text:
Benzyl butyl phthalate increases the chemoresistance to doxorubicin/cyclophosphamide by increasing breast cancer-associated dendritic cell-derived CXCL1/GROα and S100A8/A9
- Authors:
- Ya-Ling Hsu
- Jen-Yu Hung
- Eing-Mei Tsai
- Cheng-Ying Wu
- Ya-Wen Ho
- Shu-Fang Jian
- Meng-Chi Yen
- Wei-An Chang
- Ming-Feng Hou
- Po-Lin Kuo
- Published online on: September 23, 2015 https://doi.org/10.3892/or.2015.4307
- Pages: 2889-2900
Food, including milk, vegetables, vegetable oil, and even school meals have been found to contain multiple types of phthalates in recent years (1–4). These different types of phthalates are transferred to food during vegetable cultivation, food packaging and food processing (5–7). Phthalates have been detected in the serum of infants, children and adults as it is difficult to avoid daily dietary exposure at present (8,9). Moreover, metabolites of dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP) and benzyl butyl phthalate (BBP), have been found in urine, serum, breast milk and saliva. Studies have revealed that phthalate exposure is associated with many diseases, such as airway obstruction, allergies, asthma, reproductive disease and breast cancer (10–12). BBP has been demonstrated to induce neoplastic transformation of breast epithelial cells and to increase the proliferation and progression of both estrogen-dependent and -independent breast cancer stem cells and cancer cells (13–16). However, the influence of phthalates on cancer therapy has not been evaluated to date.
Breast cancer is the most common female cancer, and is one of the major causes of cancer-related mortality among women. There were nearly 1.7 million new breast cancer cases diagnosed and 521,900 deaths due to breast cancer worldwide in 2012 (17,18). Although chemotherapy significantly improves the outcome of patients with breast cancer, chemoresistance is still a major obstacle to successful treatment and such resistance to chemotherapeutic drugs frequently results in subsequent tumor recurrence and tumor metastasis (19,20). However, most of the mechanisms responsible for resistance to chemotherapeutic agents are still unknown. A better understanding of the causes and mechanisms of chemoresistance can be helpful for identifying and developing novel therapeutic agents that could decrease metastasis, chemoresistance, and even cancer-related death.
The tumor microenvironment (TME) not only plays a critical role during tumorigenesis, cancer progression and metastasis, but also influences therapeutic efficacy (21). Tumor environment-mediated drug resistance (EMDR) is mediated by a multitude of reciprocal interactions between cancer cells and various cell types existing in the TME. Tumor-associated immune cells are a hallmark of most solid malignancies, and the presence of various immune cells significantly influences clinical outcome (22). Tumor-associated macrophages have been indicated to increase the resistance of cancer against cytotoxic agents. Therefore, inhibiting the infiltration of macrophages improves the efficacy of chemotherapy and reduces cancer metastasis (23,24). Similar to macrophages, tumor-associated dendritic cells (TADCs) have been postulated as being involved in cancer progression (25–27). TADCs produce a number of potent growth factors and cytokines, which may be mediators that potentiate chemoresistance (28,29). The present study is the first to assess the effects of BBP on breast cancer, and to demonstrate that BBP induces a change in the chemo-sensitivity of breast cancer to doxorubicin/cyclophosphamide by altering the cancer microenvironment.
Materials and methods
Cell culture and conditioned medium
Human breast adenocarcinoma cell line MDA-MB-231 (ATCC HTB-26™; American Type Culture Collection, ATCC, Manassas, VA, USA) was cultured in Leibovitz medium (L15) supplemented with 1% antibiotic solution and 10% fetal bovine serum (FBS) (all from Thermo Fisher Scientific, Waltham, MA, USA) in a CO2-free incubator. Human umbilical vein endothelial cells (HUVECs) (BCRC H-UV001; Bioresource Collection and Research Center, Hsinchu, Taiwan) and 4T1 mouse mammary tumor cell line (ATCC CRL-2539; ATCC) were cultured in complete EGM2 medium (Lonza, Walkersville, MD, USA), or RPMI-1640 (Gibco-BRL, Gaithersburg, MD, USA) medium containing 10% FBS in a 5% CO2 incubator. To prepare the conditioned media (CM), the MDA-MB-231 cells (2×106/100 mm dish) were seeded, and the supernatant was harvested and filtered (0.22 mm), after 48 h of incubation.
Isolation of CD14+ monocytes and differentiation of dendritic cells
Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) provided by healthy consenting donors. PBMCs were isolated from blood by Ficoll-Hypaque gradient (GE Healthcare Bio-Sciences, Little Chalfont, UK). CD14+ monocytes were purified from PBMCs by using CD14+ monoclonal antibody-conjugated magnetic beads (MACS MicroBeads; Miltenyi Biotec Ltd., Bergisch Gladbach, Germany), according to the manufacturer's procedure. Monocyte-derived dendritic cells (mdDCs) or TADCs were generated by culturing CD14+ monocytes in RMPI-1640 medium containing control 20% L15 (for mdDCs) or MDA-MB-231-CM (for TADCs) presenting in 10 ng/ml GM-CSF and IL-4 (R&D Systems, Minneapolis, MN, USA), with or without BBP (1 or 10 µM; Sigma-Aldrich, St. Louis, MO, USA) for 5 days. The mdDC and TADC supernatants were collected and filtered (0.22 mm) to be used as CMs. The Institutional Review Board (IRB) of Kaohsiung Medical university Hospital (Kaohsiung, Taiwan) approved the study protocol, and all of the participants provided written informed consent in accordance with the Declaration of Helsinki (IRB no. KMUH-IRB-990174 and KMUH-IRB-20120362).
Measurement of secreted factors
Supernatants from the mdDCs or TADCs treated with or without BBP were collected. CXCL1/GROα and VEGF were determined by Milliplex MAP kit (Millipore, Billerica, MA, USA). S100A8 and S100A9 were assessed and quantified using the DuoSet ELISA (enzyme-linked immunosorbent assay; R&D Systems).
Cell viability/apoptosis
MDA-MB-231 cells were treated with control or doxorubicin/cyclophosphamide (10/100 µM) with or without BBP (1 µM) presenting in various CMs (20%) for 48 h. Cell viability was determined by Premixed WST-1 Cell Proliferation reagent (Clontech Laboratories Inc., Mountain View, CA, USA) in accordance with the manufacturer's instructions. Quantitative analysis of apoptosis was determined by the terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) method using the BD ApoAlert DNA Fragmentation Assay kit (BD Biosciences Clontech, Palo Alto, CA, USA).
Tube formation analysis
Tube formation assays were carried out as described previously after modification (30). Growth factor-reduced Matrigel (200 µl) was loaded in each well of a 24-well plate, which was incubated at 37°C for 60 min. HUVECs were mixed with the various CMs (20%) and the CXCL1/GROα antibody. Cell suspension solution (500 µl) was added on top of the Matrigel. The plate was then incubated at 37°C, and the formation of capillary-like tubes was detected and stained using Calcein-AM (Life Technologies, Carlsbad, CA, USA) after 10 h using a fluorescence microscope.
RNA isolation and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR)
Total RNA was isolated using TRIzol reagent (Invitrogen Life Technologies) according to the manufacturer's protocol, and reverse transcribed to cDNA using a SuperScript III Reverse Transcriptase kit (Invitrogen). PCR mixture was prepared using the SYBR Green qPCR kit (Invitrogen) and using the following primers as follows: CXCL1/GROα (forward, 5′-agggaattcaccccaagaac-3′ and reverse, 5′-TAACTATGGGGGATGCAGGA-3′); S100A8 (forward, 5′-atgccgtctacagggatgac-3′ and reverse, 5′-ACGCCCATCTTTATCACCAG-3′) and GAPDH (forward, 5′-TTCACCACCATGGAGAAGGC-3′ and reverse, 5′-GGCATGGACTGTGGTCATGA-3′). All qRT-PCR reactions were performed using the StepOne Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). Quantitative analysis normalized to GAPDH was performed according to the comparative cycle threshold (Ct) method.
CXCL1/GROα and S100A9 knockdown
CD14+ monocytes were transfected with 1 µM non-targeting, CXCL1/GROα or S100A9 Accell™ SMARTpool siRNA (Thermo Fisher Scientific) containing IL-4 and GM-CSF for 5 day. The medium containing siRNA and IL-4/GM-CSF was replaced on day 3. The knockdown efficacy of siRNA was measured by qRT-PCR.
Animal experiments and drug treatment
For the orthotopic metastasis assay, mouse breast cancer 4T1 cells were transplanted into the mammary fat pads of 8-week-old female BALB/c mice. Mice were injected once a week with either PBS vehicle, BBP, doxorubicin hydrochloride (2 mg/kg)/cyclophosphamide monohydrate (60 mg/kg) or a combination of BBP and PBS vehicle, BBP, doxorubicin hydrochloride (2 mg/kg)/cyclophosphamide monohydrate (60 mg/kg) for 3 weeks. For experiments involving CXCL1/GROα inhibition, the mice were injected intraperitoneally with either IgG (vehicle) or with CXCL1/GROα once per week (50 µg/mouse). All immunohistochemical reactions were performed on 5-µm paraffin sections. In brief, the sections were deparaffinized in xylene and rehydrated, and then incubated in target retrieval solution (DAKO) in an autoclave for 8 min to retrieve the antigens. Endogenous peroxidase activity was blocked by 10 min of incubation with a 3% solution of H2O2. The expression of CD31 antigen was assessed using the mouse monoclonal anti-CD31 (dilution 1:100) antibody. The sections were incubated with the primary antibodies overnight at 4°C. The antigens were then visualized using biotinylated antibodies and streptavidin, conjugated with horseradish peroxidase. Diaminobenzidine (DakoCytomation, Glostrup, Denmark) served as the substrate, and all of the sections were counter-stained with hematoxylin.
Isolation of dendritic cells (CD11c+F4/80−) and myeloid-derived suppressor cells (MDSCs) from the mice
Mouse mammary tumors (4T1-bearing mice) were collected and minced. Single-cell suspensions were obtained after enzymatic digestion (1 mg/ml collagenase A; Roche Diagnostics) and 100 IU/ml type I Dnase (Sigma-Aldrich) for 2 h at 37°C in RPMI-1640 medium. A single-cell suspension was filtered through a 70-µm nylon mesh (BD Biosciences), and cells were washed twice with PBS. CD11c+ cells were purified using anti-CD11c monoclonal antibody-conjugated magnetic beads (MACS MicroBeads). F4/80+ cells were depleted from CD11c+ cells by using F4/80+ antibody-biotin beads (MACS MicroBeads). MDSCs were isolated from tumors using the Myeloid-Derived Suppressor Cell Isolation kit from Miltenyi Biotec. Cell purity was checked by flow cytometric (BD Biosciences, Franklin Lakes, NJ, USA) analysis using anti- CD11b and Gr-1 antibodies (>75%), and the viability was assessed by trypan blue dye exclusion.
Statistical analysis
Data are expressed as means ± SD. Statistical analyses between the control and experimental groups were analyzed by an unpaired Student's t-test. Multiple comparisons were evaluated by one-way ANOVA, and differences in the mean values among groups were conducted by a Turkey post hoc analysis. P-values <0.05 were considered to indicate statistically significant differences.
BBP increases chemoresistance in a 4T1 orthotopic metastasis model
First, we assessed the influence of BBP on chemotherapeutic efficacy in breast cancer in a mouse model. As shown in Fig. 1, combination of doxorubicin hydrochloride (2 mg/kg body weight) and cyclophosphamide monohydrate (60 mg/kg body weight), a doublet chemotherapy frequently used in the clinic, exhibited a markedly inhibitory effect on cancer metastasis (lung, liver and peritoneal metastasis). Exposure of mice to BBP alone did not affect the metastasis of 4T1 in the mouse model, but did reduce the inhibitory effect of chemotherapy on breast cancer peritoneal metastasis in the mice (Fig. 1).
Figure 1
BBP increases anticancer drug resistance in mice. The lungs (A), liver (B) and peritoneal (C) in 4T1-bearing mice. 4T1 cells were implanted into the mammary fat pads of BALB/c mice. The mice were then randomly divided into 4 groups: a control group, a doxorubicin hydrochloride (2 mg/kg body weight) and cyclophosphamide monohydrate (60 mg/kg body weight) (1 time/week, i.p.) administration group, a BBP administration (500 mg/kg body weight) (3 times/week, i.p.) group, and a doxorubicin/cyclophosphamide + BBP group. The control group was given an equal volume of normal saline. Tumor-bearing mice were sacrificed 4 weeks after transplantation. Their organs were removed and the metastatic tumor nodules counted. All results are representative of at least three independent experiments, and each value is the mean ± SD of three determinations. The results are reported as mean ± SD; *P<0.05.
BBP increases the chemoresistance of breast cancer via the TADC-mediated response
Since exposure to BBP increases the resistance of cancer to doxorubicin/cyclophosphamide treatment, we assessed whether BBP affects the sensitivity of breast cancer to doxorubicin/cyclophosphamide. As shown in Fig. 2A, doxorubicin/cyclophosphamide (10/100 µM) decreased the cell viability of MDA-MB-231 cells ~60% after a 48-h treatment. However, BBP did not affect the sensitivity of breast cancer cells to the doxorubicin/cyclophosphamide combination (Fig. 2A). TME is considered to determine the efficacy of chemotherapy (31). To assess whether BBP increases the chemo-resistance of breast cancer by stimulating TADCs, we generated mdDCs, TADCs and BBP-stimulated mdDCs and TDACs (BBP-mdDCs and BBP-TADCs) and collected the condition media (CM) as described in Fig. 2B. MDA-MB-231 cells were treated with doxorubicin/cyclophosphamide in regular culture medium, mdDC-CM, TADC-CM, BBP-mdDC-CM or BBP-TADC-CM containing medium. TADC-CM significantly decreased the sensitivity of the MDA-MB-231 cells to doxorubicin/cyclophosphamide. BBP further desensitized breast cancer to doxorubicin/cyclophosphamide (Fig. 2C). Next, we investigated whether the chemoresistance induced by TADC-CM and BBP-TADC-CM was mediated by reducing doxorubicin/cyclophosphamide-induced apoptosis. TADC-CM markedly reduced the percentage of TunEL-positive MDA-MB-231 cells following treatment with doxorubicin/cyclophosphamide relative to mdDC-CM. A statistically significant reduction in apoptosis induction was noted after exposure to BBP-TADC-CM (Fig. 2D). These data suggest that BBP stimulated soluble factor(s) secreted from TADCs to induce doxorubicin/cyclophosphamide resistance in breast cancer.
Figure 2
TADCs contribute to BBP-mediated chemoresistance. (A) BBP did not affect the cytotoxicity of doxorubicin/cyclophosphamide in MDA-MB-231 cells. Cells were treated with control (0.1% DMSO), BBP (1 or 10 µM), doxorubicin/cyclophosphamide (10/100 µM) or doxorubicin/cyclophosphamide (10/100 µM) + BBP (1 or 10 µM) for 48 h, and cell viability was determined by WST-1. (B) Flowchart for the collection of various conditioned media (CMs). (C) TADC-CM increased the resistance of MDA-MB-231 cells against doxorubicin/cyclophosphamide. Cells were treated with control or doxorubicin/cyclophosphamide (10/100 µM) cultured in various CMs (20%) for 48 h, and cell viability was determined by WST-1. (D) TADC-CM decreased doxorubicin/cyclophosphamide-mediated apoptosis in MDA-MB-231 cells. Cell were treated with control or doxorubicin/cyclophosphamide (10/100 µM) cultured in various CMs (20%) for 48 h, and cell viability and apoptosis was determined by WST-1 and TUNEL analysis, respectively. All results are representative of at least three independent experiments, and each value is the mean ± SD of three determinations. The results are reported as mean ± SD; *P<0.05.
TADC-mediated S100A8/A9 increases breast cancer chemoresistance
Next, we assessed the influence of BBP on the expression of secretory cytokines in TADCs, which have been reported to be involved in the development of chemoresistance. The expression levels of CXCL1/GROα, S100A8 and S100A9 were increased in the TADCs, in comparison to the levels in the mdDCs. BBP further enhanced the stimulatory effect of breast cancer cells in regards to the secretion of CXCL1/GROα, S100A8 and S100A9, but not VEGF and OSM (Fig. 3A-E). Transplantation of the 4T1 cell into mice increased the expression of CXCL1/GROα, S100A8 and S100A9 in the TADCs (CD11c+F4/80−), compared to the control mice. Exposure to BBP further increased expression of CXCL1/GROα, S100A8 and S100A9 in the TADCs in the the 4T1-bearing mice (Fig. 3F and G).
Figure 3
BBP increases the expression of CXCL1/GROα and S100A8/A9 in TADCs. The effect of BBP on the expression of CXCL1/GROα (A), VEGF (B), OSM (C), S100A8 (D) and S100A9 (E) in the TADCs. mdDCs and TADCs were derived by culturing CD14+ monocytes in RPMI-1640 medium containing GM-CSF and IL-4 with or without MDA-MB-231-CM (20%) for 5 days. BBP-treated mdDCs and TADCs were generated using the same procedure but containing BBP (10 µM). The expression of various proteins in the supernatants was determined by Milliplex MAP kit. BBP increased the expression of CXCL1 (F), S100A8 (G) and S100A9 (H) in the TADCs of the mice. 4T1 cells were implanted into mammary fat pads of BALB/c mice who were then randomly divided into 2 groups: the BBP-treated group was given i.p. with BBP (500 mg/kg of body weight, 3 times/week) while the control group was given an equal volume of normal saline. Tumor-bearing mice were sacrificed 28 days after transplantation. TADCs (CD11c+F4/80−) were isolated from the mammary tumors (4T1). The proteins in the supernatant of isolated cells were determined by ELISA kits. All results are representative of at least three independent experiments, and each value is the mean ± SD of three determinations. The results are reported as mean ± SD; *P<0.05.
To explore which secretory factors contribute to the chemoresistance of MDA-MB-231 cells, we inhibited the expression of CXCL1/GROα or S100A9 using siRNA transfection. Transfection of CD14+ monocytes decreased the CXCL1/GROα and S100A9 expression by 80 and 90%, respectively (Fig. 4A). Inhibition of S100A9 expression prevented the effect of CMs of BBP-derived TADCs on the chemoresistance of the MDA-MD-231 cells (Fig. 4B). However, knockdown of CXCL1/GROα did not restore the chemosensitivity of MDA-MB-231 cells to doxorubicin/cyclophosphamide in presenting CMs of BBP-derived TADCs (Fig. 4B). Similarly, only recombinant human S100A8/A9 (rhS100A8/A9) reduced the cytotoxicity of doxorubicin/cyclophosphamide, whereas recombinant human CXCL1/GRO (rhCXCL1/GRO) did not affect the cytotoxicity of doxorubicin/cyclophosphamide in the MDA-MB-231 cells (Fig. 4C and D).
Figure 4
S100A9 contributes to TADC-mediated chemoresistance in MDA-MB-231 cells. (A) The knockdown efficacy of CXCL1/GROα and S100A9 siRNA transfection. CXCL1/GROα and S100A9 knockdown was performed by Accell scramble, CXCL1/GROα or S100A9 siRNA (1 µM). Knockdown efficacy was confirmed by qRT-PCR. (B) Inhibition of S100A9 decreased the chemoresistance induced by BBP-TADC-CM in the MDA-MB-231 cells. (C) rhS100A8/A9 protein decreased the sensitivity of MDA-MB-231 cells to doxorubicin/cyclophosphamide. (D) rhCXCL1/GROα did not affect chemoresistance induced by BBP-TADC-CM in the MDA-MB-231 cells. Cells were treated with control or doxorubicin/cyclophosphamide (10/100 µM) cultured in various CMs (20%) for 48 h, and cell viability was determined. Cells were treated with control or doxorubicin/cyclophosphamide (10/100 µM) with or without recombinant human proteins (rhS100A8/A9 and rhCXCL1, 10–1,000 ng/ml) for 48 h, and cell viability was determined. All results are representative of at least three independent experiments, and each value is the mean ± SD of three determinations. The results are reported as mean ± SD; *P<0.05; ns., not significant.
BBP increases the production of S100A8 and S100A9 in MDSCs (CD11b+Ly6CGr-1+) in breast cancer
Previous research has demonstrated that S100A8/A9 levels are associated with the infiltration of MDSCs in tumors and enhance chemoresistance (31,32). Therefore, we assessed whether BBP increases the infiltration of MDSCs in the 4T1 cell-bearing mice. As shown in Fig. 5A and B, doxorubicin/cyclophosphamide treatment decreased the infiltration of CD11b+Ly6CGr-1+ MDSCs in the tumors. BBP exposure prevented the effect of chemotherapy on the infiltration of CD11b+Ly6CGr-1+ MDSCs (Fig. 5A). However, BBP exposure did not further increase the recruitment of CD11b+Ly6CGr-1− MDSCs, regardless of doxorubicin/cyclophosphamide treatment in the mice (Fig. 5B). Next, we assessed the expression of S100A8 and S100A9 in the tumor-infiltrating CD11b+Ly6CGr-1+ MDSCs. ELISA results showed that BBP or doxorubicin/cyclophosphamide treatment alone slight enhanced the expression of S100A8 and S100A9 in the CD11b+Ly6CGr-1+ MDSCs (Fig. 5C and D). However, exposure of mice to BBP markedly enhanced the production of S100A8 and S100A9 in the CD11b+Ly6CGr-1+ MDSCs in the doxorubicin/cyclophosphamide-treated mice (Fig. 5C and D).
Figure 5
BBP increases the expression of S100A8 and S100A9 in MDSCs. BBP prevented the effect of doxorubicin/cyclophosphamide on the infiltration of CD11b+Ly6CGr-1+ MDSCs (A), but did not reverse the effect of doxorubicin/cyclophosphamide on the infiltration of CD11b+Ly6CGr-1− MDSCs (B). BBP increased S100A8 (C) and S100A9 (D) expression of MDSCs in the tumors after doxorubicin/cyclophosphamide treatment. 4T1 cells were implanted into the mammary fat pads of BALB/c mice, which were then randomly divided into 2 groups: the BBP-treated group was given i.p. with BBP (500 mg/kg of body weight, 3 times/week) while the control group was given an equal volume of normal saline. Tumor-bearing mice were sacrificed 28 days after transplantation. Two subgroups of MDSCs, CD11b+Ly6CGr-1+ and CD11b+Ly6CGr-1−, were isolated from the mammary tumors (4T1). The proteins in the supernatant of isolated cells were determined by ELISA kits. The sub-groups of immune cells were determined by staining of surface markers and by flow cytometric analysis. All results are representative of at least three independent experiments, and each value is the mean ± SD of three determinations. The results are reported as mean ± SD; *P<0.05.
BBP increases angiogenesis by TADC-derived CXCL1/GROα
Since CXCL1/GROα has been indicated to be an angiogenic factors in cancer (33), we assessed the effect of BBP on angiogenesis induced by TADCs. Compared to mdDC-CM, TADCs increased the tube formation of HUVECs. In addition, BBP increased the stimulatory effect of TADCs on tube formation (Fig. 6A). The synergistic effect of BBP on angiogenesis was prevented by the neutralizing CXCL1/GROα antibody (Fig. 6B), suggesting that CXCL1/GROα is the major angiogenic factor in TADC-mediated angiogenesis. Furthermore, exposure of mice to BBP increased the angiogenesis in primary breast cancers in vivo (Fig. 6C). To investigate whether targeting CXCL1/GROα may be a strategy to prevent BBP-induced angiogenesis, we administered the mice with neutralizing CXCL1/GROα antibody. Exposure of mice to BBP or chemotherapy increased the angiogenesis in the breast cancer. The enhancement of angiogenesis induced by BBP was prevented by the administration of the CXCL1/GROα antibody in the chemotherapy and BBP + chemotherapy-treated mice (Fig. 6D).
Figure 6
BBP increased the angiogenesis of cancer. (A) The CM of BBP-TADCs increased the tube formation of HUVECs. (B) Inhibition of CXCL1/GROα prevented BBP-TADC-CM-mediated angiogenesis. HUVECs were cultured in various CMs with or without the IgG/CXCL1 antibody in a Matrigel-coated 48-well. Cells were stained by Calcein-AM and examined by fluorescence microscope. (C) BBP increased the angiogenesis in vivo. (D) Blockade of CXCL1/GROα decreased BBP-mediated angiogenesis in mice. 4T1 cells were implanted into the mammary fat pads of BALB/c mice. The mice were then randomly divided into 4 groups: a control group, a doxorubicin hydrochloride (2 mg/kg body weight) and cyclophosphamide monohydrate (60 mg/kg body weight) (1 time/week, i.p.) administration group, a doxorubicin/cyclophosphamide + BBP (500 mg/kg body weight) + IgG (50 µg/mouse/week) group, and a doxorubicin/cyclophosphamide + BBP + CXCL1 antibody (50 µg/mouse/week) group. Angiogenesis of mammary tumors (4T1) was determined by CD31 staining.
Exposure to phthalates causes various health and reproductive problems in human. Since phthalate esters are ubiquitous in the environment and the potential for adverse effects on human health is great, an understanding of how these factors influence human health and the underlying mechanisms are urgently required. This study is the first to investigate the influence of BBP on the chemoresistance of cancer. BBP caused TADCs to produce S100A8/A9, which directly decreased the sensitivity of breast cancer cells to doxorubicin/cyclophosphamide treatment. In addition, BBP also stimulated TADCs to secrete CXCL1/GROα, which increased the angiogenesis in the tumors, resulting in increased metastasis of breast cancer. This study raises the possible impact of BBP on the chemotherapy of breast cancer.
Chronic inflammation is strongly associated with tumor initiation, progression, angiogenesis and drug resistance (34,35). Elevated inflammatory factors within the TME have been reported to mediate chemotherapeutic resistance in cancers (31,36,37). Infiltrating immune cells are an abundant component of solid tumors, and have been implicated as the major source of inflammatory cytokines/chemokines (35,38). Our data demonstrated that TADCs decreased the sensitivity of breast cancer to doxorubicin/cyclophosphamide treatment, and this effect was further exacerbated by BBP exposure. The chemoresistance of breast cancer occurred by decreasing doxorubicin/cyclophosphamide-induced apoptotic cell death, while cancer cells were nourished by BBP-stimulated TADCs. This study suggests that paracrine signals potentiated by BBP in the TME maintain cancer survival despite cytotoxic insults.
S100A8 and S100A9, EF-hand calcium-binding proteins, are recognized as pro-inflammatory factors, which contribute to various human diseases, including cancer. S100A8 and S100A9 are constitutively expressed by myeloid cells, including granulocytes, monocytes, dendritic cells and osteoclasts, but not by lymphocytes (39). Increased levels of S100A8/A9 produced by cancer and stroma cells within the TME are found in many types of cancers, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid and breast cancer (39,40). S100A8 and S100A9 proteins are considered to contribute to the overall pathogenesis of malignancies, including tumorigenesis, progression, metastasis and chemoresistance. S100A8 enhances drug resistance by increasing autophagy in leukemia cells (41). S100A8/A9 protect breast cancer cells from doxorubicin by increasing the activation of ERK1/2 and p70S6K (41). We found that BBP may increase the concentration of S100A8/A9 by two routes. First, BBP potentiates the stimulatory effect of breast cancer cells on the expression of S100A8/A9 in TADCs. Inhibition of S100A8 by siRNA prevents TADC-CM-mediated chemoresistance, supporting the specificity of the relationship of S100A8/9 with doxorubicin/cyclophosphamide resistance in breast cancer. The second source of S100A8/A9 is tumor-infiltrating MDSCs. BBP not only directly enhanced S100A8/A9 secretion, but also potentiated the hyperactivation of chemotherapy on the enhancement of S100A8 and S100A9 in tumor-infiltrating CD11b+Ly6CGr-1+ MDSCs. Elevated S100A9 levels are found in breast cancer patients after chemotherapy treatment, and this is considered to be a critical factor contributing to chemoresistance (41). The multiple effects of BBP on the expression of S100A8/A9 could provide survival signaling to breast cancer cells, enabling them to resist chemotherapy.
CXCL1/GROα is an inflammatory chemokine and potent angiogenic and lymphangiogenic growth factors, which are mediators that potentiate cancer progression and chemo-resistance (31,42,43). Phthalate esters have been indicated to induce macrophages to express inflammatory cytokine CXCL1/GROα, which is implicated as a mediator of tumor angiogenesis (43,44). The present study found that BBP increased the expression of CXCL1/GROα in TDACs in vitro and in vivo. Knockdown of CXCL1/GROα by siRNA did not affect either TADC-CM or BBP-TADC-CM-mediated chemo-resistance, suggesting they are not directly involved in the protection of cancer from anticancer drugs. However, blockade of CXCL/GROα by a neutralizing antibody decreased angiogenesis after doxorubicin/cyclophosphamide treatment in vivo, suggesting that CXCL1/GROα enhanced the development of BBP-mediated cancer relapse after chemotherapy by altering tumor angiogenesis.
This is the first study to explore the influence of BBP on chemotherapy in breast cancer. BBP stimulated TADCs and MDSCs to express S100A8/A9, which provided a direct protective effect against chemotherapy. BBP also increased TADCs to produce CXCL1/GROα, which enhanced the angiogenesis in breast cancer, resulting in increased cancer metastasis after chemotherapy (Fig. 7). This study highlights the potential interference of phthalate esters on the treatment of breast cancer with specific therapeutic regimens.
Figure 7
Proposed scheme illustrating that benzyl butyl phthalate (BBP) induces a change in the chemosensitivity of breast cancer to doxorubicin/cyclophosphamide by altering the cancer microenvironment.
This study was supported by grants from the national Science Council of Taiwan (NSC 10.628-B-037-001-MY3; NSC 101-2320-B- 037- 043-MY3; NSC 102-2628-B-037-002-MY3; NSC 102-2632-B-037-001-MY3; and NSC 102-2314-B-037-035-MY3), the Ministry of Science and Technology (MOST 103-2320-B-037-006-MY3 and MOST 103-2314-B-037-052), the Excellence for Cancer Research Center Grant, the Ministry of Health and Welfare, Executive Yuan, Taipei, Taiwan (MOHW 103-TD-B-111-05), the Kaohsiung Medical university 'Aim for the Top 500 universities Grant, grant no. KMU-DT103008', and the Kaohsiung Medical University 'Aim for the Top universities Grant, grant nos. KMU-TP103A19 and KMU-TP103A20'.
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Metals Centre provide copper and brass sales to the Gauteng Province in South Africa and now to world-wide customers. We are are trusted copper suppliers and offer the added benefit of being able to cut your orders to size.
We stock a wide range of copper products including copper sheeting and copper plate, copper wire and extrusions.
Our copper sheet ranges from .5mm to 3mm thick and our copper plate from 3mm right through to 200mm thick.
Don't forget to use the Quick Quote form in the left sidebar, our sales people are standing by to assist you with your order.You will receive your quotation within 2 hours during weekdays - mon to Fri between 8:00 and 16:30
Select from our full range of Copper Products below:
Have you seen what the Coppersmith can do for you?
Copper Profiles
Copper Bus Bar & Other Solid Copper Bars
Copper Tubing
Copper Tubing - Available upon request.
Copper Sheet and Plate
Copper Sheet Metal
Copper Plate

subset: commoncrawl


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1 Montgomery Street
Suite 1700
San Francisco, CA 94104
Office Tower Entrance is at 120 Kearny (Near the corner of Post and Kearny Streets)
Sue Kent is a director in the Firm's Assurance Services Division in San Francisco, California. She joined Marcum in 2016 via the Firm's merger with Lautze & Lautze CPAs & Financial Advisors, a full-service accounting firm in Northern California. Based in the Firm's San Francisco office, Ms. Kent has 30 years of experience spanning a broad range of industries, including family-owned businesses, law firms, beverage manufacturers and distributors, construction companies and transportation service providers. She also has expertise in not-for-profit organizations, including employee benefit plans, private foundations and, in particular, private schools.
A native of the U.K., Ms. Kent came to the United States in 2001 to join Lautze & Lautze, where she served as director of client services. She also was an instructor for the Firm's Orientation and Continuing Education programs, training new professional staff in the use of accounting-specific programs as well as training modules on a range of accounting and auditing topics.
- Institute of Chartered Accountants, England and Wales - Associate
- CPA Associates International (CPAAI)
- Association of Chartered Accountants in the United States (ACAUS)
Family-Owned Businesses
Law Firms
Beverage Manufacturers and Distributors
Construction Companies
Transportation Service Providers
Employee Benefit Plans
Private Foundations
Private Schools
Kingston Polytechnic
United Kingdom


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Minneapolis—"We think it's going to be successful across the board," Gregg Steinhafel, chief executive at Target told retail analysts in December about the special holiday gift collection, a collaboration with Neiman Marcus and some 50 fashion designers. ""It's just a matter of how you want to gauge success, is it hours, or days, or possibly a week–which might be a stretch."
But what promised to be the ultimate in "masstige" retailing apparently had less than spectacular results. Three weeks after the collection's debut Target cut prices on the entire collection and then on Jan. 1 slashed the entire collection by 70%. Neiman Marcus also had the collection on its website at 70% off.
In other words, a far cry from the hordes that scooped up its collaborations with Missoni and Jason Wu.
While Target hasn't publicly commented on the Target + Neiman Marcus Holiday Collection, retail analysts for the most part called the latest "cheap chic" merchandise ploy a failure.
Most of the criticism centered on the fact the collection, which included merchandise ranging from a bicycle to cookie cutters, didn't represent products, such as apparel and accessories that the participating designers are known for. Some consumers posted comments on Facebook saying the pricepoints were too high for Target merchandise. Calling the collection "under designed and/overpriced," one said: "I never found that 'gotta-have' item."
Martha White of Time agreed that there was a disconnection between the participating designers and the holiday gift merchandise.
"Some complained that designers like Tory Burch and Diane von Furstenberg, known for their distinctive clothes, turned out thermoses and yoga mats (respectively), instead. Oscar de la Renta—who outfits celebrities in red-carpet looks—offered pet accessories: dog bowls and rhinestone collars," White said.
While the collection may have faired better at Neiman Marcus where the full retails are relatively inexpensive compared to that store's prices, consumers complained about items were made in China.
Poor Merchandising in Stores and with Online Execution
Deborah Weinswig, retail analysts at Citi, also took Target to task in her report: "Don't Believe the Hype: Target + Neiman Marcus Holiday Collection Disappoints." She said Target may some tactical errors, too, originally stocking the collection at the back of its stores and doing a "sloppy job" with visual merchandising.
Last week, Daniel Binder, retail analyst at Jefferies & Co., downgraded Target shares, noting several holiday mishaps including the holiday gift collaboration, which he referred to as "a flop."
"While we had high hopes for Target this season, we believe the company continued to struggle in a few areas, including poor online execution, soft December sales, poor results with the Neiman Marcus merchandising initiative, increased price competition (greater price matching) and more markdowns," Binder said.
Target reported Jan. 3 that its December comparable store sales were flat (Total sales rose 0.8% to $10.1 billion).
Retail analyst Carol Spieckerman told Pioneer Press that launching its latest cheap chic collaboration during the highly competitive and promotional holiday season was a risky venture.
Nonetheless, Spieckerman said Target still benefitted from the collaboration. "It depends on how you define success," she said. "Of course, you want to sell product, but it also creates impressions, driving traffic to the stores, creating more brand impressions … there's a lot of things that you really can't measure, but offers a nice halo effect going forward."


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Official inflation figures published yesterday show that prices of goods in the economy continued to fall, but there were signs that the dampening effect of the collapse in oil prices is coming to an end.
The CSO consumer price figures for May also starkly revealed that private rents continue to soar, reflecting a chronic shortage of housing accommodation across many parts of the country as the economic recovery takes hold.
Some analysts believe the surge in private sector rents could be a huge political headache for the Coalition in the run-up to the election in less than a year's time.
Consumer prices fell by 0.3% in the year to May — the sixth successive such monthly fall — as prices for clothing, transport, food, household equipment, and maintenance all recorded falls over the year, the CSO figures show.
Prices however rose in May from April by 0.3%, led by a monthly rise in transport and communications, which may point to the waning effect of lower crude oil prices.
Prices for energy products are still down by 5.4% over the year, but have started in recent months to increase at a rapid pace.
Energy products rose 2% in the month and are now 5.5% higher over the last three months.
The price of Brent crude had plunged to $53 (€47) a barrel at the start of the year from over $110 a barrel in July last year, helping to lower prices of many manufactured goods and boosting household income.
However, the crude price has since started to increase and was trading yesterday around $65 a barrel.
That suggests prices for many products may start to rise in time.
The CSO figures show the prices of all goods decreased on an annual basis by over 3%, while the price of services, excluding mortgage interest rates, increased by 2% in the year.
Mortgage interest costs recorded a drop of 0.9% in the month and posted a huge fall of 8.2%, reflecting the political pressure on lenders to reduce the standard variable interest rates and fixed-home loan costs they charge borrowers.
However, private rents recorded a further 0.6% increase in the month and a huge rise of almost 9% in the past year.
Local authority rents have fallen by 0.3% in the past year, according to the CSO figures.
Alan McQuaid, chief economist at Merrion Capital, said: "Despite the strong recovering economy, domestic inflationary pressures in Ireland are in our view likely to remain fairly well contained in the immediate future. That said, we do expect some pick-up as the year goes on due to higher oil prices, a gradual rise in wages, and the lower euro pushing up import costs."
Article Source: http://tinyurl.com/kbwqb42


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Hawaii Eye Institute & Hawaii Allergy Institute
Honolulu, HI
The Hawaii Eye Institute and Hawaii Allergy Institute secured our services for the Interiors of their new flagship office in the Queen's Medical Center. The 4,800 square foot space features an open and inviting reception area, optical center with custom display cabinetry and lighting, laboratory, optical diagnostics, offices and fourteen treatment rooms.
Changing trends in the healthcare field have customers placing more emphasis and importance on the appearance and atmosphere of medical spaces. For their premier location in the Queen's Medical Center, the Hawaii Eye Institute and Hawaii Allergy Institute felt certain our team was the best choice to create a welcoming, refined, and distinctive look and feel for their new space.
The finished product: a sophisticated material palette derived from nature, including rich walnut wood, tropical coral stone, softly textured woven fabrics, and natural colors and patterns.


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Pancake Tortoise
Malacochersus tornieri
About This Animal
SIZE: 6 - 7 inches long
RANGE: This East African species is native to southern Kenya and northern and western Tanzania
HABITAT: Rocky hills and slopes with rocky outcrops in arid savanna and scrub areas at altitudes from 100 to 6,000 feet
DIET: A variety of fresh and dry grasses, and some fruit
ON EXHIBIT: Turtle Gallery in River Journey
The pancake tortoise has an unusually thin, flat, flexible shell. While the shell bones of most other tortoises are solid, the pancake tortoise has shell bones with many openings, making it lighter and more agile than other tortoises.
The greatest threats facing the pancake tortoise are habitat destruction and its over-exploitation by the pet trade. Given the low reproductive rate of this tortoise, populations that have been harvested may take a long time to recover.


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A 55-year-old man has been arrested as part of an investigation into human slavery allegations in Lancashire.
Police arrested the man, from Blackburn, on suspicion of slavery, servitude, forced labour and section 18 assault, at the Railway News newsagents on Railway Road in the town on Monday, July 11.
He has been bailed pending further enquiries until Thursday, October 6.
Sgt Ben Hodgkinson, from Blackburn Police, said: "This is a very sensitive investigation and we are continuing to work with partner agencies to ensure that the victim is offered adequate support.
"If you think you have come into contact with the victim or you know anything that could assist with our investigation please get in touch."
Anybody with information should contact police on 101 quoting log number LC-20160701-0556.
Alternatively, contact Crimestoppers anonymously on 0800 555111 or online at crimestoppers-uk.org.


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This week's guest: ROBBIE NORTHMAN
Savage Gear backed-Robbie Northman is based in Hoveton, Norfolk. Specialising in lure fishing, Robbie uses an array of tactics to target perch, pike, chub, zander and some saltwater species. This week he demonstrates what's known as the jika rig – a drop shot/jigging hybrid method.
A sensitive and responsive rod is essential for perch fishing, because bites can vary from delicate taps to tip-bouncing 'slams', and this isn't always down to the size of the fish. For weedless rigs potentially fished at range, I use a fairly strong set-up, including a 8 ft 3 in. 3-15 g-rated Savage Gear Finezze Softlure rod and an Okuma Epixor 20-size reel. A longer rod gives me much more control, and allows me to fish with finesse. This rod has plenty of power, and features a fastyet- forgiving tip. Regarding line choice, I tend to opt for 0.08 or 0.10 mm SG Adrenaline Braid. However, on waters where braid is banned, like today at Norfolk's Cobbleacre Park, I'll choose a fused line, such as 0.10 mm Berkley Nanofil. On the businesses end I use a 10 lb SG Fluorocarbon leader to a small snap link, unless pike are present, which is when I opt for a 10 lb wire trace. With the jika rig you simply clip your chosen hook and lure and a separate weight to the snap link on the end of your line… and that's it. It's a very adaptable set-up, allowing you to swap any of the individual components.
For shallow stillwaters, weights of 2-5 g suit most situations. On deeper venues or rivers I may step up to 8 or 10 g, depending on wind, depth and flow. Small bomb-style weights and pencil leads are often used on the jika rig, but I like to re-use my old bent or blunt jigheads, by removing the hook with cutters. Hooks are offset Gamakatsu patterns, and I choose the hook size to match the lure. For smaller lures of just 5-6 cm, a size 2 offset hook is about right. For 6-8 cm lures, a 1-1/0 hook is best, and for 7-9 cm creature baits, 1/0-2/0 hooks. Be aware that some waters only allow barbless hooks. I like to be mobile, ready to move should I spot feeding fish. I keep my spare lures, rigging kit, unhooking tools and scales in a backpack, with attachments to take a SG folding frame landing net and unhooking mat.
The stillwater that I'm fishing today receives plenty of angling pressure, and the water is very clear. I'm confident that I will get bites using the Savage Gear 3D Bleak Real Tail lures, despite bright sunlight. The perch here have plenty of small silver fish to feed on and, with livebaiting banned, a natural-looking lure may give me an edge, once I find them, or when a feeding spell occurs. I've brought along a selection of split tail and paddletail lures, creature baits and stick baits.
They can all be used with the jika presentation. A couple of other favourites are the SG T-Tail minnow, which I find is very visual, with its fat profile. Its large tail helps it fall nose first, before settling on the bottom. I also like the 3D Reaction Crayfish, as it's very realistic. The claws twist and roll on the retrieve, and the legs add lots of small movements, which will attract a predator's attention.
1. Searching a feature swim. This is where I start casting, on the left side of the swim.
2. I then fan the casts, working the water between each point.
3. There are fallen trees here to investigate, a perfect ambush point.
4. These tree roots on the inside need searching, many of them being undercut, creating a perfect sanctuary on bright days.
5. A deep gravel spot. Not visible by eye, but when searching the swim correctly you can discover all kinds of underwater features that are worth a look.
Click on picture to enlarge ↓
I like to focus my lure sessions around dawn and dusk, especially on small waters. They are usually quiet at these times in the colder months and, with lure fishing being very active, it doesn't usually take more than a few hours to get an understanding of the venue. On arrival, I always have a quick walk around, searching for any signs of fish activity and noting visible features, such as overhangs, reedbeds, islands, wind traps… anywhere where my target, perch, could be lying in wait. These areas are a good place to start and to experiment, to find the best tactic on the day. The jika rig has become a favourite of mine for targeting all waters. You can change the hooks and weights quickly to suit the depth and lure. The jika can be retrieved fast and erratic, kicking up a silt trail as it drags the bottom, but also allows you to search small pockets of water.
The free motion of the rig means that you can also rock and twitch it on the spot between pauses and bursts of movement, not unlike the drop shot, but with the benefits of a jigging set-up. When I get to a swim that I like, I quickly assess the depth. With around 4-5 ft of water today, I choose a 2 g sinker and begin working my lure. The lake is clear, carrying a slight clay haze, so I start with dark lure patterns, a T-Tail Minnow followed by a 3D Reaction Cray. No bites come my way, so I swap to a natural imitation – the 3D Bleak – dropping the hook size from a 1/0 to a 2. I work the swim in a clockwise motion, searching from left to right, combing the water for life. I alternate between erratic, fast retrieves and slow twitches, to analyse what the fish might want. In better conditions it's not so complicated, but when the going is tough, you have to be adaptable.
The natural choice 3D Bleak wins me a bite, but it's not the specimen that I'm after, but a tiddler perch the same size as my lure. You can't help but smile at the greed of little perch! After a few more 'waspy' taps, I move on, searching each swim and tempting a few more palm-sized samples, before arriving at another swim that I like the look of, with snags and tree roots. After a few casts, I find a clear gravel spot at the entrance to the main bowl of the lake. It's a small clearing surrounded by weed, no doubt cleaned by the carp, a perfect area for a perch to lie in ambush for the roach shoals. I cast again to the spot, allowing the lure to sink to the bottom, pausing for a few seconds before darting the lure a couple of inches and repeating the process. I try twitching the rod tip, making the lure shake and lift between each pause and movement. On the next bounce, I feel a jolt on the rod tip. I set the hook and feel the thuds of the perch trying to turn back into cover. After a short battle, the fish is in the net, a pristine young perch of 1 lb, hopefully a 3-pounder one day. With dusk drawing in I decide to have a few more minutes before searching the rest of the lake.


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I want to
Canberra Glassworks
Get fired up about glass. A visit to the Canberra Glassworks will inspire your students to:
- Engage in creative glass workshops
- Experience hands-on sensory learning
- Learn about the science of glass making
- Visit the oldest public building in Canberra.
Curriculum Links
The Glassworks connects to the design and technologies, visual art, history and science components of the Australian Curriculum. Relevant links may be viewed on our website under each learning program.
A school visit will answer questions such as:
- How does glass change from one material state to another?
- What temperature do the glass furnaces operate at? How does that compare to your home oven?
- How important is team work in the hotshop?
- Cost $30 per student
- Ages 8–18
- 90 minutes
Cut, shape and fuse glass to make your very own glass tile. Enliven your senses with a hands-on tour of the Glassworks. Turn up the heat, observe molten glass and artists at work in the hotshop.
- $30 per student
- Ages 8–18
- 45 minutes
Drill down and investigate the science of glass. Observe molten glass and its transformative properties through a live hotshop demonstration. Learn about the impact of temperature on the molecular structure of glass.
- $40 per student
- Ages 8–18
- 90 minutes
Students can work together creatively by making a large glass tile that demonstrates planning and design solutions. Explore the Glassworks and view the current exhibition through an artist-led tour.


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About this site | Who is Steve? | Svengalie | Greenlaning | Geocaching | The Old Man Mask | Gallery | Memorial Events | Comments/BlogMemories
Other stuff: Why? | Support | Goodbye Steve
Below are events that have happened or will be happening, in tribute to Steve, there may also be more information on the Facebook.
Do let us know if you have anything planned in the future If you have any videos from the day, or previous events, that you would like added here please email us at
Also see the Geocaching page for Memorial Geocaches
Rides for Svengalie 2012 - 2018 - will take you to the Memorial ride pageLondon Marathon 2014 - In Memory of Sven Music Event - 2012
The London Marathon 2014 - in memory of Steve
On 13th April 2014 Steve's brother Chris ran the London Marathon in memory of Steve, we were so proud to see him running and were thrilled for him when he crossed the line and collected his marathon medal. We know that Steve would have been very proud too, although we also know he would have said he was mad to run 26.2 miles just for him!
Chris has also raised almost £4500.00 for The Mental Health Foundation, one of who's mission is to help prevent suicide. Did you know that suicide remains the most common cause of death in men under the age of 35 ? Research shows men going through divorce and separation from their children are highly affected.
We will never know the torment Steve was going through but if Chris's fundraising can save just one person from going through the same, or if it can save one family from going through what we went through, and still do go through every day, then it will be worthwhile. As we face the future without Steve we are aware that no one knows who is next to be affected, it could be you or your family, I truly hope it is not, but together we can make a difference. Donations can still be made for a short time at: http://uk.virginmoneygiving.com/chris_love
We would like to thank every single one of you who donated, many of you did not even know Chris and had never met Steve either, yet you were moved enough to donate - THANK YOU!
We would also like to thank Podcacher.com for sharing the information about Chris's fundraising during one of their pod casts to the geocaching world: http://www.podcacher.com/2013/11/show-443-0-cache-me-if-you-can/
Our Dad, the marathon man!
Music Event
A music event organised by Steve's friends Chris and Paul Morton took place on Sunday 15th April 2012, in Nottinghamshire. Chris, Paul and Steve had grown up together, living just a few doors apart.
A great atmosphere was achieved as everyone came together to enjoy the bands.
The Chase started off the event. An excellent, talented young group.
Outroads, the Sheffield based band had many in tears as they gave their live rendition of their song 'My Angels', this had been one of Steve's favourite songs of late and he and Nicole would turn up the volume and sing at the top of their voices as they drove around! It was also played at his funeral.
See Outroads performance here:
Dreaded Monkey completed the trio of bands, with Paul ending the event by singing a song which he wrote during the emotional time after Steve's death, 'Love (A Falling Star)'. A beautiful and emotive song, thank you Paul.
If you would like to know more about the bands who took part or book them for a performance (we can highly recommend them) see here -
Outroads Facebook page: http://www.facebook.com/pages/Outroads/341480720723
The Chase - Contact the via Dreaded Monkey.
Dreaded Monkey - Facebook page: http://www.facebook.com/DreadedMonkeyMusic
Event page:
Dreaded Monkey official version of Love (A Falling Star) released June 2012:
Geocache Spoilers
Geocaching was one of Steve's hobbies, he formed this Channel to promote it to everyone. Like he says "Not really spoilers"www.youtube.com/geocachespoilers
Facebook Tribute Page
Messages from those who loved him from around the world
RIP Svengalie
You Tube
See Steve's videos and exploits on his You Tube Channel.
Copyright © Svengalie.co.uk


text: Elevate the ambiance of your next party or celebration. Our performers are experienced in creating emotion and atmosphere through movement and dance. Dancers can be costumed to fit a theme for your paprty, wheter it's a birthday or holiday celebration. Invite your guests to join in on a whimsical journey and leave them reminiscing long after.


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Spring 2007 sees the return of the UK's original and premier 60s show as Flying Music embark on their 22nd birthday tour of The Solid Silver 60s Show, stopping at Darlington Civic Theatre on Saturday, March 24.
This unique, national tour celebrates this fantastic achievement with the unforgettable talents of The Searchers, Wayne Fontana, Merseybeats and very special guest John Walker (of The Walkers Brothers), with The Dakotas.
Don't miss this fantastic evening of entertainment - the only place to hear the classic hits performed by the original hitmakers.
For further information contact the box office on 01325 486555


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About Simon Benfeldt Jørgensen
I have a Master in Digital Media Engineering from DTU. I have a broad understanding of programming from both a backend perspective, but also the frontend. My interests are in data mining and the use of it in products that are useful for people. Big data, business intelligence, social media and mobile applications are some of my main interest of IT.
Cheif Technology Officer (CTO)
From Sep 2015 to May. 2016
Co-founder and CTO of the Selfie-dating app Blume. Featured on TechCrunch, Forbes, ProductHunt etc.
iOS development (Objective C and Swift).
Using different Frameworks and SDKs
✓ Parse,
✓ Fabric – Crashlytics
✓ Branch.io
✓ Sinch
and other Frameworks
Blume is the honest dating app that is solving the biggest problem in the online dating industry; the uncertainty about who's actually behind the profile you are matching. On Blume you connect via profiles, but match via selfies. This makes you certain about people's true identity, thus creating a safe and trusted environment where people can be themselves. You will never have to worry about who you are truly chatting with, or meeting up with in real life. You match with real people, like real life.
Blume's main screen shows you people nearby. If two people 'Like' each other, they connect. Both parties now have to send a selfie to each other where they can place a text on it, which works as a great ice-breaker.
Once both parties have sent a selfie, it's time to reveal each other. Now you can see the other person's selfie for 7 seconds where you have to make your choice. If the 'Like' is mutual, you match!
The text placed on the selfies are now automatically transferred into the chat to get the conversation going straight away. Over 65% of people who match initiate a conversation.
★ iOS ★ Objective-C ★ Software development ★ Product management ★ UX ★ Forex ★ APIs ★ Product development
Community Manager and App. Developer
From Jan 2014 to Jun. 2015
Working with software development for an open foreign exchange platform. Using the lean approach for product development in order to deliver the best user experience of applications to the platform. Working with 3rd party APIs and integration of those in the applications.
★ UX ★ JAVA ★ Software development ★ Product management ★ Community Management ★ Forex ★ APIs ★ Product development
Software Reporting Developer
From July 2012 to now
For the logistics department of DFDS I programmed and report-developed using Crystal Reports, Visual Studio, SQL and other tools. Implementing business logic into reports used by customers and internally, require inside industry knowledge and programmable logical skills.
★ Reporting ★ SQL and Stored procedures ★ Crystal reports ★ Transport business logic ★ C# coding ★ Database ★ Business intelligence
Communication system student assistant
University of Copenhagen
Aug. 2010 – Aug. 2012
Working in the department of Koncern-IT. Administrating the database of the phone and data subscriptions the University of Copenhagen had for its employees. Also using the helpdesk system for reducing errors on invoicing.
★ Phone & ADSL billing system ★ Helpdesk ★ Billing interface ★ Microsoft Acces databases
Car sales assistant
Peugeot Taastrup
June 2007 – Dec. 2009
Working as a sales assistant for a big car house in Taastrup. Helping the salesmen with paperwork and getting the cars ready for the customers. Also advising customers with their new car investment.
★ Sales ★ Customer service
Overall Skills
BSc, IT and Communications technology
Danmarks Tekniske Universitet
2010 – 2013
Doing my bachelor my focus was on programming and communication technology, which also is reflected in my final bachelor thesis about indoor positioning in hospitals using Wi-Fi.
Relevant Courses taken:
★ Introductory Programming (02101) ★ Advanced Engineering Mathematics 1 (01005) ★ Algorithms and Data Structures 1 (02105) ★ Software Engineering 1 (02161) ★ Introduction to Communication Technology (34310) ★ Programming Projects in IT and Communication Technology (34319) ★ Advanced Engineering Mathematics 2 (01035) ★ Human Computer Interaction (02811) ★ CMC and Distributed Work (02832) ★ Statistics (02402) ★ Programming with Matlab (02631) ★ Theory of science in engineering (42610) ★ Project work – Bachelor in IT and Communication Technology (34229) ★ Chemistry (26027) ★ Discrete Mathematics★ (01017) ★ Logical Systems and Logic Programming (02156) ★ Mobile Communication (34330) ★ Development of Software Products *** Taught by Microsoft (02165) ★ Artificial Intelligence (02180) ★ Data logic (02281) ★ Project Management (42430) ***in cooperation with DFDS ★ Datamining (02281)
Programming Skills
Other Skills
Crystal Reports
At DFDS I was responsible for the logistics reports. The logistic application was based on a SQL database. In the application, reports could be generated. All the reports was developed using Crystal reports.
★ SQL ★ Crystal reports ★ MS Visual Studio
Project management
I am a certificated project leader having taken the ISO21500
(Project Management) course and have worked with an IT-integration
project of a maintenance product in cooperation with DFDS.
Certificated at DS Certificering in June 2013.
Making websites for small companies and for spare time projects I've a good understanding for designing webpages and getting users to visit those pages. Using technologies like WordPress, Google Analytics, Google Adwords, SEO, xml and ftp the optimization for getting users to visit increases.


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The Health and Retirement Study shows that 56% of Americans over 50 leave their jobs before being ready to retire. more...
December 5 , 1933 : Prohibition ended in the US. more...
Learn something new every day
More Info... by email
Human resources consulting is a type of advisory or counseling service that businesses and corporations use to improve the leadership's relationship with employees. One way of looking at this sort of consulting is to describe it as a means of optimizing "human capital." In this context, human capital refers to the economic advantages that employees bring to a company by virtue of the training, experience, and skills that they possess. Most companies seek the services of a human resources consulting firm at some point in order to help them realize the competitive advantages that can be gained by enhancing their human capital and by making their human resource processes more effective. These sorts of services are particularly popular in moments of corporate transition, growth, and merger, when executives want an outside opinion about how internal processes and policies could be made more effective.
One of the biggest goals of human resources consulting, sometimes simply called "HR consulting," is to give corporate leaders concrete ideas about how to improve the overall happiness or wellbeing of employees. Most companies have internal HR departments that oversee things like benefits, payroll, and general employee activities. In large companies and in divisions that have been around for a long time, though, HR staff may no longer be getting a complete or accurate idea about how their policies are actually impacting the employees on a personal level. Dedicated consulting firms can often fill this gap.
Consultants commonly assist with developing systems to manage and reward current employees, and frequently also set up rubrics to objectively evaluate employee satisfaction. They can also help companies select cost-effective employee healthcare plans and benefit programs, and can offer advice on how to manage employees in a merger and acquisition situation. Additionally, consultants can evaluate which business functions should remain in-house and which business functions can be effectively outsourced.
Making sure that companies have the right hiring processes in place is another big part of the job in most cases. Consultants can look at how jobs are advertised, how the interview process is carried out, and how offers are made and make broad suggestions about how to add more diversity or attract people with different educational backgrounds or expertise. Getting the right people in the right jobs is often a big part of corporate success, and also usually leads to better retention and improved on-the-job satisfaction.
In many cases, consultants can also train managers and other leaders in how to better engage with their subordinates. Sometimes the relationship between the consultancy firm and the company can be longstanding, and consultants might be embedded into different divisions for weeks or months at a time — but not always. In some cases, consultants work at a much greater distance, and evaluate things more or less on paper only. These services are typically a lot less expensive, but are more limited, too.
Many HR consulting firms have developed proprietary software and support tools for use on more "remote" jobs. These can assist companies on a long-term basis with managing their human resource functions. Companies should usually educate themselves on what types of tools are available and how those tools can enhance their human resource operations before deciding whether to adopt them.
Companies are usually wise if they define the scope of the project they want accomplished and identify what specific goals they want to achieve before reaching out to consulting firms. Different firms have different areas of expertise, and it is important to narrow down the purpose before seeking bids. Having a clearly defined purpose can also help prevent cost overruns.
It's usually a good idea for executives to obtain several bids from different consulting firms. During this process, businesses should request and review the consultants' references and verify that they have worked on projects similar to the one at hand. Additionally, a company should ensure they have a chance to interview the individual or individuals who will actually be assigned. Depending on the scope of the project, a firm might assign anywhere from just one consultant to ten or more. Meeting these people upfront can help leaders ascertain whether or not there's a good fit.
HR consulting firms employ individuals with a variety of backgrounds and experience. Entry-level positions in the field generally involve working as an analyst. This type of position typically requires an undergraduate degree in a subject such as statistics, risk management, business, or finance. Individuals seeking a more senior position will usually need at least some prior experience working in human resources or a consulting field. Advanced degrees are also advantageous, and firms are more likely to hire individuals that possess a master's degree in business administration (MBA) or a related field.
One of our editors will review your suggestion and make changes if warranted. Note that depending on the number of suggestions we receive, this can take anywhere from a few hours to a few days. Thank you for helping to improve wiseGEEK!


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STARmeterSEE RANK
Up 4,947 this week
Libby Holman (1904–1971)
Libby Holman's life was one of early poverty, extraordinary talent, scandal, fabulous wealth and tragedy. She's the stuff books and movies are ripe for. Born into a once-prosperous Jewish family in Ohio, her family's stock brokerage business collapsed in 1904 when her uncle disappeared after embezzling nearly $1 million, leaving her innocent ... See full bio »
Born:in Cincinnati, Ohio, USA
Died:(age 67) in Stamford, Connecticut, USA


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Kentucky Horse Park Offers Help to Hurricane Irma Evacuees
200 Stalls Available for Horses in Potential Path of Hurricane
The Kentucky Horse Park has opened stabling to horses that are being evacuated from areas expected to be impacted by Hurricane Irma. 200 stalls are available on a first-come, first-serve basis beginning today until September 17 for $20 per stall per night.
"Although we have limited capacity, it's important for us to help however we can," said Laura Prewitt, Executive Director of the Kentucky Horse Park.
Due to contractual obligations with scheduled horse shows, no pasturing, lunging or riding will be possible. A negative Coggins test is required for stabling.
To reserve stalls, please contact Sheila Forbes in the park's Equine Operations Department, at 859/259-4290 or at [email protected]. Any additional information will be made available on the park's website at www.kyhorsepark.com.


text: Winter just returned to Germany, everything is covered in snow. Time to snuggle under a blanket and enjoy some heartwarming spirits. I've selected some bottles that all have aged in various casks or barrels to receive a delicious finish. from left to right: Northoff "Alte Post" A barrel aged Korn, rested for 27 months in Pedro Ximenez Sherry cask 0,5l/ €39,- Basic Barrique Vodka aged 6 months in … [Read more...] about From a barrel


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The culturally adapted psychological intervention C-MAP utilizes problem solving components within a brief intervention that can be widely utilized in clinical practice. It has recently been shown that it is feasible to carry out large randomized control trials to evaluate psychological interventions in self-harm patients in low and middle income countries (14) and shows reduction in repetition of self-harm. Thus a strong rationale exists for the robust evaluation of C-MAP in order to clearly determine the clinical and cost effectiveness of this intervention.
Suicide: A global public health problem
- Every 40 seconds someone dies of suicide.
- Suicide ranked amongst the leading causes of death in many countries.
- Each year more than 800,000 people worldwide kill themselves.
- More than 75% of these are in the low and middle income countries (LAMIC).
- Suicide is the second leading cause of death among 15 – 29 year olds.
- There is no official data on suicide from Pakistan.
- Both suicide and attempted suicide are illegal acts, as well as socially and religiously condemned.
Self harm: A predictor of Suicide
- A prior history of self-harm is the strongest predictor of a future suicide attempt or completed suicide
- For each suicide there are more than 20 people attempting suicide.
- In the year following a suicide attempt, the risk of a repeat attempt or death by suicide may be up to 100 times greater than that seen in people who have never attempted suicide
Causes of self harm
Problem Solving Skills
People who attempt suicide have poor problem solving skills.


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On June 10, 2015, plaintiffs California Outdoor Equity Partners, LLC, AMG Outdoor Advertising, and J. Keith Stephens filed suit against the defendant, City of Los Angeles alleging that the City's restrictions on off-site commercial billboards, Section 14.4.4.B.11 of the Los Angeles Municipal Code ("LAMC"), violated plaintiffs' free speech and equal protection rights. Plaintiffs alleged that they were licensed by the State of California to lease to the public "off-premises" or "offsite" outdoor advertising signs. The City of Los Angeles filed a motion to dismiss.
In its Free Speech Claims, the plaintiffs challenged the ordinance's: distinction between offsite and onsite content; its distinctions between "certain speakers" (those who have "grandfathered" rights, including CBS Outdoor ("CBS") and Clear Channel Outdoor ("CCO")), the operators of onsite signs and the operators of noncommercial signs, and street banners) and between certain types of signs; and its allowance for many exceptions to the ordinance's ban. This argument was rejected, however, because the distinction between offsite and onsite signs has been repeatedly upheld as content-neutral and valid. Moreover, the City was entitled to treat signs permitted before the offsite and supergraphic sign bans differently than other signs because preserving legally nonconforming billboards still furthered the City's significant interest in reducing blight and increasing traffic safety. Finally, the court rejected the notion that a higher degree of protection existed for commercial speech under the California Constitution. Accordingly, the court dismissed the plaintiffs' Free Speech claims.
As to the Equal Protection claims, plaintiffs alleged that the City had selectively granted CBS and CCO the right to operate offsite commercial billboards, while denying that right to Plaintiffs. However, Plaintiffs, as would-be new billboard operators who do not own grandfathered pre-ban billboards, were not found to be similarly situated to existing operators who had grandfathered pre-ban billboards (such as the two companies actually named in the complaint, CBS and Clear Channel). As a result, these claims were likewise dismissed.
California Outdoor Equity Partners, LLC v City of Los Angeles, 2015 WL 7259731 (CD CA. 11/16/2015)


text:
We're a Curated T-Shirt Gallery Newsletter in Your Inbox. Join us.
Subscribe and We'll Let You Know When Awesome T-Shirt Designs & Great Deals Become Available
It's free. No spam. Unsubscribe whenever you want.
See the most fascinating T-shirt designs from all over the world delivered to your email every day!
A Newsletter Showcasing Cool & Incredible T-Shirts
A Curated Gallery of Awesome
T-Shirts in Each Newsletter
We are T-shirt aficionados who spend all day with one purpose: Find awesome T-shirts and deals. Take advantage and subscribe. You'll love it.
Designs You Want
Not just random picks, but empirically-backed, rigorously picked and ranked by our team and members.
Super T-Shirt Deals
We keep searching to get bargains, discounts, or special deals with providers for you.
Wide Selection
T-shirts for men, women, about quotes, funny images, beautiful art, and so much more. Pick your genre.
Innovative Concepts
T-shirts that are spill-resistant, blink real lights, make actual guitar sounds, and more. You name it.
Community Ranking
T-shirt Fanatics Who Find and Rank Tees
We're not just sending you arbitrary designs or links, but vetted assets using our rigorous standards and voted on by our team as well as our members!
A Few Examples Featured in the Newsletter
No need to keep looking for great tees and deals. We'll do it for you.
Paparoni & Slice
A Happy Slice Off the Old Pie
You Wanna Piece of Me-at?
Let's Just Say I'm on a Diet
Tee-rannosaurus Retch
Vomiting Rainbows Long Before Unicorns
Didn't Choose the Pug Life
The Pug Life Chose Tee
Writable Chalkboard Tee
* – Chalk & Ideas Not Included
Attention Wore
It's Just a Shirt Wound
Shirt of Actual Sound
* – Other Instruments Sold Separately
The Flasher Really Flashes
Won't Take Pics. Just Your Attention
Spill Resistant Shirt
Repels Everything Except its Owner
Curated by Experts and the Community
Your Platform for T-Shirt Discovery
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Join the Community
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We find the best deals available, and even partner with providers to bring you special treats & discounts.
More Design Examples
Here are more designs you can expect in each email. And where to get them.
Direct to the Point, and the Fun Parts
A unique newsletter from what I'm used to. Not much longform chitchat, instead there's good visuals and links to wherever they're available for purchase, just the way I like it.
Colin Long
Former Skeptic is a Full Convert
My coworkers love it! This is how the skeptic in me finally gave in and I gave it a try. Never regretted it, and so glad I dove in.
Carol Nguyen
Like My Own Private T-Shirt Finder
It's like a personal shopper on steroids– hyperfocused on T-shirts and hitting homeruns in each issue. Instead of all that time searching, I can just pick from an already great list and buy.
Toran Adhikari
Curated Hit List
Really nice designs. But what I really like is the obvious but cool feature of not just showing artful designs, but including links to where to actually buy them.
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Act Now — You'll Love It
All These and More When You Subscribe. Best of All, It's Free
A gallery of awesome T-shirts direct to your email inbox, with other perks and things to love in each issue. So come and join the party!


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The UCBSA has decided to withdraw Andre Nel from the South Africa A tour in Australia. The decision follows Nel's arrest early on the 11th by police in Hobart, Tasmania, on a charge of drunken driving. The Hobart police released Nel into the custody of SA A team management as an alternative to proceeding with prosecution.
Nel will return to South Africa as soon as possible and the matter has been referred to the Disciplinary Committee of the UCBSA for their deliberation. Should the Disciplinary Committee decide to hold a hearing into the matter, this will be done as soon as possible and the media will be advised accordingly.
Neither Andre Nel nor the UCBSA will discuss this matter with the media pending a meeting to be scheduled between Nel and the UCBSA on his return to South Africa.
Team management has not requested a replacement player.


text:
This is not an offer for credit and should be used for estimation purposes only based on the information you provided. You should not base your decision on this estimate alone. Title, registration, tax and other fees, and personal circumstances such as employment status and personal credit history, were not considered in the calculations.
Front - Two four-piston hydraulic calipers with 310 mm disks; ABS
Rear - Single one-piston hydraulic caliper with 256 mm disk; ABS
Front - 90 / 90-21
Rear - 150 / 70R-18
Standard position - 34.3 in.
Low position - 33.5 in.
Honda Selectable Torque Control
Throttle by wire
SHOWA EERA® electronic suspension
Cruise control
Heated grips
We are in the process of adding model data for the new 2020 Honda models. We do everything we can to ensure that all of our information is correct; however, during the initial entry process, we reserve the right to make additions, deletions, or modifications to model specifications, features, images and prices displayed on this and any associated webpage at any time without prior notice. Please contact your local dealer to confirm the information.


text:
About this Research Topic
Deep learning featured among the 2013 top 10 technology breakthroughs in the MIT Technology Review. Currently it is an active research area for academic, industrial and government labs. Deep learning neural networks have enabled state-of-the-art machine learning results to approach human level performance in difficult machine perception tasks such as speech, language, and visual perception. Given the prominence of this topic in scholarly pursuit, and its overlap with many parts of neuromorphic engineering, it is ideally suited and timely for a Research Topic, one that highlights the technical strengths of the neuromorphic community. We will focus on hardware and neuromorphic accelerators, which will specifically leverage our strengths while making this Research Topic highly relevant for Frontiers in Neuromorphic Engineering.
The Research Topic will be focussed on various implementation aspects for deep learning architectures. One particular interest is efficient on-line learning algorithms implemented in hardware. State-of-the-art deep convolutional neural networks have achieved remarkable performances by using the back-propagation algorithm to fine tune the weights of the connections between layers. The storage of billions of meticulously tuned weights (as done in state-of-the-art deep neural networks) is the main bottleneck for hardware implementation of deep neural networks. More importantly, the training of the deep learning neural networks is quite time consuming. Hence efficient online-learning algorithms are vital for the deployment of deep learning on dedicated hardware. Papers on this aspect of deep learning will be prioritised. Furthermore, most of the widely used deep learning models are convolutional neural networks, deep belief networks, and deep networks with stacked auto-encoders. We will also invite papers that realised such algorithms as custom hardware using state-of-the-art IC design techniques, where the power, speed and complexity are optimised for these applications. Lastly, since typical deep learning architectures are inspired by biology, while not exactly being neurophysiologically plausible, we will also encourage papers that attempt to close the loop between biology, algorithms, and hardware.
Relevant topics include:
• Non-spiking hardware implementations of deep learning (analogue, digital, mixed-signal implementations);
• Spiking hardware implementations of deep learning (analogue, digital, mixed-signal implementations);
• Neuromorphic sensors combined with deep learning neural networks;
• Hardware models of biology inspired learning, such as learning with Cortical Circuits.
The resulting collection of original research articles, reviews and commentaries will be a reference for deep learning in neuromorphic systems, fostering the research progress through discussions and new collaborations among the different researchers in our community.
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.


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A sheriff asked for a medical report on an offender who has failed to complete his hours of unpaid work in the community.
Solomon MacDonald (21) supposedly injured himself while carrying out the work segment of his community payback order and that was his excuse for not showing up to complete the hours he still had to do.
MacDonald, 16 Bridgeness Road, Bo'ness, appeared at Falkirk Sheriff Court last Thursday having pled guilty to two assaults he committed in Hillcrest Drive, Alloa, on May 31, 2014. The court heard he only had six hours left after he completed 12 hours in one day.
Sheriff Derek Livingston fixed a review of the order for January 5 and asked for a medical report.


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I've had this idea for a quite time now (few years I guess), but haven't released it because it felt so stupid. Yes, just good old fashioned stupid, simple, idea. But it has some extremely good benefits that cannot be ignored.
If you check out my programming experiments from the past 10 years you'll see a lot of particles. For some reason I keep on coming back to them. Always looking for ways to get more of them to the screen. But also trying to find new ways to render them, not just how they move, but also what sort of pixels I can draw to/with them.
Today I would like to introduce a new way of rendering particles.
→ Read the rest of this entry


text:
Masters and Mavericks in Global Marketing: Episode 2 with Jason Barrett
For our second Masters & Mavericks podcast Elliot sat down with Jason Barrett, a social media influencer and strategist, who is the Founder and CEO of...Read More
For our second Masters & Mavericks podcast Elliot sat down with Jason Barrett, a social media influencer and strategist, who is the Founder and CEO of...Read More
One day, a successful Client Services Director from a well-known international ad agency came to us and said that he was stumped. The global campaign that his...Read More
In less than a couple of decades, social media has become a global phenomenon. Membership growth dramatically increases year over year, and our most trusted platforms...Read More
Masters and Mavericks is an exclusive podcast dedicated to innovation in global marketing. Hosted by Textappeal and Newsroom founder Elliot Polak, Masters and Mavericks is a monthly...Read More
When launching a global campaign brands face many hurdles, from simply reaching a target market to figuring out what kind of methods best engage individual consumers....Read More
Businesses We Like: For once, here's a blurb not about the benefits of Textappeal or NewsroomWW, but someone else's business that I happen to think...Read More
Find Out What Happens When Three Golfers Are Pitted Up Against a 1934km "course" in a Nissan X-Trail...Read More
If business class travelers are an airline's bottom line, then why did Air France reach out to children to promote its brand?...Read More
Textappeal are to support the SEA LIFE brand in helping to promote their ethos and enabling it to resonate with an audience across 13 markets in...Read More
Elliot Polak talks about the most common error brands make when they first attempt to implement an international campaign....Read More


text:
Gambler and show paradise Las Vegas: For the first time ever, Frank M. Rinderknecht, boss of the Swiss powerhouse of ideas Rinspeed, celebrates a world premiere outside his native Alpine country and presents the hybrid sports car "Ʃtos" at the CES 2016 in Las Vegas. The car visionary says: "The major and especially the disruptive innovations in future automotive engineering w" />
Gambler and show paradise Las Vegas: For the first time ever, Frank M. Rinderknecht, boss of the Swiss powerhouse of ideas Rinspeed, celebrates a world premiere outside his native Alpine country and presents the hybrid sports car "Ʃtos" at the CES 2016 in Las Vegas. The car visionary says: "The major and especially the disruptive innovations in future automotive engineering will come from the digital realm. That is why all major manufacturers and suppliers are now present at the CES Consumer Electronic Show."
The Swiss progressive thinker approached the mega topic of "driverless cars" largely from the point of view of drivers and passengers, and has generated a number of equally inspiring and emotional ideas. They include an intuitive, adaptive autopilot capable of learning. The resulting and much-debated question "How much man should, must or may be in a machine?" will be discussed for a long time.
The interior adapts to the particular driving situation as if by magic: In autonomous mode, the steering wheel folds up elegantly and retracts completely into the dashboard. The two curved widescreens individually move closer to the occupants to provide a better view. "It really has the power of magic!"
To provide the passengers with a unique infotainment experience, the Rinspeed "Ʃtos" uses the innovative Harman Connected Car technologies. Just like a personal assistant, the system operates in a thinking, courteous and anticipatory manner. In addition, it delivers perfect entertainment, connectivity and maximum safety.
As is its tradition, the Helvetian think tank studies existing digital possibilities - and demonstrates new ones. It has fitted its sporty hybrid with a drone that has its own landing pad on the rear end. The many benefits this offers are evident: For example, it could fetch a bouquet of flowers the driver ordered online and even deliver it directly to the lucky recipient. It could also take a video of the wild ride on the favorite fun road and stream it live to friends!
No doubt, Frank M. Rinderknecht presents himself as a visionary and magician in Las Vegas. And, because a great show also definitely requires extraordinary head-turning packaging, the Swiss national opted to use special innovative surface finishes in the "Ʃtos" that are still completely alien to car designers. Touch it, feel it - it's magic!
The Rinspeed "Ʃtos" is already the twenty-second concept vehicle designed in-house at the Swiss "innovation lab."
The partners and suppliers in the realization of the "Ʃtos" are:
4erC GmbH - www.4erc.ch
Barlog plastics GmbH - www.barlog.de
Borbet Vertriebs GmbH - www.borbet.de
Carl F. Bucherer - www.carl-f-bucherer.com
Corning Inc. - www.corning.com
Eberspächer Climate Control Systems GmbH & Co. KG - www.eberspaecher.com
Esoro AG - www.esoro.ch
EVA Fahrzeugtechnik GmbH - www.evafahrzeugtechnik.de
Ernst & Young GmbH - www.de.ey.com/automotive
GF Automotive - www.gfau.com
Harman International, Inc. - www.harman.com
Harting KGaA - www.harting.com
Inrix Inc. - www.inrix.com
Luxoft - www.luxoft.com
NXP Semiconductors Germany GmbH - www.nxp.com
Putzier Oberflächentechnik GmbH - www.putzier.com
Rehau AG + Co - www.rehau.com
Schoeller Spinning Group - www.schoeller-wool.com
SIX Group - www.six-group.com
Stahl Holdings BV - www.stahl.com
Strähle+Hess GmbH - www.straehle-hess.de
ZF TRW - www.trw.com
Vollmond Werbeagentur - www.agentur-vollmond.de
Vites GmbH - www.vites.de
Weidplas GmbH - www.weidplas.com