Citations

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

AbstractTeams are the building blocks of the healthcare system, with growing evidence linking the quality of healthcare to team effectiveness, and team effectiveness to team training. Simulation has been identified as an effective modality for team training and assessment. Despite this, there are gaps in methodology, measurement, and implementation that prevent maximizing the impact of simulation modalities on team performance. As part of the 2017 Academic Emergency Medicine Consensus Conference “Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes,” we explored the impact of simulation on various aspects of team effectiveness. The consensus process included an extensive literature review, group discussions, and the conference “workshop” involving emergency medicine physicians, medical educators, and team science experts. The objectives of this work were to: 1) explore the antecedents and processes that support team effectiveness, 2) summarize the current role of simulation in developing and understanding team effectiveness, and 3) identify research targets to further improve team‐based training and assessment, with the ultimate goal of improving healthcare systems.

The present analyses provide separate norms for persons ages 56 to 93 years for each story from the Logical Memory subtests of the revised edition of the Wechsler Memory Scale. Norms for immediate (I) and delayed (II) trials are presented. Following our past Mayo's Older Americans Normative Studies (MOANS) methods, we established the need for age adjustments (but not education adjustments) based on multiple regression analyses. Norms with added reliability based on the method of overlapping intervals were developed. We present means and standard deviations for 3-year interval age groups from age 61 to 88 years.

Esophageal varices are a significant complication of portal hypertension. Endoscopic variceal ligation (EVL) is one of the clinical standards for treating these varices and preventing their hemorrhage. Limitations of EVL include the risk of stricture formation and postband ulcer bleeding due to the damage caused to the esophageal mucosa, as well as the need for multiple endoscopic treatment sessions to eradicate the varices. The goal of this study is to develop a device and evaluate the technical feasibility of microwave ablation to seal esophageal varices, while preventing thermal damage to the surface mucosal tissue. A microwave applicator with a directional radiation pattern was developed for endoscopic ablation of esophageal varices. Electromagnetic and bioheat transfer computational models were employed to optimize the design of the microwave applicator and evaluate energy delivery strategies for this application. Experiments in ex vivo and in vivo tissue were employed to verify simulation results. Simulations predicted enhanced heating performance of the antenna using an angled monopole radiating element. Further, simulations indicate that while the endoscopic cap attenuated electric fields in tissue, it also enhanced surface cooling of tissue, increasing the likelihood of preserving mucosal tissue. Experiments in ex vivo tissue indicated the feasibility of sealing veins with 77 W microwave power delivered for 30 s. In vivo experiments demonstrated the ability to seal veins, while preserving surface tissue. This study demonstrated the technical feasibility of microwave thermal ablation for treating esophageal varices using a 2.45 GHz water-cooled directional microwave applicator.

Background Bowel flaps are a good and reliable method to restore the continuity of the aerodigestive tract. Radiated fields, contaminated recipient sites, or depleted recipient vessels may increase the risk for ischemic injury after transfer. During ischemic events, we believe that bowel conduits with serosa have a delayed neovascularization process at its new recipient site.We conducted an ischemia/reperfusion murine model to understand the difference among bowel conduits with and without serosa. Materials and Methods Two groups of rats were compared: control group (jejunal conduit with serosa) and a target group (jejunal conduit without serosa). These conduits were harvested from the peritoneal cavity and transferred into a subcutaneous pocket. After 72 hours of transfer and pedicle ligation, histological changes related to ischemia/reperfusion were assessed. In addition, tissue markers of angiogenesis (CD34), ischemia (lactate dehydrogenase [LDH]), and inflammation (interleukin [IL]-1β and IL-6) were analyzed. Results Two groups (n = 20) of male rats were analyzed. Histology showed intact jejunal mucosa in the target group. The control group showed decreased number of mucin, globet cells, decreased height, and fragmentation of villi with the absence of intestinal glands. Markers of angiogenesis (CD34) were higher in the target group. In addition, markers of ischemia (LDH) (p = 0.0045) and inflammation (IL-1b, p = 0.0008, and IL-6, p = 0.0008) were significantly lower in the target group as compared with the control group. Conclusions In circumstances in which the recipient site does not offer an adequate and healthy bed or a vascular insult occurs, bowel flaps with less amount of serosa may be able to neovascularize faster thereby increasing its chances of survival.

AbstractNeurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full‐length (TrkB‐TK+) and truncated TrkB receptors (TrkB‐TK‐) in the human SEZ from infancy to middle age (n = 26–35, 41 days to 43 years). We further measured TrkB‐TK+ and TrkB‐TK‐ mRNAs in the SEZ from young adulthood into ageing (n = 50, 21–103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB‐TK‐ mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB‐TK+ mRNA remained stable. TrkB‐TK‐ mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete‐scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB‐TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.

AbstractThis work is to show which is more relevant to cause local failures (LFs) due to patient setup uncertainty between the planning target volume (PTV) underdosage and the potential target underdosage subject to patient setup uncertainties in head and neck (H&N) cancer treated with volumetric‐modulated arc therapy (VMAT). Thirteen LFs in 10 H&N patients treated by VMAT were analyzed. Measures have been taken to minimize the chances of insufficient target delineation for these patients and the patients were clinically determined to have LF based on the PET/CT scan results by an experienced radiologist and then reviewed by a second experienced radiation oncologist. Two methods were used to identify the possible locations of LF due to underdosage: (a) examining the standard VMAT plan, in which the underdosed volume in the nominal dose distribution (UVN) was generated by subtracting the volumes receiving the prescription doses from PTVs, and (b) plan robustness analysis, in which in addition to the nominal dose distribution, six perturbed dose distributions were created by translating the CT iso‐center in three cardinal directions by the PTV margin. The coldest dose distribution was represented by the minimum of the seven doses in each voxel. The underdosed volume in the coldest dose distribution (UVC) was generated by subtracting the volumes receiving the prescription doses in the coldest dose distribution from the volumes receiving the prescription doses in the nominal dose distribution. UVN and UVC were subsequently examined for spatial association with the locations of LF. The association was tested using the binominal distribution and the Fisher's exact test of independence. We found that of 13 LFs, 11 were associated with UVCs (P = 0.011), while three were associated with UVNs (P = 0.99). We concluded that the possible target underdosage due to patient setup uncertainties appeared to be a more relevant factor associated with LF in VMAT for H&N cancer than the compromised PTV coverage at least for the patients included in this study.

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two‐dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross‐validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross‐validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%‐81.1%). Overall cross‐validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%‐94.5%) for center 1, 90.0% (95% CI, 81.9%‐95.3%) for center 2, and 86.7% (95% CI, 77.9%‐92.9%) for automated analysis. Conclusion : 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (H epatology 2017;66:1474–1485)

Abstract Background Unsedated transnasal esophagoscopy (TNE) may offer a less expensive, mobile alternative to sedated esophagogastroduodenoscopy (EGD) for evaluations of reflux related complications. Comparisons of imaging quality by these methods are lacking. Methods Two reviewers evaluated videos of TNE and EGD procedures, performed during a community randomized study comparing endoscopic techniques. Subjects were randomized to EGD, TNE in endoscopy suite, or TNE in mobile research unit. Endoscopic quality was assessed using a validated scoring tool. Results In total, 115 videos (58 EGD, 28 endoscopy suite TNE, and 29 mobile TNE) were reviewed. Overall quality scores for TNE and EGD were excellent without a statistically significant difference (P = 0.30). There were no differences in gastroesophageal junction (GEJ) visualization scores, though EGD scored higher in esophageal passage (P < 0.05) and TNE scored higher in esophageal intubation (P < 0.05). There was no significant difference in any quality score between mobile TNE and gastrointestinal suite TNE. Conclusion Esophageal assessment with TNE or EGD was comparable in overall quality and GEJ visualization. TNE quality was not affected by procedure location. TNE is a feasible option for endoscopic assessment of reflux complications.