An easy-to-implement global procedure for testing the four assumptions of the linear model is proposed. The test can be viewed as a Neyman smooth test and it only relies on the standardized residual vector. If the global procedure indicates a violation of at least one of the assumptions, the components of the global test statistic can be utilized to gain insights into which assumptions have been violated. The procedure can also be used in conjunction with associated deletion statistics to detect unusual observations. Simulation results are presented indicating the sensitivity of the procedure in detecting model violations under a variety of situations, and its performance is compared with three potential competitors, including a procedure based on the Box-Cox power transformation. The procedure is demonstrated by applying it to a new car mileage data set and a water salinity data set that has been used previously to illustrate model diagnostics.

Background & Aims During tumorigenesis, loss of rapid messenger RNA (mRNA) decay allows for overexpression of cancer-associated genes. The RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) bind AU-rich elements in the 3′ untranslated region of many cancer-associated mRNAs and target them for stabilization or rapid decay, respectively. We examined the functions of HuR and TTP during colon tumorigenesis and their ability to regulate cyclooxygenase (COX-2), a mediator of prostaglandin synthesis that increases in the colon tumor microenvironment. Methods We evaluated expression of HuR and TTP during colorectal tumorigenesis and in colon cancer cells and associated them with COX-2 expression. HuR and TTP-inducible cells were created to investigate HuR- and TTP-mediated regulation of COX-2. Results In normal colon tissues, low levels of nuclear HuR and higher levels of TTP were observed. By contrast, increased HuR expression and cytoplasmic localization were observed in 76% of adenomas and 94% of adenocarcinomas, and TTP expression was lost in >75% of adenomas and adenocarcinomas. Similar results were obtained for HuR and TTP mRNA levels in normal and staged tumor samples. In both adenomas and adenocarcinomas, COX-2 overexpression was associated with increased HuR and decreased TTP (P < .0001); similar associations were observed in colon cancer cells. HuR overexpression in cells up-regulated COX-2 expression, whereas overexpression of TTP inhibited it; limited TTP expression antagonized HuR-mediated COX-2 overexpression. Conclusions Increased expression of the mRNA stability factor HuR and loss of the decay factor TTP occurs during early stages of colorectal tumorigenesis. These changes promote COX-2 overexpression and could contribute to colon tumorigenesis.

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3 + T cells that express tumor necrosis factor-α and IFN-γ. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser 15) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 ± 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 ± 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis. Cancer Prev Res; 3(4); 549-59. ©2010 AACR.

Abstract:The problem of non-parametric estimation for the distribution function governing the time to occurrence of a recurrent event in the presence of censoring is considered. We derive Nelson-Aalen and Kaplan-Meier-type estimators for the distribution function, and establish their respective finite-sample and asymptotic properties. We allow for random observation periods for each subject under study and explicitly account for the informative sum-quota nature of the data accrual scheme. These allowances complicate technical matters considerably and in particular invalidate the direct use of Martingale methods. Consistency and weak convergence of our estimators are obtained by extending an approach due to Sellke (1988), who considered a single renewal process (i.e., recurrent events on a single subject) observed over an infinite time period. A useful feature of the present analysis is that strong parallels are drawn to the usual "single-event" setting, providing a natural route towards developing extensions that involve covariates (e.g., weighted log-rank tests, Cox-type regression and frailty models). Another advantage is that we obtain explicit, closed-form expressions for the asymptotic variances for these estimators. This enables for instance the characterization of the efficiency loss resulting from employing only the first, possibly right-censored, observation per subject. An interesting feature of these results is the prominent role of the renewal function. Finally, we discuss the case of correlated recurrence times, propose an estimator in the case where the within-unit interoccurrence times follow a gamma frailty model, and compare the performance of our estimators to an estimator recently proposed by Wang and Chang (1999 Abstract The problem of nonparametric estimation for the distribution function governing the time to occurrence of a recurrent event in the presence of censoring is considered. We derive Nelson-Aalen and Kaplan-Meier-type estimators for the distribution function, and establish their respective finite-sample and asymptotic properties. We allow for random observation periods for each subject under study and explicitly account for the informative sum-quota nature of the data accrual scheme. These allowances complicate technical matters considerably and in particular invalidate the direct use of martingale methods. Consistency and weak convergence of our estimators are obtained by extending an approach due to Sellke (1988), who considered a single renewal process (i.e., recurrent events on a single subject) observed over an infinite time period. A useful feature of the present analysis is that strong parallels are drawn to the usual "single-event" setting, providing a natural route towards developing extensions that involve covariates (e.g., weighted log-rank tests, Cox-type regression and frailty models). Another advantage is that we obtain explicit, closed-form expressions for the asymptotic variances for these estimators. This enables for instance the characterization of the efficiency...

The mechanisms that control extracellular serotonin levels in vivo are not well-defined. This shortcoming makes it very challenging to diagnose and treat the many psychiatric disorders in which serotonin is implicated. Fast-scan cyclic voltammetry (FSCV) can measure rapid serotonin release and reuptake events but cannot report critically important ambient serotonin levels. In this Article, we use fast-scan controlled adsorption voltammetry (FSCAV), to measure serotonin’s steady-state, extracellular chemistry. We characterize the “Jackson” voltammetric waveform for FSCAV and show highly stable, selective, and sensitive ambient serotonin measurements in vitro. In vivo, we report basal serotonin levels in the CA2 region of the hippocampus as 64.9 ± 2.3 nM (n = 15 mice, weighted average ± standard error). We electrochemically and pharmacologically verify the selectivity of the serotonin signal. Finally, we develop a statistical model that incorporates the uncertainty in in vivo measurements, in addition to electrode variability, to more critically analyze the time course of pharmacological data. Our novel method is a uniquely powerful analysis tool that can provide deeper insights into the mechanisms that control serotonin’s extracellular levels.

Critical functions of intra-axonally synthesized proteins are thought to depend on regulated recruitment of mRNA from storage depots in axons. Here we show that axotomy of mammalian neurons induces translation of stored axonal mRNAs via regulation of the stress granule protein G3BP1, to support regeneration of peripheral nerves. G3BP1 aggregates within peripheral nerve axons in stress granule-like structures that decrease during regeneration, with a commensurate increase in phosphorylated G3BP1. Colocalization of G3BP1 with axonal mRNAs is also correlated with the growth state of the neuron. Disrupting G3BP functions by overexpressing a dominant-negative protein activates intra-axonal mRNA translation, increases axon growth in cultured neurons, disassembles axonal stress granule-like structures, and accelerates rat nerve regeneration in vivo.

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 p.p.m., equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents but it also treats colitis. Inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also downregulated by American ginseng. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation and subsequent epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC.

Highlights d Pde11a KO mice show no social memory at 24 h yet stronger social memory at 7 days d This transient amnesia correlates with alterations in functional connectivity and NR1 d Restoration of PDE11A to ventral CA1 is sufficient to reverse phenotypes d Long-term memory is not linear; remote memory can be decoupled from recent