Erratum to Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China(2011-2017):a multicenter retrospective study from CGGA

In the published version of Figure 21,an error appeared in Figure 2C on page 1468.In Figure 2C,the Kaplan-Meier estimation of the overall survival of patients with recurrent DG classified according to molecular subtypes was mistakenly covered by the curves of patients with primary DGs during the figure layout process,while the number statistic under the figure is correct.Figure 2C has been updated to correct this mistake.The error does not affect the conclusions of this article.We apologize for the error and for any confusion that it might have caused.

Clinical management and survival outcomes of patients withdifferent molecular subtypes of diffuse gliomas in China(2011–2017):a multicenter retrospective study from CGGA

Objective:We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas(DGs)in the Chinese population.Methods:In total,1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors.The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing,and 1p/19q codeletion was detected with fluorescence in situ hybridization.The median clinical follow-up time was 1,076 days.T-tests and chi-square tests were used to compare clinicopathological characteristics.Kaplan‒Meier and Cox regression methods were used to evaluate prognostic factors.Results:Our cohort included 15.5%lower-grade gliomas,IDH-mutant and 1p/19q-codeleted(LGG-IDHm-1p/19q);18.1%lowergrade gliomas,IDH-mutant(LGG-IDHm);13.1%lower-grade gliomas,IDH-wildtype(LGG-IDHwt);36.1%glioblastoma,IDHwildtype(GBM-IDHwt);and 17.2%glioblastoma,IDH-mutant(GBM-IDHm).Approximately 63.3%of the enrolled primary gliomas,and the median overall survival times for LGG-IDHm,LGG-IDHwt,GBM-IDHwt,and GBM-IDHm subtypes were 75.97,34.47,11.57,and 15.17 months,respectively.The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%.We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors.We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm,and in prolonging post-relapse survival for the 2 recurrent GBM subtypes.Conclusions:By controlling for molecular subtypes,we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.

Molecular phenotypes of human parvovirus B19 in patients with myocarditis

AIM:To investigate molecular phenotypes of myocardial B19V-infection to determine the role of B19V in myocarditis and dilated cardiomyopathy(DCM).METHODS:Endomyocardial biopsies(EMBs) from 498 B19V-positive patients with myocarditis and DCMwere analyzed using molecular methods and functional experiments.EMBs were obtained from the University Hospitals of Greifswald and Tuebingen and additionally from 36 German cardiology centers.Control tissues were obtained at autopsy from 34 victims of accidents,crime or suicide.Identification of mononuclear cell infiltrates in EMBs was performed using immunohistological staining.Anti-B19V-IgM and anti-B19V-IgG were analyzed by enzyme-linked immunosorbent assay(ELISA).B19V viral loads were determined using in-house quantitative real-time polymerase chain reaction(PCR).For B19V-genotyping a new B19V-genotype-specific restriction fragment length polymorphism(RFLP)-PCR was established.B19V-genotyping was verified by direct DNAsequencing and sequences were aligned using BLAST and BioEdit software.B19V P6-promoter and HHV6-U94-transactivator constructs were generated for cell culture experiments.Transfection experiments were conducted using human endothelial cells 1.Luciferase reporter assays were performed to determine B19Vreplication activity.Statistical analysis and graphical representation were calculated using SPSS and Prism5 software.RESULTS:The prevalence of B19V was significantly more likely to be associated with inflammatory cardiomyopathy(iCMP) compared to uninflamed DCM(59.6% vs 35.3%)(P < 0.0001).The detection of B19V-mRNA replication intermediates proved that replication of B19V was present.RFLP-PCR assays showed that B19V-genotype 1(57.4%) and B19V-genotype 2(36.7%) were the most prevalent viral genotypes.B19V-genotype 2 was observed more frequently in EMBs with iCMP(65.0%) compared to DCM(35%)(P = 0.049).Although there was no significant difference in gender-specific B19V-loads,women were more frequently infected with B19V-genotype 2(44.6%) than men(36.0%)(P = 0.0448).Coinfection with B19V and other cardiotropic viruses was found in 19.2% of tissuesamples and was associated with higher B19V viral load compared to B19V-monoinfected tissue(P = 0.0012).The most frequent coinfecting virus was human herpes virus 6(HHV6,16.5%).B19V-coinfection with HHV6 showed higher B19V-loads compared to B19V-monoinfected EMBs(P = 0.0033),suggesting that HHV6 had transactivated B19V.In vitro experiments confirmed a 2.4-fold increased B19V P6-promoter activity by the HHV6 U94-transactivator.CONCLUSION:The finding of significantly increased B19V loads in patients with histologically proven cardiac inflammation suggests a crucial role of B19V-genotypes and reactivation of B19V-infection by HHV6-coinfection in B19V-associated iCMP.Our findings suggest that B19V-infection of the human heart can be a causative event for the development of an endothelial cell-mediated inflammatory disease and that this is related to both viral load and genotype.

Microbiome changes in esophageal cancer:implications for pathogenesis and prognosis

Esophageal cancer(EC)is an aggressive malignancy with a poor prognosis.Various factors,including dietary habits,and antacid and antibiotic use,have been shown to influence the esophageal microbiome.Conversely,enrichment and diversity of the esophageal microbiome can also impact its function.Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC,thus suggesting the potential contribution of the esophageal microbiome to EC development.Additionally,distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy,indicating the role of the esophageal microbiome in modulating treatment outcomes.In this review,we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases,with a focus on identifying microbial communities associated with EC pathogenesis and prognosis.Understanding the role of the microbiome in EC may aid in early detection and optimized treatment strategies,ultimately leading to better outcomes for patients.

Roles of TGF-β family signaling in stem cell renewal and differentiation

Transforming growth factor （TGF）-βs and their family members, including bone morphogenetic proteins （BMPs）, Nodal and activins, have been implicated in the development and maintenance of various organs, in which stem cells play important roles. Stem cells are characterized by their ability to self-renew and to generate differentiated cells of a particular tissue, and are classified into embryonic and somatic stem cells. Embryonic stem （ES） cells self-renew indefinitely and contribute to derivatives of all three primary germ layers. In contrast, somatic stem cells, which can be identified in various adult organs, exhibit limited abilities for self-renewal and differentiation in most cases. The multi-lineage differentiation capacity of ES ceils and somatic stem cells has opened possibilities for cell replacement therapies for genetic, malignant and degenerative diseases. In order to utilize stem cells for therapeutic applications, it is essential to understand the extrinsic and intrinsic factors regulating self-renewal and differentiation of stem cells. More recently, induced pluripotent stem （iPS） cells have been generated from mouse and human fibroblasts that resemble ES cells via ectopic expression of four transcription factors, iPS cells may have an advantage in regenerative medicine, since they overcome the immunogenicity and ethical controversy of ES cells. Moreover, recent studies have highlighted the involvement of cancer stem cells during the formation and progression of various types of cancers, including leukemia, glioma, and breast cancer. Here, we illustrate the roles of TGF-β family members in the maintenance and differentiation of ES cells, somatic stem cells, and cancer stem cells.

Infrequent p53 gene mutation and expression of the cardia adenocarcinomas from a high-incidence area of Southwest China

INTRODUCTIONAdenocarcinomas of the cardia are the lesionsarising from the proximal stomach or within 3 cm ofthe gastroesophageal junction.These cancerstended to be advanced at the time of presentation,usually with poor prognosis.In recent decade,the incidence of adenocarcinoma of gastric eardiaand esophagus are increasing steadily,while therehas been a decrease in the proportion of the cancersarising from the distal stomach.The

Gastric adenocarcinoma arising in gastritis cystica profunda presenting with selective loss of KCNE2 expression

Gastritis cystica profunda(GCP) is a rare condition caused by ectopic entrapment of gastric glands,probably secondary to the disruption of muscularis mucosae.GCP is often associated with gastric adenocarcinoma,and loss of the KCNE2 subunit from potassium channel complexes is considered a common primary target molecule leads to both GCP and malignancy.In this study,we,for the first time,analyzed the expression of KCNE2 in surgically excised tissue from human gastric cancer associated with GCP and confirmed that reduced KCNE2 expression correlates with disease formation.

Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis

AIM: To investigate the role that the hedgehog (Hh) signaling pathway, which includes sonic hedgehog (Shh), Patched (Ptc), Smoothened (Smo) and Gli-1, plays in hu- man gastrointestinal stromal tumors (GISTs). METHODS: Surgically resected specimens from pa- tients with GISTs, leiomyomas and schwannomas were examined by immunohistochemical staining for aberrant expression of hedgehog signaling components, Shh, Ptc, Smo and Gli-1, respectively. RESULTS: In GISTs, 58.1% (18 of 31), 77.4% (24 of 31), 80.6% (25 of 31) and 58.1% (18 of 31) of the specimens stained positive for Shh, Ptc, Smo and Gli-1, respectively. In leiomyomas, 92.3% (12 of 13), 92.3% (12 of 13), 69.2% (9 of 13) and 92.3% (12 of 13) stained positive for Shh, Ptc, Smo and Gli-1, respectively. In schwannomas, 83.3% (5 of 6), 83.3% (5 of 6), 83.3% (5 of 6) and 100% (6 of 6) stained positive for Shh, Ptc, Smo and Gli-1, respectively. Immunohistochemistry revealed that the expressions of Shh and Gli-1 were sig- nificantly higher in leiomyomas than in GISTs (P < 0.05, respectively). Shh expression strongly correlated with the grade of tumor risk category and with tumor size (P < 0.05, respectively). However, the expressions of Ptc and Smo did not correlate with histopathological differentiation. CONCLUSION: These results suggest that the Hh sig- naling pathway may play an important role in myogenic differentiation and the malignant potential of human in-testinal stromal tumors.

Relationship between therapeutic efficacy of arterial infusion chemotherapy and expression of P-glycoprotein and p53 protein in advanced hepatocellular carcinoma

AIM： To investigate the relationship between the chemotherapeutic drug efficacy and the expression of P-glycoprotein （PGP） and p53 protein in advanced hepatocellular carcinoma （HCC）. METHODS： The study was conducted on 41 patients with advanced HCC who were treated by repeated arterial infusion chemotherapy. Biopsy specimens from the tumor were collected before the start of treatment in all the patients, and the specimens were stored frozen until immunohistochemical staining, which was performed after the start of treatment, to detect PGP and p53 protein expressions. Twenty of the fortyone patients were treated with an anthracycline drug （epirubicin hydrochloride; anthracycline group）, and the remaining 21 were treated with a non-anthracycline drug （mitoxantrone hydrochloride in 11 patients and carboplatin in 10 patients; non-anthracycline group）. The relationship between the chemotherapeutic efficacy and the results of immunostaining were compared between the two groups. RESULTS： Before the start of the treatment, PGPpositive rate was 90.2% （strongly-positive, 36.6%） and p53 protein-positive rate was 34.1% （strongly-positive, 19.5%）. In the anthracycline group, the response rate was 40.0%. The number of patients showing poor response to the treatment was significantly larger in the patients with strongly positive PGP expression （P= 0.005）, and their prognoses were poor （P= 0.001）. in the nonanthracycline group, the response rate was 42.9%,and there was no significant relationship between the chemotherapeutic drug efficacy and the PGP or p53 protein expression. When only the data from the 11 patients treated with anthraquinone drug, mitoxantrone, were analyzed, however, the number of patients who showed poor response to treatment was significantly higher among the p53-positive patients （P= 0.012）, irrespective of the survival outcome. CONCLUSION： The chemotherapeutic efficacy with an anthracycline drug for advanced HCC can be predicted by immunohistochemical analysis of PGP expression. Similarly, immunostaining to evaluate p53 protein may be useful to predict the response in patients treated with an anthraquinone drug.

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients

AIM：To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal adenocarcinoma. METHODS：Methylation-specific polymerase chain reaction （MSPCR） was used to examine the promoter methylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal disease （30 with benign gastric disease and 30 with benign colorectal disease）, and 30 healthy donor controls. Apaired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postopertive serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent surgical therapy. RESULTS：The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric （34.0%） and colorectal （28.9%） adenocarcinoma patients were significantly higher than those in patients with benign gastric （3.3%） or colorectal （6.7%） disease or in healthy donors （0%） （P 〈 0.01）. The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION：Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomarker for gastric and colorectal cancer.

High concentrations of human β-defensin 2 in gastric juice of patients with Helicobacter pylori infection

MIA： Human β-defensin （HBD）-1 and HBD-2 are endogenous antimicrobial peptides. Unlike HBD-1, the HBD-2 expression is augmented by Helicobacter pylori （H pylon）. We sought to determine HBD-1 and HBD-2 concentrations in gastric juice during Hpylori infection. METHODS： HBD-1 and HBD-2 concentrations were measured by radioimmunoassay in plasma and gastric juice of 49 Hpylori-infected and 33 uninfected subjects and before and after anti-H pyloritreatment in,13 patients with Hpylori-associated gastritis. Interleukin （IL）-1β and IL-8 concentrations in gastric juice were measured by enzyme-linked immunosorbent assay （ELISA）. Histological grades of gastritis were determined using two biopsy specimens taken from the antrum and corpus. Reverse phase high performance liquid chromatography （RP-HPLC） was used to identify HBD-2. RESULTS： HBD-2 concentrations in gastric juice, but not in plasma, were significantly higher in Hpylori-positive than -negative subjects, albeit the post-treatment levels were unchanged. Immunoreactivity for HBD-2 was exclusively identified in Hpylori-infected mucosa by RPHPLC. HBD-2 concentrations in gastric juice correlated with histological degree of neutrophil and mononuclear cell infiltration in the corpus. IL-1β levels correlated with those of IL-8, but not HBD-2. Plasma and gastric juice HBD-1 concentrations were similar in H pylori-infected and uninfected subjects. CONCLUSION： Our results place the β-defensins, especiallyHBD-2, in the front line of innate immune defence. Moreover, HBD-2 may be involved in the pathogenesis of Hpylori-associated gastritis, possibly through its function as immune and inflammatory mediator.

Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary

AIM： To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS： We examined 42 cases of gallbladder carcinoma： 22 Japanese and 20 Hungarian cases, p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of flve-microsatellite markers （BAT-25, BAT-26, D2S123, DSS346, and D17S250）. RESULTS： Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases （11/22 vs 6/18, P = 0.348）. Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant （0/11 vs 2/6,P = 0.110）. K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 （42.1%） ]apanese cases were MSI-high （presence of novel peaks in more than one of the five loci analyzed）, whereas only 1 of 15 （6.7%） Hungarian cases was MSI-high （P = 0.047）. CONCLUSION： It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis.

Expression of pituitary tumor transforming gene in human gastric carcinoma

AIM:Pituitary tumor transforming gene (PTTG1) is overexpressed in a variety of tumors, including carcinomas of the lung, breast, colon, as well as in leukemia, lymphoma and pituitary adenomas.However,there is little information on its expression in gastric carcinoma. We sought to investigate the expression of PTTG1 in gastric carcinoma and to explore the relationship between its expression and clinicopathological factors.METHODS:We studied 75 primary human gastric adenocarcinomas, including 17 mucosal carcinomas, 21 submucosal infiltrative carcinomas, 12 carcinomas invading proprial muscle layers, 6 carcinomas reaching the subserosa,and 19 carcinomas penetrating the serosal surface.Immunohistochemical analysis was performed using paraffinembedded sections of gastric adenocarcinomas.RESULTS: PTTG1 was expressed heterogeneously in carcinomas. Positive PTTG1 staining was observed in 65.3% of the carcinomas (49 of 75). Its expression did not correlate significantly with either the histological type or the depth of infiltration of the gastric carcinomas.However,a statistical analysis showed significant differences between the primary adenocarcinomas and the associated metastatic lymph nodes.CONCLUSION: The results of this study demonstrate that PTTG1 expression is enhanced in metastatic lymph nodes in comparison to that in primary carcinomas. We suggest that PTTG1 may contribute to lymph node metastases in gastric carcinoma.

Antibiotics resistance rate of Helicobacter pylori in Bhutan

AIM:To survey the antibiotic resistance pattern of Helicobacter pylori(H.pylori)strains isolated from Bhutanese population.METHODS:We isolated 111 H.pylori strains from the gastric mucosa of H.pylori-infected patients in Bhutan in 2010.The Epsilometer test was used to determine the minimum inhibitory concentrations(MICs)of amoxicillin(AMX),clarithromycin(CLR),metronidazole(MNZ),levofloxacin(LVX),ciprofloxacin(CIP),and tetracycline(TET).RESULTS:Nineteen of the isolated H.pylori strains were susceptible to all antibiotics tested.The isolated strains showed the highest rate of antibiotic resistance to MNZ(92/111,82.9%).Among the 92 MNZresistant strains,74 strains(80.4%)showed high-level resistance(MIC≥256 g/mL).Three strains were resistance to LVX(2.7%).These strains were also resistance to CIP.None of the strains showed resistance to CLR,AMX and TET.CONCLUSION:CLR-based triple therapy is a more effective treatment approach over MNZ-based triple therapy for H.pylori infection in Bhutan.

Prevalence of Helicobacter pylori infection and atrophic gastritis in patients with dyspeptic symptoms in Myanmar

AIM: To survey the detailed analyses for Helicobacter pylori(H. pylori) infection and gastric mucosal status in Myanmar.METHODS: A total of 252 volunteers with dyspeptic symptoms(155 female and 97 male; mean age of 43.6 ± 14.2 years) was participated in Yangon and Mandalay. The status of H. pylori infection was determined based on 5 different tests including rapid urease test, culture, histology, immunohistochemistry and serology. Histological scores were evaluated according to the update Sydney system and the Operative Link for Gastritis Assessment system. Pepsinogen(PG)Ⅰand PG Ⅱ were measured using enzyme-linked immunosorbent assays.RESULTS: The overall prevalence of H. pylori infectionwas 48.0%. There was no relationship between age and infection rate. Even in young group(less than 29 years old), the H. pylori infection rate was relatively high(41.9%). The prevalence of H. pylori infection was significantly higher in Yangon than that of Mandalay. H. pylori infection was significantly associated with the presence of gastric mucosal atrophy. All 7 subjects with peptic ulcer were infected with H. pylori. Although H. pylori-positive subjects showed stronger gastritis than H. pylori-negative subjects, most cases had mild gastritis.CONCLUSION: We revealed the prevalence of H. pylori infection in patients with dyspeptic symptoms in Myanmar. The H. pylori infection was a risk factor for peptic ulcer and stronger gastritis.

Elucidation of the relationship of BNIP3 expression to gemcitabine chemosensitivity and prognosis

AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic cancer cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreaticcancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer.

Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma

A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy,in addition to HCCs,an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe,and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly,extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule,a hepatic progenitor cell marker,was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC,and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB.

Expression of β-catenin in hepatocellular carcinoma

AIM: The beta-catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis. The mechanism underlying the development as well as its prognosis of hepatocellular carcinoma (HCC) has remained unclear. The purpose of this study is to analyze the expression of beta-catenin in HCC in relation to histological grades and viral hepatitis backgrounds. METHODS: Thirty-two sections were selected at random from autopsy and surgical cases of HCC. Immuohistologically, the location and positivity of beta-catenin expression in HCC was examined. RESULTS: Normal hepatocytes did not express beta-catenin. In 78% of HCC beta-catenin was expressed at the membrane of the cells, with or without cytoplasmic and/or nuclear expression. The tumor cells with well-and moderately-differentiated grades expressed frequently at the membrane and cytoplasm compared with poorly-differentiated type. Nuclear expression of beta-catenin was prone to occur in the tumor cells of poorly-differentiated grade. There were 15% of hepatitis C virus (HCV) backgrounds with nuclear expression. In contrast, there was 38% with nuclear expression in hepatitis B virus (HBV) backgrounds. In nonB-nonC hepatitis, no case expressed nuclear beta-catenin. CONCLUSION: The beta-catenin expression in HCC cells was heterogenous among types of hepatitis viral infection. Wnt signaling pathway might be deeply involved in less-differentiated HCC and HBV background. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant melanoma.Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand(RANKL),which promotes osteoclast differentiation and activation.Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth,causing bone pain and hypercalcaemia.Furthermore,RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor,RANK.Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis,and a human monoclonal anti-RANKL antibody,denosumab,has been used in the clinic.However,orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients.Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models.Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis.AS2676293 suppressed RANKLmediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10,which is known not to trigger osteoclast activation.Based on the results from this study,RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.

Extremely high prevalence of Helicobacter pylori infection in Bhutan

AIM: To revealed the prevalence of Helicobacter pylori (H. pylori ) infection in the Bhutanese population. METHODS: We recruited a total of 372 volunteers (214 females and 158 males; mean age of 39.6 ± 14.9 years) from three Bhutanese cities (Thimphu, Punaka, and Wangdue). The status of H. pylori infection was determined based on five different tests: the rapid urease test (CLO test), culture, histology, immunohistochemistry (IHC), and serum anti H. pylori -antibody. RESULTS: The serological test showed a significantly higher positive rate compared with the CLO test, culture, histology and IHC (P < 0.001, P < 0.001, P=0.01, and P=0.01, respectively). When the subjects were considered to be H. pylori positive in the case of at least one test showing a positive result, the overall prevalence of H. pylori infection in Bhutan was 73.4%. The prevalence of H. pylori infection significantly decreased with age (P < 0.01). The prevalence of H. pylori infection was lower in Thimphu than in Punakha and Wangdue (P=0.001 and 0.06, respectively). The prevalence of H. pylori infection was significantly higher in patients with peptic ulcers than in those with gastritis (91.4% vs 71.3%, P=0.003). CONCLUSION: The high incidence of gastric cancer in Bhutan may be attributed to the high prevalence of H. pylori infection.