Citations

Abstract Purpose: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival. Experimental Design: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates. Results: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004). Conclusion: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.

AbstractPrimary systemic amyloidosis (AL) is a rare monoclonal plasma cell (PC) disorder characterized by the deposition of misfolded immunoglobulin (Ig) light chains (LC) in vital organs throughout the body. To our knowledge, no cell lines have ever been established from AL patients. Here we describe the establishment of the ALMC-1 and ALMC-2 cell lines from an AL patient. Both cell lines exhibit a PC phenotype and display cytokine-dependent growth. Using a comprehensive genetic approach, we established the genetic relationship between the cell lines and the primary patient cells, and we were also able to identify new genetic changes accompanying tumor progression that may explain the natural history of this patient's disease. Importantly, we demonstrate that free lambda LC secreted by both cell lines contained a beta structure and formed amyloid fibrils. Despite absolute Ig LC variable gene sequence identity, the proteins show differences in amyloid formation kinetics that are abolished by the presence of Na2SO4. The formation of amyloid fibrils from these naturally secreting human LC cell lines is unprecedented. Moreover, these cell lines will provide an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology.

ObjectiveTo evaluate the image quality of coronal reformatted CT images compared with direct coronal CT images.Study DesignCross‐sectional.Subjects and MethodsPatients who underwent paranasal sinus CT scans using both direct coronal images (DC) and axially acquired images with coronal reconstructions (CR) were consecutively enrolled. Two reconstruction groups were evaluated: group CR1 with 1‐mm axial collimation and group CR2 with 0.625‐mm axial collimation. Scans were presented in a randomized, blinded fashion to two sinus surgeons and a neuroradiologist.ResultsWhen compared with CR1, DC images had higher image quality for each of five key anatomic landmarks (P <. 0001). DC images were more likely to be adequate preoperative imaging (P <. 0001). When compared with CR2, improved DC image quality was noted in the majority of key anatomic landmarks. No difference was noted in the “adequacy rating” between the DC and CR2 (0.625 mm) protocols.ConclusionThe 0.625‐mm reformatted images were judged to be adequate preoperative imaging. The additional information provided by multiple‐image planes make reformatted 0.625‐mm axial images an acceptable approach.

Cholangiocytes, the epithelial cells lining bile ducts, provide the first line of defense against lumenal microbes in the biliary system. Recent advances in biliary immunity indicate that cholangiocytes express a variety of pathogen‐recognition receptors and can activate a set of intracellular signaling cascades to initiate a profound antimicrobial defense, including release of proinflammatory cytokines and chemokines, production of antimicrobial peptides and maintenance of biliary epithelial integrity. Cholangiocytes also interact with other cell types in the liver (for example, lymphocytes and Kupffer cells) through expression and release of adhesion molecules and immune mediators. Subsequently, through an intricate feedback mechanism involving both epithelial and other liver cells, a set of intracellular signaling pathways are activated to regulate the functional state of cholangiocyte responses during microbial infection. Thus, cholangiocytes are actively involved in mucosal immunity of the biliary system and represent a fine‐tuned, integral component of liver immunity.

Background. Annual foot examinations (FE) constitute a critical component of care for diabetes. Documented evidence of FE is central to quality-of-care reporting; however, manual abstraction of electronic medical records (EMR) is slow, expensive, and subject to error. The objective of this study was to test the hypothesis that text mining of the EMR results in ascertaining FE evidence with accuracy comparable to manual abstraction. Methods. The text of inpatient and outpatient clinical reports was searched with natural-language (NL) queries for evidence of neurological, vascular, and structural components of FE. A manual medical records audit was used for validation. The reference standard consisted of 3 independent sets used for development (n=200 ), validation (n=118 ), and reliability (n=80 ). Results. The reliability of manual auditing was 91% (95% confidence interval [CI]= 85— 97) and was determined by comparing the results of an additional audit to the original audit using the records in the reliability set. The accuracy of the NL query requiring 1 of 3 FE components was 89% (95% CI= 83— 95). The accuracy of the query requiring any 2 of 3 components was 88% (95% CI= 82— 94). The accuracy of the query requiring all 3 components was 75% (95% CI= 68— 83). Conclusions. The free text of the EMR is a viable source of information necessary for quality of health care reporting on the evidence of FE for patients with diabetes. The low-cost methodology is scalable to monitoring large numbers of patients and can be used to streamline quality-of-care reporting.