The effect of vaginal pH on labor induction with vaginal misoprostol

Objective.?To estimate the association of vaginal pH on the induction to vaginal delivery interval in labor induction with vaginal misoprostol.

Methods.?Women presenting at term with intact membranes for labor induction were recruited. The pH of the vagina was measured during a digital examination of the cervix to determine the Bishop Score. Labor was induced with 25?μg of vaginal misoprostol placed every 6?h until spontaneous rupture of membranes or active labor occurred. The primary outcome was the induction to vaginal delivery interval in the lower pH (?<?5) versus higher pH (???5) group. Secondary outcomes assessed maternal and neonatal morbidities. Sample size calculated a priori estimated 120 subjects were required for a power of 95% and a 2-tailed α of 0.05.

Results.?120 women met inclusion criteria and had available pH data. There was no difference in the induction to vaginal delivery interval in the lower pH (1455?min) versus higher pH group (1295 minutes, Mean difference 160[?147,468] P?=. 30). No difference was observed for operative delivery rates or neonatal outcomes.

Conclusion.?The pH of the vagina may not affect the length of the induction to vaginal delivery interval in women undergoing labor induction with vaginal misoprostol. Further research is required to determine factors that may influence the efficacy of vaginal misoprostol when used for labor induction.     

Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma

Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma.We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs.Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses.Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies.     

Role of biomarkers in the diagnosis and prognosis of acute kidney injury in patients with cardiorenal syndrome

Cardiac and renal disease frequently coexist but have long been difficult to diagnose in a timely manner and treat effectively. Noninvasive and cost-effective biomarkers are needed to help identify cardiac patients who are at risk of acute kidney injury early in the course of disease. Biomarkers can provide insights into underlying mechanisms and lead to a better understanding of complex disease states such as the cardiorenal syndrome, which can lead to better therapies and, ultimately, to improved patient outcomes. The natriuretic peptides are established biomarkers in heart failure and have set the standard for how a well-validated biomarker can be useful for diagnosis/prognosis, monitoring response to therapy and chronic disease management. For patients with acute kidney injury in the setting of cardiac disease, new biomarkers such as neutrophil gelatinase-associated lipocalin, cystatin C, kidney injury molecule-1 and IL-18 are emerging as early signals of renal dysfunction prior to any elevations in serum creatinine. Other promising candidate biomarkers for the early diagnosis of acute kidney injury include osteopontin, N-acetyl-b-d-glucosaminidase, stromal cell-derived factor-1 and exosomes. More research with all of these novel biomarkers is needed; however, the early results are very promising.     

Targeting the oncogene eIF4E in cancer: From the bench to clinical trials

Identifying and targeting specific oncogenes, with the hope that the resultant therapies may eventually prove to exert positive clinical effects, is a major effort in the area of cancer therapeutics. The eukaryotic translation initiation factor, eIF4E, is overexpressed in many cancers, including acute myeloid leukemia. The role of eIF4E in oncogenic transformation and the development of a means to directly target its activity with ribavirin are discussed here. Results from early stage clinical trials and factors contributing to the development of clinical resistance to ribavirin are also described.     

Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma

To assess the accumulation of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of patients with glioma and to define their heterogeneity and their immunosuppressive function. Peripheral blood mononuclear cells (PBMCs) from healthy control subjects and from patients with newly diagnosed glioma were stimulated with anti-CD3/anti-CD28 and T cells assessed for intracellular expression of interferon (IFN)-γ. Antibody staining of PBMCs from glioma patients and healthy donors (CD33, HLADR, CD15, and CD14) followed by 4-color flow cytometry analysis-defined MDSC levels in the peripheral blood. To assess the role of MDSCs in suppressing T cell IFNγ production, PBMCs were depleted of MDSCs using anti-CD33 and anti-CD15 antibody-coated beads prior to T cell stimulation. Enzyme-linked immunosorbent assays were used to assess plasma arginase activity and the level of granulocyte colony-stimulating factor (G-CSF). Patients with glioblastoma have increased MDSC counts (CD33+HLADR-) in their blood that are composed of neutrophilic (CD15(+); >60%), lineage-negative (CD15(-)CD14(-); 31%), and monocytic (CD14(+); 6%) subsets. After stimulation, T cells from patients with glioblastoma had suppressed IFN-γ production when compared with healthy, age-matched donor T cells. Removal of MDSCs from the PBMCs with anti-CD33/CD15-coated beads significantly restored T cell function. Significant increases in arginase activity and G-CSF levels were observed in plasma specimens obtained from patients with glioblastoma. The accumulation of MDSCs in peripheral blood in patients with glioma likely promotes T cell immune suppression that is observed in this patient population. Increased plasma levels of arginase and G-CSF may relate to MDSC suppressor function and MDSC expansion, respectively, in patients with glioma.     

Theranostic Gd(III)-lipid microbubbles for MRI-guided focused ultrasound surgery

We have synthesized a biomaterial consisting of Gd(III) ions chelated to lipid-coated, size-selected microbubbles for utility in both magnetic resonance and ultrasound imaging. The macrocyclic ligand DOTA-NHS was bound to PE headgroups on the lipid shell of pre-synthesized microbubbles. Gd(III) was then chelated to DOTA on the microbubble shell. The reaction temperature was optimized to increase the rate of Gd(III) chelation while maintaining microbubble stability. ICP-OES analysis of the microbubbles determined a surface density of 7.5 × 10⁵ ± 3.0 × 10⁵ Gd(III)/μm² after chelation at 50 °C. The Gd(III)-bound microbubbles were found to be echogenic in vivo during high-frequency ultrasound imaging of the mouse kidney. The Gd(III)-bound microbubbles also were characterized by magnetic resonance imaging (MRI) at 9.4 T by a spin-echo technique and, surprisingly, both the longitudinal and transverse proton relaxation rates were found to be roughly equal to that of no-Gd(III) control microbubbles and saline. However, the relaxation rates increased significantly, and in a dose-dependent manner, after sonication was used to fragment the Gd(III)-bound microbubbles into non-gas-containing lipid bilayer remnants. The longitudinal (r₁) and transverse (r₂) molar relaxivities were 4.0 ± 0.4 and 120 ± 18 mM⁻¹s⁻¹, respectively, based on Gd(III) content. The Gd(III)-bound microbubbles may find application in the measurement of cavitation events during MRI-guided focused ultrasound therapy and to track the biodistribution of shell remnants.