Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors.

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.

Profiles of Radioresistance Mechanisms in Prostate Cancer.

Radiation therapy (RT) is commonly used for the treatment of localized prostate cancer (PCa). However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently causing metastasis and cancer recurrence. Understanding the molecular events that cause radioresistance in PCa will enable us to develop adjuvant treatments for enhancing the efficacy of RT. Radioresistant PCa depends on the elevated DNA repair system and the intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and scavenge anti-cancer regimens, whereas the elevated heat shock protein 90 (HSP90) and the epithelial-mesenchymal transition (EMT) enable radioresistant PCa cells to metastasize after exposure to radiation. The up-regulation of the DNA repairing system, ROS, HSP90, and EMT effectors has been studied extensively, but not targeted by adjuvant therapy of radioresistant PCa. Here, we emphasize the effects of ionizing radiation and the mechanisms driving the emergence of radioresistant PCa. We also address the markers of radioresistance, the gene signatures for the predictive response to radiotherapy, and novel therapeutic platforms for targeting radioresistant PCa. This review provides significant insights into enhancing the current knowledge and the understanding toward optimization of these markers for the treatment of radioresistant PCa.

Extracellular redox state shift: A novel approach to target prostate cancer invasion.

AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2•- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.

Use of the SONET score to evaluate Urgent Care Center overcrowding: a prospective pilot study.

OBJECTIVES: To derive a tool to determine Urgent Care Center (UCC) crowding and investigate the association between different levels of UCC overcrowding and negative patient care outcomes. DESIGN: Prospective pilot study. SETTING: Single centre study in the USA. PARTICIPANTS: 3565 patients who registered at UCC during the 21-day study period were included. Patients who had no overcrowding statuses estimated due to incomplete collection of operational variables at the time of registration were excluded in this study. 3139 patients were enrolled in the final data analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: A crowding estimation tool (SONET: Severely overcrowded, Overcrowded and Not overcrowded Estimation Tool) was derived using the linear regression analysis. The average length of stay (LOS) in UCC patients and the number of left without being seen (LWBS) patients were calculated and compared under the three different levels of UCC crowding. RESULTS: Four independent operational variables could affect the UCC overcrowding score including the total number of patients, the number of results pending for patients, the number of patients in the waiting room and the longest time a patient was stationed in the waiting room. In addition, UCC overcrowding was associated with longer average LOS (not overcrowded: 133±76 min, overcrowded: 169±79 min, and severely overcrowded: 196±87 min, p<0.001) and an increased number of LWBS patients (not overcrowded: 0.28±0.69 patients, overcrowded: 0.64±0.98, and severely overcrowded: 1.00±0.97). CONCLUSIONS: The overcrowding estimation tool (SONET) derived in this study might be used to determine different levels of crowding in a high volume UCC setting. It also showed that UCC overcrowding might be associated with negative patient care outcomes.

The inaccuracy of determining overcrowding status by using the national ED overcrowding study tool.

BACKGROUND: Emergency department (ED) crowding has become more common, and perceptions of crowding vary among different health care providers. The National Emergency Department Overcrowding Study (NEDOCS) tool is the most commonly used tool to estimate ED crowding but still uncertain of its reliability in different ED settings. OBJECTIVE: The objectives of this study are to determine the accuracy of using the NEDOCS tool to evaluate overcrowding in an extremely high-volume ED and assess the reliability and consistency of different providers' perceptions of ED crowding. MATERIAL AND METHODS: This was a 2-phase study. In phase 1, ED crowding was determined by the NEDOCS tool. The ED length of stay and number of patients who left without being seen were analyzed. In phase 2, a survey of simulated ED census scenarios was completed by different providers. The interrater and intrarater agreements of ED crowding were tested. RESULTS: In phase 1, the subject ED was determined to be overcrowded more than 75% of the time in which nearly 50% was rated as severely overcrowded by the NEDOCS tool. No statistically significant difference was found in terms of the average length of stay and the number of left without being seen patients under different crowding categories. In phase 2, 88 surveys were completed. A moderate level of agreement between health care providers was reached (κ = 0.5402, P < .0001). Test-retest reliability among providers was high (r = 0.8833, P = .0007). The strength of agreement between study groups and the NEDOCS was weak (κ = 0.3695, P < .001). CONCLUSION: Using the NEDOCS tool to determine ED crowding might be inaccurate in an extremely high-volume ED setting.

Using the LACE index to predict hospital readmissions in congestive heart failure patients.

BACKGROUND: The LACE index has been used to predict the risk of unplanned readmission within 30 days after hospital discharge in both medical and surgical patients. The aim of this study is to validate the accuracy of using the LACE index in CHF patients. METHODS: This was a retrospective study. The LACE index score was calculated on each patient who was admitted to hospital due to an acute CHF exacerbation. Operational and clinical variables were collected from patients including basic clinical characteristics, length of hospitalization, comorbidities, number of previous ED visits in the past 6 months before the index admission, and the number of post discharge ED revisits at 30, 60, and 90 days. All variables were analyzed by multivariate logistic regression to determine the association between clinical variables and the hospital unplanned readmissions. C-statistic was used to discriminate those patients with high risk of readmissions. RESULTS: Of the 253 patients included in the study, 24.50% (62/253) experienced unplanned readmission to hospital within 30 days after discharge. The LACE index was slightly higher in patients readmitted versus patients not readmitted (12.17 ± 2.22 versus 11.80 ± 1.92, p = 0.199). Adjusted odds ratios based on logistic regression of all clinical variables showed only the number of previous ED visits (OR 1.79, 95% CI 1.30-2.47, p < 0.001), history of myocardial infarction (OR 2.51, 95% CI 1.02-6.21, p = 0.045), and history of peripheral vascular disease (OR 10.75, 95% CI 1.52-75.73, p = 0.017) increased the risk of unplanned readmission within 30 days of hospital discharge. However, patients with high LACE scores (≥10) had a significantly higher rate of ED revisits (15.04% vs 0%) within 30 days from the index discharge than those with low LACE scores (p = 0.030). CONCLUSION: The LACE index may not accurately predict unplanned readmissions within 30 days from hospital discharge in CHF patients. The LACE high risk index may have utility as a screening tool to predict high risk ED revisits after hospital discharge.