Pathobiology of the neutrophil-intestinal epithelial cell interaction:Role in carcinogenesis

The role of chronic inflammation,acting as an independent factor,on the onset of gastrointestinal carcinogenesis is now well accepted.However,even if there is an increase in the number of elements directly involving polymorphonuclear leukocytes (PMNL),as a major actor in digestive carcinogenesis,the different cellular and molecular events occurring in this process are still not completely understood.The transepithelial migration of PMNL,which is the ultimate step of the afflux of PMNL into the digestive mucosa,is a complex phenomenon involving sequential interaction of molecules expressed both on PMNL and on digestive epithelial cells.Chronic inflammatory areas rich in PMNL [so-called (chronic active inflammation)] and iterative transepithelial migration of PMNL certainly evoke intracellular signals,which lead toward progressive transformation of epithelia.Among these different signals,the mutagenic effect of reactive oxygen species and nitrates,the activation of the nuclear factor-κB pathway,and the modulation of expression of certain microRNA are key actors.Following the initiation of carcinogenesis,PMNL are involved in the progression and invasion of digestive carcinomas,with which they interact.It is noteworthy that different subpopulations of PMNL,which can have some opposite effects on tumor growth,in association with different levels of transforming growth factor-β and with the number of CD8 positive T lymphocytes,could be present during the development of digestive carcinoma.Other factors that involve PMNL,such as massive elastase release,and the production of angiogenic factors,can participate in the progression of neoplastic cells through tissues.PMNL may play a major role in the onset of metastases,since they allow the tumor cells to cross the endothelial barrier and to migrate into the blood stream.Finally,PMNL play a role,alone or in association with other cell parameters,in the initiation,promotion,progression and dissemination of digestive carcinomas.This review focuses on the main currently accepted cellular and molecular mechanisms that involve PMNL as key actors in digestive carcinogenesis.

Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

Regulation of the m RNA half-life in breast cancer

The control of the half-life of m RNA plays a central role in normal development and in disease progression. Several pathological conditions, such as breast cancer, correlate with deregulation of the half-life of m RNA encoding growth factors, oncogenes, cell cycle regulators and inflammatory cytokines that participate in cancer. Substantial stability means that a m RNA will be available for translation for a longer time, resulting in high levels of protein gene products, which may lead to prolonged responses that subsequently result in over-production of cellular mediators that participate in cancer. The stability of these m RNA is regulated at the 3'UTR level by different mechanisms involving m RNA binding proteins, micro-RNA, long non-coding RNA and alternative polyadenylation. All these events are tightly interconnected to each other and lead to steady state levels of target m RNAs. Compelling evidence also suggests that both m RNA binding proteins and regulatory RNAswhich participate to m RNA half-life regulation may be useful prognostic markers in breast cancers, pointing to a potential therapeutic approach to treatment of patients with these tumors. In this review, we summarize the main mechanisms involved in the regulation of m RNA decay and discuss the possibility of its implication in breast cancer aggressiveness and the efficacy of targeted therapy.

Gravitational Model of the Three Elements Theory: Mathematical Explanations

The aim is to parse the mathematical details related to the gravitational model of the three elements theory [1]. This model is proven to be coherent and really compatible with relativity. The Riemannian representation of space-time which is used in this model is proven to be legal. It allows to understand relativity in a more human sensitive manner than Minkowskian usual representation.

Gravitational Model of the Three Elements Theory

The gravitational model of the three elements theory is an alternative theory to dark matter. It uses a modification of Newton’s law in order to explain gravitational mysteries. The results of this model are explanations for the dark matter mysteries, and the Pioneer anomaly. The disparity of the gravitational constant measurements might also be explained. Concerning the Earth flyby anomalies, the theoretical order of magnitude is the same as the experimental one. A very small change of the perihelion advance of the planet orbits is calculated by this model. Meanwhile, this gravitational model is perfectly compatible with restricted relativity and general relativity, and is part of the three element theory, a unifying theory.

Role of robotic assistance in the learning of laparoscopy:Comparison of novice students’results in two FLS trials

Background: To investigate the learning curve of “robotic surgery” versus “conventional laparoscopy” in two trials of the FLS program in a population of medical students with no experience in laparoscopy. Methods: A prospective trial. Students, all novices in training and surgical practice, were randomized into 2 groups: the “traditional laparoscopy” group and the “robotic assistance” group. Students were evaluated during two tests from the FLS: peg transfer and intracorporeal knot tying. Results: The median laparoscopic knot completion time was significantly lower in the “robotic surgery” group (p = 0.038). Conclusions: Robotic assistance training in neophytes is effective in improving the completion time of laparoscopic knots.

Laparoscopic sleeve gastrectomy and gastroesophageal reflux

Bariatric surgery is the only effective procedure that provides long-term sustained weight loss. Sleeve gastrectomy(SG) has emerged over the last few years to be an ideal bariatric procedure because it has several advantages compared to more complex bariatric procedures,including avoiding an intestinal bypass. However,several published follow-up studies report an increased rate of gastroesophageal reflux(GERD) after a SG. GERD is described as either de novo or as being caused by aggravation of preexisting symptoms. However,the literature on this topic is ambivalent despite the potentially increased rate of GERDs that may occur after this common bariatric procedure. This article reviews the mechanisms responsible for GERD in obese subjects as well as the results after a SG with respect to GERD. Future directions for clinical research are discussed along with the current surgical options for morbidly obese patients with GERD and undergoing bariatric surgery.

Nutritional issues in patients with obesity and cirrhosis

Obesity and metabolic syndrome are considered as responsible for a condition known as the non-alcoholic fatty liver disease that goes from simple accumulation of triglycerides to hepatic inflammation and may progress to cirrhosis.Patients with obesity also have an increased risk of primary liver malignancies and increased body mass index is a predictor of decompensation of liver cirrhosis.Sarcopenic obesity confers a risk of physical impairment and disability that is significantly higher than the risk induced by each of the two conditions alone as it has been shown to be an independent risk factor for chronicliver disease in patients with obesity and a prognostic negative marker for the evolution of liver cirrhosis and the results of liver transplantation.Cirrhotic patients with obesity are at high risk for depletion of various fat-soluble,water-soluble vitamins and trace elements and should be supplemented appropriately.Diet,physical activity and protein intake should be carefully monitored in these fragile patients according to recent recommendations.Bariatric surgery is sporadically used in patients with morbid obesity and cirrhosis also in the setting of liver transplantation.The risk of sarcopenia,micronutrient status,and the recommended supplementation in patients with obesity and cirrhosis are discussed in this review.Furthermore,the indications and contraindications of bariatric surgery-induced weight loss in the cirrhotic patient with obesity are discussed.

Fault activation and induced seismicity in geological carbon storage--Lessons learned from recent modeling studies

In the light of current concerns related to induced seismicity associated with geological carbon sequestration(GCS),this paper summarizes lessons learned from recent modeling studies on fault activation,induced seismicity,and potential for leakage associated with deep underground carbon dioxide(CO2) injection.Model simulations demonstrate that seismic events large enough to be felt by humans require brittle fault properties and continuous fault permeability allowing pressure to be distributed over a large fault patch to be ruptured at once.Heterogeneous fault properties,which are commonly encountered in faults intersecting multilayered shale/sandstone sequences,effectively reduce the likelihood of inducing felt seismicity and also effectively impede upward CO2leakage.A number of simulations show that even a sizable seismic event that could be felt may not be capable of opening a new flow path across the entire thickness of an overlying caprock and it is very unlikely to cross a system of multiple overlying caprock units.Site-specific model simulations of the In Salah CO2storage demonstration site showed that deep fractured zone responses and associated microseismicity occurred in the brittle fractured sandstone reservoir,but at a very substantial reservoir overpressure close to the magnitude of the least principal stress.We conclude by emphasizing the importance of site investigation to characterize rock properties and if at all possible to avoid brittle rock such as proximity of crystalline basement or sites in hard and brittle sedimentary sequences that are more prone to injection-induced seismicity and permanent damage.

450 nm diode laser:A new help in oral surgery

AIM To describe the performance of 450 nm diode laser in oral surgery procedures.METHODS The case described consisted of the removal of a lower lip fibroma through a blue diode laser(λ = 450 nm). RESULTS The efficacy of this device, even at very low power(1W, CW), allows us to obtain very high intra and postoperative comfort for the patient, even with just topical anaesthesia and without needing suture. The healing process was completed in one week and, during the follow-up, the patient did not report any problems, pain or discomfort even without the consumption of any kind of drugs, such as painkillers and antibiotics. The histological examination performed by the pathologist showed a large area of fibrous connective tissue with some portions of epithelium-connective detachments and a regular incision with very scanty areas of carbonization.CONCLUSION The 450 nm diode laser proved of being very efficient in the oral soft tissue surgical procedures, with no side effects for the patients.

净化理论:精神分析与戏剧

和悲剧有关的净化概念,是亚里士多德在其著作《诗学》中提出的。几个世纪以来,这一创新而又让人费解的概念引发了广泛的评论和激烈的争议。1895年,弗洛伊德和布洛伊尔在他们的合著《歇斯底里研究》中重新考虑了这一概念,并提出了名为"宣泄净化疗法"的治疗手段。本文在仔细研究弗洛伊德和拉康关于悲剧净化理论的作品的基础上,考察了其对于精神分析治疗的隐含意义。本文引用了弗洛伊德《戏剧中的变态角色》(1905)和拉康对索福克勒斯的《安提戈涅》的评述(1960),意图论证净化理论与其说是一种与精神发泄有关的释放机制,倒不如说它本身就是一个实际的分析过程。在此过程中,主体被揭示,并得以直面自己神秘的欲望。

The astrophysical gravitational wave stochastic background

A stochastic background of gravitational waves with astrophysical origins may have＇resulted from the superposition of a large number of unresolved sources since the beginning of stellar activity. Its detection would put very strong constraints on the physical properties of compact objects, the initial mass function and star for- marion history. On the other hand, it could be a ＇noise＇ that would mask the stochastic background of its cosmological origin. We review the main astrophysical processes which are able to produce a stochastic background and discuss how they may differ from the primordial contribution in terms of statistical properties. Current detection methods are also presented.

Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors

Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially in very elderly patients,have been raised recently.The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications,in usual conditions of care of the very elderly.Methods Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort.Prescriptions were screened for the presence of P-gp inhibitors(Group A)or not(Group B).Results Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B(A vs.B:182.2±147.3 vs.93.7±64.9 ng/m L).One third of the patients from Group A had dabigatran concentrations that were deemed"out of range"versus none in Group B(P=0.05).This was associated with more frequent bleeding complications in Group A(A:30.4%,B:8.6%,P=0.04).Conclusion In our cohort of very elderly patients,at least,the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.

A Joint Mobility Management Approach and Data Rate Adaptation Algorithm for IEEE 802.15.4/ZigBee Nodes

This paper presents an original approach to reduce energy consumption in an IEEE 802.15.4/ZigBee cluster tree network related to a backbone network. Our approach uses an enhanced mobility management of end devices combined with a rate adaptation algorithm. The mobility management approach anticipates link disruption and relies on a speculative algorithm that does not require scanning neighbor cells. The joint mobility management and rate adaptation methods are based on the link quality indicator (LQI). It is demonstrated that even in a noisy environment, the energy consumption as well as the latency of mobile devices can be significantly reduced.

Flexible manipulation of Omb levels in the endogenous expression region of Drosophila wing by combinational overexpression and suppression strategy

Manipulating an exogenous or endogenous gene of interest at a defined level is critical for a wide variety of experiments.The Gal4/UAS system has been widely used to direct gene expression for studying complex genetic and biological problems in Drosophila melanogaster and other model organisms.Driven by a given tissue-specific Gal4,expressing UAS-transgene or UAS-RNAi(RNA interference)could be used to up-or down-regulate target gene expression,respectively.However,the efficiency of the Gal4/UAS system is roughly predefined by properties of transposon vector constructs and the insertion site in the transgenic stock.Here,we describe a simple way to modulate optomotor blind(omb)expression levels in its endogenous expression region of the wing disc.We co-expressed UAS-omb and UAS-omb-RNAi together under the control of dpp-Gal4 driver which is expressed in the omb expression region of the wing pouch.The repression effect is more sensitive to temperature than that of overexpression.At low temperature,overexpression plays a dominant role but the efficiency is attenuated by UAS-omb-RNAi.In contrast,at high temperature RNAi predominates in gene expression regulation.By this strategy,we could manipulate omb expression levels at a moderate level.It allows us to manipulate omb expression levels in the same tissue between overexpression and repression at different stages by temperature control.

Scenario-based verification in presence of variability using a synchronous approach

This paper presents a new model of scenarios, dedicated to the specification and verification of system be- haviours in the context of software product lines （SPL）. We draw our inspiration from some techniques that are mostly used in the hardware community, and we show how they could be applied to the verification of software components. We point out the benefits of synchronous languages and mod- els to bridge the gap between both worlds.

How will telomeric complex be further contributed to our longevity?—The potential novel biomarkers of telomere complex counteracting both aging and cancer

With the smooth move towards the coming expected clinical reports of anticancer pharmaceutical molecules targeting telomeres and telomerase,and also with the exciting success in the extension of lifespan by regulating telomerase activity without increased onset of oncogenesis in laboratory mouse models(Garcia-Cao et al.,2006;Jaskelioff et al.,2011),we are convinced that targeting telomeres based on telomerase will be a potential approach to conquer both aging and cancer and the idea of longevity seems to be no more mysterious.More interestingly,emerging evidences from clinical research reveal that other telomeric factors,like specifi c telomeric binding proteins and nonspecific telomere associated proteins also show crucial importance in aging and oncogenesis.This stems from their roles in the stability of telomere structure and in the inhibition of DNA damage response at telomeres.Uncapping these proteins from chromosome ends leads to dramatic telomere loss and telomere dysfunction which is more abrupt than those induced by telomerase inactivation.Abnormal expression of these factors results in developmental failure,aging and even oncogenesis evidenced by several experimental models and clinical cases,indicating telomere specifi c proteins and its associated proteins have complimentary roles to telomerase in telomere protection and controlling cellular fate.Thus,these telomeric factors might be potential clinical biomarkers for early detection or even therapeutic targets of aging and cancer.Future studies to elucidate how these proteins function in telomere protection might benefit patients suffering aging or cancer who are not sensitive to telomerase mediation.

Clinical impact of omega-3 fatty acids (Ω3 FA) supplementation on liver surgery

Omega-3 fatty acids(Ω3 FA)are essential nutritional components with beneficial effects on fatty liver and metabolic syndrome affecting blood lipid profiles,membrane lipid composition,eicosanoid biosynthesis,cell signaling cascades,and gene expression(1).They are also involved in a number of metabolic process,including inhibition of several aspects of inflammation,such as leucocyte chemotaxis,adhesion molecule expression and leucocyte-endothelial adhesive interactions,production of eicosanoids like prostaglandins and leukotrienes,production of inflammatory cytokines and T cell reactivity(2).Ω3 FA are particularly abundant in fish and other seafood.