This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC₅₀ = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Objective:To investigate the independent risk factors for fever after endoscopic radiofrequency ablation (RFA).Methods:From January 2016 to April 2021, 51 patients with early esophageal cancer, who were treated with RFA in the Department of Gastroenterology, Changhai Hospital and whose lesion range exceeded 3/4 of the circumference of esophagus, were included in the case-control study. Patients were divided into fever group ( n=15) and non-fever group ( n=36) according to whether they had fever after operation. The general condition of patients, family history of gastrointestinal tumors, lesion length, lesion range, ablation energy and ablation times were mainly collected for univariate analysis. The variables with P<0.1 were further included in multivariate logistic regression analysis to explore the independent risk factors for fever after RFA. Results:Univariate analysis showed that the lesion length ( t=-3.89, P<0.001), lesion range ( χ2=11.52, P=0.001) and ablation energy ( P=0.001) were significantly different between the two groups. Pearson correlation showed that there was a significant positive correlation between lesion length and lesion circumference ( r=0.71, P<0.001), and the lesion range was determined by the lesion circumference length. Therefore, the two variables of lesion length and ablation energy were finally included in the logistic regression analysis. Logistic regression analysis showed that the risk of fever after RFA was 1.21 times as high as that before when the length of esophageal lesions increased by 1 centimeter (95% CI: 1.01-1.43, P=0.037). The risk of fever after RFA using 12 J ablation energy was 0.43 times as high as that using 10 J ablation energy (95% CI: 0.22-0.85, P=0.015). Conclusion:Lesion length and ablation energy are independent risk factors for fever after esophageal RFA. Patients with long segment early esophageal cancer and using low ablation energy are more likely to have fever after RFA.

Objective:To investigate the long-term survival and safety in patients with muscle-invasive bladder cancer (MIBC) who experienced a noninvasive down-staging (≤pT 1)after transurethral resection of bladder tumor (TURBT) plus systemic chemotherapy and received bladder-sparing treatment. Methods:The records of patients with MIBC who underwent maximal TURBT plus systemic chemotherapy-guided bladder-sparing treatment were reviewed retrospectively from Dec 2013 to Dec 2020. Eventually, 22 patients who achieved noninvasive down-staging underwent conservative management. The total patient cohort contained 10 males and 12 females. A majority of patients had single lesion and stage T2 disease. The median age of the patients was 66 years and the median tumor size was 3.0 cm. All patients underwent maximal TURBT to resect all visible diseases and followed by 3-4 cycles platinum-based systemic chemotherapy. After achieving noninvasive down-staging, 14 patients received concurrent chemoradiotherapy, and the other 8 patients underwent surveillance. Overactive bladder symptom score (OABSS) was used to assess the bladder function after treatment.Results:Twelve patients achieved pT 0 and 10 patients were down-staged to cT a-T 1. At a median follow-up of 36.7 months, 90.9%(20/22) patients retained their bladder function successfully. Among the 14 patients who received concurrent chemoradiotherapy, 4 had grade 3 or 4 adverse events. Among the 8 patients who underwent surveillance, 3 had grade 3 or 4 adverse events after systemic chemotherapy.Nine patients experienced tumor recurrence in the bladder, and 2 patients died of bladder cancer. Seven (31.8%) patients experienced Ⅲ/Ⅳ grade complications. The 5-year recurrence-free survival (RFS) and overall survival (OS) in patients achieved pT0 were 66.7% and 100.0%, respectively. The 5-year RFS and OS in patients achieved cTa-T1 were 40% and 72%, respectively. The OABSS score of 20 patients who retained their bladder successfully was (1.00±1.03). Conclusions:MIBC patients who achieved noninvasive down-staging might be candidates for the bladder-sparing treatment with maximum TURBT followed by systemic chemotherapy.The patients who achieved pT 0 might have better prognosis with functional bladder.

Purpose: Reduced quality of life after cystectomy has made bladder preservation a popular research topic for muscle-invasive bladder cancer (MIBC). Previous research has indicated significant tumor downstaging after neoadjuvant chemotherapy (NAC). However, maximal transurethral resection of bladder tumor (TURBT) was performed before NAC to define the pathology, impacting the real evaluation of NAC. This research aimed to assess real NAC efficacy without interference from TURBT and apply combined modality therapies guided by NAC efficacy. Materials and Methods: Patients with cT2-4aN0M0 MIBC were confirmed by cystoscopic biopsy and imaging. NAC efficacy was assessed by imaging, urine cytology, and cystoscopy with multidisciplinary team discussion. Definite responders (≤ T1) underwent TURBT plus concurrent chemoradiotherapy. Incomplete responders underwent radical cystectomy or partial cystectomy if feasible. The primary endpoint was the bladder preservation rate. Results: Fifty-nine patients were enrolled, and the median age was 63 years. Patients with cT3-4 accounted for 75%. The median number of NAC cycles was three. Definite responders were 52.5%. The complete response (CR) was 10.2%, and 59.3% of patients received bladder-sparing treatments. With a median follow-up of 44.6 months, the 3-year overall survival (OS) was 72.8%. Three-year OS and relapse-free survival were 88.4% and 60.0% in the bladder-sparing group but only 74.3% and 37.5% in the cystectomy group. The evaluations of preserved bladder function were satisfactory. Conclusion After stratifying MIBC patients by NAC efficacy, definite responders achieved a satisfactory bladder-sparing rate, prognosis, and bladder function. The CR rate reflected the real NAC efficacy for MIBC. This therapy is worth verifying through multicenter research.

【Objective】 To investigate the clinical application of self-developed magnetic anchoring device for assisting thoracoscopic pulmonary resection. 【Methods】 Eleven patients underwent thoracoscopic pulmonary assisted with resection magnetic anchoring technique at the Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, from March to May 2019. Their clinical data were retrospectively analyzed. The operation time, blood loss, blood transfusion volume, postoperative hospital stay, and postoperative complications were recorded. 【Results】 There were seven male and four female patients, with the average age of (51.6±13.9) years (range from 22 to 69 years). Three single-port and eight single-utility-port thoracoscopic surgeries were performed. Magnetic instruments provided good surgical field exposure in all operations. Among 11 surgeries, one was converted to thoracotomy and one to three-hole surgery due to enlargement and adhesion of hilar lymph nodes. The operation time was (107.8±63.1) minutes (range of 27-182 minutes). The blood loss was 50 (10-50)mL (range of 5-1 000 mL). No blood transfusion was needed during the operation. The postoperative hospital stay was (5.0±1.8) days (range of 3-9 days). No postoperative complications occurred in all the patients. 【Conclusion】 Magnetic anchor technique can effectively alleviate the "chopstick effect" in thoracoscopic surgery. Magnetic anchor technique is safe and feasible in assisting thoracoscopic pulmonary resection.

Objective To evaluate the clinical value of endoscopic retrograde pancreatic drainage ( ERPD) in patients with pancreatic fistula. Methods Data of 42 patients with pancreatic fistula, who were treated with ERPD at Changhai Hospital and Henan Provincial People's Hospital from June 2013 to September 2018,were collected. The pancreatic fistula curative rate, healing duration of pancreatic fistula, and the incidence of complications were analyzed. Results Among 42 patients with pancreatic fistula,there were 30 males(71. 4％) and 12 females(28. 6％) with mean age of 41. 5±12. 8 years old. Pancreatic duct stents of 37 cases ( 88. 1％) went across the fistula. The overall curative rate was 90. 5％( 38/42 ) . The median healing duration of pancreatic fistula was 32. 0 d (8-183 d). The healing time of pancreatic fistula after injury(19. 0±9. 9 d,t=3. 50,P=0. 002) and of pancreatic fistula after surgery(20. 3±10. 7 d,t=3. 35, P=0. 003) were shorter than that of pancreatic fistula after acute severe pancreatitis (60. 0±48. 6 d). The healing time of pancreatic fistula with pancreatic pseudocysts was longer than that of pancreatic fistula without pancreatic pseudocysts (65. 3±55. 4 d VS 32. 6±23. 6 d, t=2. 21,P=0. 040). There were no significant differences in pancreatic fistula curative rate, pancreatic healing duration and times of ERCP in pancreatic fistula at different position. Postoperative stent-related complications occurred in 2 patients ( 4. 8％) , and 1 patient (2. 4％) developed mild pancreatitis. Conclusion ERPD is an important treating method with good therapeutic effect and low complications for pancreatic fistula.

Objective To evaluate the efficacy and safety of endoscopic submucosal excavation (ESE) and submucosal tunneling endoscopic resection (STER) for gastroesophageal junction (GEJ)submucosal tumors (SMTs) originating from the muscularis propria(MP) layer.Methods Clinical data of sixty-one patients with GEJ SMTs originating from the MP layer who were treated with ESE(ESE group,n=39) or STER(STER group,n=22) between January 2013 and December 2015 in Changhai Hospital were retrospectively analyzed.Outcomes and complications in the two groups were compared.Results Single lesion in 61 patients were all resected by therapeutic endoscopy successfully.Operation time in the STER group was shorter than that of the ESE group(47.27±20.89 min VS 66.56±40.07 min,P＜0.05).There was no significant difference in number of hemostatic clips between the two groups[7.10±5.57 VS 8.00± 1.88,P＞0.05].Hospitalization time of STER group was shorter than that of the ESE group [3.0(1.25) d VS 4.0 (1.00) d,P＜0.05].One patient developed delayed hemorrhage in ESE group,while no other complications occurred in either group.The wound healed in both groups under gastroscopy,and no residual or recurrent tumors were detected during the follow-up period.Conclusion Both STER and ESE can be used for GEJ SMTs originating from the MP layer,but STER is more safe and efficient.

Objective To explore a scientific and reasonable fiscal input mechanism for public hospitals, in order to fully leverage the policy guidance and efficiency of such funding.Methods With literature review, expert consultation and demonstration, a basic subsidy model for public hospitals was established.According to the past operation data of 4 public hospitals in Baoshan district of Shanghai, the study figured out specific subsidy standards.Results The basic subsidy for public hospitals should be determined according to the number of approved beds, the number of outpatients and emergency visits, hospital bed days, surgeries, key services, and the quality and efficiency of work.In Baoshan district, the standard reference value of subsidy for each approved bed, each outpatient and emergency visit, each bed-day, each surgical operation is 42 096 yuan, 27.9 yuan, 104.9 yuan and 244 yuan respectively.The standard value of subsidy is 100 yuan per bed for critically ill inpatients.For patients under clinical pathway management, the subsidy is 300 yuan per case, and for hospital maternal care, it is 150 yuan per person.Conclusions The basic subsidy model for public hospitals has overcome the shortcomings of fiscal input based on hospital scale or hospital workload, and established an incentive mechanism to promote the implementation of key services.These measures can improve the operation mechanism of public hospitals and encourage them to play their role of public welfare as designed.

Objective To investigate the therapeutic value of endoscopic papillectomy (EP) for duodenal papilla lesion.Methods Patients with duodenal papilla lesion treated with EP from June 2007 to December 2015 were enrolled.The clinical characteristics,EP technical features,complications,the treatment,postoperative recurrence were analyzed.Results A total of 43 patients were enrolled.The mean diameter of the lesion was 22.8±1.2 mm.Thirty-two patients (69.8％) received en bloc resection,and 11 (25.6％) received endoscopic piecemeal mucosal resection (EPMR).After the operation,duodenal papilla lesions recurred in 3 patients (7.0％),5 patients (11.6％) had delayed bleeding,4 (9.3％) had postoperative pancreatitis,6 (14.0％) had long-term bile duct stricture.Intraoperative pancreatic stenting (OR =0.000,95％ CI:0.000-) was the independent protective factor for postoperative pancreatitis.Pancreatic duct dilation (OR =13.500,95％ CI:1.400-130.191) was the independent risk factor for postoperative bile duct stenosis.Conclusion EP is minimally invasive with rapid recovery and less cost,and could be recommended for duodenal papilla lesions.