Hepatocellular carcinoma (HCC) is a highly vascular tumour that expresses vascular endothelial growth factor (VEGF). Various studies have evaluated the prognostic value of VEGF levels in HCC. Its overall test performance remains unclear, however. The aim was to perform a systematic review and meta-analysis of prognostic cohort studies evaluating the use of VEGF as a predictor of survival in patients with treated HCC. Eligible studies were identified through multiple search strategies. Studies were assessed for quality using the Newcastle–Ottawa Tool. Data were collected comparing disease-free and overall survival in patients with high VEGF levels as compared to those with low levels. Studies were pooled and summary hazard ratios were calculated. A total of 16 studies were included for meta-analysis (8 for tissue and 8 for serum). Methodological analysis indicated a trend for higher study quality with serum studies as compared to tissue-based investigations. Four distinct groups were pooled for analysis: tissue overall survival (
n
=251), tissue disease-free survival (
n
=413), serum overall survival (
n
=579), and serum disease-free survival (
n
=439). High tissue VEGF levels predicted poor overall (HR=2.15, 95% CI: 1.26–3.68) and disease-free (HR=1.69, 95% CI: 1.23–2.33) survival. Similarly, high serum VEGF levels predicted poor overall (HR=2.35, 95% CI: 1.80–3.07) and disease-free (HR=2.36, 95% CI 1.76–3.16) survival. A high degree of inter-study consistency was present in three of four groups analysed. Tissue and serum VEGF levels appear to have significant predictive ability for estimating overall survival in HCC and may be useful for defining prognosis in HCC.
Autoimmunity presumably manifests as a consequence of a shortfall in the maintenance of peripheral tolerance by CD4+CD25+ T regulatory cells (Tregs). However, the mechanism underlying the functional impairment of Tregs remains largely undefined. In this study a glutamic acid decarboxylase (GAD) diabetogenic epitope was expressed on an Ig to enhance tolerogenic function, and the resulting Ig-GAD expanded Tregs in both young and older insulitis-positive, nonobese diabetic (NOD) mice, but delayed autoimmune diabetes only in the former. Interestingly, Tregs induced at 4 wk of age had significant active membrane-bound TGF-β (mTGF-β) and sustained protection against diabetes, whereas Tregs expanded during insulitis had minimal mTGF-β and could not protect against diabetes. The Tregs probably operate suppressive function through mTGF-β, because Ab blockade of mTGF-β nullifies protection against diabetes. Surprisingly, young Tregs that modulated pathogenic T cells maintained stable frequency over time in the protected animals, but decreased their mTGF-β at the age of 8 wk. More strikingly, these 8-wk-old mTGF-β-negative Tregs, which were previously protective, became unable to confer resistance against diabetes. Thus, a developmental decline in active mTGF-β nullifies Treg function, leading to a break in tolerance and the onset of diabetes.
IL-10, a powerful anti-Th1 cytokine, has shown paradoxical effects against diabetes. The mechanism underlying such variable function remains largely undefined. An approach for controlled mobilization of endogenous IL-10 was applied to the NOD mouse and indicated that IL-10 encounter with diabetogenic T cells within the islets sustains activation, while encounter occurring peripheral to the islets induces tolerance. Insulin β-chain (INSβ) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSβ triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSβ delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSβ was unable to suppress the disease in 10-wk-old insulitis-positive animals whose diabetogenic T cells have populated the islets. This is not due to irreversibility of the disease because soluble Ig-INSβ did delay diabetes in these older mice. Evidence is provided indicating that upon migration to the islet, T cells were activated and up-regulated CTLA-4 expression. IL-10, however, reverses such up-regulation, abolishing CTLA-4-inhibitory functions and sustaining activation of the islet T lymphocytes. Therefore, IL-10 supports T cell tolerance in the periphery, but its interplay with CTLA-4 sustains activation within the islets. As a result, IL-10 displays opposite functions against diabetes in young vs older insulitis-positive mice.
Guided growth with the eight-plate is a commonly used technique to correct angular limb deformities in children. However, the optimal combination of plate size, screw size, and screw configuration has not been determined. Using osteotomized femoral sawbones and a rail frame, we developed a growth model to examine the effect of these variables at 6-month, 12-month, and 18-month growth increments. The mean annual coronal plane change was 11.3°. Screw size and plate size were not associated with the rate of angular correction. Screw configuration was important, with parallel screws resulting in optimal correction at all time points compared with divergent screws (P<0.05).
This study suggests that the pathology technician is an important healthcare-related factor influencing lymph node recovery after gastrectomy. In identifying potential areas benefiting from a systems improvements approach, focus on the technical aspects of specimen processing may be of benefit in maximizing the number of lymph nodes recovered.
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