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.

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Objective Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading cause of hospitalization and death in patients with chronic obstructive pulmonary disease (COPD). Exploring the prognostic factors of AECOPD patients will assist in optimizing treatment strategies and standardizing disease management. Methods This study retrospectively collected the clinical data of 664 patients with AECOPD admitted to the Respiratory Department of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2013 to September 2019. The 3-year survival rate and treatment of the patients were investigated. According to whether the patients died,they were divided into a non-survivors group and a survivors group,and clinical data such as basic information,comorbidities,and auxiliary examination results were compared between the two groups. Incorporating clinical experience of researchers and previous research evidence,a secondary screening of variables was conducted to ultimately determine the covariates to be included in the multifactorial Cox proportional hazards regression model,and the factors affecting the 3-year survival rate of the patients were analyzed. Results A total of 664 cases were included in this study,including 362 males and 302 females,with an average age of (77.25±6.89) years old. The 3-year all-cause mortality rate of older hospitalized patients with AECOPD was 20.48％(136 patients). Older age (HR:1.071,95％CI:1.040-1.102,P<0.001);smoking history (HR:1.788,95％CI:1.173-2.723,P=0.007);Charlson comorbidity index (HR:1.209,95％CI:1.029-1.421,P=0.022);lower arterial partial pressure of oxygen (HR:1.014,95％CI:1.006-1.022,P<0.001);higher brain natriuretic peptide(HR:1.001,95％CI:1.000-1.001,P=0.025);cor pulmonale(HR:1.896,95％CI:1.235-2.908,P=0.004);respiratory failure (HR:2.437,95％CI:1.378-4.311,P=0.003);TCM syndrome differentiation elements,including kidney (HR:1.639,95％CI:1.055-2.546,P=0.028) and fluid retention (HR:2.512,95％CI:1.653-3.816,P<0.001),were independent risk factors for 3-year all-cause death of older hospitalized patients with AECOPD. Long-term regular use of bronchiectasis (HR:0.474,95％CI:0.324-0.695,P<0.001) was an independent protective factor for 3-year all-cause death. Conclusion The 3-year survival rate of elderly hospitalized patients with AECOPD is relatively low,with the TCM syndrome elements manifested as lung-kidney qi deficiency,yang deficiency with water retention,and blood stasis obstruction. Patients with moderate to severe impairment of lung function due to COPD have an increased risk of death within 3 years. Therefore,for such patients,nourishing lung-kidney qi,resolving phlegm and water retention,activating blood circulation to remove blood stasis and dredging collaterals,combined with regular use of bronchodilators,may help improve their 3-year survival rate.

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 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.

{L-End}Objective To analyze the effects of night shift work and overweight/obesity on blood pressure of workers in chemical fiber industry. {L-End}Methods A total of 1 004 workers of a chemical fiber factory were selected as the study subjects using convenient sampling method, and their blood pressure and body mass index were measured. Multiple linear regression model was used to analyze the relationship between night shift work and blood pressure, and multiple logistic regression was used to assess the independent impact and combined impact of night shifts and overweight/obesity on the risk of hypertension. {L-End}Results Compared with the non-night shift workers, the prevalence of hypertension in night shift workers was increased (5.3% vs 13.0%, P<0.05), with elevated systolic and diastolic blood pressure (both P<0.05). The results of multiple linear regression analysis showed that the systolic blood pressure and diastolic blood pressure of the night shift workers were higher than those of the non-night shift workers (both P<0.05), and the systolic blood pressure and diastolic blood pressure of overweight/obesity workers were higher than those of non-overweight/obesity workers (both P<0.01). The results of multiple logistic regression analysis showed that the risk of hypertension in night shift workers and overweight/obesity workers was higher than that in non-night shift workers and non-overweight/obesity workers [odds ratio (OR) and 95% confidence interval (CI) were 2.49 (1.04-5.99) and 2.65 (1.77-3.95), both P<0.05]. Night shift work and overweight/obesity showed a synergistic effect on blood pressure of workers. Compared to non-overweight/obesity non-night shift workers, overweight/obesity night shift workers had a higher risk of hypertension (OR=4.93, 95%CI: 1.70-14.29, P<0.01). {L-End}Conclusion Night shift work could lead to elevated blood pressure in workers in the chemical fiber industry, which is a potential risk factor for hypertension. The synergistic effect of night shift work and overweight/obesity may contribute to the increased risk of hypertension.

Objective:To explore the change in cerebral blood flow when healthy subjects swallow hot and ice water, and to verify the sensitivity of functional near-infrared spectroscopy (fNIRS) in identifying liquid temperatures while swallowing as a basis for applying it in diagnosis and intervention.Methods:Sixteen healthy subjects swallowed hot and ice water in randomized order while the process was recorded using fNIRS. The activation at rest and when swallowing hot and ice water was compared pairwise.Results:Compared with the resting state, 19 channels were activated during the swallowing of the hot and ice water. The common activated areas were S1, M1, PMC, SMA, Wernicke′s area, the somatosensory association cortex, the visual association cortex and the frontal eye field. However, the dorsal lateral prefrontal cortex was activated only when swallowing hot water, and the subcentral area was activated only when swallowing ice water. The SMA and PMC were significantly more activated when swallowing hot water than ice water.Conclusions:Multiple brain regions are activated and participate in regulating swallowing. The PMC and SMA areas can distinguish hot water from ice water swallowing.

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.

【Objective】 To compare the similarities and differences of polymerized human cord hemoglobin (PolyCHb) and free hemoglobin (FHb) on partial coagulation indexes in vitro, so as to analyze the effect of PolyCHb on coagulation dysfunction. 【Methods】 Using normal saline, two concentrations of FHb and PolyCHb and 36% methemoglobin-containing PolyCHb to mix with fresh whole blood or plasma-rich plasma (PRP) in equal proportions, and incubate at 37°C for 30 minutes to detect prothrombin time (PT), activated partial thromboplastin time (APTT), coagulation factor Ⅱactivity (FⅡ∶C), coagulation factor Ⅴactivity (FⅤ∶C), coagulation factor Ⅷactivity (FⅧ∶C), coagulation factor Ⅸactivity (FⅨ∶C), von Willebrand factor (vWF) and platelet P-selectin (CD62P). 【Results】 1) NaCl group: PT(22.68±1.76) s; APTT(59.58±7.52) s; FⅡ∶C(45.91±3.27) %; FⅤ∶C(30.86±4.43) %; FⅧ∶C(41.32±12.94) %; FⅨ∶C(23.96±5.10) %; vWF (2.14±0.54) mg/L; CD62P(7.44±4.47) %. This group kept as a diluted control. 2) 2% FHb group compared with 7% FHb group: FⅧ∶C (42.16±12.31) %vs (56.64±12.22 ) % (P<0.05). No significant difference was found in other indexes (P>0.05). 3) There is no significant difference between 2% PolyCHb group and 7% PolyCHb group (P>0.05). 4) There is no significant difference between 2% FHb group and 2% PolyCHb group (P>0.05). 5) 7% FHb group compared with 7% PolyCHb group: PT(23.31±1.34)s vs (21.97±1.56)s (P<0.05); APTT(50.12±5.72)s vs (55.43±5.43)s (P<0.05); FⅧ∶C (56.64±12.22) %vs (42.37±13.00)% (P<0.05); vWF (1.41±0.30) mg/L vs (2.25±0.41) mg/L (P< 0.05). No significant difference was found in other indexes (P>0.05). 6) 7% PolyCHb group Compared with Met-PolyCHb group: APTT(55.43±5.43) s vs (46.33±4.86)s (P<0.05); FⅧ∶C (42.37±13) %vs (60.51±10.16) % (P<0.05). No significant difference was found in other indexes (P>0.05). 【Conclusion】 The effect of PolyCHb on coagulation markers is different from FHb. At the concentration of this study, PolyCHb will not cause coagulation disorders. However, if the methemoglobin (MetHb) content is too high, it will activate the intrinsic coagulation pathway.