Antiproliferative profile of sirolimus and mycophenolate mofetil: impact of the SI/MPL ratio

BACKGROUND: Recently, preliminary data of the ORBIT study have been presented; coronary restenosis after oral treatment with sirolimus (SRL) was merely 7.7%. The present study thought to investigate the antiproliferative profile of SRL and mycophenolate mofetil (MMF), both as individual compounds and as a combined therapy. METHODS AND RESULTS: Proliferation studies were carried out with smooth muscle cells of human coronary arteries (human coronary smooth muscle cells, HCMSMC). SRL (0.01-1000 ng/ml) and MMF (0.005-500 microg/ml) were added in six descending concentrations, cell proliferation was studied at day 5. To characterize the clinical relevance of the data, the authors calculated a SI/MPL ratio between a significant antiproliferative effect (SI) in vitro and the maximal systemic plasma level (MPL) in vivo. The SI/MPL ratios of SRL and MMF were 0.16 and 0.014, respectively. Second, SRL (1 and 0.1 ng/ml) was combined with four concentrations of MMF (0.5 and 0.05 microg/ml) and MMF was combined with four concentrations of SRL. Additive and overadditive antiproliferative effects were found, no destruction of alpha-tubulin was detected. CONCLUSIONS: Thus, SRL and MMF exhibit dose-dependent direct antiproliferative effects with SI/MPL ratios smaller than one. Both agents, as individual compounds or as combined therapy, are candidates for an oral therapy of human coronary restenosis.     

Neutralization of tumor-derived soluble glucocorticoid-induced TNFR-related protein ligand increases NK cell anti-tumor reactivity

NK cell anti-tumor reactivity is governed by a balance of activating and inhibitory receptors including various TNF receptor (TNFR) family members. Here we report that human tumor cells release a soluble form of the TNF family member Glucocorticoid-Induced TNFR-Related Protein (GITR) ligand (sGITRL), which can be detected in cell culture supernatants. Tumor-derived sGITRL concentration-dependently reduced NK cell cytotoxicity and IFN-gamma production, which could be overcome by neutralization of sGITRL using a GITR-Ig fusion protein. Although sGITRL did not induce apoptosis in NK cells, it diminished nuclear localized RelB, indicating that sGITRL negatively modulates NK cell NF-kappaB activity. Furthermore, we detected substantial levels of sGITRL in sera of patients with various malignancies, but not in healthy controls. Presence of sGITRL-containing patient serum in cocultures with tumor cells significantly reduced NK cell cytotoxicity and IFN-gamma production, which could again be restored by neutralization of sGITRL. The strong correlation of tumor incidence and elevated sGITRL levels indicates that sGITRL is released from cancers in vivo, leading to impaired NK cell immunosurveillance of human tumors. Our data suggest that determination of sGITRL levels might be implemented as a tumor marker in patients, and GITRL neutralization may be used to improve immunotherapeutic strategies relying on NK cell reactivity.     

Automatic control of the inspired oxygen fraction in preterm infants: a randomized crossover trial

In preterm infants receiving supplemental oxygen, manual control of the inspired oxygen fraction is often time-consuming and inappropriate. We developed a system for automatic oxygen control and hypothesized that this system is more effective than routine manual oxygen control in maintaining target arterial oxygen saturation levels. We performed a randomized controlled crossover clinical trial in 12 preterm infants receiving nasal continuous positive airway pressure and supplemental oxygen. Periods with automatic and routine manual oxygen control were compared with periods of optimal control by a fully dedicated person. The median (range) percentage of time with arterial oxygen saturation levels within target range (87-96%) was 81.7% (39.0-99.8) for routine manual oxygen control, 91.0% (41.4-99.3) for optimal control, and 90.5% (59.0-99.4) for automatic control (ANOVA: p = 0.01). Pairwise post hoc comparisons revealed a statistically significant difference between automatic and routine manual oxygen control (Dunnett's test: p = 0.02). The frequency of manual oxygen adjustments was lowest in automatic control (Friedman's test: p < 0.001). Automatic oxygen control may optimize oxygen administration to preterm infants receiving nasal continuous positive airway pressure and reduce nursing time spent with oxygen control.     

MR spectroscopic imaging and diffusion-weighted imaging of prostate cancer with Gleason scores

Purpose:

To investigate functional changes in prostate cancer patients with three pathologically proven different Gleason scores (GS) (3+3, 3+4, and 4+3) using magnetic resonance spectroscopic imaging (MRSI) and diffusion‐weighted imaging (DWI).

Materials and Methods:

In this study MRSI and DWI data were acquired in 41 prostate cancer patients using a 1.5T MRI scanner with a body matrix combined with an endorectal coil. The metabolite ratios of (Cho+Cr)/Cit were calculated from the peak integrals of total choline (Cho), creatine (Cr), and citrate (Cit) in MRSI. Apparent diffusion coefficient (ADC) values were derived from DWI for three groups of Gleason scores. The sensitivity and specificity of MRSI and DWI in patients were calculated using receiver operating characteristic curve (ROC) analysis.

Results:

The mean and standard deviation of (Cho+Cr)/Cit ratios of GS 3+3, GS 3+4, and GS 4+3 were: 0.44 ± 0.02, 0.56 ± 0.06, and 0.88 ± 0.11, respectively. For the DWI, the mean and standard deviation of ADC values in GS 3+3, GS 3+4, and GS 4+3 were: 1.13 ± 0.11, 0.97 ± 0.10, and 0.83 ± 0.08 mm²/sec, respectively. Statistical significances were observed between the GS and metabolite ratio as well as ADC values and GS.

Conclusion:

Combined MRSI and DWI helps identify the presence and the proportion of aggressive cancer (ie, Gleason grade 4) that might not be apparent on biopsy sampling. This information can guide subsequent rebiopsy management, especially for active surveillance programs. J. Magn. Reson. Imaging 2012;36:697–703. © 2012 Wiley Periodicals, Inc.     

Common variants of IL6, LEPR, and PBEF1 are associated with obesity in Indian children

The increasing prevalence of obesity in urban Indian children is indicative of an impending crisis of metabolic disorders. Although perturbations in the secretion of adipokines and inflammatory molecules in childhood obesity are well documented, the contribution of common variants of genes encoding them is not well investigated. We assessed the association of 125 common variants from 21 genes, encoding adipocytokines and inflammatory markers in 1,325 urban Indian children (862 normal weight [NW group] and 463 overweight/obese [OW/OB group]) and replicated top loci in 1,843 Indian children (1,399 NW children and 444 OW/OB children). Variants of four genes (PBEF1 [rs3801266] [P = 4.5 × 10(-4)], IL6 [rs2069845] [P = 8.7 × 10(-4)], LEPR [rs1137100] [P = 1.8 × 10(-3)], and IL6R [rs7514452] [P = 2.1 × 10(-3)]) were top signals in the discovery sample. Associations of rs2069845, rs1137100, and rs3801266 were replicated (P = 7.9 × 10(-4), 8.3 × 10(-3), and 0.036, respectively) and corroborated in meta-analysis (P = 2.3 × 10(-6), 3.9 × 10(-5), and 4.3 × 10(-4), respectively) that remained significant after multiple testing corrections. These variants also were associated with quantitative measures of adiposity (weight, BMI, and waist and hip circumferences). Allele dosage analysis of rs2069845, rs1137100, and rs3801266 revealed that children with five to six risk alleles had an approximately four times increased risk of obesity than children with less than two risk alleles (P = 1.2 × 10(-7)). In conclusion, our results demonstrate the association of the common variants of IL6, LEPR, and PBEF1 with obesity in Indian children.