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We hypothesized that cells bearing a single inherited "hit" in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. We report here on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation-carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations, that were validated independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of "one-hit" represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.
The notion of multistep carcinogenesis posits that rate-limiting mutations accumulate in a single cell and its progeny, marking recognizable histopathological transitions in the target tissues (1, 2). The time required for this accumulation affords the opportunity to test whether pharmacological and/or dietary interventions can delay or prevent the transition to malignancy (3). Early targeted intervention would be optimally performed on persons with a very high risk of developing a specific cancer, as with those individuals who carry a germline mutation in a gene known to impose such a risk. Rationale for such an intervention is provided by early studies that demonstrated that cells heterozygous for a cancer-predisposing mutation could show abnormalities in tissue cultures; "one-hit" effects in heterozygous cells were seen in morphologically normal cultured fibroblasts and in epithelial cells derived from Familial Adenomatous Polyposis (FAP) patients (4-6). Furthermore, we have recently reported specific changes in protein expression in colonic epithelial cells from FAP patients (7). Support for the significance of these early changes comes from observations of similar aberrations in corresponding cancer cells, (7, 8, 9). Such changes may play a role in progression to malignancy and therefore constitute targets for strategies to delay or prevent such progression in FAP and in other genetic predispositions to cancer.
With this rationale in mind we have undertaken an investigation of two of the most common predisposing genes, BRCA1 (10, 11) and BRCA2 (12, 13, and references therein) in two important target tissues, breast and ovary. We note that previous reports on benign cells associated with breast cancer already suggest the possibility of such heterozygous effects.
We have compared the transcriptomes of primary breast and ovarian epithelial cultures from patients predisposed to cancer, bearing monoallelic BRCA1 or BRCA2 mutations, with corresponding cultures from control individuals. We demonstrate that the morphologically normal epithelial cells from mutation carriers exhibit abnormalities in a gene-specific and tissue-specific manner, consistent with detectable single-hit effects. These alterations constitute possible molecular targets for intervention on the path to cancer.
All subjects were recruited with the approval of the FCCC Institutional Review Board, irrespective of gender, race and age. Individuals with a personal history of cancer and subjects treated previously with either chemotherapy or radiation were ineligible. Eligible cases included unaffected at-risk women in the Fox Chase Family Risk Assessment Program who were shown to be carriers of BRCA1 or BRCA2 mutations. In particular, six BRCA1, six BRCA2 mutation carriers, and six healthy controls were accrued for breast specimens and an equal number for ovary specimens. Normal breast and ovary specimens were obtained by prophylactic oophorectomy or mastectomy or breast reduction surgery.
Surgical breast specimens were placed in transport medium (serum-free Ham's F-12), containing 100 U/ml penicillin, 100 μg/ml of streptomycin, 10 μg/ml ciprofloxacin, 10 μg/ml gentamicin, 2.5 μg/ml of Amphotericin B and 100 U/ml of Nystatin. The tissue was finely minced using sterile disposable scalpels and transferred to a tube containing 25 ml of 200 U/ml solution of collagenase (Sigma) prepared in DMEM with 2 g/l of NaHCO3, supplemented with 160 U/ml of Hyaluronidase, 0.5 μg/ml hydrocortisone, 10 μg/ml insulin, 10 ml of Antibiotic/Antimycotic (Gibco) and 10% horse serum. The tissue was digested overnight at 37°C in a rotating water bath and then centrifuged at 2200 rpm for 10 minutes. The supernatant was carefully decanted to a sterile tube. The tissue was rinsed four times with transport medium, resuspended in culture medium, and centrifuged one last time. The tissue was then plated in a swine skin gelatin (Sigma)-coated T-25 flask. Cells were cultured for 24 hours in High Calcium Medium and then refed with Low Calcium Medium 24 hours later. High Calcium Medium consists of DMEM/F12 1:1 without calcium (Gibco), supplemented with 5% chelated horse serum, 20 ng/ml EGF, 100 ng/ml cholera toxin, 10 μg/ml insulin, 0.5 μg/ml hydrocortisone, 1.05 mM calcium chloride, 100 U/ml penicillin, 100 μg/ml streptomycin, 10 μg/ml ciprofloxacin, and 0.25 μg/ml Amphotericin B. Low Calcium Medium was the same recipe supplemented with 0.04 mM calcium chloride (14). Cells were cultured four to six weeks until the flask was confluent.
Oophorectomy specimens were collected under aseptic conditions and placed in transport medium (M199:MCDB105, 1:1) supplemented with 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM L-glutamine. The ovaries were processed to establish epithelial cell cultures by gently scraping the ovarian surface with a rubber policeman. Cells were centrifuged and resuspended in fresh medium (M199:MCDB105, 1:1), supplemented with 5% FBS, penicillin, streptomycin, glutamine and 0.3 U/ml insulin, and transferred to tissue culture flasks coated with skin gelatin; they were refed every four days and passaged once they reached confluency.
All the breast and ovarian samples were treated with the same tissue-specific culture conditions, including timing for passaging and harvesting. Importantly, all the samples were de-identified, including notation on carrier or control status, and no significant difference in growth or apoptosis among them was noted. At harvest, all cultures were in log phase.
Total RNA was prepared from cultured cells by extraction in guanidinium isothiocyanate-based buffer containing β-mercaptoethanol and acid phenol. RNA integrity was evaluated on the Agilent 2100 Bioanalyzer. All samples showed distinct peaks corresponding to intact 28S and 18S ribosomal RNAs and therefore were included in the analysis. Amplification of total RNAs was achieved using the one-cycle Ovation™ biotin system (NuGEN Technologies, Inc., San Carlos, CA) as previously described (15).
For each sample a total of 2.2 μg of ssDNA, labeled and fragmented with the NuGEN kit, was hybridized to Affymetrix arrays (Human U133 plus 2.0), following the manufacturer's instructions as previously described (15). After washing and staining with biotinylated antibody and streptavidin phycoerythrin, the arrays were scanned with the Affymetrix GeneChip Scanner 3000 for data acquisition.
Validation of microarray findings was conducted by real-time RT-PCR, using TaqMan Low Density Arrays (LDA, microfluidic cards from Applied Biosystems). A 48-gene custom made array (44 candidate biomarkers + 4 housekeeping genes) was designed and prepared by Applied Biosystems. The entire panel of 48 genes was tested across breast and ovarian samples. All samples were tested in quadruplicate to ensure accuracy and reproducibility.
Data were obtained in the form of threshold-cycle number (Ct) for each candidate biomarker identified and the housekeeping gene HPRT1 for each genotype (BRCA1, BRCA2, WT). For each gene, the Ct values were normalized to the housekeeping gene and the corresponding ΔCt values obtained for each genotype. Relative quantitation was computed using the Comparative Ct method (Applied Biosystems Reference Manual, User Bulletin #2) between BRCA1 mutants and WT primary cell RNAs. The relative quantitation is the ratio of the normalized amounts of target for BRCA1 mutant for WT RNAs, and is computed as 2^(-ΔCt) where ΔCt is the difference between the mean ΔCt values for BRCA1 mutant and the mean ΔCt values for WT RNAs. We repeated the relative quantitation analyses for BRCA2 mutant and WT RNA samples.
We considered breast and ovarian samples for each of the three genotypes: BRCA1, BRCA2 and mutation negative or wild type (WT). There were 6 biological replicates in each experimental condition resulting in a total of 18 samples for each target organ. For each sample, we obtained probe-level data in the form of raw signal intensities for 54675 probe sets from Affymetrix.CEL files. Raw data for each target organ were preprocessed separately using the Robust Multi-chip Average (RMA) method proposed by Irizarry et al. (16, 17).
We applied the variance-stabilizing and normalizing logarithmic transformation to the data before analysis, and used the Local Pooled Error (LPE) method (18) for class comparisons. LPE is based on pooling errors within genes, and between replicate arrays for genes whose expression values are similar. All comparisons were two-sided. The Benjamini-Hochberg step-up method (19) was applied to control the False Discovery Rate (FDR). Genes were defined as differentially expressed, based on statistical significance as well as biological significance. Genes showing an FDR of less than the desired cut-off were considered statistically significant. We accepted an FDR cutoff of 0.20 for breast and 0.10 for ovary. These cut-offs were selected in order to obtain similar numbers of genes. Biological significance was measured as fold change; i.e., the ratio of the mean expression profiles between two conditions. Genes showing more than 2-fold change in either direction (up or down regulated) were considered biologically significant. Differentially expressed genes from each of the above filters were combined, and a list of common genes showing statistical and biological significance was identified. These genes were subsequently validated using RT-PCR. The analytical tools available in the R/BioConductor package (http://www.r-project.org, http://www.bioconductor.org), bioNMF (20) and TMev (http://www.tm4.org) were utilized in these computations.
Pathway and association analyses were conducted to obtain additional insight into the functional relevance of the changes observed. Up and down regulated genes for these exploratory analyses were selected as described above, but using a more relaxed p-value cutoff of 0.001. Gene ontology (GO) functional categories enriched in differentially expressed genes were identified using conditional hyper-geometric tests in the GOstats package (R/BioConductor). A p-value cut off of 0.01 was used in selecting GO terms. Furthermore, gene networks were generated using Ingenuity Pathways Analysis version 6.5 (Ingenuity® Systems, www.ingenuity.com). Gene Set Enrichment Analysis (GSEA) (21) was performed against the lists of differentially expressed genes for BRCA1-WT and BRCA2-WT comparisons. Gene sets from MSigDB (21), including positional, curated, motif and computational sets, were tested. Default parameters were chosen, except that the maximum intensity of probes was only selected while collapsing probe sets for a single gene.
Next we compiled and analyzed publicly available microarray gene expression data from the following: i) a study of mammary gland side population cells (22); ii) a study of two different human breast epithelial cell types, BPEC (breast primary epithelial cells) and HMEC (human mammary epithelial cells), compared to their transformed counterparts (23); iii) a molecular characterization of cancer stem cells in MMTV-Wnt1 murine breast tumors (24); iv) profiles of hereditary breast cancer (25) and v) a set of annotated genes involved in DNA damage repair. The data from these studies were analyzed (a description of the methods is given in supplementary materials). The differentially expressed genes between BRCA1, BRCA2 and WT from our study were compared against the above mentioned gene sets using GSEA.
We are interested in the growth behavior of cells that are precursors of cancer; therefore, we chose to study primary cells multiplying in culture. Morphologically normal primary breast and ovarian epithelial cells were established from BRCA1 and BRCA2 mutation carriers and mutation-negative individuals (Fig. 1). Demographic and mutation data of mutation carriers and control individuals are shown in Table 1. The Table shows that our population is mostly Caucasian, and that carriers and controls are well matched for age, race, parity, menopausal status and body mass index, with the only exception being the group of BRCA1 carriers donating ovarian epithelial cells in which there is a predominance of pre-menopausal women. This is due to the fact that carriers of highly penetrant BRCA1 mutations were advised to undergo prophylactic oophorectomy. We conducted microarray studies of these primary epithelial cultures in order to identify differentially expressed genes between BRCA1 mutant and BRCA2 mutant single-hit cells and WT cells, for each target organ.
Class comparison analyses (BRCA1 vs. wild type, and BRCA2 vs. wild type) revealed notable changes in gene expression, indicating that heterozygous mutations in BRCA1 and BRCA2 do indeed affect the expression profiles of cultured primary epithelial cells from the relevant target organs, breast and ovary.
Table 2 summarizes selected gene expression fold-changes on a linear scale in breast cells versus controls. The secretoglobin family of genes (SCGB2A1, SCGB2A2 and SCGB1D2), of unknown function, is highly up-regulated in BRCA1 mutant breast cells. The genes have been recently described as novel serum markers of breast cancer with significant prognostic value (26, 27); approximately 80% of all breast cancers overexpress this complex (26). In BRCA1 cells, we observed 3-fold up-regulation of mammaglobin (SCGB2A2, FDR:0.06, P value:4×10-10) and 12-fold increase of lipophilin B and C (SCGB1D2 and SCGB2A, FDR:0.06, P value:2×10-8 and FDR:0.16, P value:0.0002, respectively). We also detected in BRCA1 cells a 3-fold up-regulation of the chitinase 3-like 1 gene (FDR:0.06, P value:1.2×10-7), that has proliferative effects on stromal fibroblasts and chemotactic effects on endothelial cells. It can promote angiogenesis, and high serum levels of this protein have been found in patients with glioblastoma (28). IGFBP5 was 10-fold up-regulated in BRCA2 breast cells (FDR: 0.04, P value:1.9×10-7). It is involved in the stimulation of growth and binding to extracellular matrix, independently of IGF, and is highly overexpressed in breast cancer tissues (29).
Several cell-to-cell interactions and cell-to-matrix adhesion genes were found to be downregulated in breast cells, including those that code for tensin 4 (TNS4, fold change: 0.26, FDR:0.06, P value:2.2×10-7 in BRCA1 and fold change: 0.5, FDR:0.03, P value:3.7×10-6), mucin 16 (MUC16, fold change: 027, FDR:0.08, P value:3×10-5 in BRCA1 and fold change: 024, FDR:0.03, P value:2×10-6 in BRCA1) (in both BRCA1 and BRCA2) and for keratin 14 (KRT14, fold change: 0.5, FDR:0.12, P value:0.0001 in BRCA1 and fold change: 0.5, FDR:0.03, P value:2.2×10-10 in BRCA2) (in BRCA2). Lack of tensin 4 expression has been reported in prostate and breast cancers (30), suggesting that the down-regulation of tensin expression is a functional marker of cell transformation. Also, loss of keratins, which are necessary for proper structure and function of desmosomes, can cause an increase in cell flexibility and deformability, and may enable a tumor cell to detach from its epithelial layer, and metastasize. Finally, mucin 1 (MUC1 or CA15-3), known to be over-expressed in breast cancer (31), is down-regulated in 'single-hit' BRCA1 cells (fold change: 0.5, FDR:0.99, P value:0.02). Overrepresentation of even one glycoprotein may affect cell surface protein distribution, with effects on other membrane proteins, such as the downregulation of genes encoding mucin 16 and mucin 1 that we have detected in mutant breast cells. A box plot representation of the top differentially expressed genes for breast epithelial cells is shown in Fig. 2A.
Table 3 summarizes expression changes for selected genes in ovarian epithelial cultures. For example, 5-fold down-regulation of the cyclin B1/cdc2 complex (CDC2, FDR:0.04, P value:7×10-5), a key regulator controlling the G2M checkpoint, was observed in BRCA1 mutant ovarian cells. Multiple genes implicated in the mitotic spindle checkpoint, such as nucleolar and spindle-associated protein 1 (NUSAP-1, fold change: 0.08, FDR:0.02, P value:9×10-9 in BRCA1) were down-regulated. NUSAP-1 plays a crucial role in spindle microtubule organization, whereas CENP-A, which is down-regulated in BRCA2 mutants of breast cells (fold change: 0.5, FDR:0.03, P value:9×10-6), is essential for centromere structure, function and kinetochore assembly. Since BRCA1 and BRCA2, in addition to their role in DNA repair, are also involved in checkpoint pathways, we suggest that inappropriate expression of these proteins could induce abnormal kinetochore function and chromosome mis-segregation, a potential cause of aneuploidy and a critical contributor to oncogenesis. Among up-regulated genes in BRCA1 heterozygous ovarian epithelial cells is SAA2, an acute phase component of the innate immune system (fold change: 6.4, FDR:0.02, P value:2×10-7), a candidate marker of epithelial ovarian cancer (32, 33 and references therein). Among the differentially expressed genes in BRCA2 mutant ovarian epithelial cells, matrix metalloproteinase 3 (MMP3) was upregulated 9- to 12-fold (FDR:0.1, P value:2×10-7); the same tendency has been reported for MMP1 and MMP2 in ovarian cancers (34, 35). Our data also show upregulation of COX1 (cyclooxygenase 1, PTGS1, fold change: 6.6, FDR:0.1, P value:8×10-9) in BRCA2 ovarian epithelial cells, a finding that is consistent with the reported up-regulation of COX1, but not COX2, in ovarian cancer (36, 37). A box plot representation of the top differentially expressed genes for ovarian epithelial cells is shown in Fig. 2B.
A validation study on select genes for breast and ovary was performed with total RNA using quantitative, real-time RT-PCR on low-density arrays (LDA). We selected 44 candidate biomarker genes and 4 housekeeping genes, and the entire panel of 48 genes was tested by the Comparative C1 method across all breast and ovarian samples in quadruplicate using a custom-made array, to ensure accuracy and reproducibility. The real-time RT-PCR validation results and the comparisons with the original Affymetrix data are shown in Tables 2 and and3,3, for breast and ovary, respectively. There was a good correlation (Spearman's ρ) between microarray and LDA data for fold changes of candidate biomarkers in breast and ovarian cultures heterozygous for BRCA1 (0.94 in each case). For candidate biomarkers originally identified in breast and ovarian cultures for one genotype (BRCA1 or BRCA2), there was also a moderate to good correlation between microarray and LDA data for the other genotype (BRCA2 or BRCA1). This is described in more detail in the Supplemental Section and the results are presented in Supplemental Table S1.
In order to define the biological underpinnings of the observed gene expression differences, we conducted additional mining of the microarray data using gene ontology, pathway and association analyses. Gene ontology analysis revealed overrepresentation of several biological processes in BRCA1 and BRCA2 mutant cells (Fig. 3) (see supplementary information). Next, using differentially expressed genes as input to Ingenuity pathway analysis software, we generated networks and overlaid pathways onto genes to understand their interactions and functional importance. In the case of breast BRCA1 cells, two gene networks had many down-regulated genes involved in G2/M DNA damage checkpoint regulation, DNA damage response, p38 MAPK signaling and tight junction signaling. Genes such as ATR, PMS1 and MCM6 that are involved in BRCA1-related DNA damage response were up-regulated in BRCA1 heterozygous cells (Fig. 4A). Similarly, in breast BRCA2 cells, one significant network was identified that contained genes involved in G1/S checkpoint regulation and ephrin receptor signaling (Fig. 4B). In BRCA1 ovarian cells, two significant networks, involved in cell cycle control (G2/M DNA damage checkpoint regulation) and pyrimidine metabolism, and in glucocorticoid receptor signaling, contained down-regulated genes (Fig. 4C). We did not find any significant networks for genes differentially expressed in ovarian BRCA2 heterozygous cells.
In order to identify unifying biological themes central to mutant breast and ovarian cells in comparison to WT cells, we used GSEA for the detection of complex relationships among co-regulated genes. GSEA is an analytical methodology that allows the evaluation of lists of differentially expressed genes of interest against known biological modules, such as gene sets specific to pathways, processes and profiles, of previous profiling experiments (21). To determine whether any specific pathway or profile is enriched in the four different gene lists, we tested 1,892 curated gene sets obtained through MsigDB which is a constituent database of gene sets available through GSEA. Table S3 shows the gene sets from MsigDb that are enriched in breast and ovarian samples. Fig. 5A is a heatmap of differentially expressed genes in both breast and ovary showing various gene sets that were identified to be enriched. We did not find any significant enrichment for canonical pathways. However, we found a variety of gene sets that are listed in Table S3. Among these, we found two stem cell-related gene sets.
Since the gene expression profiles in BRCA1 and BRCA2 mutant cells have similarities to those of stem and progenitor cells, we tested the four gene lists from this study against a cohort of gene sets obtained from various studies including breast stem cells from both human and mouse and DNA repair genes (22-24). Breast BRCA1 and BRCA2 cells show significant enrichment with the differentially expressed gene sets of transformed human mammary epithelial cells (HMEC) vs. control HMEC cells and breast primary epithelial cells (BPEC) vs. control BPEC population (Fig. 5B). We observed that down-regulated genes from breast BRCA1 heterozygous cells show significant association with transformed HMEC and BPEC cells suggesting that BRCA1 'single-hit' cells and transformed breast primary cells share a common fingerprint.
Finally, we compared our breast BRCA1 dataset to three datasets of Hedenfalk et al. on sporadic breast cancers as well as breast cancers in families with BRCA1 and BRCA2 mutations (25). The GSEA comparison revealed that our breast epithelial BRCA1 dataset is most similar to the BRCA1 tumors with matching hits corresponding to the following genes: KRT8, TGFB1, S100A2, S100P, EPHA2, TRIM29, OSBP2, FLNB and MUC1. Fig. 5B shows genes from BRCA1 and BRCA2 mutant and sporadic tumors associated with breast BRCA1 heterozygous cells. These genes have already been implicated in breast cancer. For instance, decreased levels of KRT8 in cytoplasm are detected in breast cancer cells (38). TGFB1 is highly expressed in sporadic breast tumors or tumors from BRCA1 and BRCA2 kindreds, whereas in heterozygous BRCA1 breast cells it is downregulated. Calcium binding proteins A2 and P are downregulated across all tissues. Aberrant expression of S100A2 has been implicated in breast cancer. In all genes that are common to three tumor types (BRCA1, BRCA2 and sporadic) and heterozygous BRCA1 cells, expression of TGFB1 is observed to be different. This finding confirms our hypothesis of the earliest significant molecular changes in "one-hit" cells and their relationship with transformed breast cells.
Our study demonstrates that mRNA expression profiles are altered in morphologically normal breast and ovarian epithelial cells heterozygous for mutation in BRCA1 or BRCA2, and include functionally critical genes. Remarkably, these single-hit cells bear significant transcriptomic changes that share features of the profiles of the corresponding cancer cells. It is well known that BRCA1- and BRCA2-mutant breast cancers exhibit distinct expression profiles (25), and the same is true for ovarian cancer (39). In the case of our single-hit breast and ovarian epithelial cell cultures, gene expression differences related to a given genotype clearly emerge when supervised methods are used (Tables 2 and and3),3), and they are reflected in separate clusters (Fig. 3). On the other hand, genome-wide unsupervised analyses using hierarchical clustering and non-negative matrix factorization revealed clusters that differentiate tissue of origin but not genotype (see supplemental material, Fig. S2).
Although these specific molecular changes are yet to be placed in the context of cancer initiation and progression, it should be noted that both BRCA proteins have clear functional links to transcription. Indeed, both are mediators of the cellular response to DNA damage that includes a transcriptional component (40, 41). Of course, damage does occur in normal cells as a consequence of physiological DNA replication processes, although it is repaired with high efficiency (42), and BRCA1 and BRCA2 are part of a protein complex with RNA polymerase II and the CBP and p300 histone acetyltransferases that is involved in chromatin remodeling and transcription (43). Because of these links to transcription (44), alterations in the levels of BRCA1 and BRCA2 proteins in single-hit cells might be expected to lead to multiple gene expression differences.
Intriguingly, some of the gene expression profiles enriched in breast BRCA1 one-hit cells are similar to those detected in stem and progenitor cells (Fig. 5A). This does not appear to be true for one-hit BRCA2 breast epithelial cells. Indeed, recent findings from the Wicha laboratory indicate that the BRCA1 gene is involved in regulating stemness and differentiation of breast progenitor cells (45). Also, more recently, human mammary epithelial cells from BRCA1-mutation carriers were found to form progenitor cell colonies on semisolid medium with higher plating efficiency as compared to mammary epithelial cells from reduction mammoplasty controls (46).
In general, we found more expression changes in BRCA1 vs. WT cells than with BRCA2 vs. WT cells (Table 2), which may reflect the fact that BRCA2 is primarily involved in double-strand break repair, whereas BRCA1 may also bridge double-strand break repair and signal transduction pathways. Thus, BRCA1 may act both as a sensor of DNA damage and as a repair factor, whereas BRCA2 is thought to be involved primarily in actual repair. Even small alterations in levels of the sensor (BRCA1) may have phenotypic consequences in terms of differentially expressed genes. This is reminiscent of animal models with hypomorphic alleles of the mismatch repair protein MSH2 (part of the damage sensor) that are proficient for mismatch repair per se but defective for activation of the cellular DNA damage response (47).
An additional important finding from this study is that some of the molecular changes detected correspond to candidate biomarkers described previously for breast and ovarian cancer, such as mammaglobin and serum amyloid protein for breast and ovarian cancer, respectively (Tables 2 and and3).3). Furthermore, GSEA analysis reveals that the dataset of breast epithelial BRCA1 one-hit cells shows similarities to that of hereditary breast carcinomas associated with BRCA1 mutations (Fig. 5B).
In conclusion, the findings from this study are largely consistent with what is known about the pathophysiology of BRCA1 and BRCA2 and sporadic cancers. However, there are genes with abnormal patterns of expression that seem unrelated. Both their number and their unrelatedness are unexplainable based on what is known about BRCA1 and BRCA2 cancers, but they may be early changes associated indirectly with cancer initiation (7, 8). For example, heterozygosity may trigger a phenomenon such as induction of expression of siRNAs, each of which might affect the expression of multiple genes
In principle, therefore, the genetic approach used in this study may serve as a model for the identification of biomarkers for epithelial malignancies in general, and for the use of such markers as targets for chemoprevention measures that would decrease the probability of a second "hit" or greatly reduce its occurrence.
We thank Dr. Jeff Boyd for critical reading of the manuscript and R. Sonlin for expert secretarial assistance. We thank the Fannie E. Rippel Biotechnology Facility, the Biomarker and Genotyping Facility, the Cell Culture Facility, and the Biosample Repository at the Fox Chase Cancer Center for technical support.
Grant support: This study was supported by NIH contracts N01 CN-95037, N01-CN-43309, the Ovarian Cancer SPORE at FCCC (P50 CA083638), NIH grant P30 CA06927, an appropriation from the Commonwealth of Pennsylvania to the Fox Chase Cancer Center, and the Eileen Stein Jacoby Fund.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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About us
What is TCC
Strategic Objectives
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Sound Cloud
Teacher Creativity Center Research Publications
Success Stories
Success Story-Al-Dahireyyah
Social Audit Success Stories
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Launching the Global Action Week 2014 Activities
Monitors quench citizens' thirst for improved service delivery in Palestine
Equal right, equal opportunity: inclusive education for children with disabilities
The Central Arbitration for the Social Audit Project
Closing a Training Session on Project Citizen
Students in Palestine empowered to make a difference in their communities through Social Audit Project
-Master of Arts in Human Rights and Conflict Management (a.y. 2013-2014).
dvv international, UNESCO, UIL and ICAE launch 2nd Global Report for Adult Learning and Education
The Second Political Participation Conference Issued a Request to the International Social Forum for the Need to Adopt A global Social Feminist Forum in 2014
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Palestinian Feminist Educational Forum
Chronicles from Rio+20
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The Global Campaign for Education Kicks Off
Global Campaign for Education- Media Outreach about the Realities of Childhood in Palestine
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Ameria School Students Brief Jenin Governor on Pollution Issues
Meeting with Coordinators of Local Educational Councils
600 Students Implement the Social Audit Project
Local Educational Councils- Training Workshop in Development of Intervention Projects to Improve the Educational Environment
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الحملة العالمية للتعليم
مسابقة " أفضل معلم في العالم "
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فينود راينا
Towards Creative Change in Palestinian Education
TCC launches Inclusive summer camps for children with disabilities
Teacher Creativity Center-Ramallah-27/07/2016- Teacher Creativity Center in cooperation with the national commission for summer camps has launched 2 summer camps in Silet Althaher town in Jenin and Kafr Aboush town in Tulkarem. Nearly, 172 child aged between 7-12 years old (42 child with disabilities) have participated in the camp which also targeted children with intellectual disabilities, where the camp started on 23th of July to the 5th of August 2016 , funded by the national commission for summer camps and they are implemented in partnership with the CBR program.
These camps include many activities, events and entertainment picnics, in addition to sport, drama, writing, national education and arts corners. A group of volunteers and supervisors who are educated well in handling with people with disabilities managed the participation of children in different entertainment games like Dabka, dancing and smart games.. All of these manners contribute in refining their personalities, increasing their focus and making them more inclusive with other children.
For her part, the project coordinator named Rawan Khayyat said, "These summer camps are one of the important activities which working on accepting the presence of people with disabilities in their community especially intellectual disabilities. Moreover, they have the right to live their life as other children, and this absolutely leads to creating an inclusive education". She added.
These camps come to support the main goal of the "Towards an inclusive environment" which implemented by TCC and funded by the Swedish Organization for Individual Relief in order to promote the integration of people with intellectual disabilities in Public schools by contributing to a social, economic and political environment fit with the inclusive education for children in the north of the west bank.
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PLEASE DO NOT, I REPEAT, DO NOT PAY UNTIL I SEND YOU AN INVOICE BECAUSE ebays shipping figures are wrong and insurance is required in the U.S. on comic totals over $25.00. If you pay before I invoice you then I will have no choice but to utter the famous Cheech and Chong quote--"Bailiff, whack his pee-pee!" Ok, it's time for me to sell my Silver Age collection. I have thousands of early Silver Age beauties both Marvel and D.C. Items and publishers will vary week to week so keep watching. O.K. time for D.C'S long running series WORLD'S FINEST featuring Superman, Batman, The Atom, Green Arrow, Hawkman, Teen Titans, Wonder Woman, Aquaman and many other superheroes! This comic is WORLDS FINEST #101. It is a VG+/FN- copy. LIGHT TO MODERATE general wear and very slight edge tanning. The inside is all t The inside paper is GREAT- CREAMY WHITE TO WHITE and SUPPLE! I ship one way and ONE WAY ONLY--USPS PRIORITY MAIL. are the NEW rates for the United States but I repeat--DO NOT PAY UNTIL I SEND YOU AN INVOICE: 1-2 comics--$5.65, 3-4 comics--$6.90. 5-30 comics--$10.00. FOREIGN WINNERS--I can ship up to 5 regular comics for $11.95 to most countries. More than 5 and foreign shipping varies according to total weight. Combine purchases and save money. CHECK my feedback and VIEW my other items--YOU WONT BELIEVE some of the comics I am auctioning. ... read more


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UCAS, Penpals, MacBook, Xmrv, Studying, Writing Letters to Pen Pals, Psychology, Reading and Writing, What ever does not cause my M.E. or fIBRO to flare up so its a very short list, Drinking Tea and Coffee, Chronic Pain Awareness, I Hate Football, "Stand up for what you believe in, even if it means standing alone.", Rainbows, M&M's, Hugging, Chocolate chip cookies, Isn't it wierd that Cher Lloyd was 4th and her calling number is 04.. One direction were 3rd & their one was 03 Rebecca Furguson was 2nd and her's was 02 and Matt Cardle's was 1st and his one was 01!!..............They had it planned all along! xxxxx, Writing Songs, Dear Parents. Jasmine was in a relationship with a dirty homeless boy named Aladdin. Snow White lived alone with 7 men. Pinnochio was a liar. Robin Hood was a thief. Tarzan walked around without clothes on. A stranger kissed sleeping beauty and she marrie, Texting, Being With Friends, Connie Beauchamp, Philosophy, Fibro, Writing, Writing Long Letters, iPod,
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Last updated July 2011: 3733 words, another 267 words to go till my target


text:
Eating globs of cookie dough by the spoonful (completely guilt free) is something dreams are made of!
This doughy recipe of delight is something I made up during a sugar craving meltdown. Instead of reaching for a tray of place-and-bakes, I did a little research and made up these easy options that will cure any cookie-dough craving!!
Almonds (pure- with no oil or salt)
Canned Pumpkin
Ripe Banana
Coconut Butter
Unsweetened coconut flakes
** Extra- (for the less healthy version)
Dark chocolate chips
Gluten free boxed cake mix
1. Grind two handfuls of almonds in a food processor.
2. Add one ripe banana and 1/2 a 15oz can of pure pumpkin. Blend.
3. Add cinnamon and allspice to taste.
(I like a lot!)
4. One tablespoon of softened coconut butter. And 1 tablespoon of unsweetened coconut.
—to keep it Whole30 approved, stop there! Put in refrigerator for a few hours before rolling it into balls over the unsweetened coconut.—-
5. Mix in 2 tablespoons of gluten free cake mix. (This make it more doughy and sweeter)
5. Gently stir in 2 tablespoons of dark chocolate chips.
—cover and refrigerate for a few hours before serving. I like it cold. Or just eat it right from the mixing bowl!!
—It's surprisingly VERY VERY filling! This is a single serving, but I doubt you can finish all of it in one sitting!!


text:
Compact orthoalgebras
Author: Alexander Wilce
Journal: Proc. Amer. Math. Soc. 133 (2005), 2911-2920
MSC (2000): Primary 06F15, 06F30; Secondary 03G12, 81P10
DOI: https://doi.org/10.1090/S0002-9939-05-07884-6
Published electronically: May 2, 2005
MathSciNet review: 2159769
Full-text PDF Free Access
Abstract | References | Similar Articles | Additional Information
Abstract: We initiate a study of topological orthoalgebras (TOAs), concentrating on the compact case. Examples of TOAs include topological orthomodular lattices, and also the projection lattice of a Hilbert space. As the latter example illustrates, a lattice-ordered TOA need not be a topological lattice. However, we show that a compact Boolean TOA is a topological Boolean algebra. Using this, we prove that any compact regular TOA is atomistic , and has a compact center. We prove also that any compact TOA with isolated is of finite height. We then focus on stably ordered TOAs: those in which the upper set generated by an open set is open. These include both topological orthomodular lattices and interval orthoalgebras - in particular, projection lattices. We show that the topology of a compact stably-ordered TOA with isolated is determined by that of its space of atoms.
- 1. M. K. Bennett and D. J. Foulis, Interval and scale effect algebras, Adv. in Appl. Math. 19 (1997), no. 2, 200–215. MR 1459498, https://doi.org/10.1006/aama.1997.0535
- 2. Gunter Bruns and John Harding, Algebraic aspects of orthomodular lattices, Current research in operational quantum logic, Fund. Theories Phys., vol. 111, Kluwer Acad. Publ., Dordrecht, 2000, pp. 37–65. MR 1907155
- 3. Tae Ho Choe and Richard J. Greechie, Profinite orthomodular lattices, Proc. Amer. Math. Soc. 118 (1993), no. 4, 1053–1060. MR 1143016, https://doi.org/10.1090/S0002-9939-1993-1143016-9
- 4. Tae Ho Choe, Richard J. Greechie, and Yunki Chae, Representations of locally compact orthomodular lattices, Topology Appl. 56 (1994), no. 2, 165–173. MR 1266141, https://doi.org/10.1016/0166-8641(94)90017-5
- 5. D. J. Foulis, R. J. Greechie, and G. T. Rüttimann, Filters and supports in orthoalgebras, Internat. J. Theoret. Phys. 31 (1992), no. 5, 789–807. MR 1162623, https://doi.org/10.1007/BF00678545
- 6. D. J. Foulis and C. H. Randall, What are quantum logics and what ought they to be?, Current issues in quantum logic (Erice, 1979) Ettore Majorana Internat. Sci. Ser.: Phys. Sci., vol. 8, Plenum, New York-London, 1981, pp. 35–52. MR 723148
- 7. R. J. Greechie, D. Foulis, and S. Pulmannová, The center of an effect algebra, Order 12 (1995), no. 1, 91–106. MR 1336539, https://doi.org/10.1007/BF01108592
- 8. Peter T. Johnstone, Stone spaces, Cambridge Studies in Advanced Mathematics, vol. 3, Cambridge University Press, Cambridge, 1982. MR 698074
- 9. Gudrun Kalmbach, Orthomodular lattices, London Mathematical Society Monographs, vol. 18, Academic Press, Inc. [Harcourt Brace Jovanovich, Publishers], London, 1983. MR 716496
- 10. Leopoldo Nachbin, Topology and order, Translated from the Portuguese by Lulu Bechtolsheim. Van Nostrand Mathematical Studies, No. 4, D. Van Nostrand Co., Inc., Princeton, N.J.-Toronto, Ont.-London, 1965. MR 0219042
- 11. H. A. Priestley, Ordered topological spaces and the representation of distributive lattices, Proc. London Math. Soc. (3) 24 (1972), 507–530. MR 0300949, https://doi.org/10.1112/plms/s3-24.3.507
- 12. S. Pulmannová and Z. Riečanová, Block-finite atomic orthomodular lattices, J. Pure Appl. Algebra 89 (1993), no. 3, 295–304. MR 1242723, https://doi.org/10.1016/0022-4049(93)90058-2
- 13. Riecanova, Z., Order-Topological Lattice Effect Algebras, preprint, 2003.
- 14. Alexander Wilce, Test spaces and orthoalgebras, Current research in operational quantum logic, Fund. Theories Phys., vol. 111, Kluwer Acad. Publ., Dordrecht, 2000, pp. 81–114. MR 1907157
- 1.
- Bennett, M. K., and Foulis, D. J., Interval effect algebras and unsharp quantum logics, Advances in Applied Math. 19 (1997), 200-219. MR 1459498 (98m:06024)
- 2.
- Bruns, G., and Harding, J., The algebraic theory of orthomodular lattices, in B. Coecke, D. J. Moore and A. Wilce (eds.), Current Research in Operational Quantum Logic, Kluwer: Dordrecht (2000). MR 1907155
- 3.
- Choe, T. H., and Greechie, R. J., Profinite Orthomodular Lattices, Proc. Amer. Math. Soc. 118 (1993), 1053-1060. MR 1143016 (93j:06008)
- 4.
- Choe, T. H., Greechie, R. J., and Chae, Y., Representations of locally compact orthomodular lattices, Topology and its Applications 56 (1994) 165-173. MR 1266141 (95c:06017)
- 5.
- Foulis, D. J., Greechie, R. J., and Ruttimann, G. T., Filters and Supports on Orthoalgebras Int. J. Theor. Phys. 31 (1992) 789-807. MR 1162623 (93c:06014)
- 6.
- Foulis, D. J., and Randall, C. H., What are quantum logics, and what ought they to be?, in Beltrametti, E., and van Fraassen, B. C. (eds.), Current Issues in Quantum Logic, Plenum: New York, 1981.) MR 0723148 (84k:03142)
- 7.
- Greechie, R. J., Foulis, D. J., and Pulmannová, S., The center of an effect algebra, Order 12 (1995), 91-106. MR 1336539 (96c:81026)
- 8.
- Johnstone, P. T., Stone Spaces, Cambridge: Cambridge University Press, 1982.MR 0698074 (85f:54002)
- 9.
- Kalmbach, G., Orthomodular Lattices, Academic Press, 1983.MR 0716496 (85f:06012)
- 10.
- Nachbin, L., Topology and Order, van Nostrand: Princeton 1965.MR 0219042 (36:2125)
- 11.
- Priestley, H. A., Ordered Topological Spaces and the Representation of Distributive Lattices, Proc. London Math. Soc. 24 (1972), 507-530. MR 0300949 (46:109)
- 12.
- Pulmannová, S., and Riecanova, Z., Block-finite Orthomodular Lattices, J. Pure and Applied Algebra 89 (1993), 295-304. MR 1242723 (94j:06016)
- 13.
- Riecanova, Z., Order-Topological Lattice Effect Algebras, preprint, 2003.
- 14.
- Wilce, A., Test Spaces and Orthoalgebras, in Coecke et al (eds.) Current Research in Operational Quantum Logic, Kluwer: Dordrecht (2000). MR 1907157 (2003c:81018)
Retrieve articles in Proceedings of the American Mathematical Society with MSC (2000): 06F15, 06F30, 03G12, 81P10
Retrieve articles in all journals with MSC (2000): 06F15, 06F30, 03G12, 81P10
Additional Information
Alexander Wilce
Affiliation: Department of Mathematics, Susquehanna University, Selinsgrove, Pennsylvania 17870
Email: firstname.lastname@example.com
DOI: https://doi.org/10.1090/S0002-9939-05-07884-6
Keywords: Orthoalgebra, effect algebra, orthomodular lattice, topological lattice, quantum logic
Received by editor(s): August 22, 2003
Received by editor(s) in revised form: June 10, 2004
Published electronically: May 2, 2005
Communicated by: Lance W. Small
Article copyright: © Copyright 2005 American Mathematical Society
The copyright for this article reverts to public domain 28 years after publication.


text:
Research Awards are a chance to fund a specific type of cancer research. Your Research Award will help fund a Cancer Council research grant at a leading Victorian hospital, university, or research centre.
Donors and fundraising supporters who contribute $5,000 or more are invited to accept a Research Award. The award can be in your name, your organisation's name, or can be named in honor of someone you care about. You'll be acknowledged for your generosity in the Cancer Council Annual Review.
Please note that all Research Grants are subject to availability.For more details, email email@example.com or call 1300 65 65 85.
We rely on generous donations to help fund the fight against cancer and we're committed to maximising their impact.
Our funds are directed to:


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Tottenham start to look real deal
THE word all over Tottenham Hotspur's website yesterday was "delighted". The club was delighted to announce each of its three deadline-day signings — Jermaine Jenas, Lee Young Pyo and Grzegorz Rasiak — and it is a fair bet that most of the club's supporters feel the same way.
After seasons of underachievement, Tottenham are being spoken of as a team with the potential to finish in the top five
Of course, the regularity of false dawns over White Hart Lane means that no one in North London will be counting chickens, especially since the usual calculations associated with the club concern the number of players in the treatment-room.
But the strength of the squad should be able to cover most eventualities. It is the largest…


text:
Mineral County Schools 36 Baker Place, Keyser, WV 26726 Phone: 304-788-4200 Fax: 304-788-4204
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Free and Appropriate Education
The Mineral County Board of Education is committed to providing a free appropriate public education to children with exceptionalities identified in accordance with applicable State and Federal laws, rules, and regulations. Exceptional students are those children and young adults between the ages of three and twenty-one whose exceptionality meets the criteria established by West Virginia Board of Education Policy 2419. Categories of exceptionalities include:
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Please wait for 10 seconds when game is loading..
Create a more beautiful character of Ben 10. With a lot of clothes and accessories available you can achieve different costumes for your hero. Select the desired accessory and drag it to the character. Use your imagination and be more creative than ever with this ben10 dress up game.
This game is played with the mouse only


text:
Michael C.
Riverside, CA, 92507
Joined on May, 2014
Gender: Male
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Weekdays after 2PM
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Up to 20 minutes away for no additional charge
Up to 45 minutes away for a flat fee
Up to 45 minutes away for a flat fee
EducationCal State San Bernardino History major senior.
ExperienceHas worked in after school programs for 9 years. I enjoy working with student who want to succeed. I have taken history courses in World History, Middle East, China, Latin America, United States, African American, Africa, And European.
HobbiesMy life goal is to become a High School history teacher and then get into administration. In my free time I play softball and Bass Guitar.
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As a nurse clinician in the comprehensive hemophilia treatment center at Nationwide Children's Hospital for nearly 30 years, Charmaine Biega, RN, has watched her patients endure hundreds of needle sticks for infusions and other procedures which can mean tears, frustration, wiggling and – in some cases – lifelong anxiety about the medical system and treatments that patients with hemophilia need to survive. But when she administered six-year-old Brody Bowman's infusion this month in clinic, he was doing something she had never seen him do before a needle stick: having fun.
That is because several of her patients are enrolled in a pilot study which is testing a first of its kind virtual reality experience developed by the hemophilia team and design experts from Nationwide Children's and students from The Ohio State University. The virtual reality game, Voxel Bay, was specifically created for her patient population to fully engage them in an immersive environment of penguins, pirates and hermit crabs during infusions and other procedures.
"Brody just started getting his treatments through IV on a regular basis and was having a really rough time," said Charmaine. "But the first time he used the game in clinic, he was so completely engaged in the game when the IV was administered, he just barely flinched. The difference in how patients react during a procedure when they are playing these interactive games is remarkable."
By News Medical


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Need to get in touch?
If you want to contact the Pagan Federation North West District use the addresses below. (National and other Regional PF contacts addresses can be found on the Links page.)
District Manager: Robin
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and PF North West Children and Families Officer: Rachael
Postcode areas CA and LA
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Local Contact for the Isle of Man: David
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Contact c/o the District Manager firstname.lastname@example.com
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I have been sitting I this chair for 3hours and my xbox is not letting me sign in what is up with it i mean if you guys are going to send out an cbox that won't let anyone sign in then why send out the Xbox. ??
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text:
With only a couple games left on most teams schedules there is still a lot up for grabs in the Eastern Conference. Two of the Division leads are being contested, with 10 teams in the running for the 8 playoff positions.
The Buffalo Sabres have locked up the Northeast Division lead and the top seed in the East with Tuesday nights victory in Pittsburgh.
The New Jersey Devils need only a win or a Penguins loss to guarantee them the Atlantic Division and the second overall seed in the East.
Last years Stanley Cup Champions, the Carolina Hurricanes, have been eliminated from playoff contention, leaving the Atlanta Thrashers and Tampa Bay Lightning vying for the Southeast Division and third seed in the East. The Thrasher's could lock up the division with a win and a Lightning regulation loss.
The Ottawa Senators are currently sitting in the fourth seed, and are preparing for a first round match up with the second place finisher in the Atlantic, either the Penguins or Devils. They could pick up home ice advantage with in win against the Penguins on Thursday night.
Seeds 6, 7, and 8 are still highly contested, with the Lightning in the most unique situation. With them not out of the running for the Southeast, they could finish with the third seed. However, it is also possible for them to miss out on the playoffs entirely. They could guarantee themselves a spot by picking up a point, with either a win or an overtime or shootout loss against the Florida Panthers on Friday night.
The New York Ranger's are in a similar situation, a win on Thursday against the Canadiens, and they are in. A loss, and they would drop to the 8th spot in the East. The Montreal Canadiens are battling with their northern counterparts, the Toronto Maple Leafs, who find themselves a point out of the playoffs.
While the New York Islander's have not been mathematically eliminated, they find themselves on a narrow path. They could max out their points at 92 by winning their last 3 games, and still be eliminated with a Montreal win.


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Connectivity, not just social connections
The internet was abuzz last week with news of Facebook buying Oculus Rift for $2bn. Facebook might have paid the big bucks for the virtual reality headset manufacturer, but I would argue that its purchase of a small company called Ascenta, for the much less princely sum of $2m, is far more important.
Ascenta, which is based in Somerset not Silicon Valley, makes solar-powered unmanned aircraft. And while Facebook teaming up with Oculus Rift raises the possibility of a virtual reality social network, Facebook's investment in drones offers the potential to bring the internet to the 4 billion people around the world who can't currently access it, a decidedly more important endeavour.
Mark Zuckerberg explained (in a Facebook post, of course) how his company is building drones, satellites and lasers to beam the internet from the sky, with the goal of delivering connectivity to everyone. You can find out more about science behind the technology in the video below. The brains behind Ascenta will be developing connectivity aircraft, and will join experts from the fields of aerospace and communications technology, including former NASA engineers, who work at Facebook's Connectivity Lab inventing new technology so people in hard to reach parts of the world can get online. Facebook is one of founding partners of Internet.org, a global alliance of companies, including Nokia and Samsung, dedicated to bringing affordable internet access to the two thirds of the world's population that can't get online.
That's a pretty big goal, and Facebook's ambitions have been met with some cynicism, with critics arguing that bringing the internet to more people around the world is just part of Zuckerberg's primary goal of getting more people on Facebook, extending the platform's existing user base of 1.2 billion to parts of Africa that were until now unfamiliar with the big blue thumb. As Ovum analyst Mark Little told the BBC: 'Zuckerberg is pushing this as an altruistic way of connecting more people in the world - the net as a basic human right - but by increasing the total of net connections it also increases Facebook's members and the amount of sharing done, which in turn creates more space for advertising and drives its revenues in a massive way.'
Facebook isn't the only tech company out there making it their goal to spread the internet around the world. Google, for example, is trying to achieve the same through projects like Google Loon, which uses high-altitude balloons to connect people in rural areas. Contagious was impressed enough with Google Loon that we put the balloon on our Issue 36 cover last year (admittedly, we were also motivated by the fact that it made for a pretty gorgeous cover image). But Google has been met with much the same criticisms as Facebook, namely that its actions are self-motivated.
And when faced with Google and Facebook's connectivity endeavours people have also asked how does access to the internet compare with access to clean drinking water, healthcare, and basic sanitation? Sure, back in 2011 the UN declared that disconnecting people from the internet was a human rights violation and against international law, but is it a less important human right? Microsoft founder Bill Gates might be a big believer in the digital revolution, but speaking to Bloomberg Businesweek about Google Loon he said: 'When you're dying of malaria, I suppose you'll look up and see that balloon, and I'm not sure how it'll help you. When a kid gets diarrhea, no, there's no website that relieves that.'
Not to go against Bill Gates, but I'm not sure that's a fair argument. You can't pit one human right against another. One philanthropic cause can't outrank another. It's true that the people who live in many parts of the world that don't have access to clean water or electricity have more pressing concerns than being able to get online. But at the same time access to the internet will definitely help the efficiency of aid work in hard-to-reach areas.
And as Zuckerberg said in a paper detailing his investment in connective drone technology, the internet enables people to 'participate in the knowledge economy', helping them gain access to jobs, healthcare, education and financial services and helping them 'have a greater say in their societies'. The Facebook founder cites a study by Deloitte that found that the internet is an important driver of economic growth in developing countries and he argues that 'Expanding internet access could create another 140 million new jobs, lift 160 million people out of poverty, and reduce child mortality by hundreds of thousands of lives.
Internet.org already has quite a good track record of getting people in developing countries connected, having managed to give 3 million people access to mobile data in the Philippines and Paraguay. Whatever Facebook's motivations are behind its work with Internet.org, and I think they probably do go beyond the altruistic, it's inconsequential. Getting people online in far-flung parts of the world will improve their lives by giving them access to information and opportunities. So even if these people ultimately end up Liking posts and reading news feeds, I hope Zuckerberg succeeds.


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Book Review ~ Faithful, Kim Cash Tate
I love good books, you know that, but when it comes to great books I want to shout from the rooftops and tell everyone I know about them.
That's what this book, Faithful, is...a great book!
Just last week I received a package from Women of Faith (and y'all know how much I big puffy heart Women of Faith) with two books inside. Squeallll...books, Women of Faith, woohoo, that was a great day!
Any who, one of the books immediately caught my eye and that was this one, Faithful, by Kim Cash Tate. I love the cover, then when I flipped it over and read the back I knew that I had to read this book as soon as there was a crack in my schedule.
The opportunity came Friday evening when everything else in Mel's World was settled a bit, so I grabbed my coffee and book then went out back to our sweet little quiet room. I was absolutely riveted.
Page after page I was more deeply invested into the characters, three girlfriends and the commitments they made to God, the highs and lows of sticking with those commitments and the bumpy road along the way.
There were times when I giggled to myself while reading it, times when I was plain ole mad and other times when I just sat there and cried. This book hit just about every emotion I had but not for any other reason that it could be any one of our lives or our friends lives.
Here's what the back of the cover says;
Three life-long friends experience life-altering struggles. Will they find the strength to be faithful to the covenants they've made with God...and each other?
Cydney Sanders thought she knew God's plan for her life. She'd marry, have kids, and then snap her body back into shape with Tae Bo. But she's celebrating her fortieth birthday as the maid of honor at her little sister's wedding . . . and still single. Why would God give her this desire to marry, but no husband? And why is her life suddenly complicated by the best man-who's the opposite of what she wants in a husband?
Cydney's best friend Dana has the perfect marriage. But when Dana discovers her husband's affair, her world goes into a tailspin. And Phyllis is out of hope after six years of unanswered prayers for her husband to find faith. When she runs into an old friend who is the Christian man she longs for, she's faced with an overwhelming choice.
With life falling apart around them, can they trust God like never before?
I haven't started the other book that came in my little package (Angel Song by Sheila Walsh & Kathryn Cushman) yet, but I can't wait to see where the pages of that book takes me.
Right now I already have two or three of my girlfriends that I am thinking of sharing Faithful with. I can't wait to see what they think of it so we can chat about it. There are so many things in this book that could lead to some really amazing discussion time.
If you are looking for a great Christian Fiction book this fall, then Faithful is exactly what you are looking for!
What are some Christian Fiction books you are reading right now?
I'd love to hear, I'm always looking for great books!
Disclaimer - I received a copy of Faithful, by Kim Cash Tate, from Women of Faith as a gift for being an event group leader. I am doing a review of the book completely on my own and the opinions expressed are my own and from my heart.


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Free Sheet Music | Turkish March for Piano Solo – 2 Levels
September 6, 2008
Free Printable Sheet Music
Here are two versions of this popular piano solo. The first is a shorter version, great for the 4th or 5th year piano student. The second is a the full work, best for advanced high school students and above. Enjoy!
Turkish March for Piano Solo/Level 5
Turkish March for Piano Solo/Advanced
Composer Biography
Wolfgang Amadeus Mozart (27 January 1756 – 5 December 1791) was a prolific and influential Austrian composer of the Classical era. His more than 600 compositions include works widely acknowledged as pinnacles of symphonic, concertante, chamber, piano, operatic, and choral music, and he is among the most enduringly popular of classical composers.
Mozart was born in Salzburg into a musical family and showed indications of prodigious abilities at a very young age. When he was five years old, he could both read and write music and had precocious skills as a keyboard and violin player. Much of his childhood and adolescence was taken up with tours, which included performances before many of the royal courts of Europe. In 1773, aged 17, he accepted a post as a court musician in Salzburg, but was unhappy with his low pay and limited opportunities. Over the next eight years, he frequently traveled in search of a better position and composed abundantly. This situation continued until his dismissal from Salzburg in 1781 by his employer, the Prince-Archbishop, and his subsequent departure for Vienna.
More "The Piano Student" Free Sheet Music Posts
Level 1/Easy Piano Solos
Level 2/Easy Piano Solos
Level 3/Intermediate Piano Solos
Level 4/Intermediate Piano Solos
Level 5/Intermediate Piano Solos


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I really don't want to hear from Trump opposition. I know that side and understand that side.
Help me understand the other side.
Thoughts? Support or against and why?
Working to abolish "Obama Care" with out a replacement. (Although it wouldn't go into effect until early 2020, after the next election)
Censoring scientists?
Working to demolish the EPA?
"Muslim ban" clearly didn't ban countries Trump has business ties to.
Trump is threatening China.
Trump is working on a bill to launch a war against Iran.
Trump has threatened to invade Mexico.
It has not even been 2 weeks.
I think most Trump supporters support the idea of most his positions but not necessarily his implementation. There is a smart way to address the root of the problems you listed but the bottom line is the average person is not smart and they are the ones who vote. Anyone who is confused how people can support Trump is just overestimating how many actually support him vs a republican administration. The reason for the few that support him and all his flaws is the same reason as a few on the left support things like full on communism.
Tagging @SkyzykS here. Sorry to throw your name into the ring, pal, but you seem like the guy who best fits this description from some of the PWI discussions...?
I noticed how right leaning this forum is yet couldn't think of too many big Trump supporters, even someone like Zeb is just blindly following because of the R party so even if he claimed to support Trump I don't really count him.
I don't think that all the bad press about trump is warrented, just most of it.
While I'm a limited govenment type and therefore must disagree with nearly all of his policies there's a side to Trump that most people pro and con are missing.
He is "Sun Tzu"-ing his way through politics in a way that defies all conventions. The man only fights where he is strong and doesn't bother to engage where he is weak.Strong: Illegal immigration, endless mentions Weak: tax returns, not a word.
If you go through some concepts of The Art of War and apply it to Trump it all comes into clear focus.
While most people see an arrogant man with a chemical imbalance I see a guy skating circles around the establishment (politics, media, law). It's not about the constitution, it's not about truth, it's not even about Trump, it's about winning. I think he will accomplish a chunk of his agenda before they figure out this game.
I think he truly wants the US to win and cut better deals with the rest of the world. But his methods will annoy absolutely everyone, in every party. He doesn't care.
Not so fast. Do I believe in the republican philosophy of government? Yes. Was I for Donald Trump from day one? No. I was a Marco Rubio supporter. When he left the race I was for Ted Cruz. In fact, I was for just about any one of the 16 other republican candidates other than Donald Trump. I found him crass and not a full fledged republican, more of a populist...which he is.
However, when he won the republican nomination I knew that he would be better than Hillary. I was not blinded like one particular fence rider who said she'd be better in the short and long term. Ha. Really now. Do you think Hillary would have just nominated the likes of Justice Gorsuch, a conservative, as a Supreme Court Judge? She would have loaded the court with lefties. How is that good for us in the "long term"? It isn't. Would Hillary have a tax plan that lowers taxes on small business which creates jobs? Nope. Would Hillary enforce immigration laws? Nope. Does Hillary care about gun owners rights and the second amendment? Nope. Get the idea?
As I have maintained all along Trump was a better choice than Hillary. And even though he has only been in office not even two full weeks he has not yet disappointed me in terms of his policies. However, as you stated, I am not at all fond of the way he does business. But, that is something I am glad to put up with given the choice which was offered.
So blind supporter? No. If I was I would not say that he is a crass, overbearing and at times profane individual who needs to bone up on various policy issues BEFORE he opens his mouth. But...better than Hillary? Oh yes...by a country mile!
!!! Not Smart and Voted? WTF!
I'll have to get back to it in a little while. I'm in the midst of an argument over voltage drop in welding systems on another forum.
Fucker tried hittin me with ohms law. He's getting owned!
Giggling like a schoolgirl reading a passed note.Damn. You can take them out of the Philly, but ,,,,
Thanks people!
See you guys at the gym
LOL, realized after I posted that I left the end of that phrase still hanging around...
On a more sincere note, the reason I tagged you is that, a few times, you've articulated some reasons why you like (some of) Trump's ideas while also keeping his limitations in perspective.
Frankly, even when I've disagreed with your conclusion, I can still walk away appreciating the logic that went into your argument(s).
Read it. Nope. This reminds me when the Obama supporters kept swooning that their man was playing "four dimensional chess."
"The supreme art of war is to subdue the enemy without fighting" - Trump's entire game is the opposite. He starts all kinds of unnecessary fights with all kinds of unnecessary people. He has no discipline, he jumps at every provocation, real and imagined, wasting enormous capital and time, and as a result is always putting strains on valuable relationships.
So Sun Tzu never fought any battles? Just outmanuvered opponents? When you made that observation my first thought was "so Trump took what he could use and missed the overarching lesson of the text." That sounds exactly like something he would do.
I'm not saying Trump is some master tactician, I don't even like the guy. He acts childish far too often. But underestimating him hasn't worked so far.
Just one example: Romney was by far the Reps best chance at offering a conciliatory candidate that the progressive press wouldn't evicerate and maybe pull some Democrat voters. He couldn't survive the 47% comment or the binders full of women gaff. Do I even need to list Trump's gaffs? "Grab her by the pussy", "I could shoot someone", to list all of them would take T-Nation's server down.
Trump isn't half as good as HE thinks he is. But he's smarter than his opponents give him credit for. Did he cheat to win? Probably. Last time I checked Belichik has 4 rings and doesn't care about his image either.
Hillary cheated and lost. She had the entire DNC behind her, given certain debate questions in advance. She was even given super delegates. Of course she did win the primary. But, she had a tough time in the general election even with the left wing media in her hip pocket.
I agree with a number of your points, but I think your description points to the better explanation that Trump succeeded despite his actions, not because if them. It certainly wasn't some intentional strategy in Sun-Tzu-esque fashion - it was a stumbling, drunken sprint to the finish line against a uniquely awful opponent.
Hell, even on election night Team Trump didn't think he would win.
To Trump's credit, he tapped into a very legitimate populist anger (not all of it the bad kind of populism, either). In fact, I read somewhere that a Democratic insider said that had Trump ran for the Democratic nomination on his populist theme that he'd have beaten Hillary for the nomination. He deserves credit for pouncing on that when others completely missed it.
Some of that was just accidental on his part, if we're all honest, but credit where credit is due.
This, though, deserves a rebuttal. If he did, that isn't anything we should be ok with.
Interesting alternate-reality question, IMO.
Politicians lie, cheat, imbezzle, oppress, occaisionally murder etc... this is a fundamental law of nature. People with political power over others always abuse that power, every time. It's the degree of abuse that determines whether people will put up with it.
If he did it I hope they can prove it and prosecute him. I won't lose any sleep over it either way. The law is only for the little people after all.
Guys, don't mind the naysayer. He just hasn't done The Procedure yet.
Here you go, TB. Lots of advice here that will help you let go of that unseemly notion that you ought not to shrug dull-eyed at what was "probably" a joint Trump-Putin scheme to cheat in the election:
PS: the irony, the world-rending irony of the name of the franchise used above as (incomprehensible) justification for not really caring about what happened in the 2016 election.
You mean the "Patriots"? You do realize that the "founding fathers" were TRAITORS right? They were British subjects who didn't like their treatment as subjects. Had they lost the war they would have all been hung. History would remember them as "the colonist insurrection of 1776" or some such. Talk about irony.
The only thing that made them "Patriots" was that they won. Winning changes everything.
Of course Trump conspiring with Putin would be the largest American scandal OF ALL TIME and cause a crazy constitutional crisis and possibly civil war if it went really sideways. The problem is you need to PROVE it. With Trump installing his own FBI, CIA etc... chiefs I don't see how that happens.


text:
Cape Of Storms left today's rival Sir Louis and the rest of the field trailing in his wake when winning here recently. He was allowed to make the running on that occasion and he could well follow up if unchallenged for the lead here. However, there is also a chance he could set the race up for ACE OF SPIES. Conor Dore's charge won off a higher mark over C&D in August and this contest could pan out in his favour. He gets the nod with Apache Ridge looking best of the remainder.
Ace of Spies (IRE) 15-2 (9-6) In touch, ridden and headway over 1f out, not troubled leaders, 5th of 12, 7l behind Alpha Tauri (9-6) at Southwell 7f hcp (0-65) (6) fbs.
Apache Ridge (IRE) 11-4fav (9-3) Tracked leaders, ridden over 2f out, hung left over 1f out, no impression and soon beaten, 5th of 9, 5l behind Ajara (9-1) at Wolverhampton 6f sell stks (6) pol.
Cape of Storms 11-4fav (9-7) Made all, driven clear over 1f out, ran on well, won at Southwell 6f hcp 0-60 (6) fbs beating Sir Louis (9-4) by 3 1/2l, 9 ran.
Bel Cantor 16-1 (8-8) Towards rear, ridden over 2f out, some headway over 1f out, never dangerous, 7th of 14, 10l behind McConnell (9-6) at Southwell 1m hcp 0-70 (5) fbs in Nov.
Decider (USA) 16-1 (8-5) Took keen hold, tracked leading pair, hung badly right bend into straight 2f out, ridden and kept on inside final furlong, 4th of 8, 3l behind Brandywell Boy (9-4) at Lingfield 5f sell stks (6) pol.
Sir Louis 9-1 (9-4) Held up in touch, headway 3f out, soon chasing leaders, stayed on well inside final furlong, no chance with winner, 2nd of 9, 3 1/2l behind Cape of Storms (9-7) at Southwell 6f hcp 0-60 (6) fbs.
Darcy's Pride (IRE) 15-2 (8-11) Reared start, always in rear, never a factor, 8th of 9, 14l behind Kheley (8-7) at Southwell 5f app hcp 0-55 (6) fbs.
Ballyvonane (USA) 25-1 (8-6) Keen held up, headway 2f out, ridden to go 3rd over 1f out, no extra inside final furlong, 5th of 8, 6l behind Super Frank (9-6) at Lingfield 6f hcp 0-60 (6) pol.
Fyodorovich (USA) 16-1 (8-0) Dwelt, towards rear and keen, ridden over 2f out, never dangerous, 9th of 12, 8l behind Final Salute (8-8) at Southwell 6f hcp 0-60 (6) fbs in Nov.


text:
Heart of Melbourne Apartment - With Parking
Apartment, Melbourne City
Rated 5 out of 5 stars 84 reviews
Confirmation within 24hr
From $203 per night {{quote.pricing.message}} Total {{quote.pricing.price | format:'currency':'short'}} for
Min 1 - 5 nights stay
This spacious modern apartment offers quality group and family accommodation.
Located on Flinders Street, directly across from Flinders Street Station, Federation Square, Forum Theatre and much much more. This location is unbeatable when visiting Melbourne City as everything is at your door step.
Enjoy the Melbourne inner city living experience in this first class location. Step out of the apartment building to find yourself surrounded by Flinders Street Station, Federation Square, Yarra River, Arts Centre, National Gallery of Victoria, Forum Theatre, Hosier Lane, ACMI Australian Centre of the Moving Image - Gallery, restaurants, cafes, shopping, public transport, free tourist tram, tourist bus and tourist attractions
Near By Attractions -
National Gallery of Victoria
Melbourne Museum
Tennis Centre
Immigration Museum
Melbourne Aquarium
Melbourne Cricket Ground
Theatres - Forum, The Art Centre, CUB Malthouse, Regent, Her Majesty's, Athenaeum and Princess
Federation Square
Queen Victoria Market
Free City Circle Tram
Crown Entertainment Complex
Eureka Skydeck
Melbourne Zoo
Royal Exhibition Buildings and Gardens
Old Melbourne Gaol
Luna Park
Shrine of Remembrance
Melbourne Star Observation Wheel
South Melbourne Market
Just to name a few
The Apartment Offers ……….
Beds -
First Bedroom – Queen Bed or two singles - TV in bedroom
Second Bedroom – Two Single Beds or made up as a queen bed
Lounge Room – Two Double sofa beds
Portable Cot – Linen not provided
Bathroom -
Walk in shower
Washing machine
Clothes Dryer
Hair Dryer
Towels, bath mat and hand towel
Hand wash and toilet rolls
Clothes horse, iron and ironing board
Kitchen -
Electric oven and stove top
Refrigerator, Dishwasher, Microwave
Kettle, toaster, tea pot and coffee plunger
Pots and Pans, platters, serving bowls, dinner ware, glasses, chopping boards, cutlery and utensils
Dishwashing liquid, dishwasher tablets, sponges, garbage bags
Tea, Coffee and Sugar
Foil, glad wrap, tea towels and napkins
Lounge/Dining Room -
Two Leather Couches Sofa beds
Large wooden dining table with 8 chairs
Music Player – iPod Doc
TV and DVD
Additional Items -
High Chair and portable cot
Small selection of DVDs
Board Games, Children's DVDs and a good selection of toys
Parking for one vehicle $30 per night - discounted for long stays
Grocery Stores -
Coles, Woolworths and IGA supermarkets are located within a short walk of the apartment.
Access -
There are several stairs upon entry to the apartment building.
The apartment is single story with no stairs internally.
The apartment is located on the second floor and can be accessed via stairs or the lift.
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text:
A minimally invasive option for treating severe aortic stenosis
What is TAVR?
Transcatheter Aortic Valve Replacement (TAVR) is a minimally invasive procedure that allows the heart's aortic valve to be replaced using a catheter. TAVR is an alternative to traditional open heart surgery.
What are the Benefits of TAVR?
The benefits of this procedure are that it is less invasive and offers a quicker recovery and a shorter hospital stay than conventional open heart surgery. Typically, patients are up and moving just hours after the procedure and return home within a few short days. Additionally, the TAVR procedure is an option for many patients who are not suitable candidates for open heart surgery due to advanced age or other limiting health factors.
Am I a Candidate for TAVR?
If you have been diagnosed with severe aortic stenosis you may be a candidate for this procedure. Aortic stenosis occurs when the opening of the aortic valve becomes restricted and narrow due to a buildup of calcium on the valve leaflets. Aortic stenosis is most commonly a degenerative condition occurring in patients 65 and older as a result of wear and tear on the aortic valve. To compensate, the heart must work harder to pump blood through the constricted valve, which can weaken the heart. Aortic stenosis can result in disabling and life-threatening symptoms of congestive heart failure, including shortness of breath, chest discomfort, dizziness or lightheadedness, syncope or fainting, fatigue and swelling.
How is the TAVR Procedure Performed?
First, a small incision is typically made in the groin area and a catheter (thin, flexible tube) with a small, uninflated balloon attached to the tip is threaded through a blood vessel. Once the catheter reaches the damaged valve, the balloon is inflated to stretch the valve opening and allow more blood to flow through it. The balloon is then deflated and guided back through the vessel and removed. A new catheter containing the heart valve is then reinserted into the blood vessel. The new heart valve is threaded to the heart and into the damaged valve where it is released. The new heart valve will take the place of the damaged one.
Why Choose Ohio State for Your TAVR Procedure?
At Ohio State, you will be evaluated and treated by our world-class team of heart valve experts, ensuring you receive the most comprehensive care available, often as part of a one-step evaluation. Our patients are treated and cared for in the Richard M. Ross Heart Hospital, which has an entire floor dedicated to patients undergoing cardiac catheterization procedures such as aortic valve replacement. You will be cared for in a private, spacious room by a team of nurses and support staff who are experienced in caring for patients who have undergone your procedure.
Advancing Care for Heart Valve Diseases at Ohio State
Transcatheter Aortic Valve Replacement
Minimally invasive treatment for severe aortic stenosis
How the TAVR Procedure Works
This video shows how the Transcatheter Aortic Valve Replacement (TAVR) procedure is performed.
Life-Saving Valve Replacement
Learn how the team at Ohio State saved Veneta's life with a transcatheter aortic valve replacement procedure.
Heart Valve Surgery: What to Expect
When a patient suffers narrowing or leakage of the heart valves, testing may reveal that the patient needs valve repair or replacement. Juan Crestanello, MD, a cardiovascular surgeon at Ohio State's Wexner Medical Center explains the general process of heart valve surgery.


text:
Wolf Trailer (2007)
20 September 2007 Adventure, Drama 69 mins
The life of a small Siberian village totally depends on the breeding of reindeer. With the advent of new times the wolves have started to behave cruelly. They decimate the reindeer herd by sucking out their blood, not by killing and eating them. They just leave the bodies there. The shepherds ask Nikolai Szergeievich (who is generally believed to be the offspring of shamans) to help them.
Watch the official Wolf 2007 trailer in HD below or find more Wolf videos on Vidimovie.


text:
Giovanni Trapattoni has revealed that he is "evaluating" Anthony Pilkington ahead of the Republic of Ireland's crucial World Cup qualifiers against Sweden and Austria.
The Norwich winger, who had pulled out of no fewer than five squads in the past, joined up with the Boys in Green on Monday for first time and came through the morning training unscathed.
"He is good," Trapattoni said. "He had a little knee problem, but I am evaluating his situation at the moment. I have also to think about the opponent, Sweden."
Shane Long, Robbie Brady and Marc Wilson all missed the first training session, but the trio are expected to train on Tuesday.
Stoke midfielder Wilson bruised his foot playing for his club on Saturday and will have a scan to assess the damage, but Trapattoni is confident that he will be able to take part in Tuesday's session.
"Probably, yes," said the Italian tactician when asked if Wilson would train. "Today I saw the knock on the ankle. He continued to play without problem [against West Ham]. He has a little bit of pain. I have no doubt about his fitness."
Defender Richard Dunne, who has played three Championship games for QPR, including their 1-0 win at Leeds, sat out the second half of training this morning as a precaution, but Trapattoni hinted that the 33-year-old would be involved in the Sweden clash.
He said: "I spoke with him, I saw the game [against Leeds], he was very well, I'm sure he can be with us in the game [against Sweden]."
Trapattoni indicated that goalkeeper David Forde would return to the side, having missed the friendly against Wales with a knee injury. The Millwall shot-stopper underwent surgery last month but returned to action for his club against Brighton on Saturday.
"We have a muscular situation. But he has played in his club without problems," he said. "In training I spoke with [goalkeeping coach] Alan Kelly, he's normal. At this moment I watch what happens. If he's okay we can continue with him."
Captain Robbie Keane and Darren O'Dea will join up with the squad tonight after both featuring for their clubs on Sunday.


text:
President Rodrigo Duterte on Monday reiterated that "big-time" shabu dealers and mayors involved in the illegal drug trade have no place under his administration.
In his typical swear-ridden speech delivered during the mass oath-taking of new government appointees, Duterte defended anew his anti-drug war that is blamed for the death of over 6,000 people, about 2,000 of them in police operations.
"Huwag na tayong magbolohan. For as long as I am president, itong malalaking shabu dealers, mamamatay talaga ito," he said.
The tough-talking Duterte said mayors involved in the illegal drug trade will suffer the same fate as the shabu dealers.
"Sabihin ko talaga sa kanila (mayors), 'Ganoon kakapal 'yung ipinakita ko sa inyo eh. Hanapin mo 'yung pangalan mo diyan, mayor. T*** i** 'pag nandiyan 'yung pangalan mo, may problem ka'. Talagang papatayin kita," he said, referring to his list of personalities involved in illegal drugs.
He also threatened that he could "deprive" these mayors of their supervisory powers over the police and pull out their security.
"Talagang sabi ko, huwag ninyo akong lokohin. Kaya sabi ko, the first thing that I would do is to deprive you of the supervisory powers over the police. Second is I will — tanggalin ko lahat ng security mo," the former Davao City mayor said.
Duterte said towns with a thriving "shabu business" shows the mayor is not performing his duties properly.
Perhaps to cite as an example, Duterte mentioned the case of Albuera, Leyte Mayor Rolando Espinosa, who was killed inside his detention cell in Baybay Provincial Jail when he allegedly tried to shoot it out with the police who were serving a search warrant.
Espinosa and his son, Kerwin, were both linked to the illegal drug trade in Eastern Visayas.
"Itong si Albuera, eh namatay siya in a very… Eh wala akong pakialam. Ang sabi ng pulis lumaban, and then I will stick with the story of the police because the police is under me," he said.


text:
Bradley and Hubbard
(c) Vin Callcut 2002-2017. Small extracts can be used with acknowledgements to 'Oldcopper.org' website.
Helpful comments are very welcome.
Bradley and Hubbard 1852- 1940s, Walter Hubbard & his brother-in-law, Nathaniel Lyman Bradley, started making cast iron clocks, tables, frames, andirons, lamps, chandeliers, sconces and sewing machines in 1854 in Meriden, Connecticut. The company became Bradley & Hubbard Manufacturing Co. in 1875. The Charles Parker Company bought the firm in 1940.
The Page below copied from:
Now replaced by http://www.si.edu/oahp/bradley_hubbard/Marks.htm
or may have moved elsewhere on the Smithsonian website.
This mark, consisting of raised san serif letters, is found on cast iron match safes, lamp bases, andirons and fire tools.
The basic elements of this mark are the letters "B&H" with printer's flowers above and below. Several variations of this mark have been found: some have raised circles with recessed lettering(above), in others the circle is recessed and the letters raised, and in still others, the raised letters are encircled by a raised ring. This mark is found on bookends, vases, candle sticks, andirons, and fireplace tools.
In this mark, plain san serif raised letters are set within two concentric raised rings. This mark was found on the inside of an electric ceiling light fixture.
In this mark, raised san serif letters are surrounded by a single raised oval ring. Found on iron match safes, andirons, and fireplace tools.
|The triangle and lantern mark.
The most commonly found Bradley and Hubbard mark is the triangle and lantern design. It was devised sometime after the 1875 reorganization when the company was renamed The Bradley and Hubbard Manufacturing Company, possibly as late as ca.1902. This mark appears on a wide variety of objects made over a long period of time.
This mark is found stamped into brass cigar and cigarette boxes, desk sets, ash trays, lamps, vases, tobacco jars, and candle sticks dating from ca.1920-1940.
Dating to the turn of the twentieth century, this paper label was attached to the felt pads on the bottoms of bookends, lamps, candle sticks, ink wells, and sculptures.
This paper label differs from the previous example with the addition of several design elements: first, the lineMeriden Conn. along the bottom edge; second, the black background; third, the metallic gold letters and borders; and finally the more elegant and articulated lantern design. This redesigned mark appears in the 1934 Bradley and Hubbard catalogueDistinctive Metalware for Home and Office (above).
On heavier pieces of brass and iron work, the mark was cast directly into the piece. On brass (above top) it is found on ink wells, candle sticks, and lamp bases.
On iron pieces (above bottom) it is found on fire place tools, andirons, ink wells, match safes, weighted bases for candle sticks, and lamps.
This mark is found on the oil font filler caps of Bradley and Hubbard's kerosene burning lamps produced during the 1880's and well into the twentieth century.
This mark is found on the wick raising knob of lamps fitted with the duplex burner.
The B&H (above & below) refers to the patented central draft Bradley and Hubbard kerosene burners. Usually found stamped or embossed into the body of the oil font.
This simple san serif text mark is usually found stamped into the metal frame of slag glass lamp shades.


text:
I've been deeply frustrated. I suspect a lot of you have been too.
We're facing such huge challenges and all you hear through the media are demagogic chants like "drill, drill, drill."
Skyrocketing energy prices. The climate crisis. Unraveling financial markets. Wars that just happen to be in places with a lot of oil. These are all just different faces of exactly the same thing. As I've said in the past, we're borrowing money from China to buy oil from the Persian Gulf to burn it in ways that destroy the future of human civilization. And every bit of that has to change.
We all know what we have to do. Ask anybody on the street and they'll tell you. We need to "Repower America" -- invest in ourselves, here at home, with clean, economical energy technologies that we know work. And be the global leader as these technologies take off around the world.
And ask anyone, and they'll also tell you why it isn't happening: the oil and coal lobbies -- and the politicians who do their bidding.
It's very simple.
So the Alliance for Climate Protection has put together an ad that tells this simple story. And we're going to put it on national cable TV.
If we can raise an additional $80,000 online, we'll also put it on 60 Minutes and 20/20 this coming week. Wouldn't that be great?
Can you help? Just go here:
Here's the script:
The solution to our climate crisis seems simple.And you can view the ad on our donation page, here:
Repower America with wind and solar.
End our dependence on foreign oil. A stronger economy.
So why are we still stuck with dirty and expensive energy?
Because big oil spends hundreds of millions of dollars to block clean energy.
Lobbyists, ads, even scandals.
All to increase their profits, while America suffers.
Breaking big oil's lock on our government ...
Now that's change.
We're the American people and we approve this message.
We're taking on the oil and coal lobbies, because there's simply no other choice. We need your help.
Al Gore