text:
- Open Access
Mechanistic added value of a trans-Sulfonamide-Platinum-Complex in human melanoma cell lines and synergism with cis-Platin
Molecular Cancer volume 16, Article number: 45 (2017)
Cisplatin is a potent antitumor agent. However, toxicity and primary and secondary resistance are major limitations of cisplatin-based chemotherapy, leading to therapeutic failure. We have previously reported that mono-sulfonamide platinum complexes have good antitumor activity against different tumoral cell lines and with a different and better cytotoxic profile than cisplatin. Besides, N-sulfonamides have been used extensively in medicinal chemistry as bactericides, anticonvulsant, inhibitors of the carbonic anhydrase, inhibitors of histone deacetylases, and inhibitors of microtubule polymerization, among others.
We aimed to compare the cytotoxic effects of cisplatin and a trans-sulfonamide-platinum-complex (TSPC), in two human melanoma cell lines that differ in their TP53 status: SK-MEL-5, TP53 wild type, and SK-MEL-28, TP53 mutated. We performed cytotoxicity assays with both drugs, alone and in combination, cell cycle analyses, western blotting and immunoprecipitation, and fluorescence immunocytochemistry.
TSPC had similar antiproliferative activity than cisplatin against SK-MEL-5 (3.24 ± 1.08 vs 2.89 ± 1.12 μM) and higher against SK-MEL-28 cells (5.83 ± 1.06 vs 10.17 ± 1.29 μM). Combination of both drugs inhibited proliferation in both cell lines, being especially important in SK-MEL-28, and showing a synergistic effect. In contrast to cisplatin, TSPC caused G1 instead G2/M arrest in both cell lines. Our present findings indicate that the G1 arrest is associated with the induction of CDKN1A and CDKN1B proteins, and that this response is also present in melanoma cells containing TP53 mutated. Also, strong accumulation of CDKN1A and CDKN1B in cells nuclei was seen upon TSPC treatment in both cell lines.
Overall, these findings provide a new promising TSPC compound with in vitro antitumor activity against melanoma cell lines, and with a different mechanism of action from that of cisplatin. Besides, TSPC synergism with cisplatin facilitates its potential use for co-treatment to reduce toxicity and resistance against cisplatin. TSPC remains a promising lead compound for the generation of novel antineoplastic agent and to explore its synergism with other DNA damaging agents.
Cisplatin (cis-diamminedichloroplatinum(II) or CDDP) is one of the most successful traditional antitumoral metal compounds used in oncology. Its mode of action is mediated by its interaction with DNA to form DNA adducts, which activate several signal transduction pathways leading to cell death [1, 2]. However, it is associated with different adverse side effects, such as dose-limiting nephrotoxicity, peripheral neuropathy, electrolyte disturbance, tinnitus and hearing loss . In addition, primary or secondary resistance to CDDP may occur, leading to therapeutic failure [2, 4]. Many platinum compounds have been designed with the aim to broaden the spectrum of activity, reduce side effects, and overcome resistance to CDDP [5–8].
On the other hand, N-sulfonamides have been used extensively in medicinal chemistry as inhibitors of histone deacetylases and microtubule polymerization, among other targets [9–11]. Besides the large number of publications concerning to the use of sulfonamides, the synthesis of platinum compounds containing sulfonamides in their structure has been scarce. The most promising results are given by those compounds which activate alternative signaling pathways [12, 13]. Therefore, research on new metallodrugs remains an area of interest, especially those with different mechanisms of action from CDDP.
Recently, we published the synthesis and evaluation of a series of trans-sulfonamide platinum complexes showing antitumor activity . Among these compounds, trans-Dichlorido [(rac)-2-(5-(dimethylamino)naphthalene-1-sulfonamido)cyclohexylamino] (dimethylsulfoxide)platinum(II) (hereinafter TSPC), (Fig. 1) demonstrated similar or superior activity than CDDP against a panel of tumor cell lines, including melanoma. Melanoma is a particularly aggressive cancer that has poor prognosis due to resistance to multiple chemotherapy regimens, including in most cases CDDP [15, 16]. This highlights the urgency of implementing treatment strategies for melanoma with more effective and less toxic novel drugs.
Therefore, we decided to study several mechanistics aspects of TSPC in two melanoma cell lines with a different TP53 status: SK-MEL-5 (TP53 wild-type) and SK-MEL-28 (TP53 mutated) . TP53 is a tumor suppressor protein that facilitates antitumor drug response using a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis , whose role in the mode of action of CDDP has been extensively described . These functions usually cease once TP53 mutates, as occurs in nearly 50% of cancers, and some TP53 mutants even exhibit gain-of-function effects, which can lead to even greater drug resistance . It is therefore important to test the effectiveness of new drugs in TP53 mutants.
In this study, we show the in vitro antitumor activity of TSPC and CDDP in these melanoma cell lines and mechanistic differences in cell cycle effects. We also aim to explore if these differential effects might be used as a basis for a synergism between both compounds.
Cell lines and reagents
Human melanoma cell lines SK-MEL-5 and SK-MEL-28 were obtained from American Type Culture Collection (ATCC, Manassas, VA) in February 2010. Low passage cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin and 2 mM L-glutamine, under standard culture conditions (37 °C, 95% humidified air and 5% CO2). RPMI 1640 and other culture materials were from Lonza Ltd. (Verviers, BEL). TSPC was synthesized and characterized in the Inorganic Chemistry Department of the Universidad Autónoma de Madrid (Spain), as previously reported . CDDP was obtained from Selleck Chemicals LLC (Houston, TX). Drugs were dissolved in dimethyl sulfoxide (DMSO) at 100 mM of stock solution, and stored at −20 °C until use.
Briefly, cells were seeded in a 96-well flat-bottom plate at 5000 cells/well and cultured for 24 h prior to exposure to CDDP or TSPC at varying concentrations, from 0 to 100 μM for 72 h. For combination assays, cells were treated with CDDP ranging from 0.5 to 10 μM and two different doses of TSPC (1 and 5 μM). Results were expressed as a percentage relative to vehicle-treated control (0.1% DMSO was added to untreated cells). Viability was determined using the WST-1 method (Roche, Mannheim) following the manufacter’s instructions. The 50% inhibitory concentration (IC50) was calculated by nonlinear regression fit of the mean values of the data obtained in at least three independent experiments using GraphPad Prism software version 5.0 (San Diego, CA).
The type of drug interaction was analysed by the Chou-Talalay method . This method provides a combination index (CI) that allows quantitative determination of drug interactions, where CI < 1, 1, and >1 indicate synergism, additive effect or antagonism, respectively, considering synergism as more than additive effect and antagonism as less than additive effect. This method also provides a dose reduction index (DRI) that measure how many-fold the dose of a drug can be reduced in combination with respect to the drug alone. The CI and the DRI were calculated using the CompuSyn software (Comb ComboSyn Inc, Paramus, NJ).
Cell cycle and apoptosis analysis
Cells were treated for 24 h with equimolar concentrations of either CDDP or TSPC. The cell cycle progression was examined by flow cytometry after staining with propidium iodide (PI). DNA content and cell cycle analyses were performed by using a FACScalibur flow cytometer and the CellQuest software (Becton Dickinson Biosciences). Apoptosis was studied with the APO-BrdUTunel assay kit (Life Technologies Inc. Gaithersburg, MD) following the experimental protocol provided by the manufacturer, and analyzed with a FACScalibur flow cytometer and the CellQuest software (BD Biosciences). All experiments were performed in triplicate.
Western blot and immunoprecipitation assays
Cells untreated (control) or treated with equimolar concentrations of either CDDP or TSPC for 24 h were lysed with MCL1 lysis buffer in the presence of protease and phosphatase cocktail inhibitor (Sigma-Aldrich Co. LLC, St Louis, MO) following the manufacter’s protocol. Total protein concentrations were determined using the BCA protein assay kit (Thermo Scientific Meridian Rd, Rockford, IL). Protein lysates (30 μg) were subjected to SDS-PAGE on 15% polyacrylamide gel. The separated proteins were transferred on to PVDF membrane followed by blocking with 5% non-fat milk powder (w/v) in TTBS (10 mM Tris, 100 mM NaCl, 0.1% Tween 20). Membranes were probed for the protein levels of TP53, CDKN1A (p21Cip1), CDKN1B (p27Kip1), CDKN2B (p15INK4b), CDK2, CDK4, CCND1 (Cyclin D1), CCNE2 (Cyclin E2), phospho-CDK1 (P-cdc2) and GAPDH using specific primary antibodies (Cell Signaling Tech Inc, Danvers, MA) diluted 1/1000 in blocking solution followed by peroxidase-conjugated appropriate secondary antibody (Santa Cruz Biotechnology Inc, Dallas, TX), and visualized by Immun-Star WesternC kit (Bio-Rad) detection system. Results were scanned with Image Quant LAS 4000 Imaging densitometer and quantify with Image Quant TL software (GE healthcare, Life Sciences). To ensure that control cells gave reproducible baseline protein levels, we carefully maintained cells cultures in a constant semiconfluent and logarithmically growing state throughout each experiment.
Pierce Classic IP Kit (Thermo Scientific) was used for immunoprecipitation assays, and manufacturer’s instructions were followed. Thereby, 1 mg of protein was immunoprecipitated using CDK2 primary antibody (Cell Signaling Tech Inc, Danvers, MA). The immune complex eluted was subjected to SDS-PAGE and trans-blotted into PVDF membranes as described above. Membranes were probed for the protein levels of CDK2, CDKN1A and CDKN1B.
Cells were cultured in coverslip glasses for 24 h with equimolar concentration of either CDDP or TSPC. Untreated cells were used as control. After exposure to the drugs, cells were fixed with 4% formaldehyde and permeabilized with PBS/triton (0.1%). For immunofluorescence labeling, cells were incubated with anti-human CDKN1A (1:1000) or CDKN1B (1:1000) monoclonal antibodies (Cell Signaling Tech Inc, Danvers, MA) followed by a secondary antibody conjugated to Alexa Fluor 488 (Life Technologies Inc; Gaithersburg, MD). Nuclei were stained with 2-(4-amidinophenyl)-1H-indole-6-carboxamidine (DAPI) (Life Technologies Inc. Gaithersburg, MD). Images from six to ten fields per sample of at least three independent experiments were taken with a LSM 510 Meta Confocal Microscope (Zeiss, Germany).
To study the effects of duration of platinum exposure on cell proliferation, cells were treated with CDDP or TSPC at their corresponding IC50 for 72 h, or with CDDP 1 μM (SK-MEL-5) or 3 μM (SK-MEL-28) and TSPC 1 or 5 μM in combination assays. After this time, cells were washed with PBS and put in drug-free medium to recover. Viable cell number was assessed with Trypan blue and a Neubauer chamber for 7 days of recovery.
Results are expressed as the mean ± SD, and data are representative of at least three different experiments. Analysis of variance (ANOVA) one way, followed by Dunnett’s t-test was used to examine differences between groups. For recovery experiments, cell growth was fit to a Gompertz function, typical of cell growth and characterized by a lag period, an exponential and a saturation phase. All the statistical tests were conducted at the two-side 0.05 level of significance.
TSPC inhibits growth and induces G1 arrest in human melanoma SK-MEL-5 and SK-MEL-28 cells
Based on our promising previous work with TSPC  we decided to study its effect in two melanoma cell lines: SK-MEL-5 (TP53 wild-type) and SK-MEL-28 (TP53 mutated). First, we analysed TSPC antiproliferative activity. As shown in Fig. 2a, TSPC treatment inhibited the growth of human melanoma SK-MEL-5 and SK-MEL-28 cells in a dose-dependent manner. The IC50 of this compound (3.24 ± 1.08 μM) was similar to the one obtained with CDDP (2.89 ± 1.12 μM) in SK-MEL-5, and significantly lower (p < 0.05) in SK-MEL-28 (5.83 ± 1.06 μM vs 10.17 ± 1.29 μM).
Next, we examined its effect on cell cycle progression and in apoptosis induction. Consistent with the results on cell growth inhibition, TSPC treatment for 24 h induced a significant (p < 0.05) increment of cell number in G1 phase in both melanoma cell lines (Fig. 2b), whereas CDDP treatment induced S arrest, as has been previously described elsewhere . Apoptosis was not observed by TUNEL assay after 24 h treatment with neither CDDP nor TSPC, which is consistent with the subG1 cell population identified in cell cycle analyses (Figs. 2b and c). These effects were apparent in both cell lines after a 24-h exposure to any of the two compounds.
Effect of TSPC on G1 cell cycle regulators
Based on the G1 arrest induced by TSPC in both cell lines, we assessed the effect of this compound on the cell cycle regulatory molecules that play important roles in G1 phase of cell cycle progression. TP53 is the most important tumor suppressor protein associated with the G0-G1 arrest in cell cycle, and a key protein in CDDP mode of action and resistance. Since SK-MEL-28 has a mutation in TP53, we also examined the protein expression of the cyclin-CDK inhibitors (CKIs) CDKN1A (p21Cip1), CDKN1B (p27Kip1), and CDKN2B (p15INK4b).
Western blot analysis showed that TSPC treatment strongly increased the protein levels of CDKN1A and CDKN1B and had no effect on TP53 levels in both cell lines (Fig. 2d). The observed strong induction in CDKN1A and CDKN1B protein levels by TSPC was not due to an overall change in protein levels as confirmed by probing the same membranes with GAPDH antibody (Fig. 2d). Thus, treatment of SK-MEL-5 and SK-MEL-28 cells with TSPC caused an increased in CDKN1A and CDKN1B expression, with correlated with the G1 arrest at 24 h. Conversely, CDDP increased the protein levels of TP53 in both cell lines accompanied by an increase in CDKN1A in SK-MEL-5 but not in SK-MEL-28. CDDP also slightly decreased the protein levels of CDKN1B in both cell lines. No differences were observed in CDKN2B levels with any treatment.
We also assessed the effect of TSPC on the protein levels of CDKs and cyclins involved in G1 phase and G1 to S phase transition of cell cycle. As shown in Fig. 2d, drug treatments did not show any detectable change in the protein levels of CDK2 and CDK4, and only a slight increase in cyclin D1 with TSPC in SK-MEL-5 was observed. On the other hand, cyclin E2 levels were strongly increased by CDDP, and conversely reduced by TSPC in both cell lines.
In order to assess the mechanism of action of CDDP in the absence of TP53, we also examined the phosphorylation state of CDK1 (cdc2), which have been shown to be associated with S and G2/M arrest and with CDDP mechanism of action. Western blot analysis showed that CDDP treatment strongly induced the protein levels of phospho-CDK1 in both cell lines, while TSPC had no effect (Fig. 2d). Densitometric analysis of proteins from Fig. 2d is show in Fig. 3.
TSPC inhibits CDK2-cyclin E via CDKN1A and CDKN1B
Since up-regulation in CKIs levels was observed, and these proteins exert their inhibitory effect and G1 cell cycle arrest by direct binding to CDK2-cyclin E complexes, we next examined CDK2-CKIs binding by immunoprecipitation assay. As shown Fig. 4, TSPC treatment showed an increased binding of CDKN1A and CDKN1B with CDK2 in both cell lines. CDDP also showed an increased binding of CDKN1A, bigger than that observed with TSPC in SK-MEL-5.
The inhibitory effect of CKIs on CDK-cyclin complexes occurs in the nucleus, so we next examined by immunofluorescence and confocal microscopy the localization of CKIs in this cell lines. As shown in Fig. 5a, both CDKN1A and CDKN1B were mainly localized in the nucleus in untreated cells. TSPC exposure induced an increase of CDKN1A and CDKN1B in the nucleus in SK-MEL-5 and SK-MEL-28, while CDDP treatment seemed to slightly modified CDKN1B levels in both cell lines. No CDKN1A staining was perceivable in SK-MEL-28 in control and CDDP-treated cells. Confocal images matched the results obtained by western blot (Fig. 2d).
In addition, we determined the percentage of nuclear CDKN1A and CDKN1B staining in cell lines exposed to CDDP or TSPC. As shown in Fig. 5b, cells treated with TSPC had a higher percentage of nuclear CDKN1A and CDKN1B than cells treated with CDDP (SK-MEL-5: CDKN1A 25.36 ± 11.53 vs 5.45 ± 4.16; CDKN1B 54.04 ± 10.36 vs 30.70 ± 8.85) (SK-MEL-28: CDKN1A 15.31 ± 5.28 vs 1.5 ± 0.63; CDKN1B 62.11 ± 10.50 vs 23.53 ± 8.31). No significant changes of CDKN1A and CDKN1B subcellular location were observed after treatment with CDDP. By contrast, a significant increase in the nuclear staining of both CKIs after exposure to TSPC was seen.
TSPC in combination
Once analysed the effect of TSPC on cell cycle and cell growth, we next examined how long this effect would last. Cell treated with TSPC recovered a normal proliferation rate after drug removal. However, cell treated with CDDP did not recover (Fig. 6a). Seeing these results, as well as the differential effects in cell cycle, we thought it could be interesting to explore evidences for synergism using both drugs in combination. As shown in Fig. 6b, addition of TSPC to CDDP increased cell death in a dose dependent manner in both cell lines, being especially important in the case of SK-MEL-28 with TSPC 5 μM. In fact, the analysis of these drugs interaction by the Chou-Talalay method showed that this increment in cell death was due to a synergistic effect between the drugs (CI < 1; logCI < 0) in SK-MEL-28 at almost every dose and, in SK-MEL-5 at the highest doses of CDDP (Fig. 6c). Due to this synergism, there was a favourable DRI (DRI > 1; logDRI > 0) in CDDP dose and in some doses of TSPC in SK-MEL-5 and in both CDDP and TSPC in SK-MEL-28 (Fig. 6d).
Taking into consideration this synergism we studied whether cells treated with both drugs in combination were able to recover after drug removal. For this purpose we treated cells with CDDP at a dose lower than their respective IC50: 1 μM (SK-MEL-5) or 3 μM (SK-MEL-28), and TSPC 1 or 5 μM. In all the cases cells recovered in the same way (Fig. 6e).
Platinum complexes are widely used in cancer therapy. The successful clinical applications of CDDP have inspired the synthesis and investigation of numerous platinum compounds as drug candidates. All the commercially available platinum compounds are based in a cis-isomerism.
In this study, the cellular and molecular effects of the trans-platinum derivative TSPC were investigated and directly compared with those of CDDP in SK-MEL-5 and SK-MEL-28 melanoma cell lines. The choice of these cell lines were made on the basis of TP53 status, and in our previous cytotoxicity results in a panel of different cell lines .
TSPC showed to be as active as CDDP in SK-MEL-5 and more active in SK-MEL-28, the TP53 mutant line. TP53 plays a very important role in CDDP cytotoxicity , so it is not surprising that a TP53 mutant line show some resistance to this drug [21, 22]. On the other hand, and according to the results obtained in this work, TSPC mode of action is clearly TP53-independent, as there is no change in this protein levels after TSPC treatment, neither in SK-MEL-5 nor in SK-MEL-28 cell lines.
Upon 24 h incubation with TSPC, cells were arrested in G1 phase that suggest cell cycle delay for a DNA damage response, DNA repair and/or apoptosis. One goal of this study was to define the cell cycle regulatory pathway responsible for the G1 arrest. The results obtained in these two cell lines with different TP53 status show that TSPC inhibits cell proliferation through cell cycle arrest at G1 phase, likely due to the up-regulation of CDK inhibitors CDKN1A and CDKN1B. Progression through the G1 phase of the cell cycle is controlled by CDK4-cyclin D complexes, while CDK2-cyclin E complexes are required for proper G1/S transition and initiation of S . CDKs are negatively regulated by the binding of CDK inhibitors. INK4 family inhibitors, as CDKN2B, prevent cyclin D binding to CDK4, while CDKN1A and CDKN1B bind to CDK2-cyclin E complexes and inhibit CDK2 activity . Our results showed that neither CDK4, nor cyclin D1, nor CDKN2B were affected by TSPC in SK-MEL-28 cells. Only a slight increase in cyclin D1 was observed in SK-MEL-5 cells but such levels might be insufficient to induce G1 progression effectively. However, CDKN1A and CDKN1B protein levels were clearly enhanced after TSPC treatment, and cyclin E2 levels were reduced in both cell lines. Besides, co-immunoprecipitation assays showed that both CDKN1A and CDKN1B bind to CDK2 after TSPC treatment. Thus, it can be inferred that TSPC induces G1 arrest in SK-MEL-5 and SK-MEL-28, via CDKN1A and CDKN1B binding to CDK2-cyclin E complexes in a TP53-independent manner (Fig. 7). The cell cycle arrest is a common cellular response to DNA damage and is viewed as a delay period in DNA replication during which the cell can attempt to repair the damage. If this attempt fails, cell death pathways will be activated [25, 26]. Our present findings indicate that the G1 arrest is associated with an induction of CDKN1A and CDKN1B proteins, and that this response is also seen in melanoma cells containing TP53 mutated.
On the other hand, cells incubated with CDDP were arrested in S and G2/M phase. Several reports have previously described that CDDP induces S- and G2/M-phase arrests in a sequential manner . These arrests are associated with phosphorylation and proteosomal degradation of CDC25 phosphatase, with the consequence that CDK within the CDK2/cyclin A and CDK1/cyclin B complexes remain in the inhibitory tyrosine phosphorylated state . Besides, CDKN1A can bind these CDKs and inhibit these complexes , and as an inhibitor of CDC2 phosphorylation, CDKN1A can be involved in both G1 and G2 cell cycle arrest . Our data from the present study are in line with these previously published studies as CDK1 remain phosphorylated after CDDP treatment, and CDKN1A binds to and inhibit CDK2. However, this setting is different to that of TSPC, where CDC2 remains hypophosphorylated. So, it seems that TSPC has a different mode of action from that of CDDP.
The cell cycle regulatory function of both CDKN1A and CDKN1B is associated with its nuclear localization, but the protein can also localize in the cytoplasm where they could exert different functions . In the nucleus, in addition to the regulation of the cell cycle progression, CDKN1A and CDKN1B are also involved in a variety of transcriptional responses . In the cytoplasm, CDKN1A can initiate antiapoptotic responses by inhibiting proapoptotic kinase ASK1  or by binding to procaspase 3, thus preventing its proteolytic activation . In a more general sense, it has been suggested that the subcellular localization of CDKN1A defines its function as a tumor suppressor (nuclear localization) or oncoprotein (cytoplasmic localization) . Indeed, some human cancers display elevated levels of cytoplasmic CDKN1A or cytoplasmic CDKN1B, which is associated with poor prognosis [35–38], and badly response to cisplatin based treatment [39, 40]. In our experiments, the increased nuclear localization of CDKN1A and CDKN1B in both melanoma cell lines after TSPC treatment supports the antitumor activity of this compound.
Recovery experiments showed that while CDDP effect, at least at IC50 dose, was permanent, TSPC treatment was transitory. This is not necessarily a negative result, but it implies that TSPC treatment should be frequent. Thus, in regard to clinical treatment, it would be useful to find an easy and sequentially way of TSPC administration.
CDDP is one of the most potent antitumor agents known. However, toxicity and resistance are major limitations of CDDP-based chemotherapy [1, 2]. Thus, the potential for use of TSPC in combination with CDDP was explored in terms of eventual synergism. In both cell lines tested, our data show a synergistic effect and a favorable DRI when cells are simultaneously treated with both CDDP and TSPC, which could lead to resistance minimization. This synergy is likely to be due to the mechanistic differences between CDDP and TSPC.
In this study we present a new promising TSPC compound with in vitro antitumor activity against SK-MEL-5 and SK-MEL-28 melanoma cell lines, with a different mechanism of action that of CDDP. From our results it can be inferred that TSPC induces cell cycle G1 arrest probably mediated by CDKN1A and CDKN1B inhibitors in a TP53-independent manner. CDK2-cyclin E complexes are required for G1/S transition. By co-immunoprecipitation assays, we show that CDKN1A and CDKN1B bind to CDK2 after TSPC treatment, inhibiting CDK2 activity. Besides, synergy between TSPC and CDDP facilitates its potential use for co-treatment to reduce toxicity and resistance against CDDP. On the other hand, TSPC remains a promising lead compound for the generation of novel drug candidates with different cytotoxicity profiles from those of CDDP. Moreover, these results could have therapeutic implications for TSPC, because the majority of human solid tumors contain a mutant TP-53 or deleted TP53 gene and are inherently resistant to commonly used DNA-damaging agents.
Cisplatin or cis-diamminedichloroplatinum(II)
Dose reduction index
Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47):7265–79.
Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–83.
Gasser G, Ott I, Metzler-Nolte N. Organometallic anticancer compounds. J Med Chem. 2010;54(1):3–25.
Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, et al. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One. 2014;9(2), e88193.
Dilruba S, Kalayda GV. Platinum-based drugs: past, present and future. Cancer Chemother Pharmacol. 2016;77(6):1103–24.
Herrera JM, Mendes F, Gama S, Santos I, Navarro Ranninger C, Cabrera S, et al. Design and biological evaluation of new platinum(II) complexes bearing ligands with DNA-targeting ability. Inorg Chem. 2014;53(23):12627–34.
Cetraz M, Sen V, Schoch S, Streule K, Golubev V, Hartwig A, et al. Platinum(IV)-nitroxyl complexes as possible candidates to circumvent cisplatin resistance in RT112 bladder cancer cells. Arch Toxicol. 2017;91(2):785–97.
Ma J, Wang Q, Yang X, Hao W, Huang Z, Zhang J, et al. Glycosylated platinum(iv) prodrugs demonstrated significant therapeutic efficacy in cancer cells and minimized side-effects. Dalton Trans. 2016;45(29):11830–8.
Chang JY, Hsieh HP, Chang CY, Hsu KS, Chiang YF, Chen CM, et al. 7-Aroyl-aminoindoline-1-sulfonamides as a novel class of potent antitubulin agents. J Med Chem. 2006;49(23):6656–9.
Liu Z, Zhou Z, Tian W, Fan X, Xue D, Yu L, et al. Discovery of novel 2-N-aryl-substituted benzenesulfonamidoacetamides: orally bioavailable tubulin polymerization inhibitors with marked antitumor activities. ChemMedChem. 2012;7(4):680–93.
Del Solar V, Quinones-Lombrana A, Cabrera S, Padron JM, Rios-Luci C, Alvarez-Valdes A, et al. Expanding the synthesis of new trans-sulfonamide platinum complexes: cytotoxicity, SAR, fluorescent cell assays and stability studies. J Inorg Biochem. 2013;127:128–40.
Cossa G, Gatti L, Zunino F, Perego P. Strategies to improve the efficacy of platinum compounds. Curr Med Chem. 2009;16(19):2355–65.
Lovejoy KS, Serova M, Bieche I, Emami S, D’Incalci M, Broggini M, et al. Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells. Mol Cancer Ther. 2011;10(9):1709–19.
Perez C, Diaz-Garcia CV, Agudo-Lopez A, Del Solar V, Cabrera S, Agullo-Ortuno MT, et al. Evaluation of novel trans-sulfonamide platinum complexes against tumor cell lines. Eur J Med Chem. 2014;76:360–8. doi:10.1016/j.ejmech.2014.02.022.
Godoy LC, Anderson CT, Chowdhury R, Trudel LJ, Wogan GN. Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin. Proc Natl Acad Sci U S A. 2012;109(50):20373–8.
Alrwas A, Papadopoulos NE, Cain S, Patel SP, Kim KB, Deburr TL, et al. Phase I trial of biochemotherapy with cisplatin, temozolomide, and dose escalation of nab-paclitaxel combined with interleukin-2 and interferon-alpha in patients with metastatic melanoma. Melanoma Res. 2014;24(4):342–8.
O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, et al. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res. 1997;57(19):4285–300.
Martinez-Rivera M, Siddik ZH. Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem Pharmacol. 2012;83(8):1049–62.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440–6.
He G, Kuang J, Khokhar AR, Siddik ZH. The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog. Gynecol Oncol. 2011;122(2):402–9.
Park CM, Park MJ, Kwak HJ, Moon SI, Yoo DH, Lee HC, et al. Induction of p53-mediated apoptosis and recovery of chemosensitivity through p53 transduction in human glioblastoma cells by cisplatin. Int J Oncol. 2006;28(1):119–25.
Florea AM, Busselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers. 2011;3(1):1351–71.
Collins I, Garrett MD. Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol. 2005;5(4):366–73.
Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14(2):159–69.
Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 2002;1(8):639–49.
Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA. Activation of p21-Dependent G1/G2 arrest in the absence of DNA damage as an antiapoptotic response to metabolic stress. Genes Cancer. 2011;2(9):889–99.
Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, et al. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell. 2013;23(5):618–33.
Lavecchia A, Di Giovanni C, Novellino E. CDC25 phosphatase inhibitors: an update. Mini Rev Med Chem. 2012;12(1):62–73.
Romanov VS, Pospelov VA, Pospelova TV. Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis. Biochemistry (Mosc). 2012;77(6):575–84.
Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400–14.
Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 2003;13(2):65–70.
Abella N, Brun S, Calvo M, Tapia O, Weber JD, Berciano MT, et al. Nucleolar disruption ensures nuclear accumulation of p21 upon DNA damage. Traffic. 2010;11(6):743–55.
Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, et al. Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. Embo J. 1999;18(5):1223–34.
Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M. Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene. 1998;17(8):931–9.
Bales ES, Dietrich C, Bandyopadhyay D, Schwahn DJ, Xu W, Didenko V, et al. High levels of expression of p27KIP1 and cyclin E in invasive primary malignant melanomas. J Invest Dermatol. 1999;113(6):1039–46.
Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y, et al. Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res. 2004;10(11):3815–24.
Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 2000;183(1):10–7.
Winters ZE, Leek RD, Bradburn MJ, Norbury CJ, Harris AL. Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/neu in breast cancer and is an independent predictor of prognosis. Breast Cancer Res. 2003;5(6):R242–9.
Koster R, di Pietro A, Timmer-Bosscha H, Gibcus JH, van den Berg A, Suurmeijer AJ, et al. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J Clin Invest. 2010;120(10):3594–605.
Xia X, Ma Q, Li X, Ji T, Chen P, Xu H, et al. Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer. BMC Cancer. 2011;11:399.
The authors thank F. Bartolomé for assisting with confocal microscopy studies.
This work was supported by Fundación Mutua Madrileña (MMA 2013/0069). A.A.-L. received grant support from “Red Temática de Investigación Cooperativa en Cáncer” (ISCiii, Spain). E.P.-G., C.P., and C.V.D.-G., received grant support from Ministerio de Sanidad y Política Social (TRA-151, EC10-228) and from Fundación Mutua Madrileña (MMA 2010/018) (Spain). M.T.A.-O., received grant support from MINECO (Innpacto-2012-1311-300000, Spain). J.A. thanks the Spanish Government for their Ramón y Cajal contract.
Availability of data and materials
The authors declare that all data generated or analysed during this study are included in this published article.
JA, CN-R, JAL-M and MTA-O design the study. AA-L, EP-G, JA, CP, CVD-G, LP-R, SC, CN-R and, HC-F participated in the data collection and generation of results. JA, AA-L and MTA-O analyzed and interpreted data. AA-L and MTA-O drafted the article which was revised and approved by all authors.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
About this article
Cite this article
Agudo-López, A., Prieto-García, E., Alemán, J. et al. Mechanistic added value of a trans-Sulfonamide-Platinum-Complex in human melanoma cell lines and synergism with cis-Platin. Mol Cancer 16, 45 (2017). https://doi.org/10.1186/s12943-017-0618-7
- Cell Cycle control
- Mechanisms of action


Bass said three teams inquired about the availability of Davis before the NBA draft this week.They also feature other areas of memorabilia such as sports, historical and movie related items!Highest-Paid Athletes 1.But ultimately, it’s all going to come down to how we execute on Sunday and how they execute on Sunday.Spears of the Denver Post reports: The Denver Nuggets’ coaching search is taking a few different turns.
When I got the X-rays and they figured out it was broken, I went back and looked at how I did in those games and I ended up doing pretty good, he said.Hunt returned to football on Sunday, playing in an NFL game for the first time since he was suspended for eight games by the league following two violent, off-field altercations, one in which he shoved and kicked a woman during an argument.I didn’t do anything wrong.I have a lot of respect for him for where he came from.He was on a gaudy pace last season in his five starts.
A rematch is likely to take place in November or December, though a make your own football jersey is yet to be decided.In an odd circumstance, the best-of-seven 1912 create your own jersey design Series needed eight games to decide a winner.It can be an explosive package for us.I love to make spectacular plays.Head coach Dan Quinn led the Falcons to the Super Bowl only three years ago, but now it’s clearly time for him to go.Comfort with the franchise and making the best decision for his family were the main factors in staying.
Sportsnet cameras showed a handful of Sharks fans outside the arena getting psyched up to go watch Game 6.Before long, Witt was surfing Long Beach and Lido Beach before practice and flying to Hawaii, Costa Rica, Nicaragua, even South Africa in the off-season.The Rangers reconvene for practice on Monday, and conclude their homestand on Tuesday night against the Tampa Bay Lightning, when they will try to return to what propelled them to their rout of the Sabres.Cesar Ruiz C Michigan New Orleans 25.
– Jon Martin NOTE: listed Holiday custom jerseys as his favorite holiday song, which we 100% agree with, but unfortunately is not available on Spotify so cannot be included in the playlist.We got ourselves in the spot we’re in, we’ve got to grind our way out of it.
Guys understand we need to be here.Washington fans might lead the pack in terms of unreasonable, unfounded optimism about their team.Jay Cutler looked good throwing the ball.
8 – Rajon Rondo scored 11 points Saturday on 4-of-8 shooting as the Los Angeles Lakers topped the Golden State Warriors 125.49ers EDU is out front in using sport to promote STEAM literacy and we are excited to partner with Jesse and the 49ers on this program.We were winning our battles in the O-zone and in the D-zone, so we just got to stick with it and keep that momentum going for us in the second game.Unhealthy Ingredients: High fructose corn syrup, caramel coloring You’ll find this on our list of 20 Foods Pretending To Be Something They’re Not.We just wanted, behind Romo, to develop a quarterback for the future.
With that, here is a ranking of the 25 best MLB teams of the 2010s.New York is cognizant of the fact that Gleyber Torres and Aaron Judge among others will soon need significant raises, and the Yankees also know pitching is the reason they lost in the ALCS.As a result, they’re unlikely to affect your health by a significant amount.


text:
EAST BRUNSWICK, N.J. — Bluestar Silicones has announced it has named Freeman Manufacturing and Hisco Inc. as its two authorized national U.S. distributors for the company's moldmaking and aerospace silicone product lines.
"We are excited by the experience and service focus these two distributors bring to our moldmaking and aerospace customer base in the U.S. marketplace," said Reeshemah Chatham, market manager for Moldmaking and Sealing & Bonding markets in North America.
"Both Freeman and Hisco embrace and emulate our Bluestar Silicones model of providing service with a personal touch," continued Ms. Chatham. "We are confident that these two distributors can offer our customers the highest service levels and technical competencies in the industry. We are proud to partner with them."
Freeman Manufacturing & Supply Co. is headquartered in Avon, OH, and has 12 branch locations across North America. Hisco Inc. is headquartered in Houston, Texas, and has over 25 branch locations throughout North America.
Bluestar Silicones offers a full range of silicone solutions for the moldmaking and special effects markets. The company recently launched a website dedicated to moldmaking at www.bluesilmoldmaking.com.

domain: economics


text:
Group's quilts comfort families of sick children
BURLINGTON – The whirring of sewing machines and chatter fill the Boone County Senior Center in the R.C. Durr YMCA on a cold.
The women inside chat and laugh as they cut, place and sew materials for blankets that will be donated to the Ronald McDonald House in Cincinnati.
It's the second time the group has met for the Comfort Quilts for Kids program. Groups around the area participate in the program, but this is the first group in Northern Kentucky.
Nora Kelly, from the Harrison, Ohio, area, started the program six years ago. In that time, different groups have made more than 5,000 quilts.
She was led to start the program from "up above." Urged to "make a quilt," Kelly says "I didn't need to make a quilt and it was loud and clear to make a quilt, so I had to take classes."
Kelly witnessed volunteers making blankets for a hospital on a quilting trip to Hershey, Penn., "and that's where I thought 'I wonder if this is where I'm being led,'" she said.
According to the Ronald McDonald House Charities Greater Cincinnati website, rmhcincinnati.org, they provide a "home-away-from-home" for families and children receiving medical treatment at Cincinnati Children's Hospital Medical Center and other area hospitals.
The Cincinnati house has served more than 23,000 families since opening in 1982 and serves 46 states and 30 countries, the site reads.
Each family entering the Ronald McDonald House receives a welcome bag with a few items, including a quilt.
The quilts are all "very individual, just like the children," Kelly said.
"I think it's a tremendous way for the whole Greater Cincinnati area ... to support what the Ronald McDonald House does for ... not just our community but the whole world," Burlington quilter Joan Walter said. "They help children and families from all over the world, so it's a great way for the Cincinnati community to support them."
Senior center director Diana Tripp says one of the YMCA's main goals is social responsibility.
"So the idea of being able to get seniors involved in something that helps others, especially children, we were just thrilled to death," she said. "We thought it was a fantastic match."
"As part of our mission at the YMCA, we constantly look for ways in which we can support our community outside of our walls," said R. C. Durr YMCA executive director Jacob Brooks. "The Ronald McDonald House is such a wonderful establishment and does a great job of meeting the needs of families who are experiencing a difficult situation. We are pleased to take part in the Comfort Quilt program as a way to support the Ronald McDonald House and hopefully put a smile on the face of a child who is in their care.
"The Comfort Quilts program also allows for our active older adults to utilize their talents and support a cause that (they) believe in as well."
The group meets noon to 3 p.m. on the fourth Monday each month at the Boone County Senior Center at the R.C. Durr YMCA, 5874 Veterans Way, Burlington. Participants don't have to be members of the YMCA.
For more information about the senior center, call 859-334-6518. For more information about Comfort Quilts for Kids, visit bit.ly/rmhquilts.
Want to continue the conversation? Tweet at @SSalmonsNKY

domain: news


. . . Peter Roskam, the Republican candidate for a House seat from a suburban Chicago district, who said during a debate with Tammy Duckworth, his Democratic opponent, that she wanted America to "cut and run" from Iraq.
Duckworth is a former National Guard pilot who lost both her legs in Iraq last year when her helicopter was shot down by a rocket-propelled grenade.


text:
This laundry room makeover is sponsored by The Home Depot. This post includes affiliate links. Have you ever seen a before picture where you think “good luck because that’s not even a room.”? This is one of those before pictures. Technically, this is my laundry room. Well, maybe saying “room” is too generous; spooky, dreary […]
Crystel Montenegro is the creative force behind "Crystel Montenegro Home," a thriving DIY blog born from a passion for home transformations on a budget. While navigating life with a husband in medical school and raising their growing family, Crystel discovered the empowering world of DIY. Her blog not only showcases her journey from simple tasks to complex projects but also serves as a beacon of inspiration for countless readers, proving that with a touch of creativity and determination, every home can be a masterpiece.

domain: artistic


text:
It has been ages since i last did a smokey eye, so i decided to try one out recently and this is how it turned out
|She just had to have a picture of herself taken first before i could take mine, lol. Isnt she cute?|
i cant remember what i used for the eyes but im quite sure it was the Bobbi Brown single shadows. As for face and lips, it was the usual.


text:
Hour of Code
Our Coding Club members have been invited to participate in the global Hour of Code today. We are running sessions throughout the day working around the various commitments our club members have.
Mr Pocock kicked off the first session looking at A.L.I.C.E the Artificial Intelligence Foundation. Throughout the day the club members will be using their Grok Learning subscription to explore the programming language Python to build a friendly chatbot called “Eliza”. Can she fool your friends into thinking she’s a human?
The Hour of Code is becoming bigger each year as more and more students from countries around the globe connect through coding.

domain: hobby


text:
Disappointingly, however, that is not the food system that exists.
It’s common to hear conversations about the problems with our “broken” food system that blame one culprit or indicate that there is one solution to potentially “fix” the myriad problems. In his book “Fair Food,” Oran B. Hesterman aptly points out that depending on who is speaking, the “problem with food” can be any of a number of things: pesticides, corporate agriculture, bad policy, too much processed food, soda machines in schools, genetically modified organisms, food deserts, subsidies, lack of food labeling, migrant labor, soil erosion, “Big Ag” lobbyists, unfair treatment of farmworkers, and more.
They are all correct.
In October of 2014, the James Beard Foundation hosted its fifth annual Food Conference. It brought together many of the most forward-thinking leaders currently focusing on food-systems change. On day one of the conference, Mark Bittman, the (now former) food writer for The New York Times, opened a conversation with the statement, “In order to change food, we have to change everything.”
He, too, is correct.
TAKING A CLOSER LOOK
Today there are an estimated 793 million people worldwide who are chronically undernourished. Most of these people do not know where or how they will get their next meal. In the US alone, in 2014, there were 48.1 million Americans who lived in food-insecure households; of those Americans, 15.3 million were children.
Allow me to repeat that: 15.3 million children in the US don’t know where they will get their next meal, or if they will get one at all. When was the last time you wondered if there would be anything for you to eat for your next meal?
Worse still, a child born in America today has a 1-in-3 chance of eventually being diagnosed with Type 2 diabetes. For a child of color, that number jumps to 1 in 2.
In Washington, DC, our nation’s capital, there are two neighborhoods that are eight miles apart. The difference between the average life expectancies in these neighborhoods is 16 years. The cause of this difference is not crime or disaster: it is diet-related illness. Those in predominantly white, affluent neighborhoods have access to the means to procure, prepare, and eat food that nourishes them. By contrast, those in the poorer, predominantly black neighborhoods of DC are having their lives cut short because they do not have access to the same kind of nourishing, healthy, sustainable food. There are many components to food access: geographic access, related to food deserts; financial access, in terms of healthy food being affordable; cultural access to having food that is appropriate for the communities in which it is being consumed; social access promoting the preparation and consumption of healthy food; and much more. Unfortunately, this food access challenge, one of many symptoms of our broken system, is not unique to DC. Poverty and poor health are a vicious, reinforcing cycle.
Here in the US, we have spent the last 300+ years building what has become our modern-day system. It started by using forced labor to work land that colonizers claimed as their own. With the Industrial Revolution, the system became capable of transporting food over long distances, enabling people to move to and thrive in cities and have fewer people produce enough food for the masses. After World War II, many munitions factories and chemical weapons producers became involved in industrial agriculture — producing tractors rather than tanks, tools rather than guns, and fertilizers and pesticides rather than war chemicals.
The US began to produce so much food that there was a surplus, and we began to sell the excess on the global market at prices that smallholder farmers in developing countries could not compete with. In an effort to help them compete, we have started exporting our model of food production, which is based on heavy chemical inputs and unmeasured externalized costs.
Meanwhile, not only are we sicker as a nation than we ever have been, but our industrial methods of food production are responsible for polluting our air, water, and soils, while at the same time reducing biodiversity. Our planet is warming at a rate that we can only hope to slow down, at best, in order to make the impending catastrophic changes manageable for our species — despite the ecological collapse of others. All in the name of “cheap” food.
The most recent dietary guidelines promoted by the United States Department of Agriculture include a plate of 50 percent fruits and vegetables. Yet our most recent farm bill appropriates 64 percent of its subsidies to corn, soybeans, and other grain, and 0.45 percent to fruits and vegetables. It is no wonder, then, that a burger and fries cost $4 and a healthy salad is $8. What would our food system look like if we aligned our policies and corresponding financial support to the nutritional guidelines we promote?
According to the Food and Agriculture Organization of the United Nations, there are an estimated 500 million family farms on the planet. On average, each of those farms has five people working on it. That means that roughly one-third of the human species works on smallholder farms worldwide. And yet we are actively trying to sell them a model that is currently making us and our planet sick — to the point where the future, if we continue on this path, does not have a healthy prognosis.
FIXING THE PROBLEMS
If we are going to fix food, we have to fix everything. This is what makes food not just a personal or political issue: it makes it a social justice issue. We cannot have an honest conversation about food until we have honest conversations about racism, classism, and sexism. We cannot talk about new solutions until we talk about the inequalities rife in politics, health care, education, or global trade agreements. We cannot propose ideas about how to feed the world until we acknowledge the perverse incentives created by short-term profit motives, the havoc wreaked by externalized costs, and how rapid climate change is going to upend food production as we know it. If we continue to approach food as if there is a one-size-fits-all solution for all communities, then we will continue to perpetuate these problems. Thankfully, there are a rapidly growing number of people who are taking back the food system and creating solutions that work with and for the communities in which they live.
“If we are going to fix food, we have to fix everything. This is what makes food not just a personal or political issue: it makes it a social justice issue.”
There are many others. Perhaps the most powerful group of people, however, are those who have not taken action yet. Everyone can do something to move toward rethinking what our food system could and should look like. What that something is depends on the individual; plant something, grow something, shop at a farmers market, advocate for a farmers market if your community doesn’t have one, vote for leaders who support better food policy, bring the food discussion to schools, and if nothing else, try to cook more. People tend to use a lot less high-fructose corn syrup, xantham gum, and monosodium glutamate when they prepare their own food.
For my part, I am humbled and honored to be able to commit my life to building a more equitable food system — after all, if we want to fix food, we have to fix everything. It will take decades to change the system, but if we’re going to have equitable access to sustainable, real, healthy food, we must work together to build something that will nourish the minds, bodies, and souls of future generations.
And maybe, just maybe, we can save our planet in the process.
Tom McDougall is a food systems activist based in Washington, DC. He founded 4P Foods, a Benefit Corporation, in 2014 in an effort to build a more equitable food system. Tom likes big ideas, collaborating with passionate people, camping, and eating kohlrabi. He can be contacted at [email protected].
4 individuals making a difference
RONNIE WEBB AND JOELLE ROBINSON, FOUNDERS OF THE GREEN SCHEME, are working to bring access to healthy food to low-income neighborhoods in Washington, DC. They work closely with members of different communities within the city to create solutions specific to their needs. They help establish urban community gardens, offer social entrepreneurship training and mentoring, provide nutrition and fitness classes, and more. They are empowering these communities to take back their right to healthy food by creating long-term solutions designed by and for local people.
NAVINA KHANNA, CO-FOUNDER AND FIELD DIRECTOR OF LIVE REAL, has committed her life to building a more just and sustainable food system. From her base in Oakland, CA, she uses the tools of community organizing, personal empowerment and grassroots activism from other social justice movements to build a more cohesive food movement in local, regional, and national food communities. She is advocating loudly for the idea that we can rebuild our relationships with one another, and with our planet, by rebuilding our relationship with food.
DANIELLE NIERENBERG, THROUGH HER ORGANIZATION FOOD TANK, is “building a global community for safe, healthy, nourished eaters.” Nierenberg and her team find and highlight innovative, sustainable ideas for alleviating hunger, obesity, and poverty around the world. She is organizing people and networks to not only be part of the conversation, but to take action on building a more just and equitable food system.

domain: food


text:
© 2019 The Author(s). Background: Given the limitation of pharmacological treatments to treat cognitive symptoms in patients with Major Depressive Disorder (MDD), cognitive remediation programs has been proposed as a possible procognitive intervention but findings are not conclusive. This study investigates the efficacy of an INtegral Cognitive REMediation (INCREM) that includes a combination of a Functional Remediation (FR) strategy plus a Computerized Cognitive Training (CCT) in order to improve not only cognitive performance but also the psychosocial functioning and the quality of life. Methods: A single blind randomized controlled clinical trial in 81 patients with a diagnosis of MDD in clinical remission or in partial remission. Participants will be randomized to one of three conditions: INCREM (FR + CCT), Psychoeducation plus online games and Treatment As Usual (TAU). Intervention will consist in 12 group sessions, of approximately 110 min once a week. The primary outcome measure will be % of change in psychosocial functioning after treatment measured by the Functional Assessment Short Test (FAST); additionally, number of sick leaves and daily activities will also be recorded as pragmatic outcomes. Discussion: To our knowledge, this is the first randomized controlled clinical trial using a combination of two different approaches (FR + CCT) to treat the present cognitive deficits and to promote their improvements into a better psychosocial functioning. Trial registration: Clinical Trials NCT03624621. Date registered 10th of August 2018 and last updated 24th August 2018.
- Clinical trial
- Cognitive remediation
- Computerized cognitive training
- Functional remediation

domain: medical


text:
2020 Verde River Watershed Report Card
Watershed report cards are powerful tools to describe ecosystem status, increase public awareness, and inform and influence decision makers to improve the health of a watershed. This is the first Verde River Watershed Report Card. It is the collective effort of dozens of stakeholders throughout the Verde watershed. Indicators in the report card were selected to assess the health of three different values in the Verde watershed: Water, Habitat, and Communities. Overall, the Verde watershed earned a score of 57%, a C+.

domain: biology


text:
Learning how to correct a marriage requires a lots of work. It takes each spouse to be www.mybeautifulbride.net/brazilian-brides/ aware of their very own emotions and find out to value themselves. This involves self-awareness, humility, and credibility. It also needs the relationship to get nurtured and improved. There is no fast solution for a romantic relationship.
First of all, you will need to understand the issues that are causing the relationship to break straight down. Make sure to speak openly and honestly about any kind of problems you could have with your partner. This means getting a dialogue and understanding your partners’ pros and cons. It also means forgiving each other for previous mistakes.
Forgiveness is vital when learning how to resolve a relationship. By finding out how to forgive your companion, you can move past the flaws you’ve made inside the relationship. You need to forget about the past and offer your partner the chance to prove all their worth. It could be difficult, nonetheless it’s a major part of restoration your relationship. Remember it might take time and effort to fix a relationship, thus be patient and try not to rush the process.
Speaking honestly on your partner is certainly probably the most effective ways following an accident a romantic relationship. You must consult your partner what they would do differently the next time, and be honest about the issues behind the issues. This will offer you a better concept of how to resolve a relationship and retreat to on the right track. If you can possibly do this, you can be certain your partner will certainly feel free to forgive you for your mistakes and start once more.
Another important part of learning to fix a relationship is always to accept your responsibility. You need to acknowledge that you caused the circumstance in the first place. If you are not ready to accept responsibility, your partner will have trouble assuming that you are seriously interested in fixing that. However , this step can be problematic and can be an excellent hurdle to overcome.
Last but not least, in order to understand how to fix a romantic relationship, you must understand how to give your spouse the freedom to be themselves. If you have been critical in the past, you may have to change your tendencies, and this is going to lead to romance repair. This procedure will also choose a partner feel better about themselves.
Understanding how to fix a relationship is mostly a process that will require hard work by both companions. Make sure that your lover is equally committed to producing the relationship do the job. Getting a relationship back on track will take period, but it is definitely possible. The most important factor is to be genuine with your partner regarding what’s bothering you. Using this method, your partner can feel closer to you, and you’ll end up being less likely to leave your frustration get the best of you.
Using a specialist therapist is a crucial step to fixing a relationship. The individual will help you reinforce emotional addition and value between the a couple. When lovers act improperly, insensitively, or non-collaboratively, the relationship will separate. Such habits are often a sign of inferior relating units, which are seen as a stonewalling, defensiveness, and struggling without restoration. Insecure relating models can cause critical health risks and may lead to severe relationship breakdowns.

domain: sociology


text:
Jacob W. Grimm (1785-1863) and his brother Wilhelm K. Grimm (1786-1859) pioneered the study of German philosophy, law, mythology and folklore, but they are best known for their collection of fairy tales. These include such popular stories as Red Riding Hood, Sleeping Beauty and The Frog Prince. Commonly referred to now as Grimm's Fairy Tales, their collection was published as Kinder-und-Hausmarchen (Children's and Household Tales, 1812-15). The brothers were born thirteen months apart in the German province of Hesse, and were inseparable from childhood. Throughout their lives they showed a marked lack of sibling rivalry. Most of their works were written together, a practice begun in… childhood when they shared a desk and sustained throughout their adult lives. Since their lives and work were so collaborative, it is difficult now to differentiate between them, but of course there were differences.- Jacob, who studied for a time in Paris, was fascinated with variant spellings of older words. He articulated "Grimm's Law," the rules of which are still used today to determine correspondences between the consonants of German and languages in the Indo-European family. Jacob was bolder and more experimental than Wilhelm, and was rumored to be a lively dancer. Throughout his life, Jacob kept rigidly to schedule and could be extremely focused on work that demanded close attention to detail. He never married, but was a loving uncle to Wilhelm's children. Jacob and Wilhelm Grimm are buried side by side in Berlin.
Bernadette Watts has loved to draw since her childhood in England. She created her first picture book under the influence of Beatrix Potter. Watts studied at the Maidstone Art School in Kent and is the illustrator of North South fairy tales The Snow Queen and The Ugly Duckling.


text:
Delphi Rubidoux was out of the country when her coven was tried and found guilty of breaking High Council Law. They were disavowed and their powers stripped from them. If Delphi is found on the island by the Council they will take her power. She's been hiding in fear of them for over a year. When she came home, she found it stripped by locals of almost everything that made it livable. She was alone with no furniture, no electricity, and no refrigeration. She hides in fear of the Council until local fisherman ventures out to the island and rescues her from loneliness and despair. But, Delphi's not alone. The ghost of Clovis Rubidoux who built the mansion on the island has been watching her. He's been waiting for
the spirit of his beloved Collette to return and has decided she hides in Delphi. When Branson arrives and gets Delphi's attention, the jealous wraith strikes. He's determined to reunite with Collette and believes he must sap Delphi's life force to release it. Branson has been told all his life to fear the evil witches out on Rubidoux island. He certainly doesn't expect to fall in love with one. Branson must unite with the other witch coven of the bayou to fight Clovis and save Delphi.

domain: literature


text:
HARRIS COUNTY, Texas - One of two brothers already facing charges in connection with a deadly birthday party shooting at a Cypress-area home is now charged with murder.
Randy Stewart is charged in the death of Qu'eric Richardson, who was shot and killed at a home in the 7300 block of Enchanted Creek in November 2013.
Stewart, 18, has been in the Harris County Jail since his November arrest and charged with aggravated assault with a deadly weapon in connection with the shooting.
In February of this year, Stewart and his brother, Marvin, were also charged with tampering with evidence. Marvin Stewart is not in custody.
Richardson, 17, and Arielle Olivia Shepherd, also 17, were killed, and about 20 others injured, when suspects started firing guns during a house party that had been advertised as a birthday celebration on Twitter and other social media networks.
Investigators are still actively looking into the death of Shepherd.
According to the Harris County Sheriff's Office, the gun in the tampering case has not been found despite an extensive search.
Anyone with information is urged to call Crime Stoppers at 713-222-TIPS or submit a tip via the iWatchHarrisCounty app.
Copyright 2014 by Click2Houston.com. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

domain: law


text:
Exactly how Does the bitcoin Swap Job?
The bitcoin phenomenon has created rather a hype in the economic planet, even amongst those who have certainly not read about it. A cryptocoin, or virtual currency, substitution, is actually merely a business that allows customers to trade digital unit of currencies or cryptosurfs for typical amount of money, such as typical fiat money or gold. The significant charm of trading bitcoin is actually that a person carries out not need to have to keep sizable quantities of money - in fact, the additional amount of money that you are actually securing, the much less unstable the market place will certainly be. This makes it best for little investors and folks living in remote places where banking and money are actually not conveniently readily available. Additionally, with the dryness of traditional possessions like gold, the existence of the sort of exchanging can provide an excellent means to branch out one's profile, irrespective of their danger tolerance level.
In its own a lot of general type, bitcoins are in fact a peer-to-peer digital money unit that functions without any central agency or even bank. Primarily, anybody can produce a distinct wallet referred to as a "bitcoin wallet" as well as allows their computer system to serve as a virtual hosting server where all transactions are actually refined. Deals are created in between managers utilizing their exclusive tricks. These deals are run through the Internet and could be checked out by any person worldwide.
As an ingenious innovation, bitcoins possess a couple of specific attributes that prepare it in addition to typical remittance systems. Initially, there is no third party associated with the method of transferring funds from one handle to an additional. Instead, each deal is actually completely secured to ensure that the person triggering the transaction recognizes precisely who is bring in the repayment and also at what address the cash is actually heading to be transferred. This function was just one of the primary reasons the bitcoin sensation ended up being therefore preferred to begin with - no one would certainly ever understand that a criminal would want to capitalize on the device as well as use it to acquire unauthorized funds.
Second of all, there is no bodily product that could be supported by a bitcoin. The bitcoin functions solely digitally. This creates it necessary that electronic unit of currencies including bitcoins have an integrated financial unit. Transactions are generally cleared up through "casting" pieces which are after that kept in a special paper phoned the" bitcoin journal". Purchases are actually recorded in this ledger, which is likewise known as the "blockchain", and also simply a single social ledger each time exist.
Purchases on the bitcoin are actually worked out through "bitcoin miners". When a transaction happens, the transaction gets documented in to the "blockchain" and is actually incorporated to the data bank.
The way how the bitcoin works is such that it makes use of a special kind of technology referred to as "bitcoin bladders". Through showing to various other customers of the bitcoin that the existing hash bitcoin is legitimate, a brand-new block can easily be actually added to the ledger.
Several styles of bodily areas and also providers approve as well as promise companies for the bitcoin substitution. There are additionally "virtual substitutions" like those located on online supply swaps like those NYSE and NASDAQ.
Any individual can engage in the buying and also selling of bitcoins with no one over the table. Along with no core authority to known as the gos, there is no stress for the bitcoin neighborhood to take or even reject any kind of offered deal.

domain: finance


text:
'MADELINE IN NEW YORK' to Launch N-Y Historical Society's July 2014 Exhibitions
New-York Historical Society has announced its July 2014 temporary and permanent exhibitions. Details below!
All exhibitions are presented at the New-York Historical Society unless otherwise noted.
July 04, 2014 - October 19, 2014
To celebrate the 75th anniversary of Madeline's publication, the New-York Historical Society will honor the beloved schoolgirl and her creator Ludwig Bemelmans with an exhibition of more than 90 original artworks. In addition to drawings from all six Madeline books, the exhibition will also feature Bemelmans' drawings of the old Ritz Hotel in New York, murals from a rediscovered Paris bistro, panels from the Onassis yacht, and a cache of fabrics based on an early picture book.
June 20, 2014 - February 08, 2015
Salon Style is a method of hanging a gallery that emphasizes the complexity and richness of a collection, often done in the collections of the European royal courts to connote taste and opulence. By the nineteenth century Salon Style was used by private art clubs to squeeze as many works into a gallery as possible. This installation displays numerous gems from the New-York Historical Society's permanent collection in nineteenth-century Salon Style, showcasing the depth and range of our holdings. Everything from self-portraits of Asher Durand to Hudson River School landscapes to religious and history paintings will be on view, in close proximity that unites these typically separate styles.
June 13, 2014 - September 21, 2014
The American Jewish Joint Distribution Committee (JDC) was founded in New York City in 1914 as a response to the plight of Jews in Europe and Palestine at the outset of World War I. Since then, JDC has become a premiere humanitarian organization helping Jews and non-Jews the world over in times of need. On the occasion of its 100 year anniversary, this exhibition will recount the history of the JDC from its creation to its most recent relief activities rebuilding Jewish communities of the former Soviet Union, and in aiding Filipinos in the wake of the devastation of Typhoon Haiyan. Included in this celebratory exhibition will be photographs, objects, and films that bring the JDC's poignant stories to life.
April 4, 2014 - August 17, 2014
To mark the 150th anniversary of the Civil War (1861-1865), the New-York Historical Society presents a groundbreaking traveling exhibition, Homefront & Battlefield: Quilts & Context in the Civil War, organized by the American Textile History Museum. The exhibition uses quilts, textiles, clothing, and other artifacts to connect deeply moving and insightful personal stories about the war, its causes, and its aftermath with the broader national context and public history.
March 14, 2014 - July 20, 2014
This exhibition covers the pioneering history of the African-American basketball teams that existed in New York City and elsewhere from the early 1900s through 1950, the year the National Basketball Association became racially integrated. Just after the game of basketball was invented in 1891, teams were often called "fives" in reference to their five starting players. Dozens of all-black teams emerged during the Black Fives Era, in New York City, Washington, Pittsburgh, Philadelphia, Chicago, Atlantic City, Cleveland, and other cities where a substantial African-American population lived. The Black Fives Era came to an end in the late 1940s with the growth in stature of black college basketball programs combined with the gradual racial integration of previously whites-only collegiate basketball conferences and professional basketball leagues. The overarching significance of the Black Fives Era is that it is as much about the forward progress of black culture as a whole as it is about the history of basketball. This history is relevant today not only as a realization of our collective basketball roots but also as a search for identity.
July 05, 2014 - September 28, 2014
Note: This exhibition takes place at House 18 in Nolan Park on Governors Island.
NYC & the Civil War, is presented by the New-York Historical Society in commemoration of the sesquicentennial anniversary of the war that divided the nation. The exhibition portrays the complexities that arose in our city during the period of the American Civil War. While there were no battles in New York, the city itself embodied many of the tensions that tore the nation in two. Using reproductions of photographs, newspapers, and works of art, our Student Historian Teen Leaders have curated a nuanced view of the Civil War showing multiple perspectives and many surprises. Located in Building 18 in Nolan Park, the exhibition is free and runs every weekend from July 5th through September 28th, and beginning July 12th will feature hands-on activities for all ages.
Explore 300 years of New York and American history through the eyes and lives of children of the past! The DiMenna Children's History Museum is a museum-within-a-museum and occupies the New-York Historical Society's entire lower level. It includes character-based pavilions, a children's library, a Whiz Bang Quiz Machine, and interactive exhibits and games. The DCHM encourages children to identify with the people whose enterprise and creativity changed the course of our history. All ages can enjoy and learn in DCHM, but the exhibits are targeted at age 8-13.
Dedicated to telling the story of America through the lens of New York, this new gallery features such works as a piece of ceiling from Keith Haring's "Pop Shop;" Here is New York, a rotating selection from the approximately 6,200 photographs taken by the people of New York City on September 11, 2001, and immediately afterward; History Under Your Feet, an educational scavenger hunt for visitors featuring our "history manholes;" and Liberty/Liberté, an installation by New York-based artist Fred Wilson. This permanent installation provides an overview of New-York Historical's diverse collections and orients visitors to the experiences and exhibitions waiting deeper in the Museum.
For more information, call (212) 873-3400 or go online at www.nyhistory.org.
MUSEUM AND STORE HOURS:
Tuesday - Thursday: 10 am-6 pm
Friday: 10 am-8 pm (pay as you wish from 6 pm-8 pm)
Saturday: 10 am-6 pm
Sunday: 11 am-5 pm
Adults - $19
Teachers and Seniors - $15
Students - $12
Children (5-13)- $6
Children (4 and under) -free


text:
Fallen Toronto Police Const. John Zivcic’s was laid to rest at Toronto Congress Centre on Monday. Tom Zivcic gave this emotional speech during his brother’s funeral.
Video: Composer Robbie Roth discusses ‘Flashdance the Musical’
680News music and entertainment reporter Rudy Blair speaks with composer Robbie Roth about how the music for Flashdance the Musical was created. The show runs from May 27-Jun. 8 at the Ed Mirvish Theatre in Toronto.


AN ORDINANCE APPROPRIATING THE AMOUNT OF P2,000.00 FOR THE EXPENSES OF THE SOUND SYSTEM TO BE USED DURING THE DA ACHIEVEMENT DAY ON NOVEMBER 5-6, 1991 OUT OF THE UNAPPROPRIATED SURPLUS OF THE GENERAL FUND, CY 1991.
(Sponsored by: Vice Mayor Gabino C. Redulla)
BE IT ORDAINED, by the Sangguniang Bayan of Maribojoc, Bohol, that:
SECTION 1: That the amount of P2,000.00 is hereby appropriated for the expenses of the sound system to be used during the DA Achievement Day on November 5-6, 1991 out of the unappropriated surplus of the General Fund, CY 1991.
SECTION 2: That this ordinance shall take effect upon approval.
Approved: October 24, 1991
Let copies be furnished the Budget Officer and the Municipal Treasurer, Maribojoc, Bohol for their appropriate action.
ATTY. JOSE E. VELOSO
ALBERTO E. ARANGOSO


text:
Officials spar over Hempstead Village makeover
The Village of Hempstead signed a major deal to redevelop its downtown business district.
Mayor Wayne Hall announced Tuesday that the developer Renaissance Downtown would head the project.
Donald Monti, the development company's CEO, says the project will add more than 10,000 construction jobs, 6,000 permanent jobs and more than $2 billion in economic activity.
But some residents say the project is too ambitious for the village's limited space.
The plan calls for turning 14 parking lots into sites for new buildings, which critics say will result in less parking, more traffic and overcrowding.
Hempstead Town Councilwoman Dorothy Goosby says it's especially problematic that the plan would replace a public parking garage on Washington Avenue with 336 new apartments.
Village Trustee Donald Ryan scolded Monti face to face.
"What you have done is a disservice to our residents, and I'm disappointed in you," Ryan said. "I'm sorry we brought you on as our master developer because your approach is simply for you and not for us."
But Mayor Hall maintains that the village needs the redevelopment, and says that the project has gone through many public hearings.
Opponents say they're exploring legal options to block the project. Groundbreaking is set for April.


text:
There was an election today in Colombia and the FARC lost by landslide. In every major city of Colombia hundreds thousands of people, all in white shirts went out to demand that the FARC stops violence, that it surrenders the bodies of the 11 provincial legislators who had been held as hostages for FIVE years and who were killed by the FARC. The FARC tried to pin the deaths on a military operation but so far it seems that there is only the FARC to be blamed for these deaths. It is known that the FARC hostage guards have orders to kill the hostages if they try to escape or if some authority were to stand a chance to free them.
Amazingly, part of the reason of the march is to reject the preposterous FARC demand that the bodies will only be returned to the grieving families if Uribe's government gives up control of some areas, demilitarization being an euphemism for FARC ruled areas where they can indoctrinate and recruit in peace poor peasants to be sent elsewhere in Colombia. Thus the FARC can keep perpetuating and drug lords can keep planting coca and laboratories to process cocaine. Oh yes, the paramilitary AUC are also involved in the lucrative drug trafficking, but that should not detract from the fact that the FARC has long been financing their "liberation" activities in part through drug trafficking, now made easy by the friendly Venezuelan government. That today the interior ministry of Venezuela, Pedro Carroña, claims again that his cops are increasing the volume of seized drugs does not mean he is telling us if it is due to a more efficient security system or to an increased drug passage through Venezuela.
Today images coming from Colombia were truly impressive. Medellin, Cali, Cartagena, Baranquilla, Bogota held at the same time immense rallies, even if it was a working day. I suppose that some activities were also held in minor centers but these news have not reached Venezuela. The fact of the matter is that the FARC has suffered a major PR set back and today's millions are the harbinger of a country becoming more resolute in confronting the FARC. The BBC in Spanish has a link with some pictures but Colombian newspapers tomorrow will surely have better material. By the way the BBC does not dare to pronounce the word million, probably still having a romantic look at the FARC, but the Colombian police reports 3.5 million in total for the 4 largest cities of Colombia.
And what has been Venezuela reaction after the announced murder of 11 Colombian hostages? Nothing until today, and just some declaration at the exit from our independence day ceremonies by our foreign minister Maduro. That is right, Venezuela had to wait for a week until finally it had some form of public, but informal, declaration. Everyday the sympathies of chavismo for the FARC are harder and harder to hide. Oh yes, there are regular declarations for peace in Colombia but whenever Venezuela is pressed on the FARC it dodges the issue with a lame "it is an internal issue of Colombia" while at the same time interfering with any other government that dares to express a slight dissension with Chavez. Colombia has to be the only government that chavismo "does not declare on". I mean, as a neighboring country I understand the prudence. But considering the track record of Chavez with other countries, the ambiguity in Colombia is at best hypocrisy.
But I am afraid that Colombia has more to fear from Venezuela than the ambiguity of whomever serves Chavez at Casa Amarilla. Venezuela is running ahead with its weapon purchases, and most of them from Russia now as apparently no one else is either willing to sell, or is deemed worthy enough of chavismo. Apparently the 5 submarines deal will go ahead, and will be accompanied by a variety of ships and tanks, in addition to the planes and helicopters and hundred of thousand of KAL already here. The question of why all these weapons is becoming more and more pressing.
Anyone able to read a map knows perfectly well that strategically there is only one border from where war could come from, or started against: it is the Colombian border. Brazil is too far, a single route that never ends through a deep jungle is all that links it to Venezuela. And even if the border is crossed it would still be hundreds of miles until the XXI century bandeirantes could reach any real Venezuelan objective. Besides, has not Brazil grown a huge trade balance in its favor with Venezuela? Why conquer it when you can buy it?
Trinidad and Guyana? Gimme a break!
The US? It is becoming everyday less dependent on Venezuelan oil, which probably suits it fine as Venezuelan oil production is going down anyway according to any serious observer. Besides the US does not need to invade Venezuela: a blockade will be enough since we must import 60% of our food. A percentage that seems to be increasing yearly as Chavez remains in office. Oh yes, the subs!!! Well, if they are good enough they might sink a couple of US ships before they are sunk themselves. The US will send old ships first, with as little crew as possible and that will be all that it takes to starve Venezuela.
So, why the arms build up? A fear of Colombia invasion? True, Colombia could well seize Zulia and this one could well accept going to Colombia if Chavez creates his life long dictatorship. But will the world accept such a land grab? Will even the US accept Colombia to grab Zulia? This would create such a regional instability that it is not worth it. That is, as long as Chavez keeps pumping oil, even to sell to the Chinese.
No, one reason is becoming clearer as days go by: the target of the Venezuelan weapon build up is probably nothing else but Colombia. It could be either to counter a US-Colombo invasion or to promote a Venezuelan invasion to Colombia. The beauty of this last scheme is that a strong Venezuelan army does not need to invade Colombia, it just needs to threaten to do so UNLESS Colombia gives favorable terms to the FARC, terms that will eventually result with the FARC taking control of Bogota. And then Chavez thinks that the FARC will follow its leadership. We are talking here a post Uribe period.
For a while with the AUC/paramilitary scandal it seemed that Uribe was weakening and the FARC might have thought about putting renewed pressure on his government. But today huge rallies in Colombia reveal that Uribe has still a few good days ahead of him. Maybe even Venezuela was surprised and decided at the last minute to finally send a condolence message, when it realized that the assassination of 11 legislators was a major FARC blunder. That is fine after all, Venezuela needs at least two more years to strengthen its army and shut down Chavez internal opposition once and for all. Then as Uribe prepares to leave office, the time of danger will come. Before 2011?

domain: politics


text:
A Mad Wicked Folly
June 30, 2014
— book review, Sharon Biggs Waller, young adult fiction
3 out of 5 stars✰✰✰
Victoria is a 17-year-old girl living during the Edwardian era in London. She has everything a girl could possibly want, except for the one thing that means anything to her. Victoria loves to draw and wants nothing more than to go to college to become a great artist. However, her father refuses to allow her to do so because it isn’t the “done” thing. All Victoria’s father wants is for her to have a good marriage, and be a dutiful wife and daughter.
Upon reading this book’s summary I thought to myself “this main character sounds like a spoiled brat. I may hate her.” I was pleasantly surprised at how likable I found Victoria. She isn’t at all like I pictured her. She’s smart and completely in love with her art. She is relatable and for this I like her.
I found this book to be very likable, from the characters down to the writing style of the author. Personally, I have always liked historical fiction, though because it is a little dry it isn’t something I read frequently. I thought this book was well written, and that the characters were well-developed.
In the end I gave this book a 3 star rating because I enjoyed it, but it wasn’t all enthralling as I prefer my books to be. Also, I was disappointed that the book didn’t cover more of the relationship development between Victoria and Will. The book felt a little rushed at the end in my opinion, which unfortunately seems to be unbelievably common in writing today. I do hope that Walker writes more young adult fiction.

domain: entertainment


text:
I am often unsure what to make of people, faced with teaching from scripture, want to encourage us to consider the “pastoral implications”. Whether it be facing the biblical teaching on marriage and its implications for same-sex attracted people, the doctrine of complementarianism and its implications for gender roles or that vexed issue of the ordinances and who it is appropriate to welcome into the church and what is demanded on those who would seek to be welcomed. All of these are examples of teaching on which the Bible has something specific to say but some are keen to encourage us to be aware, and even to moderate what we perceive to be the biblical position, based on “pastoral concerns”.
My major concern with the call to be mindful of the pastoral implications is that it so often sounds to me like a call to set aside what the bible clearly teaches on a matter so we can make people who will not abide by it feel more comfortable. Of course, I would love it if a church altered its position on any number of things to align with my views and welcome me. But I, ironically, wouldn’t want to join the church that did that in the face of what it actually believed on the matter at hand. A church willing to change its position in the face of what it thinks the Bible is teaching in order to welcome those who see no reason to abide by such things is not, in my view, being faithful. It is placing the desire to welcome over and above what the Lord explicitly commands and sets aside the very grounds by which Jesus says we ought not to welcome.
Of course, everyone agrees with this when it concerns matters they reckon to be sinful. You don’t get many genuine evangelicals arguing that our churches should become affirming despite teaching clearly about Jesus’ views on marriage and same-sex relationships. Their uniform understanding of what is and is not sin in these circumstances mean most are quite ready to say that we ought not to welcome those who would ride roughshod over the commands of Christ in this area.
The issue tends to come when one party considers a matter one of sin and faithfulness while the other does not. The argument in such circumstances boils down to I do not find this sinful so you should welcome me. There seems to be little recognition that I might find it sinful so cannot welcome you if you refuse to acknowledge it is so.
There is also little recognition, when it comes to this pastoral argument, that none of us think the pastoral answer to sin is to welcome the person doing it and to say no more about it, content to let them continue in it. We can say all we like that the matter is “second order” or whatever, but since when is it “pastoral” to let people continue in sin? Since when is it “pastoral” to welcome them in when we are convinced Jesus says we are only to welcome them if they address that particular thing? Are we not called to remove people from the church who are in sin, not to welcome them and comfort them in their ongoing sinfulness? It seems strange to me that we would welcome those Jesus has told us not to welcome, on terms he has told us not to welcome them on, and then to argue that we are somehow being pastoral in doing so.
Now, don’t get me wrong. I think in any area there may be pastoral issues involved. If we are calling people to do A, B or C because Jesus says so and we cannot welcome them into the church until they do/stop doing those things, there are pastoral implications. In a sense, everything is pastoral. Everything will have pastoral implications that must be worked through, both welcoming and not welcoming, affirming and challenging. The question is not whether there will be pastoral implications, but how we address the pastoral implications.
It is all very well worrying about the pastoral implications for the individuals (which tends to occupy our thoughts) but there seems to be little concern for the pastoral implications for the rest of the church. If we welcome this person sleeping with their unmarried partner, what are we communicating to the church about the need to remain faithful in our singleness or in our marriages? Pastoral implications abound. In the lesser order, but nevertheless serious matter, of the ordinances – welcoming this unbaptised person and admitting that non-member to the table – what are we communicating to those who profess faith about baptism, membership and the Lord’s Supper? If these are all things we can agree to disagree on, we can take or leave, that are “second order” issues not to split hairs about, can we be overly surprised if one unbaptised person and non-member who professes faith is admitted to the table that nobody else in the church sees baptism or membership as overly important when they can access the privileges of membership apart from the those things? If we think Jesus did actually teach a mode of baptism, can we be very surprised if those who reject it see no reason to do anything to obey Jesus on this matter when we ourselves are telling them it just doesn’t really matter.
But which of the commands of Christ do we have liberty to say that about? Which commands of his does Jesus say the pastorally appropriate thing to do is to set it aside because it isn’t that important? Which of them does Jesus say we can agree to disagree about it and we don’t need to call to repentance those who will not do what Jesus says (so we believe) they ought to do? If the answer is none of them, what business do we have suggesting the pastoral response is the one that disregards them?
In the end, the pastoral thing to do is to point people to Christ and to call them to faithfulness in him. If we think Jesus has put things in place that matter for the local church, being pastoral must mean faithfully standing on those things Christ has called the church to stand on. It cannot be pastoral to encourage people to set aside Jesus’ commands and to say they simply do not matter. The pastoral implications of doing that, I would argue, are far worse.