A randomized, double-blind, placebo controlled, phase 3 trial to evaluate the efficacy and safety of cetagliptin added to ongoing metformin therapy in patients with uncontrolled type 2 diabetes with metformin monotherapy.

AIM: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. METHODS: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance. RESULTS: After 24 weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17 ± 0.794%, -1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment ß-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. CONCLUSIONS: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy.

Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

Infectious waste management during a pandemic: A stochastic location-routing problem with chance-constrained time windows.

The COVID-19 pandemic has presented tremendous challenges to the world, one of which is the management of infectious waste generated by healthcare activities. Finding cost-efficient services with minimum threats to public health has become a top priority. The pandemic has induced extreme uncertainties, not only in the amount of generated waste, but also in the associated service times. With this in mind, the present study develops a mixed-integer linear programming (MILP) model for the location-routing problem with time windows (LRPTW). To handle the uncertainty in the amount of generated waste, three scenarios are defined respectively reflecting different severity levels of a pandemic. Furthermore, chance constraints are applied to deal with the variation of the service times at small generation nodes, and time windows at the transfer facilities. The complexity of the resulting mathematical model motivated the application of a branch-and-price (B&P) algorithm along with an ɛ -constraint technique. A case study of the situation of Wuhan, China, during the initial COVID-19 outbreak is employed to examine the performance and applicability of the proposed model. Our numerical tests indicate that the B&P algorithm outperforms CPLEX in the computational times by more than 83% in small-sized problem instances and reduces the gaps by at least 70% in large-scale ones. Through a comparison with the current and deterministic systems, our proposed stochastic system can timely adjust itself to fulfill nearly four times the demand of other systems in an extreme pandemic scenario, while maintaining a cost-efficient operation with no outbreak.

A bi-objective robust optimization approach for the management of infectious wastes with demand uncertainty during a pandemic.

The current global COVID-19 pandemic attracts public attention to the management of waste generated by health-care activities. Due to the hazardous nature, infectious waste requires the design of a multi-tiered system to provide cost-efficient and eco-friendly services of waste collection, transportation, treatment, and final disposal. However, the impact of uncertainties has not been well studied in the existing literature. Considering the presence of random waste generation during a pandemic, we aim to answer the following questions: 1) where to locate temporary transfer stations and temporary treatment centers; 2) how to plan collection tours among the small generation nodes and temporary transfer stations; 3) how to plan the direct transportation from large generation nodes to treatment centers; 4) how to transport waste from temporary transfer stations to treatment centers, and 5) how to transport wastes from treatment centers to disposal facilities. The relevant cost and associated risk are respectively formulated and assessed using a scenario-based bi-objective robust approach. The complexity of the resulting mathematical model motivated the adaption and comparison of three multi-objective optimization approaches, including the goal programming method, a lexicographic weighted Tchebycheff approach, and an augmented ϵ-constraint solution technique. A case study based on the real situation in Wuhan, China, during the COVID-19 outbreak is conducted to demonstrate the workability of the proposed model and provide managerial insights for infectious waste management. The computational results show that our proposed model can more than double the demand fulfillment rate at an approximately 40% lower cost when facing a distinctively high increment in the amount of infectious waste.

JRL-YOLO: A Novel Jump-Join Repetitious Learning Structure for Real-Time Dangerous Object Detection.

Campus security incidents occur from time to time, which seriously affect the public security. In recent years, the rapid development of artificial intelligence has brought technical support for campus intelligent security. In order to quickly recognize and locate dangerous targets on campus, an improved YOLOv3-Tiny model is proposed for dangerous target detection. Since the biggest advantage of this model is that it can achieve higher precision with very fewer parameters than YOLOv3-Tiny, it is one of the Tinier-YOLO models. In this paper, the dangerous targets include dangerous objects and dangerous actions. The main contributions of this work include the following: firstly, the detection of dangerous objects and dangerous actions is integrated into one model, and the model can achieve higher accuracy with fewer parameters. Secondly, to solve the problem of insufficient YOLOv3-Tiny target detection, a jump-join repetitious learning (JRL) structure is proposed, combined with the spatial pyramid pooling (SPP), which serves as the new backbone network of YOLOv3-Tiny and can accelerate the speed of feature extraction while integrating features of different scales. Finally, the soft-NMS and DIoU-NMS algorithm are combined to effectively reduce the missing detection when two targets are too close. Experimental tests on self-made datasets of dangerous targets show that the average MAP value of the JRL-YOLO algorithm is 85.03%, which increases by 3.22 percent compared with YOLOv3-Tiny. On the VOC2007 dataset, the proposed method has a 9.29 percent increase in detection accuracy compared to that using YOLOv3-Tiny and a 2.38 percent increase compared to that employing YOLOv4-Tiny, respectively. These results all evidence the great improvement in detection accuracy brought by the proposed method. Moreover, when testing the dataset of dangerous targets, the model size of JRL-YOLO is 5.84 M, which is about one-fifth of the size of YOLOv3-Tiny (33.1 M) and one-third of the size of YOLOv4-Tiny (22.4 M), separately.

Optimization of total phenolic content from Terminalia chebula Retz. fruits using response surface methodology and evaluation of their antioxidant activities.

Ultrasonic-assisted extraction (UAE), using aqueous ethanol as the solvent, was firstly applied to extract phenolic compounds from Terminalia chebula Retz. fruits (T. chebula fruits). In this study, ethanol concentration (%), ultrasonic intensity (W/cm2), particle diameter (mm), extraction temperature (°C), ultrasonic time (min), liquid-solid ratio (mL/g) and extraction cycle were investigated by single-factor experiment and then optimized using a Box-Behnken design. The optimized result for UAE was 68% ethanol concentration, ultrasonic intensity of 3.6 W/cm2, solid-liquid ratio of 23 mg/mL, particle size of 0.18 mm and ultrasonic time of 20 min for 2 times at 70 °C. The yield of total phenolic was 448.7 ± 2.15 mg GAE/g DW under the above optimum conditions, which agreed with the predicted value (447.8 mg GAE/g DW). Compared to conventional solvent extraction (CSE), UAE extracts showed excellent DPPH radical, DPPH, ABTS scavenging activities and reducing power in a dose-dependent manner, and better than that of CSE extracts. Additionally, the extract of the T. chebula fruits was analyzed by HPLC-ESI/MS. In summary, UAE could effectively extract phenolic compounds from T. chebula fruits. In addition, the extract could be used as a potential source of natural antioxidants.

[Transvaginal endoscopic resection of rectal tumor: a report of 2 cases].

Two female patients with rectal tumor undergoing proctectomy via vagina, namely natural orifice transluminal endoscopic surgery (NOTES), are reported. The operations were performed on June 8 and August 10, 2010, respectively. No Trocar was used in the abdomen except for the transumbilical incision. There were no visible scars in the abdomen. Tubulovillous adenoma and moderately differentiated adenocarcinoma were diagnosed respectively through postoperative pathological examination. Both patients resumed normal work and life at the most recent follow up. Sexual life was satisfactory.

[The effect of As2O3 on induction of apoptosis and inhibition of telomerase activity in colon cancer LS-174T cells].

OBJECTIVE: To study the impact of arsenic trioxide (As2O3) on human colorectal carcinoma LS-174T cells and their activity of telomerase. METHODS: LS-174T cells and xenograft model of nude mice were treated with As2O3. The inhibitory effect of As2O3 on survival of LS-174T cells was determined by MTT assay. Apoptosis was determined by electron microscopy and fluorescence microscopy. Cell cycle was assessed by flow cytometry. Telomerase activity in LS-174T cells was determined by PCR-ELISA kit. RESULTS: With the increasing concentration of As2O3, the ratio of living cells to dead cells decreased significantly, and the IC50 value was 5.23 micromol/L. Apoptosis curve appeared after 24 h and cells turned to apoptosis in a time-dependent manner. As2O3 inhibited the telomerase activity in cell extraction, obviously in a concentration-dependent and time-dependent manner. Inhibitiory effect of As2O3 on xenograft model of nude mice was observed by tumor volume and weight measurement, showing a significant difference between As2O3 and control groups (P < 0.05). CONCLUSION: Both the experiments in vitro and in vivo showed an inhibitory effect of As2O3 on colonrectal cancer S-174T cell growth, probably by induction of apoptosis and inhibition of telomerase activity.

[Radiosensitivity on colorectal neoplasms by recombinant adenoviral-mediated wild-type p53 gene].

OBJECTIVE: To study the radiosensitization on the cells of colorectal cancer transfected with recombinant adenovirus vector-mediated wild-type p53. METHODS: SW480 cells transfected by wild-type p53 were treated with 4 Gy and 6 Gy radiation. The expression of recombinant adenovirus vector-mediated wild-type p53 gene was detected by Western blotting. The inhibition rate of SW480 cells was examined by MTT, apoptotic rate by TdT-mediated dUTP nick end labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) by immunohistochemical method. RESULTS: SW480 cells transfected by wild-type p53 were inhibited significantly by 4 Gy and 6 Gy radiation. The level of apoptosis increased and the expression of PCNA decreased. CONCLUSION: Cells of colorectal carcinoma transfected with wild-type p53 increases their radiation sensitivity.

[Inducement of FLICE inhibitory protein antisense oligonucleotides on apoptosis of human gastric cancer cell line BGC823].

BACKGROUND & OBJECTIVE: Cellular FLICE inhibitory protein (cFLIP) plays an important role in cell apoptosis, researches of antisense oligonucleotides (ASODN) of cFLIP gene may provide a new method or protocol for treatment of human gastric cancer. This study was to explore effect of cFLIP ASODN on apoptosis of human gastric cancer cell line BGC823. METHODS: Human cervical cancer cell line HeLa was used as control, cFLIP ASODN was introduced into BGC823 cells and HeLa cells, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were used to detect cFLIP(L/S) (cellular FLIP(Short) and cellular FLIP(long)) mRNA and protein. The 5'FAM-conjugated ASODN was created complementary to a sequence that included the start site of FLIP open reading frame. After introducing, MTT was used to detect cell inhibition rate,TUNEL and flow cytometry (FCM) were used to detect cell apoptosis, and Western blot was used to detect protein level of cFLIP. RESULTS: The encoding mRNA and protein of cFLIP(L) and cFLIP(S) can be detected in both HeLa and BGC823 cells. MTT revealed that cFLIP ASODN significantly inhibited proliferation of BGC823 cells (P< 0.05) in a concentration-dependent manner. TUNEL staining detected positive FLIP expression, specific apoptotic peak can be detected before G1 peak by FCM, and Western blot revealed that protein level of cFLIP(L) and cFLIP(S) decreased significantly (P< 0.05). CONCLUSION: The cFLIP(L/S) mRNA and encoded proteins expressed in both HeLa and BGC823 cells. ASODN may down-regulate cFLIP(L/S) protein level, and initiate apoptosis of BGC823 cells.

Relations of the type and branch of surface N-glycans to cell adhesion, migration and integrin expressions.

The relations between the structure of cell surface N-glycans to cell behaviors were studied in H7721 human hepatocarcinoma cell line, which predominantly expressed complex-type N-glycans on the surface. 1-Deoxymannojirimycin (DMJ) and swaisonine (SW), the specific inhibitor of Golgi alpha-mannosidase II or I, were selected to block the processing of N-glycans at the steps of high mannose and hybrid type respectively. All-trans retinoic acid (ATRA) and antisense cDNA of N-acetylglucosaminyltransferase-V (GnT-V) were used to suppress the expression of GnT-V and decreased the GlcNAc beta1,6-branching or tri-/tetra-antennary structure of surface N-glycans. The structural alterations of N-glycans were verified by sequential lectin affinity chromatography of [3H] mannose-labeled glycans isolated from the cell surface. The cell adhesions to fibronectin (Fn) and human umbilical vein epithelial cell (HUVEC), as well as cell migration (including chemotaxis and invasion) were selected as the parameters of cell behaviors. It was found that cell adhesion and migration were significantly decreased in SW and DMJ treated cells, suggesting that complex type N-glycan is critical for the above cell behaviors. ATRA and antisense GnTV enhanced cell adhesion to Fn but reduce cell adhesion to HUVEC and cell migration. These results reveal that cell surface complex-type N-glycans with GlcNAc beta1,6 branch are more effective than those without this branch in the cell adhesion to HUVEC and cell migration, but N-glycan without GlcNAc beta1,6-branch is the better one in mediating the cell adhesion to Fn. The integrin alpha5beta1 (receptor of Fn) on cell surface was unchanged by DMJ and SW. In contrast, ATRA up regulated alpha5, but not beta1, and antisense GnT-V decreased both alpha5 and beta1. This findings suggest that both the structure of N-glycan and the expression of integrin on cell surface are two of the important factors in the determination of cell adhesion to Fn, a complex biological process.

Regulation on the expression and N-glycosylation of integrins by N-acetylglucosaminyltransferase V.

The expressions of integrin alpha5, beta1, and alpha6 were studied in H7721 cells by means of flow cytometric and RT-PCR method after transfected with sense and antisense cDNA of N-acetylglucosaminyltransferase V (GnT-V). The transfected cells were characterized by Northern blot. It was found that the order of expression from high to low was beta1>alpha5>alpha6. Transfection of sense GnT-V up-regulated alpha5 and alpha6, but not beta1 subunit, while antisense GnT-V down-regulated alpha5 and beta1, but not alpha6. The alterations of surface integrin subunits were quite compatible with the changes of their mRNAs. Using enzyme-labeled lectin analysis, it was shown that alpha5 subunit contained only C(2)C(2) biantennary N-glycan, which was not regulated by sense and antisense GnT-V. In contrast, beta1 subunit contained both biantennary and tri-/tetra-antennary N-glycans with GlcNAcbeta1,6Manalpha1,6-branch, and the latter was up- and down-regulated by the sense and antisense GnT-V, respectively. Therefore, the amount of biantennary N-glycans on beta1 subunit, but not the integrin protein, was correlated to the cell adhesion to fibronectin and laminin, which was reduced and elevated in the sense and antisense GnT-V-transfected cells, respectively, as we previously reported.

Alteration in the expression of early stage processing enzymes of N-glycan during myeloid and monocytoid differentiation of HL-60 cells.

The expressions of the enzymes participating in the early stage of N-glycan processing, Golgi alpha-Mase-I, alpha-Mase-II and GnT-I, GnT-II, were studied before and after HL-60 cells were differentiated to myelocytes or monocytes induced by ATRA or PMA, respectively. It was found that alpha-Mase-I activity and GnT-I mRNA were decreased by both ATRA and PMA, while alpha-Mase-II and GnT-II were altered insignificantly. The down-regulation of alpha-Mase-I and GnT-I was cell specific, since ATRA up-regulated alpha-Mase-I and GnT-I in the H7721 hepatocarcinoma cell line. However, in H7721 cells, PMA also decreased alpha-Mase-I and GnT-I, and both ATRA and PMA also did not obviously change the expressions of alpha-Mase-II and GnT-II.

Lewis Antigens, alpha1,3 Fucosyltransferses and the Metastatic Potential of Human Primary Liver Cancer.

In order to study the expression of Lewis antigens and the subtypes of alpha1,3 fucosyltransferase(alpha1,3FucT) in human primary liver cancer, and their relations with the cancer cell embolus formation, as well as the expression of nm23-H1, a metastatic suppressor gene, Lewis antigens were detected with immunohistochemical method, and the mRNA of alpha1,3 FucTs and nm23-H1 were determined with Northern blot. Results showed that the positive rates of the expression of four Lewis antigens, sialyl Lewis X(Sle(x)), Lewis X(Le(x)), sialyl dimeric Lewis X(SDLe(x)) and sialyl Lewis A(Sle(a)), in human primary liver cancer were about 80%. The expression of Sle(x) was rather higher, Le(x) and Sle(a) were lower, but the expression of SDLe(x) was only in trace amount. The four Lewis antigens were not expressed in the liver regions adjacent to the cancer tissues. The transcriptional level of alpha1,3 FucT-III/VI mRNA in cancer tissues was higher than that in the adjacent regions, especially in the cancer tissues of patients with portal vein cancer cell embolus(CCE). However, the expression of alpha1,3 FucT-III/VI mRNA was not different in the adjacent regions in spite of the presence or absence of CCE in the patients. In contrast, the expression of alpha1,3 FucT-VII was rather lower and identical to each other both in cancer tissues and adjacent regions. In addition, it was found that the expression of nm23-H1, a metastasis suppressor gene, was markedly lower in the cancer tissues of patients with CCE than that in the non-CCE patients and the adjacent regions. Furthermore, the expression of nm23-H1 was negatively related to the expression of alpha1,3 FucT-III/VI. These results indicated that the expression of alpha1,3 FucT-III/VI and its product Sle(x) were correlated with CCE (metastatic potential), and the down-regulation of alpha1,3 FucT-III/VI and Sle(x) may be one of the mechanisms of nm23-H1 to inhibit liver cancer metastasis.