Analytic lymph node number establishes staging accuracy by occult tumor burden in colorectal cancer.

BACKGROUND AND OBJECTIVES: Recurrence in lymph node-negative (pN0) colorectal cancer suggests the presence of undetected occult metastases. Occult tumor burden in nodes estimated by GUCY2C RT-qPCR predicts risk of disease recurrence. This study explored the impact of the number of nodes analyzed by RT-qPCR (analytic) on the prognostic utility of occult tumor burden. METHODS: Lymph nodes (range: 2-159) from 282 prospectively enrolled pN0 colorectal cancer patients, followed for a median of 24 months (range: 2-63), were analyzed by GUCY2C RT-qPCR. Prognostic risk categorization defined using occult tumor burden was the primary outcome measure. Association of prognostic variables and risk category were defined by multivariable polytomous and semi-parametric polytomous logistic regression. RESULTS: Occult tumor burden stratified this pN0 cohort into categories of low (60%; recurrence rate (RR) = 2.3% [95% CI 0.1-4.5%]), intermediate (31%; RR = 33.3% [23.7-44.1%]), and high (9%; RR = 68.0% [46.5-85.1%], P \u3c 0.001) risk of recurrence. Beyond race and T stage, the number of analytic nodes was an independent marker of risk category (P \u3c 0.001). When \u3e12 nodes were analyzed, occult tumor burden almost completely resolved prognostic risk classification of pN0 patients. CONCLUSIONS: The prognostic utility of occult tumor burden assessed by GUCY2C RT-qPCR is dependent on the number of analytic lymph nodes

Molecular staging individualizing cancer management

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, ∼30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy. J. Surg. Oncol. 2012; 105:468-474. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc

A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome.

BackgroundAngelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 - 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain.ResultsA potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events.ConclusionsThis study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies.Trial registrationNCT00348933 . Registered 6 July 2006

Simulation and Characterization of a Miniaturized Scanning Electron Microscope

A miniaturized Scanning Electron Microscope (mSEM) for in-situ lunar investigations is being developed at NASA Marshall Space Flight Center with colleagues from the University of Alabama in Huntsville (UAH), Advanced Research Systems (ARS), the University of Tennessee in Knoxville (UTK) and Case Western Reserve University (CWRU). This effort focuses on the characterization of individual components of the mSEM and simulation of the complete system. SEMs can provide information on the size, shape, morphology and chemical composition of lunar regolith. Understanding these basic properties will allow us to better estimate the challenges associated with In-Situ Resource Utilization and to improve our basic science knowledge of the lunar surface (either precluding the need for sample return or allowing differentiation of unique samples to be returned to Earth.) The main components of the mSEM prototype includes: a cold field emission electron gun (CFEG), focusing lens, deflection/scanning system and backscatter electron detector. Of these, the electron gun development is of particular importance as it dictates much of the design of the remaining components. A CFEG was chosen for use with the lunar mSEM as its emission does not depend on heating of the tungsten emitter (lower power), it offers a long operation lifetime, is orders of magnitude brighter than tungsten hairpin guns, has a small source size and exhibits low beam energy spread

Are the average gait speeds during the 10 meter and 6 minute walk tests redundant in Parkinson disease?

Published in final edited form as: Gait Posture. 2017 February ; 52: 178–182. doi:10.1016/j.gaitpost.2016.11.033.We investigated the relationships between average gait speed collected with the 10Meter Walk Test (Comfortable and Fast) and 6Minute Walk Test (6MWT) in 346 people with Parkinson disease (PD) and how the relationships change with increasing disease severity. Pearson correlation and linear regression analyses determined relationships between 10Meter Walk Test and 6MWT gait speed values for the entire sample and for sub-samples stratified by Hoehn & Yahr (H&Y) stage I (n=53), II (n=141), III (n=135) and IV (n=17). We hypothesized that redundant tests would be highly and significantly correlated (i.e. r>0.70, p<0.05) and would have a linear regression model slope of 1 and intercept of 0. For the entire sample, 6MWT gait speed was significantly (p<0.001) related to the Comfortable 10 Meter Walk Test (r=0.75) and Fast 10Meter Walk Test (r=0.79) gait speed, with 56% and 62% of the variance in 6MWT gait speed explained, respectively. The regression model of 6MWT gait speed predicted by Comfortable 10 Meter Walk gait speed produced slope and intercept values near 1 and 0, respectively, especially for participants in H&Y stages II-IV. In contrast, slope and intercept values were further from 1 and 0, respectively, for the Fast 10Meter Walk Test. Comfortable 10 Meter Walk Test and 6MWT gait speeds appeared to be redundant in people with moderate to severe PD, suggesting the Comfortable 10 Meter Walk Test can be used to estimate 6MWT distance in this population.This study was funded by the Davis Phinney Foundation, the Parkinson's Disease Foundation, and the National Institutes of Health (R01 NS077959, K12 HD055931, UL1 TR000448). The funding sources had no input related to study design, data collection, or decision to submit for publication. (Davis Phinney Foundation; Parkinson's Disease Foundation; R01 NS077959 - National Institutes of Health; K12 HD055931 - National Institutes of Health; UL1 TR000448 - National Institutes of Health

Glycaemic index, glycaemic load and risk of endometrial cancer: a prospective cohort study

Objective High-glycaemic-load diets may increase endometrial cancer risk by increasing circulating insulin levels and, as a consequence, circulating oestrogen levels. Given the paucity of epidemiological data regarding the relationship between the dietary glycaemic index and glycaemic load and endometrial cancer risk, we sought to examine these associations using data from a prospective cohort study. Design, setting, and subjects We examined the association between dietary glycaemic load and endometrial cancer risk in a cohort of 49 613 Canadian women aged between 40 and 59 years at baseline who completed self-administered food-frequency questionnaires between 1982 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow-up ending between 1998 and 2000. Results During a mean of 16.4 years of follow-up, we observed 426 incident cases of endometrial cancer. Hazard ratios for the highest versus the lowest quartile level of overall glycaemic index and glycaemic load were 1.47 (95% confidence interval (CI) = 0.90–2.41; P for trend = 0.14) and 1.36 (95% CI = 1.01–1.84; P for trend = 0.21), respectively. No association was observed between total carbohydrate or total sugar consumption and endometrial cancer risk. Among obese women (body mass index \u3e 30 kg m−2) the hazard ratio for the highest versus the lowest quartile level of the glycaemic load was 1.88 (95% CI = 1.08–3.29; P for trend = 0.54) and there was a 55% increased risk for the highest versus the lowest quartile level of glycaemic load among premenopausal women. There was also evidence to support a positive association between glycaemic load and endometrial cancer risk among postmenopausal women who had used hormone replacement therapy. Conclusions Our data suggest that diets with the high glycaemic index or high glycaemic load may be associated with endometrial cancer risk overall, and particularly among obese women, premenopausal women, and postmenopausal women who use hormone replacement therapy

Molecular and Functional Mapping of EED Motifs Required for PRC2-Dependent Histone Methylation

Polycomb Group (PcG) proteins represent a conserved family of developmental regulators that mediate heritable transcriptional silencing by modifying chromatin states. One PcG complex, the PRC2 complex, is composed of several proteins, including the histone H3 lysine 27 (H3K27) methyltransferase EZH2 and the WD-repeat protein EED. Histone H3K27 can be mono- (H3K27me1), di- (H3K27me2), or trimethylated (H3K27me3). However, it remains unclear what regulates the number of methyl groups added to H3K27 in a particular nucleosome. In mammalian cells, EED is present as four distinct isoforms, which are believed to be produced by utilizing four distinct, in-frame translation start sites in a common Eed mRNA. A mutation that disables all four EED isoforms produces defects in H3K27 methylation.1 To assess the roles of individual EED isoforms in H3K27 methylation, we first characterized three of the four EED isoform start sites and then demonstrated that individual isoforms are not necessary for H3K27me1, H3K27me2, or H3K27me3. Instead, we show that the core WD-40 motifs and the histone binding region of EED alone are sufficient for the generation of all three marks, demonstrating that EED isoforms do not control the number of methyl groups added to H3K27

Using beet pulp to adapt cattle to finishing diets compared to traditional grain adaptation with alfalfa hay

A study was conducted to compare grain adaptation programs using beet pulp (BP) to traditional grain adaptation with alfalfa hay (AH). Yearling crossbred steers (n = 232; BW = 326 ± 14.5 kg) were separated into 3 weight blocks, stratified by BW, and assigned randomly, within strata, to 18 feedlot pens, with 12 or 13 steers per pen. Treatments were imposed during grain adaptation (21 d) using 3 grain adaptation programs. Within each grain adaptation program, 4 step rations were fed for 3, 4, 7, and 7 d. Each program increased dry-rolled corn inclusion while roughage inclusion decreased. In the control treatment (CON), AH inclusion decreased from 46 to 6% and pressed BP (24% DM) was held constant at 6% in all step rations. Beet pulp adaptation programs included a low BP treatment (LOBP) where BP was decreased from 18 to 6% and AH from 34 to 6% or a high BP treatment (HIBP) in which both BP and AH were decreased from 26 to 6%. On d 22 through the remainder of the finishing period cattle were fed a common diet (62% dry rolled corn, 20% wet distillers grains with solubles, 6% AH, 6% BP, 0.25% urea, and 5.75% liquid supplement DM basis). During grain adaptation, cattle fed CON tended (P = 0.07 for overall F test, P = 0.02 for mean comparison) to have greater DMI than HIPB and LOPB was intermediate (9.9, 9.5, and 9.7 kg, respectively). Gain and G:F were not different (P \u3e 0.19) among treatments during the grain adaptation period. However, based off of carcass adjusted final BW, steers adapted using HIBP and LOBP tended (P = 0.07 for overall F-test, P = 0.04 for mean comparison) to have greater ADG compared with CON (1.65, 1.72, and 1.73 kg, respectively). Overall G:F was not different (P = 0.11) among treatments. Dry matter intakes were not different across all treatments (P = 0.58). Carcass characteristics were not affected by adaptation method (P \u3e 0.31). Replacing up to 50% of AH with BP during grain adaptation increased ADG and may be used as an alternative to conventional adaptation programs

Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer.

CONTEXT: The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology (pN0) reflects the presence of occult metastases. Guanylyl cyclase 2C (GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk. OBJECTIVE: To examine the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase-polymerase chain reaction, with recurrence and survival in patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals) provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months (range, 2-63 months) for disease recurrence or death. MAIN OUTCOME MEASURES: Time to recurrence (primary outcome) and disease-free survival (secondary outcome) relative to expression of GUCY2C in lymph nodes. RESULTS: Thirty-two patients (12.5%) had lymph nodes negative for GUCY2C (pN0 [mol-]), and all but 2 remained free of disease during follow-up (recurrence rate, 6.3%; 95% confidence interval [CI], 0.8%-20.8%). Conversely, 225 patients (87.5%) had lymph nodes positive for GUCY2C (pN0 [mol+]), and 47 developed recurrent disease (20.9%; 95% CI, 15.8%-26.8%) (P = .006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 (mol+) exhibited earlier time to recurrence (adjusted hazard ratio, 4.66; 95% CI, 1.11-19.57; P = .04) and reduced disease-free survival (adjusted hazard ratio, 3.27; 95% CI, 1.15-9.29; P = .03). CONCLUSION: Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer

Law as a Tool for Preventing Chronic Diseases: Expanding the Spectrum of Effective Public Health Strategies

Law, which is a fundamental element of effective public health policy and practice, played a crucial role in many of public health's greatest achievements of the 20th century. Still, conceptual legal frameworks for the systematic application of law to chronic disease prevention and control have not been fully recognized and used to address public health needs. Development and implementation of legal frameworks could broaden the range of effective public health strategies and provide valuable tools for the public health workforce, especially for state and local health department program managers and state and national policy makers. In an effort to expand the range of effective public health interventions, the Centers for Disease Control and Prevention will work with its partners to explore the development of systematic legal frameworks as a tool for preventing chronic diseases and addressing the growing epidemic of obesity, heart disease, stroke, and other chronic diseases and their risk factors