Carboxyhaemoglobin levels and their determinants in older British men

Background: Although there has been concern about the levels of carbon monoxide exposure, particularly among older people, little is known about COHb levels and their determinants in the general population. We examined these issues in a study of older British men.Methods: Cross-sectional study of 4252 men aged 60-79 years selected from one socially representative general practice in each of 24 British towns and who attended for examination between 1998 and 2000. Blood samples were measured for COHb and information on social, household and individual factors assessed by questionnaire. Analyses were based on 3603 men measured in or close to (< 10 miles) their place of residence.Results: The COHb distribution was positively skewed. Geometric mean COHb level was 0.46% and the median 0.50%; 9.2% of men had a COHb level of 2.5% or more and 0.1% of subjects had a level of 7.5% or more. Factors which were independently related to mean COHb level included season (highest in autumn and winter), region (highest in Northern England), gas cooking (slight increase) and central heating (slight decrease) and active smoking, the strongest determinant. Mean COHb levels were more than ten times greater in men smoking more than 20 cigarettes a day (3.29%) compared with non-smokers (0.32%); almost all subjects with COHb levels of 2.5% and above were smokers (93%). Pipe and cigar smoking was associated with more modest increases in COHb level. Passive cigarette smoking exposure had no independent association with COHb after adjustment for other factors. Active smoking accounted for 41% of variance in COHb level and all factors together for 47%.Conclusion: An appreciable proportion of men have COHb levels of 2.5% or more at which symptomatic effects may occur, though very high levels are uncommon. The results confirm that smoking (particularly cigarette smoking) is the dominant influence on COHb levels

Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis

INTRODUCTION: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. METHODS: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. RESULTS: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. CONCLUSION: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection

High-throughput genomic technology in research and clinical management of breast cancer. Molecular signatures of progression from benign epithelium to metastatic breast cancer

It is generally accepted that early detection of breast cancer has great impact on patient survival, emphasizing the importance of early diagnosis. In a widely recognized model of breast cancer development, tumor cells progress through chronological and well defined stages. However, the molecular basis of disease progression in breast cancer remains poorly understood. High-throughput molecular profiling techniques are excellent tools for the study of complex molecular alterations. By accurately mapping changes in the genome and subsequent biological/molecular pathways, the chances of finding potential novel treatment targets as well as intervention strategies are enhanced, and ultimately lives can be saved. This review provides a brief summary of recent progress in identifying molecular markers for invasiveness in early breast lesions

The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma.

BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology

The application of digital volume correlation (DVC) to evaluate strain predictions generated by finite element models of the osteoarthritic humeral head

Continuum-level finite element models (FEMs) of the humerus offer the ability to evaluate joint replacement designs preclinically; however, experimental validation of these models is critical to ensure accuracy. The objective of the current study was to quantify experimental full-field strain magnitudes within osteoarthritic (OA) humeral heads by combining mechanical loading with volumetric microCT imaging and digital volume correlation (DVC). The experimental data was used to evaluate the accuracy of corresponding FEMs. Six OA humeral head osteotomies were harvested from patients being treated with total shoulder arthroplasty and mechanical testing was performed within a microCT scanner. MicroCT images (33.5 µm isotropic voxels) were obtained in a pre- and post-loaded state and BoneDVC was used to quantify full-field experimental strains (≈ 1 mm nodal spacing, accuracy = 351 µstrain, precision = 518 µstrain). Continuum-level FEMs with two types of boundary conditions (BCs) were simulated: DVC-driven and force-driven. Accuracy of the FEMs was found to be sensitive to the BC simulated with better agreement found with the use of DVC-driven BCs (slope = 0.83, r2 = 0.80) compared to force-driven BCs (slope = 0.22, r2 = 0.12). This study quantified mechanical strain distributions within OA trabecular bone and demonstrated the importance of BCs to ensure the accuracy of predictions generated by corresponding FEMs

Immunophenotypic features of tumor infiltrating lymphocytes from mammary carcinomas in female dogs associated with prognostic factors and survival rates

<p>Abstract</p> <p>Background</p> <p>The immune system plays an important role in the multifactorial biologic system during the development of neoplasias. However, the involvement of the inflammatory response in the promotion/control of malignant cells is still controversial, and the cell subsets and the mechanisms involved are poorly investigated. The goal of this study was to characterize the clinical-pathological status and the immunophenotyping profile of tumor infiltrating lymphocytes and their association with the animal survival rates in canine mammary carcinomas.</p> <p>Methods</p> <p>Fifty-one animals with mammary carcinomas, classified as carcinomas in mixed tumors-MC-BMT = 31 and carcinomas-MC = 20 were submitted to systematic clinical-pathological analysis (tumor size; presence of lymph node and pulmonary metastasis; clinical stage; histological grade; inflammatory distribution and intensity as well as the lymphocytic infiltrate intensity) and survival rates. Twenty-four animals (MC-BMT = 16 and MC = 8) were elected to the immunophenotypic study performed by flow cytometry.</p> <p>Results</p> <p>Data analysis demonstrated that clinical stage II-IV and histological grade was I more frequent in MC-BMT as compared to MC. Univariate analysis demonstrated that the intensity of inflammation (moderate/intense) and the proportion of CD4⁺(≥ 66.7%) or CD8⁺T-cells (<33.3%) were not associated with worse survival rate. Multivariate analysis demonstrated that only lymphocytic infiltrate intensity ≥ 600 (<it>P </it>= 0.02) remained as independent prognostic factor. Despite the clinical manifestation, the lymphocytes represented the predominant cell type in the tumor infiltrate. The percentage of T-cells was higher in animals with MC-BMT without metastasis, while the percentage of B-lymphocytes was greater in animals with metastasized MC-BMT (<it>P </it>< 0.05). The relative percentage of CD4⁺T-cells was significantly greater in metastasized tumors (both MC-BMT and MC), (<it>P </it>< 0.05) while the proportion of CD8⁺T-cells was higher in MC-BMT without metastasis. Consequently, the CD4⁺/CD8⁺ratio was significantly increased in both groups with metastasis. Regardless of the tumor type, the animals with high proportions of CD4⁺and low CD8⁺T-cells had decreased survival rates.</p> <p>Conclusion</p> <p>The intensity of lymphocytic infiltrate and probably the relative abundance of the CD4⁺and CD8⁺T-lymphocytes may represent important survival prognostic biomarkers for canine mammary carcinomas.</p

Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

<p>Abstract</p> <p>Background</p> <p>The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies.</p> <p>Methods</p> <p>We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis.</p> <p>Results</p> <p>SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter.</p> <p>Conclusions</p> <p>These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies.</p

Microenvironmental Influences that Drive Progression from Benign Breast Disease to Invasive Breast Cancer

Invasive breast cancer represents the endpoint of a developmental process that originates in the terminal duct lobular units and is believed to progress through stages of increasing proliferation, atypical hyperplasia, and carcinoma in situ before the cancer acquires invasive and metastatic capabilities. By comparison with invasive breast cancer, which has been studied extensively, the preceding stages of benign breast disease are more poorly understood. Much less is known about the molecular changes underlying benign breast disease development and progression, as well as the transition from in situ into invasive disease. Even less focus has been given to the specific role of stroma in this progression. The reasons for lack of knowledge about these lesions often come from their small size and limited sample availability. More challenges are posed by limitations of the models used to investigate the lesions preceding invasive breast cancer. However, recent studies have identified alterations in stromal cell function that may be critical for disease progression from benign disease to invasive cancer: key functions of myoepithelial cells that maintain tissue structure are lost, while tissue fibroblasts become activated to produce proteases that degrade the extracellular matrix and trigger the invasive cellular phenotype. Gene expression profiling of stromal alterations associated with disease progression has also identified key transcriptional changes that occur early in disease development. In this review, we will summarize recent studies showing how stromal factors can facilitate progression of ductal carcinoma in situ to invasive disease. We also suggest approaches to identify processes that control earlier stages of disease progression