Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.

Objective:To investigate the expression of coxsackievirus-adenovirus receptor (CAR) in thymic carcinoma and the relationship between CAR and the antitumor activity of oncolytic adenovirus H101.Methods:The expression of CAR in thymic carcinoma tissues and cells were detected by RT-qPCR and Western blot. H101 expression and virus titers in Bcap-37, MP59 and T1889 cells after infection were detected by RT-qPCR and 50% tissue culture infectious dose (TCID 50). The proliferation activity and apoptosis rates of T1889 cells infected with H101 at different multiplicity of infection (MOI) were detected by CCK-8 and flow cytometry. CAR expression in T1889 cells treated with different concentrations of trichostatin A (TSA), a histone deacetylase inhibitor, was detected. H101 expression and virus titers in the TSA-treated and H101-infected cells were detected. Cell activity was detected by CCK-8. The phosphorylation levels of MARK and ERK1/2 and the expression of CAR at protein level in TSA-treated or TSA+ TBHQ (ERK activator) treated cells were detected. Results:CAR expression at both mRNA and protein levels were significantly lower in thymic carcinoma tissues than in adjacent normal tissues ( P<0.01), and lower in MP59 and T1889 cells than in thymic epithelial cells (TEC) and Bcap-37 cells ( P<0.01). H101 expression in MP59 and T1889 cells and the titers of H101 in culture supernatants were significantly lower than those in Bcap-37 cells ( P<0.01). Compared with Bcap-37 cell, the activity of MP59 and T1889 cells was significantly increased and the apoptosis rates were significantly decreased 48 h after H101 infection ( P<0.01). The expression of CAR at both mRNA and protein levels in T1889 cells treated with different concentrations of TSA increased in a dose-dependent manner. When T1889 cells were treated with 0.25 μmol/L of TSA, the expression of H101 at mRNA level and H101 titers were significantly increased ( P<0.05); the phosphorylation levels of MAPK and ERK1/2 proteins were continuously decreased; the expression of CAR was continuously increased. Compared with the TSA treatment group, the expression of CAR at protein level in the TSA+ TBHQ treatment group decreased significantly ( P<0.01), and the p-ERK1/2/ERK1/2 ratio increased significantly ( P<0.01). Conclusions:TSA could up-regulate CAR expression in thymic carcinoma by inhibiting the MARK/ERK1/2 pathway, thereby enhancing the antitumor activity of H101.

Objective:To explore the safety and short-term and long-term efficacy of robot-assisted radical esophageal cancer surgery.Methods:A prospective randomized controlled trial was conducted. Patients who were preoperatively diagnosed as stage 0-IIIB esophageal squamous cell carcinoma and suitable for minimally invasive surgery in our hospital from January 1, 2014 to June 30, 2018 were prospectively enrolled. Those of age ≥75 years having received preoperative neoadjuvant therapy, contradicted to anesthesia or operation due to severe complications, with history of thoracotomy or laparotomy, with concurrent malignant tumors, without complete informations or refusing to participate in this study were excluded. Participants were randomly divided into the thoracoscopy-laparoscopy group and the robot group using a random number table in ratio of 1:1. Preoperative clinicopathological data, surgical data and postoperative outcomes were recorded. The patients were followed up mainly by telephone. Follow-up endpoint was recurrence of esophageal cancer and death. Kaplan-Meier method was used to estimate survival rate. The survival difference between the two groups was analyzed using the log-rank test.Results:According to above criteria, a total of 192 esophageal cancer patients were enrolled finally, including 144 males and 48 females with mean age of (61.9±8.6) years. The robot group had 94 cases, including 72 males and 22 females with mean age of (61.3±8.2) years, and the thoracoscopy-laparoscopy group had 98 cases, including 72 males and 26 females with mean age of (62.4±9.1) years. There were no significant differences in baseline data between the two groups (all P>0.05). Operation was abandoned in one case in each group due to extensive pleural cavity metastasis and one case in each group was converted to thoracotomy. The success rate of operation was 97.9% (92/94) in the robot group and 98.0% (96/98) in the thoracoscopy-laparoscopy group (χ 2=0.002, P=0.996). The number of lymph nodes dissected in the robot group was significantly higher than that in the thoracoscopy-laparoscopy group (29.2±12.5 vs. 22.8±13.3, t=3.433, P=0.001), while there were no significant differences in operative time, intraoperative blood loss, R0 resection rate, postoperative 30-day mortality, postoperative hospital stay, ICU stay, time to withdrawal of chest drainage tube, ICU readmission, and postoperative morbidity of complications between the two groups (all P>0.05). The median follow-up time was 21 (3 to 57) months. During the follow-up, 3 cases and 4 cases were lost, and 2 cases and 3 cases died of other diseases in the robot group and in the thoracoscopy-laparoscopy group respectively. Recurrence occurred in 39 cases during follow-up, including 14 recurrences in the robotic group with 1- and 3-year recurrence-free survival rates of 92.4% and 87.6% respectively and the median recurrence time of 15 (9 to 42) months. There were 25 recurrences in the thoracoscopy-laparoscopy group with 1- and 3-year recurrence-free survival rates of 81.7% and 67.9% respectively and the median recurrence time of 9 (3 to 42) months. There was significant difference in recurrence-free survival between the two groups (χ 2=4.193, P=0.041). Conclusions:The robotic surgical system has good oncology effect and surgical safety in the radical operation of esophageal cancer, which deserves further research and promotion.

Objective:To explore the safety and short-term and long-term efficacy of robot-assisted radical esophageal cancer surgery.Methods:A prospective randomized controlled trial was conducted. Patients who were preoperatively diagnosed as stage 0-IIIB esophageal squamous cell carcinoma and suitable for minimally invasive surgery in our hospital from January 1, 2014 to June 30, 2018 were prospectively enrolled. Those of age ≥75 years having received preoperative neoadjuvant therapy, contradicted to anesthesia or operation due to severe complications, with history of thoracotomy or laparotomy, with concurrent malignant tumors, without complete informations or refusing to participate in this study were excluded. Participants were randomly divided into the thoracoscopy-laparoscopy group and the robot group using a random number table in ratio of 1:1. Preoperative clinicopathological data, surgical data and postoperative outcomes were recorded. The patients were followed up mainly by telephone. Follow-up endpoint was recurrence of esophageal cancer and death. Kaplan-Meier method was used to estimate survival rate. The survival difference between the two groups was analyzed using the log-rank test.Results:According to above criteria, a total of 192 esophageal cancer patients were enrolled finally, including 144 males and 48 females with mean age of (61.9±8.6) years. The robot group had 94 cases, including 72 males and 22 females with mean age of (61.3±8.2) years, and the thoracoscopy-laparoscopy group had 98 cases, including 72 males and 26 females with mean age of (62.4±9.1) years. There were no significant differences in baseline data between the two groups (all P>0.05). Operation was abandoned in one case in each group due to extensive pleural cavity metastasis and one case in each group was converted to thoracotomy. The success rate of operation was 97.9% (92/94) in the robot group and 98.0% (96/98) in the thoracoscopy-laparoscopy group (χ 2=0.002, P=0.996). The number of lymph nodes dissected in the robot group was significantly higher than that in the thoracoscopy-laparoscopy group (29.2±12.5 vs. 22.8±13.3, t=3.433, P=0.001), while there were no significant differences in operative time, intraoperative blood loss, R0 resection rate, postoperative 30-day mortality, postoperative hospital stay, ICU stay, time to withdrawal of chest drainage tube, ICU readmission, and postoperative morbidity of complications between the two groups (all P>0.05). The median follow-up time was 21 (3 to 57) months. During the follow-up, 3 cases and 4 cases were lost, and 2 cases and 3 cases died of other diseases in the robot group and in the thoracoscopy-laparoscopy group respectively. Recurrence occurred in 39 cases during follow-up, including 14 recurrences in the robotic group with 1- and 3-year recurrence-free survival rates of 92.4% and 87.6% respectively and the median recurrence time of 15 (9 to 42) months. There were 25 recurrences in the thoracoscopy-laparoscopy group with 1- and 3-year recurrence-free survival rates of 81.7% and 67.9% respectively and the median recurrence time of 9 (3 to 42) months. There was significant difference in recurrence-free survival between the two groups (χ 2=4.193, P=0.041). Conclusions:The robotic surgical system has good oncology effect and surgical safety in the radical operation of esophageal cancer, which deserves further research and promotion.

The occlusal interference model in rats was established. In the masseter the level of MDA was increased, but both SOD and GPX were decreased in the presence of the occlusal interference, while the expression of UCP3 was higher than that in the control group (P ＜ 0. 05) .The findings indicate that the occlusal interference can induce the oxidative damage of masseter in rats, which has a correlation with UCP3.

Objective To compare the safety and effectiveness of endoscopic retrograde biliary drainage ( ERBD ) and endoscopic nasobiliary drainage ( ENBD ) in treatment of acute cholangitis. Methods A retrospective analysis was performed on data of 272 patients with acute cholangitis who underwent emergent endoscopic retrograde cholangiopancreatography ( ERCP ) in Beijing Chaoyang Hospital from January 2009 to June 2017. Patients were divided into ERBD group ( n=143) and ENBD group ( n=129) according to the drainage measures. In the ERBD group, there were 63 cases of gradeⅠ(mild) acute cholangitis, 51 of grade Ⅱ ( moderate) , and 29 of grade Ⅲ ( severe) , and the corresponding cases in the ENBD group were 54, 37 and 38, respectively. The rate of improvement of inflammation, ERCP-related complications and interventions to drainage were compared between the two groups in all patients and each grade. Results The rates of improvement of inflammation in the ERBD group and the ENBD group were 89. 5％ (128/143) and 94. 6％ (122/129), respectively, in overall patients (χ2=2. 399, P=0. 126), 93. 7％ (59/63) and 98. 1％ (53/54), respectively, in grade Ⅰ patients (χ2 =0. 548, P=0. 459), 90. 2％ (46/51) and 94. 6％ (35/37), respectively, in grade Ⅱ patients (χ2=0. 125, P=0. 724), and 79. 3％ (23/29) and 89. 5％ (34/38), respectively, in grade Ⅲ patients (χ2=0. 657, P=0. 418). The incidence of ERCP-related complications in the ERBD group and the ENBD group were 11. 9％ ( 17/143) and 7. 8％ ( 10/129) , respectively, in overall patients (χ2=1. 298, P=0. 225) , 9. 5％ ( 6/63) and 7. 4％( 4/54) , respectively, in grade Ⅰ patients (χ2=0. 006, P=0. 939) , 13. 7％ ( 7/51) and 8. 1％ ( 3/37) , respectively, in grade Ⅱ patients (χ2=0. 230, P=0. 632), and 13. 8％ (4/29) and 7. 9％ (3/38), respectively, in grade Ⅲ patients (χ2=0. 144, P=0. 705) . There were no significant differences in the rate of improvement of inflammation and ERCP-related complications between the two groups. The incidences of interventions to drainage in the ERBD group and the ENBD group were 10. 5％ ( 15/143 ) and 3. 1％(4/129), respectively, in overall patients (χ2=5. 699, P=0. 017), 6. 3％ (4/63) and 1. 9％ (1/54), respectively, in grade Ⅰ patients (χ2 = 0. 548, P = 0. 495 ) , 9. 8％ ( 5/51 ) and 5. 4％ ( 2/37 ) , respectively, in grade Ⅱ patients (χ2=0. 125, P=0. 724), and 20. 7％ (6/29) and 2. 6％ (1/38), respectively, in grade Ⅲ patients (χ2 = 3. 965, P= 0. 046 ) . There were significant differences in the incidence of interventions to drainage between the two groups in overall and gradeⅢpatents. Conclusion ERBD and ENBD are equally safe and effective in treatment of different grades of acute cholangitis, but ENBD can reduce the incidence of interventions to drainage.

Objective: To investigate the molecular characterization of adult diarrhea cases caused by enterotoxic Escherichia coli (ETEC) and explore the practical model of epidemiology for laboratory technique and data needs based on the surveillance network. Methods: Epidemiological design and sampling targeted adult cases ETEC caused diarrhea in epidemic season. The enterotoxin type, serogroup, resistance, colonization factor and molecular type of ETEC were identified. Multiple dynamic phenotypic characteristics of ETEC were indicated by multidimensional and multivariable data. Results: From 2016 to 2018, 84 eligible ETEC strains were detected. The dominant serums/toxins were O∶6 (STh), O∶25 (LT), O∶159 (STh), O∶153 (STh). O∶6 (STh+CS21), which replaced O∶25 and O∶159 as the popular clones in 2018. Six cases of O∶153 (STh+CFA/I+CS8+PT34) in outbreak in 2017 were imported ones. The resistance rates of ETEC strains detected in adults to sulfasoxazole, naproxinic acid, ampicillin and azithromycin were more than 30%, multidrug resistance (MDR) reached 58.3%. Serum/toxin types suggested that attenuated strains were more likely to become MDR. Molecular typing confirmed that the genetic similarity of the dominant clone of O∶6 serogroup (PT20-24) was higher than O∶25 and O∶159. There was a high correlation between the minimal inhibitory concentration (MIC) of azithromycin and the resistant gene mphA (87.5%, 28/32). O∶6 (STh+CS21+mphA) resistant clone was first detected in 2016. Conclusion A new epidemic clone in adult ETEC diarrhea cases in Shanghai was O∶6 (STh+CS21+mphA). For the first time the association between azithromycin resistance gene mphA and a serum group of ETEC was observed. Multidimensional and multivariate analysis techniques based on epidemiology can help reveal the potential transmission pattern of ETEC for the accurate surveillance and early warning of outbreaks.

Objective To investigate the effects of ursolic acid and rhynchophylline in Uncariae Ramulus Cum Uncis on human hepatoma HepG2 cells; To discuss its antihepatoma mechanism. Methods Culture the human hepatoma HepG2 cells with 50, 25, 12.5, 6.25 μmol/L ursolic acid, rhynchophylline for 24, 48, 72 hours respectively. 1%DMSO was set as negative control group. CCK-8 based cytotoxicity assay was used to detect the growth of HepG2. Acridine orange fluorescent staining was used to observe human hepatoma HepG2 cells cultured with 50 μmol/L ursolic acid, rhynchophylline and 1%DMSO for 48 hours were observed. Results Ursolic acid significantly acted as a disincentive to the growth of HepG2 cells, which was in positive correlation with time and concentration. Inhibited effect by rhynchophylline on HepG2 cell proliferation was weaker than ursolic acid. Pathological observation showed that most of the cells in rhynchophylline group showed cell shrinkage, dense pulp coating and nuclear staining edge set, and most of the cells in the ursolic acid group showed apoptosis late changes, such as nuclear cleavage and apoptotic bodies. Conclusion Ursolic acid and rhynchophyllinein Uncariae Ramulus Cum Uncis can inhibit the proliferation of HepG2 cells and can induce apoptosis.

Based on the suMmary of the implementation of two-way referral system in Changning district,the article describes the system construction,path design,information platform support and achievements,taking into account of general practitioners,specialist and patients.Through a series of reforms,a two-way referral service and its operation mechanism with the local characteristics has been established in Changning district,which guides the first contact care at community and two-way referral as a rational medical service system.

Objective To explore the circadian rhythm of neurally mediated syncope (NMS)in children. Methods There were 21 6 children with NMS included in the study,including 91 male and 1 25 female,aged from 4 to 1 7 years old with a mean age of (1 1 .34 ±2.65)years,who came from the Specialist Syncope Outpatient Department or Inpatient Department of the Second Xiangya Hospital of Central South University from December 201 3 to October 201 5. The patients were divided into vasovagal syncope (VVS)group and postural tachycardia syndrome (POTS)group ac-cording to head -up tilt test (HUTT)results,including 1 78 VVS patients and 38 POTS patients.Ninety -four patients with NMS were in the <1 2 years old group[(8.88 ±1 .88)years old]and 1 22 subjects with NMS were in the ≥1 2 years old group[(1 3.24 ±1 .1 8)years old].All patients or guardians were carefully asked about the number of synco-pal attacks and the periods in which episodes occurred in before HUTT [24 hours of a day were divided into 4 periods:morning (0600 AM-1 200 AM),afternoon (1 200 AM-1 800 PM),evening (1 800 PM-2400 PM), night (0000 AM-0600 AM)].Results (1 )General data:the total syncopal episodes of 21 6 children with NMS were 61 4 episodes,including 1 78 VVS patients with 471 syncopal episodes in total and 1 43 attacks of 38 children with POTS.There were 273 episodes of 94 patients in the <1 2 years old group and 341 episodes of 1 22 subjects in the ≥1 2 years old group.There were no significant differences in the diurnal variation of syncopal episodes between the VVS group and POTS group regarding age and gender (P >0.05).(2)The number of syncopal episodes in patients with VVS which occurred in the morning hours was strikingly higher than that of afternoon,evening or nighttime (P <0.05).But there was no significant difference in the frequency of episodes in different periods through the day in the POTS group (P >0.05).Patients with VVS had a higher proportion of episodes in the morning but a lower proportion in the evening when compared with the POTS group (P <0.05).(3)The male children with NMS tended to have a higher proportion of episodes in the morning than the female patients(χ2 =1 1 .001 ,P =0.01 2).(4)There seemed to be no difference in the frequency of syncopal episodes through the day between the <1 2 years old group and the ≥1 2 years old group(χ2 =1 .995,P =0.573).Conclusions The frequency of syncopal episodes in children with VVS displayed a clear circadian rhythm,with a peak in the morning,but the POTS patients did not show a circadian variation.The male children with NMS tended to have a higher proportion of episodes in the morning than the female patients.