Colorectal cancer (CRC) is a heterogeneous disease, including at least three major forms: hereditary, sporadic and colitis-associated CRC. A large body of evidence indicates that genetic mutations, ...epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC. As elevated cyclooxygenase-2 (COX-2) expression was found in most CRC tissue and is associated with worse survival among CRC patients, investigators have sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXIBs) on CRC. The epidemiological studies, clinical trials and animal experiments indicate that NSAIDs are among the most promising chemopreventive agents for this disease. NSAIDs exert their anti-inflammatory and antitumor effects primarily by reducing prostaglandin production by inhibition of COX-2 activity. In this review, we highlight breakthroughs in our understanding of the roles of COX-2 in CRC and inflammatory bowel disease. These recent data provide a rationale for re-evaluating COX-2 as both the prognostic and the predictive marker in a wide variety of malignancies and for renewing the interest in evaluating relative benefits and risk of COXIBs in appropriately selected patients for cancer prevention and treatment.
PROSTAGLANDINS AND CANCER Wang, D; DuBois, R N
Gut,
01/2006, Letnik:
55, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over ...the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.
Experimental data are presented for low-energy singly charged ion transport between two insulating parallel plates. Using a beam intensity of approximately 20 pA, measurements of the incoming and ...transmitted beams provide quantitative temporal information about the charge deposited on the plates and the guiding probability. Using a smaller beam intensity (~ 1 pA) plate charging and discharging properties were studied as a function of time. These data imply that both the charge deposition and decay along the surface and through the bulk need to be modeled as acting independently. A further reduction of beam intensity to ~ 25 fA allowed temporal imaging studies of the positions and intensities of the guided beam plus two bypass beams to be performed. SIMION software was used to simulate trajectories of the guided and bypass beams, to provide information about the amount and location of deposited charge and, as a function of charge patch voltage, the probability of beam guiding and how much the bypass beams are deflected plus to provide information about the electric fields. An equivalent electric circuit model of the parallel plates, used to associate the deposited charge with the patch voltage implies that the deposited charge is distributed primarily on the inner surface of the plates, transverse to the beam direction, rather than being distributed throughout the entire plate.
Salmonella is a human pathogen that frequently infects poultry flocks. Consumption of raw or undercooked contaminated poultry products can induce acute gastroenteritis in humans. Faced with the ...public health concerns associated with salmonellosis, the European Union has established a European regulation forcing member states to implement control programs aimed at reducing Salmonella prevalence in poultry production, especially at the primary production level. The purpose of the present review article is to summarize the current research and to suggest future developments in the area of Salmonella control in poultry, which may be of value to the industry in the coming years. The review will focus especially on preventive strategies that have been developed and that aim at reducing the incidence of Salmonella colonization in broiler chickens at the farm level. In addition to the usual preventive hygienic measures, other strategies have been investigated, such as feed and drinking water acidification with organic acids and immune strategies based on passive and active immunity. Modification of the diet by changing ingredients and nutrient composition with the intent of reducing a bird's susceptibility to Salmonella infection also has been examined. Because in ovo feeding accelerates small intestine development and enhances epithelial cell function, this approach could be an efficient tool for controlling enteric pathogens. Feed additives such as antibiotics, prebiotics, probiotics, and synbiotics that modify the intestinal microflora are part of another field of investigation, and their success depends on the additive used. Other control methods such as the use of chlorate products and bacteriophages also are under study.
Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the ...relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.
IL-17 is a cytokine implicated in the regulation of inflammation. We investigated the role of this cytokine in neutrophil recruitment using a model of LPS-induced lung inflammation in mice. In the ...bronchoalveolar lavage, LPS induced a first influx of neutrophils peaking at day 1, followed by a second wave, peaking at day 2. IL-17 levels were increased during the late phase neutrophilia (day 2), and this was concomitant with an increased number of T cells and macrophages, together with an increase of KC and macrophage-inflammatory protein-2 levels in the lung tissue. Intranasal treatment with a neutralizing murine anti-IL-17 Ab inhibited the late phase neutrophilia. In the bronchoalveolar lavage cells, IL-17 mRNA was detected at days 1, 2, and 3 postchallenge, with a strong expression at day 2. This expression was associated with CD4(+) and CD8(+) cells, but also with neutrophils. When challenged with LPS, despite the absence of T cells, SCID mice also developed a neutrophilic response associated with IL-17 production. In BALB/c mice, IL-15 mRNA, associated mainly with neutrophils, was evidenced 1 day after LPS challenge. In vitro, IL-15 was able to induce IL-17 release from purified spleen CD4(+) cells, but not spleen CD8(+) or airway neutrophils. We have shown that IL-17, produced mainly by CD4(+) cells, but also by neutrophils, plays a role in the mobilization of lung neutrophils following bacterial challenge. In addition, our results suggest that IL-15 could represent a physiological trigger that leads to IL-17 production following bacterial infection.
Summary
Background
Lower gastrointestinal effects of non‐steroidal anti‐inflammatory drugs (NSAIDs) are much more poorly characterized than upper gastrointestinal effects.
Aim
To determine if NSAIDs ...increase lower gastrointestinal adverse effects and if the risk with non‐selective NSAIDs is greater than with cyclooxygenase‐2‐selective inhibitors (coxibs).
Methods
Computerized databases were searched to identify studies of NSAID use reporting on lower gastrointestinal integrity (e.g. permeability), visualization (e.g. erosions, ulcers) and clinical events.
Results
Designs in 47 studies were randomized (18), case–control (14), cohort (eight) and before‐after (seven). Non‐selective‐NSAIDs had significantly more adverse effects vs. no NSAIDs in 20 of 22 lower gastrointestinal integrity studies, five of seven visualization studies, seven of 11 bleeding studies (OR: 1.9–18.4 in case–control studies), two of two perforation studies (OR: 2.5–8.1) and five of seven diverticular disease studies (OR: 1.5–11.2). Coxibs had significantly less effect vs. non‐selective‐NSAIDs in three of four integrity studies, one endoscopic study (RR mucosal breaks: 0.3), and two randomized studies (RR lower gastrointestinal clinical events: 0.5; haematochezia: 0.4).
Conclusions
An increase in lower gastrointestinal injury and clinical events with non‐selective‐NSAIDs appears relatively consistent across the heterogeneous collection of trials. Coxibs are associated with lower rates of lower gastrointestinal injury than non‐selective‐NSAIDs. More high‐quality trials are warranted to more precisely estimate the effects of non‐selective‐NSAIDs and coxibs on the lower gastrointestinal tract.
We report on the Delta *g-ray activity of the high-synchrotron-peaked BL Lacertae object Markarian 421 (Mrk 421) during the first 1.5 years of Fermi operation, from 2008 August 5 to 2010 March 12. We ...find that the Large Area Telescope (LAT) Delta *g-ray spectrum above 0.3 GeV can be well described by a power-law function with photon index Delta *G = 1.78 ? 0.02 and average photon flux F(> 0.3 GeV) = (7.23 ? 0.16) X 10--8 ph cm--2 s--1. Over this time period, the Fermi-LAT spectrum above 0.3 GeV was evaluated on seven-day-long time intervals, showing significant variations in the photon flux (up to a factor ~3 from the minimum to the maximum flux) but mild spectral variations. The variability amplitude at X-ray frequencies measured by RXTE/ASM and Swift/BAT is substantially larger than that in Delta *g-rays measured by Fermi-LAT, and these two energy ranges are not significantly correlated. We also present the first results from the 4.5 month long multifrequency campaign on Mrk 421, which included the VLBA, Swift, RXTE, MAGIC, the F-GAMMA, GASP-WEBT, and other collaborations and instruments that provided excellent temporal and energy coverage of the source throughout the entire campaign (2009 January 19 to 2009 June 1). During this campaign, Mrk 421 showed a low activity at all wavebands. The extensive multi-instrument (radio to TeV) data set provides an unprecedented, complete look at the quiescent spectral energy distribution (SED) for this source. The broadband SED was reproduced with a leptonic (one-zone synchrotron self-Compton) and a hadronic model (synchrotron proton blazar). Both frameworks are able to describe the average SED reasonably well, implying comparable jet powers but very different characteristics for the blazar emission site.
The oral microbiome is an important predictor of health and disease. We recently reported significant yet modest effects of HIV under highly active antiretroviral therapy (ART) on the oral microbiome ...(bacterial and fungal) in a large cohort of HIV-positive (HIV
) and matched HIV-negative (HIV
) individuals. As it was unclear whether ART added to or masked further effects of HIV on the oral microbiome, the present study aimed to analyze the effects of HIV and ART independently, which also included HIV
subjects on preexposure prophylaxis (PrEP) therapy. Cross-sectional analyses of the effect of HIV devoid of ART (HIV
ART
versus matched HIV
subjects) showed a significant effect on both the bacteriome and mycobiome (
< 0.024) after controlling for other clinical variables (permutational multivariate analysis of variance PERMANOVA of Bray-Curtis dissimilarity). Cross-sectional analyses evaluating the effects of ART (HIV
ART
versus HIV
ART
subjects) revealed a significant effect on the mycobiome (
< 0.007) but not the bacteriome. In parallel longitudinal analyses, ART (before versus after the initiation of ART) had a significant effect on the bacteriome, but not the mycobiome, of HIV
and HIV
PrEP subjects (
< 0.005 and
< 0.016, respectively). These analyses also revealed significant differences in the oral microbiome and several clinical variables between HIV
PrEP subjects (pre-PrEP) and the HIV-matched HIV
group (
< 0.001). At the species level, a small number of differences in both bacterial and fungal taxa were identified within the effects of HIV and/or ART. We conclude that the effects of HIV and ART on the oral microbiome are similar to those of the clinical variables but collectively are modest overall.
The oral microbiome can be an important predictor of health and disease. For persons living with HIV (PLWH), HIV and highly active antiretroviral therapy (ART) may have a significant influence on their oral microbiome. We previously reported a significant effect of HIV with ART on both the bacteriome and mycobiome. It was unclear whether ART added to or masked further effects of HIV on the oral microbiome. Hence, it was important to evaluate the effects of HIV and ART independently. For this, multivariate cross-sectional and longitudinal oral microbiome analyses (bacteriome and mycobiome) were conducted within the cohort, including HIV
ART
subjects and HIV
and HIV
(preexposure prophylaxis PrEP) subjects before and after the initiation of ART. While we report independent significant effects of HIV and ART on the oral microbiome, we conclude that their influence is similar to that of the clinical variables but collectively modest overall.
Synopsis The transmission of a 1 keV Ar+ beam between two glass plates was studied. We present experimental data with the goal to provide quantitative information about the buildup and decay of ...charge on the glass plates and how this correlates with the observed guiding.
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