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BioMed Research International / 2011 / Article
AbstractIntroductionConclusionsReferencesCopyright
Protein Acetylation and the Physiological Role of HDACs
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Histone Deacetylase Inhibitors in the Treatment of Hematological Malignancies and Solid Tumors
Mario Federico1,2 and Luigi Bagella 1,3
1Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
2Section of Medical Oncology, Department of Surgical and Oncological Sciences, University of Palermo, 90127, Palermo, Italy
3Division of Biochemistry and Biophysics, Department of Biomedical Sciences, Medical School, National Institute of Biostructures and Biosystems, University of Sassari, Viale San Pietro, 43/b, 07100 Sassari, Italy
Academic Editor: Christian Seiser
Received19 Jul 2010
Accepted12 Oct 2010
The human genome is epigenetically organized through a series of modifications to the histone proteins that interact with the DNA. In cancer, many of the proteins that regulate these modifications can be altered in both function and expression. One example of this is the family of histone deacetylases (HDACs), which as their name implies remove acetyl groups from the histone proteins, allowing for more condensed nucleosomal structure. HDACs have increased expression in cancer and are also believed to promote carcinogenesis through the acetylation and interaction with key transcriptional regulators. Given this, small molecule histone deacetylases inhibitors have been identified and developed, which not only inhibit HDACs, but can also lead to growth arrest, differentiation, and/or apoptosis in tumors both in vitro and in vivo. Here, we will discuss some of the recent developments in clinical trials utilizing HDACs inhibitors for the treatment of both hematological malignancies as well as solid tumors.
DNA is woven together with proteins into an intricate organization of both extended euchromatin and condensed heterochromatin. The posttranslational modifications of the histone proteins involved in this structure regulate the epigenetic organization of the genome. This genomic organization is often altered on an epigenetic level, including the phosphorylation, acetylation, methylation, ubiquitination, sumoylation, and ADP-ribosylation of the eight histones within the nucleosome (H2A, H2B, H3, and H4).
In 1964, Mirsky and Allfrey published the first reports of histone acetylation and methylation being involved in RNA synthesis in a reversible fashion and being highly associated with open chromatin [1, 2]. Today, it is known that histone acetyltransferases transfer the acetyl group from acetyl-CoA forming ε-N-acetyl lysine on conserved lysines of the N-terminal tails of histones H3 and H4 (and to a lesser extent H2A and H2B), resulting in an open nucleosomal structure. This can be reversed by histone deacetylases (HDACs) of which, in mammals, there are currently 18 identified and have been divided into four classes based on cellular localization and function [3]. Class I includes HDACs 1, 2, 3, and 8 which are all nuclear and ubiquitously expressed. Class II, being able to shuttle back and forth between the nucleus and the cytoplasm and believed to be tissue restricted, includes HDACs 4, 5, 6, 7, 9, and 10; within this class, HDACs 6 and 10 (class IIb) have two catalytic sites, are expressed only in the cytoplasm, and are involved in a variety of biological processes. Class III contains the structurally diverse NAD+-dependent sirtuin family, which does not act primarily on histones [4]. Finally, the ubiquitously expressed HDAC11 represents Class IV, which has previously been characterized as being part of both Class I and Class II (Figure 1). Nonhistone targets of HDACs include p53, E2F, GATA-1, YY1, RelA, Mad-Max, c-Myc, NF-κB, HIF-1α, Ku70, α-tubulin, STAT3, Hsp90, TFIIE, TFIIF, and hormone receptors explaining the diverse biological effects that HDACs can impart to the cell ([5–17] for review, see [18, 19]).
The histone deacetylase, family. Schematic representations of class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), class III (SIRT1), and class IV (HDAC11). Structure and Length of HDACs are shown. The total number of amino acid residues (aa) is depicted on the right, next to each HDAC. The enzymatic domains and the nucleus localization sequences are highlighted in brown and black, respectively.
Knockout mice for HDACs 1 and 2 display embryonic or perinatal lethality and class II HDACs knockouts, while viable and fertile (except for HDAC7) have significant developmental abnormalities [20–22]. HDACs expression, and activity can be altered in many cancers and in both lymphoma and leukemia HDACs is associated with the function of oncogenic-translocation products, such as PML-RARα in acute promyelocytic leukemia [23–25]. Furthermore, with the discovery of specific pan-HDACs inhibitors, it has been shown that blocking HDACs function can cause cell-cycle arrest and differentiation through the increased expression of p21WAF1/CIP1 [26, 27], affect tumor survival by blocking angiogenesis through the increased acetylation of HIF-1α [9], affect protein degradation through the acetylation of Hsp90 [13], and increase the expression of pro-apoptotic factors [28–31], making HDACs inhibitors a good candidate for single-agent cancer therapy and even combination therapy with conventional chemotherapeutics and radiation. Here, we will discuss the latest clinical advances in HDACs inhibitors.
2. HDACs Inhibitor Classifications
Riggs and colleagues identified the HDACs inhibitor prototype sodium butyrate to be an effective inhibitor of deacetylase activity [32, 33]. This was found to be non-competitive, reversible and specific for HDACs activity [34–36]. Sodium butyrate was also found to induce differentiation, RNA synthesis and strongly inhibit cell growth in the G1 phase of the cell cycle [37]. These findings paved the road for development of more specific and effective HDACs inhibitors to use in the clinic. HDACs inhibitors can be divided into four major structural classes: (1) small molecular weight carboxylates; (2) hydroxamic acids; (3) benzamides; and (4) cyclic peptides [19, 38, 39]. Pan-HDACs inhibitors include vorinostat, panobinostat, belinostat and isotype/class-specific HDACs inhibitors include romidepsin, mecetinostat (MGCD0103) and entinostat [39]. Vorinostat (Zolinza) and Romidepsin (Istodax) are the only HDACs inhibitors currently approved by the U.S. Food and Drug Adminitration (FDA) for the treatment of refractory cutaneous T-cell lymphoma (CTCL) [40, 41].
All HDACs inhibitors available or in development target the zinc molecule found in the active site of Class I, II, and IV HDACs and are characterized by their ability to inhibit the proliferation of transformed cells in culture and tumor growth in animal models by inducing cell-cycle arrest, differentiation, and/or apoptosis (Figure 2). It has been shown that HDACs inhibitors can selectively induce the expression of less than 10% of genes, some of which are involved in the inhibition of tumor growth (e.g., p21WAF1, p27Kip and p16ink4a) [19, 26, 38]. Furthermore, evidence shows that more genes may be repressed after HDACs inhibitors treatment than activated, this could be due to a chromatin conformation in a hyperacetylated state that represses transcription, the release of transcriptional repressors from HDACs protein complexes, the activation or inactivation of nonhistone transcriptional repressors and many other plausible explanations. Unfortunately, the mechanism of action is not completely elucidated, and there are also no substantiated HDAC or HAT measurements that can predict tumor response to HDACs inhibitors treatment. Otherwise, HDACs inhibitors induce broad hyperacetylation in both tumor and normal tissues, which can be used as a biomarker for drug activity. However, steps will need to be taken to further characterize the molecular mechanisms behind HDACs inhibitors function as well as predictive markers of response to further implement them functionally in the clinic.
Mechanism of action of histone deacetylases inhibitors. It has been proposed that there are specific sites in the promoter region of a subset of genes that recruit the transcription factor complex (TFC) with histone deacetylases (HDACs). With inhibition of HDACs by HDACs inhibitors, histones are acetylated, and the DNA that is tightly wrapped around a deacetylated histone core relaxes. The accumulation of acetylated histones in nucleosomes leads to increased transcription of this subset of genes, which, in turn leads to downstream effects that result in cell-growth arrest, differentiation, and/or apoptosis.
3. HDACs Inhibitors in Clinical Trials
From the initial discovery of sodium butyrate, there has been tremendous interest and investigation in HDACs inhibitors, today there are at least 15 HDACs inhibitors that are currently under clinical investigation for both hematological malignancies and solid tumors, both for single-agent and combination therapy [42]. Initial molecules included valproic acid, phenyl-butyrate, SAHA (vorinostat), trapoxin A, oxamflatin, depudepsin, depsipeptide (romidepsin, Istodax) and trichostatin A [38, 43], which have paved the way to the second-generation HDACs inhibitors such as the hydroxamic acids: belinostat (PDX101), LAQ824, and panobinostat (LBH589), and the benzamides: entinostat (MS-27-275), CI994, and MGCD0103 (mocetinostat) [44]. Here, we will discuss some of the recent clinical trials regarding several of the most promising HDACs inhibitors (Table 1).
HDACs inhibitor class HDACs inhibitors Other common identifiers Clinical trial phase Structure
Small molecular weight carboxylates Valprioc acid Depakene, Depakote, Depakote ER, Depakote Sprinkle FDA-approved for epileps, seizures, mania, bipolar disorders, migranes Phase I/II in hematological malignancies and solid tumors
Hydroxamic Acids Vorinostat Suberoylanilide hydroxamic acid, (SAHA), Zolinza FDA-approved for CTCL Phase I/II in hematological malignancies and solid tumors
Panobinostat LBH589 Phase I/II in hematological malignancies and solid tumors
Belinostat PXD101 Phase I/II in hematological malignancies and solid tumors
Benzamides Entinostat MS-27-275, MS-275, SNDX-275 Phase I/II in hematological malignancies and solid tumors
MGD0103 Mocetinostat Phase I/II in hematological malignancies and solid tumors
Cyclic tetrapeptides Romidepsin Depsipeptide, Istodax, FK228, FR901228 FDA-approved for CTCL Phase I/II in hematological malignancies and solid tumors
Table of HDACs inhibitors discussed in this paper, organized by class (refer to text for references).
4. Vorinostat
In 2006, two phase II trials led vorinostat (Zolinza) to be approved by the U.S. FDA for the treatment of refractory cutaneous T-cell lymphoma CTCL [40]. A multicenter phase IIB trial enrolled a total of 74 patients for progressive, persistent, or recurrent CTCL who had received at least two prior therapies. Patients were treated daily with 400 mg of orally administered vorinostat and showed an overall response rate of 29.7%, a 6.1 month median duration of response, and a 9.8 month median time to progression [45]. Similar findings were published in a phase II study with a similar patient population [46]. When considering all patients from these trials together, 26% of patients experienced thrombocytopenia, 14% anemia, and only 5% of patients experienced grade 3 to 5 adverse events, including thrombocytopenia, pulmonary embolism, fatigue, and nausea. The most common adverse events were diarrhea, fatigue, and nausea. From the larger multicenter trial, 6 patients continued treatment with vorinostat for 2 years or longer with continued clinical effect (one complete remission (CR), four partial remission (PR), and one stable disease (SD)) [47].
A phase II clinical trial tested the use of vorinostat in other hematological malignancies, including relapsed diffuse large B-cell lymphoma (DLBCL), where out of 18 patients, one resulted in a CR and one in SD with grade 1 and 2 toxicities, but was concluded to have an overall minimal effect in treating DLBCL [48]. A second trial tested vorinostat in patients with lymphoma showing promising results. Out of 17 patients with relapsed indolent non-Hodgkin's lymphoma four patients achieved CR, two had PRs and four patients remained with SD [49].
A dose-escalation phase I trial was also performed for oral vorinostat as a single-agent therapy in acute myeloid leukemia (AML). Out of 41 total patients enrolled, 31 with AML, three with myelodysplastic syndrome (MDS), four with chronic lymphocytic leukemia (CLL), two with acute lymphoblastic leukemia, and one with chronic myeloid leukemia (CML). The maximum tolerated dose (MTD) was 200 mg when given twice daily and 250 mg when given three times daily, each given for 14 days in a 21-day cycle. The dose limiting toxicities (DLT) were again nausea, vomiting, and diarrhea. Seven of the patients with AML showed hematologic responses, including two CRs and two CRs with incomplete recovery [50].
Vorinostat has also been tested for use in treating several solid tumors, including platinum-resistant epithelial ovarian cancer, primary peritoneal carcinoma, and nonsmall cell lung carcinoma (NSCLC). After encouraging results from a phase I dose-escalation trial of vorinostat combined with carboplatin and paclitaxel in advanced solid malignancies, resulting in 11 out of 25 patients (10 of 19 with NSCLC and 1 of 4 with head and neck cancer) achieving a PR [51], a phase II National Cancer Institute-sponsored study has been carried out and results recently published [52]. This phase II randomized, double-blinded, placebo-controlled trial enrolled 94 patients with previously untreated stage IIIB or IV NSCLC to receive Carboplatin and Paclitaxel with either Vorinostat (400 mg daily on days 1 through 14 of each treatment cycle) or placebo. In the Vorinostat arm, a favorable trend toward improvement in median PFS (6 months versus 4,1 months in the placebo arm) and OS (13 months in the Vorinostat arm versus 9,7 months in the placebo arm) was clearly shown although at the price of an increased toxicity. Grade 4 thrombocytopenia was more frequent in the Vorinostat arm (18% versus 3% in the placebo arm) as well as grade 2-3 nausea, diarrhea, and fatigue. Moreover, 26% of patients in the Vorinostat arm discontinued therapy after the first cycle in comparison to 16% of the ones enrolled in the placebo arm. Comparably, the proportions of patients who completed all 6 cycles scheduled were 41% and 29%, respectively, for the placebo and Vorinostat arm.
Several trials also tested the efficacy of Vorinostat as single agent in different solid tumor sites (head and neck, breast, colorectal, and prostate cancer) and all reported a considerably high rate of adverse effects limiting the possibility of a reliable efficacy assessment. The most common adverse event reported in those trials were: fatigue (from 62% to 81%), nausea (from 58% to 74%), anorexia (from 58% to 81%), vomiting (from 33% to 56%), and thrombocytopenia (from 17% to 50%) [53–55].
Vorinostat is potentially also an attractive candidate for association with radiation since HDACs inhibition decreases cellular ability to repair DNA double-strand breaks both by Homologous Repair (HR) and Non-Homologous End Joining (NHEJ) [56, 57], thus resulting in a potent in vivo radiosensitizing effect [58]. A Phase I trial recently tested Vorinostat in combination with pelvic palliative radiotherapy (3 Gy per fraction up to 30 Gy) for gastrointestinal tumors. Vorinostat was administered orally once daily 3 hours before each radiotherapy fraction at doses ranging from 100 mg to 400 mg. The most common, any grade, adverse effects reported were fatigue, nausea, anorexia, and vomiting, respectively, in 94%, 65%, 59%, and 47% of patients [59].
5. Romidepsin
Romidepsin (Istodax, Gloucester Pharmaceuticals) is a natural compound isolated from Chromobacterium violaceum. It is a bicyclic tetrapeptide and is sometimes referred to as depsipeptide after the class of molecules to which it belongs. It was first tested for antibacterial activity, but it was found to have strong cytotoxic activity against different tumor cell lines, and later on mice. Romidepsin is mainly targeting class I HDACs, and it has also been recently approved by the FDA for treatment of CTCL. Two phase II multicentric single arm trials collected cumulatively 167 patients with refractory CTCL (mostly in advanced stages) treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. The endpoint for both studies was the overall response rate (ORR). Median time to first response was 2 months in both studies and ORR was 34% and 35%, respectively. The median duration of response was 15 and 13.7 months, respectively. Adverse effects observed in both studies were similar to the toxicities observed in phase I trials. Common (any grade) adverse effects included nausea (56% and 86%, resp.), fatigue (53% and 77%), vomiting (34% and 52%), and anorexia (23% and 54%). Furthermore, consistently with the toxicity pattern shown by Romidepsin in Phase I studies [60], ECG changes were also noted in a large proportion of patients of the study (up to 50%) consisting of T-wave flattening, ST tract depression, and QT interval prolongation. Cardiotoxicity, which has not been frequently found after Vorinostat treatments, seems to be a more specific side effect of Romidepsin and has been explained as being dependent upon the interaction of the drug with the HERG K+ channels [3]. Romidepsin has also been initially tested clinical conditions other than CTCL. In some Phase I/II trials, single-agent Depsipeptide has shown a limited clinical benefit in treating refractory neoplasms, including AML/MDS, CLL, lung cancer, hormone refractory prostate cancer, and renal cell cancer [61–66].
6. Mecetinostat (MGCD0103)
Mecetinostat (MGCD0103) is a class I isotype-selective orally available benzamide HDACs inhibitor. Early clinical trials have demonstrated activity in hematological malignancies, including myeloid leukemia and lymphoma and was well tolerated with DLTs of fatigue, nausea, vomiting, and diarrhea. A phase I trial resulted in a bone marrow CR in three of 29 patients with AML at a MTD of 60 mg/m2 administered three times weekly [67]. A phase II study in adults with relapsed or refractory DLBCL (33 patients) or follicular lymphoma (FL—17 patients) also demonstrated significant anticancer activity. Most of the 17 patients with DLBCL that were reassessed by CT after treatment showed a decrease in tumor volume, as well as one CR and 3 PRs. Out of ten patients with FL, one achieved PR. Grade 3 toxicities or greater included fatigue, neutropenia, thrombocytopenia, and anemia [68]. A phase II trial was also conducted in patients with relapsed or refractory Hodgkin's lymphoma. A treatment schedule of 110 mg or 85 mg three times per week in a 4-week cycle were given to 23 and 10 patients, respectively. From the 21 patients evaluated from the 110 mg cohort, there was an ORR of 38% (2 had CRs, and 6 had PRs). The patients who had CRs remained with progression free survival for >270 and >420 days, respectively. From the 10 patients in the 85 mg cohort, all 5 that were evaluated demonstrated tumor reductions of ≥30%, with one PR and 2 SDs [69].
Aside from the beneficial effects demonstrated in hematological malignancies, MGCD0103 also demonstrated clinical benefits in solid tumor treatment. A phase I trial in patients with advanced solid tumors given MGCD0103 three times per week for 2 of every 3 weeks showed tolerable DLTs of fatigue, nausea, vomiting, anorexia, and dehydration. After four or more cycles, SD was observed in five of 32 patients. A phase II dose of 45 mg/m2/day was recommended [70]. Phase I/II studies in solid tumors were also conducted in combination with gemcitabine. Phase I included patients with refractory solid tumors. Phase II was limited to gemcitabine naive patients with locally advanced or metastatic pancreatic cancer. During a 28-day cycle patients received MGCD0103 three times per week in a dose ascending design targeting a DLT of <33%. Gemcitabine was administered three times per cycle weekly at 1000 mg/m2. Out of the 14 patients evaluated, there were 2 PRs in patients with pancreatic carcinoma, one PR in a patient with nasopharyngeal cancer, and one PR in a patient with cutaneous T-cell lymphoma. The phase II trial is ongoing at a dose of 90 mg for patients with pancreatic cancer [71].
7. Panobinostat (LBH589)
Panobinostat is a hydroxamate that has shown potential in early phase I and II clinical trials. In an initial trial, 15 patients with AML, ALL, or MDS were treated with 4.8 to 14 mg/m2 panobinostat administered intravenously as a 30-minute infusion. Transient blast cell reductions occurred in 8 of 11 patients with peripheral blasts. Four patients exhibited a DLT of grade 3 QTcF prolongation at 14 mg/m2, which were asymptomatic and cleared after treatment ended. Common toxicities included nausea, diarrhea, vomiting, hypokalemia, loss of appetite, and thrombocytopenia [72]. CTCL patients (stage IB-IVA), including Mycosis Fungoides (MF) and Sezary Syndrome (SS), who have failed two or more previous therapies were enrolled in a phase II clinical trail. Panobinostat was administered at 20 mg orally on days 1, 3, and 5 weekly until disease progression or intolerance to two groups of patients, one who had received prior treatment with oral bexorotene and a second without. The best overall responses were 3 PRs and 4 SDs. ECG monitoring of QTcF prolongation was performed, without any >500 ms [73].
8. Belinostat (PXD101)
Belinostat has shown promising anticancer activity in both hematologic malignancies as well as solid tumors. In a trial enrolling 16 patients with advanced hematological neoplasms, belinostat was administered intravenously at one of three dose levels: 600, 900, and 1000 mg/m2/d. While no CRs or PRs were noted, intravenous administration was well tolerated, and five patients (including two with DLBCL) achieved SDs after 2–9 treatment cycles. There were no grade 3 or 4 hematological toxicities (except one case of grade 3 lymphopenia), and the most common adverse effects were nausea, vomiting, fatigue and flushing. There were two grade 4 renal failures in patients with multiple myeloma (MM). The recommended dose for phase II studies was 1000 mg/m2/d, intravenously administered on days 1–5 of a 21-day cycle for patients with hematological neoplasia [74].
For solid tumors, Belinostat was tested in a phase I study of patients with advanced refractory cancers. The 46 patients received six dose levels, ranging from 150 to 1200 mg/m2/d over a 5-day cycle. DLTs were fatigue, diarrhea, atrial fibrillation, and grade 2 nausea/vomiting, which led to inability to complete the full cycle. 39% of patients resulted in SD. Of the 24 patients treated at the MTD, which was determined to be 1000 mg/m2/d, 50% achieved SD [75]. Patients with platinum resistant epithelial ovarian cancer (EOC) are resistant to conventional chemotherapy. Belinostat was administered intravenously at 1000 mg/m2/d on days 1–5 of a 21-day cycle to metastatic or recurrent platinum resistant EOC and low malignant potential (LMP) ovarian tumors. Of the 18 patients with LMP, 1 had PR, 10 had SDs. Median PFS in LMP was 13.4 months. Patients with EOC 9 had SD with a median PFS of 2.3 months [76].
9. Entinostat (MS-27-275)
Clinical trials of Entinostat, a benzamide derivative, initiated in 2005 with a Phase I study enrolling patients with advanced solid tumors or lymphoma. Entinostat was administered to a total of 22 patients once a week for 4 weeks during a 6-week cycle. The MTD was determined to be 6 mg/m2, and the common DLTs were hypophophatemia, hyponatremia, and hypoalbuminemia, which were all reversible [77]. After the analysis of three different dose schedules, 4 mg/m2 weekly or 2 to 6 mg/m2 every other week, for three weeks in a 28-day cycle; the biologically relevant plasma concentrations and antitumor activity were determined [78].
In solid tumors, a phase I combination therapy trial was performed on ten patients with an advanced NSCLC. Patients were treated with 5-azacitidine (AZA), a DNA methyltransferase inhibitor, subcutaneously on days 1–6 and 8–10 along with a fixed dose (7 mg/m2) on day 3 and 10 of a 28-day cycle of entinostat. The dose of AZA was varied by cohort using a standard dose assessment. No DLTs were observed in the 30 mg/m2 dose cohort. However, in the 40 mg/m2 cohort, after one week, a patient was replaced due to rapidly progressing disease, and another patient experienced a grade 3 neutropenia and thrombocytopenia. The common toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and cytopenias. One patient had a PR, which continued longer than 8 months. Two patients had SDs and the remaining patients had PODs [79].
10. Valproic Acid
Valproic acid (VPA) has been increasingly studied in clinical trials for a variety of cancer types as a single agent or in combination with other therapies. In solid tumors, VPA was analyzed for activity in 12 patients with cervical cancer. Three four-patient dose cohorts were formed, for 20 mg/kg, 30 mg/kg, and 40 mg/kg administered orally for five days over a six-day protocol. Tumor-deacetylase activity decreased in eight patients in a statistically significant manner. A grade 2 depression in level of consciousness was registered in 9 patients [80]. Another phase I study in 26 patients revealed neurocognitive impairment, with grade 3 or 4 neurological side effects in 8 of the 26 patients. When administered intravenously the MTD was determined to be 60 mg/kg/d [81]. A phase II study for the treatment of advanced solid tumors with hydralazine and VPA revealed clinical benefit in 80% (12) of patients with cervix, breast, lung, testis, and ovarian carcinomas. Four patients had PRs and eight SDs, and the most common toxicity was hematological [82].
VPA has been more frequently studied in the use of combination therapies, specifically with all transretinoic acid (ATRA). From a study of 75 patients with AML/MDS, 66 were initially treated with VPA monotherapy followed by ATRA in nonresponsive or relapsed patients. VPA was administered for a median treatment duration of 4 months and ATRA, 2 months. 24% of patients showed hematological improvement with a median response duration of 4 months. Four out of 10 relapsed patients, when administered ATRA had a second response and both treatments were well tolerated [83]. VPA was also combined with both AZA as well as ATRA in patients with AML or high-risk MDS. A total of 53 patients were treated with AZA at the fixed dose of 75 mg/m2 daily for 7 days, ATRA at 45 mg/m2 orally daily for 5 days starting on day 3, and VPA, which was dose escalated and administered orally daily for 7 days concomitantly. The ORR was found to be 42%, the median remission duration was 26 weeks, the MTD for VPA was 50 mg/kg daily for 7 days and the DLT was reversible neurotoxicity [84]. In another study of patients with AML/MDS, increasing doses of VPA administered orally and concomitantly with a fixed dose of decitabine (15 mg/m2 by intravenous daily infusion) for 10 days revealed a safe daily dose of 50 mg/kg. 22% (12) of patients had an objective response, this included 10 CRs and 2 CRs with incomplete platelet recovery [85].
11. Associations of HDACs Inhibitors with Other Target Drugs
Despite the very high number of gene products potentially deregulated in solid tumors, high throughput screening analyses suggest that mutations often occur in genes that collaborate in a relatively limited pool of common cell signaling pathways [86]. This hypothesis may have a great relevance in the clinic. In fact, having at hand several classes of effective "pathway-oriented" target drugs, and admitting that a tumor may be driven by a limited number of deregulated pathways, it possible that the concomitant use of a combination of drugs directed against different pathways functionally related may result in an improved antineoplastic effect or in the overcoming of drug resistance.
Recent studies on multiple myeloma (MM) models suggest that HDACs inhibitors may synergize with proteasome inhibitors. Although the molecular mechanism underlying this effect is not completely understood several means have been proposed [87] and encouraging data has come from the early clinical experimentation, including a phase I trial [88] of randomized patients with relapsed/refractory MM to receive Vorinostat (200 mg twice daily or 400 mg once daily for 14 days) in combination with bortezomib (0.7 or 0.9 mg/m2 on days 4, 8, 11, and 15 or 0.9 or 1.1 or 1.3 mg/m2 on days 1, 4, 8, and 11). Among 34 evaluable patients, the best response to vorinostat plus bortezomib was a partial response (PR) in 9 (26%) patients, minimal response (MR) in 7 (21%) patients, and stable disease (SD) in 18 (53%) patients. Mean duration of SD was 89 days, range 9–369 days. Of the 13 evaluable patients who had previously been treated with bortezomib, 5 achieved a PR, 1 had an MR, and 7 had SD. Eleven of the 34 patients enrolled (32.4%) discontinued treatment due to adverse effects (AEs). Most common AEs were fatigue, nausea, diarrhea, and hematological toxicities. A phase II open label study from the same group is currently ongoing. Another Phase I trial accrued 23 heavily pretreated (median of 7 previous regimens) patients with relapsed/refractory MM to receiving escalating doses of Bortezomib (1 or 1.3 mg/m2 on days 1, 4, 8, and 11 and Vorinosat 100 mg twice daily, 200 mg twice daily, and 400 mg once daily, or 500 mg once daily for 8 days each 21-day cycle). Overall response rate was 42%, two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade >3 toxicities were myelosuppression ( ), fatigue ( ), and diarrhea ( ). In the same setting of patients with relapsed/refractory MM, the combination of Romidepsin and Bortezomib and Dexamethasone has also shown promising results. In a Phase I/II trial, of 18 evaluable patients, this schedule resulted in a overall response rate of 67%. The most common drug related grade 3 toxicities included fatigue (2 pts.), neutropenia (1 pts.), sepsis (2 pts.), and peripheral neuropathy (1 pts). Preclinical data seems to confirm a synergic effect of Panobinostat and Bortezomib, and a Phase I trial is currently ongoing (NCT00532389). These encouraging results are paving the way to a relevant number of trials testing the association of different HDAC and Proteasome inhibitors, and results are expected in a relatively short time.
12. HDACs Inhibitor-Related Toxicity
The relationship between the toxicity of HDACs inhibitors and their pharmacodynamic/pharmacokinetic properties is still largely unknown. This makes it difficult to optimize HDACs inhibitors treatment. Studies in preclinical models have shown that HDACs inhibitors are a class of agents that has been generally well tolerated and proved a very good toxicity profile in comparison with other chemotherapeutic drugs used in cancer therapy. The main adverse effect is fatigue, which is generally mild and tolerable in most patients, but in 30% of patients, it can be severe enough to cause drug discontinuation. Gastrointestinal toxicities are also common side effects and include anorexia, nausea, vomiting, and diarrhea. Overall, they are mild and controllable with symptomatic treatment. Biochemical disorders such as hypokalemia, hyponatremia, hypocalcemia, hyperglycemia, hypophosphatemia, and hypoalbuminemia are common with various HDACs inhibitors, while neurocortical disturbances including somnolence, confusion, and tremor are observed mainly with phenylbutyrate and valproic acid. All these side effects are generally reversible upon cessation of administration of the drug.
Another side effect of histone deacetylase inhibitors is transient thrombocytopenia that is relatively common with most HDACs inhibitors [89], it is generally mild, although has been dose limiting in some studies.
A significant adverse reaction regards the cardiotoxicity. Early studies in preclinical animal models have shown that various HDACs inhibitors such as Romidepsin are able to cause myocardial inflammation and cardiac enzyme elevation. These studies represent a controversial issue since high doses of HDACs inhibitors were used [90, 91] compared to the doses that were confirmed appropriate for use in Phase I trials. Specifically, the effect of Romidepsin on cardiac function was assessed in 42 patients with T-cell lymphoma. They received a total of 736 doses of Romidepsin and an intensive cardiac monitoring was evaluated [92]. Grade I (T-wave flattening) and grade II (ST segment depression) ECG changes occurred in more than half of the ECGs obtained post treatment; however, these changes were reversible and of short duration, with no elevation in cardiac enzymes and no significant changes in left ventricular ejection fraction.
In addition, cardiac dysrhythmias were observed in a small number of patients but most of these patients had pretreatment documented dysrhythmias. Similar ECG changes and QT-interval prolongation have been reported in other Phase I/II Romidepsin studies [60, 66, 93–96]. In other Romidepsin studies, there have been reports of sudden death; however, the relationship to the drug remains unclear. In particular, a Phase II study of 15 patients with metastatic neuroendocrine tumors, administered with standard doses of Romidepsin reported one sudden death in a 48-year-old patient [66]. However, this patient had a history of hypertension, and a biventricular hypertrophy was revealed by postmortem examination, both are known risk factors for sudden death. Cardiotoxicity may be a class effect of HDACs inhibitors, being more frequent with Romidepsin and other class-I inhibitors rather than Vorinostat and other pan-HDAC inhibitors but it is unlikely that these side reactions are limited just to those HDACs inhibitors. Additional parallel cardiotoxicity studies with other various HDACs inhibitors are necessary.
Possible room for improvement could be in the development of isoform-selective HDACs inhibitors (extensively reviewed in [97]). It is known from knockout studies that the deletion of some specific HDACs isoforms can cause precise phenotypic defects. In particular, mice lacking some of the HDACs isoforms (namely, HDAC2, HDAC3, HDAC5, and HDAC9) show severe cardiac malformations and dysfunctions [98, 99], suggesting that HDACs inhibitors, specific for other HDACs could possibly have a better cardiotoxicity profile still retaining the full pro-apoptotic action. Furthermore the introduction of reliable sensitivity biomarkers in the design of trials will allow a better stratification of patients thus minimizing the risk of exposure of the unresponsive subjects to HDACs treatment and toxicity. Recently, a genome-wide loss-of-function screening was undertaken to reveal genes that govern tumor cell sensitivity to HDAC inhibitors in a sarcoma cell model, and HR23B, a protein involved in shuttling ubiquitinated proteins to the proteasome was identified as a potential biomarker [100]. HR23B expression was further investigated in 21 skin biopsies from 20 patients with CTCL enrolled in a Vorinostat Phase II trial [46] and analyzed by immunohistochemistry. The proportion of patients with a strong HR23B staining who had a clinical response was 69%, thus suggesting a pretty high positive predictive value (PPV). Similar PPV for HR23B were obtained when looking at patients treated with other HDACs inhibitors [101].
13. Conclusions
HDAC, inhibitors represent a promising new group of anticancer agents, even though the mechanisms of HDAC inhibitor-induced tumor cell death require further elucidation. While vorinostat and romidepsin are the only US FDA-approved HDACs inhibitors currently utilized in cancer therapy, as we have shown here, there are many HDACs inhibitors that are presently under intense clinical investigation, both as single agents and combination therapies. These will hopefully be able to further improve the range of treatment options available for hematologic malignancies as well as for solid tumors.
As we come closer to understanding the molecular mechanisms inherently responsible for tumorigenesis, as well as the full range of HDACs inhibitor cellular actions, we will be able to target in a more appropriate way and be able to pair cancer therapies for clinical use. In order to establish rigorous patient selection criteria and optimal drug combinations to properly design further trials and maximize the clinical gain, the bridge between the biological function and the therapeutic benefit of these drugs needs to be further elucidated.
This work was supported by grants from "Fondazione Banco di Sardegna" to L. Bagella.
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Copyright © 2011 Mario Federico and Luigi Bagella. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Mmmmm. Sony Chumby! Don't know? Google Chumby. Do want! Needs Hulu tho.
Sony Dash ready to hit the market: "
Back at CES 2010 we saw that Sony unveiled the Dash during their press conference, and while this was never going to be a game changer of any kind, it was still nice to see yet another touchscreen device ready to hit the market. Well, a good 4 months or so has elapsed since then, and it is finally good to know that Sony will be introducing its Dash Wi-Fi touchscreen device to the market at last, where you are able to receive real-time, personalized Internet content that is pushed to you regardless of whether you are at home or at the office. The Sony Dash has been tagged with a $199 price tag, where you can purchase it online from SonyStyle.com or pick it up from other Sony Style retail stores and authorized dealers nationwide.
You get a 7″ color touchscreen display to view all the relevant information being shown, where the Dash will rely on a current wireless internet connection in order to receive a continuous display of your selections from more than 1,000 free apps, where many of them are offered via Chumby Industries, Inc., where among these include news, calendars, weather, sports, and social networking. Not only that, with the use of BRAVIA Internet Video, the Sony Dash is able to let you be entertained via TV episodes, films and additional video content and music from a host of other providers such as CBS, Netflix, YouTube, Pandora and Slacker amongst others.
You will be pleased to know that the Dash will boast a playlist of your own personalized internet world which is constantly refreshed and pushed to you, hence helping you save time since there is less need to search for your favorite content or to log onto your favorite sites. Apart from all of the above mentioned, the Sony Dash also doubles up as an alarm clock, letting you wake up through your favorite music videos, internet radio or other video content instead of the standard alarm clock buzzer which is old hat by now. Nice to know that multi-tasking is also supported, which means you can refer to a recipe in the kitchen while having some MP3 files playing in the background.


text:
Q: Ruby on Rails -- Using multiple has_many associations to the same model I have a simple program where an event can be created by a user, and the Event class knows who created it:
class Event < ActiveRecord::Base

  # the owner of the event
  belongs_to :user

end

class User < ActiveRecord::Base

  # a user has 0 to n created events
  has_many :events

end

So far so good, I get the correct association behaviour when I call "event.user" for example, and only the creator of the event can perform CRUD operations on his/her event.
However I want the ability for a user to save events (not in the database sense, just so they can view it in their dashboard or such), and I want to just use these two models. I tried adding a "user_saved_id" to the Event model as a new column to keep track of the users which save it like the following:
class Event < ActiveRecord::Base

  # the owner of the event
  belongs_to :user

end

class User < ActiveRecord::Base

  # a user has 0 to n created events
  has_many :events

  # a user has 0 to n saved events, including the created event
  has_many :saved_events, foreign_key: 'user_saved_id', class_name: "Event"

end

However I am having no such luck. When I try to initialize an event creator to have automatically saved his/her own event when he/she creates it for example, I get an " undefined method `each' " in the create method below (I am using the devise gem, and "current_user" is a helper function which returns the id of the current signed in user):
# POST /events
# POST /events.json
  def create
    @event = Event.new(event_params)

    # associate an event with its creator, works correctly
    @event.user = current_user

    # initialize a user to have saved his own events, not working
    @event.user.saved_events = current_user
 ...

I would greatly appreciate any pointers I can get on where I am getting it wrong, if I got the association relationship wrong, and if I am overthinking it and there is a simpler way to go about it. Thanks very much in advance.

A: If you want a User to be given the ability to "save" an event (in the sense of a dashboard, not a database), why not add a save_for_later flag to Event?
rails g migration add_save_for_later_to_events save_for_later:boolean
Then in your Event model, you can add the following scope:
scope :flagged_events_for, (lambda do |user|
    where('user_id = ? AND save_for_later = ?', user.id, true)
  end)

You'll then be able to "ask" the Event model for appropriate instances of itself elsewhere in your app, with Event.flagged_events_for(user)

A: The problem with adding the user to the event as user_saved_id, is that only 1 user will ever be able to save that event.   If I understand correctly, you would like a user to be able save events (That they may or may not have created?) to be shown in their Dashboard.  In this case you are going to need something like a has_and_belongs_to_many or a has_many through type relationship, and thus another table. Perhaps something like using the has_many through.
class SavedEvent < ActiveRecord::Base
  belongs_to :user
  belongs_to :event
end

class User < ActiveRecord::Base

 # a user has 0 to n created events
  has_many :events
  has_many :saved_events

  # a user has 0 to n saved events through the favorites table
  has_many :later_events,  through: :saved_events
 end

when you create your SavedEvent, you can use the created_at timestamp to show when the user saved it, or can also store other information/metadata about saving it.
having the reverse set it event would allow you easily get the list of users who have saved this Event via event.saved_users.  (sorry naming things is one of those hard problems)
class Event < ActiveRecord::Base

  # the owner of the event
  belongs_to :user
  has_many :saved_events
  has_many :saved_users, through: :saved_events

end

then creating a new event would be
def create
  #wrap in transaction
  Event.transaction do
   #build the event through the association
   @event = current_user.events.create!(event_params)
   #save it to the current users saved events
   current_user.saved_events.create!(event: @event)
  end
 end

the transaction and the ! methods just make it so that it will roll back if it cannot create the event and add to saved events, and not wind up with an event that isn't in the saved/later events table when created.
When another user wants to save the event, in your controller for that, you just need to do current_user.saved_events.create(event: event) for them, and it will save it.
Then in your dashboard you can do current_user.later_events and get a collection of all events that they have saved.

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Welcome to the Ford Kuga pictures gallery. View Ford Kuga picture (high quality) from all angles and views. Exterior and interior images of Ford Kuga will give you the necessary details of Ford Kuga car. As pictures says thousands words, Ford Kuga pics here is equivalent to reading multiple reviews. Ford Kuga photos listed here are not just for aesthetic but also to clearly explain you the functional elements of the car like steering wheel,dashboard, instrument panel and seats. Detailed images also helps you understand fit and finish of the Ford Kuga. Click on the Ford Kuga picture to view it in larger resolution.
Ford Kuga Pictures, Ford Kuga pics, Ford Kuga images, Photos of Ford Kuga exterior and interior.


A learning organization is an organization that is great at empowering employees to think critically and creatively to challenge the status quo. It is an environment where new knowledge is regularly gained, transferred and used to modify behaviors.
For the small business owner, creating a learning culture is key for long-term growth and sustainability.
Learning organizations have visionary leaders that are quick to empower their employees for growth. They understand that the business environment is highly competitive and fast paced and also that customers preferences keep changing in the midst of numerous options. A learning organization is always thinking of the next improvement it can make to move its company forward. Where it is not able to provide training, it generously rewards and recognizes staff that gain this knowledge.
Is your Business a Learning Organization?
How long have your core processes remained the same?
Do you have an active means of collecting and measuring customer and staff feedback?
Do your employees feel emboldened to suggest new ideas and voice their opinions?
Do your employees constantly fear that they will be reprimanded for their mistakes?
Does the management take ownership of both successes and failures or do they take successes and pass failures off to staff?
If you do feel you are lacking in any of the above areas then begin your journey to becoming a learning organization. Start by taking some time out this week to brainstorm with your team. You will be amazed at the huge boost in morale and ideas you will come up with. Transforming to a learning organization takes time and effort but the rewards impact not only the staff but the shareholders as well.


text:
Features, Our Articles, Wartime, Women in History February 23, 2013 June 14, 2014
Anastasia: The Great Imposter
by Annabelle
Grand Duchess Anastasia Nikolaevna of Russia (June 18 1901 – July 17, 1918) was the youngest daughter of Tsar Nicholas II of Russia, the last sovereign of Imperial Russia. She had three older sisters' named Olga, Tatiana and Maria and a younger brother, Alexei. On 17th July 1918, soon after her seventeenth birthday, Anastasia and her family were assassinated in an extrajudicial killing by forces of the Bolshevik secret police.
The Russian Royal Family.
Source: en.wikipedia.org
Or at least that is how the story goes…
The location of her burial was unknown during the decades of Communist rule, which resulted in persistent rumours of her possible escape. In 1991 the remains of the Tsar, his wife and three of their daughters were found in a mass grave near Ekaterinburg.
Anastasia's and her brother were missing.
Enter 28 year old Miss Anna Anderson (16 December 1896 – 12 February 1984). Much like the 1997 Disney movie, Anastasia, Anderson famously claimed to be the missing Grand Duchess.
Most members of Grand Duchess Anastasia's family and those who had known her, including her tutor, said Anderson was an impostor but others were convinced she was the real Anastasia. In 1927, a private investigation funded by the Tsarina's brother identified Anderson as Franziska Schanzkowska, a Polish factory worker with a history of mental illness.
It was brought to light that Anderson was institutionalised in a mental hospital after a suicide attempt in Berlin, 1920. This did nothing to help legitimise her case. After a lawsuit lasting many years, the German courts ruled that Anderson had failed to prove she was Anastasia. However, the mass media coverage brought her claim great notoriety.
Anna Anderson who famously, and falsely, claimed to be the Grand Duchess, Anastasia
Source: www.planetacurioso.com
Between 1922 and her death in 1984, Anderson lived in Germany and the United States with various supporters in nursing homes and at least one asylum.
Unfortunately for Anna her claim to the Duchy was about as legitimate as my claim to the British throne. After the collapse of communism in the Soviet Union, the locations of the two missing bodies were finally revealed. In January 2008, Russian forensic scientists announced through DNA testing they could confirm that the charred remains of a young boy and a young woman found near Ekaterinburg in August 2007 were most likely those of the thirteen-year-old Alexei and one of the four Romanov grand duchesses.
Unlike the Disney movie there is no fairy-tale ending here. The evidence proves conclusively that the remains of all four sisters have now been accounted for, and tragically none of them escaped an untimely death.
To conclusively draw a line under Miss Anderson's elaborate claims, DNA tests were made on available pieces of her tissue and hair. Unsurprisingly there was no relation between her tissue and that of the Imperial family.
Anderson's claims may sound ludicrous today, but it is worth remembering that at the time the body of Anastasia was still missing. Anna gained notoriety because in times of tragedy people hold on to hope. Regardless of its political significance, what a wonderful story it would have made had little Anastasia survived.
On the other hand if you were hoping for a happy ending…
Please see Disney's 1997 film 'Anastasia'
Source: danielleehowe.com
anastasia, house of Romanov, romanov, russia
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3rd party script wont load in editor. help!
I have a Product recommendations script generated by Barilliance. it loads and inserts script into the DOM on the page. I am trying to AB test the page with and without recommendations.
It will not load in the Editor. even with safe mode turned off and allow secure content enabled. I cannot see the Barilliance script loading and inserting their recommendations. So therefore I dont know how to select their content and turn it off for 50% of the traffic.
Re: 3rd party script wont load in editor. help!
I understand that you would like to A/B the presence of the recommendation block on the page.
Before we go further, are you able to load the rest of the page in the Visual Editor or is it the full page that doesn't load in the Visual Editor?
You can test if this work by using some of our Quality Assurance tools to test the experiment before it goes live. We have a dedicated article on this topic that may be of interest to you. You can check it out by clicking here.
You will need to replace BARILLIANCESCRIPT with whatever URL is in your script.


Description: In the second chapter of the book of John, Jesus preforms his first miracle. At this wedding, they all celebrate the joining of two people whom are Jesus' friends. Jesus will have his own wedding celebration, one day. Pastor Josh takes us from the wedding in John, to Jesus' upcoming wedding celebration in Revelation.
In the second chapter of the book of John, Jesus preforms his first miracle. At this wedding, they all celebrate the joining of two people whom are Jesus' friends. Jesus will have his own wedding celebration, one day. Pastor Josh takes us from the wedding in John, to Jesus' upcoming wedding celebration in Revelation.


84th Annual Oscars. The Nominated Films of 2011.
Who Will Win: Opinions vary on this but I'm going with the most serious entry, Raju. Amir thinks Tuba Atlantic is the best and will win.
An 85 year old barber in Alabama recalls the civil rights movement. His barbershop was a civil rights hub.
described as "a visual tone poem about the ephemeral nature of life and the healing power of Japan's most beloved flower"
Who will win? the winner in terms of buzz is SAVING FACE so let's predict that one.
a child's view of an lazy Sunday at Grandma's place.
a young boy learns his family trade.
will screen before Pixar's Brave next summer.
a young man walks past a chicken. Which is the real city slicker?
This funny short about a dapper young englishman relocating to the Calgary prairie is already an award winner in Canada.
What will win? I think it's going to be THE FANTASTIC FLYING BOOKS (review)... but LA LUNA and WILD LIFE also have passionate fans. Amir likes Wild Life best.
The West Memphis Three get another film. A very popular documentary series.
PROJECT NIM Red Box Films about a human/chimp cohabitation sign language experiment in the 70s.
What will win? This seems wide open with presumed accessible frontrunner Project Nim and other hit docs like Buck and Bill Cunningham New York out of the running. Time to hunt all of these down. In the end I'm guessing PINA but I'm not at all confident about that guess.
This festival hit about a pianist and a singer is much different than what they normally go for, but more adventurous voters might get swept up in it.
Sequel fatigue is a non-existent concept with general audiences. Box office receipts prove there's no such thing. But Oscar isn't the Emmys and sometimes they like to move on. Will they?
The Shrek franchise's best character gets his own franchise kickoff ...and warm reviews.
This weird and wonderful hit about a pet lizard abandoned in the desert still looks like a winner.
What will win? I think it's obviously going to be RANGO but who knows? None of the animated films were nominated in additional categories as sometimes happen with the big Pixar efforts. I like Rango the best but I have not seen Chico and Rita which Jose is rooting for.


text:
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La Masia: The famous well is running dry
Rob Palmer opinion
...were those of John Terry, Frank Lampard and Dennis Wise. In Spain no club reflected the local area with greater pride and basked in their famous youth system more than FC Barcelona. When you go on the Camp Nou stadium tour they boast of the famous
The Malaga fine art collection makes way for Picasso
Daryl Finch 1 september 1997
The Malaga Museo de Bellas Artes, the province's fine art collection, closed its doors to the public on 1 September 1997 - the start of a protracted and emotional saga which would only get its happy ending at the end of last year, almost twenty years
Over 35,000 visitors expected at twelfth Festival of Three Cultures
Eugenio Cabezas
For the twelfth consecutive year, the Festival of Three Cultures in Frigiliana got under way on Thursday and will be on until Sunday. It is one of the most hotly-anticipated events in the Axarquía and all happens in the town that boasts some of the w
Malaga-based cooperative puts first solar-powered vehicles on the market
The first hundred solar-powered vehicles in the world, invented by the Malaga cooperative Evovelo and which is made of renewable products, will be delivered to their buyers from the start of March. The car, Mö, can carry two people and is marketed
Costa del Golf Tour gets off to a flying start in Marbella
ALBERTO GÓMEZ MALAGA
European Tour. The course boast 45 holes in total and opened in 1959, making it one of the oldest on the Costa del Sol. The second, and final chance to get to the final, will be at Cabopino, also in Marbella.
How the tables have turned!
...replacement Ousmane Dembélé was crocked early on and Luis Suárez has taken three months to crank up his engines. Some are coaches, some are managers and Valverde has proven to be both. He's coached his team to make the most of what they have and they boast
Ken Campbell
...kill any creature in the forest. The Gods were angered by this boast and so sent Scorpio the scorpion to sting Orion in the heel and kill him. Orion and Scorpio are now placed on opposite parts of the sky and never appear in the sky together. Looking
Costa del Sol journalists glimpse the Torremolinos of the future
Tony Bryant TORREMOLINOS
Members of the foreign media sector on the Costa del Sol learned more of Torremolinos council's plans and expectations for the future at a social forum held in the town last week. The meeting, under the title of 'Torremolinos, rebirth of an icon',
Malaga celebrates another Michelin star, this time for Bardal in Ronda
MARina MARTÍNEZ
The Michelin Guide for Spain and Portugal 2018 was officially presented in Tenerife this week and, as expected, Malaga province can boast another star, this time for Bardal, Benito Gómez's restaurant in Ronda which was previously the prestigious
Calling for back up
Rob Palmer a look at la liga
...forwards a few days and there's another first for Real Madrid, their bus negotiating Wembley Way. Surely, even the celebrated superstars who boast every medal in world football would be up for this one? It appeared not as Tottenham Hotspur swept their


text:
Messi vs Ronaldo will be known as the greatest individual sports rivalry of all time
by HWA Magic / On December 12, 2020
Juventus' 3-0 away victory over Barcelona at the Nou Camp this morning may have seen the curtain close on what has been an absolutely epic duel between two of the greatest to ever kick a ball – Lionel Messi and Cristiano Ronaldo.
It's one of those endless debates that people either get excited about discussing or bored out of their brains because the topic never seems to go away.
How can it possibly go away, though? To witness not only one, but two of the best to play our game at the very same time, at the very same peak of their powers is pretty damn special and all football lovers should respect and admire these legends, whether you are a fan of them or not.
They've constantly pushed each other to limits I don't even think they thought were possible. It's hard not to think that they're saying to themselves, "if you can score a hattrick, then I can do the exact same tomorrow", because they are both great professionals and want to be the best, no matter what. It's an extra motivation factor to lead them onto greatness. Just fascinating to watch.
(VI Images/Getty Images)
Some insane stats from two of the best footballers of all time
Ronaldo has scored 134 Champions League goals compared to Messi's 118. Equal third are Robert Lewandowski and Raul on 71.
Messi edges in front with six FIFA Ballon d'Or awards compared to Ronaldo's five. Johan Cruyff, Michel Platini and Marco van Basten sit on three each in third.
Ronaldo trails Messi by four titles with 20 compared to the Argentine's 24.
I could go on and on with that list of stats, but words just can't describe how dominant and forceful they have been to the rest of their competitors, both individually and as a team for about 15 years now. To be able to consistently put up 30-60+ goals per season for that duration of time, year in, year out, is simply astonishing.
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In 36 head-to-head matches played, Messi leads with 22 goals scored to Ronaldo's 19 and is on top in the win count by 16-10-10. The willingness to outshine each other whenever they meet would most certainly be applauded by all football fans.
On the international stage, I can agree that they have both underperformed. Messi has been heavily criticised by failing to carry Argentina to a World Cup or Copa America at the final hurdle, losing multiple finals. Ronaldo at least played a massive role in winning Euro 2016 with Portugal, but at the same time, it can be argued that he should've done more in the four World Cups he's represented his country in.
Cristiano Ronaldo (Jay Barratt/Getty Images)
The only other rivalry across sport that I can make a case to compete against the Messi versus Ronaldo duel would have to be tennis champions Roger Federer and Rafael Nadal. Tennis is an individual sport, so for them to accomplish so much in their respective careers having to problem solve on their own and not have any teammates to help them in the key moments of a match must be recognised for sure.
To have 40 grand slams between them split 20 each is incomprehensible. Roger and Rafa also push one another to become the greatest and strive towards winning as much silverware as possible which makes their head to head clashes so thrilling to watch.
However, I just can't put any other rivalry above the one between Messi and Ronaldo. For the number of records they have broken, the amount of ridiculously high-quality goals scored, whether it be Messi's run from halfway against Getafe in 2007 or Ronaldo's famous bicycle kick goal against Juventus in 2018 and along with the highlights they have blessed us with to watch over and over again… nothing compares to it and it helps the argument on whether football is the most technically difficult sport to play.
Sports opinion delivered daily
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Comparing them individually to decide who is greater is a separate debate that can be saved for when they both retire.
They possess two different styles of play, which are both obviously very effective and help their respective club and national teams in different ways, whether it be the passing and dribbling ability of Messi, or the sheer power and finishing of Ronaldo.
Let's pray that this morning's clash between Juve and Barcelona was not the last time two legends of the world game face off. It may well have been, though.
All we can do is enjoy the rivalry while it lasts.
Read more: theroar.com.au
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Visual music, expanded cinema, live cinema, VJing, live audiovisual performance—these are concepts enough to create some confusion in the wide realm of today's artistic audiovisual production. While each of these concepts is widely propagated and suggestive of its own line of history and shared practices, they are not as yet sufficiently defined for theoretical debate and clear practical use.
To untangle this confusion was the aim of the project, The Audiovisual Breakthrough, which brought together six international researchers to solve the problem in a collaborative effort. This book is the result. Its main purpose is to make the entangled complexities of the field manageable by putting forth and elaborating on definitions for the five main concepts named above. This book is addressed to artists, curators, researchers, students, and teachers within these practices, and to anyone working at their intersection with other fields of knowledge.
Eva-Maria Offermann's design takes up the topics addressed by the texts and develops a parallel argument: Typographically, the chosen font, GT Cinetype, is based on the design of cinematic subtitles, thus opening a rich set of references up to the cinematic context and, in consequence, to moving images, to projections, and to translations from one medium to the other.
The motif underlying the layout is the grid as structural reference to musical composition. The grid becomes visible in information graphics, whose reduced simplicity reminds of notations. The idea of notation is developed further by the use of certain signs: re-notation at the end of every paragraph in the texts, indicated by a continually changing sign.
Cinematicity and notation therefore serve as the main elements in the design concept to express the idea of translations, which is so fundamental for audiovisual thought.
← Sharon Kivland. The Natural Forms, Part II.