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1.  Stool DNA and Occult Blood Testing for Screen Detection of Colorectal Neoplasia 
Annals of internal medicine  2008;149(7):441-W81.
Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting.
To compare stool DNA and fecal blood testing for detection of screen-relevant neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas >1 cm).
Blinded, multicenter, cross-sectional study.
Communities surrounding 22 participating academic and regional health care systems in the United States.
4482 average-risk adults.
Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy.
Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P < 0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P < 0.001) and 24% by HemoccultSensa (P < 0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P < 0.001) and 17% by HemoccultSensa (P < 0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030).
Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers.
Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.
PMCID: PMC4016975  PMID: 18838724
2.  Spatial Stochastic Dynamics Enable Robust Cell Polarization 
PLoS Computational Biology  2013;9(7):e1003139.
Although cell polarity is an essential feature of living cells, it is far from being well-understood. Using a combination of computational modeling and biological experiments we closely examine an important prototype of cell polarity: the pheromone-induced formation of the yeast polarisome. Focusing on the role of noise and spatial heterogeneity, we develop and investigate two mechanistic spatial models of polarisome formation, one deterministic and the other stochastic, and compare the contrasting predictions of these two models against experimental phenotypes of wild-type and mutant cells. We find that the stochastic model can more robustly reproduce two fundamental characteristics observed in wild-type cells: a highly polarized phenotype via a mechanism that we refer to as spatial stochastic amplification, and the ability of the polarisome to track a moving pheromone input. Moreover, we find that only the stochastic model can simultaneously reproduce these characteristics of the wild-type phenotype and the multi-polarisome phenotype of a deletion mutant of the scaffolding protein Spa2. Significantly, our analysis also demonstrates that higher levels of stochastic noise results in increased robustness of polarization to parameter variation. Furthermore, our work suggests a novel role for a polarisome protein in the stabilization of actin cables. These findings elucidate the intricate role of spatial stochastic effects in cell polarity, giving support to a cellular model where noise and spatial heterogeneity combine to achieve robust biological function.
Author Summary
Cell polarity is the fundamental process of breaking symmetry to create asymmetric cellular structures. It is an open question how randomness (stochasticity) in the cell hinders or helps cell polarity. In this work, we focus on the ability of yeast cells to sense a spatial gradient of mating pheromone and respond by forming a projection in the direction of the mating partner. A key element is the polarisome, which is at the tip of the mating projection. We introduce the first model of polarisome formation in yeast. The model is well-supported by experimental data. We perform modeling to explore the role of noise in the formation of the polarisome. By running simulations with and without noise, we arrive at the surprising conclusion, that gradient-dependent polarization is enhanced by stochasticity. Both the tight localization (amplification) and the ability to respond to directional change of the input (tracking) are enhanced by stochastic dynamics, resulting in a more robust behavior. Mutants in which key polarisome proteins have been deleted exhibit broader, noisier polarisome than the wild type. The mutant phenotype is accurately captured by our stochastic simulations. These results demonstrate the importance of stochasticity in the study of cell polarity.
PMCID: PMC3723497  PMID: 23935469
3.  Selecting One of Several Mating Types through Gene Segment Joining and Deletion in Tetrahymena thermophila 
PLoS Biology  2013;11(3):e1001518.
In Tetrahymena, a multi-sexed single-celled organism, the sex of the progeny is randomly determined by site-specific recombination events that assemble one complete gene pair and delete all others.
The unicellular eukaryote Tetrahymena thermophila has seven mating types. Cells can mate only when they recognize cells of a different mating type as non-self. As a ciliate, Tetrahymena separates its germline and soma into two nuclei. During growth the somatic nucleus is responsible for all gene transcription while the germline nucleus remains silent. During mating, a new somatic nucleus is differentiated from a germline nucleus and mating type is decided by a stochastic process. We report here that the somatic mating type locus contains a pair of genes arranged head-to-head. Each gene encodes a mating type-specific segment and a transmembrane domain that is shared by all mating types. Somatic gene knockouts showed both genes are required for efficient non-self recognition and successful mating, as assessed by pair formation and progeny production. The germline mating type locus consists of a tandem array of incomplete gene pairs representing each potential mating type. During mating, a complete new gene pair is assembled at the somatic mating type locus; the incomplete genes of one gene pair are completed by joining to gene segments at each end of germline array. All other germline gene pairs are deleted in the process. These programmed DNA rearrangements make this a fascinating system of mating type determination.
Author Summary
Tetrahymena thermophila is a single-celled organism with seven sexes. After two cells of different sexes mate, the progeny cells can be of any one of the seven sexes. In this article we show how this sex decision is made. Every cell has two genomes, each contained within a separate nucleus. The germline genome is analogous to that in our ovaries or testes, containing all the genetic information for the sexual progeny; the somatic or working genome controls the operation of the cell (including its sex). We show that the germline genome contains a tandem array of similarly organized but incomplete gene pairs, one for each sex. Sex is chosen after fertilization when a new somatic genome is generated by rearrangement of a copy of the germline genome. One complete sex gene pair is assembled when the cell joins DNA segments at opposite ends of the array to each end of one incomplete gene pair; this gene pair is thus completed and becomes fully functional, while the remaining sex gene pairs are excised and lost. The process involves programmed, site-specific genome rearrangements, and the physically independent rearrangements that occur at opposite ends of the selected gene pair happen with high reliability and precision.
PMCID: PMC3608545  PMID: 23555191
5.  Randomized Phase II Trial of Sulindac, Atorvastatin and Prebiotic Dietary Fiber for Colorectal Cancer Chemoprevention 
Sulindac, atorvastatin or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects age ≥ 40 years, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required ≥ 5 rectal ACF at baseline. Intervention assignments were: (A) atorvastatin 20 mg qd; (B) sulindac 150 mg bid; (C) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (D) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and post-intervention, respectively. The median (standard deviation) for %ΔACF was 5.6 (−69–143%), −18.6 (−83–160%), −3.6 (−88-83%) and −10.0 (−100–117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within arm (p=0.12–0.59) nor between arm (p=0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also appeared to have similar effects on mucosal proliferation and apoptosis (p > 0.05 for each comparison). Data from this multi-center, phase II trial do not provide convincing evidence of CRC risk reduction from six month interventions with atorvastatin, sulindac or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.
PMCID: PMC3046804  PMID: 21209397
Colorectal cancer; chemoprevention; clinical trial; phase II
6.  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families 
PLoS ONE  2012;7(2):e31039.
Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
PMCID: PMC3270040  PMID: 22312439
7.  Members of the NuRD Chromatin Remodeling Complex Interact with AUF1 in Developing Cortical Neurons 
Cerebral Cortex (New York, NY)  2008;18(12):2909-2919.
Chromatin remodeling plays an important role in coordinating gene expression during cortical development, however the identity of molecular complexes present in differentiating cortical neurons that mediate the process remains poorly understood. The A + U–rich element-binding factor 1 (AUF1) is a known regulator of messenger RNA stability and also acts as a transcription factor upon binding to AT-rich DNA elements. Here we show that AUF1 is specifically expressed in subsets of proliferating neural precursors and differentiating postmitotic neurons of the developing cerebral cortex. Moreover, AUF1 is coexpressed with histone deacetylase 1 (HDAC1) and metastasis-associated protein 2 (MTA2), members of the nucleosome remodeling and histone deacetylase complex. AUF1 specifically and simultaneously binds to HDAC1, MTA2, and AT-rich DNA element, its gene regulatory function is modulated by the extent of histone acetylation and in animals lacking AUF1, the composition of the complex is modified. These results suggest that AUF1 is involved in integrating genetic and epigenetic signals during cortical development through recruiting HDAC1 and MTA2 to AT-rich DNA elements.
PMCID: PMC2724833  PMID: 18413351
cerebral cortex; epigenetics; gene expression; histone acetylation; neuronal differentiation; progenitors
8.  Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial 
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18–0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011–0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074–0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.
PMCID: PMC2562024  PMID: 18841250
9.  Modeling the Drosophila melanogaster Circadian Oscillator via Phase Optimization 
Journal of biological rhythms  2008;23(6):525-537.
The circadian clock, which coordinates daily physiological behaviors of most organisms, maintains endogenous (approximately 24 h) cycles and simultaneously synchronizes to the 24-h environment due to its inherent robustness to environmental perturbations coupled with a sensitivity to specific environmental stimuli. In this study, the authors develop a detailed mathematical model that characterizes the Drosophila melanogaster circadian network. This model incorporates the transcriptional regulation of period, time-less, vrille, PAR-domain protein 1, and clock gene and protein counterparts. The interlocked positive and negative feedback loops that arise from these clock components are described primarily through mass-action kinetics (with the exception of regulated gene expression) and without the use of explicit time delays. System parameters are estimated via a genetic algorithm-based optimization of a cost function that relies specifically on circadian phase behavior since amplitude measurements are often noisy and do not account for the unique entrainment features that define circadian oscillations. Resulting simulations of this 29-state ordinary differential equation model comply with fitted wild-type experimental data, demonstrating accurate free-running (23.24-h periodic) and entrained (24-h periodic) circadian dynamics. This model also predicts unfitted mutant phenotype behavior by illustrating short and long periodicity, robust oscillations, and arrhythmicity. This mechanistic model also predicts light-induced circadian phase resetting (as described by the phase-response curve) that are in line with experimental observations.
PMCID: PMC2675948  PMID: 19060261
circadian rhythms; phase; positive/negative feedback
10.  Gallbladder and Small Intestinal Regulation of Biliary Lipid Secretion during Intraduodenal Infusion of Standard Stimuli 
Journal of Clinical Investigation  1983;71(3):596-603.
The gallbladder and small intestine are reservoirs for the bile acid pool during its enterohepatic circulation and, as such, may regulate biliary secretion of bile acid. During studies of biliary bile acid secretion, a stimulus to gallbladder contraction is continuously infused into the duodenum. Under these conditions, it is assumed that the gallbladder is tonically contracted and that the rate of bile acid secretion into the duodenum equals the hepatic bile acid secretion rate. However, secretion rates vary by as much as 100%, depending upon which of two standard stimuli is used. Therefore, we studied the role of gallbladder emptying and small intestinal transit in determining biliary lipid secretion rate and composition during infusion of these stimuli in five healthy subjects. Each subject was studied with a liquid formula containing 40% of calories as fat, and with an amino acid solution for 10 h. Bile acid, phospholipid, cholesterol, and markers were measured in duodenal bile and hourly secretion rates were calculated by marker dilution technique. Real-time gallbladder sonographs and serum pancreatic polypeptide levels were obtained every 30 min. Small bowel transit time was estimated levels were obtained every 30 min. Small bowel transit time was estimated by the breath hydrogen response after giving lactulose intraduodenally.
During liquid formula infusion, gallbladder emptying was more complete, small intestinal transit was faster, and pancreatic polypeptide levels were higher. Secretion rates of all lipids were greater and molar percent cholesterol was lower. For the combined data from both infusions, the secretory relationships of cholesterol to bile acid, cholesterol to phospholipid, and phospholipid to bile acid were curvilinear.
We conclude that more complete gallbladder emptying and faster intestinal transit increase the enterohepatic cycling of bile acids and lower the molar percent cholesterol of bile. Some of the fluctuation observed in biliary lipid secretion rates, especially during amino acid infusion, is due to gallbladder refilling and emptying.
PMCID: PMC436908  PMID: 6826724
11.  Implementation quality of whole-school mental health promotion and students’ academic performance 
This paper argues for giving explicit attention to the quality of implementation of school-wide mental health promotions and examines the impact of implementation quality on academic performance in a major Australian mental health initiative.
Hierarchical linear modelling was used to investigate change in standardised academic performance across the 2-year implementation of a mental health initiative in 96 Australian primary (or elementary) schools that was focused on improving student social-emotional competencies.
After controlling for differences in socioeconomic background, a significant positive relationship existed between quality of implementation and academic performance. The difference between students in high- and low-implementing schools was equivalent to a difference in academic performance of up to 6 months of schooling.
Key Practitioner Message
Given the known relationship between student academic achievement and mental health, many nations are mounting school-based mental health interventions: however, the quality of program implementation remains a concern
The Australian KidsMatter primary school mental health intervention enabled the development of an Implementation Index allowing schools to be grouped into low- to high- implementing schools
The quality of implementation of KidsMatter appears to be positively associated with the level of student academic achievement, equivalent to 6 months more schooling by Year 7, over and above any influence of socioeconomic background
PMCID: PMC3320658  PMID: 22518095
Mental health; academic performance; intervention quality; primary school children; social-emotional competencies

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