KAP Degradation by Calpain Is Associated with CK2 Phosphorylation and Provides a Novel Mechanism for Cyclosporine A-Induced Proximal Tubule Injury

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA

Benefit-Cost Analysis Using Data Envelopment Analysis Benefit-Cost Analysis using Data Envelopment Analysis

Abstract Benefit-cost analysis is required by law and regulation throughout the federal government. Rober

Performance evaluation based on multiple attributes with nonparametric frontiers

Performance rating and comparison of a group of entities is frequently based on the values of several attributes. Such evaluations are often complicated by the absence of a natural or obvious way to weight the importance of the individual dimensions of the performance. This paper proposes a framework based on nonparametric frontiers to rate and classify entities described by multiple performance attributes into 'performers' and 'underperformers'. The method is equivalent to Data Envelopment Analysis (DEA) with entities defined only by outputs. In the spirit of DEA, the weights for each attribute are selected to maximize each entity's performance score. This approach, however, results in a new linear program that is more direct and intuitive than traditional DEA formulations. The model can be easily understood and interpreted by practitioners since it conforms better to the practice of evaluating and comparing performance using standard specifications. We illustrate the model's use with two examples. The first evaluates the performance of employees. The second is an application in manufacturing where multiple quality attributes are used to assess and compare performance of different manufacturing processes.Performance evaluation Data Envelopment Analysis (DEA) Linear programming

Analysis of local control outcomes and clinical prognostic factors in localized pelvic Ewing sarcoma patients treated with radiation therapy: A Report from the Children\u27s Oncology Group

Purpose: To identify potential clinical prognostic factors associated with a higher risk of local recurrence in localized pelvic Ewing sarcoma (ES) patients treated with radiation therapy. Methods: Data for 101 patients treated with definitive radiotherapy (RT) or both surgery and radiation (S+RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review, so surgery alone patients were not included. Cumulative incidence rates for local failure at 5-years from time of local control were calculated accounting for competing risks. Results: The most common pelvic subsite was sacrum (44.6%). RT was utilized in 68% of patients and S+RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S+RT (p=0.046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (p=0.02, vs. sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, p=0.06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (p=0.04). Multivariable analysis demonstrated RT alone (HR 5.1, p=0.04), tumor subsite (particularly ischiopubic-acetabulum tumors, HR 4.6, p=0.02), and increasing volume per 100 mL (HR 1.2, p=0.01) were associated with a higher incidence of local recurrence. Conclusions: Combination surgery and RT is associated with improved local control in patients with pelvic ES compared to definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features