J. Larson

To investigate chromosomal events that underlie formation and progression of meningiomas, we have examined a set of 18 benign (WHO grade I), 15 atypical (grade II), and 13 anaplastic/malignant (grade III) meningiomas for loss of heterozygosity (LOH) on chromosomes 1p, 6p, 9q, 10q, and 14q. Frequent loss of loci on these chromosomes was seen in grade II and grade III tumors, specifically, 14q (II and III, 47 and 55%), 1p (40 and 70%), and 10q (27 and 40%). In contrast, LOH for these loci was infrequent in benign meningiomas, specifically, 14q (0%), 1p (11%), and 10q (12%). The smallest common regions of deletion that could be defined were 14q24-q32, 1p32-pter, and 10q24-qter. These observations indicate the likely presence of tumor suppressor genes in these regions that are involved in the development of WHO grade II and grade III meningiomas. Because LOH for loci on chromosomes 1p and 10q was found in tumors of all grades and because the frequency of LOH in all three regions increased with tumor grade, these results would support a model for the formation of aggressive meningiomas through tumor progression.

A plasmid encoding the human developmentally regulated endothelial locus-1 (hDel-1) protein formulated with poloxamer 188 is a potential gene therapy for peripheral arterial disease in man. As a prelude to clinical trials, the biodistribution and safety of this therapy were evaluated after intramuscular and intravenous administration in mice and rabbits. In mice, plasmid DNA persisted at the intramuscular injection site for at least 28 days, but was barely detectable in distal tissues by 24 h and essentially cleared by 28 days. By 24 h after intravenous administration, plasmid DNA was readily detected in blood, muscle, and lungs but sporadically and at low levels in other tissues. At 28 days, plasmid DNA was readily detectable only at the intravenous injection site (tail) after low- and high-dose administration, and sporadically in blood and muscle after high-dose administration. In rabbits, the highest intramuscular (4.2 mg kg(-1)) or intravenous (3.7 mg kg(-1)) dose caused no deaths; no treatment-related clinical signs; no changes in body weight, clinical pathology parameters, ophthalmology, ECG, or histopathology; and no detectable increase in antinuclear antibodies by 28 days. The results supported testing of hDel-1 plasmid-based gene therapy in phase I clinical trials.

Background: Simultaneous pancreas-kidney transplantation (SKPTx) is an accepted treatment option for patients with type 1 diabetes mellitus (T1DM) with advaced renal disease but outcomes in type 2 DM (T2DM) are still controversial. Objectives: To compare one-year outcomes of SKP recipients with T1DM and T2DM. Methods: Retrospective analysis of SPK transplant performed between October, 2009 and October, 2012. All patients underwent enteric and portal drainage and received induction with anti-thymocyte globulin followed by maintenance with tacrolimus, mychophenolate mofetil and steroids. Outcomes and baseline characteristics were evaluated using the chi-square test and the two-sample t-test. Results: Fifty-eight patients received a SPKTx: 41% were T1DM and 59% T2DM. No differences were observed in patient gender, race, BMI at transplant, donor age, or incidence of hypertension, hyperlipidemia or heart failure. Patients with T1DM were younger (37.9 vs. 47.1 years p<0.001) and had lower c-peptide level (0.77 vs. 6.25 ng/ml p=<0.001). Length of stay (13.6 vs.16.2 days, p=0.32) and number of readmissions at one year (2.1 vs. 2.1, p=0.95) were also similar between groups. Patients with T2DM experienced an significant increase in their BMI at one year compared with T1DM (T2DM by 2.64 kg/M2 vs. -0.23 kg/M2, p=0.02). Rejection rate at one year was similar between T1DM and T2DM groups (9.1 vs. 12.5%, p=0.68). Patient (97.1 vs. 100%, p=0.38) and graft survival (94.1 vs. 100%, p=0.48) statistically different between T1DM and T2DM groups. Discussion: T2DM recipients of SPKTx can achieve good outcomes comparable to T1DM patients. Increase BMI after SPKTx in T2DM could be a negative risk factor for long-term patient and graft survival and warrants further evaluation.