WITHDRAWN: Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of ß-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.

Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study.

[Optimization of Operative Procedure in Total Laparoscopic Pancreaticoduodenectomy (with Video)].

OBJECTIVE: To optimize operative procedure on intraoperative exploration, resection and reconstruction in total laparoscopic pancreaticoduodenectomy (LPD). METHODS: The clinical data of patients who underwent total LPD in West China Hospital (and Shangjin Hospital) of Sichuan University from Dec. 2015 to Dec. 2017 were retrospectively analyzed. The diagnosis of the patients included ampullar cancer, distal common bile duct cancer, benign and maligant tumors of pancreatic head and chronic pancreatitis of pancreatic head. The patients were divided into experimental group and control group according to weather the optimization of operative procedure was used. The position and Trocar arrangement in both groups were same. Two Chief Surgeons Model was used in experimental group, the procedure was divided into three key steps: laparoscopic exploration, resection and reconstruction, each followed anticlockwise operative process, from left to right, from shallow to deep (see the Videos 1 to 3 in Supplemental Contents, http://ykxb.scu.edu.cn/article/doi/10.12182/202007606108). As to control group, the chief operation was finished by chief surgeon and no specific operative procedure was applied. All the patients were followed up to postoperative 90 d. RESULTS: A total of 146 patients were collected, including 76 patients undergoing LPD with optimization of operative procedure and 70 patients in the control group. There was no significant difference in preoperative data between the two groups regarding to ASA scoring, age, gender, body mass index and laboratory tests ( P>0.05). Compared with the control group, the operative time in the experimental group was significantly shorter (341 min vs. 397 min, P<0.05), estimated blood loss was significantly reduced (110 mL vs. 180 mL, P<0.05). The conversive rate, transfusion rate, length of postoperative hospital stay, number of harvested lymph nodes, post pancreatectomy hemorrhage, bile leakage, pancreatic fistula (Grade B+C), reoperation, the occurrence of severe postoperative morbidity (Clavien-Dindo Ⅲ-Ⅳ), and postoperative 90 d mortality were no statistically difference. CONCLUSION: With Two Chief Surgeons Model combined with anticlockwise operative process could optimize operative procedure in total LPD. It is safe and feasible, and could shorten the operation time and reduce intraoperative blood loss.

[The Pedicled Teres Hepatis Ligament Flap Wrap Around the Gastroduodenal Artery Stump to Prevent Postoperative Hemorrhage after Laparoscopic Pancreatoduodenectomy (with Video)].

OBJECTIVE: To explore the feasibility and safety of teres hepatis ligament flap plasty around the gastroduodenal artery (GDA) stump to prevent postoperative hemorrhage after laparoscopic pancreatoduodenectomy (LPD). METHODS: A total of 108 patients with GDA stump wrapped by pedicled teres hepatis ligament after LPD in our center were included for analysis from March 2018 to March 2019. After completion of LPD, teres hepatis ligament was dissected from the ventral abdominal cephalad along the ventral attachment, and the teres hepatis ligament was separated from the falciform ligament by ultrasonic scalpel or Ligasure. At the junction to the liver, the teres hepatis ligament is freed from the ventral hepatic surface. The junction between liver and teres hepatis ligament should not be cut off to ensure blood supply. Division of the GDA was performed using a Prolene 4-0 suture stitch or two clamps as a standard (see the Video 1 in Supplemental Contents, http://ykxb.scu.edu.cn/article/doi/10.12182/20200760602). The pedicled teres hepatis ligament then was used to completely cover the skeletonized GDA stump, and part of the common hepatic artery and the proper hepatic artery. The mobilized ligament can be transposed without tension. RESULTS: A total of 108 patients completed the procedure of GDA stump wrapped with pedicled teres hepatis ligament during LPD. There were no complications caused by GDA stump after operation. The main steps to wrap the GDA stump took an average of 10 min. Clinically relevant postoperative pancreatic fistula (CR-POPF) occurred in 8 cases (7.4%) (including 6 cases of grade B pancreatic fistula and 2 cases of grade C pancreatic fistula), and intra-abdominal infection in 8 cases (7.4%), including 3 cases (2.8%) of intra-abdominal abscess, postoperative gastrointestinal ulcer bleeding occurred in 2 cases (1.9%), and no intra-abdominal hemorrhage occurred. CONCLUSION: It is a safe and feasible procedure of wrapping GDA stump with pedicled teres hepatis ligament to prevent postoperative hemorrhage after LPD. The procedure is easy to perform without relevant additional surgical trauma or prolongation of the operation time.

Noninvasive model for predicting future ischemic strokes in patients with silent lacunar infarction using radiomics.

BACKGROUND: This study aimed to investigate integrating radiomics with clinical factors in cranial computed tomography (CT) to predict ischemic strokes in patients with silent lacunar infarction (SLI). METHODS: Radiomic features were extracted from baseline cranial CT images of patients with SLI. A least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was used to select significant prognostic factors based on ModelC with clinical factors, ModelR with radiomic features, and ModelCR with both factors. The Kaplan-Meier method was used to compare stroke-free survival probabilities. A nomogram and a calibration curve were used for further evaluation. RESULTS: Radiomic signature (p < 0.01), age (p = 0.09), dyslipidemia (p = 0.03), and multiple infarctions (p = 0.02) were independently associated with future ischemic strokes. ModelCR had the best accuracy with 6-, 12-, and 18-month areas under the curve of 0.84, 0.81, and 0.79 for the training cohort and 0.79, 0.88, and 0.75 for the validation cohort, respectively. Patients with a ModelCR score < 0.17 had higher probabilities of stroke-free survival. The prognostic nomogram and calibration curves of the training and validation cohorts showed acceptable discrimination and calibration capabilities (concordance index [95% confidence interval]: 0.7864 [0.70-0.86]; 0.7140 [0.59-0.83], respectively). CONCLUSIONS: Radiomic analysis based on baseline CT images may provide a novel approach for predicting future ischemic strokes in patients with SLI. Older patients and those with dyslipidemia or multiple infarctions are at higher risk for ischemic stroke and require close monitoring and intensive intervention.

Effects of different carbohydrases on the physicochemical properties of rice flour, and the quality characteristics of fermented rice cake.

The rice flours were hydrolyzed using α-amylase (A), α-amylase and xylanase (AX), and α-amylase, xylanase and ß-amylase (AXB). The effects of different enzymatic rice flour hydrolysates (ERH) on the quality of the fermented rice cake (FRC) were determined at 25 °C for 4 days. ERH had higher porosity, water absorption index, water solubility index and lower viscosity than the control. Moisture content of FRC center decreased significantly after 4 days. Specific volumes of fresh A-, AX- and AXB-FRC were higher than the control. Color of fresh A-FRC was closer to that of the control. AXB-FRC had lower hardness and firming rate than other samples during storage. After 4 days of storage, FRC with ERH had lower endotherm enthalpy and more uniform and clearer pore structure than the control. Therefore, the ERH with single or mixed enzymes could improve the structure of FRC, and extend its shelf-life.

[Predictive Value of POSSUM and P-POSSUM Scoring System for Risk Assessment in Laparoscopic Pancreatoduodenectomy].

OBJECTIVE: To evaluate the clinical predictive ability of POSSUM and P-POSSUM scoring system in laparoscopic pancreatoduodenectomy (LPD). METHODS: There were 132 consecutive LPD performed in West China Hospital of Sichuan University from February 2014 to July 2017. The clinical data were retrospective collected, including 12 preoperative physiological variables, 6 operative severity variables, and complications and mortality The postoperative expected mortality and morbidity were calculated by POSSUM and P-POSSUM score, and compared with measured morbidity and mortality. The clinical predictive ability of POSSUM and P-POSSUM system was evaluated by the receiver operating characteristic (ROC) curve and hierarchical analysis. RESULTS: The area under ROC curve ( AUC) was 0.83. The preoperative physiological score (PS) and POSSUM score of the patients with complications were higher, and the difference was statistically significant ( P<0.01). For the prediction of complications after LPD, the expected value was the most accurate to the measured value when POSSUM score was >0.4-0.6. POSSUM scoring system had no significant difference in predicting the incidence of complications for benign and malignant lesions ( P>0.05), with a higher predictive value for malignant tumors. It was valuable in predicting the incidence of complications in male and female, and there was no significant difference in expected value between the sexes. Expected morbidity rate by POSSUM scoring system was 36.6% and measured morbidity rate was 33.3%. The expected and measured morbidities had no significantly differences. The expected mortality was 7.0% and measured mortality rate was 1.5%. The expected and measured mortality had no significantly differences. Expected mortality by P-POSSUM system was 1.6%, the expected and measured mortality had no significantly differences. CONCLUSION: POSSUM and P-POSSUM scoring system had high value for predicting LPD postoperative morbidity and mortality of LPD patients.

Improving antitumor outcomes for palliative intratumoral injection therapy through lecithin- chitosan nanoparticles loading paclitaxel- cholesterol complex.

BACKGROUND: Intratumoral injection is a palliative treatment that aims at further improvement in the survival and quality of life of patients with advanced or recurrent carcinomas, or cancer patients with severe comorbidities or those with a poor performance status. METHODS: In this study, a solvent-injection method was used to prepare paclitaxel-cholesterol complex-loaded lecithin-chitosan nanoparticles (PTX-CH-loaded LCS_NPs) for intratumoral injection therapy, and the physicochemical properties of NPs were well characterized. RESULTS: The particle size and zeta potential of PTX-CH-loaded LCS_NPs were 142.83±0.25 nm and 13.50±0.20 mV, respectively. Release behavior of PTX from PTX-CH-loaded LCS_NPs showed a pH-sensitive pattern. The result of cell uptake assay showed that PTX-CH-loaded LCS_NPs could effectively enter cells via the energy-dependent caveolae-mediated endocytosis and macropinocytosis in company with the Golgi apparatus. Meanwhile, PTX-CH-loaded LCS_NPs had a better ability to induce cell apoptosis than PTX solution. The in vivo antitumor results suggested that PTX-CH-loaded LCS_NPs effectively inhibited mouse mammary cancer growth and metastasis to distant organs and significantly improved the survival rate of tumor-bearing mice by intratumoral administration. CONCLUSION: In general, our study demonstrated that PTX-CH-loaded LCS_NPs used for palliative treatment by intratumoral injection showed improved safety and antitumor efficacy, which provided an alternative approach in the field of palliative chemotherapy.

Laparoscopic Roux-en-Y duodenojejunostomy for annular pancreas in adults: case report and literature review.

Annular pancreas is in adults is a rare congenital anomaly which incidence varied from 0.005% to 0.015%. Although 33% of the cases are symptomatic, the symptoms are most commonly associated with gastric outlet obstruction. Here we presented an adult diagnosed with annular pancreas treated by laparoscopic Roux-en-Y side to side duodenojejunostomy.

Comparison of Laparoscopic and Open Pancreaticoduodenectomy for the Treatment of Nonpancreatic Periampullary Adenocarcinomas.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD), a surgical option for nonpancreatic periampullary adenocarcinoma (NPPA), is a complex procedure that has become increasing popular. However, there is no consensus as to whether this technique should be performed routinely. Our aim was to evaluate the outcomes of LPD compared with open pancreaticoduodenectomy (OPD). MATERIALS AND METHODS: From October 2010 to September 2015, 58 LPDs were performed to treat NPPA and were compared with 58 OPDs, which can theoretically be carried out by laparoscopic approach. Patients were also matched based on their demographic data and pathologic diagnosis. Demographic information, intraoperative and postoperative data, pathologic data, and follow-up evaluation data were collected at our center. RESULTS: All patients had a median follow-up of 34 months (range, 8 to 60 mo). Overall median survival during the study between the groups was not different (P=0.760). No significant differences between the 2 groups were found in terms of patient demographics, short-term complications, pathologic outcomes, or tumor-node-metastasis stage. With regard to operative time, the LPD group was slightly longer than the OPD group (P<0.001). There were significant differences between groups in the time to the first passage of flatus and the time to oral intake (P<0.001). However, no differences were seen in blood loss, length of intensive care unit stay, node positive, or R0 resection between the laparoscopic and open groups. CONCLUSIONS: This study found that LPD is a feasible, safe, and effective method for the treatment of NPPA compared with OPD and may be a preferred method for surgeons to choose.

The long-term impact of cefalexin on organic substrate degradation and microbial community structure in EGSB system.

In order to investigate long-term effect of cefalexin (CFX) on the performance of expanded granular sludge bed (EGSB) system and microbial community structure, two 1.47 L EGSB reactors E1 and E2 were designed and run for 224 days treating with synthetic antibiotic wastewater. For the purpose of comparison, E1 was fed with synthetic antibiotic industry wastewater with CFX added as the test reactor, while, E2 was fed without any CFX added as the control reactor (E2). The addition of CFX resulted in the continual increasing of soluble COD (sCOD) and accumulation of VFAs in the effluent of E1 system. Besides, it was found that the accumulation of CFX by-products D-1, D-2 and D-3 was negative correlation with sCOD removal efficiency. Furthermore, the microbial community structures were also investigated. For the bacterial community, Gelria and Syntrophorhabdus which can ferment propionate and other organic pollutants as their substrate were obviously enriched in E1 system. For the archaea, there was more functional diversity in E1 system than in E2 system. Furthermore, fungi also played an important role on the removal of complex organics in E1 system.

Establishment of thermophilic anaerobic terephthalic acid degradation system through one-step temperature increase startup strategy - Revealed by Illumina Miseq Sequencing.

Over recent years, thermophilic digestion was constantly focused owing to its various advantage over mesophilic digestion. Notably, the startup approach of thermophilic digester needs to be seriously considered as unsuitable startup ways may result in system inefficiency. In this study, one-step temperature increase startup strategy from 37 °C to 55 °C was applied to establish a thermophilic anaerobic system treating terephthalic acid (TA) contained wastewater, meanwhile, the archaeal and bacterial community compositions at steady periods of 37 °C and 55 °C during the experimental process was also compared using Illumina Miseq Sequencing. The process operation demonstrated that the thermophilic TA degradation system was successfully established at 55 °C with over 95% COD reduction. For archaea community, the elevation of operational temperature from 37 °C to 55 °C accordingly increase the enrichment of hydrogenotrophic methanogens but decrease the abundance of the acetotrophic ones. While for bacterial community, the taxonomic analysis suggested that Syntrophorhabdus (27.40%) was the dominant genus promoting the efficient TA degradation under mesophilic condition, whereas OPB95 (24.99%) and TA06 (14.01%) related populations were largely observed and probably take some crucial role in TA degradation under thermophilic condition.

Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

AIM: To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS: Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS: LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION: ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

454-Pyrosequencing Reveals Microbial Community Structure and Composition in a Mesophilic UAFB System Treating PTA Wastewater.

To well understand the community structure and composition of mesophilic microorganisms in anaerobic system fed with PTA wastewater, an up-flow anaerobic fixed bed reactor was continuously run at 33 and 37 °C for 75 and 60 days, respectively. Both fluorescence in situ hybridization analysis and 454-pyrosequencing were applied to investigate the microbial distinction within mesophilic ranges. A preferable performance was achieved at 37 than 33 °C. The taxonomic complexities of two samples were further compared at phylum, class, and genus levels. Notably, microbial diversity differed a lot and the change of populations was observed mainly in the shared OTUs. Genus level analysis showed that when temperature was increased to 37 °C, the abundance of Thauera and Hydrogenophaga (ß-Proteobacteria) decreased by 93.75 and 61.47 %, respectively, whereas that of Syntrophorhabdus (δ-Proteobacteria) increased from 4.93 to 16.01 %. Furthermore, the dominant archaeal Methanobacterium at both temperatures indicated the prevailing contribution of hydrogenotrophic methanogens in mesophilic anaerobic system.

Performance and microbial community profiles in an anaerobic reactor treating with simulated PTA wastewater: from mesophilic to thermophilic temperature.

Performance and microbial community profiles in a hybrid anaerobic reactor treating synthetic PTA wastewater (contained the major pollutants terephthalate and benzoate) were studied over 220 days from 33 °C to 52 °C. Results indicated that PTA treatment process was highly sensitive to temperature variations in terms of COD removal. Operation at 37 °C showed the best performance as well as the most diverse microbial community revealed by 16S rRNA gene clone library and T-RFLP (terminal restriction fragment length polymorphism). Finally, the anaerobic process achieved a total COD removal of 77.4%, 91.9%, 87.4% and 66.1% at 33, 37, 43 and 52 °C. While the corresponding TA removal were 77.6%, 94.0%, 89.1% and 60.8%, respectively. Sequence analyses revealed acetoclastic Methanosaeta was preponderant at 37 °C, while hydrogenotrophic genera including Methanobrevibacter and Methanofollis were more abundant at other temperatures. For bacterial community, 16 classes were identified. The largely existent Syntrophorhabdus members (belonging to δ-Proteobacteria) at 37 °C was likely to play an important role in mesophilic anaerobic wastewater treatment system contained terephthalate. Meanwhile, ß-Proteobacteria seemed to be favored in an anaerobic system higher than 43 °C.