Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats.

A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.

Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma.

Myxoma virus (MyxV) is a rabbit-specific poxvirus. However, its ability to selectively target tumor cells has established it as a safe and effective anticancer therapy. To strengthen its preclinical efficacy, transgenes that can prolong cancer cell infection and enhance anti-tumor effector functions are currently being investigated. We engineered MyxV armed with CD47, to turn on a 'do not eat me' signal within infected cells with actively replicating viruses, and with IFN-γ to further activate host immune anticancer responses. Tumor suppressive activities were significantly enhanced by the dual-armed MyxV_CD47/IFN-γ compared to parental MyxV or single-armed MyxV_CD47 or MyxV_IFN-γ. In addition, significant increases in IFN-γ+ CD8+T-cells and CD4+ T-cells populations within tumor-infiltrating lymphocytes (TIL) were observed after MyxV_CD47/IFN-γ treatment. Notably, all groups treated with MyxV showed a marked reduction in Foxp3+ CD4+ regulatory T-cells (Tregs) within TIL. We also show that MyxV infection induces PD-L1 up-regulation in cancer cells, and combinational treatment of MyxV with anti-mouse PD-L1 antibodies (αPD-L1) further controlled tumor burden and increased survival in the syngeneic melanoma model B16F10. Our data demonstrate that a CD47 and IFNγ dual-armed MyxV is an effective oncolytic viral immunotherapeutic. These findings strongly support further preclinical investigations to develop next-generation MyxV-based immunotherapy approaches.

Comparison of Fused Diffusion-Weighted Imaging Using Unenhanced MRI and Abbreviated Post-Contrast-Enhanced MRI in Patients with Breast Cancer.

Background and Objectives: To determine the percentage of breast cancers detectable by fused diffusion-weighted imaging (DWI) using unenhanced magnetic resonance imaging (MRI) and abbreviated post-contrast-enhanced MRI. Materials and Methods: Between October 2016 and October 2017, 194 consecutive women (mean age, 54.2 years; age range, 28-82 years) with newly diagnosed unilateral breast cancer, who underwent preoperative 3.0 T breast MRI with DWI, were evaluated. Both fused DWI and abbreviated MRI were independently reviewed by two radiologists for the detection of index cancer (which showed the most suspicious findings in both breasts), location, lesion conspicuity, lesion type, and lesion size. Moreover, the relationship between cancer detection and histopathological results of surgical specimens was evaluated. Results: Index cancer detection rates were comparable between fused DWI and abbreviated MRI (radiologist 1: 174/194 [89.7%] vs. 184/194 [94.8%], respectively, p = 0.057; radiologist 2: 174/194 [89.7%] vs. 183/194 [94.3%], respectively, p = 0.092). In both radiologists, abbreviated MRI showed a significantly higher lesion conspicuity than fused DWI (radiologist 1: 9.37 ± 2.24 vs. 8.78 ± 3.03, respectively, p < 0.001; radiologist 2: 9.16 ± 2.32 vs. 8.39 ± 2.93, respectively, p < 0.001). The κ value for the interobserver agreement of index cancer detection was 0.67 on fused DWI and 0.85 on abbreviated MRI. For lesion conspicuity, the intraclass correlation coefficients were 0.72 on fused DWI and 0.82 on abbreviated MRI. Among the histopathological factors, tumor invasiveness was associated with cancer detection on both fused DWI (p = 0.011) and abbreviated MRI (p = 0.004, radiologist 1), lymphovascular invasion on abbreviated MRI (p = 0.032, radiologist 1), and necrosis on fused DWI (p = 0.031, radiologist 2). Conclusions: Index cancer detection was comparable between fused DWI and abbreviated MRI, although abbreviated MRI showed a significantly better lesion conspicuity.

Antibacterial and antibiofilm activities of cinnamon essential oil nanoemulsion against multi-species oral biofilms.

Cinnamon essential oil (CEO) has antibacterial properties, but its ability to suppress the formation of multi-species oral biofilms has not been fully elucidated. This study evaluated the antibacterial and antibiofilm activities of cinnamon essential oil nanoemulsion (CEON) against oral biofilms formed using a microcosm biofilm model. The biofilms were formed on bovine enamel specimens over a 7-day period, during which all specimens were treated with one of three solutions: 5% CEON (n = 35), 0.5% cocamidopropyl betaine (n = 35), or 0.12% chlorhexidine gluconate (CHX; n = 35). Antibacterial and antibiofilm activities were determined by the red/green ratios (R/G values) of 7-day-old mature biofilms photographed with quantitative light-induced fluorescence-digital, the number of aciduric bacterial colony-forming units (CFUs) within each biofilm, and the absorbance of bacterial suspensions. One-way and repeated-measures analysis of variance were performed to compare differences among the three solutions. R/G values were lowest in the 0.12% CHX group, but not significantly differ from the 5% CEON group. The number of CFUs and absorbance were lowest in the 5% CEON group. This study showed that nanoemulsified CEO inhibited the maturation of multi-species oral biofilms and the growth of oral microorganisms in biofilms, including aciduric bacteria that cause dental caries.

The effect of indirect vision skills on head and shoulder posture amongst Korean dental hygienists.

OBJECTIVES: This study aimed to investigate the effects of indirect vision skills on head and shoulder posture in dental hygienists. MATERIALS AND METHODS: This cross-sectional study included a total of 100 female clinical dental hygienists. It evaluated musculoskeletal symptoms of the neck, shoulders and back, head and shoulder posture (craniovertebral angle [CVA] and sagittal shoulder posture angle [SSPA]). Indirect vision skills were assessed using the O'Connor tweezer test under indirect vision with a mirror. To analyse factors associated with the CVA and SSPA, an independent t test, one-way ANOVA, and multiple linear regression analysis were conducted, respectively. RESULTS: The body region in which the greatest number of symptoms of work-related musculoskeletal disorders was recognised was the neck (89.0%). In the multiple linear regression model, which adjusted for other factors associated with musculoskeletal disorders, dental hygienists with poor indirect vision skills showed relatively small SSPA value (P < .05). However, indirect vision skills were not associated with the CVA value. CONCLUSIONS: Good indirect vision skills contribute to the prevention of rounded shoulders in dental hygienists. Therefore, where possible, dental hygienists should perform clinical procedures using indirect vision with a dental mirror to maintain a balanced posture and reduce flexion of the back or the neck. A dental hygiene curriculum should include training to improve clinical skills, as well as education regarding dental ergonomics and a monitoring system to determine whether ergonomic principles are well observed.

Image quality and radiation dose of CT venography with double dose reduction using model based iterative reconstruction: comparison with conventional CT venography using filtered back projection.

Background Computed tomography venography (CTV) at low kVp using model-based iterative reconstruction (MBIR) can enhance vascular enhancement with noise reduction. Purpose To evaluate image qualities and radiation doses of CTV at 80 kVp using MBIR and a small iodine contrast media (CM) dose and to compare these with those of CTV performed using a conventional protocol. Material and Methods Sixty-five patients (mean age = 58.1 ± 7.2 years) that underwent CTV for the evaluation of deep vein thrombosis (DVT) and varicose veins were enrolled in this study. Patients were divided into two groups: Group A (35 patients, 80 kVp, MBIR, automatic tube current modulation, CM = 270 mg/mL, 100 mL) and Group B (30 patients, 100 kVp, filtered back projection [FBP], 120 fixed mA, CM = 370 mg/mL, 120 mL). Objective and subjective image qualities of inferior vena cava (IVC), femoral vein (FV), and popliteal vein (PV) were assessed and radiation doses were recorded. Results Mean vascular enhancement in group A was significantly lower than in group B ( P < 0.01). Noise in group A was significantly lower than in group B except for PV and contrast-to-noise ratio were not significantly different in the two groups ( P > 0.05). In addition, radiation dose in group A was significantly lower than in group B ( P < 0.001). Subjective image quality comparison revealed group A was statistically inferior to group B except for subjective image noise. Conclusion CTV at 80 kVp using MBIR with small iodine contrast dose provided acceptable image quality at a lower radiation dose than conventional CTV using FBP.

The influence of the adiponectin gene on adiponectin concentrations and parameters of metabolic syndrome in non-diabetic Korean women.

BACKGROUND: Concentrations of adiponectin, the protein product of the adipocyte C1q and collagen-domain-containing (ADIPOQ) gene are associated with type 2 diabetes and coronary artery disease. We investigate the association of single-nucleotide polymorphisms (SNPs) in the ADIPOQ gene with adiponectin concentrations, and to parameters of metabolic syndrome. METHODS: 867 unrelated, non-diabetic Korean women, 20 to 69 y, were genotyped for 8 SNPs in the ADIPOQ gene (-11391G>A, -11377C>G, H241P, Y111H, G90S, R221S, 45T>G, 276G>T). Adiponectin, a homeostasis model assessment of insulin resistance (HOMA-IR), and metabolic parameters were measured. RESULTS: Carriers of genotype T/T at position 276 had significantly higher adiponectin concentrations than G/G carriers (P=0.005). Homozygous carriers of the TG haplotype (i.e., individuals who were T/T at 45 and G/G at 276) and heterozygous carriers of the TG haplotype (TG/X) had lower adiponectin concentrations than non-TG carriers (P<0.001). Significant associations between SNP at 276 and serum concentrations of triglyceride (P=0.013), insulin (P=0.013) and HOMA-IR (P=0.012) were found. The 45-276 haplotypes had associations identical to the 276G>T SNP. In subgroup analysis, subjects carrying the TG haplotype had significantly lower adiponectin concentrations than non-TG carriers in both normal weight (P<0.001) and overweight-obese (P=0.009) subgroups. The association of the TG haplotype with increasing insulin concentrations was significant among overweight-obese subjects (P=0.004), but was not significant among normal weight subjects. A similar association was found between the 45-276 haplotype and HOMA-IR. CONCLUSION: There is a strong association of the adiponectin SNP276 genotypes and the adiponectin 45-276 haplotypes with circulating adiponectin concentrations in non-diabetic Korean women. In addition, this haplotype is associated with increased insulin concentrations and insulin resistance index only in overweight-obese individuals.