The interest in covalent drugs has resurged in recent decades, spurring the development of numerous specialized computational docking tools to facilitate covalent ligand design and screening. Herein, we present CarsiDock-Cov, a new paradigm distinguishing itself as the first deep learning (DL)-guided approach for covalent docking. CarsiDock-Cov retains the core components of its non-covalent predecessor, leveraging a DL model pretrained on millions of docking complexes to predict protein-ligand distance matrices, along with a dedicated-designed geometric optimization procedure to convert these distances into refined binding poses. Additionally, it incorporates several key enhancements specifically tailored to optimize the protocol for covalent docking applications. Our approach has been extensively validated on multiple public datasets regarding the docking and screening of covalent ligands, and the results indicate that our approach not only achieves comparably improved applicability compared to its non-covalent predecessor, but also exhibits competitive performance against various state-of-the-art covalent docking tools. Collectively, our approach represents a significant advance in covalent docking methodology, offering an automated and efficient solution that shows considerable promise for accelerating covalent drug discovery and design.

Objective:To explore the function and mechanism of transcription factor En1 in esophageal squamous cell carcinoma (ESCC).Methods:The correlations of En1 with prognosis were analyzed using the overall survival data of 9 397 pan-cancer patients and progression-free survival data of 4 349 pan-cancer patients from The Cancer Genome Atlas (TCGA) database. The En1 expression data in 53 and 155 cases of ESCC and their paired adjacent tissues were from Gene Expression Omnibus (GEO) database and National Genomics Data Center-Genome Sequence Archive(NGDC-GSA)database. Lentivirus was used to generate En1 stable knockout cell lines KYSE180 and KYSE450. The proliferation ability of the cells was detected by cell counting kit 8 and clone formation assay. The migration ability of the cells was detected by Transwell assay. The effect of En1 on the proliferation of ESCC was detected by xenograft experiment in BALB/c-nu/nu mice. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of En1, glioma-associated oncogene family zinc finger 1 (GLI1), glioma-associated oncogene family zinc finger 2 (GLI2) and smoothened (SMO).Results:Pan-cancer data from TCGA showed that patients with low En1 expression had longer overall survival and progression-free survival than patients with high En1 expression ( P< 0.001). Data from GEO and GSA databases also showed a high expression level of En1 in ESCC tissues compared with paired tissues ( P＜0.001). Proliferation was inhibited after knockout of En1 in KYSE180 and KYSE450 cells ( P＜0.001). The colony formation numbers decreased. The colony formation numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 138.33±23.07 and 127.00±19.70, respectively, significantly lower than that of the shNC group 340.67±12.06 ( P<0.001). The colony formation numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 65.33±2.52 and 9.00±3.00, respectively, significantly lower than that of the shNC group 139.00±13.00 ( P<0.001). The migration numbers was inhibited after knockout of En1 [the Transwell numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 66.67±12.66 and 71.33±11.02, respectively, significantly lower than that of the shNC group 334.67±16.56 ( P<0.001). The Transwell numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 112.33±14.57 and 54.33±5.51, respectively, significantly lower than that of the shNC group 253.33±21.03 ( P<0.001)]. Xenograft model showed a slower growth rate of shEn1#1 and shEn1#2 cell lines ( P＜0.001). The tumor weights of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were (0.046±0.026)g and (0.047±0.025)g, respectively, significantly lower than that of the shNC group (0.130±0.038)g ( P＜0.001). After knockdown of En1, the relative expression levels of GLI1 in KYSE180 cells of the shEn1#1 group and the shEn1#2 group were 0.326±0.162 and 0.322±0.133, and the relative expression levels of GLI1 in KYSE450 cells of the shEn1#1 and shEn1#2 groups were 0.131±0.006 and 0.352±0.050, respectively, which were all lower than that in the shNC group ( P＜0.01). After knockdown of En1, overexpression of GLI1 attenuated the inhibitory effect of knockdown of En1 on cell proliferation ( P＜0.001), colony formation[the colony formation numbers of the shEn1#1-GLI1 group were 151.00±9.54, higher than 102.33±10.02 ( P=0.004) of the shEn1#1-vector group] and migration [the migration numbers of the shEn1#1-GLI1 group were 193.67±10.07, higher than 109.33±11.50 ( P<0.001) in the shEn1#1-vector group]. In clinical samples of ESCC, major regulatory factors of the Hedgehog pathway were up-regulated and the pathway was activated. Conclusion:En1 promotes the proliferation and migration of ESCC cells by regulating the Hedgehog pathway and can be used as a new potential target for targeted therapy of ESCC.

Objective:To explore the clinical efficacy of endoscopic sleeve gastrectomy (ESG) in the treatment of obesity.Method:A 26 year old female patient was admitted on October 20, 2022 due to a progressive increase in weight for 2 years. Her body mass index (BMI) was 30.04 kg/m 2, body fat percentage was 39.2%, and visceral fat grade was 15. ESG was performed using the OverStitch SX endoscopic suture system. Result:The surgery was successful, with approximately 5 ml of intraoperative bleeding.The patient discharged on the first day after surgery. Two weeks after surgery, small bowel follow-through showed a tubular shape of the stomach. At 6 months after surgery, the BMI was 25.2 kg/m 2, body fat percentage was 32%, visceral fat grade was 10. The total body weight loss rate (%TBWL) at 6 months after surgery was 16%, and the excess weight loss rate (%EWL) was 54.5%. Conclusion:ESG is effective for the treatment of obesity.

Objective:To explore the function and mechanism of transcription factor En1 in esophageal squamous cell carcinoma (ESCC).Methods:The correlations of En1 with prognosis were analyzed using the overall survival data of 9 397 pan-cancer patients and progression-free survival data of 4 349 pan-cancer patients from The Cancer Genome Atlas (TCGA) database. The En1 expression data in 53 and 155 cases of ESCC and their paired adjacent tissues were from Gene Expression Omnibus (GEO) database and National Genomics Data Center-Genome Sequence Archive(NGDC-GSA)database. Lentivirus was used to generate En1 stable knockout cell lines KYSE180 and KYSE450. The proliferation ability of the cells was detected by cell counting kit 8 and clone formation assay. The migration ability of the cells was detected by Transwell assay. The effect of En1 on the proliferation of ESCC was detected by xenograft experiment in BALB/c-nu/nu mice. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of En1, glioma-associated oncogene family zinc finger 1 (GLI1), glioma-associated oncogene family zinc finger 2 (GLI2) and smoothened (SMO).Results:Pan-cancer data from TCGA showed that patients with low En1 expression had longer overall survival and progression-free survival than patients with high En1 expression ( P< 0.001). Data from GEO and GSA databases also showed a high expression level of En1 in ESCC tissues compared with paired tissues ( P＜0.001). Proliferation was inhibited after knockout of En1 in KYSE180 and KYSE450 cells ( P＜0.001). The colony formation numbers decreased. The colony formation numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 138.33±23.07 and 127.00±19.70, respectively, significantly lower than that of the shNC group 340.67±12.06 ( P<0.001). The colony formation numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 65.33±2.52 and 9.00±3.00, respectively, significantly lower than that of the shNC group 139.00±13.00 ( P<0.001). The migration numbers was inhibited after knockout of En1 [the Transwell numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 66.67±12.66 and 71.33±11.02, respectively, significantly lower than that of the shNC group 334.67±16.56 ( P<0.001). The Transwell numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 112.33±14.57 and 54.33±5.51, respectively, significantly lower than that of the shNC group 253.33±21.03 ( P<0.001)]. Xenograft model showed a slower growth rate of shEn1#1 and shEn1#2 cell lines ( P＜0.001). The tumor weights of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were (0.046±0.026)g and (0.047±0.025)g, respectively, significantly lower than that of the shNC group (0.130±0.038)g ( P＜0.001). After knockdown of En1, the relative expression levels of GLI1 in KYSE180 cells of the shEn1#1 group and the shEn1#2 group were 0.326±0.162 and 0.322±0.133, and the relative expression levels of GLI1 in KYSE450 cells of the shEn1#1 and shEn1#2 groups were 0.131±0.006 and 0.352±0.050, respectively, which were all lower than that in the shNC group ( P＜0.01). After knockdown of En1, overexpression of GLI1 attenuated the inhibitory effect of knockdown of En1 on cell proliferation ( P＜0.001), colony formation[the colony formation numbers of the shEn1#1-GLI1 group were 151.00±9.54, higher than 102.33±10.02 ( P=0.004) of the shEn1#1-vector group] and migration [the migration numbers of the shEn1#1-GLI1 group were 193.67±10.07, higher than 109.33±11.50 ( P<0.001) in the shEn1#1-vector group]. In clinical samples of ESCC, major regulatory factors of the Hedgehog pathway were up-regulated and the pathway was activated. Conclusion:En1 promotes the proliferation and migration of ESCC cells by regulating the Hedgehog pathway and can be used as a new potential target for targeted therapy of ESCC.

Objective:To construct a nomogram model for predicting frailty in elderly hypertensive patients, and to evaluate the discrimination and consistency of the model.Methods:A total of 317 patients with essential hypertension who were admitted to Hebei Eighth People′s Hospital from February 2021 to June 2022 were taken, they were divided into modeling group (190 cases) and verification group (127 cases) according to the proportion of 6∶4, the patients in the modeling group were divided into the asthenic group (45 cases) and the non asthenic group (145 cases) according to whether the patients in the modeling group had asthenia. The nomograph model was constructed based on the results of Logistic analysis.Results:The age, obesity or overweight ratio, diabetes ratio and systolic blood pressure in the frail group were significantly higher than those in the non-frail group: (76.25 ± 3.64)years vs.(70.44 ± 3.82) years, 51.11%(23/45) vs. 24.83%(36/145), 46.67%(21/45) vs. 17.24%(25/145), (156.46 ± 18.64) mmHg (1 mmHg = 0.133 kPa) vs. (143.25 ± 12.38) mmHg, and the mini-nutrition assessment summary form (MNA-SF) score was significantly lower than that in the non-frail group: (11.45 ± 2.06) scores vs. (13.12 ± 1.22) scores, there were statistical differences ( P<0.05). Logistic results showed that age, body mass index, diabetes, and systolic blood pressure were the risk factors for frailty ( P<0.05). The receiver operating characteristic (ROC) curve evaluation showed that the area under the curve (AUC) in the modeling group was 0.998, and AUC in the validation group was 0.954. The Hosmer-Lemeshow goodness of fit test showed: modeling group χ2 = 6.18, P = 0.627; validation group χ2 = 6.58, P = 0.582. Conclusions:The nomogram prediction model of frailty risk in elderly hypertensive patients has good consistency and differentiation

Objective To explore the effect of pregabalin on sleep of patients after video-assisted thoracic surgery(VATS).Methods 120 cases of patients undergoing VATS under general anesthesia were randomly divided into 75 mg pregabalin group(group A),150 mg pregabalin group(group B),and placebo group(group C),with 40 patients in each group.On the night of the operation,the morning and evening of the first day and the second day after the operation,the patients in the three groups were given one tablet of pregabalin(75 mg),one tablet of placebo with the same shape and smell,two tablets of pregabalin(150 mg)and two tablets of placebo with the same shape and smell respectively.Athens insomnia scale(AIS)was used to evaluate the incidence of postoperative sleep disturbance(PSD)on the night of operation,and the patients'sleep quality every night from one night before operation to the 2nd day after operation was assessed using the St.Mary's Hospital sleep questionaire(SMH).Pittsburgh sleep quality index(PSQI)was used to evaluate the patients'sleep quality one day before the operation,7 days after operation,and 1 month after the operation.The digital rating scale(NRS)was used to evaluate the patients'pain at the incision and the surgical side.The remedial analgesia,incidence of adverse events in the 72 h postoperative period,and patient satisfaction score were recorded.Results The incidence of PSD in group A,group B and group C was 45.0％,42.5％and 72.5％,respectively,the incidence of group A and group B was significantly lower than in group C(group A,B and C compared in pairs,P＜0.016 7).The SMH scores in group A and group B were significantly higher than in group C on the day of operation,the first day and the second day after operation(group A,B and C compared in pairs,P＜0.016 7).The incidence of NRS scores in groups A and B at the incision and postoperative remedial analgesia was significantly lower than in group C on postoperative day 1 and postoperative day 2(group A,B and C compared in pairs,P＜0.016 7).There was no statistically significant difference in the pain scores at the incision and shoulder among the three groups at the remaining time points.The postoperative patient satisfaction scores were significantly higher in group A and group B than in group C(P＜0.01).The incidence of dizziness in group B was significantly higher than in the other two groups(P＜0.016 7).Conclusion Oral administration of pregabalin(75 mg/150 mg)for 3 days after VATS can reduce the incidence of PSD and improve the quality of sleep that night,but oral administration of 150 mg pregabalin may increase the incidence of dizziness.

Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Objective To provide some evidence for early empirical treatment of infections caused by Pseudanonas aeruginosa(PA)and establish a certain foundation for further studies on its resistance mechanisms.Analyzed the resistance rate of PA and the phenotype characteristics for seven years at this hospital.Methods Using Whonet 5.6 software,the drug sensitivity data of PA isolated and reported from clinical specimens at Kunming First People's Hospital from 2016 to 2022 were analyzed annually.Imipenem,meropenem,ceftazidime,and cefepime were the main observation objects,statisticaly analyze the resistance of other antibiotics under different drug resistance combinations of the above-mentioned drugs Results A total of 1 920 strains of PA were detected in 7 years,with polymyxins exhibiting the lowest resistance rate at 1%.The average resistance rates for Amikacin,Gentamicin and Tobramycin were 6.4%,8.6%and 5.1%,respectively.The resistance rates of Quinolones,Piperacillin/Tazobactam,Ceftazidime,and Cefepime were similar,ranging from 10%～20%.Imipenem and Meropenem did not show better sensitivity,with resistance rates of 21.3%and 18.4%,respectively.The resistance rates of major antibiotics have fluctuated over the past 7 years,mostly increasing from 2017 to reaching a peak in 2018 and then falling back.And then stabilized with the domestic average level.1 393 strains were sensitive to Imipenem,and the sensitivity rate of Meropenem in this part was 96.2%.1 451 strains were sensitive to Imipenem,and 89%of them were sensitive to Meropenem at the same time.369 strains were both resistant to Imipenem and Meropenem,and 33.1%of them were sensitive to Ceftazidime.The more resistant to β-lactam,the lower the sensitivity rate to Amikacin and Ciprofloxacin.Conclusion The overall drug sensitivity of PA in this hospital is relatively good.Should adhere to strict management of antibiotic use.Aminoglycosides can be the preferred drugs for empirical treatment,followed by Quinolones,and Carbapenems and Ceftazidime are also candidates.PA has diverse resistance mechanisms to β-lactam antimicrobials,and carbapenem-resistant strains can be mediated by different mechanisms or jointly.

Objective To investigate the expression level of serum ubiquitin-conjugating enzyme 2C(UBE2C)and tripartite motif-containing protein 27(TRIM27)in patients with endometrial cancer(EC)and their correlation with pathological parameters.Methods A total of 96 EC patients from March 2020 to March 2023 were selected as EC group;65 patients with endometrial atypical hyperplasia(EAH)as EAH group,and 80 healthy subjects as the control group.Enzyme linked immunosorbent assay was applied to analyze the expression level of serum UBE2C and TRIM27.The relationship between serum UBE2C,TRIM27,and pathological data was analyzed;receiver operating characteristic was applied to evaluate the predictive value of serum UBE2C and TRIM27 level for EC.Results The level of serum UBE2C and TRIM27 of EC patients was obviously higher than that in healthy subjects(P<0.05),and was correlated with tumor diameter,tumor differentiation,lymph node metastasis,FIGO stage,muscle layer invasion depth,cervical involvement,estrogen receptor expression,and progestogen receptor expression(P<0.05).There was positive correlation between serum UBE2C and TRIM27(r=0.475,P<0.001);and the level of serum UBE2C and TRIM27 was positively correlated with tumor diameter,lymph node metastasis,FIGO stage,and depth of musclular invasion,but negatively with tumor differentiation,estrogen receptor expression,and progestogen receptor expression(P<0.05).The combination of UBE2C and TRIM27 had obviously higher AUC in evaluating EC than single detection(ZUBE2C-combination=3.406,P<0.001,ZTRIM27-combination=3.285,P=0.001).Conclusion The expression level of UBE2C and TRIM27 in serum of EC patients is up-regulated,which is closely related to pathological parameters.The level of serum UBE2C and TRIM27 can provide reference for early diagnosis of EC.

Objective To investigate the predictive value of lactic acid to albumin ratio in the in-hospital mortality of the patients with intra-abdominal infection sepsis in ICU.Methods The clinical data in 175 pa-tients with sepsis caused by intra-abdominal infection admitted and treated in the intensive care medicine de-partment of this hospital from January 2018 to December 2021 were retrospectively analyzed.The patients were divided into the survival group (n=94) and death group (n=81) according to whether or not having in-hospital death.The general data,blood lactic acid and albumin levels of the patients at admission were collect-ed,and the LAR value was calculated.The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of LAR for the in-hospital mortality of sepsis patients in ICU.The Cox regression analysis and Kaplan-Meier curves were used to analyze the independent correlation between LAR and ICU mortality. Results There were statistically significant differences in the acute physiology and chronic health scoring sys-tem Ⅱ (APACHⅡ) score,sequential organ failure assessment (SOFA) score,mean arterial pressure,oxygen-ation index,PCT,lactic acid,albumin,LAR and the proportion of surgical patients between the two groups (P<0.05).The area under the curve (AUC) of LAR for predicting the prognosis in the patients with ICU sepsis was 0.765 (95％CI:0.695-0.835),which was higher than that of the APACHEⅡscore,SOFA score,lactic acid and PCT.With LAR=1.295 as the cutoff value,the sensitivity and specificity for its prediction were 0.679 and 0.707,respectively.The Kaplan-Meier curve showed that the ICU motality rate in high LAR (LAR≥1.29) was higher than that in low LAR,and the difference was statistically significant(63.2％ vs. 41.5％,P<0.05).The Cox regression analysis results showed that the mortality in sepsis showed the increas-ing trend with the LAR level increase (P<0.05).Conclusion LAR is an influencing factor of the death in the intra-abdominal infection sepsis in ICU,which could effectively predict the risk of in-hospital death of the patients.