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

Long-term, treatment-free survival in select patients with distant metastatic papillary thyroid cancer

Well-differentiated thyroid carcinoma (WDTC) generally has a favorable prognosis. However, patients with distant metastatic disease experience progression of disease with a higher mortality. A subset of patients not previously described may challenge the conventional dogma regarding the progressive nature of all metastatic WDTC. Through analysis of our database, we identified patients with distant metastatic WDTC and persistent, minimally progressive disease. In all patients, persistent metastatic disease was confirmed via tissue biopsy, abnormal PET scan, and/or biochemical elevations in thyroglobulin or antibody levels. Progression of disease was monitored clinically and with repeat imaging. We describe five patients with WDTC and pulmonary metastases, aged 8–43 years at diagnosis. All patients underwent initial surgery and radioactive iodine (RAI) ablation, with some receiving multiple treatments. Persistent pulmonary metastatic disease was confirmed over decades (mean 22 years, range 8–42 years) with minimal progression despite no further treatment beyond thyroid hormone suppression. Persistent disease was biopsy-proven in all patients at a mean of 9.6 years from last RAI treatment. All patients had elevated thyroglobulin or anti-thyroglobulin antibody levels, while three demonstrated metabolically active disease with positive FDG uptake on PET scan, and one patient with persistent radioactive iodine avid pulmonary metastasis 36 years after her last RAI treatment. This case series demonstrates that some patients with distant metastases, even if metabolically active and radioactive iodine resistant, remain stable for decades without further treatment. Clinical awareness of such patients and continual reassessment of disease risk following initial therapy are crucial as aggressive treatment may not be necessary

A noninvasive multi-analyte diagnostic assay: Combining protein and DNA markers to stratify bladder cancer patients

Purpose: The authors recently reported the development of a noninvasive diagnostic assay using urinary matrix metalloproteinases (MMPs) as monitors of disease-free status and bladder cancer in high-risk populations. Using an approach called clinical intervention determining diagnostic (CIDD), they identified with high confidence those patients who could be excluded from additional intervention. To maximize performance, MMPs were combined with DNAbased markers and CIDD was applied to a population of patients undergoing monitoring for recurrence. Patients and methods: Urine samples were obtained from 323 patients, 48 of whom had a recurrence and 275 of whom did not have cancer upon cytoscopic evaluation. Twist1 and Nid2 methylation status was determined using methylation-specific polymerase chain reaction, FGFR3 mutational status by quantitative PCR, and MMP levels by enzyme-linked immunosorbent assay. Results: Using a combination of these DNA and protein markers, the authors identified with high confidence (97% negative predicted value) those patients who do not have cancer. Cutoffs were adjusted such that at 92% sensitivity, 51% of disease-free patients might be triaged from receiving further tests. Conclusion: The multi-analyte diagnostic readout assay described here is the first to combine protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of patients undergoing bladder cancer recurrence screening increase the sensitivity and negative predictive value at an established MMP protein cutoff. This noninvasive urinary diagnostic assay could lead to the more efficient triage of patients undergoing recurrence monitoring

Gender-specific 30-day outcomes after carotid endarterectomy and carotid artery stenting in the Society for Vascular Surgery Vascular Registry

ObjectiveAlthough the optimal treatment of carotid stenosis remains unclear, available data suggest that women have higher risk of adverse events after carotid revascularization. We used data from the Society for Vascular Surgery Vascular Registry to determine the effect of gender on outcomes after carotid endarterectomy (CEA) and carotid artery stenting (CAS).MethodsThere were 9865 patients (40.6% women) who underwent CEA (n = 6492) and CAS (n = 3373). The primary end point was a composite of death, stroke, and myocardial infarction at 30 days.ResultsThere was no difference in age and ethnicity between genders, but men were more likely to be symptomatic (41.6% vs 38.6%; P < .003). There was a higher prevalence of hypertension and chronic obstructive pulmonary disease in women, whereas men had a higher prevalence of coronary artery disease, history of myocardial infarction, and smoking history. For disease etiology in CAS, restenosis was more common in women (28.7% vs 19.7%; P < .0001), and radiation was higher in men (6.2% vs 2.6%; P < .0001). Comparing by gender, there were no statistically significant differences in the primary end point for CEA (women, 4.07%; men, 4.06%) or CAS (women, 6.69%; men, 6.80%). There remains no difference after stratification by symptomatology and multivariate risk adjustment.ConclusionsIn this large, real-world analysis, women and men demonstrated similar results after CEA or CAS. These data suggest that, contrary to previous reports, women do not have a higher risk of adverse events after carotid revascularization

Using Student Achievement Data to Support Instructional Decision Making

As educators face increasing pressure from federal, state, and local accountability policies to improve student achievement, the use of data has become more central to how many educators evaluate their practices and monitor students’ academic progress (Knapp et al., 2006). Despite this trend, questions about how educators should use data to make instructional decisions remain mostly unanswered. In response, this guide provides a framework for using student achievement data to support instructional decision making. These decisions include, but are not limited to, how to adapt lessons or assignments in response to students’ needs, alter classroom goals or objectives, or modify student-grouping arrangements. The guide also provides recommendations for creating the organizational and technological conditions that foster effective data use. Each recommendation describes action steps for implementation, as well as suggestions for addressing obstacles that may impedeprogress. In adopting this framework, educators will be best served by implementing the recommendations in this guide together rather than individually

The Scientific Method as a Scaffold to Enhance Communication Skills in Chemistry

Scientific success in the field of chemistry depends upon the mastery of a wide range of soft skills, most notably scientific writing and speaking. However, training for scientific communication is typically limited at the undergraduate level, where students struggle to express themselves in a clear and logical manner. The underlying issue is deeper than basic technical skills; rather, it is a problem of students’ unawareness of a fundamental and strategic framework for writing and speaking with a purpose. The methodology has been implemented for individual mentorship and in our regional summer research program to deliver a blueprint of thought and reasoning that endows students with the confidence and skills to become more effective communicators. Our didactic process intertwines undergraduate research with the scientific method and is partitioned into six steps, referred to as “phases”, to allow for focused and deep thinking on the essential components of the scientific method. The phases are designed to challenge the student in their zone of proximal development so they learn to extract and ultimately comprehend the elements of the scientific method through focused written and oral assignments. Students then compile their newly acquired knowledge to create a compelling and logical story, using their persuasive written and oral presentations to complete a research proposal, final report, and formal 20 min presentation. We find that such an approach delivers the necessary guidance to promote the logical framework that improves writing and speaking skills. Over the past decade, we have witnessed both qualitative and quantitative gains in the students’ confidence in their abilities and skills (developed by this process), preparing them for future careers as young scientists

Evaluation of noise regression techniques in resting-state fMRI studies using data of 434 older adults

Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer\u27s Disease (rrAD) trial included hypertensive older adults (60-84 years old) at elevated risk of developing Alzheimer\u27s Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults

Rationale and Methods for a Multicenter Clinical Trial Assessing Exercise and Intensive Vascular Risk Reduction in Preventing Dementia (rrAD Study)

Alzheimer\u27s Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer\u27s Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664