Code De-Escalation: Decreasing restraint use during agitation management in a community hospital emergency department.

INTRODUCTION: Restraint use in the emergency department (ED) can pose significant risks to patients and health care workers. We evaluate the effectiveness of Code De-escalation- a standardized, team-based approach for management and assessment of threatening behaviors- in reducing physical restraint use and workplace violence in a community ED. METHODS: A retrospective observational study of a pathway on physical restraint use among patients placed on an involuntary psychiatric hold in a community ED. This pathway includes a built-in step for the team members to systematically assess perceptions of threats from the patient behavior and threats perceived by the patient. Our primary outcome was the change in the rate of physical restraint use among patients on an involuntary psychiatric hold. Our secondary outcome was the change in the rate of workplace violence events involving all ED encounters. We evaluated our outcomes by comparing all encounters in a ten-month period before and after implementation, and compared our results to rates at neighboring community hospitals within the same hospital network. RESULTS: Pre intervention there were 434 ED encounters involving a psychiatric hold, post-intervention there were 535. We observed a significant decrease in physical restraint use, from 7.4% to 3.7% (ARR 0.028 [95% CI 0.002-0.055], p < 0.05). This was not seen at the control sites. CONCLUSIONS: A standardized de-escalation algorithm can be effective in helping ED's decrease their use of physical restraints in management of psychiatric patients experiencing agitation.

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.

BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

Emergency department visits for dental problems among adults with private dental insurance: A national observational study.

OBJECTIVE: Dental insurance may be a protective factor in reducing unnecessary emergency department (ED) use for nontraumatic dental pain. The purpose of this study was to 1) characterize patient demographics and identify risk factors associated with ED utilization for dental problems among individuals dually enrolled in medical and dental insurance and 2) investigate antibiotic and opioid prescription patterns among these patients following discharge. Further study of this unique population may provide insight into other causes of unmet dental need beyond lack of dental insurance. METHODS: Claims data from a large national managed health care plan from 2015 to 2018 were used to evaluate ED use for dental problems in patients with synchronous medical and dental insurance. National counts for ED visits, total visit costs, primary diagnoses, and outpatient treatments for antibiotics and opioids were assessed. Multivariable regression was used to assess any associated demographic and health-related variables. RESULTS: 1492 unique patients were admitted to the ED for dental pain and 429,376 unique patients presented for other symptoms. Utilization rates for nontraumatic dental pain were estimated to be 0.4% of all ED visits, with an average cost of $1487 per visit. Within three days following discharge from the ED, 58% of patients filled an opioid prescription and 38% filled an antibiotic prescription. Patients who presented for dental ED pain were more likely to be younger, live in a ZIP code with a lower median household income, have more medical comorbidities, and receive fewer preventive dental procedures within the prior year. CONCLUSION: Our findings demonstrate a low rate of ED utilization for nontraumatic dental pain among dentally insured patients and highlight the protective value of prior dental visits for reducing ED use. Given high rates of antibiotic and opioid prescription fill following discharge, comprehensive ED guidelines regarding appropriate antibiotic and opioid treatment pathways may be helpful to provide more definitive care to patients with dental insurance.

Complete genome sequence of a novel reassortant H3N3 avian influenza virus.

Aquatic birds are known to be a reservoir for the most common influenza A viruses (IAVs). In the annual surveillance program, we collected the feces of migratory birds for the detection of IAVs in South Korea in November 2016. A novel reassorted H3N3 avian influenza virus (AIV) containing genes from viruses of wild and domestic birds was identified and named A/aquatic bird/South Korea/sw006/2016(H3N3). The polymerase basic 2 (PB2) and non-structural (NS) genes of this isolate are most closely related to those of wild-bird-origin AIV, while the polymerase basic 1 (PB1), polymerase acidic (PA), hemagglutinin (HA), nucleoprotein (NP), neuraminidase (NA), and matrix (M) genes are most closely related to those of domestic-bird-origin AIV. A/aquatic bird/South Korea/sw006/2016 contains PA, NP, M, and NS genes were most closely related to those of AIV subtype H4 and PB2, PB1, and HA genes that are most closely related to those of AIV subtype H3N8, while the NA gene was most closely related to those of subtype H10, which was recently detected in humans in China. These results suggest that novel reassortment of AIV strains occurred due to interaction between wild and domestic birds. Hence, we emphasize the need for continued surveillance of avian influenza virus in bird populations.

Estimating Direct and Indirect Protective Effect of Influenza Vaccination in the United States.

With influenza vaccination rates in the United States recently exceeding 45% of the population, it is important to understand the impact that vaccination is having on influenza transmission. In this study, we used a Bayesian modeling approach, combined with a simple dynamical model of influenza transmission, to estimate this impact. The combined framework synthesized evidence from a range of data sources relating to influenza transmission and vaccination in the United States. We found that, for seasonal epidemics, the number of infections averted ranged from 9.6 million in the 2006-2007 season (95% credible interval (CI): 8.7, 10.9) to 37.2 million (95% CI: 34.1, 39.6) in the 2012-2013 season. Expressed in relative terms, the proportion averted ranged from 20.8% (95% CI: 16.8, 24.3) of potential infections in the 2011-2012 season to 47.5% (95% CI: 43.7, 50.8) in the 2008-2009 season. The percentage averted was only 1.04% (95% CI: 0.15, 3.2) for the 2009 H1N1 pandemic, owing to the late timing of the vaccination program in relation to the pandemic in the Northern hemisphere. In the future, further vaccination coverage, as well as improved influenza vaccines (especially those offering better protection in the elderly), could have an even stronger effect on annual influenza epidemics.

Effect of embedded shot on trace element concentrations in livers of Anseriformes species.

Trace elements were analyzed in the liver of white-fronted geese (Anser albifrons, n=15), mallards (Anas platyrhynchos, n=4) and spot-billed ducks (Anas poecilorhyncha, n=13) found dead in Gimpo, Korea. All mallards and eight spot-billed ducks had embedded lead shot. Embedded shot could be affected elevated trace element concentrations on geese and ducks. Element concentrations of cadmium (Cd), lead (Pb), chromium (Cr), aluminum (Al), copper (Cr), manganese (Mn) and zinc (Zn) differed among species and white-fronted geese without embedded shot had the lowest concentrations for all elements (geomean 0.36, 0.43, 0.07, 1.46, 7.60, 2.61 and 13.5µg/g dw, respectively). Cadmium in four (3.27-7.77µg/g dw) of 32 individuals and Pb in eight (5.07-9.72µg/g dw) of 32 individuals exceeded a tentative threshold effect level of Cd (>3.0µg/g dw) and Pb (>5.0µg/g dw) for birds; all geese and ducks for Cr (0.07-0.43µg/g dw) were within the background level (<4.0µg/g dw). All trace element concentrations were much greater in waterfowl species with embedded shot than without shot. Essential trace elements such as Cr, Al (geomean 1.46-37.3µg/g dw), Cu (7.60-57.1µg/g dw), Mn (2.61-27.6µg/g dw) and Zn (13.5-176µg/g dw) were within the normal range and were probably maintained by normal homeostatic mechanisms.

Timing of influenza A(H5N1) in poultry and humans and seasonal influenza activity worldwide, 2004-2013.

Co-circulation of influenza A(H5N1) and seasonal influenza viruses among humans and animals could lead to co-infections, reassortment, and emergence of novel viruses with pandemic potential. We assessed the timing of subtype H5N1 outbreaks among poultry, human H5N1 cases, and human seasonal influenza in 8 countries that reported 97% of all human H5N1 cases and 90% of all poultry H5N1 outbreaks. In these countries, most outbreaks among poultry (7,001/11,331, 62%) and half of human cases (313/625, 50%) occurred during January-March. Human H5N1 cases occurred in 167 (45%) of 372 months during which outbreaks among poultry occurred, compared with 59 (10%) of 574 months that had no outbreaks among poultry. Human H5N1 cases also occurred in 59 (22%) of 267 months during seasonal influenza periods. To reduce risk for co-infection, surveillance and control of H5N1 should be enhanced during January-March, when H5N1 outbreaks typically occur and overlap with seasonal influenza virus circulation.

Modeling the effect of different vaccine effectiveness estimates on the number of vaccine-prevented influenza-associated hospitalizations in older adults.

We compared influenza vaccine-prevented hospitalizations in adults aged ≥65 years for a range of hypothetical effectiveness estimates. During 2012-2013, a vaccine with 10% effectiveness (66% coverage) would have averted approximately 13 000 hospitalizations, and a vaccine with 40% effectiveness would have averted approximately 60 000 hospitalizations. Annual vaccination is merited in this vulnerable population.

VEGF-C mediates RhoGDI2-induced gastric cancer cell metastasis and cisplatin resistance.

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression is correlated with tumor growth, metastasis and chemoresistance in gastric cancer. However, the mechanisms by which RhoGDI2 promotes tumor cell survival and metastasis remain unclear. In this study, we clearly demonstrate that RhoGDI2 upregulates VEGF-C expression and RhoGDI2 expression is positively correlated with VEGF-C expression in human gastric tumor tissues as well as parental gastric cancer cell lines. VEGF-C depletion suppressed RhoGDI2-induced gastric cancer metastasis and sensitized RhoGDI2-overexpressing cells to cisplatin-induced apoptosis in vitro and in vivo. Secreted VEGF-C enhanced gastric cancer cell invasion and conferred cisplatin resistance to RhoGDI2-overexpressing cells. We also show that RhoGDI2 positively regulates Rac1 activity in gastric cancer cells. Inhibition of Rac1 expression suppressed RhoGDI2-induced VEGF-C expression, and this inhibition was associated with decreased invasiveness and increased sensitivity to cisplatin in RhoGDI2-overexpressing cells. Our results indicate that RhoGDI2 might be a potential therapeutic target for simultaneously reducing metastasis risk and enhancing chemotherapy efficacy in gastric cancer.

Estimated influenza illnesses and hospitalizations averted by vaccination--United States, 2013-14 influenza season.

The Advisory Committee on Immunization Practices recommends annual influenza vaccination for all persons aged ≥6 months to reduce morbidity and mortality caused by influenza in the United States. CDC previously developed a model to estimate that annual influenza vaccination resulted in 1.1-6.6 million fewer cases and 7,700-79,000 fewer hospitalizations per season during the 2005-2013 influenza seasons. For the 2013-14 influenza season, using updated estimates of vaccination coverage, vaccine effectiveness, and influenza hospitalizations, CDC estimates that influenza vaccination prevented approximately 7.2 million illnesses, 3.1 million medically attended illnesses, and 90,000 hospitalizations associated with influenza. Similar to prior seasons, fewer than half of persons aged ≥6 months are estimated to have been vaccinated. If influenza vaccination levels had reached the Healthy People 2020 target of 70%, an estimated additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations associated with influenza might have been averted. For the nation to more fully benefit from influenza vaccines, more effort is needed to reach the Healthy People 2020 target.

A Cost-Effectiveness Analysis of Adjuvant Nivolumab for Patients with Resected Esophageal Cancer or Gastroesophageal Junction Cancer in France.

INTRODUCTION: Esophageal and gastroesophageal junction cancer (EC/GEJC) is a poor prognosis disease with a high risk of recurrence even in patients curatively resected. Adjuvant nivolumab is currently used for patients with completely resected (R0) EC/GEJC who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. This study aimed to determine the cost effectiveness of nivolumab in this indication in France according to the collective perspective excluding indirect costs. MATERIALS AND METHODS: A simplified four-health-state semi-Markov model was developed to model EC/GEJC patients who have residual disease after neoadjuvant chemoradiotherapy followed by R0 over a 15-year time horizon, comparing adjuvant nivolumab versus surveillance, which was the recommended French clinical practice before immunotherapy arrival. Time-to-recurrence (TTR) from CheckMate 577 was used to inform transition from disease-free to post-recurrence health state; patients who recurred were split according to the distribution of type of recurrence observed during the trial. Post-recurrence survival (PRS) according to the type of recurrence was derived from a real-world registry. RESULTS: Adjuvant treatment with nivolumab led to an incremental survival gain of 1.19 years (+ 34%), mostly in the disease-free state, an incremental cost of €48,634 and QALY of 0.98 resulting in an incremental cost-utility ratio (ICUR) of €49,572/QALY with limited uncertainty. 'Cure assumption' at 5 years had an important impact on the results (€41,115/QALY; - 17%), as that tends to increase life-years and QALYs while costs remain the same. Probabilistic sensitivity analyses confirmed reference ICUR (€52,542/QALY) with 80% probability of nivolumab being cost effective at a willingness-to-pay threshold of €75,000/QALY. CONCLUSIONS: Our analysis suggests that adjuvant nivolumab is cost effective in the treatment of EC/GEJC patients who have residual disease after neoadjuvant CRT followed by R0 resection. Compared with previously evaluated cost-effectiveness analyses for other immune-checkpoint inhibitors indicated in metastatic settings, ICUR appears particularly low in this early setting thanks to the important impact on health outcomes and capped treatment duration.

Cost-effectiveness analysis of 3 radiation treatment strategies for patients with multiple brain metastases.

Background: Patients diagnosed with multiple brain metastases often survive for less than 2 years, and clinicians must carefully evaluate the impact of interventions on quality of life. Three types of radiation treatment are widely accepted for patients with multiple brain metastases: Whole brain radiation therapy (WBRT), hippocampal avoidance whole-brain radiation therapy (HA-WBRT), and stereotactic radiosurgery (SRS). WBRT, the standard option, is less costly than its newer alternatives but causes more severe adverse effects such as memory loss. To determine whether the cost-effectiveness ratio of HA-WBRT and SRS are superior to WBRT, we used published data to simulate cases of multiple brain metastases. Methods: We designed a Markov model using data from previously published studies to simulate the disease course of patients with 5 to 15 brain metastases and determine the cost-effectiveness of HA-WBRT and SRS relative to WBRT. Incremental cost-effectiveness ratios (ICERs) were calculated and compared against a willingness-to-pay threshold of $100 000 per quality-adjusted life year. Results: SRS met the threshold for cost-effectiveness, with ICERs ranging $41 198-$54 852 for patients with 5 to 15 brain metastases; however, HA-WBRT was not cost-effective, with an ICER of $163 915 for all simulated patients. Model results were robust to sensitivity analyses. Conclusions: We propose that SRS, but not HA-WBRT, should be offered to patients with multiple brain metastases as a treatment alternative to standard WBRT. Incorporating these findings into clinical practice will help promote patient-centered care and decrease national healthcare expenditures, thereby addressing issues around health equity and access to care.

Time Series Analysis of Congestive Heart Failure Discharges in Florida (USA) Post Tropical Cyclones.

OBJECTIVES: The aim of this study was to analyze congestive heart failure (CHF) discharges in Florida (USA) post tropical cyclones from 2007 through 2017. METHODS: This was a retrospective longitudinal time series analysis of hospital CHF quarterly discharges across Florida using the Healthcare Cost and Utilization Project (HCUP) database. The autoregressive integrated moving average (ARIMA) model was used with correlated seasonal regressor variables such as cyclone frequency, maximum cyclone wind speed, average temperature, and reports of influenza-like illness (ILI). RESULTS: A total of 3,372,993 patients were identified, with average age in each quarter ranging 72.2 to 73.9 years and overall mortality ranging 4.3% to 6.4%. The CHF discharges within each year peaked from October through December and nadired from April through June with an increasing overall time trend. Significant correlation was found between CHF discharge and the average temperature (P <.001), with approximately 331.8 less CHF discharges (SE = 91.7) per degree of increase in temperature. However, no significant correlation was found between CHF discharges and frequency of cyclones, the maximum wind speed, and reported ILI. CONCLUSIONS: This study suggests that with the current methods and the HCUP dataset, there is no significant increase in overall CHF discharges in Florida as a result of recent previous cyclone occurrences.

Correlation between pathologic complete response, event-free survival/disease-free survival and overall survival in neoadjuvant and/or adjuvant HR+/HER2-breast cancer.

Purpose: The study's purpose was to evaluate the correlation between overall survival (OS) and its potential surrogate endpoints: pathologic complete response (pCR) and event-free survival (EFS)/disease-free survival (DFS) in neoadjuvant and/or adjuvant HR+/HER2- breast cancer. Methods: Systematic search was performed in MEDLINE, EMBASE, Cochrane Library databases and other relevant sources to identify literature that have reported outcomes of interest in the target setting. The strength of correlation of EFS/DFS with OS, pCR with OS, and pCR with EFS/DFS was measured using Pearson's correlation coefficient (r) based on weighted regression analysis. For Surrogate Endpoint-True Endpoint pairs where correlation was found to be moderate, surrogate threshold effect (STE) was estimated using a mixed-effects model. Sensitivity analyses were conducted on the scale and weights used and removing outlier data. Results: Moderate correlation was observed of relative measures [log(HR)] of EFS/DFS and OS (r = 0.91; 95% CI: 0.83, 0.96, p < 0.0001). STE for HREFS/DFS was estimated to be 0.73. Association between EFS/DFS at 1, 2 and 3 years with OS at 4- and 5-year landmarks was moderate. Relative treatment effects of pCR and EFS/DFS were not strongly associated (r: 0.24; 95% CI: -0.63, 0.84, p = 0.6028). Correlation between pCR and OS was either not evaluated due to inadequate sample size (relative outcomes) or weak (absolute outcomes). Results obtained in the sensitivity analyses were similar to base scenario. Conclusion: EFS/DFS were moderately correlated with OS in this trial-level analysis. They may be considered as valid surrogates for OS in HR+/HER2- breast cancer.

Prognostic Performance of Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation III, and Simplified Acute Physiology Score II Scores in Patients with Suspected Infection According to Intensive Care Unit Type.

We investigated the prognostic performance of scoring systems by the intensive care unit (ICU) type. This was a retrospective observational study using data from the Marketplace for Medical Information in the Intensive Care IV database. The primary outcome was in-hospital mortality. We obtained Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) III, and Simplified Acute Physiology Score (SAPS) II scores in each ICU type. Prognostic performance was evaluated with the area under the receiver operating characteristic curve (AUROC) and was compared among ICU types. A total of 29,618 patients were analyzed, and the in-hospital mortality was 12.4%. The overall prognostic performance of APACHE III was significantly higher than those of SOFA and SAPS II (0.807, [95% confidence interval, 0.799-0.814], 0.785 [0.773-0.797], and 0.795 [0.787-0.811], respectively). The prognostic performance of SOFA, APACHE III, and SAPS II scores was significantly different between ICU types. The AUROC ranges of SOFA, APACHE III, and SAPS II were 0.723-0.826, 0.728-0.860, and 0.759-0.819, respectively. The neurosurgical and surgical ICUs had lower prognostic performance than other ICU types. The prognostic performance of scoring systems in patients with suspected infection is significantly different according to ICU type. APACHE III systems have the highest prediction performance. ICU type may be a significant factor in the prognostication.

Proteomics-based strategy to delineate the molecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastric cancer.

Rho GDP dissociation inhibitor 2 (RhoGDI2) was initially identified as a regulator of the Rho family of GTPases. Our recent works suggest that RhoGDI2 promotes tumor growth and malignant progression, as well as enhances chemoresistance in gastric cancer. Here, we delineate the mechanism by which RhoGDI2 promotes gastric cancer cell invasion and chemoresistance using two-dimensional gel electrophoresis (2-DE) on proteins derived from a RhoGDI2-overexpressing SNU-484 human gastric cancer cell line and control cells. Differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 47 differential protein spots were identified; 33 were upregulated, and 14 were downregulated by RhoGDI2 overexpression. Upregulation of SAE1, Cathepsin D, Cofilin1, CIAPIN1, and PAK2 proteins was validated by Western blot analysis. Loss-of-function analysis using small interference RNA (siRNA) directed against candidate genes reveals the need for CIAPIN1 and PAK2 in RhoGDI2-induced cancer cell invasion and Cathepsin D and PAK2 in RhoGDI2-mediated chemoresistance in gastric cancer cells. These data extend our understanding of the genes that act downstream of RhoGDI2 during the progression of gastric cancer and the acquisition of chemoresistance.

Disease-free survival as a surrogate endpoint for overall survival in adults with resectable esophageal or gastroesophageal junction cancer: A correlation meta-analysis.

OBJECTIVES: To evaluate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) using aggregate-level data from resectable esophageal or gastroesophageal junction cancer (EC/GEJC) trials assessing therapies in (neo)adjuvant and perioperative settings. METHODS: A systematic literature review was conducted to identify trials reporting OS and DFS, or compatible progression-free survival (PFS). Bivariate random-effects meta-analysis was used to estimate correlation between the treatment effects on DFS/PFS and OS, and weighted linear regression models assuming trial sample sizes as weights were used to estimate surrogacy equations. The primary analysis consisted of trials across all treatment settings, and secondary analysis consisted of trials only in the adjuvant setting. Leave-one-out cross-validation (LOOCV) was performed to measure the stability and predictive accuracy of the surrogacy equations while surrogate threshold effects (STE)-the minimum treatment effect on DFS/PFS that would translate into a positive OS benefit-were derived to measure their usefulness. RESULTS: The primary analysis included 26 trials. The estimated correlation coefficient between the hazard ratio (HR) of DFS/PFS (HRDFS/PFS) and HR of OS (HROS) was 0.83 (95% confidence interval [CI]: 0.70-0.90). The estimated surrogacy equation was log(HROS) = 0.80 × log(HRDFS/PFS) with a corresponding STE of 0.82. Reported HROS was within the 95% prediction interval of the predicted HROS from the model for more than 95% of the trials in the LOOCV, indicating a valid model. Secondary analysis included 7 trials with an estimated correlation coefficient of 0.76 (95% CI: 0.18-0.95). Through LOOCV, the surrogacy equation in the adjuvant setting was deemed valid. CONCLUSIONS: Our meta-analysis suggests that HRDFS/PFS -where DFS/PFS is defined as time from resection to disease recurrence (local, locoregional, or distant) or death-is correlated to HROS, and a valid and useful surrogate predictor for HROS in the neoadjuvant, perioperative, or adjuvant settings.

A Knock-In Mouse Model of Thymoma With the GTF2I L424H Mutation.

INTRODUCTION: The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear. METHODS: To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors. RESULTS: We observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas. CONCLUSIONS: We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies.

Gadd45b mediates Fas-induced apoptosis by enhancing the interaction between p38 and retinoblastoma tumor suppressor.

Gadd45b has been known as a positive mediator of apoptosis induced by certain cytokines and oncogenes. Here, we identified Gadd45b as an effector of Fas-induced apoptosis and found that p38-mediated Rb hyperphosphorylation is one of the mechanisms of Fas-induced apoptosis in murine hepatocyte AML12 cells. Gadd45b has been shown to activate p38 through its physical interaction with MTK1 and induce apoptosis. However, in this study, we have showed that the function of Gadd45b during Fas-induced apoptosis in AML12 cells is different from that reported in previous studies. Depletion of Gadd45b expression did not inhibit the phosphorylation of p38, but it suppressed p38-mediated Rb phosphorylation and apoptosis in response to Fas stimulation by reducing the interaction between p38 and Rb. Ectopic expression of Gadd45b was sufficient to enhance this interaction. These findings suggest that Gadd45b mediates p38-induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes.

PLCγ is required for RhoGDI2-mediated cisplatin resistance in gastric cancer.

Rho GDP dissociation inhibitor 2 (RhoGDI2) is a regulator of the Rho family GTPases. Recent work from our laboratory suggests that RhoGDI2 expression potentially enhances resistance to cisplatin as well as promotes tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that phospholipase C-gamma (PLCγ) is required for RhoGDI2-mediated cisplatin resistance and cancer cell invasion in gastric cancer. The levels of phosphorylated PLCγ are markedly enhanced in RhoGDI2-overexpressing SNU-484 cells and, by contrast, repressed in RhoGDI2-depleted MKN-28 cells. Depletion of PLCγ expression or inhibition of its activity not only significantly increases cisplatin-induced apoptosis but also suppresses the invasive ability of RhoGDI2-overexpressing SNU-484 cells. Taken together, our results suggest that PLCγ plays a key role in RhoGDI2-mediated cisplatin resistance and cell invasion in gastric cancer cells.