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

A Benzimidazole Proton Pump Inhibitor Increases Growth and Tolerance to Salt Stress in Tomato

Pre-treatment of tomato plants with micromolar concentrations of omeprazole (OP), a benzimidazole proton pump inhibitor in mammalian systems, improves plant growth in terms of fresh weight of shoot and roots by 49 and 55% and dry weight by 54 and 105% under salt stress conditions (200 mM NaCl), respectively. Assessment of gas exchange, ion distribution, and gene expression profile in different organs strongly indicates that OP interferes with key components of the stress adaptation machinery, including hormonal control of root development (improving length and branching), protection of the photosynthetic system (improving quantum yield of photosystem II) and regulation of ion homeostasis (improving the K+:Na+ ratio in leaves and roots). To our knowledge OP is one of the few known molecules that at micromolar concentrations manifests a dual function as growth enhancer and salt stress protectant. Therefore, OP can be used as new inducer of stress tolerance to better understand molecular and physiological stress adaptation paths in plants and to design new products to improve crop performance under suboptimal growth conditions.Highlight: Omeprazole enhances growth of tomato and increases tolerance to salinity stress through alterations of gene expression and ion uptake and transport

Abstract C54: Reducing time-to-treatment in underserved Latinas with breast cancer: The Six Cities Study

Abstract Background: Breast cancer is the leading cause of Latina cancer deaths. Time from diagnosis to treatment is critical in optimizing care. Patient navigation (PN) holds promise for timely breast cancer treatment promotion, yet efficacy among underserved women is insufficiently documented. Methods: Redes En Acción: The National Latino Cancer Research Network evaluated a theory-driven, culturally-sensitive PN program for Latinas with breast cancer in six U.S. cities. We analyzed 109 Latinas diagnosed with breast cancer from July 2008-January 2011 (42 navigated, 67 controls). We evaluated proportions of women treated within 30 and 60 days of diagnosis and overall time to treatment. Women were navigated by locally trained navigators, or non-navigated. Kaplan-Meier, Cox proportional hazards and logistic regression models were used to determine group differences. Results: A higher percentage of navigated subjects initiated treatment within 30 days (66.7% versus 56.7%, p=0.045) and 60 days (97.8% versus 78.4%, p=0.021). Overall navigated women experienced shorter time to treatment initiation (HR=1.60, p=0.000). These results were independent of stage at diagnosis, cancer clinic and participant characteristics. Five navigator activities were associated with faster treatment times: accompaniment (p=0.006), transportation arrangements (p=0.013), patient telephone support (generally emotional support, p=0.034), patient-family telephone support (p=0.030), and Spanish-English language translation services (p=0.002). Conclusions: Patient-centered navigation to assist Latina women with breast cancer diagnoses increases the proportion of women beginning treatment within 30 and 60 days of diagnosis and significantly reduces overall time from diagnosis to treatment. Improvement appears to be associated with specific navigator activities. Citation Format: Amelie G. Ramirez, Eliseo J. Perez-Stable, Frank Penedo, Gregory A. Talavera, J. Emilio Carillo, Maria F. Fernandez, Alan E.C. Holden, Edgar Munoz, Kipling Gallion. Reducing time-to-treatment in underserved Latinas with breast cancer: The Six Cities Study. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C54. doi:10.1158/1538-7755.DISP13-C54</jats:p

Abstract 4450: Navigating Latinas with breast screen abnormalities to diagnosis: The Six Cities Study

BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in Latinas, chiefly because of later diagnosis. The time from screening to diagnosis is critical to optimizing cancer care, yet the efficacy of navigation in reducing it is insufficiently documented. Here, the authors evaluate a culturally sensitive patient navigation program to reduce the time to diagnosis and increase the proportions of women diagnosed within 30 days and 60 days. METHODS: The authors analyzed 425 Latinas who had Breast Imaging Reporting and Data System (BI-RADS) radiologic abnormalities categorized as BI-RADS-3, BI-RADS-4, or BI-RADS-5 from July 2008 to January 2011. There were 217 women in the navigated group and 208 women in the control group. Women were navigated by locally trained navigators or were not navigated (data for this group were abstracted from charts). The Kaplan-Meier method, Cox proportional hazards regression, and logistic regression were used to determine differences between groups. RESULTS: The time to diagnosis was shorter in the navigated group (mean, 32.5 days vs 44.6 days in the control group; hazard ratio, 1.32; P = .007). Stratified analysis revealed that navigation significantly shortened the time to diagnosis among women who had BI-RADS-3 radiologic abnormalities (mean, 21.3 days vs 63.0 days; hazard ratio, 2.42; P < .001) but not among those who had BI-RADS-4 or BI-RADS-5 radiologic abnormalities (mean, 37.6 days vs 36.9 days; hazard ratio, 0.98; P = .989). Timely diagnosis occurred more frequently among navigated Latinas (within 30 days: 67.3% vs 57.7%; P = .045; within 60 days: 86.2% vs 78.4%; P = .023). This was driven by the BI-RADS-3 strata (within 30 days: 83.6% vs 50%; P < .001; within 60 days: 94.5% vs 67.2%; P < .001). A lack of missed appointments was associated with timely diagnosis. CONCLUSIONS: Patient-centered navigation to assist Latina women with abnormal screening mammograms appeared to reduced the time to diagnosis and increase rates of timely diagnosis overall. However, in stratified analyses, only navigated Latinas with an initial BI-RADS-3 screen benefited, probably because of a reduction in missed diagnostic appointments