgical field for the surgeons,can clearly identify the important anatomical structure during the operation and can remove the cyst wall tissue as much as possible,thereby reducing the damage and reducing the recurrence rate of the lesion.This article combines the characteristics of maxillofacial surgery with clinical treatment experience,summarizes relevant literature from both domestic and international sources,and engages in discussions with experts in order to provide reference for the clinical treatment of jaw cystic lesions with endo-scope assisted curettage.