OBJECTIVE -Dysregulation of matrix metalloproteinase (MMP)-2 may contribute pathologically to the development of diabetes complications, including diabetic retinopathy and coronary and peripheral arterial disease. Our objective was to explore whether systemic MMP-2 dysregulation could be demonstrated in type 1 diabetes and to determine how MMP-2 concentration relates to disease status.RESEARCH DESIGN AND METHODS -In this cross-sectional study, MMP-2 concentrations and MMP-2 activity were measured in plasma and timed urine samples from 93 type 1 diabetic and 50 healthy control subjects, aged 14 -40 years. Relationships between MMP-2 concentrations in these biological fluids and subject characteristics (sex, age, and duration of type 1 diabetes), indexes of glycemic control (A1C, fasting plasma glucose, and continuous glucose monitoring system average daily glucose), and measurements of renal function (urinary albumin excretion and glomerular filtration rate) were examined.RESULTS -Urine and plasma MMP-2 concentrations and plasma MMP-2 activity were all significantly elevated in type 1 diabetic subjects compared with those in control subjects. Urine MMP-2 concentrations, in particular, were correlated with several clinical parameters that infer increased risk for diabetic comorbidity and specifically for diabetic nephropathy, including higher A1C, longer duration of disease, evidence of renal hyperfiltration, and the presence of microalbuminuria.CONCLUSIONS -Urine and plasma MMP-2 concentrations are dysregulated in type 1 diabetes; urinary excretion of MMP-2, in particular, might provide a unique biomarker of diabetes-induced intrarenal pathologic processes. Diabetes Care 30:2321-2326, 2007M atrix metalloproteinases (MMPs) constitute a group of enzymes that hydrolyze protein components of the extracellular matrix (1). The subgroup of MMPs known as gelatinases, specifically gelatinase A (MMP-2) and gelatinase B (MMP-9) digest collagen, denatured collagens (i.e., gelatins), laminin, elastin, and fibronectin, among other substrates (2), and have been implicated in the pathological processes that contribute to fibrotic diseases, tumor progression, and inflammation (1,3,4).Dysregulation of gelatinase activity has also been implicated in the pathophysiology of diabetes complications. Specifically, gelatinase concentrations are increased in the systemic circulation ) and in the vitreous (MMP-2 [6] and MMP-9 [7]) of type 1 diabetic patients with diabetic retinopathy. Elevated retinal levels of MMP-2 and MMP-9 have also been demonstrated in an animal model of diabetic retinopathy (8). Increased circulating concentrations of MMP-2 have been observed in pediatric patients with type 1 diabetes who developed microangiopathy over a 5-year interval (9). Systemic concentrations of MMP-2 and MMP-9, in addition to gelatinase activity levels, are also increased in patients with type 2 diabetes and peripheral arterial disease (10).Data suggesting a link between MMP-2 dysregulation and diabetic nephropathy also exist but appear contra...
: Non-surgical treatments for cervical intraepithelial neoplasia 2/3 (CIN2/3) are needed as surgical treatments have been shown to double preterm delivery rate. The goal of this study was to demonstrate safety of a human papillomavirus (HPV) therapeutic vaccine called PepCan, which consists of four current good-manufacturing production-grade peptides covering the HPV type 16 E6 protein and skin test reagent as a novel adjuvant.: The study was a single-arm, single-institution, dose-escalation phase I clinical trial, and the patients (n = 24) were women with biopsy-proven CIN2/3. Four injections were administered intradermally every 3 weeks in limbs. Loop electrical excision procedure (LEEP) was performed 12 weeks after the last injection for treatment and histological analysis. Six subjects each were enrolled (50, 100, 250, and 500 μg per peptide). : The most common adverse events (AEs) were injection site reactions, and none of the patients experienced dose-limiting toxicities. The best histological response was seen at the 50 μg dose level with a regression rate of 83% (n = 6), and the overall rate was 52% (n = 23). Vaccine-induced immune responses to E6 were detected in 65% of recipients (significantly in 43%). Systemic T-helper type 1 (Th1) cells were significantly increased after four vaccinations ( = 0.02). : This study demonstrated that PepCan is safe. A significantly increased systemic level of Th1 cells suggests that which induces interleukin-12 (IL-12) , may have a Th1 promoting effect. A phase II clinical trial to assess the full effect of this vaccine is warranted.
In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500μg per peptide dose, the 50μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50μg dose (7 of 14) and 100μg dose (3 of 6), and 45% overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in 3 subjects after vaccination, and the viral loads significantly decreased in 9 subjects in whom HPV 16 infection was detected at entry and exit (p=0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p=0.02 and p=0.0004 after 2 and 4 vaccinations respectively). T-helper type 2 cells initially increased after 2 vaccinations (p=0.01), but decreased below the baseline level after 4 vaccinations although not significantly. Pre-vaccination regulatory T-cell levels were significantly lower in histological responders compared to non-responders (p=0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.
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