Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Objective:To investigate the prevalence and risk factors of the 4 most common functional gastrointestinal disorders (FGID) among school-aged children in Shanghai.Methods:A cross-sectional questionnaire survey was conducted from January to December 2019. Using stratified cluster sampling, 26 097 students in grades 1-12 from Huangpu and Jiading District, Shanghai were enrolled. The questionnaire of pediatric gastrointestinal symptoms-Rome Ⅳ (QPGS-Ⅳ) and the pediatric quality of life inventory (PedsQL) were used to assess the prevalence and health-related quality of life (HRQoL) of functional dyspepsia (FD), irritable bowel syndrome (IBS), functional abdominal pain-not otherwise specified (FAP-NOS), and functional constipation (FC). Multivariate Logistic regression analysis was performed to identify correlations between sociodemographic factors, lifestyle habits, comorbidities and 4 major FGID. A trend chi-square test was used to explore the relationship between HRQoL scores and FGID prevalence.Results:A total of 26 097 valid participants (26 097/27 036, 96.5%) were included in the study, with the age of (10.8±3.1) years and 12 441 cases (47.7%) were female. The prevalence of FC was found to be the highest (5 537 cases, 21.2%), followed by IBS (797 cases, 3.1%), FAP-NOS (267 cases, 1.0%) and FD (218 cases, 0.8%). Multivariate Logistic regression analysis revealed the following findings: junior high school (FD: OR=1.88 (95% CI 1.35-2.61); IBS: OR=1.42 (95% CI 1.18-1.71); FAP-NOS: OR=1.39 (95% CI 1.02-1.90)), senior high school (FD: OR=2.67 (95% CI 1.84-3.86);IBS: OR=2.36 (95% CI 1.93-2.89) ;FAP-NOS: OR=2.20 (95% CI 1.56-3.11)) and frequent respiratory infections (FD: OR=2.15 (95% CI 1.45-3.18); IBS: OR=2.59 (95% CI 2.12-3.16); FAP-NOS: OR=1.49 (95% CI 1.00-2.21)) were common risk factors for FD, IBS and FAP-NOS. Allergic symptoms (FD: OR=2.21 (95% CI 1.56-3.14); IBS: OR=2.30 (95% CI 1.04-1.51); FAP-NOS: OR=2.54 (95% CI 1.85-3.50); FC: OR=1.09 (95% CI 1.01-1.17)) was a common risk factor for FD, IBS, FAP-NOS and FC. Family history of allergy was a risk factor for IBS ( OR=1.41 (95% CI 1.20-1.65)) and FAP-NOS ( OR=1.33 (95% CI 1.01-1.74)). Female exhibited increased risks for FD ( OR=1.49 (95% CI 1.13-1.96)), IBS ( OR=1.50 (95% CI 1.30-1.74)) and FC ( OR=1.10 (95% CI 1.03-1.17)). The presence of dietary bias was associated with of IBS ( OR=1.46 (95% CI 1.26-1.69)) and FC ( OR=1.26 (95% CI 1.19-1.34)); late bedtime ( OR=1.32 (95% CI 1.06-1.64)) and allergen exposure ( OR=1.25 (95% CI 1.04-1.51)) were risk factors for IBS. Insufficient sleep ( OR=1.11 (95% CI 1.02-1.21)), insufficient outdoor time ( OR=1.20 (95% CI 1.01-1.43)) and severe lack of outdoor time ( OR=1.48 (95% CI 1.23-1.76)) were significant risk factors for FC. Pet ownership ( OR=1.39 (95% CI 1.07-1.81)) was a risk factor for FAP-NOS. HRQoL scores were significantly lower in children with FD, IBS, or FAP-NOS compared to non-FGID peers (all P<0.05). χ2 trend test analysis showed that the Pearson correlation coefficients between the prevalence of FD, IBS, FAP-NOS, FC and HRQoL scores were -0.93, -0.93, -0.97 and -0.84, respectively. Conclusions:The prevalence of FGID among school-aged children in Shanghai varies by sub-type. FC was the most prevalence. Junior and senior high school, female sex, allergic symptoms and frequent respiratory infections were major risk factors. Meanwhile, dietary bias, late bedtime, insufficient outdoor time and pet ownership were associated with specific subtypes. The HRQoL is significantly reduced in children with FD, IBS and FAP-NOS.

Objective:To investigate microstructural alterations in the optic chiasm and optic radiations of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) based on diffusion kurtosis imaging (DKI).Methods:This study was a cross-sectional study. Retrospective analyses were conducted on the clinical and imaging data of 63 patients with relapsing-remitting MS (RRMS) and 62 patients with NMOSD diagnosed at First Affiliated Hospital of Chongqing Medical University from January 2019 to December 2023. According to the occurrence of optic neuritis (ON), they were categorized into ON-positive MS (ON+MS) group (40 cases), ON-negative MS (ON-MS) group (23 cases), ON-positive NMOSD (ON+NMOSD) group (40 cases) and ON-negative NMOSD (ON-NMOSD) group (22 cases). In addition, 40 healthy controls were enrolled during the same period. DKI data of all subjects were collected, and DKI post-processing was performed to obtain fractional anisotropy (FA), mean kurtosis (MK), axial kurtosis (AK), and radial kurtosis (RK) values of the optic chiasm and bilateral optic radiations. The scores of the mini-mental state examination (MMSE), montreal cognitive assessment (MoCA), and expanded disability status scale (EDSS) were obtained. The Kruskal-Wallis test was used to analyze the differences in DKI parameters of the optic chiasm and bilateral optic radiation among the 5 groups, and the Holm-Bonferroni method was employed for multiple comparison correction in pairwise comparisons.Results:There were statistically significant overall differences in the DKI parameters of the optic chiasm and bilateral optic radiations among healthy control group, ON+MS group, ON-MS group, ON+NMOSD group, and ON-NMOSD group (all P0.05). The FA value of the optic chiasm in ON+NMOSD group was significantly lower than that of healthy control group and ON-MS group, as well as ON-NMOSD group ( P0.05). The FA value of the left optic radiation in ON+NMOSD group was lower than that in healthy control group and the ON-MS group. The RK value of the optic chiasm in ON+MS group was lower than that in the healthy control group and ON-NMOSD group ( P0.05). The MK and RK values of the left optic radiation in ON-MS group were significantly lower than those in the ON+NMOSD group and ON-NMOSD group ( P0.05). Conclusions:NMOSD and RRMS patients demonstrate varying degrees of microstructural damage in the optic chiasm and optic radiations. Differences of DKI parameters suggest different pathological mechanisms of visual pathway damage between NMOSD and MS, which may be helpful for early detection of occult visual pathway lesions.

Objective:To investigate microstructural alterations in the optic chiasm and optic radiations of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) based on diffusion kurtosis imaging (DKI).Methods:This study was a cross-sectional study. Retrospective analyses were conducted on the clinical and imaging data of 63 patients with relapsing-remitting MS (RRMS) and 62 patients with NMOSD diagnosed at First Affiliated Hospital of Chongqing Medical University from January 2019 to December 2023. According to the occurrence of optic neuritis (ON), they were categorized into ON-positive MS (ON+MS) group (40 cases), ON-negative MS (ON-MS) group (23 cases), ON-positive NMOSD (ON+NMOSD) group (40 cases) and ON-negative NMOSD (ON-NMOSD) group (22 cases). In addition, 40 healthy controls were enrolled during the same period. DKI data of all subjects were collected, and DKI post-processing was performed to obtain fractional anisotropy (FA), mean kurtosis (MK), axial kurtosis (AK), and radial kurtosis (RK) values of the optic chiasm and bilateral optic radiations. The scores of the mini-mental state examination (MMSE), montreal cognitive assessment (MoCA), and expanded disability status scale (EDSS) were obtained. The Kruskal-Wallis test was used to analyze the differences in DKI parameters of the optic chiasm and bilateral optic radiation among the 5 groups, and the Holm-Bonferroni method was employed for multiple comparison correction in pairwise comparisons.Results:There were statistically significant overall differences in the DKI parameters of the optic chiasm and bilateral optic radiations among healthy control group, ON+MS group, ON-MS group, ON+NMOSD group, and ON-NMOSD group (all P0.05). The FA value of the optic chiasm in ON+NMOSD group was significantly lower than that of healthy control group and ON-MS group, as well as ON-NMOSD group ( P0.05). The FA value of the left optic radiation in ON+NMOSD group was lower than that in healthy control group and the ON-MS group. The RK value of the optic chiasm in ON+MS group was lower than that in the healthy control group and ON-NMOSD group ( P0.05). The MK and RK values of the left optic radiation in ON-MS group were significantly lower than those in the ON+NMOSD group and ON-NMOSD group ( P0.05). Conclusions:NMOSD and RRMS patients demonstrate varying degrees of microstructural damage in the optic chiasm and optic radiations. Differences of DKI parameters suggest different pathological mechanisms of visual pathway damage between NMOSD and MS, which may be helpful for early detection of occult visual pathway lesions.

Objective:To investigate the prevalence and risk factors of the 4 most common functional gastrointestinal disorders (FGID) among school-aged children in Shanghai.Methods:A cross-sectional questionnaire survey was conducted from January to December 2019. Using stratified cluster sampling, 26 097 students in grades 1-12 from Huangpu and Jiading District, Shanghai were enrolled. The questionnaire of pediatric gastrointestinal symptoms-Rome Ⅳ (QPGS-Ⅳ) and the pediatric quality of life inventory (PedsQL) were used to assess the prevalence and health-related quality of life (HRQoL) of functional dyspepsia (FD), irritable bowel syndrome (IBS), functional abdominal pain-not otherwise specified (FAP-NOS), and functional constipation (FC). Multivariate Logistic regression analysis was performed to identify correlations between sociodemographic factors, lifestyle habits, comorbidities and 4 major FGID. A trend chi-square test was used to explore the relationship between HRQoL scores and FGID prevalence.Results:A total of 26 097 valid participants (26 097/27 036, 96.5%) were included in the study, with the age of (10.8±3.1) years and 12 441 cases (47.7%) were female. The prevalence of FC was found to be the highest (5 537 cases, 21.2%), followed by IBS (797 cases, 3.1%), FAP-NOS (267 cases, 1.0%) and FD (218 cases, 0.8%). Multivariate Logistic regression analysis revealed the following findings: junior high school (FD: OR=1.88 (95% CI 1.35-2.61); IBS: OR=1.42 (95% CI 1.18-1.71); FAP-NOS: OR=1.39 (95% CI 1.02-1.90)), senior high school (FD: OR=2.67 (95% CI 1.84-3.86);IBS: OR=2.36 (95% CI 1.93-2.89) ;FAP-NOS: OR=2.20 (95% CI 1.56-3.11)) and frequent respiratory infections (FD: OR=2.15 (95% CI 1.45-3.18); IBS: OR=2.59 (95% CI 2.12-3.16); FAP-NOS: OR=1.49 (95% CI 1.00-2.21)) were common risk factors for FD, IBS and FAP-NOS. Allergic symptoms (FD: OR=2.21 (95% CI 1.56-3.14); IBS: OR=2.30 (95% CI 1.04-1.51); FAP-NOS: OR=2.54 (95% CI 1.85-3.50); FC: OR=1.09 (95% CI 1.01-1.17)) was a common risk factor for FD, IBS, FAP-NOS and FC. Family history of allergy was a risk factor for IBS ( OR=1.41 (95% CI 1.20-1.65)) and FAP-NOS ( OR=1.33 (95% CI 1.01-1.74)). Female exhibited increased risks for FD ( OR=1.49 (95% CI 1.13-1.96)), IBS ( OR=1.50 (95% CI 1.30-1.74)) and FC ( OR=1.10 (95% CI 1.03-1.17)). The presence of dietary bias was associated with of IBS ( OR=1.46 (95% CI 1.26-1.69)) and FC ( OR=1.26 (95% CI 1.19-1.34)); late bedtime ( OR=1.32 (95% CI 1.06-1.64)) and allergen exposure ( OR=1.25 (95% CI 1.04-1.51)) were risk factors for IBS. Insufficient sleep ( OR=1.11 (95% CI 1.02-1.21)), insufficient outdoor time ( OR=1.20 (95% CI 1.01-1.43)) and severe lack of outdoor time ( OR=1.48 (95% CI 1.23-1.76)) were significant risk factors for FC. Pet ownership ( OR=1.39 (95% CI 1.07-1.81)) was a risk factor for FAP-NOS. HRQoL scores were significantly lower in children with FD, IBS, or FAP-NOS compared to non-FGID peers (all P<0.05). χ2 trend test analysis showed that the Pearson correlation coefficients between the prevalence of FD, IBS, FAP-NOS, FC and HRQoL scores were -0.93, -0.93, -0.97 and -0.84, respectively. Conclusions:The prevalence of FGID among school-aged children in Shanghai varies by sub-type. FC was the most prevalence. Junior and senior high school, female sex, allergic symptoms and frequent respiratory infections were major risk factors. Meanwhile, dietary bias, late bedtime, insufficient outdoor time and pet ownership were associated with specific subtypes. The HRQoL is significantly reduced in children with FD, IBS and FAP-NOS.

Background::Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods::Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. Results::Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter –42 bp to –28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression. Conclusions::This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

【Objective】 To investigate the effect of polymerized human cord hemoglobin (PolyCHb) on the chemosensitivity of human breast cancer MCF-7 cell subcutaneous xenografts in nude mice and its mechanism. 【Methods】 The MCF-7 cells in exponential growth phase were collected and made into suspension cells at a density of 5×10⁷ cells/mL.Subsequently, the cells were inoculated subcutaneously in the right limb of 18 BALB/c-nu nude mice with 0.2 mL cells per mouse to establish subcutaneous xenograft.When the tumor volume reached about 100 mm³, they were randomly divided into chemotherapy group: doxorubicin 5 mg·kg^-1, once/week; chemotherapy + PolyCHb group: in addition to doxorubicin (chemotherapy group), PolyCHb 600 mg·kg^-1, 3 times/week; the control group: normal saline 90 mg·kg^-1, once/week; all were injected through tail vein continuously for 4 weeks.From the day of injection (d 0), the tumor volume of each group of nude mice was measured every 3 days, and the tumor growth curves were drawn accordingly.After 38 days, the tumor growth observation was completed.The tumor was removed and weighed to calculate the tumor inhibition rate.HE staining, immunohistochemistry and TUNEL method were used to observe the pathological changes of tumor tissue, detect the expression of HIF-1α, and detect tumor cell apoptosis respectively.The content of reactive oxygen species (ROS) of each group was determined by fluorescence staining. 【Results】 The tumor volume (mm³) of chemotherapy + PolyCHb group, chemotherapy group and the control group at day 38 were 196.35±103.45 vs 316.29±62.88 vs 519.42±177.33 (P<0.05), and the tumor inhibition rate (%) of chemotherapy + PolyCHb treatment group and chemotherapy group was 62.20 vs 39.11, respectively.HE staining and TUNEL detection showed that cell necrosis and apoptosis in the growth area of tumor tissue increased in chemotherapy + PolyCHb group.Immunohistochemistry and fluorescence staining showed that HIF-1α expression in chemotherapy + PolyCHb group decreased and reactive oxygen species (ROS) content increased. 【Conclusion】 PolyCHb increases the chemosensitivity of subcutaneous xenograft in nude mice with breast cancer, and its mechanism may be related to the increase of ROS in tumor tissue and the promotion of tumor cell apoptosis.

【Objective】 To investigate the application prospect of platelet-rich plasma lysate (PL) microneedles in the treatment of wound healing by optimizing the preparation process and evaluating the activity of platelet growth factor. 【Methods】 Firstly, hyaluronic acid (HA) was used as needle matrix material, and the concentration of HA was preliminarily determined by investigating the fluidity of HA solution, shape of needle, pressure change performance and puncture performance.Combined with the results of HA dissolution in PL, mechanical properties of PL microneedles and skin puncture, the preparation process of platelet-rich plasma lysis microneedles (PLMN) was optimized to investigate the growth factor activity of PLMN and evaluate the effect of PLMN on wound healing in rats. 【Results】 When the concentration of HA was 30 mg/mL, the solution had good fluidity.The HA microneedles could pierce three layers of sealing film, with the puncture rate at 70%, and the solution had good mechanical properties.When HA was dissolved in PL at a concentration of 30 mg/mL at 4℃, the solution had no crystallization and was with good fluidity.The prepared PLMN showed good needle shape and no bending under HD microscope and scanning electron microscope.In vitro transdermal simulation results showed that PLMN could penetrate 4 layers of sealing membrane, and the puncture rate of the first three layers was more than 85%.In vivo lysis experiment showed that PLMNs could be completely dissolved within 10 min after being inserted into the body.Forty minutes later, the micropores left after the insertion of the microneedle were almost closed, without redness, swelling, erythema and other adverse reactions.In vitro and in vivo transdermal experiments showed that clear blue holes were visible after PLMNs penetrated the skin stain, indicating that the microneedles could pierce the skin barrier.Growth factor detection results showed that the content of platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGFβ1) in platelet lysate were (17.67±1.23) ng/mL and (105.95±2.16) ng/mL, respectively.After PLMNs were prepared and stored at room temperature for 1 week, the content of PDGF-BB(ng/mL) and TGFβ1(ng/mL) were 15.48±2.12 and 56.26±1.53, respectively.Compared with PL(vs 17.67±1.23 and 105.95±2.16), the content of PDGF-BB and TGFβ1 decreased, but still maintained the activity of growth factors.The results of wound healing experiment in rats showed that the wound healing rate (%) of PLMN group on the third day was significantly different from that of the control group(52.51±6.15 vs 33.31±3.60, P<0.05). 【Conclusion】 The PLMN prepared in this experiment has good mechanical properties and can successfully pierce the skin cuticle.It can also maintain the activity of growth factors, and has a good effect on wound healing in rats, which provides a new idea for minimally invasive treatment in the field of tissue repair.

Background::Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods::Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results::A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions::The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Objective To effectively use the clinical data generated in daily operation and to realize information networking based on the existing resources of radiotherapy department. To improve quality management efficiency in radiotherapy process. Methods The radiotherapy process and required documents were analyzed. The reporting tool Microsoft Report Builder, which is based on SQL database, was applied to design the patient documents by extracting and analyzing a large number of data generated by Aria, the existing network of our radiotherapy department. PDCA Tools was used to analyze the weak links in the process. Reports with quantitative indices have been designed according to corresponding countermeasures, so as to improve quality control level of the process. Results More than one thousand patients were treated in our department since 2020. All patient documents of radiotherapy can be archived and inquired online after registration only once. 13 daily statistical reports, 5 quarters and 3 annual reports were scheduled according to practical demands. The waiting time before radiotherapy was shortened from 16.2 days to 14.8 days after operating the reporting system 3 months later. The staff could master the treatment progress of patients easily and patients who interrupted the treatment were found in time. Conclusion The reporting tools can realize patient information extraction and networked management effectively in radiotherapy process. Staff efficiency of personnel work and communication was improved. The resource allocation was optimized according to the report data in real time, improving the efficiency and quality of radiotherapy. This method is generally applicable and practical to radiotherapy department.