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.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Objective To investigate the clinical features of chronic hepatitis C(CHC)patients with hepatitis C virus genotype 3(HCV GT3)infection and the risk factors for disease progression.Methods A multicenter retrospective cohort study was conducted among 1 002 CHC patients from 11 clinical centers in Northwest China from December 2017 to November 2023,and according to their genotype,they were divided into GT1,GT2,GT3,and GT6 groups.Clinical features were compared between the patients with different genotypes.The one-way analysis of variance was used for comparison of normally distributed continuous data between groups,and the Scheffe test was used for further comparison between two groups.The Kruskal-Wallis H test was used for comparison of data with skewed distribution between groups;the chi-square test or Fisher test was used for comparison of categorical data between groups.The multivariate logistic regression analysis was used to explore the influencing factors for the progression of CHC to liver cirrhosis.Results In terms of the genotype,there were 427 patients with GT1 infection,242 with GT2 infection,299 with GT3 infection(210 patients with GT3a infection,87 with GT3b infection,and 2 with unclassified genotype),and 34 with GT6 infection.The patients with GT3 infection had a significantly younger age than those with GT1 infection(51.3±0.5 years vs 53.2±0.6 years,P<0.05)or GT2 infection(51.3±0.5 years vs 53.7±0.8 years,P<0.05),and for the patients with liver cirrhosis,the patients with GT3 infection had a significantly younger age than those with GT1 infection(52.1±0.5 years vs 59.4±0.9 years,P<0.001)or GT2 infection(52.1±0.5 years vs 58.1±1.1 years,P<0.001).Among the patients with GT3 infection,male patients accounted for 77.9%and the patients with liver cirrhosis accounted for 46.2%,which were significantly higher than those among the patients with GT1,GT2 or GT6 infection(all P<0.001).At baseline,the patients with GT3 infection had significantly higher levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)than those with GT1 or GT2 infection,significantly higher aspartate aminotransferase-to-platelet ratio index(APRI)and fibrosis-4(FIB4)than those with GT1,GT2 or GT6 infection,a significantly lower platelet count(PLT)than those with GT2 or GT6 infection,a significantly higher level of alpha-fetoprotein than those with GT2 or GT6 infection,and a significantly lower level of albumin(Alb)than those with GT6 infection(all P<0.05).There were no significant differences between the patients with GT3a infection and those with GT3b infection in age,sex,the proportion of patients with liver cirrhosis,comorbidities,HCV RNA quantification,PLT,ALT,AST,alkaline phosphatase,Alb,APRI,and FIB-4(all P>0.05).The multivariate logistic regression analysis showed that PLT≤150×109/L(odds ratio[OR]=10.72,95%confidence interval[CI]:5.76-35.86,P<0.001)and Alb≤35 g/L(OR=3.74,95%CI:1.22-11.45,P=0.021)were risk factors for liver cirrhosis.Conclusion Most CHC patients with GT3 infection are male in Northwest China,and compared with the patients with other genotypes,such patients tend to have a younger age of onset and higher degrees of liver inflammation activity and fibrosis.Low PLT and a low level of Alb are risk factors for progression to liver cirrhosis in CHC patients with GT3 infection.

Aim To investigate the effect of Panax no-toginseng saponins(PNS)on the interaction between endometrial cancer cells and macrophages by regulating the epidermal growth factor receptor(EGFR)/heat shock protein 27(HSP27)axis.Methods Ishikawa cells were divided into Control,DDP,PNS-treated,M2-CM,M2-CM+DDP,M2-CM+PNS,M2-CM+PNS+oe-NC,M2-CM+PNS+oe-EGFR,PNS(200 mg·L-1)+oe-NC,PNS(200 mg·L-1)+oe-EG-FR,oe-NC,oe-EGFR,oe-EGFR+si-NC,and oe-EG-FR+si-HSP27 groups.MTT assay was used to detect cell proliferation,Transwell assay for cell invasion,TUNEL assay for cell apoptosis,qRT-PCR for macro-phage polarization markers CD86 and CD163 mRNA levels,ELISA for iNOS and IL-12 levels,and West-ern-blot for EGFR and HSP27 protein expression.A nude mouse xenograft tumor model was established and treated with PNS to evaluate the effect of PNS in vivo.Results Compared with the Control group,PNS and DDP significantly inhibited the proliferation and inva-sion of Ishikawa cells and induced apoptosis.M2-CM treatment inhibited M1 macrophage markers,promoted M2 macrophage markers,and induced Ishikawa cell growth,but this effect was reversed by PNS treatment.EGFR was confirmed as a target of PNS,and compared with the M2-CM+PNS+oe-NC group,EGFR overex-pression promoted M2 macrophage marker levels,in-duced Ishikawa cell proliferation and invasion,and in-hibited apoptosis.Knockdown of HSP27 reversed the effect of EGFR overexpression on the biological behav-ior of Ishikawa cells.Animal experiments showed that PNS could inhibit tumor growth and reduce the positive expression of CD163,EGFR,and HSP27 in tumor tis-sues.Conclusion PNS affects the interaction be-tween macrophages and EC cells by regulating the EG-FR/HSP27 axis,thereby participating in EC progres-sion.

Objective:To investigate the effects of two anastomosis methods on perioperative and pathological outcomes during totally laparoscopic right hemicolectomy (TLRH).Methods:In a national multicenter snapshot study, 1,854 patients who underwent laparoscopic right hemicolectomy were enrolled from 52 tertiary hospitals across China. The post-hoc analysis based on this study compared the data of 303 patients who underwent TLRH. Patients were divided into the antiperistaltic group (33 cases) and the isoperistaltic group (270 cases) according to type of anastomosis. Due to the significant difference in sample size between the two groups, propensity score matching (PSM) was performed to eliminate the influence of baseline characteristic discrepancies. The matching was based on the following known confounding factors: age, gender, body mass index (BMI), history of abdominal surgery, and history of diabetes, with a caliper value of 0.2. Perioperative and pathological outcomes were compared between the two groups.Results:After PSM, 33 patients were included in the antiperistaltic group and 65 patients in the isoperistaltic group. There were no statistically significant differences in baseline data between the two groups (all P>0.05). No significant differences were observed between the two groups in terms of operation time, blood loss, time to first defecation, time to first oral intake, or the incidence and grading of complications either (all P>0.05). However, length of postoperative hospital stay in the isoperistaltic group was significantly shorter than that in the antiperistaltic group, however (7.0 [6.0, 9.0] days vs. 8.0 [7.0, 10.5] days, P=0.049). In terms of pathological outcomes, there were also no statistically significant differences between the two groups in the number of harvested lymph nodes or the number of positive lymph nodes (all P>0.05). Conclusions:The two digestive tract reconstruction modalities, antiperistaltic and isoperistaltic anastomosis, have comparable perioperative safety and efficacy in TLRH. The isoperistaltic group had better outcomes in terms of postoperative hospital stay.

Objective To investigate the clinical features of chronic hepatitis C(CHC)patients with hepatitis C virus genotype 3(HCV GT3)infection and the risk factors for disease progression.Methods A multicenter retrospective cohort study was conducted among 1 002 CHC patients from 11 clinical centers in Northwest China from December 2017 to November 2023,and according to their genotype,they were divided into GT1,GT2,GT3,and GT6 groups.Clinical features were compared between the patients with different genotypes.The one-way analysis of variance was used for comparison of normally distributed continuous data between groups,and the Scheffe test was used for further comparison between two groups.The Kruskal-Wallis H test was used for comparison of data with skewed distribution between groups;the chi-square test or Fisher test was used for comparison of categorical data between groups.The multivariate logistic regression analysis was used to explore the influencing factors for the progression of CHC to liver cirrhosis.Results In terms of the genotype,there were 427 patients with GT1 infection,242 with GT2 infection,299 with GT3 infection(210 patients with GT3a infection,87 with GT3b infection,and 2 with unclassified genotype),and 34 with GT6 infection.The patients with GT3 infection had a significantly younger age than those with GT1 infection(51.3±0.5 years vs 53.2±0.6 years,P<0.05)or GT2 infection(51.3±0.5 years vs 53.7±0.8 years,P<0.05),and for the patients with liver cirrhosis,the patients with GT3 infection had a significantly younger age than those with GT1 infection(52.1±0.5 years vs 59.4±0.9 years,P<0.001)or GT2 infection(52.1±0.5 years vs 58.1±1.1 years,P<0.001).Among the patients with GT3 infection,male patients accounted for 77.9%and the patients with liver cirrhosis accounted for 46.2%,which were significantly higher than those among the patients with GT1,GT2 or GT6 infection(all P<0.001).At baseline,the patients with GT3 infection had significantly higher levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)than those with GT1 or GT2 infection,significantly higher aspartate aminotransferase-to-platelet ratio index(APRI)and fibrosis-4(FIB4)than those with GT1,GT2 or GT6 infection,a significantly lower platelet count(PLT)than those with GT2 or GT6 infection,a significantly higher level of alpha-fetoprotein than those with GT2 or GT6 infection,and a significantly lower level of albumin(Alb)than those with GT6 infection(all P<0.05).There were no significant differences between the patients with GT3a infection and those with GT3b infection in age,sex,the proportion of patients with liver cirrhosis,comorbidities,HCV RNA quantification,PLT,ALT,AST,alkaline phosphatase,Alb,APRI,and FIB-4(all P>0.05).The multivariate logistic regression analysis showed that PLT≤150×109/L(odds ratio[OR]=10.72,95%confidence interval[CI]:5.76-35.86,P<0.001)and Alb≤35 g/L(OR=3.74,95%CI:1.22-11.45,P=0.021)were risk factors for liver cirrhosis.Conclusion Most CHC patients with GT3 infection are male in Northwest China,and compared with the patients with other genotypes,such patients tend to have a younger age of onset and higher degrees of liver inflammation activity and fibrosis.Low PLT and a low level of Alb are risk factors for progression to liver cirrhosis in CHC patients with GT3 infection.

Aim To investigate the effect of Panax no-toginseng saponins(PNS)on the interaction between endometrial cancer cells and macrophages by regulating the epidermal growth factor receptor(EGFR)/heat shock protein 27(HSP27)axis.Methods Ishikawa cells were divided into Control,DDP,PNS-treated,M2-CM,M2-CM+DDP,M2-CM+PNS,M2-CM+PNS+oe-NC,M2-CM+PNS+oe-EGFR,PNS(200 mg·L-1)+oe-NC,PNS(200 mg·L-1)+oe-EG-FR,oe-NC,oe-EGFR,oe-EGFR+si-NC,and oe-EG-FR+si-HSP27 groups.MTT assay was used to detect cell proliferation,Transwell assay for cell invasion,TUNEL assay for cell apoptosis,qRT-PCR for macro-phage polarization markers CD86 and CD163 mRNA levels,ELISA for iNOS and IL-12 levels,and West-ern-blot for EGFR and HSP27 protein expression.A nude mouse xenograft tumor model was established and treated with PNS to evaluate the effect of PNS in vivo.Results Compared with the Control group,PNS and DDP significantly inhibited the proliferation and inva-sion of Ishikawa cells and induced apoptosis.M2-CM treatment inhibited M1 macrophage markers,promoted M2 macrophage markers,and induced Ishikawa cell growth,but this effect was reversed by PNS treatment.EGFR was confirmed as a target of PNS,and compared with the M2-CM+PNS+oe-NC group,EGFR overex-pression promoted M2 macrophage marker levels,in-duced Ishikawa cell proliferation and invasion,and in-hibited apoptosis.Knockdown of HSP27 reversed the effect of EGFR overexpression on the biological behav-ior of Ishikawa cells.Animal experiments showed that PNS could inhibit tumor growth and reduce the positive expression of CD163,EGFR,and HSP27 in tumor tis-sues.Conclusion PNS affects the interaction be-tween macrophages and EC cells by regulating the EG-FR/HSP27 axis,thereby participating in EC progres-sion.

Objective:To investigate the effects of two anastomosis methods on perioperative and pathological outcomes during totally laparoscopic right hemicolectomy (TLRH).Methods:In a national multicenter snapshot study, 1,854 patients who underwent laparoscopic right hemicolectomy were enrolled from 52 tertiary hospitals across China. The post-hoc analysis based on this study compared the data of 303 patients who underwent TLRH. Patients were divided into the antiperistaltic group (33 cases) and the isoperistaltic group (270 cases) according to type of anastomosis. Due to the significant difference in sample size between the two groups, propensity score matching (PSM) was performed to eliminate the influence of baseline characteristic discrepancies. The matching was based on the following known confounding factors: age, gender, body mass index (BMI), history of abdominal surgery, and history of diabetes, with a caliper value of 0.2. Perioperative and pathological outcomes were compared between the two groups.Results:After PSM, 33 patients were included in the antiperistaltic group and 65 patients in the isoperistaltic group. There were no statistically significant differences in baseline data between the two groups (all P>0.05). No significant differences were observed between the two groups in terms of operation time, blood loss, time to first defecation, time to first oral intake, or the incidence and grading of complications either (all P>0.05). However, length of postoperative hospital stay in the isoperistaltic group was significantly shorter than that in the antiperistaltic group, however (7.0 [6.0, 9.0] days vs. 8.0 [7.0, 10.5] days, P=0.049). In terms of pathological outcomes, there were also no statistically significant differences between the two groups in the number of harvested lymph nodes or the number of positive lymph nodes (all P>0.05). Conclusions:The two digestive tract reconstruction modalities, antiperistaltic and isoperistaltic anastomosis, have comparable perioperative safety and efficacy in TLRH. The isoperistaltic group had better outcomes in terms of postoperative hospital stay.

Objective To investigate the ameliorative effect of sulforaphane on inflammatory response and airway remodeling in rats with chronic obstructive pulmonary disease(COPD).Methods Seventy-five SD rats were randomly divided into the normal group,the model group,and the low-,medium-,and high-dose groups of sulforaphane,with 15 rats in each group.Except for the normal group,the COPD model was prepared in the remaining group using aroma smoke inhalation combined with intratracheal droplet lipopolysaccharide(LPS)method.After the successful modelling,the rats were administered the drug by gavage for 28 days.At the end of the administration,the general conditions of the rats in each group were observed,and the lung function[forced vital capacity(FVC),peak expiratory flow-rate(PEF),forceful expiratory volume in 1 second(FEV1)]was examined,and the pathological changes of the lung tissues were observed by hematoxylin-eosin(HE)staining method,and the indexes of airway remodeling(thickness of the bronchial wall,thickness of the smooth muscle)were measured;the enzyme-linked immunosorbent assay(ELISA)was used to examine the lung function of the rats.The levels of inflammatory factors[tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β)]were detected in lung tissue by enzyme-linked immunosorbent assay(ELISA),and changes in the protein expressions of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear transcription factor κB(NF-κB)were detected in lung tissue by Western Blot.Results(1)The rats in the model group had dry and lack of glossy fur,obvious coughing and nose scratching,shortness of breath,slow movement,and preferred to arch their backs and lie curled up;the rats in the low-,medium-and high-dose groups of sulforaphane showed significant improvement in shortness of breath,coughing,and other abnormal manifestations.(2)HE staining showed that the airway wall and smooth muscle of rats in the model group were thickened,the airway epithelium was damaged,and alveolar destruction,fusion,and massive infiltration of inflammatory cells were seen;the histopathological changes in the lungs of rats in the low-,medium-and high-dose groups of sulforaphane improved to varying degrees,with the airway wall becoming thinner,the degree of alveolar destruction being reduced,and the infiltration of inflammatory cells being reduced.(3)Compared with the normal group,FVC,PEF and FEV1 were significantly reduced in the model group(P＜0.05),and the levels of TNF-α and IL-1β,bronchial wall thickness,smooth muscle thickness,and the expression levels of TLR4,MyD88 and NF-κB were significantly increased in the model group(P＜0.05);and in comparison with the model group,the levels of FVC,PEF,and FEV1 were significantly increased in the rats in the sulforaphane low-,medium-,and high-dose groups(P＜0.05),and the levels of TNF-α,IL-1β,bronchial wall thickness,smooth muscle thickness,and the expression levels of TLR4,MyD88,and NF-κB were significantly decreased(P＜0.05)compared with the model group.Conclusion Sulforaphane helps to inhibit the inflammatory response,attenuate airway remodeling,and improve the pathological injury and lung function of lung tissue in rats with COPD,and its mechanism may be related to the inhibition of TLR4,MyD88,and NF-κB protein expressions.

Objective Reliability and validity of the Chinese version of disability attitude scales(DAS-CN)toward disabled persons were created and tested to provide an assessment instrument for measuring the attitude of medical staff toward disabled persons in China.Methods Authorised by the author of DAS in August 2020,based on BRISLIN translation model,the English version of DAS was translated into Chinese followed by back translation,cultural debugging and then put it into pre-experiment in September 2020.The reliability and validity of the finalised DAS-CN were further tested in a survey with 400 randomly selected medical staff in rehabilitation from 8 general hospitals in Jinzhou,Panjin,Yingkou and Fushun in Liaoning Province,China by using the convenience sampling method in March 2021.Results A total of 357 surveyees completed the survey.The localised DSA-CN was composed of 4 dimensions with a total of 20 items,including 4 items in clinical knowledge and skills,4 in clinical responsibility,8 in clinical behaviour and 4 in emotional response.The Cronbach α coefficient of the scales was 0.943,with the split-half reliability and test-retest reliability at 0.824 and 0.899,respectively.The Cronbach α coefficient of each dimension was 0.843～0.944,and the split half reliability was 0.854～0.904.The test-retest reliability ranged from 0.701 to 0.913.The KMO value of exploratory factor analysis was 0.921.The Bartrett spherical test value was 5534.981(P<0.01).The total explanatory rate of variation was 73.050%.Conclusion The Chinese version of Disability Attitude Scales(DSA-CN)has good reliability and validity.Therefore,DSA-CN can be used as an instrument in investigation of the current status about the attitudes towards the disabled persons among the medical staff in China.