BAG-1L promotes keratinocyte differentiation in organotypic culture models and changes in relative BAG-1 isoform abundance may lead to defective stratification.

In keratinocytes the human Bag-1 gene produces three different protein isoforms from a single messenger RNA, BAG-1L, BAG-1M and BAG-1S. In this study we questioned whether BAG-1L or the shorter isoforms would promote keratinocyte differentiation in organotypic cultures of HaCaT. HaCaT parental and vector cells showed stratification, but terminal differentiation was not complete. Cultures overexpressing BAG-1L isoform-specifically were of increased thickness, demonstrated pronounced expression of basal cytokeratin 5 and ß1-integrin, suprabasal involucrin, cytokeratin 1 and plasma membrane-localised filaggrin, and a marked keratinized layer of cells at the surface. We were unable to overexpress BAG-1S and BAG-1M isoform-specifically. Overexpression of BAG-1M gave rise to organotypic cultures intermediate in differentiation to controls and those overexpressing BAG-1L. Cells overexpressing BAG-1S also exhibited elevated endogenous BAG-1. These produced slow growing cultures with high levels of basal cytokeratin 5, but little involucrin or cytokeratin 1. Suprabasal ß1-integrin and Ki67 positive cells indicated defective stratification. The results suggest that BAG-1L potentiates epidermal differentiation, but disruption in the relative balance of isoforms towards overexpression of BAG-1S can lead to defective tissue patterning. Hence, a delicate balance of BAG-1 isoforms may be required to regulate normal epidermal stratification and differentiation, with important implications for aberrant differentiation in cancer.

Pelvic exenteration in gynecologic oncology: a single institution study over 20 years.

OBJECTIVE: The profile of women with gynecologic malignancies treated with pelvic exenteration has changed since the initial description of this procedure. We sought to evaluate our experience with pelvic exenteration over the last 20 years. METHODS: Patients who underwent anterior, posterior, or total pelvic exenteration for vulvar, vaginal, and cervical cancer at Barnes-Jewish Hospital between January 1, 1990 and August 1, 2009 were identified through hospital databases. Patient characteristics, the indications for the procedure, procedural modifications, and patient outcomes were retrospectively assessed. Categorical variables were analyzed with chi-square method, and survival data was analyzed using the Kaplan-Meier method and log rank test. RESULTS: Fifty-four patients were identified who had pelvic exenteration for cervical, vaginal, or vulvar cancer. Recurrent cervical cancer was the most common procedural indication. One year overall survival from pelvic exenteration for the entire cohort was 64%, with 44% of patients still living at 2 years and 34% at 50 months. Younger age was associated with improved overall survival after exenteration (p = 0.01). Negative margin status was associated with a longer disease-free survival (p=0.014). Nodal status at the time of exenteration was not associated with time to recurrence or progression, site of recurrence, type of post-operative treatment, early or late complications, or survival. CONCLUSIONS: Despite advances in imaging and increased radical techniques, outcomes and complications after total pelvic exenteration in this cohort are similar to those described historically. Pelvic exenteration results in sustained survival in select patients, especially those that are young with recurrent disease and pathologically negative margins.

Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Mortality of United Kingdom acrylonitrile workers--an extended and updated study.

The mortality experience of 2763 men employed between 1950 and 1978 for at least 1 year at 6 factories involved in the polymerization of acrylonitrile and the spinning of acrylic fiber was followed to the end of 1991. Overall, cancer deaths did not exceed the expected numbers. There were, however, excess cancer deaths among the workers in the jobs more highly exposed to acrylonitrile. The excesses did not reach conventional levels of statistical significance apart from an excess of lung cancer among workers under 45 years of age. Detailed analyses provided no consistent support for a causal association between acrylonitrile exposure and carcinogenesis. The limitations of the study, including a lack of information on smoking habits and very limited estimates of acrylonitrile exposure, need to be borne in mind.

Titanium nanomaterial removal and release from wastewater treatment plants.

Titanium (Ti) occurs naturally in soils and as highly purified titanium dioxide (Ti5O2) in many commercial products that have been used for decades. We report for the first time the occurrence, characterization, and removal of nano- and larger-sized Ti at wastewater treatment plants (WWTPs). At one WWTP studied in detail, raw sewage contained 100 to nearly 3000 microg TVL Ti larger than 0.7 microm accounted for the majority of the Ti in raw sewage, and this fraction was well removed by WWTP processes. Ti concentrations in effluents from this and several other WWTPs ranged from <5 to 15 microg/L and were nearly all present in the < 0.7 microm size fraction. As Ti was removed, it accumulated in settled solids at concentrations ranging from 1 to 6 microg Ti/mg. Ti-containing solids were imaged in sewage, biosolids, and liquid effluent as well as in commercial products containing engineered TiO2. Single nanoparticles plus spherical aggregates (50 nm to a few hundred nanometer in size) composed of sub-50 nm spheres of Ti and oxygen only (presumably TiO2) were observed in all samples. Significantly larger silicate particles containing a mixture of Ti and other metal atoms were also observed in the samples. To support the field work, laboratory adsorption batch and sequencing batch reactor experiments using TiO2 and activated sludge bacteria verified that adsorption of TiO2 onto activated sludge biomass occurs. Monitoring for TiO2 in the environment where WWTP liquid effluent is discharged (rivers, lakes, oceans) or biomass disposed (landfills, agriculture and soil amendments, incinerator off-gas or residuals) will increase our knowledge on the fate and transport of other nanomaterials in the environment

Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation.

Oral squamous cell carcinoma (OSCC) is a lethal disease and early death usually occurs as a result of local invasion and regional lymph node metastases. Current treatment regimens are, to a certain degree, inadequate, with a 5-year mortality rate of around 50% and novel therapeutic targets are urgently required. Using expression microarrays, we identified the eps8 gene as being overexpressed in OSCC cell lines relative to normal oral keratinocytes, and confirmed these findings using RT-PCR and western blotting. In human tissues, we found that Eps8 was upregulated in OSCC (32% of primary tumors) compared with normal oral mucosa, and that expression correlated significantly with lymph node metastasis (P=0.032), suggesting a disease-promoting effect. Using OSCC cell lines, we assessed the functional role of Eps8 in tumor cells. Although suppression of Eps8 produced no effect on cell proliferation, both cell spreading and migration were markedly inhibited. The latter cell functions may be modulated through the small GTP-ase, Rac1 and we used pull-down assays to investigate the role of Eps8 in Rac1 signaling. We found that alphavbeta6- and alpha5beta1-integrin-dependent activation of Rac1 was mediated through Eps8. Knockdown of either Eps8 or Rac1, inhibited integrin-dependent cell migration similarly and transient expression of constitutively active Rac1 restored migration of cells in which Eps8 expression had been suppressed. We also showed that knockdown of Eps8 inhibited tumor cell invasion in an organotypic model of OSCC. These data suggest that Eps8 and Rac1 are part of an integrated signaling pathway modulating integrin-dependent tumour cell motility and identify Eps8 as a possible therapeutic target.

Glial cells as targets for cytotoxic immune mediators.

Oligodendrocytes and Schwann cells are the glia principally responsible for the synthesis and maintenance of myelin. Damage may occur to these cells in a number of conditions, but perhaps the most studied are the idiopathic inflammatory demyelinating diseases, multiple sclerosis in the CNS, and Guillain-Barré syndrome and its variants in the peripheral nervous system (PNS). This article explores the effects on these cells of cytotoxic immunological and inflammatory mediators: similarities are revealed, of which perhaps the most important is the sensitivity of both Schwann cells and oligodendrocytes to many such agents. This area of research is, however, characterised and complicated by numerous and often very substantial inter-observer discrepancies. Marked variability in cell culture techniques, and in assays of cell damage and death, provide artifactual explanations for some of this variability; true inter-species differences also contribute. Not the least important conclusion centres on the limited capacity of in vitro studies to reveal disease mechanisms: cell culture findings merely illustrate possibilities which must then be tested ex vivo using human tissue samples affected by the relevant disease.

Comparison of lung cancer incidence rates by histological type in high and low incidence countries, with reference to the limited role of smoking.

To find a clue to lung cancer etiology in Japan, differences in the pattern of lung cancer histology and related time trends between Osaka, Japan, and the North West Region of England were investigated. Material comprised all incident lung cancer cases registered in both regional registries (14,521 in the Osaka Cancer Registry and 29,859 in the North West Regional Cancer Registry). (1) The age-standardized incidence rate of lung cancer was higher in the North West Region than in Osaka (80.4 among males and 20.9 among females per 100,000 population in 1979-82 versus 32.1 and 9.2 respectively). (2) A higher proportion of adenocarcinoma was observed in Osaka (36.3% in males and 62.0% in females) than in the North West Region (12.3% and 18.9% respectively). (3) Using the relative frequencies of each histological type according to sex and age-group, age-standardized incidence rates were calculated for the main lung cancer histological types. It was shown that the incidence rates of adenocarcinoma were similar in the two areas (10.6 in males and 5.3 in females in Osaka versus 10.0 and 3.5 in the North West Region, respectively) while those of squamous cell and small cell carcinomas were much higher in the North West Region than in Osaka. (4) Time trends of incidence rates showed an increase only for adeno- and small cell carcinomas in Osaka. Slight increases were observed for adenocarcinoma in both sexes and for squamous cell carcinoma in females in the North West Region. (5) Considering cigarette consumption and the relative risks of smoking in the two areas, the possible existence of other risk factors for adenocarcinoma in both sexes in Japan, besides active smoking, was suggested.

Byssinosis in the cotton waste industry.

A cross-sectional survey was carried out on 772 workers in 27 mills in the North of England involved in the processing of cotton waste. The overall prevalence of byssinosis as defined by Schilling's criteria was 9.8 per cent with 5.4 per cent having grades 2 and 3. The prevalence in workers who had only ever had cotton waste exposure (5 per cent) was significantly less than for those who had mixed waste and raw cotton exposure. There was no clear relationship between prevalence of byssinosis and years of exposure or dust levels.

Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study.

The authors examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Subjects in this updated and expanded multinational study coordinated by the International Agency for Research on Cancer were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, mortality from soft-tissue sarcoma (6 deaths; standardized mortality ratio (SMR) = 2.03, 95% confidence interval (CI) 0.75-4.43) was higher than expected from national mortality rates. Mortality from all malignant neoplasms (710 deaths; SMR = 1.12, 95% CI 1.04-1.21), non-Hodgkin's lymphoma (24 deaths; SMR = 1.39, 95% CI 0.89-2.06), and lung cancer (225 deaths; SMR = 1.12, 95% CI 0.98-1.28) was slightly elevated. Risks for all neoplasms, for sarcomas, and for lymphomas increased with time since first exposure. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from all neoplasms (398 deaths; SMR = 0.96, 95% CI 0.87-1.06), non-Hodgkin's lymphoma (9 deaths; SMR = 1.00), and lung cancer (148 deaths; SMR = 1.03) was similar to that expected, and mortality from soft-tissue sarcoma was slightly elevated (2 deaths; SMR = 1.35). In a Poisson regression analysis, workers exposed to TCDD or higher chlorinated dioxins had an increased risk for all neoplasms (rate ratio = 1.29, 95% CI 0.94-1.76) compared with workers from the same cohort exposed to phenoxy herbicides and chlorophenols but with minimal or no exposure to TCDD and higher chlorinated dioxins. These findings indicate that exposure to herbicides contaminated with TCDD and higher chlorinated dioxins may be associated with a small increase in overall cancer risk and in risk for specific cancers.