期刊,世界胃肠病学杂志（英文版） 2012年卷42期_国家学术搜索

期刊信息/Journal information

世界胃肠病学杂志（英文版）

主　　编：潘伯荣

出版周期：周刊

国际刊号：1007-9327

电子邮箱：wjg@wjgnet.com

电　　话：010-85381901-628

邮政编码：100025

地　　址：北京市朝阳区东四环中路62号楼远洋国际中心D座903室

世界胃肠病学杂志（英文版）/Journal World Journal of GastroenterologyCSCDCSTPCDSCI

查看更多>>主要报道和刊登国内外、特别是我国消化病学者具有创造性的、有较高学术水平的基础和临床研究论文、研究快报等. 对具有中国特色的研究论文, 如食管癌、胃癌、肝癌、大肠癌、病毒性肝炎、幽门螺杆菌、中医中药、中西医结合和基于作者自己研究工作为主的综述性论文, 将优先发表. 读者对象为基础研究或临床研究的消化专业工作者。

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Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

Masatoshi Kudo

6005-6017页

查看更多>>摘要：Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth,invasion,and metastasis,and enabled the development of molecular-targeted agents.To date,sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase Ⅲ randomized controlled trials,and has been approved worldwide.Phase Ⅲ clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing.Those agents target the vascular endothelial growth factor,platelet-derived growth factor receptors,as well as target the epidermal growth factor receptor,insulinlike growth factor receptor and mammalian target of rapamycin,in addition to other molecules targeting other components of the signal transduction pathways.In addition,the combination of sorafenib with standard treatment,such as resection,ablation,transarterial embolization,and hepatic arterial infusion chemotherapy are ongoing.This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways.Finally,the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed.

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PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease

Silvia SookoianCarlos J Pirola

6018-6026页

查看更多>>摘要：Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD).However,the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3,also known as adiponutrin).A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G,a coding variant that encodes an amino acid substitution I148M) is significantly associated with fatty liver and histological disease severity,not only in adults but also in children.Nevertheless,how PNPLA3 influences the biology of fatty liver disease is still an open question.A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function.We revise here the published data about the role of the I148M variant in lipogenesis/lipolysis,and suggest putative areas of future research.For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation,and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3' UTR region (hsa-miR-769-3p and hsa-miR-516a-3p).In addition,interesting unanswered questions remain to be explored.For example,PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity,and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element,corroborated by the DNase I hypersensitivity site peak.Finally,an interaction between PNPLA3 and glycerol3-phosphate acyltransferase 2 is suggested by data miming.

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Human endogenous retroviruses and cancer: Causality and therapeutic possibilities

Christina S MullinsMichael Linnebacher

6027-6035页

查看更多>>摘要：A substantial part of the human genome is derived from transposable elements; remnants of ancient retroviral infections.Conservative estimates set the percentage of human endogenous retroviruses (HERVs)in the genome at 8％.For the most part,the interplay between mutations,epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells.We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy.It has been shown that at least in some cases,tumor cells expressing HERV open reading frames (ORFs) thus gain tumor-promoting functions.However,since these proteins are not expressed in healthy tissues,they become prime target structures.Of potential pharmacological interest are the prevention of HERV transposition,the inhibition of HERV-encoded protein expression and the interference with these proteins' activities.Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries.The development of new tumor (immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects.Finally,we postulate on main future research streams in order to stimulate discussion on this hot topic.

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Celiac disease: Prevalence, diagnosis, pathogenesis and treatment

Naiyana GujralHugh J FreemanAlan BR Thomson

6036-6059页

查看更多>>摘要：Celiac disease (CD) is one of the most common diseases,resulting from both environmental (gluten) and genetic factors [human leukocyte antigen (HLA) and nonHLA genes].The prevalence of CD has been estimated to approximate 0.5％-1％ in different parts of the world.However,the population with diabetes,autoimmune disorder or relatives of CD individuals have even higher risk for the development of CD,at least in part,because of shared HLA typing.Gliadin gains access to the basal surface of the epithelium,and interact directly with the immune system,via both bans-and para-cellular routes.From a diagnostic perspective,symptoms may be viewed as either "typical" or "atypical'; In both positive serological screening results suggestive of CD,should lead to small bowel biopsy followed by a favourable clinical and serological response to the gluten-free diet (GFD) to confirm the diagnosis.Positive anti-tissue transglutaminase antibody or antiendomysial antibody during the clinical course helps to confirm the diagnosis of CD because of their over 99％ specificities when small bowel villous atrophy is present on biopsy.Currently,the only treatment available for CD individuals is a strict life-long GFD.A greater understanding of the pathogenesis of CD allows alternative future CD treatments to hydrolyse toxic gliadin peptide,prevent toxic gliadin peptide absorption,blockage of selective deamidation of specific glutamine residues by tissue,restore immune tolerance towards gluten,modulation of immune response to dietary gliadin,and restoration of intestinal architecture.

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Current progress in the treatment of chronic hepatitis C

Alexandra AlexopoulouGeorge V Papatheodoridis

6060-6069页

查看更多>>摘要：Over the last decade,the standard of care for the treatment of chronic hepatitis C has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV)which results in sustained virological response (SVR)rates of 75％-85％ in patients with genotypes 2 or 3 but only of 40％-50％ in patients with genotype 1.Currently,there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV),which are the focus of this review.Boceprevir and telaprevir,two first-generation NS3/4A HCV protease inhibitors,have been recently licensed in several countries around the world to be used in combination with PEGIFN and RBV for the treatment of genotype 1 patients.Boceprevir or telaprevir based triple regimens,compared with the PEG-IFN/RBV combination,improve the SVR rates by 25％-31％ in treatment-naive genotype 1 patients,by 40％-64％ in prior relapsers,by 33％-45％ in prior partial responders and by 24％-28％ in prior null responders.At the same time,the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45％-55％ of treatment-naive patients.There are,however,several challenges with the use of the new triple combinations in genotype 1 patients,such as the need for immediate results of HCV RNA testing using sensitive quantitative assays,new and more frequent adverse events (anemia and dysgeusia for boceprevir; pruritus,rash and anemia for telaprevir),new drug interactions and increasing difficulties in compliance.Moreover,the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients,such as null responders with cirrhosis,while there is no benefit for patients who cannot tolerate PEGIFN/RBV or who are infected with non-1 HCV genotype.Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results.Preliminary data suggest that the treatment of chronic HCV patients with well tolerated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.

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High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis

Magdy El-SalhyDoris GundersenJan Gunnar HatlebakkTrygve Hausken...

6070-6075页

查看更多>>摘要：AIM:To investigate colonic endocrine cells in lymphocytic colitis (LC) patients.METHODS:Fifty-seven patients with LC were included.These patients were 41 females and 16 males,with an average age of 49 years (range 19-84 years).Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls.These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries,where the source of bleeding was identified as haemorrhoids or angiodysplasia.They were 19 females and 8 males with an average age of 49 years (range 18-67 years).Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy.Biopsies were fixed in 4％ buffered paraformaldehyde,embedded in paraffin and cut into 5 μm-thick sections.The sections immunostained by the avidin-biotin-complex method for serotonin,peptide YY (PYY),pancreatic polypeptide (pP)enteroglucagon and somatostatin cells.The cell densities were quantified by computerised image analysis using Olympus software.RESULTS:The colon of both the patient and the control subjects were macroscopically normal.Histopathological examination of colon biopsies from controis revealed normal histology.All patients fulfilled the diagnosis criteria required for of LC:an increase in intraepithelial lymphocytes (＞ 20 lymphocytes/100 epithelial cells) and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution.In the colon of both patients and control subjects,serotonin-,PYY-,PP-,enteroglucagon-and somatostatin-immunoreactive cells were primarily located in the upper part of the crypts of Lieberkühn.These cells were basket-or flask-shaped.There was no statistically significant difference between the right and left colon in controls with regards to the densities of serotonin-and PYY-immunoreactive cells (P =0.9 and 0.1,respectively).Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6 ± 2.6 (P =0.008).In the left colon,the corresponding figures were 28.5 ± 1.9 and 42.4 ± 2.9,respectively (P =0.009).PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 (P =0.00006).In the left colon,PYY cell density in controls was 6.6 ± 1.2and in LC patients 53.3 ± 4.6 (P =0.00007).CONCLUSION:The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells,and that of PYY density might be secondary.

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Galactosylated chitosan/5-fluorouracil nanoparticles inhibit mouse hepatic cancer growth and its side effects

Ming-Rong ChengQing LiTao WanBing He...

6076-6087页

查看更多>>摘要：AIM:To observe the curative effect of galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticles in liver caner mice and its side effects.METHODS:The GC/5-FU nanoparticle is a nanomaterial made by coupling GC and 5-FU.The release experiment was performed in vitro.The orthotropic liver cancer mouse models were established and divided into control,GC,5-FU and GC/5-FU groups.Mice in the control and GC group received an intravenous injection of 200 μL saline and GC,respectively.Mice in the 5-FU and GC/5-FU groups received 200 μL (containing 0.371 mg 5-FU) 5-FU and GC/5-FU,respectively.The tumor weight and survival time were observed.The cell cycle and apoptosis in tumor tissues were monitored by flow cytometry.The expression of p53,Bax,Bcl-2,caspase-3 and poly adenosine 50-diphosphate-ribose polymerase 1 (PARP-1) was detected by immunohistochemistry,reverse transcription-polymerase chain reaction and Western blot.The serum blood biochemical parameters and cytotoxic activity of natural killer (NK) cell and cytotoxicity T lymphocyte (CTL) were measured.RESULTS:The GC/5-FU nanoparticle is a sustained release system.The drug loading was 6.12％ ± 1.36％,the encapsulation efficiency was 81.82％ ± 5.32％,and the Zeta potential was 10.34 ± 1.43 mV.The tumor weight in the GC/5-FU group (0.4361 ± 0.1153 gvs 1.5801 ± 0.2821 g,P ＜ 0.001) and the 5-FU (0.7932± 0.1283 g vs 1.5801 ± 0.2821 g,P ＜ 0.001) was significantly lower than that in the control group; GC/5-FU treatment can significantly lower the tumor weight (0.4361 ± 0.1153 g vs 0.7932 ± 0.1283 g,P ＜ 0.001),and the longest median survival time was seen in the GC/5-FU group,compared with the control (12 d vs 30 d,P ＜ 0.001),GC (13 d vs 30 d,P ＜ 0.001) and 5-FU groups (17 d vs 30 d,P ＜ 0.001).Flow cytometry revealed that compared with the control,GC/5-FU caused a higher rate of G0-G1 arrest (52.79％ ±13.42％ vs 23.92％ ± 9.09％,P =0.014) and apoptosis (2.55％ ± 1.10％ vs 11.13％ ± 11.73％,P ＜ 0.001)in hepatic cancer cells.Analysis of the apoptosis pathways showed that GC/5-FU upregulated the expression of p53 at both the protein and the mRNA levels,which in turn lowered the ratio of Bcl-2/Bax expression; this led to the release of cytochrome C into the cytosol from the mitochondria and the subsequent activation of caspase-3.Upregulation of caspase-3 expression decreased the PARP-1 at both the mRNA and the protein levels,which contributed to apoptosis.5-FU increased the levels of aspartate aminotransferase and alanine aminotransferase,and decreased the numbers of platelet,white blood cell and lymphocyte and cytotoxic activities of CTL and NK cells,however,there were no such side effects in the GC/5-FU group.CONCLUSION:GC/5-FU nanoparticles can significantly inhibit the growth of liver cancer in mice via the p53 apoptosis pathway,and relieve the side effects and immunosuppression of 5-FU.

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Small intestine contrast ultrasonography vs computed tomography enteroclysis for assessing ileal Crohn's disease

Sara OnaliEmma CalabreseCarmelina PetruzzielloFrancesca Zorzi...

6088-6095页

查看更多>>摘要：AIM:To compare computed tomography enteroclysis (CTE) vs small intestine contrast ultrasonography (SICUS) for assessing small bowel lesions in Crohn's disease (CD),when using surgical pathology as gold standard.METHODS:From January 2007 to July 2008,15 eligible patients undergoing elective resection of the distal ileum and coecum (or right colon) were prospectively enrolled.All patients were under follow-up.The study population included 6 males and 9 females,with a median age of 44 years (range:18-80 years).Inclusion criteria:(1) certain diagnosis of small bowel requiring elective ileo-colonic resection; (2) age between 18-80 years; (3) elective surgery in our Surgical Unit; and (4) written informed consent.SICUS and CTE were performed ≤ 3 mo before surgery,followed by surgical pathology.The following small bowel lesions were blindly reported by one sonologist,radiologist,surgeon and histolopathologist:disease site,extent,strictures,abscesses,fistulae,small bowel dilation.Comparison between findings at SICUS,CTE,surgical specimens and histological examination was made by assessing the specificity,sensitivity and accuracy of each technique,when using surgical findings as gold standard.RESULTS:Among the 15 patients enrolled,CTE was not feasible in 2 patients,due to urgent surgery in one patients and to low compliance in the second patient,refusing to perform CTE due to the discomfort related to the naso-jejunal tube.The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled.Differently from CTE,SICUS was feasible in all the 15 patients enrolled.No complications were observed when using SICUS or CTE.Surgical pathology findings in the tested population included:small bowel stricture in 13 patients,small bowel dilation above ileal stricture in 10 patients,abdominal abscesses in 2 patients,enteric fistulae in 5 patients,lymphnodes enlargement (＞ 1 cm) in 7 patients and mesenteric enlargement in 9 patients.In order to compare findings by using SICUS,CTE,histology and surgery,characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologistsonologist,radiologist,surgeon and anatomopathologist.At surgery,lesions related to CD were detected in the distal ileum in all 13 patients,also visualized by both SICUS and CTE in all 13 patients.Ileal lesions ＞10 cm length were detected at surgery in all the 13 CD patients,confirmed by SICUS and CTE in the same 12 out of the 13 patients.When using surgical findings as a gold standard,SICUS and CTE showed the exactly same sensitivity,specificity and accuracy for detecting the presence of small bowel fistulae (accuracy 77％ for both) and abscesses (accuracy 85％ for both).In the tested CD population,SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures (92％ vs 100％),small bowel fistulae (77％ for both) and small bowel dilation (85％ VS 82％).CONCLUSION:In our study population,CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.

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Quasispecies dynamics in main core epitopes of hepatitis B virus by ultra-deep-pyrosequencing

Maria HomsMaria ButiDavid TaberneroJosep Quer...

6096-6105页

查看更多>>摘要：AIM:To investigate the variability of the main immunodominant motifs of hepatitis B virus (HBV) core gene by ultra-deep-pyrosequencing (UDPS).METHODS:Four samples (2 genotype A and 2 genotype D) from 4 treatment-naive patients were assessed for baseline variability.Two additional samples from one patient (patient 4,genotype D) were selected for analysis:one sample corresponded to a 36-mo treatment-free period from baseline and the other to the time of viral breakthrough after 18 mo of lamivudine treatment.The HBV region analyzed covered amino acids 40 to 95 of the core gene,and included the two main epitopic regions,Th50-69 and B74-84.UDPS was carried out in the Genome Sequencer FLX system (454 Life Sciences,Roche).After computer filtering of UDPS data based on a Poisson statistical model,122 813 sequences were analyzed.The most conserved position detected by UDPS was analyzed by site-directed mutagenesis and evaluated in cell culture.RESULTS:Positions with highest variability rates were mainly located in the main core epitopes,confirming their role as immune-stimulating regions.In addition,the distribution of variability showed a relationship with HBV genotype.Patient 1 (genotype A) presented the lowest variability rates and patient 2 (genotype A) had 3 codons with variability higher than 1％.Patient 3 and 4 (both genotype D) presented 5 and 8 codons with variability higher than 1％,respectively.The median baseline frequencies showed that genotype A samples had higher variability in epitopic positions than in the other positions analyzed,approaching significance (P =0.07,sample 1 and P =0.05,sample 2).In contrast,there were no significant differences in variability between the epitopic and other positions in genotype D cases.Interestingly,patient 1 presented a completely mutated motif from amino acid 64 to 67 (E64LMT67),which is commonly recognized by T helper cells.Additionally,the variability observed in all 4 patients was particularly associated with the E64LMT67 motif.Codons 78 and 79 were highly conserved in all samples,in keeping with their involvement in the interaction between the HBV virion capsid and the surface antigens (HBsAg).Of note,codon 76 was even more conserved than codons 78 and 79,suggesting a possible role in HBsAg interactions or even in hepatitis B e antigen conformation.Sequential analysis of samples from patient 4 (genotype D) illustrated the dynamism of the HBV quasispecies,with strong selection of one minor baseline variant coinciding with a decrease in core variability during the treatment-free and lamivudinetreated period.The drop in variability seemed to result from a "steady state" situation of the HBV quasispecies after selection of the variant with greatest fitness.CONCLUSION:Host immune pressure seems to be the main cause of HBV core evolution.UDPS analysis is a useful technique for studying viral quasispecies.

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Cost of treating chronic hepatitis B: Comparison of current treatment guidelines

Monica RobotinYumi PattonMelanie KansilAndrew Penman...

6106-6113页

查看更多>>摘要：AIM:To compare program costs of chronic hepatitis B (CHB) screening and treatment using Australian and other published CHB treatment guidelines.METHODS:Economic modeling demonstrated that in Australia a strategy of hepatocellular cancer (HCC)prevention in patients with CHB is more cost-effective than current standard care,or HCC screening.Based upon this model,we developed the B positive program to optimize CHB management of Australians born in countries of high CHB prevalence.We estimated CHB program costs using the B positive program algorithm and compared them to estimated costs of using the CHB treatment guidelines published by the AsianPacific,American and European Associations for the Study of Liver Disease (APASL,AASLD,EASL) and those suggested by an independent United States hepatology panel.We used a Markov model that factored in the costs of CHB screening and treatment,individualized by viral load and alanine aminotransferase levels,and calculated the relative costs of program components.Costs were discounted by 5％ and calculated in Australian dollars (AUD).RESULTS:Using the B positive algorithm,total program costs amount to 13 979 224 AUD,or 9634 AUD per patient.The least costly strategy is based upon using the AASLD guidelines,which would cost 34％ less than our B positive algorithm.Using the EASL and the United States Expert Group guidelines would increase program costs by 46％.The largest expenditure relates to the cost of drug treatment (66.9％ of total program costs).The contribution of CHB surveillance (20.2％)and HCC screening and surveillance (6.6％) is small -and together they represent only approximately a quarter of the total program costs.CONCLUSION:The significant cost variations in CHB screening and treatment using different guidelines are relevant for clinicians and policy makers involved in designing population-based disease control programs.(C) 2012 Baishideng.All rights reserved.

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