27 research outputs found
APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.
Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis
The Elite: A high speed, low-cost general aviation aircraft for Aeroworld
The Elite is a six passenger, general aviation aircraft targeted at the upper middle class private pilot. The Elite is a low wing, conventional monoplane utilizing rudder, ailerons, and a stabilator. The Elite will create a new class of aircraft in Aeroworld. This class of aircraft will demonstrate a substantial improvement in cruise speed over the current existing commercial fleet of aircraft in Aeroworld. This new class will be capable of servicing all existing airstrips in Aeroworld, including rough and short airways. The drivers of this design were aesthetics, a high cruise speed, and take-off distance
Prediction of Ureteral Injury During Colorectal Surgery Using Machine Learning
Background Ureteral injury (UI) is a rare but devastating complication during colorectal surgery. Ureteral stents may reduce UI but carry risks themselves. Risk predictors for UI could help target the use of stents, but previous efforts have relied on logistic regression (LR), shown moderate accuracy, and used intraoperative variables. We sought to use an emerging approach in predictive analytics, machine learning, to create a model for UI. Methods Patients who underwent colorectal surgery were identified in the National Surgical Quality Improvement Program (NSQIP) database. Patients were split into training, validation, and test sets. The primary outcome was UI. Three machine learning approaches were tested including random forest (RF), gradient boosting (XGB), and neural networks (NN), and compared with traditional LR. Model performance was assessed using area under the curve (AUROC). Results The data set included 262,923 patients, of whom 1519 (.578%) experienced UI. Of the modeling techniques, XGB performed the best, with an AUROC score of .774 (95% CI .742-.807) compared with .698 (95% CI .664-.733) for LR. Random forest and NN performed similarly with scores of .738 and .763, respectively. Type of procedure, work RVUs, indication for surgery, and mechanical bowel prep showed the strongest influence on model predictions. Conclusions Machine learning-based models significantly outperformed LR and previous models and showed high accuracy in predicting UI during colorectal surgery. With proper validation, they could be used to support decision making regarding the placement of ureteral stents preoperatively
HIV-associated primary lung cancer (LC) in the era of highly active antiretroviral therapy (HAART): a multi-institutional collaboration
Attacking Malaria with Equations: Mathematical Models and Their Role in Public Health Policy
Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer
Outline
- Definitions Total Neoadjuvant Therapy (TNT): delivery of chemoradiation and chemotherapy in the neoadjuvant setting Locally advanced rectal cancer: stage II (T3, T4N0) or stage III (Tany, N1/N2)
- Introduction Evolution of Rectal Cancer treatments Ongoing problems
- Total Neoadjuvant Therapy Past trials Ongoing Trials/Futur