Citations

Abstract Purpose: Some 85% of lung cancers are smoking related. Here, we investigate the role of serine protease HtrA3 in smoking-related lung cancer. Experimental Design: We assess HtrA3 methylation and its corresponding expression in the human bronchial cell line BEAS-2B following cigarette smoke carcinogen treatment, in lung cancer cell lines and in primary lung tumors from light, moderate, and heavy smokers. We also show the effects of HtrA3 downregulation on MTT reduction and clonogenic survival with etoposide and cisplatin treatment and the corresponding effects of HtrA3 re-expression during treatment. Results: We show for the first time that HtrA3 expression is reduced or completely lost in over 50% of lung cancer cell lines and primary lung tumors from heavy smokers. Treatment of HtrA3-deficient cell lines with 5-aza-2′-deoxycytidine resulted in a dose-dependent increase in HtrA3 transcription. Further, sequence analysis of bisulfite-modified DNA from lung cancer cell lines and from primary lung tumors showed an increased frequency of methylation within the first exon of HtrA3 with a corresponding loss of HtrA3 expression, particularly in tumors from smokers. In BEAS-2B, treatment with the cigarette smoke carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone resulted in HtrA3 downregulation with a corresponding increase in methylation. Additional studies indicate resistance to etoposide and cisplatin cytotoxicity as a functional consequence of HtrA3 loss. Finally, immunohistochemical analysis of primary lung tumors revealed a strong correlation between low HtrA3 expression and heavy smoking history. Conclusions: Collectively, these results suggest that cigarette smoke–induced methylation of HtrA3 could contribute to the etiology of chemoresistant disease in smoking-related lung cancer. Clin Cancer Res; 16(2); 398–409

OBJECTIVE:The goal was to investigate the effect of a “cough trick” technique on self-reported pain of children receiving routine immunizations. The strategy requires minimal equipment, time, or training for parents, children, and nursing staff members.METHODS:A randomized, controlled, unblinded, within-subject study of 68 children receiving prekindergarten (ages 4–5) or pre–junior high school (ages 11–13) immunizations was performed. Participants were recruited from an outpatient pediatric clinic at a large public hospital in the Midwest. The strategy required a single “warm-up” cough of moderate force, followed by a second cough that coincided with needle puncture. The principle outcome was self-reported pain, although parent and nurse report of pain was used to support the accuracy of self-report. Older participants and all nurses completed a measure of their satisfaction with the procedure.RESULTS:In the initial analysis, the procedure was found not to be effective. However, post hoc tests revealed that the procedure was effective at a statistically and clinically significant level for participants identified as Hispanic white or non-Hispanic white but not for those identified as non-Hispanic black. Participants and clinic nurses found the procedure acceptable and effective.CONCLUSIONS:The results of this study suggest that the cough trick can be an effective strategy for the reduction of pain for some children undergoing routine immunizations. However, additional research is needed to clarify the observed moderation by self-identified race.

During deployment of National Guard or reserve troops to Iraq or Afghanistan, spouses on the home front have been largely invisible to our collective consciousness. A total of 18 spouses living in rural Wisconsin were interviewed to identify sources of stress and coping strategies. Stressors varied from predeployment through postdeployment, as did coping responses. During predeployment, spouses articulated that the primary stressor was their lives being “on hold.” During deployment, five stressors summarize the experience: worrying, waiting, going it alone, pulling double duty, and loneliness. Communication technology made it possible for most spouses to stay in touch using telephone, e-mail, or even Webcam. Keeping busy—managing personal, family, and household responsibilities—was the most commonly identified coping strategy. Postdeployment was a period of adjustment while couples searched for a new normal. Throughout all deployment phases, skilled and astute nurses can assist families toward health and healing.

OBJECTIVE: Despite the magnitude of the problem of catheter-associated bloodstream infections (CA-BSIs) in children, relatively little research has been performed to identify effective strategies to reduce these complications. In this study, we aimed to develop and evaluate effective catheter-care practices to reduce pediatric CA-BSIs. STUDY DESIGN AND METHODS: Our study was a multi-institutional, interrupted time-series design with historical control data and was conducted in 29 PICUs across the United States. Two central venous catheter–care practice bundles comprised our intervention: the insertion bundle of pediatric-tailored care elements derived from adult efforts and the maintenance bundle derived from the Centers for Disease Control and Prevention recommendations and expert pediatric clinician consensus. The bundles were deployed with quality-improvement teaching and methods to support their adoption by teams at the participating PICUs. The main outcome measures were the rate of CA-BSIs from January 2004 to September 2007 and compliance with each element of the insertion and maintenance bundles from October 2006 to September 2007. RESULTS: Average CA-BSI rates were reduced by 43% across 29 PICUs (5.4 vs 3.1 CA-BSIs per 1000 central-line-days; P < .0001). By September 2007, insertion-bundle compliance was 84% and maintenance-bundle compliance was 82%. Hierarchical regression modeling showed that the only significant predictor of an observed decrease in infection rates was the collective use of the insertion and maintenance bundles, as demonstrated by the relative rate (RR) and confidence intervals (CIs) (RR: 0.57 [95% CI: 0.45–0.74]; P < .0001). We used comparable modeling to assess the relative importance of the insertion versus maintenance bundles; the results showed that the only significant predictor of an infection-rate decrease was maintenance-bundle compliance (RR: 0.41 [95% CI: 0.20–0.85]; P = .017). CONCLUSIONS: In contrast with adult ICU care, maximizing insertion-bundle compliance alone cannot help PICUs to eliminate CA-BSIs. The main drivers for additional reductions in pediatric CA-BSI rates are issues that surround daily maintenance care for central lines, as defined in our maintenance bundle. Additional research is needed to define the optimal maintenance bundle that will facilitate elimination of CA-BSIs for children.

The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin–conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.