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Trichosanthin suppresses the proliferation of glioma cells by inhibiting LGR5 expression and the Wnt/β-catenin signaling pathway
Junjie Miao
Yilin Jiang
Dongliang Wang
Jingru Zhou
Cungang Fan
Feng Jiao
Jun Zhang
Yangshuo Wang
Qingjun Zhang
Affiliations: Department of Neurosurgery, Peking University People's Hospital, Beijing 100044, P.R. China
Published online on: September 18, 2015 https://doi.org/10.3892/or.2015.4290
Copyright: © Miao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Studies have indicated that trichosanthin (TCS), a bioactive protein extracted and purified from the tuberous root of Trichosanthes kirilowii (a well‑known traditional Chinese medicinal plant), produces antitumor effects on various types of cancer cells. However, the effects of TCS on glioma cells are poorly understood. The objective of this study was to investigate the antitumor effects of TCS on the U87 and U251 cell lines. The in vitro effects of TCS on these two cell lines were determined using a Cell Counting Kit‑8 (CCK‑8) assay, Annexin V‑FITC staining, DAPI staining, Transwell assays, terminal deoxynucleotidyl transferase‑mediated dUTP nick end‑labeling (TUNEL) assays, 5,5',6,6'‑tetrachloro‑1,1',3,3'‑tetraethyl‑imidacarbocyanine iodide (JC‑1) staining and western blotting, which was utilized to assess the expression of leucine‑rich repeat‑containing G protein‑coupled receptor 5 (LGR5) and key proteins in the Wnt/β‑catenin signaling pathway. Our data indicated that TCS inhibited the proliferation of glioma cells in a dose‑ and time‑dependent manner and played a role in inhibiting glioma cell invasion and migration. Additional investigation revealed that the expression levels of LGR5 and of key proteins in the Wnt/β‑catenin signaling pathway were markedly decreased after TCS treatment. The results suggest that TCS may induce apoptosis in glioma cells by targeting LGR5 and repressing the Wnt/β‑catenin signaling pathway. In the future, in vivo experiments should be conducted to examine the potential use of this compound as a novel therapeutic agent for gliomas.
Primary central nervous system tumors account for ~2% of human malignancies (1). In general, malignant glioma is the most common type of primary intracranial tumor, and the incidence of malignant glioma is increasing worldwide, primarily as a result of improvements in diagnostic imaging (2). Despite the comprehensive treatment regimen of surgery, radiotherapy and chemotherapy, resistance to standard anti-proliferative treatment with concomitant radiotherapy and chemotherapy is common and manifests as an invasive cell population that leads to tumor recurrence and death (3). Therefore, there is an urgent need for the development of a novel agent displaying glioma-specific toxicity.
Trichosanthin (TCS), a protein of ~27 kDa that is extracted from the Chinese herb Trichosanthes kirilowii Maxim, is a type I ribosome-inactivating protein (RIP) (4,5). It has been used for centuries in China as an abortifacient during early pregnancy (6). Many studies have shown that TCS has enormous potential as a therapeutic drug due to its suppression of the proliferation of various cancer cell types. Research has demonstrated that TCS restricts human choriocarcinoma cell proliferation by inducing reactive oxygen species (ROS) production (7,8). In addition, TCS suppresses the proliferation of HeLa cells by blocking the PKC/MAPK signaling pathway (9) and induces the apoptosis of cervical cancer cells by increasing the intracellular Ca2+ concentration (10) and by regulating the expression of Smac (11). Moreover, previous studies have shown that TCS suppresses the proliferation of breast cancer cells and HepA-H cells by inducing cell cycle arrest and promoting apoptosis (12–14). Furthermore, research suggests that TCS induces the apoptosis of chronic myeloid leukemia cells via endoplasmic reticulum stress, the mitochondrial-dependent apoptosis pathway and the inhibition of PKC (15,16). Studies have also revealed that TCS displays anti-HIV activity, as TCS is cytotoxic to HIV-infected macrophages and lymphocytes and decreases viral replication (17,18). Recently, a new study showed that a peptide derived from TCS suppresses the immune response by activating CD8+CD28− regulatory T cells and serves as a potential therapeutic agent for immunological diseases (19). TCS not only has inhibitory activity against various tumor cells but also shows inhibitory activity against several normal somatic cell types, including proximal tubule epithelial cells, hepatocytes and antigen-specific T cells (20–22). Previous studies have reported that TCS can cause neurological reactions in HIV-infected patients and that such toxicity may be due to the effect of TCS on HIV-infected macrophages (23). However, intravenous injections of TCS had no toxic effects on normal mouse brain or pituitary cells (24). In conclusion, since TCS displays anticancer activity in various malignant tumors, we aimed to determine whether TCS exerts antitumor effects on glioma cells. Here, we demonstrated the anti-proliferative effects and antitumor mechanisms of action of TCS on glioma cells. Our results suggest that TCS is a novel chemotherapeutic agent that may target leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) and the Wnt/β-catenin pathway in human glioma cells.
High glucose DMEM containing fetal bovine serum (FBS), penicillin G and streptomycin was purchased from Gibco (Carlsbad, CA, USA). The U87 and U251 human malignant glioma cell lines were provided by the China Infrastructure of Cell Line Resources, (Beijing, China). TCS was purchased from Shanghai Jinshan Pharmaceutical (Shanghai, China). The primary antibodies against LGR5, β-catenin, GSK-3β, c-myc and cyclin D1 used for western blot analysis were provided by Santa Cruz Biotechnology (Santa Cruz, CA, USA). The other reagents used in this study were of analytical grade.
The U87 and U251 human malignant glioma cell lines were cultured in high glucose DMEM containing 1% antibiotics and 10% FBS. The cells were cultured in an incubator at 37°C in 5% CO2 and a humidified atmosphere.
Cell morphology
U87 and U251 cells were grown in culture flasks to the logarithmic growth phase. Then, the cells were treated with TCS (20 µM). Morphological changes in the cells were observed using an inverted microscope, and the cells were photographed after treatment for 24 h.
A Cell Counting Kit-8 (CCK-8) (Dojindo, Japan) assay was utilized to evaluate cell viability. U87 and U251 cells were resuspended in complete or serum-free medium at a density of 1×104 or 5×103 cells/well and were cultured in 96-well plates. The cell samples were exposed to various concentrations (2.5, 5, 10, 20, 40 or 80 µM) of TCS for 24, 48 or 72 h. After TCS treatment, the medium was removed from each well, 10 µl of CCK-8 and 100 µl of serum-free medium were added, and the cells were incubated for 1 h at 37°C. A microplate reader was used to measure the absorbance of each well at 450 nm.
Detection of apoptosis via flow cytometry
The apoptosis of U87 and U251 cells was analyzed using an Annexin V-FITC apoptosis detection kit (Sigma-Aldrich, St. Louis, MO, USA). The cells were cultured with TCS (10, 20 µM) or vehicle (PBS) for 24 h, and then, the cells were harvested at a density of 1×106 cells/ml. The cells were washed twice with ice-cold PBS. Then, the cells (1×106) were resuspended in 195 µl of binding buffer, and 5 µl of Annexin V-FITC and propidium iodide (PI) were added to the cell suspension; subsequently, the cells were covered in aluminum foil and incubated at room temperature for 20 min. After this incubation, apoptosis was analyzed via flow cytometry.
DAPI staining
After U87 glioma cells were treated with TCS (10 or 20 µM) or PBS for 24 h, they were fixed in 4% formaldehyde and washed three times with PBS. Then, the cells were stained with DAPI staining solution (10 µg/ml) for 5 min and washed three times with PBS. The morphologic changes in the nuclei were detected using a fluorescence microscope.
Mitochondrial membrane potential measurement based on 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining
The decrease in mitochondrial membrane potential, which is a hallmark of apoptosis, was detected using a JC-1 mitochondrial membrane potential assay kit (Cayman Chemical, Ann Arbor, MI, USA). U87 glioma cells were treated with TCS (10 or 20 µM) or PBS for 24 h and then incubated in 1 ml of JC-1 working solution for 30 min at 37°C in an incubator. These cells were washed twice with ice-cold PBS, and the fluorescence intensity of the cells was then observed via fluorescence microscopy. Decreased fluorescence of the cells was observed as the mitochondrial membrane potential collapsed.
Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay
DNA fragmentation was detected using a One-Step TUNEL kit (Abnova Corporation, Taipei City, Taiwan) according to the manufacturer's instructions. Briefly, after treatment with TCS (10 or 20 µM) or PBS, U87 cells were fixed in 4% paraformaldehyde for 30 min at room temperature. Then, the cells were washed three times with PBS and permeabilized for 2 min on ice. Next, the cells were resuspended in TUNEL working solution and incubated in a humidified atmosphere shielded from light for 1 h at 37°C. Green fluorescence was detected in the FITC-labeled TUNEL-positive cells under a fluorescence microscope.
Wound healing assays were used to assess the effects of TCS on glioma cell migration. U87 cells were seeded in culture plates and incubated until they reached confluency. Subsequently, a scratch was made on the cell surface using a 10-µl pipette tip. The cells were washed with PBS and treated with TCS (5 µM) or PBS for 24 h. The width of the wound was photographed under a microscope at 0 and 24 h. In addition, the effect of TCS on glioma cell invasion was determined using Matrigel-coated Transwell assays. U87 cells were treated with DMEM containing TCS (5 µM) or PBS for 24 h. Then, the cells were trypsinized and seeded into the upper chamber of a Transwell insert at a density of 1×105. Medium containing 20% FBS was added to the lower chamber, and the cells were cultured for 24 h. The cells that invaded into the outer surface of the Transwell insert were stained with 0.5% crystal violet solution and counted using an inverted microscope.
Cellular proteins were extracted from glioma cells using lysis buffer [1 mM EDTA (pH 8.0), 50 mM Tris (pH 7.4), 150 mM NaCl, 1% NP-40, 0.1% SDS, and 0.5% sodium deoxycholate] according to the manufacturer's instructions for western blot analysis. A bicinchoninic acid protein quantitation kit (BioVision, Palo Alto, CA, USA) was used to measure the protein concentrations. The same amounts of whole-cell protein extracts from each sample were separated via SDS-PAGE and transferred to a PVDF membrane with a pore size of 0.2 µm. Subsequently, the membrane was blocked with 5% milk in TBS-T for 1 h at room temperature (RT), incubated in a primary antibody overnight at 4°C, and then incubated in a horseradish peroxidase-conjugated secondary antibody at room temperature for 2 h. After washing three times with TBS, the immunoreactive bands were detected using a gel imaging analysis system after applying a chemiluminescence working solution to the PVDF membrane according to the manufacturer's instructions.
SPSS version 19.0 was utilized for the statistical analyses, and the data are presented as the mean ± standard deviation (SD) of multiple independent experiments. Student's t-test and ANOVA were used to evaluate the differences between the means, and P<0.05 was considered to indicate a statistically significant difference.
The CCK-8 assay was used to evaluate the impact of TCS on glioma cell viability. U87 and U251 cells were treated for 24 h with TCS diluted to concentrations of 2.5, 5, 10, 20, 40 and 80 µM in complete medium; the assay results indicated that relative to the control cells, U87 cells exhibited viabilities of 95.4, 93.8, 85.9, 62.2, 44.1 and 36.2%, respectively, and U251 cells exhibited viabilities of 99.9, 92.1, 88.3, 68.8, 62.7 and 56%, respectively (n=4; P<0.05) (Fig. 1A). In addition, the IC50 values for U87 and U251 were 40 and 51.6 µM, respectively. We analyzed the change in cell viability of U87 cells after treatment with TCS concentrations of 2.5, 5, 10, 20, 40 and 80 µM in serum-free medium; compared with the control cells treated with PBS alone, U87 cells treated for 24 h exhibited viabilities of 97.7, 88.7, 78.6, 62.1, 36.2 and 27.3%, respectively, U87 cells treated for 48 h exhibited viabilities of 94.2, 82.3, 71.8, 47.8, 26.9 and 19.0%, respectively and U87 cells treated for 72 h exhibited viabilities of 86.3, 67.7, 47.3, 28.4, 17.0 and 7.9%, respectively (n=4; P<0.05) (Fig. 1B). The IC50 values of U87 cells for 24, 48 and 72 h of TCS treatment were 30.2, 20.5 and 10.0 µM, respectively. The assay results indicated that in both the presence and the absence of serum, TCS inhibited the viability of glioma cells in a dose- and time-dependent manner.
TCS inhibits the viability of glioma cells in a dose- and time-dependent manner. (A) Human malignant glioma cells (U87 and U251) were cultured in serum-containing DMEM in the presence of different concentrations of TCS (0–80 µM) for 24 h. The CCK-8 assay was used to determine cell viability. The data are presented as the mean ± SD of three independent experiments. *P<0.05 compared with the PBS-treated (control) group. (B) U87 cells were cultured in serum-free DMEM containing various concentrations of TCS (0–80 µM) for different periods (24, 48 or 72 h). Glioma cell viability was investigated using the CCK-8 assay. The data are presented as the mean ± SD of three independent experiments. *P<0.05 compared with the control group. (C) U87 and U251 cells were cultured in cell culture dishes and treated with DMEM containing TCS (20 µM) or PBS for 24 h. After treatment, the morphological changes in the glioma cells were observed via microscopy. Representative images from three independent experiments are shown.
TCS induces the apoptosis of glioma cells
To determine whether the induction of glioma cell apoptosis is related to the inhibition of proliferation, the apoptosis rate was analyzed via flow cytometry after labeling cells with Annexin V-FITC/PI. As indicated in Fig. 2, the apoptotic percentages of the U87 and U251 cells were 5.9 and 5.1%, respectively, in the PBS-treated group; 14.1 and 10.4%, respectively, in the group treated with 10 µM of TCS and 36.1 and 27.8%, respectively, in the group treated with 20 µM of TCS. Moreover, DAPI staining was used to observe morphological variations in the nuclei, and the data showed that chromatin condensation and fragmented nuclei which are typical characteristics of apoptosis, were detected following DAPI staining when U87 cells were treated with 10, 20 µM TCS for 24 h (Fig. 3A). Results also showed that the number of TUNEL-positive U87 cells was significantly increased in the TCS-treated group compared with the PBS treated group (Fig. 3B). Furthermore, JC-1 staining was used to visualize mitochondrial depolarization in glioma cells treated with TCS. The mitochondria of untreated JC-1-stained U87 cells emitted faint green fluorescence and strong orange–red fluorescence, whereas the apoptotic cells emitted green fluorescence. Compared with the control cells treated with PBS, TCS-treated U87 cells exhibited significantly decreased mitochondrial membrane potentials, as evidenced by these cells' distinct green fluorescence (Fig. 3C).
Analysis of apoptosis via Annexin V/PI staining. U87 cells were cultured in DMEM and were treated with TCS (10, 20 µM) or vehicle (PBS) for 24 h. The cells were analyzed via flow cytometry after staining with Annexin V/PI. The percentage of apoptotic cells (right lower quadrant, early apoptotic cells; right upper quadrant, late apoptotic cells) was analyzed using CellQuest Pro software. Lower graphs show the percentage of apoptotic or dead cells. *P<0.05 compared to the respective PBS-treated (control) cells. The data are presented as the mean ± SD of three independent experiments.
TCS induces apoptosis in glioma cells. (A) U87 cells were cultured in DMEM containing TCS (10, 20 µM) or PBS for 24 h, and changes in nuclear morphology were observed via DAPI staining and fluorescence microscopy. The experiment was repeated three times, and the images are representative. (B) Apoptotic cells were detected via TUNEL staining. U87 cells were treated as described above prior to TUNEL staining. The number of TUNEL-positive cells was significantly increased due to TCS treatment. Representative images of TUNEL staining are shown. (C) The mitochondrial membrane potential of glioma cells was decreased due to TCS treatment. U87 cells were treated with TCS (10, 20 µM) or PBS for 24 h, and the decrease in the mitochondrial membrane potential was observed based on JC-1 staining via fluorescence microscopy. The images are representative of three independent experiments.
TCS inhibits glioma cell migration and invasion
Wound healing and Matrigel-coated Transwell assays were used to evaluate the effect of TCS on migration and invasion. The percentage of wound repair decreased from 61.52 to 36.87% in response to TCS, and the ratio of invading cells on the lower side of the membrane was 42.57% after treatment with 5 µM TCS compared with the control (set to 100%; Fig. 4).
TCS inhibits glioma cell migration and invasion in vitro. The effects of TCS on U87 cell migration were assessed using wound healing assays. (A) Representative images of wound healing at 0 and 24 h. (B) Quantification of the wound healing assays after U87 cells were treated with TCS (5 µM) or vehicle (PBS) for 0 and 24 h. *P<0.05. Matrigel-coated Transwell assays were used to analyze U87 cell invasion. (C) Representatives images of cells that migrated through the Matrigel-coated Transwell inserts. (D) Histogram indicating the percentage of invasive cells compared with the control group. *P<0.05.
TCS inhibits the expression of LGR5 and key proteins in the Wnt/β-catenin signaling pathway in glioma cells
Studies have shown that LGR5 and the Wnt/β-catenin signaling pathway play crucial roles in the proliferation, differentiation and metastasis of cancers of varying origin (25). To further explore the suppressive mechanism of action of TCS in glioma cells, we examined the expression levels of LGR5 by immunoblotting. As shown in Fig. 5, as the TCS dose increased (0–20 µM; 24 h), the levels of LGR5 protein expression in the U87 cells markedly decreased. We also analyzed the protein levels of phosphorylated glycogen synthase kinase-3β (pGSK-3βser9), β-catenin, c-myc and cyclin D1, which are key members of the Wnt/β-catenin signaling pathway, via western blot analysis, and we found that increasing concentrations of TCS (0–20 µM; 24 h) resulted in an evident downregulation of these proteins (Fig. 5). Taken together, these results demonstrated that TCS treatment reduces the expression of LGR5 and key proteins in the Wnt/β-catenin signaling pathway in a dose-dependent manner in glioma cells.
Western blot analysis of LGR5 and Wnt/β-catenin signaling pathway proteins. U87 cells were treated with different concentrations of TCS (5, 10, or 20 µM) or vehicle (PBS) for 24 h. Protein samples were obtained from the four groups and were analyzed via western blot analysis. The results showed that the protein levels of LGR5 and key members of the Wnt/β-catenin signaling pathway (pGSK-3βSer9, β-catenin, c-myc and cyclin D1) were downregulated in response to increasing TCS concentrations. Right panel, quantitative analysis of protein expression from three independent experiments. *P<0.05 compared with the control group.
Malignant gliomas account for the majority of primary brain tumors (26). The development of neuroimaging has allowed for the early diagnosis of these gliomas, and standard treatment with surgery, chemotherapy and radiation can be provided; however, patients with malignant gliomas nonetheless have poor prognoses. According to research data, the median survival duration for malignant glioma patients after treatment is less than one year (27). Therefore, neurosurgical studies of malignant gliomas have long focused on finding more effective treatment approaches. As a newly discovered active constituent of natural products, TCS has drawn a great deal of research attention due to its antitumor effects. In the present study, we demonstrated for the first time that TCS produces anti-glioma effects by inhibiting cell viability, migration, and invasion and by inducing apoptosis. Our results revealed that TCS significantly inhibited the proliferation of the U87 and U251 cell lines, which contain large numbers of glioma stem cells, in a dose- and time-dependent manner. The IC50 values for U87 cells were lower than the corresponding IC50 values for U251 cells, indicating that U87 cells were more vulnerable than U251 cells to TCS. Therefore, U87 cells were selected for additional experimentation.
Prior research has demonstrated that inducing apoptosis in tumor cells is an important mechanism of action for many antitumor drugs. In our study, flow cytometry revealed that apoptosis occurred in glioma cells after TCS treatment. Consistent with this finding, different typical morphological characteristics of apoptotic cells, including the condensation and clustering of chromatin along the nuclear membrane, internucleosomal DNA fragmentation and a decrease in mitochondrial membrane potential, were detected in the TCS-treated U87 cells by DAPI staining, a TUNEL assay, and JC-1 staining, respectively. These results suggest that TCS inhibits the proliferation of malignant glioma cells by inducing apoptosis.
However, the mechanism by which TCS induces apoptosis in malignant glioma cells has not been well established. LGR5, a member of the G protein-coupled receptor family (28), plays an important role in embryonic development and is widely expressed in brain and spinal cord tissue (29,30). Recent studies have revealed that the overexpression of LGR5 promotes the survival and growth of different types of tumors, including colorectal carcinomas, Ewing's sarcomas and glioblastomas (31–33). Furthermore, in our previous research, we found that LGR5 expression was closely associated with the pathologic grade of gliomas; moreover, the knockdown of LGR5 was found to inhibit the proliferation of U87 cells and suppresses the growth of xenografts (34). In the present study, our findings demonstrated that TCS treatment significantly reduce the levels of LGR5, pGSK-3βSer9, β-catenin, c-myc and cyclin D1 in the U87 cells. It has been well established that LGR5, pGSK-3βSer9, β-catenin, c-myc and cyclin D1 are important proteins of the Wnt/β-catenin pathway, which is intimately involved in normal development and the regulation of cancer stem cells (35). LGR5 binds to Wnt, low-density lipoprotein receptor-related protein (LRP) and frizzled (FZD) after interaction with the ligand R-spondin (RSPO); the resulting complex promotes the phosphorylation of GSK-3βSer9 and inhibits the phosphorylation of β-catenin (36). Unphosphorylated β-catenin translocates to the nucleus and interacts with transcription factors, activating the expression of downstream genes such as c-myc and cyclin D1 and ultimately promoting cell proliferation (37). Research has reported that in colorectal cancer cells, the depletion of LGR5 can decrease the expression of c-myc and cyclin D1, which are downstream target genes of the Wnt/β-catenin pathway, and induce apoptosis via an intrinsic apoptosis pathway (38). Therefore, we believe that suppression of LGR5 expression and of the Wnt/β-catenin signaling pathway may be the mechanism by which TCS induces apoptosis in U87 cells. However, understanding the detailed mechanism will require further study.
Further studies of the efficacy of TCS in in vivo models are needed to confirm our findings, although our results have demonstrated that TCS can induce apoptosis and inhibit the invasive/metastatic potential of glioma cells; thus, this study has revealed a novel concept for the treatment of malignant gliomas.
We thank Dr Weidong Yu and Mrs. Xin Yu for providing technical assistance with western blotting, fluorescence microscopy and FACS. We would also like to thank Dr Xiangjun He and Mrs. Mei Li for providing laboratory equipment. We thank American Journal Experts (AJE) for English language editing. This study was supported by the Peking University People's Hospital Research and Development Funds (no. RDB2011-14) and by the National Natural Science Foundation of China (no. 81001009).
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Anna CH, Iida M, Sills RC and Devereux TR: Expression of potential beta-catenin targets, cyclin D1, c-Jun, c-Myc, E-cadherin, and EGFR in chemically induced hepatocellular neoplasms from B6C3F1 mice. Toxicol Appl Pharmacol. 190:135–145. 2003. View Article : Google Scholar : PubMed/NCBI
Hsu HC, Liu YS, Tseng KC, Tan BC, Chen SJ and Chen HC: LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/β-catenin signaling pathway in colorectal cancer cells. Cell Signal. 26:2333–2342. 2014. View Article : Google Scholar : PubMed/NCBI
Print ISSN: 1021-335X
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Miao, J., Jiang, Y., Wang, D., Zhou, J., Fan, C., Jiao, F. ... Zhang, Q. (2015). Trichosanthin suppresses the proliferation of glioma cells by inhibiting LGR5 expression and the Wnt/β-catenin signaling pathway. Oncology Reports, 34, 2845-2852. https://doi.org/10.3892/or.2015.4290
Miao, J., Jiang, Y., Wang, D., Zhou, J., Fan, C., Jiao, F., Liu, B., Zhang, J., Wang, Y., Zhang, Q."Trichosanthin suppresses the proliferation of glioma cells by inhibiting LGR5 expression and the Wnt/β-catenin signaling pathway". Oncology Reports 34.6 (2015): 2845-2852.
Miao, J., Jiang, Y., Wang, D., Zhou, J., Fan, C., Jiao, F., Liu, B., Zhang, J., Wang, Y., Zhang, Q."Trichosanthin suppresses the proliferation of glioma cells by inhibiting LGR5 expression and the Wnt/β-catenin signaling pathway". Oncology Reports 34, no. 6 (2015): 2845-2852. https://doi.org/10.3892/or.2015.4290


text:
Song Collection
Email about Song Collection
Cathal Pictures
McConnell & O'Connor
CATHAL McCONNELL
I Have Travelled This Country – Songs Of Cathal McConnell
Lughnasa Music ISBN 978-0-9511569-3-3
Compiled by Gerry O'Connor, edited by Sile Boylan
This is a splendid and varied collection of no less than 123 songs from a man whose contribution to the music and song tradition of Ireland is without parallel. Best known as a flute player with Boys Of The Lough, he's also a collector and a fine singer. From the village of Bellanaleck, near Enniskillen, his deep Fermanagh roots are celebrated in this volume by his lifetime friend, Gerry O'Connor of Dundalk. There are also no less than six hours of audio recording here on the enclosed 'computer-only' DVD.
Like a good man, Cathal gives credit to all his song sources, many of these being his own parents, and the current generation of McConnells are, of course, still prominent on the Irish music scene. There are a few very well-known songs here, such as Carrickfergus and Green Grows The Laurel but Cathal follows the tradition and makes them very much his own. The Fermanagh song tradition has produced a vast number of songs based on local characters and incidents, some of them humorous like the adventures of the Second Hand Trousers I Bought In Belcoo, others celebrating local places like the Lovely River Finn and yet more learned from great Ulster singers like Joe Holmes and Eddie Butcher.
This volume is beautifully produced, with introductions by Dave Richardson, a fellow 'Boy of the Lough' for many years, and also the great Ulster singer Len Graham. The book is a wonderful production and a real asset to aspiring singers, but to have the same songs performed by such a master is a real bonus for all of us - the words are one thing, but the interpretation, as Cathal knows well, is quite another.
For those with an interest in the song traditions of Ireland, this book/DVD is very welcome , but for anyone who has been unaware of the songs of Cathal McConnell (quote – "I didn't know I knew so many") I can only say that you have a real treat in store!
www.cathalmcconnell.com
Jim Bainbridge
Review Living Tradition ihavetravelledthiscountry.rtf
cathal mcconnell,

redpajama_set_name: RedPajamaCommonCrawl


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text:
∞ https://oac.cdlib.org/findaid/ark:/13030/c8np27tq/
Guide to the Lou Dunst Collection
Finding Aid Authors: Processed by Bonnie M. Harris, 2008; Laurel Schwartz, 2012.
© Copyright 2015 Special Collections & University Archives. All rights reserved.
5500 Campanile Dr. MC 8050
San Diego, CA, 92182-8050
URL: http://library.sdsu.edu/scua
Email: askscua@mail.sdsu.edu
Guide to the Lou Dunst Collection 1930/2014
Collection Title: Lou Dunst Collection
Bulk Dates: 1999-2014
Identification: MS-0529
Creator: Dunst, Lou
Physical Description: 2.50 linear ft
Repository: Special Collections & University Archives
Lou Dunst, a San Diego businessman, is a Holocaust survivor who was liberated at age nineteen along with his brother, Irving from the Ebensee Concentration Camp in Austria. Mr. Dunst has made it his life's work to educate people, especially young people, about the Holocaust. He uses his personal experiences, which include imprisonment in several concentration camps, the loss of his parents and escaping death on a daily basis. Each year since 1998 he has accompanied Jewish students on the March of the Living in Poland and Israel. He has told his story all over the world, as well as in Southern California. As a guest speaker at schools from elementary to high school to university, from Jewish to secular to Christian, Mr. Dunst has made a great impression on all those who have heard him speak. In 2014, My bargain with God, The Story of Holocaust Survivor Lou Dunst, written by Rabbi Ben Kamin was published and in 2015 a film about Lou Dunst entitled, I Had to Clean My Heart , A Survivor's Story by Robert Schnieder and Alberto Lau was released.
This collection is indexed under the following controlled access subject terms.
Dunst, Lou -- Archives
Topical Term:
Jews -- California -- San Diego
Custodial History:
The materials in this collection were donated to the Jewish Historical Society of San Diego in 2004 by Lou Dunst (#2004.03 ). It was transferred to the San Diego State Unversity Library and Information Access on July 22, 2015.
Accruals:
The first part of the collection was originally donated by Mr. Dunst in July 2004 and consisted of one VHS tape entitled "From the Ashes." Interviewer Judge Norbert Ehrenfreund and Lou Dunst, simulate the Nuremberg Trials as Mr. Dunst describes his Holocaust experiences. Additional items were added October 2009, including correspondence from school students in response to Lou Dunst's presentations about his Holocaust experiences and a DVD of Lou Dunst's 80th Birthday and reunion with his liberator. In November, 2011, Mr. Dunst added correspondence, photos and DVD's regarding the March of the Living, his speaking engagements, correspondence from school children and DVD's regarding his Holocaust experiences.
Conditions Governing Use:
The copyright interests in these materials have not been transferred to San Diego State University. Copyright resides with the creators of materials contained in the collection or their heirs. The nature of historical archival and manuscript collections is such that copyright status may be difficult or even impossible to determine. Requests for permission to publish must be submitted to the Head of Special Collections, San Diego State University, Library and Information Access. When granted, permission is given on behalf of Special Collections as the owner of the physical item and is not intended to include or imply permission of the copyright holder(s), which must also be obtained in order to publish. Materials from our collections are made available for use in research, teaching, and private study. The user must assume full responsibility for any use of the materials, including but not limited to, infringement of copyright and publication rights of reproduced materials.
Conditions Governing Access:
This collection is open for research.
Identification of item, folder title, box number, Lou Dunst Collection, Special Collections and University Archives, Library and Information Access, San Diego State University.
The collection mainly consists of correspondence received from young audiences, who have heard Mr. Dunst speak about his Holocaust experiences. There are also newspaper clippings, photos, videos and DVD's of interviews with Mr. Dunst, including a VHS tape entitled "From the Ashes." Interviewer Judge Norbert Ehrenfreund and Lou Dunst, simulate the Nuremberg Trials as Mr. Dunst describes his Holocaust experiences. The collection also includes a DVD of Lou Dunst's 80th Birthday and reunion with his liberator as well as photos and DVD's regarding the March of the Living and his Holocaust experiences.
Detailed List of Contents
Lou Dunst 80th Birthday Reunion with Liberator
Correspondence - Appreciation: Standley Jr. High, Gompers High School, Beth Israel Day School, Southwestern College 1994-1998
Correspondence - Appreciation: Beth Israel Day School, Stantana High School, Beth Am, Southwestern College 1999, 2005, 2008
Correspondence - Appreciation: Standley Junior High School 1999
Correspondence - Appreciation: Digueño Middle School 1999
Correspondence - Appreciation: school unknown 1999
Correspondence - Appreciation: Santana High School 2000
Correspondence - Appreciation: Valhalla High School, Digueño Middle School 2000
Correspondence - Appreciation: La Jolla Country Day, Digueño Middle School 2000
Correspondence - Appreciation: Standley Middle School 2001
Correspondence - Appreciation: St. John's School, Patrick Henry High School, Bishop's School 1999, 2003
Correspondence - Appreciation: Digueño Middle School, Encinitas 2004
Digueño Middle School Yearbook and Photo Album 2004-2005
Correspondence - Appreciation: Digueño Middle School, Penn Elementary 2006
Correspondence - Appreciation: Digueño Middle School, Encinitas, University City High School 2007
Correspondence - Appreciation: Patrick Henry High School, Digueño Middle School 2008
Correspondence - Appreciation: Umoja Umani Advocacy Program at Oak Park Elementary 2009
Correspondence - Appreciation: St. Augustine High School no date
Correspondence - Appreciation: Miscellaneous 2000
Correspondence - Appreciation: St. Augustine High School 2010
Correspondence - Appreciation: Digueño Middle School, Encinitas 2009-2010
Correspondence - Appreciation: Lakeside Junior High 2010
Correspondence - Appreciation: Marian / Mater Dei Catholic High School 2010
Correspondence - Appreciation: Perkins School (K-8) 2011
El Camino High School Photo Album 2009, 2011
Correspondence - Appreciation: Our Lady of Peace Academy 2010-2011
Correspondence - Appreciation: Olympic View Elementary School 2011
Correspondence - Appreciation: Torrey Pines High School, West Hills High School, Miscellaneous 2009
Correspondence - Appreciation: Barrio Logan College Institute, University of San Diego 2011
Correspondence: Miscellaneous Organizations 1995-2010
Correspondence - Judicial / Legal 2002-2006
March of the Living 2000-2006
March of the Living: Photographs 2004
Articles about Lou Dunst 1996-2010
Autobiographical Interviews 2003-2009
Correspondence - Pre-WWII c. 1930s
Correspondence - Appreciation: From the Ashes (video)
Correspondence - From Dunst 1994-1995
Photographs of Dachau Concentration Camp 1945
My Bargain with God, the Story of Holocaust Survivor Lou Dunst [Book] 2014
DVDs and VHS tape


The mystery of Michael Jackson's children took a further twist as it was claimed that he was not their biological father.
His ex-wife Debbie Rowe gave birth to the singer's two elder children, Prince Michael and Paris, during their three-year marriage. Jackson's youngest child, Prince Michael II, was born to an unnamed surrogate.
The paternity of the children born to Miss Rowe has long been questioned as both are light-skinned, fair-haired and have blue eyes.
It was claimed by TMZ, the celebrity website that broke news of Jackson's death, that a sperm donor was used. It has also been reported in the US media that Miss Rowe was not the biological mother and that she was a surrogate using donated eggs.
However, Miss Rowe's lawyer Marta Almli said the suggestion was "hurtful and insidious". She added: "Ms Rowe is the biological mother of the two eldest children."
On Monday, Jackson's mother, Katherine, 79, was granted temporary custody of the three children and lodged an application to become their legal guardian.
However, if any party were to challenge Mrs Jackson for custody, the ensuing court case could set a legal precedent as the circumstances are believed to be unique.
Jackson is also not thought to have filed legal papers to formally adopt any of his children, which could further complicate the custody situation.
Katherine Jackson said in recently filed court papers that the children have "no relationship with their biological mother".
There were also reports yesterday that Jackson never filed legal papers to adopt any of his children.
In his 2003 interview with Martin Bashir, Jackson said he used "a surrogate mother and my own sperm cells" to conceive his youngest child. "I had my own sperm cells in my other two children. They are all my children," he said.
As rumours swirled around the late entertainer's personal life, arrangements were being made for Jackson's body to return to his former home, Neverland, where fans will be allowed to pay their last respects to the singer, who died last Thursday aged 50.
The hearse will be accompanied to the ranch in Santa Barbara, California, by a 30-strong motorcade. Tens of thousands of fans are expected to line the route on Friday and to queue at the gates of Neverland where a public viewing will be held, according to the website TMZ.com, which broke the news of Jackson's death. A private funeral will take place on Sunday, according to reports last night.
Neverland was closed in 2006 after Jackson failed to keep up payments and the property has fallen into disrepair. Now there is talk of it becoming a money-spinning tourist attraction in the mould of Graceland, Elvis Presley's former home.
Documents from 2007, which came to light yesterday, help to clarify Jackson's tangled finances. They showed that the singer had debts of $331 million (£200 million) but assets of just over $576 million, which left him with a net worth of $236 million.
He also had $668,215 in cash, according to the report, which valued his 50 per cent stake in Sony/ATV Music Publishing at $390 million.


Galli pays close attention to the needs of professionals with its Office Line of furniture. Considering your budget constraint, Galli plan your office space with sketches and 3D blueprints, advise you on your global office lay-out – welcome desk, offices, meeting rooms – and and oversee the installation work. According to surface area and staff numbers, we determine your furniture requirements — style, collection, price, quantity — as well as your needs in partition walls, lighting, flooring, paint schemes, curtains and blinds.


text:
"Hail, Columbia" var, indtil den i 1931 blev erstattet af den offielt udpegede "Star-Spangled Banner", USA's uofficielle nationalmelodi. Den blev oprindelig komponeret af Philip Phile i 1789, til George Washingtons indsættelsesceremoni, under titlen "The President's March", arrangeret med tekst af Joseph Hopkinson i 1798. Den blev brugt af USA som nationalmelodi i størstedelen af det 19. århundrede, men tabte folkelig opbakning efter 1. verdenskrig. Den er nu indgangsmarch for USA's vicepræsident, og for tidligere præsidenter af USA. Den har samme funktion som "Hail to the Chief" er for præsidenten. Når sangen spilles til ære for vicepræsidenten og tidligere præsidenter indledes den altid med fire ruffles and flourishes. Derudover har sangen været brugt som stille-march under militære ceremonier, ofte mens bandet kontramarcherer.

Brug i populærkultur
I horrorfilmen Ravenous fra 1999 er et af åbningstemaerne en fortolkning af "Hail, Columbia" opført af Foster's Social Orchestra, en gruppe af ikke professionelle kunstnere.

Tekst
Hail Columbia, happy land!
Hail, ye heroes, heav'n-born band,
Who fought and bled in freedom's cause,
Who fought and bled in freedom's cause,
And when the storm of war was gone
Enjoy'd the peace your valor won.
Let independence be our boast,
Ever mindful what it cost;
Ever grateful for the prize,
Let its altar reach the skies.ChorusFirm, united let us be,
Rallying round our liberty,
As a band of brothers joined,
Peace and safety we shall find.

Immortal patriots, rise once more,
Defend your rights, defend your shore!
Let no rude foe, with impious hand,
Let no rude foe, with impious hand,
Invade the shrine where sacred lies
Of toil and blood, the well-earned prize,
While off'ring peace, sincere and just,
In Heaven's we place a manly trust,
That truth and justice will prevail,
And every scheme of bondage fail.ChorusFirm, united let us be,
Rallying round our liberty,
As a band of brothers joined,
Peace and safety we shall find.

Behold the chief who now commands,
Once more to serve his country stands.
The rock on which the storm will break,
The rock on which the storm will break,
But armed in virtue, firm, and true,
His hopes are fixed on Heav'n and you.
When hope was sinking in dismay,
When glooms obscured Columbia's day,
His steady mind, from changes free,
Resolved on death or liberty.ChorusFirm, united let us be,
Rallying round our liberty,
As a band of brothers joined,
Peace and safety we shall find.

Sound, sound the trump of fame,
Let Washington's great fame
Ring through the world with loud applause,
Ring through the world with loud applause,
Let ev'ry clime to freedom dear,
Listen with a joyful ear,
With equal skill, with God-like pow'r
He governs in the fearful hour
Of horrid war, or guides with ease
The happier time of honest peace.Chorus'''
Firm, united let us be,
Rallying round our liberty,
As a band of brothers joined,
Peace and safety we shall find.

Se også
 Hail to the Chief

Ekterne kilder/henvisninger
Ruffles and flourishes with "Hail Columbia" (MP3)
 Midi lydfil og tekst.

Amerikanske patriotiske sange

redpajama_set_name: RedPajamaWikipedia


text:
Q: ASP MVC Javascript link to uri I have a ASP.NET MVC web application and have a link that can be either a url or link to a file (network share, location file system)
Here is my html....
link

Here is my jQuery / Javascript......
jQuery('#link_id').live('click', function() {
    var location = jQuery(this).attr('link');
    window.open(location, '_blank');
});

However, I can getting an error when the link is not an web address starting with http://.
Is there a way to accomplish this so I can access web urls AND shared drives?

A: EDIT AFTER COMMENT
First of all, 'link' is not an attribute of  tag, so you can't use it like .attr('link');. I would try something like this:
`
    jQuery('#link_id').live('click', function() {

    var location = jQuery(this).text();
    var httpFoundAt=location.search("http://");
    var httpsFoundAt    =location.search("https://");

        if ((httpFoundAt==-1) && (httpsFoundAt==-1) )
        {
            location='file://' + location;

        }

    window.open(location);
});

You can check for "www" instead of http or https depending on your use case.

redpajama_set_name: RedPajamaStackExchange


I am a freelance social research consultant based in Central London. With a PhD in psychology and over ten research experience in academia, I apply behavioural and social sciences to better understand the psychological and social dimensions of transport and the environment. I am experienced in both qualitative and quantitative research techniques, often employing a mixed methods approach to data collection and analysis. I have experience working on multi-disciplinary research projects, and value the connecting of research, policy and practice.
I am available on a project-by-project basis for short and long-term works. Able to support projects at all stages of the research process: design; data collection, data input and data analysis; write reports and deliver other project outputs. I can also offer support for research proposals and grant bidding; and stakeholder and public engagement.


Mobile service businesses and contractors that manage customers, schedule jobs for employees, and create estimates/invoices for customers.
Preisinformationen Per user per month based on user role.
FieldPulse is your business hub, helping you run your mobile service or contracting business. Because you work in the office and on-the-go, FieldPulse is available on iOS, Android, and the web.
Scheduling, Customer Management, Estimates/Invoicing, Digital Payments, Timesheets, GPS-location tracking, and more.
FieldPulse gives you the tools to build your business by cutting down on paperwork, making your team more efficient, and building better relationships with your customers.
Awesome app for a company!
Kommentare: We went virtually paperless for our timesheets, and job sheets. This also helped us track our employees and their hours much easier, as well as account for their time on each job.
Vorteile: Ease of use is definitely a big one. It took no time to figure out what you were doing, and set up everything in there that you needed.
Features is pretty extensive. We have tried other apps (cheaper ones) and found that they didn't really work for our company. We didn't need the full construction app like BuilderTrend, and needed something a bit more than for service calls, and this was the perfect in the middle app!
Quality is pretty good! Has its own couple glitches, but customer service takes care of them right away!
Previously, we had a system of all paper and had a gap in our communication on the jobs and such. This app helped us go virtually paperless in our timesheets, and job sheets because now everything is accessible to our users on their phones. The amount of data that it takes is next to nothing, which was a concern of our employees.
Nachteile: It is a bit slow at times uploading and updating your lists, especially if you have a larger list.
Vorteile: By far, the best thing about FieldPulse is their customer service. It feels like they are more business partners sometimes, going above and beyond to tweak and improve their product to make my business run smoother and more efficiently.
Nachteile: Only thing I wish I could do is create custom customer statuses (categories). ex, 2017 customers, 2018 customers, ect. They kind of did this by creating customer tags, but it's not the same.


text:
The Western Front Association remembers those who served and died or survived during the First World War.
11 February 1889 MacGregor VC, Canada's most highly decorated sol…
John MacGregor was born on 11 February 1889 at Cawdor in the County of Nairnshire and was the third child of William and…
23 August 1914 : Serg-farrier Frans Raymond Paqué
Born on 1 May 1884 in Dendermonde (Belgium), a small town outside of Brussels to parents Jozef (Joseph) Leopold Paque an…
26 August 1914 : Lt Sir Robert Cornwallis Maude, 6th Viscount Haw…
Robert Cornwallis Maude, 6th Viscount Hawarden was born on 6 September 1890. He was the son of Robert Henry Maude, 5th …
1 September 1914 : 2nd Lt George Edward Cecil
The son of Lord and Lady Edward Cecil. He had a lifelong ambition to soldier. After Winchester College (1909-12) he pas…
14 September 1914 : Pte Ernest Scott
Ernest was a warehouseman at Spring Mills at Wheatley Lane near Burnley prior to the outbreak of war. A pre-war reservis…
16 September 1914 : Sdt 2e Cl Marius Labruyere, 158 RI
Born at Roanne, Loire on 13 December 1893, Marius' home address was in that town (at 146, Rue Fontalon). He was called …
20 September 1914 : 2nd Lieut. Roger Marshall
The youngest son of five children of parents Anthony and Jessie Marshall of Annstead Farm, Chathill, Northumberland. …
9 October 1914 : Lieutenant Colonel Aymer Edward Maxwell
Educated at Eton and the Royal Military Academy Sandhurst. HE was a JP, DL and County Councillor for Wigtownshire and a …
15 October 1914 : Pte Arthur William Heptinstall
Parents James (a joiner) and Ann Heptinstall. Arthur was the seventh of their children born between 1864 and 1878. Art…
17 October 1914 : 146 Cpl Emilien Leger, 99e RI.
From Ste Denis de Cabanne, Emilien was called up for his compulsory military service in 1909, he was an active army rese…
18 October 1914 : Larrett Roebuck
By 1901 the Roebuck family had moved to Rotherham and were living in Barker's Yard, off the main High Street, where he s…
22 October 1914 : Lt Henry Noel Atkinson DSO
Henry was the son of the Reverend Arthur Atkinson,Canon of Chester Cathedral, and Ursula Mary Atkinson (née Cotton-Jodre…


text:
Submit your innovation
Select a campaign for your innovation
Other innovations
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SME Innovation fund
Are you a start-up or a small medium sized enterprise working in the space of delivering improved healthcare? Do you have the potential to change how healthcare is delivered? The SME Innovation Fund can provide the support you need to help your business grow.
See Additional Info
Mercia Fund Management (MFM), a leading investment business is collaborating with the West Midlands Academic Health Science Network (WMAHSN) to help build and support healthcare businesses across the West Midlands.
This round of the SME Innovation Fund is joint with MidTECH Innovations. MidTECH Innovations is the NHS Innovation Hub for the West Midlands region and a partner of the WMAHSN. MidTECH works as the technology transfer department for the NHS in the region.
The SME Innovation Fund will provide investment and provide excellent links to the NHS, investment community and academic networks. In doing so the fund will support innovations that have the potential to deliver a high impact for society, grow the reputation of the West Midlands health services and lead the adoption of new innovations in the NHS.
Successful applicants will get:
Convertible loans of up to £50,000
Unparalleled access to future investment capital
Regular mentor workshops from industry experts including experienced life sciences entrepreneurs.
Key contacts in the NHS and healthcare sectors
A requirement of this fund is that there must be a collaboration between the applicant and a West Midlands NHS organisation. If you are unsure of this please contact us for further information.
Mercia has a strong track record of financially supporting and building life science businesses across the UK, all of which provide a scalable and innovative way of streamlining services, improving patient safety and releasing the burden of cost on the NHS. The fund will be led by Peter Dines, Investment Director and Head of Life Sciences at Mercia.
The fund has supported 10 companies to grow to date and we now have funds available to invest into a new venture. Examples of the success stories can be found in our annual report.
To apply please 'Submit your innovation' to the campaign or contact us directly as we are here to help with your application and welcome the opportunity to talk to you about your requirements. Please contact Lucy Chatwin at lucy.chatwin@wmahsn.org for further information.
Tammy Holmes
This campaign is now completely closed. You can view the status of all Innovations and the results of their evaluation & review.
39Innovations
16Votes
Submit Innovation
Heart DNA test (#2199)
Long term conditions: a whole system, person-centred approachAdvanced diagnostics, genomics and precision medicineWellness and prevention of illnessEducation, training and future workforceWealth creationDigital healthInnovation and adoptionPatient and medicines safetyPerson centred care
Idea Description
Detailed Submission Data
Innovation 'Elevator Pitch':
Heart DNA is a genetic testing kit for patients at increased risk of developing atrial fibrillation and other cardiovascular diseases, the results are reviewed and assessed by a consultant who is well informed about the patient's medical history.
Overview of Innovation:
"Heart DNA" is a genetic testing service for patients at increased risk of developing cardiovascular diseases and for cardiologists and genetic counseling officers/geneticists who would want to work with us in delivering this service to the public.
We are partnering with healthcare professionals who will review (online) the genotyping reports coming from our well established partner lab and will be giving their health assessment based on both: the patient's health profile/medical record, which our users will be asked to fill in early on our website, and on the genetic predispositions that may be found in the patients DNA. In esssence, our consultants will be able to give an informed screening assessment that covers: the detection of inherited conditions and an assessment to the patients' response to certain drugs that may well be administered to treat CVDs.
Heart DNA is a simple saliva-based test that is supported by scientifically validated research and an extensive amount of studies. Heart DNA analyses the patient's unique genetic markers, which influence a broad range of heart-related conditions, our gene panel list consistc of 96 markers that cover: Atrial Fibrillation, Coronary Artery Disease, Myocardial Infraction, Cholesterol levels, and risks for hypertension. It can also help identify a patient's propensity for increased risk towards certain heart medications, eight classes of drugs that affect the cardiovascular system are examined; anti-platelets, anti-coagulants, statins, stimulants, beta-blockers, ACE inhibitors, calcium channel blockers and hormone therapies.
Our test provides information that allows Doctors to;
1. Monitor a patient's specific health conditions thoroughly.
2. Prescribe a more optimal medication and dosage for a patient.
3. Suggest early lifestyle and diet interventions to help combat and prevent certain heart conditions.
Overall, the aim is to enable doctors and patients to bridge the gap in genetic information that has proved over an extensive amount of studies and research to be pivotal in the design of better prevention and treatments regimens. Our focus is to cause a change in the architecture of complex care routines that would address the challenges of working at scale, and which can capitalize on the associated opportunities that we will enable by striking business partnerships with medical consultants to create and deliver a distinctive competitive advantage over all competing genetic testing companies.
Stage of Development:
Trial stage - Trial stage to prove that the idea actually works as intended
Benefit to NHS:
DNA testing is not available at the point of care, regardless of its imperative potential to mitigate treatment regimens and enhance disease prevention pathways. Moreover, once an individual is diagnosed as having a cardiovascular condition, the challenge exist in prescribing the right medication at the right dose in the right time.
Tools promoting optimal direction for healthcare service and moving patients towards the digital space will be hugely disruptive in a market where faster processes and cheaper costs are imperative to its evolution. Products that can enhance the working process inside GPs offices and provide more rapid, reliable and robust diagnosis decisions within primary care, that could enhance workflow for healthcare professionals, assisting earlier triage and potentially redesigning GP care pathways; such products have the potential to save the healthcare and biotech industries over £1bn every year, just in labour time.
The current pathway to obtain a genetic test for a single cardiac condition through the NHS is lengthy, complex, costy and is not accessible for everyone; with multiple visits and referrals to see healthcare specialsits (Annex; Figure 1).
Our system workflow has been designed to empower patients within an innovative framework, that ensures having a certified partner cardiologist assessing their health condition before a patient can receive his/her genotyping results. It will also ensure that patients and doctors have an easy access for booking appointments to follow up, when the need is present. Our comprehensive service will cut down the turn around time from several months to 2 weeks with as little steps as the figure shows (Annex; Figure 2).
Moreover, our database will later provide an electronic medical record through which other healthcare consultants can opt to review when they need to access the patient's genotype before prescribing a certain drug at any stage of the patient's life. Thus, cutting down the path of trial and error before the the right medication is prescribed to the patient.
Early screening for genetic predispositions and having an early risk assessment for patients who may develop Atrial Fibrillation or any other CVD will significantly allow the NHS enhance its' treatment regimen for the general public and prevent high risk individuals from becoming patients. Thus, causing a substantial reduction in the £15bn bill of CVDs every year (BHF stats 2015).
Benefit to WM population:
The major risk factor associated with Atrial Fibrillation and all other CVDs is having a family history with the disease. By family history we are referring to the genes that have passed from the parents to their offspring, which (if found to be mutated as well) can increase the risks of that individual developing the same disease.
While it is well accepted that such risk factor could not be changed or adjusted (at least for the time being), hence the term "non-modifiable" risk factor, it is also accepted that if such risk is detected then the patient would be better positioned to manage the other "modifiable" risk factors early on, which can significantly change the course of the patient's life and the development course of his/her inherited condition.
We believe that well informed and educated individuals about their risk factors will allow them take better decisions and have more enlightened judgments when it comes to managing their risks and altering their lifestyle and daily habits. Modifiable factor like quite smoking, being fit, eating healthy and managing diabetes, obesity and cholesterol levels, are all found to be imperative in managing AF and other CVDs from an early stage; the earlier the intervention, the better the outcome.
Moreover, we believe the greatest benefit to the WM population will come at a later stage through our Data Bank which will provide the perfect reference tool to better direct prevention and treatment regimens withihn the WM population, risk factors such as race, age and sex will all be considered in the future direction of our research through our advanced and precise person-centerd system.
Current and planned activity:
Business partnerships have all been established for the development and delivery of our product/service. Funding is currenly sought to finance our outsourcing agreements:
Genotyping analysis will be conducted at a well established genotyping lab in the UK.
Our saliva collection kits will be outsourced from a supplier in the UK.
Our service content is all in place and the gene panel list has been put together through an extensive amount of well researched and accredited reference genetic testing studies, the online platform will be developed by website developement agency in Birmingham.
Our box and packaging have been designed and the order is to be placed.
An initial agreement has been established with a reputable cardiologist consultant to review the patients results and put his recommendations to each genotyping report being assessed.
A pilot study is currently being desinged by our Medical and Research Officers (both are GPs at the QE hospital).
What is the intellectual property status of your innovation?:
The company will be developing additional patents and intellectual property related to response and side effect prediction for further treatments of hypertension and other Cardiovascular disorders through its DTC kits and the databank that it will generate from its lab based genotyping services. These will be offered to the BHF and all other concerned research groups in the field of Cardiac Health.
In terms of our regulatory path, there are no specific regulations outside consumer protection, data storage, and for storing biological samples "saliva" we will apply control regs that deal directly with this.
Return on Investment (£ Value):
Return on Investment (Timescale):
Ease of scalability:
Detailed Submission
Regional Scalability:
Please refer to our commercial information section (Business Strategy)
Measurement of outcomes
We are here to help; we believe that we have a relevant and compelling solution that (if adopted) can save lives and enhance the prevention and treatment regimens for patients with cardiovascular conditions.
We will measure our performance based on the value that we are delivering. Hence, by the end of year one we are looking to exceed the 1000 kits sale and have a strong clinical data that would support our proposition, in regards to giving patients better options to mitigate their risk factors and to healthcare professionals to administer drugs that are better suited for certain subpopulations; based on genetic makeup and the health profile "environmental factors" for each individual patient.
These assessments will be made through our end of year statistical study that we will run on all patients whom we have tested.
Adoption target:
The adoption target is to demonstrate a successful, valuable and cost efficient systematic framework that would address the core objectives of the NHS Sustainability and Transformation Plans in drving a genuine chnage to patients experience and health outcomes of the longer term.
Similar Content3
WMAHSN priorities and themes addressed:
Long term conditions: a whole system, person-centred approach / Advanced diagnostics, genomics and precision medicine / Wellness and prevention of illness / Digital health / Patient and medicines safety / Person centred care
Early screening for genetic predispositions and having an early risk assessment for patients who may develop Arterial Fibrillation or any other CVD will significantly allow the NHS mitigate prevention regimen for the general public before they become patients. Thus, signinficantly reducing the £15bn bill of CVDs every year (BHF stats 2015).
Initial Review Rating
4.20 (1 ratings)
We believe that well informed and educated individuals about their risk factors will allow them take better decisions and have more enlightened judgments when it comes to managing their risk factors and altering their lifestyle and daily habits. Modifiable factor like quite smoking, being fit, eating healthy and managing diabetes, obesity and cholesterol levels, are all found to be imperative in managing AF and other CVDs from an early stage, the earlier the intervention, the better the outcome.
Moreover, we believe the greatest benefit to the WM population will come at a later stage through our Data Bank which will provide the perfect reference tool to better direct prevention and treatment regimens withihn the WM population, risk factors such as race, age and sex will all be considered in the future direction towards an advanced and precise person-centerd system.
A pilot study is currently being designed by our Medical and Research Officers (both are GPs at the QE hospital).
We are here to help; we believe that we have a relevant and compelling solution that (if adopted) can save lives and enhance the prevention and treatment regimens for patients with cardiovascular conditions.
These assessments will be made through our end of year statistical study that we will run on all the patients whom we have tested.
Strannick Technology-medical screening technology (#1943)
A medical screening technology based on a mathematical model of the autonomic nervous system & physiological systems which has significant potential to improve the cost-effectiveness of primary care
Strannik technology is based upon a mathematical model of the autonomic nervous system and physiological systems. It meets the key aims and objectives of the EC's Human Brain Project: (i) to identify what the brain does and how it does it, (ii) to develop a new generation of cognitively-based screening technology, (iii) to understand and adapt with therapeutic effect the multi-level nature of brain function. This is quite without precedent in modern medicine. The Strannik technology comprises Strannik Virtual Scanning (SVS) and Strannik Light Therapy (SLT).
The technique can be viewed in a demonstration video at the following link: www.montaguehealthcare.co.uk/presentation.php
SVS is a screening technology which has an unprecedented ability to determine the health of the patient i.e. it is able to determine 5-15 pathologies in each of the 30 main organs (including medical conditions for which the current tests are poor or for which there is currently an unmet clinical need), to differentiate between and quantify the extent of the genotype and phenotype in each pathology, and to determine the earliest onset of each pathology from its presymptomatic origins. The technique adopts a methodology more advanced than is currently used in most diagnostic technologies. It is non-invasive and more safe than contemporary diagnostic tests. The results are available in circa 20 minutes at a cost which is estimated to be 5-10 times lower than contemporary diagnostic tests. It presents the opportunity to screen the entire UK population once (or twice) each year for less than £5BN (est £3-4BN) and to reduce the cost of healthcare by an estimated £20BN pa.
(See Operating Manual: www.montaguehealthcare.co.uk/OperatingManual.pdf)
The basic methodology, and the scope of this technology, is outlined in a series of 60 peer-reviewed medical papers.
(uk.linkedin.com/pub/graham-ewing/44/386/214)
Market ready and adopted - Fully proven, commercially deployable, market ready and already adopted in some areas (in a different region or sector)
Long term conditions: a whole system, person-centred approach / Advanced diagnostics, genomics and precision medicine / Wellness and prevention of illness / Clinical trials and evidence / Digital health / Innovation and adoption / Person centred care
Strannik Virtual Scanning is able to determine all common pathologies in a single test of 20 minutes duration. In-market surveillance has indicated that SVS appears to be circa 2-23% more precise than contemporary methods of diagnosis. A recent non-clinical study in Spain (10/16) illustrated that the technology was able to determine all known medical conditions in the cohort of (20) patients.
Using the data derived from this cognitive, computer-based, test the technique determines the precise parameters of Strannik Light Therapy -which acts upon autonomic dysfunction, and (across a wide range of medical indications) appears to be typically 83-96% effective. This compares with the 50% effectiveness of drugs and also that the effectiveness of many drugs declines over a period.
reduce the flow of patients into the healthcare system;
reduce the cost and complexity of training the GP
improve the ability of the GP to identify complex medical conditions, reduce the need for repeat consultations, and/or avoid doctor errors
reduce the need for histopathology samples (nurses, rubber gloves, sampling tubes, transport costs, histopathology lab costs)
reduce expenditure in secondary care i.e. for highly expensive scans and tests;
provide health reports and increase the ability for patients to have a clear understanding of their health and assume responsibility for their health i.e. change the focus of medicine from treating the symptoms to prevention
regularly screen the health of the most at-risk patients thereby reducing the need for A&E services
improve the accuracy of drug prescribing thereby avoiding mis-prescribing of drugs
reduce the need for drugs
reduce the overall cost of healthcare by an estimated £20BN pa
"I have to hand it to you. You have correctly and in precise detail identified the five or six major items which are known to be of concern to me". Dr John Doran, Medical Director, Nottingham's Queens Medical Center, November 2003.
Support patients to obtain an early diagnosis to seek timely treatment.
Mimix Montague Healthcare is actively seeking NHS partnerships to move forward Strannik Technology. Evaluation and trials have been conducted in other countries (Russia and Spain) and a collaboration within the UK is currently being sought.
Procurement / Adoption of Strannick Technology within NHS Trusts
Evaluation / Validation / Clinical Trial - Need to gain additional validation seeking a trial centre.
Project Assistance required - The Company's development project is interested in locating possible clinical / academic collaborators.
software/copyright
The technology is immediately scaleable. In theory, and as an indication of scaleability, we could train 1000 practitioners to use Strannik technology within 4 weeks.
Strannik Virtual Scanning is unique for a number of very good reasons e.g. (i) that it can determine pathological onset from its presymptomatic origins, (ii) it can determine the full spectrum of pathologies in all organs and not just a single biomarker, (iii) it can determine genotype and phenotype, and (iv) it can determine many conditions where there is currently an unmet clinical need. Further studies are required to illustrate how such a sophisticated technology will complement the current range of biomarker tests which are generally used in clinical practice. The technique is non-invasive and has a base cost of circa £15/test thereby addressing safety and cost. The procedure is entirely non-invasive which significantly enhances the patient experience, often experienced as 'a pleasure'.
Strannik Light Therapy is based upon an understanding of how the brain regulates the autonomic nervous system. A comparison of Strannik Light Therapy with contemporary methods of treating patients is likely to enhance the patient experience, result in significantly reduced side-effects, and will be at very much lower cost.
Success will be measured by reduced number of patient consultations, lower cost of diagnosing and treating patients.
Our aim is to secure the introduction of Strannik technology to every primary care practice
Rejection Reason:
Dear Mr Ewing Thank you very much for your submission to the Meridian Innovation Health Exchange. I can confirm that we have now reviewed your submission and i regret to inform you that we have not been able to identify any clinical champions for this project. While I appreciate that Strannick are looking for support on the evaluation/evidence side, feedback from clinical / academic colleagues has not been positive and therefore we have done everything possible to engage but the appetite isn't there unfortunately. Given that our network is not focussed in exploring this area at this time we will therefore close your idea leaving it visible to our Meridian users. We wish you luck with your innovation. Regards The Meridian Team
Smartphone enabled urinalysis (#2840)
Dip.io, a CE approved product turns the smartphone into a clinical grade device enabling lay-users to test urine in their own home, with clinical accuracy and share results electronically with their clinician.
42m urine tests a year are undertaken in the NHS to screen for a wide range of conditions. Currently patients collect a sample at home and bring it to the clinic or provide a sample in the clinic where it is either tested on site or sent to a laboratory. This is inefficient, inconvenient for the patient and presents opportunity for improvement in patient experience, clinical quality and cost efficiency.
Healthy.io is the first company to turn the smartphone into a regulatory-approved clinical device. Its first product, Dip.io, uses computer vision and user centric design to turn the smartphone into a urinalysis device. Built around existing semi-quantitative urinalysis dipsticks, Dip.io complements established clinical efforts by empowering patients to test themselves at home with no quality compromise, and securely share results with a clinician.
Healthy.io is empowering patients to take urine testing into their own hands, opening up an immense opportunity to improve preventive efforts and enable early interventions. Key pathways in which digital urinalysis has strong potential to improve patients' lives and reduce cost to the NHS:
Antenatal care: women with hypertension or diabetes in pregnancy have a higher risk of developing pre-eclampsia, a leading cause of maternity morbidity. Dip.io has proven through a usability study at Johns Hopkins to improve women's experience and could reduce outpatient appointments amongst high risk pregnant women.
Chronic Kidney Disease (CKD): Home-based screening of albumin:creatinine (ACR) for people with diabetes or high blood pressure, to increase adherence to NICE CG 182 and diabetes care process beyond the current level of 50%.
Urinary tract infections (UTI): opportunity to improve self-management for patients at risk of admission from UTI (e.g. MS), reduce the 5m GP attendances for UTI in primary care and create digital pathways for pre-op assessment through using digital urine testing, within existing clinical guidelines.
Long term conditions: a whole system, person-centred approach / Digital health / Innovation and adoption / Person centred care
Benefits to NHS in line with FYFV:
Maternity Safety (Proteinuria screening): The Maternity Transformation Programme (Better Births) prioritises improvement in maternity safety and provision of consistent quality. This includes halving the rates of stillbirths, neonatal and maternal deaths by 2025. Around 15% of women with hypertension or diabetes in pregnancy have a higher risk of developing pre-eclampsia, a leading cause of maternity morbidity. Automated home-screening for proteinuria in at-risk pregnancies has the potential to early identify pre-eclampsia, save £1,500 for each avoided false negative, save up to £75m by reducing 60% of outpatient appointments (3rd trimester) and reduce antenatal consultation time by 25%.
Primary Care (Diabetes and CKD screening): Smartphone enabled self-testing offers a critical complement to existing population health efforts by shifting testing from primary care to the home. Providing alternatives to face-to-face contact frees up GP resources and nursing time. NICE recommends that every person at increased risk of CKD (people with diabetes or hypertension) needs to annually get their urine tested. However only 50% of people with diabetes and 30% of people with hypertension have a regular urine test reported. Over 1 million cases of CKD remain undetected. Diffusing Dip.io to every at risk patient (8.3m) could improve adherence with no additional overhead, reducing CKD cost by up to £1bn.
Urgent and Emergency Care (Urinary Tract Infection): Conducting common diagnostic tests at the patient's home supports "improving the ability of patients to self-care for minor illnesses" (UECR). This includes the need to anticipate recurring conditions such as UTIs. 1-3% of GP visits are UTI related and UTIs accounted for 14% of emergency hospital admissions in MS patients costing the NHS over £43 million. Dip.io offers the opportunity to improve self-management for patients at risk of admission from UTI, reduce the 5m GP attendances for UTI in primary care and create digital pathways for preop assessment within existing clinical guidelines.
Harnessing technology and innovation: Our solution leverages existing technology to transform care delivery and supports the drive to digital adoption. We easily integrate into other technologies (integrated with PKB and Allscripts) and make sure interoperability is built in. We are replicating this model for our next product to bring innovation to woundcare management.
Our smartphone-enabled digital urinalysis service aims to improve quality and efficiency of existing pathways, driving better patient outcomes and experience.
Main benefits:
Maternity safety: women with hypertension or diabetes in pregnancy have a higher risk of developing pre-eclampsia, a leading cause of maternity morbidity. NICE CG62 recommends dipstick urinalysis during each prenatal visit to screen for proteinuria, an indicator of pre-eclampsia. Increasing testing in between regular pre-natal visits could reduce Pre-eclampsia complications. Women with at-risk pregnancies receive 7-10 Dip.io kits. Following a defined frequency, the women conducts the test at home. The clinician automatically receives the results and is alerted if results are abnormal for immediate follow-up care. This model of care is being rolled out across mayor HMOs in Israel and received more than 90% preference in a Johns Hopkins usability study. Dip.io has proven to improve women's experience and could reduce outpatient appointments amongst high risk pregnant women.
Diabetes and CKD screening: NICE clinical guidelines recommend people with diabetes/hypertension need to get their urine tested annually but adherence is low e.g. only 51% of people with type 1 diabetes tested. Digital testing could improve adherence and reduce costs. Patients with no recorded albumin reading receive our smartphone urinalysis home-test. Results are immediately available to the clinician and those with abnormal results are invited to a follow-up extensive checkup. This model makes it possible to reach people at risk, who have not received appropriate testing, thus increasing adherence to CKD screening.
Urinary Tract Infection (UTI): opportunity to improve self-management for patients at risk of admission from UTI (e.g.MS), reduce the 5m GP attendances for UTI in primary care and create digital pathways for preop assessment through using digital urine testing, within existing clinical guidelines.
NHS:
North East and North Cumbria AHSN with South Tees NHS Trust to test renal clinic at home funded by Northern Counties Kidney Foundation
NeuroResponse social enterprise based at UCL on Multiple Sclerosis pathway
Modality and Yorkshire and Humber AHSN to test diabetes/CKD screening model
Howbeck Healthcare to test rollout diabetes/hypertension/CKD screening model in South Cheshire and Vale Royal
Salford NHS Trust rollout for renal patient management
Care UK rollout for uncomplicated UTI management
Applied to the Test beds, have been invited to the follow-up meeting for at risk pregnancy, UTI and renal models
Usability study in pregnant women at Johns Hopkins with 92% favourability (soon to be published)
US National Kidney Federation and Geisinger Health to improve care for people with hypertension
Dutch Kidney Foundation and Dutch Health to test population screening for ACR in at risk population compared to other method
Rolling out in two HMOs in Israel for at-risk pregnancy model
Our plan is to scale regionally and nationally through a B2B2C business model. We offer several commercial packages that differ in terms of scale, level of integration, agreement timeline and distribution/shipment method. This allows us to partner with different players within the NHS to provide them full digital capabilities through customised, white label kits, a localised application and access to our algorithm in an end-to-end service proposition. Our vision is to serve as the backbone for smartphone enabled, image based medical diagnostics and enable partners to bring our innovation to their existing user base.
Healthy.io and the Dip.io solution work together with healthcare organizations to improve efficiency, value and outcomes by digitizing existing pathways. Measure include:
Save outpatient appointment and reduce consultation time to reduce resource pressures.
Increase clinical guideline adherence, improving patient safety
Improve patient experience (e.g. minimise absence from work and avoid travel expenses)
Start with a phased roll out to try, test and scale the innovation in a regional NHS organisation. We anticipate that success from this roll out will lead to spreading the implementation of the technology to other specialties within the organisation, other hospitals/GPs within the group and to other providers and partners within the WM area.
Abdullah Sabyah
On 30/11/2016 - 10:18
Copyright © 2020 WMAHSN


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Home Sri Lanka FM Royal 90.1/107.3
FM Royal 90.1/107.3
FM Royal is a broadcasting radio channel situated in Colombo, Sri Lanka. It belongs to the Media unit and the Radio Club of the Royal College. It on-airs its transmission by using 90.1 / 107.3 MHz frequency in the English, Sinhala, and Tamil languages. Its programs based on education, information, and awareness shows about different academic and daily life topics. It has many achievements in the radio industry, such as in 1995 it provided the services for South Asian Games and in 2000 it offered live transmission of the Bradby Shield Encounter. In 2005, it introduced webcasts and became the first station that on-air transmission 24 hours a day. In 2014, it spread its transmission worldwide through mobile apps and covered the areas of three major cities: Colombo, Kandy, and Galle. It provides unique and quality transmission with the slogan of "The Right Royal Way."
FM Derana 92.2 / 92.4
Address: Royal College, Colombo
Contact Number: +94 74 065 8123
Official Website: https://www.fmroyal.com/
Facebook: https://web.facebook.com/fmroyal.royalcollege
Twitter: http://twitter.com/fmroyal
More to Listen:
Hiru FM LK
Shakthi FM 103.9/104.1
SLBC Tamil
E FM 88.3
Everlasting Radio FM 97


at the Borrowdale Country Club, Carrick Creagh Road, Helensvale.
Every Sunday the club has a roast lunch or braai which is very popular.
Activities at the club include tennis, lawn bowls, pool, billiards, horse jumping, dressage and polocrosse.
Booking essential for all functions except quiz nights.
Manager Kevin Meyer 0782 635742.


There has been a very serious accident In Old Malden Lane this morning, just after 11:00. A 39 year old woman was jogging along the road when she was hit by a van head on. The van, apparently a black Primastar Nissan van, was overtaking and must not have seen her on the other side of the road.
She was taken by air ambulance to St George's in critical condition.
Old Malden Lane is currently closed between the junctions with Cromwell Lane and Barrow Hill with officers carry out investigations.
A man in his 30s has been arrested on suspicion of dangerous driving and is currently in custody awaiting interview.
The blog wishes the young girl every hope for a recovery.
It is perhaps time to consider making this road safer for pedestrians. Several people have asked about putting in a footpath. Surely this can be done, especially if it will help avoid accidents like this one.