Nuclear translocation of beta-catenin in hereditary and carcinogen- induced intestinal adenomas

The physical interaction between beta-catenin and the adenomatous polyposis coli (APC) gene, and the ability of APC to regulate cytoplasmic levels of beta-catenin suggest a role for beta-catenin in colorectal carcinogenesis. In this study, we found that beta-catenin immunoreactivity was detected exclusively in the cell membrane and cytoplasm of morphologically normal intestinal epithelial cells with predominant distribution in the differentiated nonproliferative cell population. In contrast, beta-catenin was localized predominantly in the nucleus of adenomas from Min/+ mice and transgenic mice expressing a mutant truncated form of the APC gene (Apc(delta716) mice). Beta- catenin was expressed predominantly at the cell membrane and cytoplasm of the nontransformed rat intestinal epithelial (RIE-1) cells in culture, whereas predominantly nuclear localization of beta-catenin was observed in the human colon cancer cell line SW480. In the azoxymethane (AOM) treated rats, overexpression and nuclear localization of beta- catenin was observed in all adenomas. Previous studies have indicated the incidence of APC mutations amongst AOM-induced tumors to be 15% or less. These results demonstrate that nuclear localization of beta- catenin is a common event in colorectal tumorigenesis.      

Psychosocial Aspects of Injured Workers’ Returning to Work (RTW) in Hong Kong

Introduction: This study was designed to explore the psychosocial aspects of injured workers, their self-perceived capacity and how these factors influence their success in Return To Work (RTW). Method: Seventy-five subjects were recruited from the Hong Kong Workers’ Health Centre and were assessed on three occasions consisting of interviews and four self-rated instruments including the Chinese Lam’s Assessment of Employment Readiness (C-LASER), the SF-36 health survey, the Chinese State Trait and the Anxiety Inventory (C-STAI). Results: Results showed that the contemplation and pre-contemplation sub-scores of C-LASER appeared to be the determining factors in predicting subjects’ return-to-work status. Subjects who were more “ready for action” (the Actioners) were found to have significantly higher confidence and advocacy in job seeking than the Pre-Contemplators. Their employment readiness was shown to be affected by psychosocial factors such as perceived functioning and bodily pain, Discussion: From this study, the injured workers’ employment readiness appeared to associate with their RTW outcomes. Further studies would be needed to find out how the employment readiness of injured workers could be enhanced.     

Heterotopic bone formation in patients with DISH following total hip replacement

Radiographs of 236 patients who underwent total hip replacement (THR) were evaluated for heterotopic bone formation. There was no significant difference in the presence and degree of ossification in patients with and without diffuse idiopathic skeletal hyperostosis (DISH). The authors conclude that DISH is not a significant risk factor in the development of heterotopic bone formation following THR.     

Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen

In order to establish an animal model for studying the cause and prevention of esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus (BE), factors affecting the pathogenic processes were investigated in an esophagoduodenal anastomosis model with rats. Experiments by us and others have shown that surgical treatment produced reflux esophagitis with cell hyperproliferation, but not EAC. Additional treatment with a carcinogen has been shown to be necessary for the development of EAC, squamous cell carcinomas (SCC) or EAC/SCC mixtures. We found that the surgically treated animals developed anemia due possibly to reduced iron absorption. When the operated animals were supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis. Treatment with carcinogen, however, induced SCC in the group of rats killed after 22 weeks. The results suggest that iron overload, which is known to cause oxidative damage, is an enhancing factor for adenocarcinogenesis. The pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group resembles human esophageal adenocarcinogenesis in many features. All the BE was the specialized type with goblet cells (containing sialomucin or sulfomucin) and columnar cells (containing acid or neutral mucin) as well as an incompletely developed brush border. Almost all of the BE was located at the bottom of the esophagus and was continuous with the duodenal mucosa; dysplasia became more frequent at later time points. All of the cancers were well-differentiated mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The results are consistent with the proposed human sequence for pathogenic events of BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal anastomosis and iron treatment in rats produces a high rate of BE and EAC which are morphologically similar to human BE and EAC; this may be a useful animal model to study the development and prevention of EAC in humans.      

Evidence for cytochrome P450 2A6 and 3A4 as major catalysts for N'- nitrosonornicotine alpha-hydroxylation by human liver microsomes

The tobacco specific carcinogen N'-nitrosonornicotine (NNN), is believed to be a causative agent for esophageal cancer in smokers. NNN requires metabolic activation to exert its carcinogenic potential. Metabolism occurs through cytochrome P450 (P450) catalyzed 2'- and 5'- hydroxylation, which generates unstable metabolites that decompose to 4- hydroxy-1-(3-pyridyl)-1-butanone ('keto alcohol') and 4-hydroxy-4-(3- pyridyl)butanal, respectively. The latter cyclyzes to 5-(3-pyridyl)-2- hydroxytetrahydrofuran ('lactol'). 2'-Hydroxylation of NNN is believed to be the pathway critical for esophogeal NNN carcinogenesis in the rat. The ability of human liver microsomes and expressed human P450s to metabolize [5-(3)H]NNN to keto alcohol and lactol was determined by reverse phase HPLC with radioflow detection. At low NNN concentrations, 11 human liver microsomes metabolized NNN primarily by 5'-hydroxylation to lactol. This reaction was strongly correlated (r = 0.92) with coumarin 7-hydroxylation, suggesting that NNN 5'-hydroxylation is catalyzed mainly by P450 2A6. 2'-Hydroxylation of NNN by human liver microsomes correlated with 6beta-hydroxylation of testosterone, a P450 3A4-specific activity (r = 0.94). The relative rates of 2'- and 5'- hydroxylation by human P450s 2A6, 2E1, 2D6 and 3A4 expressed in Sf9 cells by the baculovirus-insect cell expression system, and human P450 3A4 produced by stable expression in Chinese hamster ovary cells, were determined. Human P450 2A6 metabolized 1 microM NNN exclusively by 5'- hydroxylation. The rate of lactol formation was 317 pmol/min per nmol P450. Human P450s 2E1 and 2D6 also metabolized NNN only to lactol, but at much lower rates, 0.4 and 0.8 pmol/min per nmol of P450 respectively. In contrast, the metabolism of NNN by expressed human P450 3A4 was specific for keto alcohol formation. The Km for 5'- hydroxylation by baculovirus-expressed P450 2A6 was 2.1 microM, and k(cat) was 953 pmol/min per nmol of P450. The Km for lactol formation by human liver microsomes containing high levels of P450 2A6, was 5 microM . Human liver microsomes exhibited a Km of 312 microM for keto alcohol formation. Coumarin, 8-methoxypsoralen (P450 2A6 inhibitors), and anti-2A6 monoclonal antibody were strong inhibitors of NNN-derived lactol formation in human liver microsomes. Troleandomycin, an inhibitor of P450 3A4, effectively inhibited the metabolism of NNN to keto alcohol by human liver microsomes. These results are consistent with P450 2A6 mediated 5'-hydroxylation and P450 3A4 mediated 2'- hydroxylation of NNN in human liver microsomes.      

Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases

Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.     

中医药对癌症支持性治疗的科学证据

辅助与替代疗法已被越来越多用于已发展国家的癌症患者。在各种另类疗法中,只有少数像中医药般既具坚实理论、又有完备的治病方法,包括对癌症的治疗。近年,许多证据表明中医药是有效的癌症支持性治疗,可在常规治疗的治疗期间和治疗后应用。本文特归纳一些已发表的临床报告和荟萃分析,综述中医药治疗方案对癌症支持性治疗的证据,其中包括中药材、针灸和气功治疗。     

Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential

Background  

The metastatic disease rather than the primary tumor itself is responsible for death in most solid tumors, including breast cancer. The role of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in the metastatic process has previously been established. However, in all published studies only a limited number of MMPs/MMP inhibitors was analyzed in a limited number of cell lines. Here, we propose a more comprehensive approach by analyzing the expression levels of several MMPs (MMP-2, MMP-9 and MMP-14) and MMP inhibitors (TIMP-1, TIMP-2 and RECK) in different models (five human breast cancer cell lines, 72 primary breast tumors and 30 adjacent normal tissues).