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Purpose We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor development, which mutations confer MK-2206 level of sensitivity. cells improved Akt phosphorylation concordant with an increase of MK-2206 sensitivity. Steady transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breasts cells improved MK-2206 level of sensitivity. Cell lines which were much less delicate to MK-2206 experienced lower ratios of Akt1/Akt2 and experienced much less development inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breasts malignancy xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor development. mutation, providing a technique for individual enrichment in medical trials. Intro PI3K/Akt/mTOR signaling performs key functions in cell development, proteins translation, autophagy, rate of metabolism, and cell success (1). Activation of Akt signaling plays a part in the pathogenesis of malignancy. is mutated in lots of tumor types, and PTEN manifestation is decreased in lots of malignancies, including sporadic breasts malignancy. Mutations in the gene, which encodes the catalytic subunit of PI3K, have already been reported in lots of malignancy types, and happen in a lot more than 20% of breasts malignancies (2). Although questionable, breasts cancers with an elevated degree of Akt phosphorylation/activation or a gene manifestation signature of reduction have been suggested to truly have a poor end result (3). Although mutations never have been uniformly connected with activation of Akt signaling in individual tumors (2, 4), many mutations have already been shown to possess a gain-of function, resulting in a rise in Akt phosphorylation in preclinical versions (5, 6). The prevailing preclinical data claim that most tumors expressing a minimal degree of PTEN and several having a mutant PIK3CA depend on Akt for oncogenic signaling. Lack of PTEN activity and activation of phosphatidylinositol 3-kinase (PI3K) signaling are connected with level of resistance to endocrine therapy (7, 8), and level 130-61-0 manufacture of resistance to trastuzumab (9C11). Therefore, Akt is an extremely promising focus on for breasts tumor therapy. MK-2206 (Merck Oncology) is definitely a book selective allosteric inhibitor of Akt. Stage II clinical tests of MK-2206 possess begun for the treating a number of tumor types, including breasts cancer. Thus, there's a pressing have to better understand the antitumor effectiveness of this book substance, both when utilized only and in mixture regimens, also to define markers that forecast reap the benefits of this agent. We wanted to look for the antitumor effectiveness of MK-2206 in breasts tumor cell lines with differing hereditary backgrounds. Our data display that MK-2206 inhibited Akt signaling and cell-cycle development, and improved apoptosis inside a dose-dependent way. MK-2206 level of sensitivity was significantly higher in cell 130-61-0 manufacture lines with PTEN reduction or mutation. In MK-2206Cdelicate cells, MK-2206 was synergistic with paclitaxel. MK-2206 also experienced a dose-dependent growth-inhibitory impact research and most research. research in BT474 and MCF7 had been executed with MK-2206 created in-house. For tests, 30% Captisol (CYDEX Pharmaceuticals) was utilized as a car. Rapamycin was bought from LC Laboratories, Inc. Cell development assay Antiproliferative activity was examined by sulforhodamine B (SRB) assay (12). The median inhibitory focus (IC50) Slc7a7 and mixture index (CI) had been driven from dose-response curves for 4 times treatment (13). Cell-cycle evaluation and annexin V binding assay For cell routine assay, cells which were mounted on the petridish and floating cells had been collected. Samples had been analyzed by stream cytometry and ModFit LT software program (Verity Software Home). Apoptosis was discovered utilizing the annexin V apoptosis package (Roche) based on the producers process, and cells had been analyzed by stream cytometry and FlowJo (Tree Superstar; 13). siRNA siRNA duplexes (Sigma) had been utilized to silence PTEN (14). Detrimental control siRNA was bought from Life Technology Co. Akt1-, 130-61-0 manufacture Akt2-, and Akt3-particular siRNA pool, non-targeting pool siRNA, and DharmaFECT transfection reagent had been bought from Thermo Fisher Scientific, Inc. Reverse-phase proteins arrays Reverse-phase proteins array (RPPA) evaluation was executed as defined previously (15C17). Cell lines had been treated with MK-2206 (50 nmol/L, 150 nmol/L, 500 nmol/L, 130-61-0 manufacture and 5 mol/L) or 0.1% dimethyl sulfoxide (DMSO) every day and night..
Category: Cell Cycle
Background Sufferers with pulmonary arterial hypertension (PAH) are treated with vasodilators,
Background Sufferers with pulmonary arterial hypertension (PAH) are treated with vasodilators, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylyl cyclase activators, and prostacyclin. (ETA) antagonist, ambrisentan (AMB), or a combined mix of TAD and AMB for four extra weeks. Outcomes Monotherapy with TAD or AMB resulted in humble reductions in pulmonary arterial pressure (PAP) and correct ventricular (RV) hypertrophy. On the other hand, echocardiography and intrusive hemodynamic measurements revealed that mixed TAD/AMB nearly totally reversed pulmonary hemodynamic impairment, RV hypertrophy, and RV useful deficit in SU-Hx rats. Efficiency of TAD/AMB was connected with dramatic reductions in pulmonary vascular redecorating, including suppression of endothelial cell plexiform lesions, which are normal in individual PAH. Conclusions Mixed therapy with two vasodilators that are accepted for the treating individual PAH provides unparalleled efficiency in the rat SU-Hx preclinical style of serious, angioproliferative PAH. research, GraphPad Prism software program was used to create graphs and analyze data. ANOVA with Bonferronis post-test (gene promoter harbors 15 NFAT binding sites (Amount?1E) [18]. As proven in Amount?1F, calcineurin activity (seeing that measured by RCAN1 appearance) was dramatically elevated in RVs of SU-Hx rats and had not been significantly altered by TAD or AMB treatment, which is in keeping with the minimal ramifications of these substances on RV hypertrophy (Amount?1D). Mixed PDE-5 and ETA inhibition reverses pulmonary hemodynamic impairment and RV hypertrophy in SU-Hx rats We following searched for to determine whether concurrently concentrating on PDE-5 and ETA would offer superior efficiency over monotherapy with either substance. For these research, the power of mixed TAD/AMB to change pre-existing PAH and RV hypertrophy was evaluated. Baseline echocardiographic measurements had been obtained Rab12 ahead of revealing male SD rats to SU5416 and three weeks of hypoxia, as defined above. As indicated in Amount?2A, serial echocardiography was performed to assess disease development and ramifications of dual PDE-5/ETA inhibition. Open up in another window Amount 2 Mixed PDE-5 and ET A inhibition reverses pulmonary Epigallocatechin gallate hemodynamic impairment and RV hypertrophy in SU-Hx rats. (A) Research design. Pets received 10?mg/kg each of tadalafil (TAD) Epigallocatechin gallate and ambrisentan (AMB) once daily by oral gavage beginning after week three. Epigallocatechin gallate (B) Pulmonary artery acceleration period (PAAT) and speed time essential (VTI) had been quantified using Doppler pictures. Systolic notching of PA blood circulation within an SU-Hx rat treated with automobile is normally indicated. (C and D) PAAT and VTI had been significantly low in SU-Hx rats in comparison to normoxic handles, indicating elevated pulmonary arterial pressure. PAAT and VTI had been rescued by TAD/AMB treatment. (ECG) M-mode echocardiographic pictures revealed elevated RV anterior wall structure width in SU-Hx rats, that was significantly decreased by TAD/AMB Epigallocatechin gallate treatment. For any graphs, beliefs represent mean +/?SEM. *research. WWB and RMT performed histological evaluation, and MSS executed biochemical studies. Macintosh and TAM composed the manuscript, with vital insight from all writers. All writers read and accepted the ultimate manuscript. Contributor Details Maria A Cavasin, Email: email@example.com. Kimberly M Demos-Davies, Email: firstname.lastname@example.com. Katherine B Schuetze, Email: email@example.com. Weston W Blakeslee, Email: firstname.lastname@example.com. Matthew S Stratton, Email: email@example.com. Rubin M Tuder, Email: email@example.com. Timothy A McKinsey, Email: firstname.lastname@example.com..
The molecular modeling from the phosphotyrosine (pTyr)-SH2 area interaction in the
The molecular modeling from the phosphotyrosine (pTyr)-SH2 area interaction in the Stat3:Stat3 dimerization, coupled with structural analysis from the Stat3 dimerization disruptor, S3I-201, has furnished a diverse group of analogs. xenografts. 2. Components and Strategies 2.1 Cells and reagents Regular mouse fibroblasts (NIH3T3) and counterparts transformed by v-Src (NIH3T3/v-Src), v-Ras (NIH3T3/v-Ras) or overexpressing the individual epidermal growth aspect (EGF) receptor (NIH3T3/hEGFR), as well as the individual breast cancers (MDA-MB-231) and pancreatic cancers (Panc-1) cells possess all been previously reported [15, 27-29]. The standard individual pancreatic duct epithelial cells (HPDEC) was a sort present from Dr. Tsao (OCI, UHN-PMH, Toronto) [30], the Stat3 knockout mouse embryonic fibroblasts series was generously supplied by Dr. Valerie Poli (School of Turin) [31], as well as the ovarian cancers series, A2780S was a sort present from Dr. Jin Q. Cheng (Moffitt Cancers Center and Analysis Institute). The Stat3-reliant reporter, pLucTKS3 as well as the Stat3-indie reporter, pLucSRE, as well as the v-Src changed mouse fibroblasts that stably exhibit pLucTKS3 (NIH3T3/v-Src/pLucTKS3) possess all been previously reported [15, 32, 33]. Cells had been harvested in Dulbeccos customized Eagles moderate (DMEM) formulated with 10% heat-inactivated fetal bovine serum, or regarding HPDEC, these were expanded in buy Erlotinib mesylate Keratinocyte-SFM mass media (GIBCO, Invitrogen Corp, Carlsbad, CA) supplemented with 0.2 ng EGF and 30 g/ml bovine pituitary extract, and containing antimycol. Antibodies against Stat3, pY705Stat3, Src, pY416Src, Jak1, pJak1, Shc, pShc, Erk1/2, benefit1/2, Survivin are from Cell Signaling Technology (Danvers, MA), and anti-EGFR and anti-VEGF from Santa Cruz Biotech (Santa Cruz, CA). 2.2. Cloning and Proteins Appearance The coding locations for the murine Stat3 proteins as well as the Stat3 SH2 website had been amplified by PCR and cloned into vectors pET-44 Ek/LIC (Novagen, EMD Chemical substances, Gibbstown, NJ) and pET SUMO (Invitrogen), respectively. The primers buy Erlotinib mesylate utilized for amplification had been: Stat3 Forwards: GACGACGACAAGATGGCTCAGTGGAACCAGCTGC; Stat3 Change: GAGGAGAAGCCCGGTTATCACATGGGGGAGGTAGCACACT; Stat3-SH2 Forwards: ATGGGTTTCATCAGCAAGGA; Stat3-SH2 Change: TCACCTACAGTACTTTCCAAATGC. Clones had been sequenced to buy Erlotinib mesylate verify the right sequences and orientation. His-tagged recombinant protein had been indicated in BL21(DE3) cells and purified on Ni-ion sepharose column. 2.3. Nuclear draw out preparation, gel change assays, and densitometric evaluation Nuclear extract arrangements and electrophoretic flexibility change assay (EMSA) had been completed as previously explained [28, 33]. The 32P-tagged oligonucleotide probes utilized had been hSIE (high affinity sis-inducible component from your gene, m67 variant, 5-AGCTTCATTTCCCGTAAATCCCTA) that binds Stat1 and Stat3 [34] and MGFe (mammary gland element element from your bovine -casein gene promoter, 5-AGATTTCTAGGAATTCAA) for Stat1 and Stat5 binding [35, 36]. Except where indicated, nuclear components had been pre-incubated with substance for 30 min at space temperature ahead of incubation using the radiolabeled probe for 30 min at 30 C before subjecting to EMSA evaluation. Bands related to DNA-binding actions had been scanned and quantified for every concentration of substance using ImageQuant and plotted as percent of control (automobile) against focus of compound, that the buy Erlotinib mesylate IC50 ideals had been produced, buy Erlotinib mesylate as previously reported [37]. 2.4. Immunoprecipitation, immunoblotting and densitometric analyses Immunoprecipitation from whole-cell lysates, and tumor cells lysate planning, and immunoblotting evaluation had been performed as previously explained [17, 18, 33, 38]. Main antibodies used had been anti-Stat3, pY705Stat3, pY416Src, Src, benefit1/2, Erk1/2, pJak1, Jak1, pShc, Shc, Grb 2, c-Myc, Bcl-xL, Survivin, MMP-9, and -Actin (Cell Signaling), and VEGF (Santa Cruz Biotech.). 2.5. Cell viability and proliferation assay Cells in tradition in 6-well or 96-well plates had been treated with or without S3I-201.1066 for 24-144 h and put through CyQuant cell proliferation assay (Invitrogen Corp/Life Systems Corp), or harvested, as well as the viable cells counted by trypan blue exclusion with stage comparison microscopy. 2.6. Immunofluorescence imaging/confocal microscopy NIH3T3/hEGFR cells had been cultivated in multi-cell plates, serum-starved for 8 h and treated with or without S3I-201.1066 for 30 min ahead TGFB2 of activation by rhEGF (1 g/ml) for 10 min. Cells had been set with ice-cold methanol for 15 min, cleaned three times in phosphate buffered saline (PBS), permeabilized with 0.2% Triton X-100 for 10 min, and additional washed 3-4 occasions with PBS. Specimens had been then clogged in 1% bovine serum.
Extracorporeal circulation (ECC) and hypothermia are accustomed to maintain steady circulatory
Extracorporeal circulation (ECC) and hypothermia are accustomed to maintain steady circulatory parameters and enhance the ischemia tolerance of individuals in cardiac surgery. mixture with P2Y blockers (p 0.05), while no aftereffect of hypothermic ECC or antiplatelet agencies on GPIIb/IIIa and GPIb expression and von Willebrand factor binding was observed. Exclusive P2Y and PI3K blockade or a mixture thereof inhibited P-selectin appearance on platelets and platelet-derived microparticles during hypothermic ECC (p 0.05). P2Y blockade by itself or coupled with TGX-221 avoided ECC-induced platelet-granulocyte aggregate development (p 0.05). Platelet adhesion towards the ECC surface area, platelet reduction and Macintosh-1 appearance on granulocytes had been inhibited by mixed P2Y and PI3K blockade (p 0.05). Mixed blockade of P2Y12, P2Y1 and PI3K p110 totally inhibits hypothermic ECC-induced activation procedures. This novel acquiring warrants further research and the advancement of ideal pharmacological agencies to diminish ECC- and Rabbit Polyclonal to TK hypothermia-associated problems in scientific applications. Launch Under physiological circumstances, platelets play a simple function in hemostasis, avoidance of loss of blood, and curing of vascular damage. Nevertheless, dysfunctional platelets could cause severe problems like irregular thrombus development and consecutive vessel occlusion aswell as heavy bleeding problems, which are feared unwanted effects of extracorporeal blood circulation (ECC) [1], [2]. ECC buy 5633-20-5 is utilized in lots of cardiac surgical treatments to make sure gas exchange also to maintain steady circulatory guidelines of the individual. Furthermore, hypothermia varying between 28C and 32C is definitely routinely used during cardiac procedures furthermore to ECC to improve the ischemia tolerance of the individual. Shear stress, get in touch with of blood using the artificial areas from the ECC circuit aswell as hypothermia are regarded as connected with platelet activation, which leads to disturbed platelet function and connected problems [1], [3], [4]. Furthermore, triggered platelets can result in an inflammatory response through relationships with leukocytes [5]. These platelet-leukocyte relationships are primarily mediated by binding from the platelet surface area receptor P-selectin to its counter-top receptor P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes. Subsequently, upregulation and activation from the Mac pc-1 receptor (Compact disc11b/Compact disc18) on leukocytes is definitely induced due to the P-selectin-PSGL-1 connection [5], [6]. Furthermore, it's been demonstrated that Compact disc40 ligand, which is definitely shed from platelets upon activation, also promotes Mac pc-1 upregulation [7]. Inhibition of platelet activation is definitely a possible method of inhibit platelet dysfunction and related harmful results during ECC. One pharmacological technique to inhibit platelet activation is definitely blockade from the platelet ADP receptors P2Y12 and P2Y1 [8], [9]. We've recently demonstrated that ADP takes on a major part in ECC- and hypothermia-induced platelet activation [10]. Inhibition of platelet granule launch could be accomplished during hypothermic ECC via P2Con12 blockade [11]. However, despite effective platelet safety by P2Y12 blockade, still higher examples of platelet activation in comparison to baseline ideals were noticed. Furthermore, platelet adhesion towards the ECC surface area and for that reason platelet loss cannot be avoided. Consequently, furthermore to ADP additional factors certainly activate platelets during ECC. In this respect, shear-induced activation of platelets is definitely another essential aspect during ECC [4], [12]. Shear sets off a signaling pathway, which include activation from the course Ia phosphoinositide-3-kinase (PI3Ks) p110 isoform. This leads to activation from the platelet fibrinogen receptor GPIIb/IIIa and buy 5633-20-5 platelet aggregate development [13], [14], [15], [16]. Based on these data, we hypothesize that significant platelet security during ECC and hypothermia could be achieved by mixed inhibition of P2Y12, P2Y1 and PI3K p110. To verify this, we initial described effective doses from the P2Y12 antagonist 2-MeSAMP as well as the PI3K p110 blocker TGX-221 to attain significant inhibition of platelet activation ECC model at hypothermia (28C). Outcomes Concentration-dependent Inhibition of ADP-induced P-selectin Appearance using 2-MeSAMP and TGX-221 and the result of MRS2179 buy 5633-20-5 Treatment of entire bloodstream with different concentrations of 2-MeSAMP (10 and 100 M) demonstrated that ADP-induced (last ADP focus: 20 M) P-selectin appearance is certainly even more potently inhibited with higher antagonist concentrations buy 5633-20-5 (Body 1A). The addition of MRS2179 (100 M) in the 2-MeSAMP-treated group additional decreased the appearance of platelet P-selectin appearance upon ADP activation (Body 1A). Open up in another window Body 1 Concentration-dependent inhibition of ADP-induced P-selectin appearance using buy 5633-20-5 2-MeSAMP and TGX-221.Heparinized individual whole blood.
Aim To measure the effectiveness of pegaptanib mainly because maintenance therapy
Aim To measure the effectiveness of pegaptanib mainly because maintenance therapy in neovascular age-related macular degeneration (NV-AMD) individuals after induction therapy. damp age-related macular degeneration, was allowed in the analysis eye in the researchers' discretion for medical deterioration. Outcomes Of 568 enrolled topics, 86% finished 1?yr of pegaptanib. Mean VA improvement during induction (49.6 to 65.5 characters) was very well preserved (54-week mean 61.8 characters). Mean CPT was fairly steady during maintenance (20?m boost during the research). Fifty % didn't receive unscheduled booster treatment to week 54; 46% do have one particular booster (mean 147?times after maintenance initiation). Conclusions An induction-maintenance technique, using nonselective after that selective vascular endothelial development element (VEGF) inhibitors, could possibly be regarded as for NV-AMD. This process may possess particular relevance for individuals with systemic comorbidities who need long-term anti-VEGF therapy for NV-AMD. solid course="kwd-title" Keywords: Macula, macular degeneration, pegaptanib sodium, vascular endothelial development factor CURE of neovascular age-related macular degeneration (NV-AMD) offers changed dramatically before 5?years using the clinical usage of intravitreal providers specifically targeting vascular endothelial development element (VEGF). This advancement, the culmination greater Ciluprevir than ten years of work in to the pathophysiology of NV-AMD, resulted in the authorization of two medicines as intravitreal therapies: pegaptanib sodium, an RNA aptamer focusing on VEGF165,1 and ranibizumab, a monoclonal antibody fragment that binds all VEGF isoforms.2 3 Furthermore, bevacizumab, a Ciluprevir monoclonal antibody linked to ranibizumab that also binds all VEGF isoforms, continues to be used off-label extensively to Ciluprevir take care of a number of ocular neovascular circumstances.4 The perfect utilisation of the agents continues to be a matter of argument. In pivotal tests, ranibizumab provided a Ciluprevir substantial Rabbit polyclonal to AuroraB improvement in mean visible acuity (VA) weighed against control organizations in NV-AMD individuals.2 3 It's been suggested these results could be related to its system of actions in binding all VEGF isoforms.5 However, the systemic safety of pan-VEGF agents still issues some practitioners, and the usage of the nonselective VEGF antagonist, bevacizumab, in cancer chemotherapeutic regimens continues to be associated with an elevated incidence of hypertension, blood loss and thromboembolic events.6 Whereas the dosages employed with intravitreal administration are lower, systemic publicity is likely considering that the aberrant vasculature is commonly particularly leaky. This security concern is pertinent towards the NV-AMD individual who is currently at increased threat of hypertension, heart stroke and cardiovascular disease7 and, therefore, is at higher threat of treatment-related systemic problems, specifically because anti-VEGF therapies are usually applied to a long-term basis. Pegaptanib continues to be used in scientific research for a lot more than 4?years without the looks of systemic or ocular basic safety indicators8 9 and in addition has been examined in dosages 10 times higher than those employed clinically without the evidence of an elevated threat of systemic undesireable effects.10 Its positive Ciluprevir safety profile offers resulted in attempts to mix both the effectiveness of nonspecific inhibition using the apparent safety of pegaptanib. In small-scale research, a short inductive dose of the nonspecific VEGF inhibitor was accompanied by maintenance therapy with pegaptanib and booster dosages of pegaptanib as needed.11 12 Because these research reported encouraging effects, today's exploratory research (Evaluation of Effectiveness and Security in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD; LEVEL) was undertaken as a more substantial scale application of the fundamental methodology. With this research, the security and effectiveness of pegaptanib maintenance in individuals with NV-AMD who experienced a medical improvement in disease pursuing an induction stage were assessed. Components and strategies The protocol because of this stage IV, potential, open-label, uncontrolled exploratory research was analyzed and accepted by an institutional review plank at each research site relative to the rules for the carry out of scientific analysis in the 1964 Declaration of Helsinki. The analysis is shown on http://www.clinicaltrials.gov ("type":"clinical-trial","attrs":"text message":"NCT00354445″,"term_id":"NCT00354445″NCT00354445). All research participants provided agreed upon informed consent. Entitled subjects.
Ester prodrugs from the phosphinate pseudopeptide = 3. as improved bioavailability.
Ester prodrugs from the phosphinate pseudopeptide = 3. as improved bioavailability. Bottom line Many routes to synthesize prodrug esters of methotrexate, its -glutamyl conjugate, and a phosphinate pseudopeptide had been investigated. The very best way for synthesis of the pseudopeptide POM ester prodrug uses N-Cbz vinylglycine POM ester as the main element intermediate to include the N-terminal CCP connection and (,-bis-POM)–methyleneglutarate to create the C-terminal PCC connection. Several other strategies buy Fmoc-Lys(Me,Boc)-OH became impractical for a number of factors. POM esters had been found to become quite steady under natural or light acidic circumstances but even more labile under simple conditions. Nevertheless, hydrolysis from the phosphonic pseudopeptide tetramethyl ester was inadequate under common simple conditions, whereas as the phosphinic acidity PCOMe moiety was delicate to acidity, such as for example TFA, and to halide ion. Circumstances required to impact phosphorusCcarbon bond development were also looked into and optimized. Prodrug esters 1b, 1d, and 2b and 2d had been synthesized effectively by coupling of 2,4-diamino-6-(bromomethyl)-pteridine using the = 0.4) to produce 409 mg (80%) of 5 like a colorless essential oil. 1H NMR (CDCl3): 7.32C7.42 (m, 5H), 5.74C5.91 (m, 4H), 5.45 (s, br, 1H), 5.12C5.21 (m, 2H), 4.47 (s, br, 1H), 2.49C2.54 (m, 2H), 2.25C2.27 (m, 1H), 2.01C2.06 (m, 1H), 1.20C1.32 (m, 18H). 13C NMR (CDCl3): 177.46, 177.26, 171.62, 171.01, 156.35, 136.46, 129.10, 128.92, 128.78, 128.62, 128.51, 80.32, 80.04, 67.53, 53.48, 39.01, 38.80, 30.17, 27.43, 27.28, 27.21, 27.18. ESI-HRMS (= 0.55) to provide 126 mg (70%) buy Fmoc-Lys(Me,Boc)-OH of 6 like a colorless oil. 1H NMR (CDCl3): 7.32 (s, 5H), 6.60 (d, = 7.34 Hz, 1H), 5.59C5.88 (m, 6H), 5.03 (s, 2H), 4.54C4.61 (m, 1H), 4.33C4.35 (m, 1H), 2.39C2.43 (m, 2H), 2.26C2.31 (m, 2H), 2.15C2.16 (m, 2H), 1.95C2.00 (m, 2H), 1.18 (s, 27H). 13C NMR (CDCl3): 177.55, 177.48, 177.29, 172.29, 171.73, 171.18, 170.83, 156.55, 136.54, 128.90, 128.57, 128.49, 80.35, 80.25, 80.11, 67.46, 53.76, 51.88, 46.42, 39.12, 32.13, 30.26, 27.44. ESI-HRMS (= 0.4) to provide 22 mg (45%) of 9a like a colorless essential oil. 1H NMR (CDCl3): 6.63 (s, 1H), 5.84 (d, = 5.5 Hz, 1H), 5.80 (d, = 5.5 Hz, 1H), 4.30 (dd, = 0.2) to provide 21 mg (40%) of 9b like a colorless essential oil. 1H NMR (CDCl3): buy Fmoc-Lys(Me,Boc)-OH 5.85 (d, = 5.5 Hz, 1H), 5.79 (d, = 5.5 Hz, 1H), 4.10C4.17 (m, 1H), 2.85 (s, 3H), 2.34C2.44 (m, 3H), 2.05C2.06 (m, 1H), 1.21 (s, 9H). 13C NMR (CDCl3): 177.42, 171.45, 161.34, 80.23, 49.82, 38.81, 30.25, 27.23, 21.45, 21.01. Di-= 0.6) to provide 2.1 g (90% over two measures) of 25a as an oil. 1H NMR (CDCl3): 7.81 (d, = 8.52 Hz, 2H), 7.33 (m, 5H), 7.08 (d, = 7.34 Hz, 1H), 5.18 (s, 2H), 4.66C4.68 (m, 1H), 3.35 (s, 3H), 2.20C2.44 (m, 3H), 2.04C2.09 (m, 1H), 1.41C1.50 (m, 18H). 13C NMR (CDCl3): 173.04, 171.69, 166.69, 155.45, 146.57, 136.65, 131.36, 128.92, 128.51, 128.32, 128.17, 125.40, 82.82, 81.28, 68.02, 53.30, 37.80, 32.05, 28.45, 28.42, 27.81. ESI-HRMS (= 0.3) gave 146 mg (86%) of the required product like a yellow essential oil. 1H NMR (CDCl3): 10.30 (s, br, 1H), 7.80 (d, = 8.61 Hz, 2H), 7.28C7.38 (m, 7H), 7.11 (d, = 7.50 Hz, 1H)), 5.30 (s, 2H), 4.68C4.75 (m, 1H), 3.33 (s, 3H), 2.45C2.53 (m, 2H), 2.27C2,32 Mouse monoclonal to p53 (m, 1H), 2.03C2.10 (m, 1H), 2.17 (s, 9H). 13C NMR (CDCl3): 177.75, 171.59, 167.66, 155.52, 146.69, 136.55, 131.00, 128.95, 128.57, 128.36, 128.24, 125.41, 83.32, 68.12, 53.05, 37.77, 30.69, 28.40, 28.03. ESI-HRMS (= 0.35) to yield 628 mg (86%) from the name compound was acquired as an oil. 1H NMR (CDCl3): 7.83 (d, = 8.55 Hz, 2H), 7.54 (d, = 6.81 Hz, 1H), 7.28C7.34 (m, 7H), 6.65 (d, = 7.32 Hz, 1H). 5.17 (s, 2H), 4.57C4.62 (m, 1H), 4.45C4.48 (m, 1H), 3.33 (s, 3H), 2.25C2.36 (m, 4H), 2.03C2.10 (m,.
Solitary doses of MAALOX TC and ranitidine were administered separately with
Solitary doses of MAALOX TC and ranitidine were administered separately with 1,400 mg of fosamprenavir (FPV). antacids and histamine2-receptor antagonists can be done. FPV displays pH-dependent solubility, with maximal solubility at pH 3.3 and reduced solubility in higher pHs (5). The phosphate group on FPV could bind towards the steel cations within antacids, that could either alter solubility or prevent presystemic transformation of FPV to APV. This research assessed the consequences of antacids and ranitidine on single-dose plasma APV pharmacokinetics pursuing administration of FPV. This single-dose, open up, randomized, three-way well balanced crossover research included administration of just one 1,400 mg of FPV by itself, 1,400 mg of FPV rigtht after 30 ml of dental antacid (MAALOX TC; Novartis Customer Wellness), 1,800 mg of magnesium hydroxide and 3,600 mg of lightweight aluminum hydroxide dried out gel (2,754 mg of lightweight aluminum hydroxide), and 1,400 mg of FPV 1 h after 300 mg of ranitidine. There is a 4- to 7-time washout between each treatment. Topics fasted right away, carrying on until 4 h after dosing. Drinking water was permitted advertisement libitum through the right away fast. The analysis drug was implemented with 180 ml of drinking water, and additional drinking water was permitted advertisement libitum from 2 h after dosing. The pot where MAALOX TC was implemented was rinsed, as well as the drinking water was consumed. Bloodstream samples were gathered in sodium citrate-containing pipes (Vacutainers; Becton-Dickinson) at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Ahead of evaluation, plasma was kept at or below 30C, of which heat range stability continues to be verified for 32 a few months. Plasma APV and FPV concentrations had been assessed within 4 a few months of preliminary dosing utilizing a validated high-performance liquid chromatography assay with tandem mass spectrometric recognition following solid-phase removal (the linear range for APV was 10 to 10,000 ng/ml, which for FPV was 5 to at least one 1,000 ng/ml). For APV, intra-assay accuracy, interassay accuracy (percent coefficient of deviation), and precision (percent bias) had been 13.83, 2.57, and 10.47, respectively. Pharmacokinetic evaluation of plasma APV concentration-time data was carried out making use of noncompartmental model 200 (for extravascular administration), using the log linear trapezoidal Vismodegib computation method, from the WinNonLin Professional edition 3.0 program (Pharsight Corporation, Hill Look at, Calif.). Presuming an intrasubject log region beneath the concentration-time curve (AUC) and a typical deviation for log optimum concentration of medication in serum ( em C /em utmost) of 0.26 (based on previous FPV pharmacokinetic research), it had been estimated that 24 evaluatable topics were had a need to provide 80% power for the 90% confidence intervals (CIs) of the procedure ratios to fall within 0.75 to at least one 1.33 for the AUC from 0 h to infinity (AUC0-) of plasma APV and 0.70 Vismodegib to at least one 1.43 for em C /em utmost. The CI of 0.75 to at least one 1.33 was considered clinically meaningful for the AUC0- of plasma APV; a wider CI was useful for em Vismodegib C /em utmost since Rabbit polyclonal to DPYSL3 this parameter is known as less medically relevant for efficiency indexes. Evaluation of variance, taking into consideration series, period, and treatment as set effects and subject matter within sequence like a arbitrary impact, was performed using the SAS (edition 6.12) mixed linear versions procedure. Combination remedies were in comparison to FPV only. Thirty healthy topics gave written educated consent, and 26 (24 male and 2 feminine) subjects finished the study. There have been no serious undesirable events through the study, no subject matter withdrew because of a drug-related undesirable event. Figure ?Shape11 depicts the median plasma APV concentration-versus-time profile for every from the three remedies. Plasma APV pharmacokinetic guidelines and geometric least-squares suggest treatment ratios (90% CI) are summarized in Desk ?Desk1.1. When FPV was given rigtht after 30 ml of MAALOX TC, plasma APV AUC0-, AUC0-24, and em C /em utmost were decreased by 15, 18, and 35%, respectively. When FPV was given 1 h after 300 mg of ranitidine, the AUC0-, AUC0-24, and em C /em utmost of plasma APV had been decreased by 26, 30, and 51%, respectively. Neither coadministration of MAALOX TC or of ranitidine with FPV led to a statistically factor in APV plasma focus at 12 h.
Retinoid X Receptor (RXR) regulates important cellular responses such as for
Retinoid X Receptor (RXR) regulates important cellular responses such as for example cell growth and advancement, which regulation is generally perturbed in a variety of malignancies, including Hepatocellular Carcinoma (HCC). establishes AEG-1 like a book homeostatic regulator of RXR and RXR/RAR that may donate to hepatocarcinogenesis. Focusing on AEG-1 could sensitize HCC and AML individuals to retinoid- and rexinoid-based therapeutics. and xenograft versions. AEG-1 inhibition may be an effective technique to augment ramifications of retinoids in individuals with diverse cancers indications. Materials AND METHODS Era of Alb/AEG-1 and AEG-1KO mice Era and characterization of the hepatocyte-specific AEG-1 transgenic mouse (Alb/AEG-1) in B6/CBA history have been defined previously (13). AEG-1KO mouse was produced in C57B6/129Sv history and the task is defined at length in CAY10505 the supplemental details. All animal research had been accepted by the Institutional Pet Care and Make use of Committee at Virginia Commonwealth School, and had been conducted relative to the pet Welfare Action, the PHS Plan on Humane Treatment and Usage of Lab Animals, as well as the U.S. Federal government Principles for the use and Treatment of Vertebrate Pets Used in Examining, Research, and Schooling. Tissue lifestyle HepG3, QGY-7703, THLE3, Hep3B, HuH7, and HEK-293 cells had been cultured as reported previously (12). Era of Hep-PC-4 (control clone), Hep-AEG-1C14 (a C-terminal HA-tagged AEG-1 overexpressing clone), Hep-CTRLsi (control siRNA expressing clone) and Hep-AEG-1si (expressing AEG-1 shRNA) in HepG3 history has been defined before (12, 14). A C-terminal HA-tagged AEG-1 build mutated at LXXLL theme was stably portrayed in HepG3 cells, Hep-AEG1-Lxxmut, and was produced following same protocol for Hep-AEG1C14 cells. The clones had been selected and preserved in Hygromycin CAY10505 formulated with DMEM. Principal cell lifestyle and viability assay Principal mouse hepatocytes had been isolated from p18 WT (B6/CBA), Alb/AEG-1, WT (C57B6/129Sv) and AEG-1KO mice in the Cell and Molecular Biology Primary in VCU as defined previously (13) and had been plated on collagen-coated meals (BD BioCoat collagen type I, BD Biosciences) and cultured in Williams E moderate (SIGMA) formulated with NaHCO3, L-glutamine, insulin (1.5 M) and dexamethasone (0.1 M). For MTT assays, 1.0C1.5104 mouse hepatocytes were plated in each well of the 96-well dish and treated with retinoids and rexinoids for respective period points as stated in the Body legends. Cell viability was dependant on regular MTT assay as explained (12, 15, 16). Transient transfection and luciferase reporter assays Transfections and luciferase assays had been done based on the producers protocol for human being HCC cells as explained somewhere else (14, 17, 18) and main hepatocytes (supplemental info). Each test was performed in triplicates and repeated 3 x to calculate means and regular mistake. Total RNA removal, cDNA planning and Real-time PCR Total RNA was extracted from Human being HepG3 cells, livers and hepatocytes of WT (B6/CBA and C57B6/129Sv), CAY10505 Alb/AEG-1, and AEG-1KO mouse using the QIAGEN miRNAeasy Mini Package (QIAGEN, Hilden, Germany). cDNA planning was carried out using ABI cDNA synthesis package. Real-time polymerase string response (RT-PCR) was performed using an ABI ViiA7 fast real-time PCR program and Taqman gene manifestation assays based on the producers process (Applied Biosystems, Foster Town, CA). The very best obtainable Taqman primers-probes spanning two exons for as well as for human aswell as mouse had been bought from ABI. Chromatin Immunoprecipitation (ChIP) Assay Sheared chromatin was ready following the producers guidelines and was immunoprecipitated using RXR (Santa Cruz Biotechnology), AHH3 and SRC-1 (Cell signaling) antibodies. The eluted DNA and inputs was put through PCR for and genes. For (Feeling: 5AGCTCTGTGAGAATCCTGGGAG3, Antisense: 5TAGACCCTCCT GCCTCTGAACA3) and (Feeling: 5CTGGGG CAATCAGATTCAAACC3, Antisense: 5CTCAGATAAACTGCTGGGACTC3) primers had been utilized for PCR amplification using Taq PCRx polymerase package (Invitrogen) following a producers guidelines. These PCRs had been performed without enhancers and repeated at least 3 x. Nude Mice Xenograft Research Subcutaneous xenografts had been founded in flanks of athymic nude mice using QGY-7703 cells (5 105). After a week, these mice had been injected with ATRA (10 mg/kg) or DMSO i.p., a complete of 7 shots,.
transfer of mRNA and its own enzymatic item 1,6-branch are aberrantly
transfer of mRNA and its own enzymatic item 1,6-branch are aberrantly upregulated in tumor cells and that 1,6-branch is highly involved with cancer development and metastasis. of breasts cancers [58]. This accumulating proof strongly supports the idea that GnT-V has pivotal jobs in cancer starting point, development and metastasis, and it is a promising medication target for tumor therapy. In human beings, a cDNA homologous compared to that encodes the enzyme GnT-IX(Vb) called was reported to become highly portrayed in neuroblastoma cells [72]. It had been also reported that was defined as an extremely upregulated gene in individual prostate tumor cells upon metastasis within a mouse xenograft model [73]. Furthermore, appears buy TAK-733 to be aberrantly upregulated in a variety of non-brain tumors by epigenetic systems [74]. These outcomes claim that GnT-IX is certainly involved in cancers development but its complete roles in tumor still remain to become elucidated. Open up in another window Body 3 Branch development in gene was seen in different tissue [78], which points out the very minor phenotypes in GnT-IVb-null mice. Relating to its function, GnT-IVa established fact to be engaged in insulin secretion and blood sugar fat burning capacity in the pancreas, as referred to below [80]. GnT-IVs Mctp1 had been also reported to be engaged in cancer however the comprehensive functions in tumor cells are badly understood. In a few cancers cells, GnT-IVa or GnT-IVb is certainly extremely dysregulated including in choriocarcinoma [81], pancreatic tumor [82] and hepatocarcinoma [83] and they have generally been recommended that the merchandise glycan of GnT-IV promotes invasion and metastasis. Nevertheless, further research are had a need to clarify the useful jobs of GnT-IVs and their item glycans in tumor progression. GnT-IVa is certainly highly portrayed in the pancreas and its own participation in type 2 diabetes continues to be well researched. GnT-IVa-deficient mice had been found to demonstrate hyperglycemia, decreased insulin amounts, and abnormal blood sugar tolerance [80]. This is found to become due to the dysfunction of an integral blood sugar transporter, GLUT2. in non-small-cell lung malignancy was reported to become correlated with the indegent clinical results [93,94], recommending the participation of Fut8 in malignancy development and its own potential as biomarker. Needlessly to say by the common manifestation and large quantity of primary fucose, Fut8 (agglutinin (LCA), to provide L1, L2 and L3 fractions and AFP-L3 is mainly indicated in the sera of main hepatoma patients, however, not in situations of liver organ cirrhosis. Predicated on this acquiring, AFP-L3 was accepted by the united states Food and Medication Administration (FDA) being a biomarker for the first recognition of hepatocellular carcinoma. Our glycomic evaluation uncovered that L3 demonstrated the highest degree of primary fucose among the three fractions [111]. Furthermore, fucosylated haptoglobin was also defined as a marker for numerous kinds of cancers [112,113]. Our site-specific glycomic evaluation uncovered that both primary fucose and Lewis types of fucose that's synthesized by various other Futs portrayed on haptoglobin, are elevated in various malignancies [114]. Once again, these results high light the need for primary fucose for understanding the jobs of glycans in liver organ cancers and their healing applications. The participation of primary fucose in antibody cancers therapy in addition has been reported. Antibody-dependent mobile buy TAK-733 cytotoxicity (ADCC) includes a central function in cancers therapy using antibodies [115]. Removing primary fucose from IgG-Fc promoter in individual bile duct carcinoma cells [122] which the Ets-1 amounts were extremely correlated with the degrees of GnT-V appearance in various cancers cell lines [123]. These reviews claim that the oncogenic Ets pathway is certainly directly involved with GnT-V transactivation. Various other transcription factors in charge of the legislation of transcription [124], which might explain how come barely portrayed in the buy TAK-733 liver organ. The tissue-specific appearance of GnT-IX is certainly regulated by the precise transcription elements NeuroD1 and CCCTC-binding aspect (CTCF) [64,65] but their efforts towards the cancer-related upregulation of GnT-IX remain unclear. Intriguingly, cell thickness on a lifestyle dish impacts the transcription from the GnT-III gene (transcription. Furthermore, E-cadherin–catenin complicated was been shown to be involved in this technique [125]. On the other hand, Wnt/-catenin signaling was also reported to modify GnT-III appearance [126,127]. Id of the precise transcription elements for the oncogenic transcription of promoter is certainly involved with its upregulation in ovarian cancers cells [132]. gene can be governed by DNA methylation in other styles of cancer and in addition during the procedure for EMT [31,74]; furthermore, GnT-IV genes (and transcription begin sites are customized within a neural-cell-specific way, which is certainly subsequently necessary for the effective binding of the precise transcription activators NeuroD1 and CTCF [64,65]. Such tissue-specific chromatin legislation of is certainly mediated by particular chromatin modifiers such as for example HDAC11, transcription continues to be reported to become regulated by many miRNAs in cancers cells. For instance, miRNA-198 shows.
Raynauds sensation and digital ulcerations are two common clinical features observed
Raynauds sensation and digital ulcerations are two common clinical features observed in individuals with systemic sclerosis. (SSc) is definitely a uncommon connective cells disorder that's designated by fibrosis, vascular harm, and immunologic abnormalities with differing degrees of inner organ participation. Although SSc is definitely often clinically split into two subtypes, diffuse cutaneous and limited cutaneous, based on the degree of pores and skin involvement, Raynauds trend (RP) and its own problems are universal top features of the disease influencing a lot more than 95% of individuals.1 RP in scleroderma effects from both functional and structural vascular abnormalities with marked intimal proliferation from the digital arteries. The structural component is definitely twofold. The 1st marker is definitely intimal proliferation and fibrosis leading to significant compromise from the vessel lumen. The resultant endothelial harm leads towards the upregulation of vasoconstrictive mediators while concurrently lowering the degrees of vasodilatory substances. This in conjunction with intraluminal narrowing of digital arteries creates a milieu against which digital ulcers (DUs) may occur. The practical aberration outcomes from regular vasospasm, which eventually leads to intensifying cells ischemia and the forming of oxygen-free radicals, which additional perpetuates this routine. Treatment continues to be challenging Kobe2602 IC50 because we've focused mainly on vasodilating these vessels which might not be feasible if they are inherently therefore structurally broken. RP symptoms happen in virtually all scleroderma individuals, while digital ulcerations can be found in around 30% of the individuals annual. DUs are thought as a denuded part of cells with well-demarcated edges involving lack of both dermis and epidermis.2 These ischemic lesions are usually on the fingertips. Ulcers might occur over bony protuberances, like the proximal phalanges or the elbows but they are more likely to become supplementary to taut pores and skin and trauma and so are not likely to become attentive to vasodilatory therapy. All ulcers are characteristically extremely painful and frequently bring about impaired hands function. Clinical features connected with a greater threat of digital ulcerations consist of male sex, early starting point of RP, anti-scl-70 antibodies, existence of pulmonary arterial hypertension, smoking cigarettes, and raised acute-phase reactants.3 DUs have a tendency to recur, with 66% of sufferers having several episode despite usage of vasodilators.4 They Kobe2602 IC50 contain the possibility of leading to irreversible tissues loss, and also other significant problems including osteomyelitis, gangrene, and amputation. As well as the potential for tissues loss, the amount of useful impairment is normally considerable aswell. The impairment in sufferers with consistent digital ulcerations is normally significantly higher than those without DUs. The economic burden is normally substantial aswell, as sufferers with digital ulcerations need even more hospitalizations including those for antibiotics than those without.5 Despite these findings, recent data released by Ferri et al6 display that DUs may actually be becoming much less prevalent. If they likened their scleroderma cohort enlisted from 2000 to 2011 with individual groups from old studies, there is a substantial reduction in epidermis ulcers (from 54% to 16.5%; em P /em 0.0001). This may point to an elevated physician knowing of the disease procedure and talk about the potency of the many treatment options that may potentially be utilized in Kobe2602 IC50 these individuals.6 Administration of DUs in scleroderma includes nonpharmacologic, pharmacologic, and surgical intervention. Nonpharmacologic modalities used consist of avoidance of RP causes including cold publicity, emotional tension, or medicines that promote vasoconstriction, including beta blockers, migraine medicines such as for example sumatriptan and ergotamine, contraceptive pills, particular chemotherapeutic agents such as for example cisplatin and vinblastine and amphetamines including those utilized for interest deficit hyperactivity disorder (ADHD). Smoking cigarettes cessation is completely essential to prevent further vascular insult to currently vulnerable cells. Multiple agents have already been used to counteract RP and prevent/decrease the responsibility of digital ulcerations (Desk 1), although non-e are approved in america. There were major difficulties in performing medical tests in RP and DUs. Some are linked to trial style, some linked to the issue in defining energetic DUs2, plus some are linked to having less pharmaceutical dedication to RP and DUs in scleroderma. The main drugs that people will review are calcium mineral route blockers (CCBs), CIP1 phosphodiesterase inhibitors, prostacyclin analogs, and endothelin receptor antagonists. We performed a PubMed seek out articles describing treatment modalities useful for administration of RP and DUs in the scleroderma individual population. The content articles reviewed.


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Fan of dragon shifter romance?
Then don't miss Mikhail (Brothers of Ash & Fire – Book 2) by Lauren Smith NOW LIVE & ready for #1-click. This smokin' hot, sexy and dangerous standalone is going to knock you off of your feet! If you are looking for a unique read that gives you all the feels and keeps you engrossed from beginning to end, this is the book for you! Grab your copy today for just .99 cents for a limited time only!
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If you're new to the Brothers of Ash world, then jump into Grigori! This highly rated introduction to this shifter series will capture your attention right for the start. #1-click now!
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My Review of Mikhail:
Let me just start off with the most obvious… that is one sexy man on the cover.
I have to say that after reading the first book in the series, Grigori, I expected that Mikhail would be the last story but I am glad it wasn't . After letting himself be taken advantage of, Mikhail punished himself far more than anyone – including his father – ever could. I enjoyed the brush with the historical Queen E as well as the way the treasure was handled.
Piper was spunky and bright – she made a fun pairing with Mikhail's strong yet reclusive personality.
The whole story was a nice balance of paranormal elements in a contemporary setting as well as a passionate romance. I really enjoyed reading it – did not want to put it down – finished it in one day. I would definitely recommend it.
PS: I don't suppose we can read more about Piper's friend, Jodie, with Mikhail's friend, Belishaw, can we???

subset: commoncrawl


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SUMMERVILLE, SC – In the past month, SUN News has reported several incidents involving the release of chemicals at community pools.
In a report from TV station WCSC, emergency officials transported 5 children to the hospital following a chemical release at a Summerville pool Wednesday afternoon. The children are reported to be in good condition.
Dorchester County officials say at 1:09 p.m. crews responded to the Ashborough Subdivision Pool on 208 Ashborough Ave.
When Dorchester County EMS arrived they found seven patients, all between the ages of five and twelve, coughing and feeling sick. Two children remained on-scene with a parent.
According to county officials, the chemical release possibly involved sulfuric acid and aquatic bleach, which more than likely, resulted from a malfunction from the pool.
County officials said the pool remained closed while investigations into the incident continue.
DCEMS Director, Doug Warren is "very pleased with the rapid multi-agency response to this incident. The coordinated efforts of all departments ensured each child involved was provided optimum care in the most expeditious manner."


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At Capital One, we're harnessing the unique zest for life that people have here, even as we take banking into the future. Come catch our sunny vibe and check out how our vision can be a part of your future.
Featured Jobs - Florida
Cafe Ambassador - Miami Beach/Brickell
Miami Beach, Florida
Coral Gables, Florida


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One of common myths in church today is the belief that if we do everything right, and have enough faith our lives on Earth will be filled with health, wealth, and happiness. While we will certainly avoid falling into many traps the world lays for us if we continually follow the word of God, there is one person who followed God's will perfectly from birth. That person is Christ. He, however, lived a life of poverty, rejection from people he loved and experienced one of the most painful murders that mankind has ever created.
The disciples were far from perfect, after Christ Resurrection when they had all actually walked and talked with him I doubt a single human has ever had more faith than them, yet they endured poverty, imprisonment, torture, and most an excruciating death. Yes, we have joy, but not the kind that you get when you win the lottery, the kind of joy that you get when you walk out of a prison cell and know that no matter what happens you are on your way home to someone who loves you more than his very life. If Jesus did not have enough faith to experience the kind of prosperity that many preach about today, NO ONE HAS!
Month: February 2019
Archaeology proves that Pontius Pilate existed.
Want to share the Gospel?
Burying Brahman by Terrell Clemmons – Salvo Magazine
Rabi Maharaj knew from a young age that he had been born into the highest caste of Hindu society. His father, one of the most worshipped Yogis on his home island of Trinidad, had renounced all worldly attachments to seek through meditation the ultimate goal of Hindu spirituality—Self-realization and unity with Brahman, the One Being that lies within. From before Rabi was born in 1947 until his death when Rabi was eight, he sat in the lotus position, spine straight, eyes staring yet seeing nothing, uttering not a word, day in and day out. Nothing was more important than the daily transcendental meditation, which, according to the beloved Hindu god Krishna, was the surest way to eternal Bliss.
Click on this link to find out how he was saved: Burying Brahman by Terrell Clemmons – Salvo Magazine
Johan van Hulst
Johan van Hulst was a Dutch school director, university professor, author, chess player and politician in the Christian Historical Union (CHU), a defunct political party now merged into the Christian Democratic Appeal (CDA). He received global recognition for his role in rescuing hundreds of Jewish children from the nursery of the Hollandsche Schouwburg, Amsterdam in 1943 before they would have been deported to Nazi concentration camps. For his humanitarian actions, he received the Yad Vashem Distinction as a Righteous Among the Nations from the State of Israel in 1970
Read more at: Johan van Hulst
Do you believe in the Bible or yourself?
If you believe what you like in the Gospel, and reject what you don't like, it is not the Gospel you believe, but yourself."
― Augustine
Non-Christian Apologetics
The link in this post is an Amazon.com link, if you make a purchase a small percentage will go to make Smart Christian a better site.
We are all apologist even if we are not a Christian apologist.
With every Facebook and Twitter post
"everyone is now in the business of relentless self-promotion—presenting themselves, explaining themselves, defending themselves, selling themselves or sharing their inner thoughts and emotions as never before in human history. That is why it can be said that we are in the grand secular age of apologetics."
McDowell, Josh. Evidence That Demands a Verdict: Life-Changing Truth for a Skeptical World (p. xxxiv). Thomas Nelson. Kindle Edition. Quote from Oz Guinness
The only questions are Are we willing to promote Christ, the same way that we promote ourselves, and do you do it well?


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NAMHO NEWSLETTER - No.42; Winter 2001
At the last NAMHO Council meeting the following organisations were elected to full membership of NAMHO.
Although it was arranged at the last minute, the Northern Mine Research Society's conference at Bradford was a great success. Around 50 delegates and speakers met at the Novotel in somewhat more luxurious circumstances than is usual for a NAMHO conference. The food was so good that many did not need to eat again until the middle of the following week.
The speakers were chosen to fulfil the aim of the conference, which was to demonstrate the wide range of approaches which are relevant to studying and understanding mining and smelting sites. These included detailed archaeological studies of whole landscapes or sites, museum and conservation work, mining personnel, environmental effects, the provision of timber for mining and smelting, and archive-based studies of the late mediæval and early modern periods.
Because of the Foot and Mouth restrictions, the whole weekend was devoted to mining history, with none of the field meet distractions that have become such a dominant feature of other NAMHO Conferences. Perhaps more importantly, however, it showed that mining history events do not have to look like paupers' conventions.
Mike Gill
The NAMHO 2002 Conference will be held at Aberystwyth on the 5 - 8 July 2002.
The Conference will be hosted by the Welsh Mines Society, assisted by other local mining history societies. There will be a full programme of lectures, surface walks, underground trips and social events.
If you have returned the preliminary registration form enclosed with the last Newsletter, then you will shortly be advised of the Conference details. If you haven't pre-registered but want further information, please contact
The Conference Secretary, John Hine, The Grottage, 2 Cullis Lane, Mile End, COLEFORD, GL16 7QF. Tel: 01594 833217.
It has been confirmed that Ireland Meet, that had to be cancelled due to the Foot and Mouth Disease outbreak, will now take place in September 2003. It is expected that the programme will be as that published fort he September 2001 event. Further information will be available later in the year
This museum closed for the winter, as usual, at the end of October, but it will not reopen in the spring. The last few weeks have seen the building almost emptied of exhibits, which are being stored in containers in the grounds. Major work on the shell of the building, beginning early next year, will include stripping the flagstone roof and relaying it with new timbers (where necessary), felt and insulation. The walls are to be repointed and plastered, and the wooden floor replaced with a concrete one. The extent of the work is such that the museum is not likely to reopen until the spring of 2003.
Mike Gill
Two china clay companies working deposits on the south western edges of Dartmoor in Devon have agreed to forego mineral permits that were granted 50 years ago to extend a pit and waste tips further into the Dartmoor National Park.
The two Companies, Imerys (formerly English China Clays) and Watts Blake & Bearne, were granted permits to work the area in the 1950s before the area was included within the National Park. It was also before it was mandatory to conduct any environmental damage assessment - in-deed, well into the 1960s, the nearby River Plym ran white with suspended clay and an extensive area was covered with white dust from the drying plant while 'pyramid' tips of white mica dominated the view. Expansion into the National Park would result in damage to heather moorland, numerous archaeological sites and be visible from a large area of southern Dartmoor. In the 1970's the companies agreed not to develop the area until the first decade of the 21st Century.
As the end of this voluntary agreement approached, a campaign was launched to revoke the mineral rights. The Action Committee was spearheaded by the Dartmoor Preservation Association and supported by the National Parks Authority and Devon County Council. The Companies, both of which had came under new ownership from the Continent in the late 1990s, agreed to carry out an environmental impact assessment, but indicated that they would seek compensation running into several million pounds if they gave up the mineral rights. The members of the Action Committee would have found it impossible to fund such compensation and approached the Government, arguing that it was their responsibility to fund any compensation in the public interest.
Members of the organisations making up the Action Committee were asked to write to the DETR and their local MP's, as well as other interested parties such as English Heritage and the National Trust (who owned adjacent land) to express their concern over the pending development. The government insisted it was the responsibility of the National Park Authority and Devon County Council to solve the problem and the future looked bleak for this area of moorland.
In a most welcome move, in July 2001, the two clay companies had a change of heart and agreed to give up their old mineral rights without compensation. This is a most welcome move and illustrates how mineral developers can heed the sustained pressure of public opinion.
While some may argue that mining the area would have created jobs, careful analysis of the situation had already shown that the net impact would have been a loss of jobs due to an anticipated reduction in tourism. China Clay is not a scarce commodity and credit is due to the two companies who have accepted that their responsibilities extend beyond their immediate financial gain.
Tim Smith
"The Shropshire Caving and Mining Club in Cornwall"
This is one of a series of some 50 titles available from IA Recordings of which about half are related to mineral mining, coal mining or quarrying. Cost £16-45. Available from IA Recordings, PO Box 476, Telford, Shropshire, TF7 4RB. E-mail firstname.lastname@example.com
This video is a compilation of underground, surface and working tin mines visited by the Shropshire Caving and Mining Club over a decade from 1983 and provides 144 minutes of fascinating viewing.
The use of a helmet mounted camera in several of the underground excursions, and the lack of any dubbed commentary, relying solely on ambient sounds, frequently gives the impression that you are present in the party. While a person unfamiliar with mining may consider the lack of a commentary somewhat bewildering, for those familiar with the sights and sounds underground will find the 'realism' produced by the splash of boots, the odd crack on the head and muffled curse, fascinating.
Forty-six sites are visited, in some cases the footage lasting for 15minutes or so, in others a minute or less. Most of the visits were recorded in 1993 and include visits to South Crofty and Wheal Jane when they were both working mines that had been revived by the tin price bubble of the late 80s. Both underground visits and a tour of the concentrators are included as well as visits to the Cambourne School of Mines training mines.
Visits to preserved sites include the Levant whim in steam, the Goonvean beam engine, the Tolgus streaming plant, stamps and calciner and the mining museums at Geevor and Cambourne School of Mines.
In addition to live footage, stills are also included. Each new site is well flagged at the start of a new visit by means of a map and the name of the location scrolling across the frame.
Tim Smith
"Family History"
I am researching my family history and some members of my family moved to Derbyshire in 1891. I know they lived in Somercotes and Alfreton and worked in the mines. I am intrigued as to the conditions they had to work in and in what kind of mine they would be working.
One relation I am particularly interested in is Thomas Olney, also known as David Olney, who died in 1897, at the age of 48 years, of Phthisis Pulmonalis Haemoplsis and his occupation was described as Colliery Banksman.
Are there such things as lists of workers? I would like to find out which mine he and other members of the family would be working.
Any information, or any direction to which I may be pointed, would be appreciated.
Mrs A A Fountaine, 19 Metcalfe Grove, Blakelands, MILTON KEYNES, MK14 5JY.
Roger Gosling
John A. Knight
The Trevithick Trust is pleased to announce that they have now opened the King Edward Training Mine near Camborne to the public. It will be fully open to visitors in 2002. There will almost certainly be an underground experience for visitors to the mine.
Stuart B Smith, The Trevithick Trust, Chygarth,5 Beacon Terrace, CAMBORNE, TR14 7BU. Tel: 01209 612142
Cornwall County Council has awarded the management contract for the Geevor Tin Mine Heritage Centre to Pendeen Community Heritage for a three year period. Pendeen Community Heritage is a group of local people with connections with Geevor Tin Mine who are committed to the development of the Geevor site - the largest heritage mining site in Britain - as a world class mining museum.
The contract began on 1 October 2001.
Bill Lakin, The Pendeen Community Heritage, , Bojewyan House, PENDEEN, Cornwall, TR19 7TR. Tel: 01736 787312
Roy Paulson
There are currently two proposals to extract methane gas for commercial use in the North Staffordshire area.
Take the hard work out of looking for books. The website is Britain's leading website set up in cooperation with to help members of literary and historical societies find old, rare and out-of-print books for sale in Britain in their own areas of interest.
This special website holds a selection changing each day of over half-a-million books published between 1600 and 1990 offered for sale between £5 and £5,000 by some 600 British booksellers in just about any subject you can think of.
The Clique, founded in 1890 and the world's longest, established specialist publisher of information on old, rare and out-of-print books, have now started issuing an annual cd-rom series of price-guides in this field. The new 2001 edition contains the current catalogue prices of 420,000 old books in all subjects published between 1600 and 1990.
Members can now obtain copies of this invaluable UKBW 2001 Windows cd-rom for £48. Further details are available from The Clique, 7 Pulleyn Drive, York YO24 lDY. Tel: 01904 631752 or from their website at www.clique.co.uk.
Prof Macklin of the Institute of Sciences and Geography at Aberystwyth University has stated that agricultural land in the Vale of Yorkshire has been contaminated by high levels of lead following recent heavy flooding. He states that the contamination could take 50-100 years to clear.
The research showed that 75% of the flood sediment samples taken along a 110km length of the River Swale exceeded Government guidelines for the maximum permitted lead concentrations in land upon which livestock grazes. The contamination comes from waste tips in former upland mining areas. Simulations of lead movement in the River Swale up to 2060 show that flooding in Swaledale and the Vale of York will continue to deliver contaminates to agricultural land.
At the moment, it is not known how much of this contamination could possibly get into the food chain. Is the contamination relevant if it does not get into the food chain?
The Rivers Clyde, Tyne and Aire systems are also contaminated in a similar manner.
Chris Irwin (Farmers Guardian- Sept 2001)
Ivor Brown
THE 5th INTERNATIONAL CONGRESS ON SOUTERRAINS AT LIVERPOOL
Following a successful presentation at the 2000 International Symposium on Souterrains in Croatia, the Friends of Williamson's Tunnels were invited to host the event on our own shores in 2002. The 5th International Congress on Souterrains, otherwise known as 'Souterrain2K2', will take place from 8th to 12th August this year in Liverpool.
The friendly gathering of underground enthusiasts from around Europe is a growing event and offers discussions, presentations of papers and visits to subterranean features around the conference location. This year's Liverpool event will include visits to the likes of an old (underground!) Overhead Railway station and tunnel, the working Cheshire Salt Mines, the hidden workings of the road tunnel under the Mersey and, the hosts' pet favourite, the strange 19th century Williamson's Tunnels. There is a daily charge of about £20 which covers meals, transport, facilities, etc. and delegates can join in for as many of the four days as they like.
Enthusiasts from NAMHO member organisations are invited to attend this congress, - even make a presentation or present a paper (all AV equipment is provided). Booking (as early as possible) is essential and details are available on the event web site: www.souterrain2k2.co.uk.
Otherwise, please contact the organiser, Chris Iles, tel: 07976 848 458.
Bill Douglas
1. "Tarmac Papers Vol IV", edited by R W D Fenn. Published in 2000 by Tarmac Ltd, Millfields Road, Ettingshall, Wolverhampton, WV4 6JP - Cost unknown. A5 soft covers, 343 pages - many diagrams and photos, some coloured. The production of these volumes has made available much detail on the history and archaeology of quarry sites and it is unfortunate that this volume is said to be the "last of the series". This volume maintains the high standard of the earlier volumes and in about 15 chapters covers such topics as Bronze Age Mines (West Sussex), Anglo Saxon settlements (Lincolnshire), the discovery of a Mammoth at Hoveringham and limekilns in Camarthenshire. There are also chapters on the "Cistercians and quarrying", the "Worshipful Company of Paviors" and "Nash Rocks" on the Welsh Borders.
Dr I J Brown
2. "Colossal Earthmovers" by K Haddock. Published in
2000 by MBI Publishing Company, USA. Available from Classic
Tractors, Low Green Farm, Hutton, Driffield, YO25 9PX. Cost
£9.99 post free. 996 pages, 21cm x 23cm, hardback. The large
machines once so familiar in the UK surface mines are now a dying
breed, as is their variety for they are now being replaced by
hydraulic shovels and dump trucks. Very few examples of the
earlier machines are likely to be preserved but fortunately
several new books have become available specialising in
photographs supported by captions. One such book is Colossal
Earthmovers and, although it only shows one machine in Britain
(the only preserved "Walking Dragline" in the world at
St Aidans opencast site at Leeds) with over 90 colour photos, it
is excellent value. If action is not taken soon, photos and
models will be all that can be seen in the UK of any large cable
excavators, stripping shovels, bucket wheels and continuous
planing machines. Take the opportunity now to study them before
all is lost!
Dr I J Brown
3. "Mining in Cornwall - Vol 4, Hayle, Kerrier &
Carrick" by L J Bullen. Published 2001 by Tempus in their
Images of England series. 126 pages, about 210 photos. ISBN 07524
2133 6. Cost £10.99. This is the 4th book on Cornish Mines in
this series, and more are expected. Each photo is captioned and,
considering the age of some of the photos, are surprisingly
clear. There is very little "introduction" or
"preamble" in this volume, it being assumed that the
reader is familiar with the introduction in the previous volumes
in the series. The photos show a great variety of plant and
equipment. Some are most unusual, such as an old Cornish Engine
House being used as an orebin and the manufacture of Cornish
shovels using tilthammers. Cornwall has been fortunate to have so
many persons roving around the area with cameras and it must be
unique in that so many photographs were taken of structures and
equipment without people! Whilst many of the photos are from the
early years of the 20th Century, a good number are from the
period 1960 to 1985 when so many of the mines where reopened for
prospecting. This is a fine reminder of those days when Britain
produced much of its own requirements of tin.
DR I J Brown
4. "West Shropshire Mining Fields" by Ivor J Brown.
2001. Tempus Publications Ltd., The Mill, Brimscombe Port,
Stroud, Glos. GL5 2QG. 128 pages. ISBN 0 7524 23263 0. Cost
£10.99. This little book is largely a collection of some 200 old
photographs (black & white) of the western half of the
Shropshire mining fields. These cover the Snailbeach,
Tankerville, Pennerley. Bog, Roman Gravels and several other
lesser lead mines, as well as barytes and copper mines, together
with associated mills, smelt houses and railways. A short chapter
on the Shrewsbury and northwest Shropshire coal mines is
included. The photos provide a valuable record of a defunct
industry, many showing installations which have now disappeared.
There are many groups of miners whose descendants probably still
live in the area. The book starts with a short introduction to
the area, but the sketch of the geological setting is very brief
with little said on the vein pattern or on the gangue minerals.
Each photograph has a full caption and each mine or group has
about one page of introductory historical text. These all make a
useful summary of the mining activity of the region, but it is a
pity that plans of the mineral veins, mine workings and mine
building layouts are confined to a few small sketch-maps. There
is no plan at all of the largest mine complex, Snailbeach, and as
one not so familiar with the area, I found placing some of the
photos difficult. There is a comprehensive bibliography, but some
of the entries are incomplete, lacking details of volume numbers
or publishers.
Dr T Ford
The deepest mine in the USA is likely to become a physics laboratory. Homestake Gold Mine at Lead, South Dakota, is one of the country's oldest mines and will shortly be closed. It is now over 2200m deep and the cost of conversion to a physics laboratory is likely to cost $280m. Part of the mine is already being used as a laboratory and it is intended to convert another part into an underground visitor centre to promote local tourism and ease the unemployment situation.
I J Brown (World Tunnelling Dec 2001)
NAMHO members who are aware of the Williamson's Tunnels in Liverpool will be interested to know that further major excavation work has taken place over recent months.
The Friends of Williamson's Tunnels joined forces with their colleagues at the Joseph Williamson Society to dig tons of rubble out of one section of the Georgian philanthropist's labyrinth, in order to open that section as a permanent visitor attraction from April this year. These excavations have exposed even more striking features of the labyrinth.
Currently the Friends of Williamson's Tunnels are preparing plans for submission to the local council to begin similar clearance work at another section of the tunnels, including the underground 'Banqueting Hall'. Details and photos are available at the web site: www.williamsontunnels.com.
Bill Douglas
The Beaconsfield Gold Mine in Tasmania was worked from 1877-1914. During that time over 1m tons of rock was hoisted and crushed to produce some 854,000 ounces of gold.
Gold mining started as the mining of alluvial gold in 1877 but a rich 400 yard reef was soon discovered. The three mines which worked this reef were very wet despite the installation of much expensive pumping equipment. The mines were consolidated in 1888 but eventually the water beat the miners. The cost of pumping became prohibitive and the mine was closed in 1914.
The Grubb Shaft site has been converted into the Grubb Shaft Gold & Heritage Museum.
This well established museum has become a major tourist attraction. It features a 3D model of the mine workings at the time of closure in 1914, a working model of the historical water pumps, a working 12 head stamp battery driven by a waterwheel, a complete shaft set from the Hart Shaft and old pumping equipment together with extensive photographic and other records of the old mine.
The Hart Shaft area is the New Gold Mine at which a drilling programme has indicated that the ore body will yield as much gold as the old mine. Following an extensive pumping programme, the first gold ingots from this mine were poured in 1999.
Dave Penny
The bodies of three Mexican miners were recovered and 10 were missing, presumed dead, after an accident flooded a small coal mine in northern Mexico, trapping the miners 200 feet below ground.
Four divers and about 150 other rescue workers battled against black water and collapsed tunnels in an attempt to recover the bodies from La Espuelita Coal Mine in Barroteran, about 90 miles southwest of the Texas border city of Eagle Pass.
The accident occurred Wednesday 23 January 2002. The mine is a privately owned operation known as a "pocito", where thin seams of coal are mined using methods of work that generally violate Mexican safety standards. The mine has only one vertical shaft which is used for access and coal drawing. Mines with single vertical shafts are illegal in most countries, including Mexico, because they offer no escape route if the shaft becomes blocked.
The Authorities have not determined the cause of the accident, but rescuers and mine veterans said miners digging for coal likely broke through to an adjacent abandoned tunnel that had flooded.
The disaster in Barroteran is the second in Coahuila's coal-mining region in four months. In September, a dozen miners died when a mine exploded in the village of Santa Mara, about 30 miles north of La Espuelita.
Roger Gosling (San Antonio Express-News)
Hon Secretary & Editor
Wes Taylor, 18 Station Lane,
Walton on Trent, Swadlincote, Derbys, DE12 8NA.
Tel:- 01283 713315
E-Mail: firstname.lastname@example.com
NAMHO web site: www.namho.org
Registered Charity No 297301
Registered Office, c/o Peak District Mining Museum, The Pavilion, South Parade, Matlock Bath, Matlock, Derbyshire, DE4 3NR. Tel:- Matlock (01629) 583834.
The contents of this publication are in the public domain. There is no restriction on the publication of articles from this Newsletter provided acknowledgement of the source is made in any subsequent publication. Opinions expressed in this publication are those of the authors and do not necessarily reflect the opinion of the National Association of Mining History Organisations. Copy submitted for publication is not checked by the Editor for accuracy
Return to Welsh Mines Society Home Page


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Kristen was featured in the Great Dane Review magazine.
UKC Rau Dane's Key Largo RN CD
aka "Humphrey Bogart"
DOB - September 10, 2005
Sire: Am Ch. UKC Ch. Prin-Zel's J. Barrymore v Rau, CGC, TDI
Dam: RauDane's Kaleidoscope, "Kali"
Isis - RauDane's Return To Innocence on the left - Bo is on the right
He was the only boy in his litter.
Isis on the left and Bo on the right
Bo is napping after a taping session! He is a very good boy! (04/01/2006)
Am Ch. UKC Ch. Prin-Zel's J. Barrymore v Rau, CGC, TDI
Barrymore is Bogart's father and is owned by Debbi Deniston of Prin-Zel Great Danes.
Moses, CH Chanoz Chosen One, is Bogart's Grandfather. Moses is owned by another club member, Lori Beilke of Chanoz Great Danes.


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Orange Dreamsicle 50th Anniversary Large Jar Candle
About This Fragrance
A favorite childhood summer treat you never outgrow. . . a cool blend of orange and vanilla ice cream.
Fragrance Notes:
Top: Citrus Zest, Lemon Peel
Mid: Juicy Orange, Sweet Mandarin
Base: Creamy Vanilla, Confectionary Sugar, Malt
Top note is the initial impression of the fragrance, middle note is the main body of the scent and base is its final impression.
About Large Jar Candles
Here's the perfect size candle for all your go-to fragrances. You'll get the longest burn out of its 22-oz. size—"perfect for all those dinner parties, lazy Saturdays and a season's worth of little moments. Details you should know? Each is made in America with premium-grade paraffin of the finest quality ingredients from around the world. And each wick is straightened by hand to ensure the very best quality burn. (110-150 hours burn time)
110 to 150 hours
Premium-grade paraffin wax that delivers a clean, consistent burn.
Premium quality ingredients with natural essential oils create distinctive true-to-life scents
Lab-tested to ensure the appropriate strength and consistency. 100% recyclable and accepted by most recycling centers.
Lead-free, 100% natural fibers, and hand straightened to ensure it is centered for the best burn possible.
22 oz
4" x 6.6"
We Also Recommend


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Here are the online marketing strategies that will grow your business beyond imagination:
1. Content marketing
You can use content marketing in various forms to accomplish several goals. For instance, you can create a blog to market your services or publish ebooks and then invite customers to sign up for your services or purchase your products. Come up with a broad content marketing strategy for your business and implement it consistently. Content marketing is useful and valuable to any business. In fact, your customers will expect you to have it in some form.
2. Personal branding
Successful entrepreneurs can lead startups to generate tons of momentum. By branding yourself, you leverage a more trustworthy image to promote your brand. A brand identity gives you the privilege of meeting other business people and learning from them. It also gives you the power to network and form partnerships with entrepreneurs. In terms of monetary perspective, you can brand yourself almost for free. However, you will require a significant amount of time.
3. Search engine optimization (SEO)
Successful search engine optimization will make your website more friendly to Google and improve your site's visibility on the internet. As a result, your organic traffic will increase because more people will access the services and products that you offer. You need to implement both on-page and off-page optimization so as to get the full benefits of SEO. Additionally, search engine optimization is a continuous process.
Related : SEO Tips for Beginners
4. Email marketing
Email marketing involves sending electronic mails to current or potential customers. The purpose of these emails is to acquire new customers or convince existing customers to buy something immediately. Email marketing is also aimed at creating and strengthening customer-firm relationships. Email marketing is one of the cheapest channels of advertising your products and services. You can advertise your business to hundreds of customers using a single email. Start by emailing your existing customers and use other opportunities such as social media to grow your mailing list. You can do it yourself or engage an email marketing agency.
5. Social media marketing
Social media marketing is a powerful way of achieving your marketing goals. It involves creating and sharing content on social media in order to reach prospects and customers. You can bring remarkable success to your business using social media platforms such as Twitter, Facebook, Pinterest and Instagram. Social media marketing involves activities like posting videos, text and image updates. These activities will increase audience engagement and drive more traffic to your website.
6. Conversion rate optimization
Conversion rate optimization is the process of increasing the percentage of visitors who take a desired action on your website. For example, if you sell products, you would want your visitors to make a purchase. Conversion rate optimization involves understanding the behavior of your visitors in terms of how they move through your site and what stops them from taking the intended action. You also need to know what to optimize and who to optimize for.
All the above online marketing strategies work together. This means that you cannot achieve success by relying on one method of marketing. While these marketing strategies can be pursued individually, each connects with the others in some way. Therefore, the best practice is to utilize an integrated marketing approach where all these strategies are implemented simultaneously. If you pursue them all, you will realize even higher returns than you expected.


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"Everyone has (or I presume should have) particular favorites among Shakespeare's plays, however much they worship Falstaff, Hamlet, Lear, and Cleopatra. Mine are Measure for Measure and Macbeth."
Sexual Hypocrisy in Vienna! An Introduction to William Shakespeare's Measure for Measure By Dennis Abrams ———————————— Although it's set in Vienna, Measure for Measure, Shakespeare unsettling comedy of sex in the city, seems to reflect more closely than anything else … Continue reading
Posted in Uncategorized Tagged Angelo, Barnardine, Comedy, drama, Elizabethan theater, entertainment, Introduction, language, literature, Lucio, Measure for Measure, moral decline, politics, problem play, renaissance humanism, sex, sexual hypocrisy, Shakespeare, tragedy, Troilus and Cressida, Vienna, William Shakespeare 26 Comments


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A program started in the Foothill-De Anza Community College District, geared toward encouraging the widespread adoption of "open textbooks," has grown rapidly since it was founded two years ago and was recently recognized by an interstate educational organization for its achievements.
The College Open Textbook Collaborative was honored on Nov. 12 by the Western Interstate Commission for Higher Education's Cooperative for Educational Technologies Outstanding Work Award. The WOW award recognizes the innovative use of technology in higher education.
Foothill-De Anza's Open Textbook Collaborative touts the use of digital textbooks with very flexible copyright restrictions in community colleges across the country.
The seeds for the collaborative were sown in 2007 after two professors at De Anza College, Barbara Illowsky and Susan Dean, decided that the statistics textbook they had coauthored was too expensive for many students. The two professors worked to buy the copyright back from their publisher and then published their work through Connexions, an online open educational resource repository. Students can now access their text for free and professors can pick and choose which portions of their text they would like to use in the classroom.
This approach, according to Una Daly, associate director of College Open Textbook Collaborative, is helping students get a better education and graduate earlier, especially at the community college level, where the cost of a semester's textbooks can often dwarf the cost of tuition.
Students in community colleges are often there because they cannot afford to go to a four-year school, Daly said. When those students are faced with steep textbook costs, they often choose to drop the course requiring those texts, try to get by without buying the texts or put off buying the texts until they can afford them.
"For students who are at that edge this can really make a difference," Daly said. "With an online textbook they can start using it on day one. They aren't denied the textbooks because of a lack of ability to pay."
Many students say that they prefer physical texts to digital ones, Daly said, but she believes as the technology improves these complaints may decrease. Daly is also a faculty member in the computer technology and information systems department at Foothill College.
Since it was founded in 2008, the collaborative has identified and cataloged more than 500 open community college textbooks and now counts more than 200 community colleges across the United States as members. Almost 150 of the textbooks in the collaborative's database have been peer reviewed.
These open textbooks are often free when accessed online and cheap -- between $20 and $60 -- if students want to download a copy to their computer or order a physical copy.
In addition, the flexible copyright rules allow professors to pull only those segments of a text pertinent to their lesson plans.
"Professors don't frequently find a textbook that matches their class exactly," Daly said.


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Mini Photo Prints
Our Mini Photo Prints are a simple and classy way to showcase your digital photos as quality and sturdy prints. Give them away to your friends, stick them in a scrapbook or on your walls, or carry a few in your wallet. You can print these in a square crop for a retro look, or with a 3mm white border.
pocket-sized prints


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National Oil suspends staff over Sh100 million 'lost' fuelSunday, February 17, 2019 22:00
The National Oil Corporation of Kenya (Nock) has suspended seven employees over lost Sh100 million fuel, according to preliminary findings.
The seven who are charged with stock taking were interdicted following a forensic audit on the loss that occurred between 2016 and 2018.
Nock chief executive MaryJane Mwangi said the company had invited the Directorate of Criminal Investigation (DCI) to take over the investigations.
"The DCI was actually at our offices on Thursday investigating the matter. They are supposed to be interviewing those people who had to step aside because … we don't want to run the risk of documents getting lost," she told the National Assembly Energy Committee on Thursday.
Those interdicted include the finance manager, management accountant, stock accountant, depot controller, distribution manager, territory manager and commercial manager.
Ms Mwangi said findings by auditors (KPMG) indicated that 900,000 litres were lost.
"Some of the key people who were involved in that loss when they realised what they had done they resigned," she said.
She added that Nock was waiting for the final audit report to quantify exactly how much product was lost and its value.
This is the second case the DCI is investigating at Nock in a span of six months.
It is also looking into fraudulent contractors that supplied 67,251 faulty gas cylinders under the Mwananchi gas project.
In the Headlines
Ndegwa unveils plans as he takes helm at SafaricomBy PAUL WAFULA
Local airlines seek Sh3bn bailout as coronavirus bitesBy BONFACE OTIENO
1 hour ago
Zuku reclaims top fixed internet spot from SafaricomBy JOHN MUTUA
7 hours ago
Thousands to reapply for varsity, diploma coursesBy OUMA WANZALA
10 hours ago


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Author Archives: slaterr
Sharks Holiday 2019
Sharks 2019 Holiday quote for Wengen From 16th – 23rd February 2019 (aprox 80 – 90 people / every 25 paying 1 free HP) 1 welcome drink 7 Nights' Accommodation 7 Continental buffet breakfasts 5 four course dinners with 3 choices of main course 6 Children menu up to 11 yrs 1 Cheese fondue dinner 1
Fun Races
Hi Sharks Two upcoming fun slalom races to announce: PENDLE FUN TEAM SLALOM EVENT The final meeting in Pendle's Winter Race League is Saturday 3rd March. Please register your interest with me now as I'll be submitting the teams Thursday 1st March. This is a fun Slalom event traditionally well represented by 'Sharks'. The order
Cancelled 17th February
Dear All, as the more observant among you will have noticed, we are in the middle of the Winter Olympics. You may also be aware that 4 Sharks athletes are competing in the Games this year. This Saturday Katie Summerhayes will be competing in the Slopestyle Competition (heats at 1am, and final starting at 4am).
Sharks Holiday 2019
I know that it is only October 2017, and we have not yet had our 2018 holiday in Champoluc, Italy, BUT – I am already planning our Sharks 2019 Ski holiday. Details as follows: – Date – 16th – 23rd February 2019 Venue – Falken Hotel, Wengen, Switzerland (The 'spiritual home' of Sharks) Cost –
Membership Renewal
Dear Sharks Members, It is that time of year again, when membership renewals are due. Please download the renewal form from our website, fill it in and bring it with you to your next Sharks Skiing Session, along with your membership renewal fees. 2017SharksMembershipForm Look forward to seeing you all soon, Regards Lucy Ridgeway Membership
Holiday Update
Please find attached important information about our ski trip to Champoluc in Italy next year. If you are already booked on, then please look at the information about ski groups. If you are thinking of joining us, then there are still a few places left, so get booking as soon as you can. Full details
Nick Hill
Always try to be on time but was very late to finally start skiing. After a childhood of watching Ski Sunday my first go on planks was in my mid 40s when as a family we were able to give Tom and Molly the opportunity to ski that we never had as children. Professional designer
Nicky Parr
I didn't start skiing until I was an adult, after a spectacularly failed attempt by Cam to make me a snowboarder – now both kids are much better skiers than I will ever be. Professionally I have worked at BT and Openreach for 20 years, and am a qualified CIMA accountant. Currently Head of Finance
Millie and Tom
Club Captains Please download our welcome leaflet here SHARKS Welcome Flyer


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Product Description
Wilton Large Performance Round Cake Tin Set
This Large Round Cake Tin Set from Wilton have been made from a quality aluminium that will hold its shape for years. The even-heating aluminium means that these pans are perfect for uniform baking.
Each pan has a generous 3″ depth for higher cakes. This set includes four different, sized pans ranging from 8″ to 14″.


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Alaska Native Adult Tobacco Survey Guidance Manual
Guidance Manual
This manual is a guidance tool for health professionals who plan to implement the Alaska Native Adult Tobacco Survey (AN ATS) in Alaska Native villages and communities. The AN ATS manual contains methods and strategies that organizations will need to conduct a scientifically rigorous survey. It also includes step-by-step guidance on how to conduct the AN ATS, technical information, and resources.
- Appendix A: Advance LetterCdc-pdf PDF [ 27 KB]
- Appendix B: Household ScreenerCdc-pdf PDF [ 154 KB]
- Appendix C: Informed ConsentCdc-pdf PDF [ 61 KB]
- Appendix D: Readability of the Informed Consent FormCdc-pdf PDF [ 77 KB]
- Appendix E: "Sorry I Missed You" CardCdc-pdf PDF [ 35 KB]
- Appendix F: ReceiptCdc-pdf PDF [ 64 KB]
- Appendix G: Cognitive Evaluation HighlightsCdc-pdf PDF [ 135 KB]
- Appendix H: Tribal Permission LetterCdc-pdf PDF [ 56 KB]
- Appendix I: Interviewer Training ManualCdc-pdf PDF [ 461 KB]
- Appendix J: Survey (Household List Version)Cdc-pdf PDF [ 722 KB]
- Appendix K: Survey (Member List Version))Cdc-pdf PDF [ 913 KB]
Page last reviewed: February 15, 2018


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NCAA Women's Golf Regionals: ASU, Stanford hold top spots heading into final round
Lubbock, Texas Regional
The Sun Devils turned in a strong second round to further solidify their first-place rank in Lubbock, Texas on Tuesday. Monica Vaughn moved to the first spot in the individual ranks with a 4-under score. She birdied six times, including on the 18th hole. Linnea Strom and Olivia Mehaffey also finished 3-under for the day.
.@SunDevilGolf catches fire to stretch lead at NCAA Lubbock Regional, while the top seed it in trouble: https://t.co/oc8LLGAtCr
— Golfweek (@golfweek) May 9, 2017
A strong round from Texas Tech pushed the Ducks down to third place after round two. Marcella Pranovia followed her 4-over round one with an astounding 5-under on Tuesday. Cathleen Santoso, who held a second-place spot on the individual leaderboard, fell to 10th with a 3-over round.
The Bruins dropped to sixth place, tied with Kent State and three strokes behind Texas. Lilia Vu, who led individuals after round one, fell to fourth with a 2-over second round.
The Beavs sit in 10th place after a strong performance from Susie Cavanaugh, who carded a 1-under round. Olivia Benzin and Nicole Schroeder were right behind Cavanaugh, going even par on the second day.
Alivia Brown, representing the Cougs as an individual in Texas, moved up in the ranks to a 28th spot after a 1-over round. Excluding players on teams in advancing position, Brown currently sits in 14th on the individual leaderboard and will need to do some work to reach one of the top-3, advancing spots.
Way to go Livs! She fought hard & finished the day strong! She shot 73 (40-33) & currently sits T28th @ +5. #GoCougs pic.twitter.com/Yqy1PsLddD
— WSU Women's Golf (@wsu_womensgolf) May 9, 2017
Albuquerque, New Mexico Regional
The Card reclaimed the lead that was lost midway through yesterday's first round thanks to spectacular performances by a trio of golfers. Albane Valenzuela took the top spot among individuals after a 3-under performance in round two. Shannon Aubert finished 1-under and Andrea Lee bounced back from a 3-over day to card a 2-under score Tuesday to pace Stanford. Casey Danielson also had an unusual visitor as she finished her round:
Look who showed up on #18 to watch Casey's drive!! Helped her hit a 287 yard bomb! #bullsnake pic.twitter.com/9hmBpMQPDn
— Stanford WGolf (@StanfordWGolf) May 9, 2017
The Trojans maintained their third-place position after round two thanks to yet another strong performance from Victoria Morgan. Morgan finished the first round with a par score and followed that up with a 1-under score in round two. Muni He, who finished 1-under, and Robynn Ree, who finished 2-under, paced the Trojans heading into Wednesday's final round.
Marthe Wold bested her 1-under score on Monday with a 2-under round two to keep the Bears in fifth place and qualifying contention. Maria Herraez Galvez finished the day at even par.
The Huskies sit at sixth just behind the Bears. Julianne Alvarez birdied five times and recorded a 3-under score to give her team – the reigning NCAA champs – a much-needed boost.
.@j_alvarez143 sinks her fifth birdie of the day on hole 18 to finish 3-under and is currently tied for second #NCAAWGolf pic.twitter.com/4S51knyPhf
— UW Women's Golf (@UW_WGolf) May 9, 2017
Athens, Georgia Regional
The 'Cats moved up two spots to spot on Tuesday in Georgia. Gigi Stoll followed her 1-over performance with a par in round two to give her team some momentum. Krystal Quihuis still leads Arizona, finishing with a 2-over round two after her 1-under on Monday.
Columbus, Ohio Regional
The Buffs moved up a spot on the leaderboard to ninth place, but sit just five strokes back of qualifying position. Brittany Fan birdied five times to finish 2-over in the second round and Kirsty Hodges recorded a par score to pace her team.
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