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 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 explore the prognostic value of BRCA1-associated protein 1 (BAP1) expression loss in patients with malignant mesothelioma (MM) .Methods:A total of 82 MM patients from January 1998 to December 2017 in Zhejiang Province were selected to detect the expression of BAP1 protein by immunohistochemical analysis. Kaplan-Meier method was used to draw the survival curve, and multivariate Cox proportional risk model was used to analyze the factors affecting the survival rate.Results:Among 82 MM patients, 61 (74.4%) were female, aged (57±11) years. BAP1 protein expression was deficient in 39 patients (47.6%). The survival rate was correlated with the loss of BAP1 protein expression and age (χ 2=5.27, 5.66, P=0.022, 0.017). Subgroup analysis showed that loss of BAP1 protein expression was associated with better prognosis in MM patients <57 years of age, female, pleural MM, epithelial MM, and treated with drugs or surgery ( P<0.05). Multivariate model results showed that positive expression of BAP1 protein ( HR=3.75, 95% CI: 2.23-6.30, P<0.001) and age ≥57 years ( HR=1.66, 95% CI: 1.01-2.72, P=0.049) were risk factors for survival in patients with MM. Conclusion:Loss of BAP1 protein expression may be an independent prognostic factor in patients with MM, which is associated with longer survival.

Objective:To explore the prognostic value of BRCA1-associated protein 1 (BAP1) expression loss in patients with malignant mesothelioma (MM) .Methods:A total of 82 MM patients from January 1998 to December 2017 in Zhejiang Province were selected to detect the expression of BAP1 protein by immunohistochemical analysis. Kaplan-Meier method was used to draw the survival curve, and multivariate Cox proportional risk model was used to analyze the factors affecting the survival rate.Results:Among 82 MM patients, 61 (74.4%) were female, aged (57±11) years. BAP1 protein expression was deficient in 39 patients (47.6%). The survival rate was correlated with the loss of BAP1 protein expression and age (χ 2=5.27, 5.66, P=0.022, 0.017). Subgroup analysis showed that loss of BAP1 protein expression was associated with better prognosis in MM patients <57 years of age, female, pleural MM, epithelial MM, and treated with drugs or surgery ( P<0.05). Multivariate model results showed that positive expression of BAP1 protein ( HR=3.75, 95% CI: 2.23-6.30, P<0.001) and age ≥57 years ( HR=1.66, 95% CI: 1.01-2.72, P=0.049) were risk factors for survival in patients with MM. Conclusion:Loss of BAP1 protein expression may be an independent prognostic factor in patients with MM, which is associated with longer survival.

Objective:To explore effect of IgG receptor FcγRⅡB on neuronal injury and imbalance of Th17/Treg in experi-mental autoimmune encephalomyelitis(EAE)model mice.Methods:C57BL/6 mice were randomly divided into control group,EAE group,FcγRⅡB group and EAE+FcγRⅡB group,with 15 mice in each group.EAE model was induced by subcutaneous injection of MOG35-55 peptide and treated with FcγRⅡB lentiviral solution.After modeling was established,body weight of mice was weighed every day,and neurological function was scored for 30 d;after 30 days,mice were sacrificed.HE staining was used to observe patho-logical changes of brain tissue,LFB staining was used to assess structural changes of spinal cord myelin,and immunofluorescence staining was used to detect spinal cord cerebral cortex neuron nuclear antigen(NeuN)and Caspase-3 expressions,TUNEL staining was used to detect apoptosis of neurons,ELISA was used to detect serum IL-6,IL-17,IL-10 and TGF-β levels,flow cytometry was used to analyze proportion of Th17 and Treg cells in spleen,Western blot was used to determine protein expressions of retinoic acid-related orphan receptor γt(RORγt)and Forkhead family transcription factor 3(Foxp3)in spinal cord tissue.Results:Compared with control group,mice in EAE group had decreased body weight,increased neurological function scores,obvious infiltration of inflamma-tory cells in brain tissue,and signs of demyelination in spinal cord,fluorescence expression intensity of NeuN was weakened and fluorescence expression intensity of Caspase-3 was enhanced,there were more TUNEL-positive stained cells,number of apoptotic cells was increased,levels of IL-6 and IL-17 in serum were increased,and levels of IL-10 and TGF-β were decreased,proportion of Th17 cells in spleen was increased,proportion of Treg was decreased,expression of RORγt protein in spinal cord tissue was up-regu-lated while relative expression of Foxp3 protein was down-regulated(P<0.05);compared with EAE group,weight of mice in EAE+FcγRⅡB group was increased,neurological function score was decreased,infiltration of inflammatory cells in brain tissue was reduced,demyelination of spinal cord was improved,fluorescence expression intensity of NeuN was enhanced,and fluorescence expression intensity of Caspase-3 was weakened,there were fewer TUNEL-positive stained cells,number of apoptotic cells was decreased,levels of IL-6 and IL-17 in serum were decreased,while levels of IL-10 and TGF-β were increased,at the same time,proportion of Th17 cells in spleen was decreased and proportion of Treg was increased,expression of RORγt protein in spinal cord tissue was down-regulated,while expression of Foxp3 protein was up-regulated(P<0.05).Conclusion:FcγRⅡB has neuroprotective effect on EAE mice,and can reduce infiltration of inflammatory cells and demyelination in brain tissue,whose mechanism may be related to regulation of cytokine levels and immune balance of Th17/Treg cells.

Objective:To investigate the effect of glucocorticoids on brain injury in rats with Streptococcus pneumoniae(SP)meningitis,as well as the changes of cerebrospinal fluid immunoglobulin levels under this effect.Methods:A total of 40 SD rats were divided into control group,model group,low-dose methylprednisolone sodium succinate group(Low-MSS)and high-dose methylpred-nisolone sodium succinate group(High-MSS)according to random table method,with 10 rats in each group.Except for the control group,SP meningitis models were established in other groups.Rats in Low-MSS group and High-MSS group were injected with methyl-prednisolone sodium succinate by tail vein at doses of 5 mg/kg and 10 mg/kg,respectively,once a day for 21 days.Neurobehavioral scores of rats after modeling were performed by Loeffler method;contents of immunoglobulin IgA,IgM and IgG in cerebrospinal fluid of rats were detected by immunoturbidimetry;levels of inflammatory cytokines TNF-α,IL-6 and IFN-γ in supernatant of rats brain ho-mogenate were determined by ELISA;HE staining was used to detect pathological changes of rats brain tissue;Nissl staining was used to detect the number of neuronal cells in rats brain tissue;TUNEL staining was used to detect the number of apoptotic cells in rats brain tissue;immunofluorescence staining was used to detect expressions of GFAP and S-100b,the marker proteins of rat brain tissue injury.Results:Before SP injection,there was no difference in neurobehavioral scores between control group and model group(P>0.05),at 24 h,48 h and 72 h after SP injection,neurobehavioral scores in model group were significantly lower than those in control group(P<0.05).Compared with control group,contents of IgA,IgM and IgG in cerebrospinal fluid of rats in model group were in-creased,and contents of TNF-α,IL-6 and IFN-γ in supernatant of the brain homogenate were also increased,the tissue was obviously damaged,accompanied by a large number of inflammatory cells infiltration,the number of neuronal cells were decreased,the number of apoptotic cells were increased,and the fluorescence density values of S-100b and GFAP were increased(P<0.05);compared with model group,contents of IgA,IgM and IgG in cerebrospinal fluid of rats in Low-MSS group and High-MSS group were decreased,and contents of TNF-α,IL-6 and IFN-γ in brain homogenate supernatant were also decreased(P<0.05),brain tissue damage was alleviated,inflammatory cell infiltration was significantly reduced,neuronal cells were increased,the number of apoptotic cells were decreased,and the fluorescence density values of S-100b and GFAP were also decreased(P<0.05).In addition,the improvement effect of various indexes and brain tissue damage in High-MSS group was better than that in Low-MSS group,and the difference were statistically signifi-cant(P<0.05).Conclusion:Glucocorticoid methylprednisolone sodium succinate can effectively improve the brain tissue damage in SP meningitis rats,regulate the levels of immunoglobulin IgA,IgM and IgG,and has a protective effect on SP meningitis rats.

The process of embryo implantation is a multifaceted and intricate dynamic event that includes the development of endometrial receptivity, embryo localization, adhesion, and invasion. Adhesion molecules, acting as crucial mediators of communication between cells or between cells and the extracellular matrix, are essential for the maintenance of endometrial receptivity and the regulation of embryo localization, adhesion, and invasion. However, the mechanisms by which adhesion molecules of maternal and embryo are organized to regulate key events in the peri-implantation period have yet to be fully explored. Based on recent research findings, this review provides a summary of the functions of different adhesion molecules at the maternal-fetal interface and their potential regulatory mechanisms according to the key progress of embryo implantation. In particular, we discussed the interactions between decidual immune cells and other cells mediated by adhesion molecules during the invasion process, which will provide novel perspectives into the role of adhesion molecule dysfunction in contributing to implantation failure.

The process of embryo implantation is a multifaceted and intricate dynamic event that includes the development of endometrial receptivity, embryo localization, adhesion, and invasion. Adhesion molecules, acting as crucial mediators of communication between cells or between cells and the extracellular matrix, are essential for the maintenance of endometrial receptivity and the regulation of embryo localization, adhesion, and invasion. However, the mechanisms by which adhesion molecules of maternal and embryo are organized to regulate key events in the peri-implantation period have yet to be fully explored. Based on recent research findings, this review provides a summary of the functions of different adhesion molecules at the maternal-fetal interface and their potential regulatory mechanisms according to the key progress of embryo implantation. In particular, we discussed the interactions between decidual immune cells and other cells mediated by adhesion molecules during the invasion process, which will provide novel perspectives into the role of adhesion molecule dysfunction in contributing to implantation failure.

Objective : To examine the diagnostic and prognostic value of long non-coding RNA (lncRNA) JPX in mesothelioma, so as to provide insights into diagnosis and prognosis of mesothelioma. Methods: Patients with clinically definitive diagnosis of mesothelioma from 2015 to 2019 that were sampled from asbestos processing plants in Zhejiang Province from 2015 to 2019 were recruited in the mesothelioma group, while healthy residents without asbestos exposure or asbestos-related diseases in the same area served as controls. Participants' demographics, pathologic diagnosis and imaging features were collected, and the expression of blood lncRNA JPX was detected using lncRNA microarrays. The diagnostic value of lncRNA JPX for mesothelioma was evaluated using the receiver operating characteristic (ROC) curve, and the correlation between lncRNA JPX expression and prognosis was examined among mesothelioma patients using survival analysis. Results: There were 17 subjects in the mesothelioma group, with a mean age of (65.71±8.36) years, and 34 subjects in the controls, with a mean age of (64.24±8.70) years. LncRNA microarray detected significantly high lncRNA JPX expression in mesothelioma patients, and higher blood lncRNA JPX expression was detected in the mesothelioma group than in the control group [median (interquartile range), 1.10 (1.31) vs. 0.89 (0.54); t'=-2.300, P=0.034]. The area under the ROC curve was 0.673 (95%CI: 0.507-0.839, P=0.046), and if the cutoff was 1.759, the sensitivity and specificity were 35.3% and 100.0%, respectively. Survival analysis showed no significant difference in the survival rate of mesothelioma patients between the high lncRNA JPX expression group and the low expression group (χ2=0.212, P=0.645). Conclusions LncRNA JPX overexpression is detected in the blood of patients with mesothelioma, and lncRNA JPX expression presents a diagnostic value for mesothelioma; however, it shows little prognostic value for mesothelioma.