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.

Abstract Allergic diseases can occur in all systems of the body, covering the whole life cycle, from children to adults and to old age, can be lifelong onset and even fatal in severe cases. Children account for the largest proportion of the victims of allergic disease, Children s allergies start from scratch, ranging from mild to severe, from less to more, from single to multiple systems and systemic performance, so the prevention and treatment of allergic diseases in children is of great importance, which can not only prevent high risk allergic conditions from developing into allergic diseases, but also further block the process of allergy. At present, there is no consensus on the management system of allergic children in kindergartens and primary schools. The "Consensus on Allergy Management and Prevention in Kindergartens and Primary Schools", which includes the organizational structure, system construction and management of allergic children, provides evidence informed recommendations for the long term comprehensive management of allergic children in kindergartens and primary schools, and provides a basis for the establishment of the prevention system for allergic children.

Objective:To investigate the correlation between triglyceride glucose (TyG) index and severe hypertriglyceridemic pancreatitis (HTGP), and to provide assistance for early evaluation and clinical decision-making of HTGP.Methods:From January 2016 to December 2021, the clinical data of 770 patients diagnosed with HTGP at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine were retrospectively collected. According to severity of pancreatitis, the patients were divided into mild acute pancreatitis (MAP), moderate severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) groups, and the differences in TyG index among the 3 groups was compared. According to the quartile range of the TyG index, the patients were divided into TyG Q1, Q2, Q3 and Q4 groups, and the distribution of severity of pancreatitis in each TyG index quartile group was calculated. Kruskal-Wallis H test was used for statistical analysis. Spearman correlation analysis was used to analyze the correlation between TyG index quartile range and the severity of pancreatitis. Linear trend chi-square test was used to analyze the trend of SAP incidence among groups. Binary logistic regression was used to analyze the relationship between TyG index quartile range and the risk of SAP, and the trend test was also conducted. Results:A total of 770 patients with HTGP were included, among them 330 (42.9%), 268 (34.8%) and 172 (22.3%) were MAP, MSAP and SAP, respectively. The TyG indices of MAP, MSAP and SAP group were 11.8(11.3, 12.4), 12.5(11.9, 13.2) and 12.7(12.1, 13.4), respectively, and the differences among the 3 groups were statistically significant ( H=121.77, P<0.001). The TyG index was 12.21 (11.57, 12.94) in the 770 patients. There were 192, 193, 193 and 192 patients enrolled in TyG Q1(TyG index <11.57)、 Q2(TyG index ranged from 11.57 to <12.21)、 Q3(TyG index ranged from 12.21 to <12.94) and Q4(TyG index≥12.94) group, respectively.The correlation test showed that the difference between TyG quartile range and the severity of pancreatitis was statistically significant ( ρ=0.372, P<0.001). The incidence of SAP in TyG Q1, Q2, Q3 and Q4 group was 10.9%(21/192), 14.5%(28/193), 27.5%(53/193) and 36.5%(70/192), respectively. The trend test of SAP incidence among the TyG gruops was statistically significant ( χ2 =44.33, P<0.001). After adjusting for confounding factors, taking the TyG Q1 group as a reference, the OR values of SAP risk (95% confidence interval) of the TyG Q2, Q3 and Q4 groups were 1.250 (0.619 to 2.524), 2.882 (1.506 to 5.514) and 6.660 (3.456 to 12.836), respectively, and the trend test of SAP risk showed a significant difference ( OR=2.508, 95%confidence interval 1.883 to 3.341, P<0.001). Conclusions:There is a correlation between TyG index and severity of pancreatitis in patients with HTGP. As the TyG index increases, the risk of SAP increases in HTGP patients. TyG index may be an early predictor of severe HTGP.

The myelin sheath of the central nervous system(CNS)is a multilayer lipid membrane with oligodendrocyte membrane surrounding the axon.The development of myelin sheath in children follows the corresponding laws of time and space, and this process of myelination is considered to be related to children′s proper behavior and function.The myelin sheath development of CNS in childhood is a multi-step and extremely complex process, and the integrity of myelin sheath plays a crucial role in shaping CNS function.At present, it has been found that many neurological diseases in children, such as multiple sclerosis, transverse myelitis and pediatric optic neuritis are closely related to myelin sheath abnormality.Therefore, this paper reviews the progress of myelin sheath development and related diseases in childhood, so as to provide a basis for clinical diagnosis and treatment of myelin sheath abnormalities.

Humans ; Aripiprazole/therapeutic use* ; Schizophrenia/drug therapy* ; Antipsychotic Agents/therapeutic use* ; Risperidone ; China ; Treatment Outcome

Objective:To conduct a survey on major surgeon′s mental trauma caused by iatrogenic biliary injury (IBI) during laparoscopic cholecystectomy (LC), and explore its influencing factors.Methods:The retrospective cross-sectional survey was conducted. Surgeons who have registered in Chinese College of Surgeons of Chinese Medical Doctor Association and Chinese Surgical Society of Chinese Medical Association were recruited to participate as respondents between December 1, 2018 and January 1, 2019. The survey was conducted by the questionnaires of influencing factors for surgeon′s mental trauma caused by IBI during LC. The questionnaires were distributed to participants via WeChat on the Wenjuanxin platform. Observation indicators: (1) results of questionnaire survey; (2) analysis of influencing factors for severe mental trauma of major surgeons caused by IBI during LC. Measurement data with normal distribution were expressed as Mean± SD, and count data were expressed as absolute numbers or percentages. The chi-square test was used for univariate analysis. Factors with P<0.10 in the univariate analysis were included in multivariate analysis, and Logistic regression model was used for multivariate analysis. Results:(1) Results of questionnaire survey. A total of 606 questionnaires were retrieved. ① Basic information of major surgeons: of the 606 major surgeons, there were 596 males and 10 females, aged (41±7)years, with a range from 18 to 62 years. Of the 606 major surgeons, 59.24%(359/606) came from non-teaching hospitals, and 64.03%(388/606) encounted the most impressive case of IBI during LC when they were in the primary or intermediate professional title. For 76.24%(462/606) of the major surgeons, the first case of IBI during LC was the most impressive case, and 69.80%(423/606) believed that careful operation during LC could avoid IBI. ② Patient information: of the patients with the most impressive IBI during LC in each major surgeon′s memory, there were 400 females and 206 males. The proportion of patients younger than 35 years old, in 35-65 years old and older than 65 years old was 9.57%(58/606), 65.51%(397/606), and 24.92%(151/606), respectively. ③ IBI related information: 57.43%(348/606) of the major surgeons indicated that they could receive help from senior surgeons in time for the occurrence of IBI during LC, and 78.88%(478/606) of the major surgeons invited senior surgeons to participate in the initial repair. For the most impressive case of IBI during LC, 66.83%(405/606) of the primary repair surgeries were performed during LC, 11.06%(67/606) were performed within postoperative 3 days and 22.11%(134/606) were performed after 3 days. The main repair methods included local repair, bile duct to end anastomosis, and bilioenteric anastomosis, accounting for 24.92%(151/606), 30.20%(183/606), 33.17%(201/606), respectively. The proportion of patients requiring partial hepatectomy, with perioperative death, and requiring multiple repair was 2.48%(15/606), 2.15%(13/606), and 9.24%(56/606), respectively. ④ Subsequent processing on major surgeons: after the occurrence of IBI during LC, 64.85%(393/606) of the major surgeons gained the understanding of patients and their families, 35.15%(213/606) of the major surgeons were involved in medical disputes, 15.68%(95/606) of the major surgeons received administrative punishment from the hospital. About the compensation, 14.36%(87/606) of the major surgeons had to pay for the compensation by themselves, and only 6.77%(41/606) of the major surgeons had medical liability insurance. There were 9.24%(56/606) of the major surgeons invloved in violent conflicts during the medical disputes. ⑤ Psychology-related information of major surgeons: of the 606 major surgeons, 544 had mental trauma including 279 with severe mental trauma. After the occurrence of IBI during LC, 82.01%(497/606) of the major surgeons experienced anxiety and/or depression for more than one month; 63.37%(384/606) of the major surgeons expected to avoid LC or showed tension during LC; 44.72%(271/606) of the major surgeons had a physiological response when recalling the case; 36.14%(219/606) of the major surgeons initiated the idea of not being a surgeon; 6.44%(39/606) of the major surgeons asked psychologists for help; and 5.61%(34/606) of the major surgeons had taken psychiatric drugs such as antianxiety and anti-depression drugs for more than one month. (2) Analysis of influencing factors for severe mental trauma of major surgeons caused by IBI during LC. Results of univariate analysis showed that the hospital type of the major surgeons, participation of senior surgeons in the repair, surgical method of the primary repair, IBI requiring repeated repair, medical disputes, administrative punishment from the hospital, compensation paid by the major surgeon, having medical liability insurance, violent conflicts in medical disputes were related factors for severe mental trauma of the major surgeons caused by IBI during LC ( χ2=7.688, 3.932, 19.764, 13.837, 61.488, 24.904, 30.976, 5.344, 26.285, P<0.05) . Results of multivariate analysis showed that the surgical method of the primary repair, IBI requiring repeated repair, medical disputes, administrative punishment from the hospital, compensation paid by the major surgeon, violent conflicts in medical disputes were independent risk factors for severe mental trauma caused by IBI during LC of the major surgeons ( odds ratios=1.203, 2.198, 2.922, 1.830, 2.405, 2.171, 95% confidence interval: 1.033-1.402, 1.143-4.226, 1.944-4.391, 1.083-3.093, 1.076-5.375, 1.002-4.702, P<0.05). Having medical liability insurance was an independent protective factor for severe mental trauma of the major surgeons caused by IBI during LC ( odds ratios=0.336, 95% confidence interval: 0.126-0.896, P<0.05). Conclusions:Most surgeons in China are troubled by IBI during LC, and nearly half of them suffer from severe mental trauma. Surgical method of the primary repair, IBI requiring repeated repair, medical disputes, administartive punishment from the hospital, compensation paid by the major surgeon, and violent conflicts in medical disputes are independent risk factors for severe mental trauma of major surgeons caused by IBI during LC. Having medical liability insurance is an independent protective factor for severe mental trauma of major surgeons caused by IBI during LC.

Objective To reveal pathogenesis and etiology in adrenal incidentaloma. Methods The clinical data of 116 patients with adrenal incidentaloma from January 1, 2015 to January 1, 2017 were retrospectively analyzed. Results In 116 patients with adrenal incidentaloma, 49 cases (42.2％) were male and 67 cases (57.7％) were female; there were 14 cases (12.1％) aged from 20 to 40, 63 cases (54.3％) aged from 40 to 60, and 39 cases (33.6％) > 60 years. Forty-three patients (37.1％) were found by health examination, 26 patients (22.4％) were found because of hypertension, 27 patients (23.3％) were found by CT detection because of other diseases, and 20 cases (17.2％ ) were found because of other reasons. The result of endocrine function examination showed that nonfunctioning adrenal tumor was in 56 cases (48.3％); functional adrenal tumor was in 44 cases (37.9％), among whom primary aldosteronism was in 27 cases, Cushing syndrome was in 10 cases, and pheochromocytoma was in 7 cases;nonfunctioning non- adenoma was in 16 cases (13.8％ ). Conclusions It is frequent that the adrenal incidentaloma is found by health examination. The patients with adrenal incidentaloma should examine the endocrine function and identify the benign or malignant. And if necessary, surgical treatment should be performed.

Objective To determine the age-specific normal ranges of serum prostate-specific antigen (PSA) levels in Dalian,China.Methods Serum samples were collected from 8 453 asymptomatic men who underwent health examinations at the Second Affiliated Hospital of Dalian Medical University.Results The median PSA level was 0.93 μg/L,and the interquartile level was 0.81 μg/L.The 95th percentile level was 3.49 μg/L.The 95th percentile levels according to age group were:20 to ＜30 years,0 to 1.67 μg/L;30 to ＜40 years,0 to 2.01 μg/L;40 to ＜50 years,0 to 2.41 μg/L;50 to ＜60 years,0 to 3.25 μg/L;60 to ＜70 years,0 to 3.92 μg/L;70 to ＜80 years,0 to 5.48 μg/L;and older than 80 years,0 to 9.35 μg/L.The differences between the different age groups were statistically significant (P ＜ 0.01).The serum PSA value was positively correlated with age (r =0.251,P ＜ 0.001).Conclusion There were clear differences in age-specific PSA levels in Dalian,and these were lower than the standard OESTERLING.Screening for prostate cancer according to age-specific PSA reference values may be useful in the early detection of prostate cancer and may also reduce the risk of over-diagnosis.

Aim To synthesize 8-bromo-ethoxy Rhein and investigate its mechanisms and inhibition effect on hepatitis B surface antigen ( HBsAg ) and e antigen ( HBeAg) in HepG2.2.15 cells.Methods 8-bromo-ethoxy Rhein was synthesized based on the chemical structure of Rhein , and its structure was identified by IR,1 H-NMR and 13 C-NMR spectra.MTT assay was used to test the inhibitory effect of 8-bromo-ethoxy Rhein on HepG2.2.15 cells.After the cells treatment by 8-bromo-ethoxy Rhein , the HBsAg and HBeAg in cell supernatant were detected by ELISA .The expres-sion of hepatitis B virus X gene ( HBx) was detected by Western blot .The cell cycles were examined with flow cytometry.The intracellular free calcium concentration was detected by laser scanning confocal microscopy . Results The structure of 8-bromo-ethoxy Rhein was confirmed by IR,1 H-NMR and 13 C-NMR.MTT results showed that synthetic product and Rhein could inhibit the cell proliferation in HepG2.2.15 cells.After trea-ted with 8-bromo-ethoxy Rhein and Rhein for 72 h,the half inhibitory concentration 50%( IC50 ) was 14.29 mg? L-1 and 11.59 mg? L-1 , respectively .Using non-cytotoxic dose of 8-bromo-ethoxy Rhein , the inhibitory effect on HBsAg and HBeAg was gradually enhanced with increasing 8-bromo-ethoxy Rhein concentration . The inhibitory effect of synthetic product on hepatitis B virus was better than that of Rhein .8-bromo-ethoxy Rhein could down-regulate the expression of HBx , in-tracellular calcium ion concentration and block the hepatitis B virus ( HBV ) replication.Flow cytometry results showed 8-bromo-ethoxy Rhein didn′t affect the cell cycle .Conclusions Compare with Rhein , the synthesis of 8-bromo-ethoxy Rhein shows stronger inhi-bition on hepatitis B virus in HepG2.2.15, and its mechanisms may involve down-regulating the expres-sion of HBx and reducing calcium ion concentration .