Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial

Aims: Assess the efficacy and safety of saxagliptin added to a submaximal sulphonylurea dose vs. uptitration of sulphonylurea monotherapy in patients with type 2 diabetes and inadequate glycaemic control with sulphonylurea monotherapy. Methods and patients: A total of 768 patients (18–77 years; HbA_1c screening ≥ 7.5 to ≤ 10.0%) were randomised and treated with saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg vs. glyburide 10 mg for 24 weeks. Blinded uptitration glyburide was allowed in the glyburide‐only arm to a maximum total daily dose of 15 mg. Efficacy analyses were performed using ANCOVA and last‐observation‐carried‐forward methodology. Results: At week 24, 92% of glyburide‐only patients were uptitrated to a total glyburide dose of 15 mg/day. Saxagliptin 2.5 and 5 mg provided statistically significant adjusted mean decreases from baseline to week 24 vs. uptitrated glyburide, respectively, in HbA_1c (?0.54%, ?0.64% vs. +0.08%; both p < 0.0001) and fasting plasma glucose (?7, ?10 vs. +1 mg/dl; p = 0.0218 and p = 0.002). The proportion of patients achieving an HbA_1c < 7% was greater for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (22.4% and 22.8% vs. 9.1%; both p < 0.0001). Postprandial glucose area under the curve was reduced for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (?4296 and ?5000 vs. +1196 mg·min/dl; both p < 0.0001). Adverse event occurrence was similar across all groups. Reported hypoglycaemic events were not statistically significantly different for saxagliptin 2.5 (13.3%) and 5 mg (14.6%) vs. uptitrated glyburide (10.1%). Conclusion: Saxagliptin added to submaximal glyburide therapy led to statistically significant improvements vs. uptitration of glyburide alone across key glycaemic parameters and was generally well tolerated.     

A new cancer immunotherapy via simultaneous DC‐mobilization and DC‐targeted IDO gene silencing using an immune‐stimulatory nanosystem

The activity of negative immune regulatory molecules, such as indoleamine 2,3‐oxygenase (IDO), significantly attenuates DC (Dendritic cells)‐mediated immunotherapy. We have previously reported that knockdown of IDO using siRNA can reinstall anti‐tumor immunity. However, a DC‐targeted siRNA delivery system for in vivo mobilized DCs remains to be developed, while gene silencing in mobilized DCs for cancer immunotherapy has never been explored. In our study, we developed a novel DC‐targeted siRNA delivery system, man‐GNR‐siIDO, using as a nanocarrier of siRNA specific for IDO (siIDO) and mannose (man) as a guide molecule for targeting DCs. We explored the immunostimulatory man‐GNR‐siIDO nano‐construct in DCs mobilized by Flt3‐L, a receptor‐type tyrosine kinase ligand, for lung cancer immunotherapy. In vivo DC‐targeted gene silencing of IDO resulted in robust anti‐tumor immunity as evidenced by promoting DC maturation, up‐regulating tumor antigen‐specific T‐cell proliferation and enhancing tumor‐specific cytotoxicity. A combinatorial treatment for Lewis Lung Carcinoma (LLC)‐bearing mice, with man‐GNR‐siIDO and Flt3‐L, significantly attenuated tumor growth and delayed tumor formation, suggesting the treatment feasibility of the man‐GNR‐siIDO system in Flt3‐L mobilized DCs in the immunotherapy of lung cancer. Therefore, our study highlights a clinical potential for a first‐in‐class anti‐cancer immunotherapy through simultaneous DC‐mobilization and DC‐targeted gene silencing of IDO with man‐GNR‐siIDO and Flt3‐L treatments.     

Altered glycosaminoglycan production by HL-60 cells treated with 4- methylumbelliferyl-beta-D-xyloside

Glycosaminoglycans, mainly chondroitin 4-sulfate, are located in the primary granules of human myeloid cells. These polyanionic carbohydrates are believed to play an important role in leukocyte maturation and function. To study the effect of altered chondroitin sulfate metabolism on human promyelocytic leukemia cells, we have treated HL-60 cells with 4-methylumbelliferyl-beta-D-xyloside. beta-D- Xylosides initiate the synthesis of free chondroitin sulfate chains. Cytochemical studies of treated cells demonstrated a marked increase in cytoplasmic granules stained with cationic dyes. This was confirmed by radiolabeled precursor incorporation studies that demonstrated a 344% increase in 35S-sulfate uptake into glycosaminoglycans associated with the cells and a 39% increase in incorporation into glycosaminoglycans released into the media. Chromatographic analyses of these glycosaminoglycans from treated cells demonstrated that the newly formed chondroitin sulfate chains were not attached to protein core and were of shorter length, but of greater charge density than chondroitin sulfate produced by control cells. Thus, beta-D-xyloside appears to alter the protein linkage, chain length, and sulfation of chondroitin sulfate produced by HL-60 cells, and these changes are morphologically evident. These biochemically altered cells may provide important information concerning the role of these macromolecules in myeloid development.     

The human homologue of rat NG2, a chondroitin sulfate proteoglycan, is not expressed on the cell surface of normal hematopoietic cells but is expressed by acute myeloid leukemia blasts from poor-prognosis patients with abnormalities of chromosome band 11q23

In our efforts to produce monoclonal antibodies that recognize cell- surface antigens expressed by hematopoietic precursor and stromal cells, we generated a monoclonal antibody, 7.1, which recognizes a 220- to 240-kD cell-surface protein whose N-terminal amino acid sequence is identical to the rat NG2 chondroitin sulfate proteoglycan molecule. This chondroitin sulfate proteoglycan, previously reported to be expressed by human melanoma cells, was not found to be expressed by normal hematopoietic cells, nor was it expressed on the cell surface of cell lines of hematopoietic origin including cell lines with 11q23 abnormalities. It was found on the cell surface of acute myeloid leukemia (AML) blasts and cell lines derived from nonhematopoietic tissues. Samples of leukemic marrow from 166 children with AML enrolled on Childrens Cancer Group protocol 213 were evaluated for cell-surface expression of this proteoglycan molecule. In 18 of 166 (11%) patient samples, greater than 25% of leukemic blasts expressed the NG2 molecule. These 18 patients had a poorer outcome with respect to survival (P = .002) and event-free survival (P = .035) with an actuarial survival at 4 years of 16.7%. Blast cell expression of the NG2 molecule was strongly associated with French-American-British M5 morphology (P < .0001) and abnormalities in chromosome band 11q23, site of the MLL gene. These results show that the NG2 molecule is expressed by malignant hematopoietic cells that have abnormalities in chromosome band 11q23, suggesting that antibody 7.1 may be useful in the rapid identification of this group of poor-prognosis patients.     

Exploratory factor analysis and validation study of the lifetime severity index for cocaine, Spanish version (LSI-C-Spanish)

The purpose of the study was to do an exploratory factor analysis and to examine the criterion-related and discriminant validity of the Lifetime Severity Index for Cocaine (LSI-C), Spanish version. A sample of 171 outpatients from 10 drug centers in Spain participated in the study. We conducted the factor analysis with orthogonal rotation and examined correlations between the LSI-C total score and criterion variables as well as the score obtained by a quality of life measure. The factor analysis revealed 2 principal factors that explain 65.8% of the variance. Lower LSI-C scores were associated with taking medication, receiving social help, using cocaine fewer than 30 times during the previous 6 months, and with better scores on quality of life measures. Higher LSI-C scores were associated with unstable housing, overdose, hospitalization, cocaine consumption more than 100 times during the previous 6 months, and more years of drug consumption. The LSI-C Spanish version shows acceptable criterion-related and discriminant validity.