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A Phase II Randomized, Double-blind, Presurgical Trial of Polyphenon E in Bladder Cancer Patients to Evaluate Pharmacodynamics and Bladder Tissue Biomarkers
Jason R. Gee, Daniel R. Saltzstein, KyungMann Kim, Jill Kolesar, Wei Huang, Thomas C. Havighurst, Barbara W. Wollmer, Jeanne Stublaski, Tracy Downs, Hasan Mukhtar, Margaret G. House, Howard L. Parnes and Howard H. Bailey
Jason R. Gee
Institute of Urology, Lahey Hospital and Medical Center, Burlington, Massachusetts.
For correspondence: Jason.R.Gee@Lahey.org
Daniel R. Saltzstein
Urology San Antonio Research, University of Wisconsin-Madison, Madison, Wisconsin.
KyungMann Kim
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
Jill Kolesar
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Wei Huang
Thomas C. Havighurst
Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
Barbara W. Wollmer
Jeanne Stublaski
Tracy Downs
Hasan Mukhtar
Margaret G. House
Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD.
Howard L. Parnes
Howard H. Bailey
DOI: 10.1158/1940-6207.CAPR-16-0167 Published May 2017
We performed a phase II pharmacodynamic prevention trial of Polyphenon E [a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG)] in patients prior to bladder cancer surgery. Patients with a bladder tumor were randomized to receive Polyphenon E containing either 800 or 1,200 mg of EGCG or placebo for 14 to 28 days prior to transurethral resection of bladder tumor or cystectomy. The primary objective was to compare the postintervention EGCG tissue levels in patients receiving Polyphenon E as compared with placebo. Secondary objectives included assessments of tissue expression of PCNA, MMP2, clusterin, VEGF, p27, IGF-1, IGFBP-3; correlation of tissue, plasma, and urine levels of EGCG; and EGCG metabolism by catechol-O-methyltransferase and UDP-glucuronosyltransferase pharmacogenomic mutations. Thirty-one patients (male:female, 26:5; mean age, 67.2 years) were randomized and 29 (94%) completed the study. There was not an observed significant difference (P = 0.12) in EGCG tissue levels between two Polyphenon E dosage groups combined versus placebo. However, a dose–response relationship for EGCG levels was observed in both normal (P = 0.046) and malignant bladder tissue (P = 0.005) across the three study arms. In addition, EGCG levels in plasma (P < 0.001) and urine (P < 0.001) increased and PCNA (P = 0.016) and clusterin (P = 0.008) were downregulated in a dose-dependent fashion. No pharmacogenomic relationship was observed. EGCG levels in plasma, urine, and bladder tissue followed a dose–response relationship, as did modulation of tissue biomarkers of proliferation and apoptosis. Despite the limitations of this pilot study, the observed pharmacodynamics and desirable biologic activity warrant further clinical studies of this agent in bladder cancer prevention. Cancer Prev Res; 10(5); 298–307. ©2017 AACR.
Bladder cancer is the second most common malignancy of the genitourinary tract. During the year 2016 alone, approximately 76,960 new cases will be diagnosed with an estimated 16,390 deaths occurring in the United States as a result of this disease (1). Muscle-invasive bladder cancer, a major contributor to morbidity and mortality, is initially diagnosed in as many as 30% of patients. These patients generally undergo radical cystectomy, and often neoadjuvant or adjuvant chemotherapy, for locally advanced disease. However, the remaining 70% of patients have noninvasive papillary bladder tumors (Ta), carcinoma in situ (CIS/Tis), and tumors that invade through the lamina propria (T1). These tumors are often multifocal and recurrent, and may appear anywhere in the bladder over relatively long intervals, thereby requiring long-term surveillance (2, 3). Repeated examination entails regular cystoscopic evaluation and monitoring of urine cytology and/or other diagnostic markers. As such, this closely monitored group of patients at risk for tumor recurrence and progression represents an ideal cohort for the evaluation of chemopreventive agents and an important patient population that could benefit from effective secondary chemoprevention.
Green tea consumption has been associated with a reduction in bladder cancer risk. Green tea has a higher content of catechins than black tea, and its effectiveness against cancer has been attributed to the presence of these polyphenolic antioxidants, and particularly epigallocatechin gallate (EGCG; refs. 4, 5). Early mechanistic investigations into the biological activities of green tea focused on the ability of catechins to regulate antioxidant and free radical scavenging activity, to prevent mutagenicity and genotoxicity, to regulate phase I and II enzymes (modulation of carcinogen activation and detoxification), and to inhibit markers of tumor initiation and promotion (6). More recently, research has focused on the ability of tea catechins to target multiple signaling pathways involved in carcinogenesis, angiogenesis, metastasis, and migration (7).
In terms of preclinical in vivo studies specifically related to bladder cancer, Kemberling and colleagues (8) employed an orthotopic bladder cancer model in which intravesical instillation of EGCG 200 μmol/L inhibited tumorigenesis. Furthermore, Sato described the efficacy of green tea in reducing bladder tumor growth induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats (9). Corresponding in vitro studies have evaluated the effects of EGCG in bladder cancer cell lines in which dose-dependent growth inhibition has been observed (8, 10). In prostate cancer, other potential markers of EGCG activity have been studied. Work by the Mukhtar laboratory established that green tea polyphenols inhibit prostate tumorigenesis with a marked reduction in proliferating cell nuclear antigen (PCNA; ref. 11). Caporali and colleagues found that inhibition of prostate tumorigenesis by green tea catechins in TRAMP mice was associated with accumulation of the glycoprotein clusterin (12). Furthermore, inhibition of growth with induction of apoptosis was observed in human bladder cancer cells treated in vitro and in vivo with an antisense clusterin oligodeoxynucleotide (13). Clusterin has therefore been found both to inhibit apoptosis and to inhibit proliferation in bladder cancer as well as prostate cancer and was determined to be an indicator of chemopreventive activity (12, 13). In addition, significant inhibition of serum IGF-1 levels and a corresponding increase in serum insulin-like growth factor binding protein-3, a major IGF-1 binding protein, which suppresses the mitogenic action of IGF-1, has been described in association with green tea polyphenol–induced inhibition of prostate carcinogenesis in TRAMP mice (11).
Polyphenon E (Mitsui Norin Co., Ltd.) is derived from a hot water extract of green tea leaves (Camellia sinensis species of the Theaceae family) containing 85%–95% total catechins; the main component is EGCG, which comprises 56%–72% of the material. NCI, DCP has sponsored four phase I pharmacokinetics and safety studies with Polyphenon E (14–17). These studies have established no difference in EGCG pharmacokinetics (Cmax, AUC, t1/2) between Polyphenon E and EGCG (14) as well as the lack of significant accumulation in healthy human subjects with 4-week administration of 800 mg EGCG (15). Subsequently, Chow and colleagues determined the effect of fasting on pharmacokinetics in healthy adults taking 400, 800, or 1,200 mg EGCG as Polyphenon E (16). Plasma levels of free EGCG were dramatically higher when taking Polyphenon E as a single daily dose, and also with fasting as compared with the fed state for all three dose levels. The most common adverse events were mild gastrointestinal complaints, which were more common with increasing dose and under fasting conditions. Some subjects also experienced headaches and fatigue, possibly related to study products, but not clearly associated with dose level. More recently, the safety and effects of repeated administration of Polyphenon E (800 mg EGCG every day for four weeks) on cytochrome P450 and glutathione-S-transferase (GST) activities were studied (17). Chronic Polyphenon E administration significantly increased GST enzyme activity and GSTπ enzyme levels in individuals with low baseline values, whereas a minimal effect on four major cytochrome P450 (CYP) isozymes was observed. On the other hand, alterations in EGCG metabolism could potentially affect EGCG efficacy. UDP-glucuronosyltransferases (UGT) are membrane bound, microsomal phase II enzymes localized in the endoplasmic reticulum of liver and extrahepatic tissues which participate in EGCG metabolism. EGCG is extensively glucuronidated by UGT 1A1 to an active metabolite (-)-EGCG-4"-O-glucuronide. Given the primary role of glucuronidation in preparing endogenous and exogenous compounds for elimination via the biliary and urinary tracts, this could potentially significantly affect the half-life of EGCG. In addition, catechol-containing tea polyphenols are very rapidly O-methylated by human catechol-O-methyltransferase (COMT). These genes are polymorphic, and therefore, individuals with variant UGT or COMT enzymes may have altered metabolism, efficacy, and toxicity (18, 19).
On the basis of these early phase I/II clinical studies of EGCG, in addition to promising preclinical studies of EGCG supporting its role as a potentially safe and effective cancer preventive agent in bladder cancer, we evaluated the tolerability, tissue accumulation, and biologic effects of Polyphenon E in a randomized, double-blind, placebo-controlled phase II presurgical trial in patients with bladder cancer.
The primary objective of the study was to assess the nonmalignant bladder tissue levels of EGCG. Secondary objectives included comparison of EGCG levels in nonmalignant versus malignant tissue; examination of the dose-dependent modulation of intermediate endpoint biomarkers (PCNA, MMP2, clusterin, VEGF, p27, IGF-1, IGFBP-3) in malignant and nonmalignant bladder tissue; correlation of tissue, plasma and urine levels of EGCG; examination of the levels of other catechins (epicatechin, epicatechin gallate, and epigallocatechin) in tissue, plasma, and urine; metabolism of EGCG in tissue, plasma, and urine by COMT and UGT in relation to pharmacogenomic mutations.
Study enrollment
This was a multicentered, randomized, double-blind, placebo-controlled study with a planned enrollment of 33 participants, to be randomized on a 1:1:1 basis to Polyphenon E in doses of 800 mg EGCG, 1,200 mg EGCG, or placebo orally once daily for 14–28 days prior to transurethral resection of bladder tumor (TURBT) or cystectomy. Patients meeting study inclusion criteria were males and females 18 years of age and older with an office cystoscopy diagnostic of a bladder tumor. Enrollment must have occurred within 60 days of the prestudy cystoscopy. Patients could have no evidence of distant metastasis. Patients were also candidates for either subsequent TURBT or complete or partial cystectomy and the tumor could represent either an initial primary tumor or recurrent disease of any clinical stage. Histologic diagnosis was not required for enrollment. Pre-enrollment diagnostic cystoscopy had to occur at least 90 days after treatment of the bladder with other agents such as BCG.
Patients were excluded from this study if they had any treatment for superficial or invasive bladder cancer between the diagnostic cystoscopy and curative surgery. Furthermore, patients with any prior intravesical therapy or adjuvant chemotherapy within 30 days before baseline procedures or any prior surgery to the bladder within 30 days of baseline procedures were excluded. (Biopsies were not considered surgeries.) Evidence of other cancers (excluding nonmelanoma skin cancer) or metastatic disease, prior pelvic radiation for any other reason, or concurrent systemic chemotherapy for any other cancer, excluding nonmelanoma skin cancer were also exclusion criteria. Furthermore, participants could not take NSAIDs, with the exception of ≤81 mg aspirin per day, during study participation, whereas acetaminophen was permitted for pain relief. Consumption of any green tea supplements or more than 2 cups (16 oz) of green tea in the 24 hours prior to baseline procedures was not permitted. Patients receiving any other investigational agents, or with any history of allergic reactions attributed to compounds of similar chemical or biologic composition to Polyphenon E or any of the inactive ingredients in Polyphenon E capsules were also excluded from the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements were also contraindications to study enrollment.
Study conduct
Study visits included a baseline and presurgery visit as well as weekly phone contact. At the baseline visit, eligibility and safety labs were obtained, as well as urine pharmacokinetics, plasma pharmacokinetics, serum biomarkers, and pharmacogenetics markers. Patients were then randomized to one of the three study groups (Polyphenon E in doses of 0 mg in placebo, 800 mg EGCG, or 1,200 mg EGCG). Patients were given instructions to take the study drug with food, and to refrain from consuming additional green tea, either from dietary sources or through nutritional supplementation for the duration of the study. At the time of surgery, fresh tissue was harvested. In addition, paraffin-embedded blocks were requested after processing, as well as serum specimens for safety labs, urine pharmacokinetics, plasma pharmacokinetics, and serum biomarkers.
Study agent
Polyphenon E (Mitsui Norin Co., Ltd.) is a botanical drug substance containing a mixture of catechins originating from the leaves of green tea (Camellia sinensis). To manufacture Polyphenon E, a hot water extract of green tea is extracted further with ethyl acetate. The resulting crude extract is dissolved in methanol and purified by affinity column fractionation. Once dried, the final product contains 85%–95% total catechins; the main component is EGCG, which comprises 56%–72% of the material. Other catechins present in Polyphenon E include epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), gallocatechin gallate (GCG), gallocatechin (GC), catechin gallate (CG), and catechin. Polyphenon E may also contain small quantities of caffeine (<1.0%), theobromine (<1.0%), and gallic acid (<0.5%).
The investigational product is a dark green, opaque, size 0 hard gelatin capsule containing enough Polyphenon E to deliver 200 mg EGCG per capsule. Polyphenon E capsules are manufactured, stored, distributed, and evaluated for stability under contract to NCI, DCP using current good manufacturing procedures (cGMP) as outlined in the United States Code of Federal Regulations. A placebo capsule containing 0 mg EGCG is also utilized in our study.
Tissue harvesting
Patients undergoing a cystectomy.
From the excised bladder tissue, approximately 0.5 cm2 each of normal and neoplastic urothelium was harvested. Detailed freezing instructions were included in the patient research kit. Once the specimens were frozen, the NUNC tubes were labeled (ID, time, and date of collection) and the specimens were kept in a −80°C freezer until shipping.
Patients undergoing a TURBT.
Once enough of the bladder tumor was excised for pathologic analysis, two pieces of tumor and normal urothelium, approximately 0.5 cm2 each, were harvested for research purposes. Once the specimens were frozen, the NUNC tubes were labeled (ID, time, and date of collection) and specimens were kept in a −80°C freezer until shipping.
EGCG levels and biomarker assays
HPLC assay for EGCG.
Polyphenon E is a mixture of catechins originating from the leaves of green tea, the main component is EGCG, which comprises 56%–72% of the material. Each capsule delivers 200 mg of EGCG. Other catechins present in Polyphenon E include epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), gallocatechin gallate (GCG), gallocatechin (GC), catechin gallate (CG), and catechin. Polyphenon E may also contain small quantities of caffeine (<1.0%), theobromine (<1.0%), and gallic acid (<0.5%).
Urine and plasma samples were obtained at baseline and at the end of the study during the presurgical visit. Tissue samples (both tumor and normal) were obtained at cystectomy or TURBT, depending on the patient's procedure. Plasma, urine, and EGCG, ECG, EGC, and EC were analyzed by validated liquid chromatography-mass spectrometry methods (14, 15). The lower level of quantitation is 3.12 ng/mL, and the lowest level of detection (signal-to-noise ratio, 3:1) was 0.78 ng/mL. Values lower than the level of quantitation are reported, and have CVs in excess of 15%, typically 20%–25%.
LC-MS protocol.
Two-hundred microliters of patient plasma or urine was transferred into a glass tube containing 10 μL internal standard (IS) and 10 μL 20% vitamin C solution. Ethyl gallate (Sigma-Aldrich) was used as internal standard of which a stock solution was prepared in MeOH containing 100 μg/mL ethyl gallate. The resultant mixture of plasma or urine with IS and vitamin C solution was extracted with 3 mL of methyl tert-butyl ether (MTBE) by vortex-mixing for 10 minutes and centrifuging at 2,500 rpm for 10 minutes. The upper organic phase was transferred into another glass tube and evaporated to dryness under a gentle N2 stream at room temperature. The residue was reconstituted in 100 μL of a 10% MeOH aqueous solution with 0.1% formic acid in an orbital shaker for 10 minutes. Five microliters of the supernatant was injected onto the mass spectrometer for analysis.
LC analysis was performed by using an Agilent 1100 HPLC (Agilent Technologies), equipped with a quaternary pump and a refrigerated autosampler. For chromatographic separation, a Kinetex PFP column (2.6 μm, 50 × 2.10 mm) (Phenomenex) was used. A gradient mobile phase was used, composed of 0.1% formic acid and MeOH with 0.1% formic acid at a constant flow rate of 500 μL/minute.
A triple quadruple mass spectrometer, Agilent 1100 (Agilent Technologies) equipped with a TurboIonSpray source, was used to obtain LC-MS data. TurboIonSpray source settings were as follows: ion spray voltage (IS) -5,000 V, nebulizer gas (GS1) 40, heater (TEM) 600°C, heater gas (GS2) 40, curtain gas (CUR) 20. Collision gas (CAD) was set on 6.
IHC staining.
Tissue biomarkers assayed by immunostaining included PCNA, MMP2, Clusterin, VEGF, and p27. For the immunostains, paraffin sections were cut from the blocks, approximately 4-μm thick each, and deparaffinized. After antigen retrieval, the slides were loaded onto automated IHC stainers (Lab Vision Autostainer 360 XT and Benchmark, Ventana Medical Systems, Inc.). Endogenous peroxidase quenching was done on-instrument with kit reagents (Biocare Medical) and the slides were stained at a constant incubation temperature of 42°C according to predetermined protocols: The slides were incubated with the first antibody of optimal dilution for 32 minutes at 42°C. After the washing step, the slides were incubated with a Mach 3 species-specific probe and Mach 3 HRP polymer detecting system (Biocare Medical) incorporating betazoid diaminobenzidine (DAB). Then, the immunostained slides were counterstained with hematoxylin on the instrument. Upon completion of the staining protocols, the slides were removed from the instrument and dehydrated through a series of graded alcohols, cleared in xylene, and coverslipped manually on a Tissue-Tek automated coverslipper (Sakura).
IHC scoring.
From stained slides, the IHC score was reported for normal and malignant tissue separately. The slides were scanned and the biomarker expression levels were quantitated by a Vectra system (Perkin Elmer). This quantitative system provides a continuous score of mean optical density (OD) per pixel area of IHC chromogenic response. This system greatly reduces inter- and intra-observer variation and provides accurate and reproducible measurement (20).
ELISA assay for IGF-1 and IGFBP3.
IGF-1 and IGFBP3 were evaluated by a commercially available sandwich immunoassay (Quantikine human, R&D Systems).
Genotyping by pyrosequencing for UGT and COMT.
To compare the metabolism of EGCG by COMT and UGT1A1 in relation to pharmacogenetic polymorphisms in COMT and UGT1A1 genotyping by pyrosequencing (21) was performed as described previously.
Statistical considerations
Sample size.
The sample size for each group was based on comparing the EGCG levels between the placebo group (0 mg) and the combined group of those on 800 mg and 1,200 mg of Polyphenon E. The sample size was estimated to detect the effect size (defined as the difference in the means divided by the SD) in the range of 1.12–1.30 with power 0.8–0.9 given equal sample size for each group, according to the two-sided level α = 0.05 Student t test. To account for the anticipated dilution of treatment effect due to up to 10% of the subjects being noncompliant with treatment, the sample size was inflated to 33 subjects in total, or 11 subjects on each treatment arm.
The primary analysis was a comparison of nonmalignant bladder tissue levels of EGCG between the placebo group and the Polyphenon E groups combined using Student t test. In the case of violation of normality assumptions, an appropriate transformation of the data, such as logarithm, was considered or a nonparametric test such as Wilcoxon rank-sum test was used for comparison. A dose–response relationship between nonmalignant bladder tissue levels of EGCG and the dose (0, 800, and 1,200 mg) was tested using the Jonckheere–Terpstra test. For secondary endpoints and safety data, the following analyses were used. To test for dose–response relationships for continuous data, such as levels of catechins and other intermediate endpoint biomarkers, the Jonckheere–Terpstra test was performed. To test for dose–response relationships for dichotomous data, such as the percentage of patients that had occurrence of individual adverse events, the Cochran–Armitage test was performed. To test for correlations between tissue, plasma, and urine levels of EGCG, we used Spearman rank correlation coefficients. Wilcoxon signed rank tests were used for within treatment comparison between baseline and presurgery.
Accrual and baseline characteristics
A total of 31 subjects (11 to placebo, 10 to low dose, 10 to high dose) were randomized with subject accrual from September 2008 through March 2012.
The mean age at enrollment was 67.2 years (SD 8.7). Twenty-six (84%) were males, and 5 (16%) female. Twenty-six (84%) were ECOG performance status (PS) 0, and five (16%) ECOG PS 1. Seven (23%) were considered "hispanic or latino"; 24 (77%) were not. Thirty (97%) were white, while one (3%) was African-American. The mean BMI was 30.5 (SD 6.4). Patient demographics are summarized in Table 1. The distribution of baseline demographics and vital signs across the three treatment arms appears consistent with randomization.
Two subjects dropped from the study, of which one withdrew consent. Of the 29 (94%) patients who completed study, tissue was not obtained from one, and another did not take study medication for the entire duration of the study. Altogether four patients (13%) were noncompliant.
Table 2 provides an overview of adverse events (AE) with information on the severity of reported AEs according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) grading scale for each event. For each AE, a patient was assigned to a single severity grade category based on the AE with the worst severity within that system.
For the overall summary, the maximum AE severity was severe (grade 3) for one (3%) patient, moderate (grade 2) for 5 patients (16%), mild (grade 1) for 8 (26%) patients, and no AE for 17 patients (55%). Tests for dose–response relationship with severity were significant for pain (P = 0.009) and gastrointestinal (P = 0.026) body systems. The most common adverse event was headache, followed by nausea and muscle ache. A significant (P = 0.036) dose–response relationship was observed for all head/headache events.
EGCG, ECG, EGC, and EC tissue levels
Nonmalignant bladder tissue levels (mean values) of EGCG were 0, 0.50, and 1.72 ng/mL for the placebo, low-dose, and high-dose Polyphenon E arms, respectively. The corresponding tumor tissue levels of EGCG were 0, 0, and 2.54 ng/mL. These data are displayed in Fig. 1. For normal tissue level of EGCG, 4 of 25 (16%) had nonzero values (are not "ND"), one of which is detectable but below the lower limit of quantitation ("NQ"). Our primary comparison, between the placebo group and the Polyphenon E groups combined, was not significant (P = 0.12). However, in our analysis supplemental to the primary analysis, despite the number of patients with "ND" values, we did find a dose–response relationship for normal (P = 0.046) and tumor tissue (P = 0.005).
A, Nonmalignant and malignant bladder tissue levels of EGCG for the placebo, low-dose, and high-dose Polyphenon E arms with a significant dose–response relationship for normal (P = 0.046) and tumor tissue (P = 0.005). B, Baseline and presurgical plasma levels of EGCG for the placebo, low-dose, and high-dose groups with an ordered relationship between dose and plasma concentrations (P < 0.001).
The mean differences between tumor and normal tissue levels of EGCG by treatment group were −0.57 and 0.57 ng/mL for the low-dose and high-dose arms, respectively. There is no significant dose–response relationship (P = 0.49). Normal tissue levels of EGCG were significantly correlated with tumor tissue levels (r = 0.53, P = 0.005) and end of study plasma levels (r = 0.48, P = 0.025); also, tumor tissue levels were correlated with urine levels (r = 0.56, P = 0.007). Levels of EGCG in tissue, plasma, and urine are summarized in Table 3. Almost all of the tumor and normal tissue levels of ECG, EGC, and EC are zero; none of these catechins showed even a trend for differences in tissue.
Levels of EGCG in tissue, plasma, and urine
EGCG plasma and urine levels
As expected, plasma EGCG levels were significantly higher after daily administration of Polyphenon E than at baseline by the Wilcoxon signed-rank test (P < 0.02 for each treated arm). Baseline plasma levels of EGCG were 2.66 ± 4.14 ng/mL, 1.6 ± 2.74 ng/mL, and 2.15 ± 3.58 ng/mL in the placebo, low-dose, and high-dose groups, respectively, compared with 2.94 ± 3.40 ng/mL, 78.09 ± 81.24 ng/mL, and 87.52 ± 77.46 ng/mL at the presurgical visit; there was an ordered relationship between dose and plasma concentrations by Jonckheere–Terpstra test (P < 0.001). While urine concentrations were less than 5% of corresponding plasma levels, urine EGCG levels showed a similar relationship and were also significantly higher after administration (P < 0.02 for each treated arm). Baseline urine levels of EGCG were 0.00 ± 0.00 ng/mL, 0.22 ± 0.59 ng/mL, and 0.94 ± 2.08 ng/mL in the placebo, low-dose, and high-dose groups, respectively, compared with 0.00 ± 0.00 ng/mL, 2.60 ± 1.93 ng/mL, and 4.32 ± 2.27 ng/mL at the presurgical visit; there was a dose relationship for urine concentrations (P = 0.001). Similar results were observed for plasma EGC and ECG, as well as EGC in urine with significant differences between baseline and presurgery and a dose–response relationship. Overall, catechins had plasma and urine concentrations consistent with a dose–response relationship, suggesting that increased doses lead to higher plasma and urine concentrations. Plasma EGCG levels at baseline and presurgery are shown in Fig. 1.
Tissue biomarkers
Measured levels of expression (mean values) were reported as mean optical density per pixel area for the placebo, low-dose, and high-dose Polyphenon E arms as follows: PCNA (0.41, 0.38, 0.35); MMP-2 (0.16, 0.18, 0.16); clusterin (0.074, 0.061, 0.046); VEGF (0.011, 0.021, 0.013); p27 (0.36, 0.35, 0.31). Negative dose–response relationships were observed with PCNA (P = 0.016) and clusterin (P = 0.008). A nonsignificant reduction in p27 expression (P = 0.15) was also observed. Biomarker tissue expression findings are shown in Fig. 2 and Table 4.
Measured levels of expression reported as mean optical density per pixel area for the placebo, low-dose, and high-dose Polyphenon E with negative dose–response relationships observed for PCNA (P = 0.016) and clusterin (P = 0.008).
Intermediate endpoint biomarker expression
Serum IGF-1/IGFBP-3
The presurgery levels (mean values) for the placebo, low-dose, and high-dose Polyphenon E arms were as follows: IGF-1 (131.86, 124.22, 132.27 ng/mL), IGFBP-3 (2,020.81, 1,800.08, 1,624.03 ng/mL), and IGF-1/IGFBP-3 (0.043, 0.035, 0.054). We found no dose–response relationships for IGF-1 (P = 0.266), IGFBP-3 (P = 0.533), or the IGF-1/IGFBP-3 ratio (P = 0.197).
Pharmacogenomics of EGCG by UGT and COMT
There were no significant differences found in baseline levels of plasma and urine EGCG, although there was a trend for difference between G/G and A/G (P = 0.068) for baseline plasma EGCG by COMT. Furthermore, no significant relationships were observed for genotype for presurgery levels of EGCG in urine or plasma.
Limited epidemiologic studies have implied regular consumers of tea may have a lower risk of bladder cancer (22, 23). A study by Bianchi and colleagues suggests that individuals consuming greater than 5 cups of tea daily may have a decreased incidence of bladder cancer, although these findings are tempered somewhat by borderline significance and a lack of a dose–response relationship (24). Nevertheless, consistent with these data, geographic areas with relatively high consumption of green tea in Japan have a lower incidence of bladder cancer as compared with the United States and western European countries. Interestingly, Japanese families who immigrate to the United States have twice the incidence of bladder cancer as those families that reside in Japan (25). Epidemiologic and laboratory studies provide ample justification for the further study of green tea and EGCG in bladder cancer patients, although to date efficacy in a randomized trial has not been demonstrated. To our knowledge, this is the first clinical trial to explore both tissue accumulation and biologic efficacy of EGCG in patients with bladder cancer.
Our primary objective of this study was to evaluate tissue levels of EGCG in nonmalignant bladder tissue. The demonstration of tissue accumulation in our study implies the bioavailability of EGCG to confer biologic activity locally, to induce biologic change in both premalignant and malignant tissue. In this study, we were able to demonstrate statistically significant tissue accumulation in a dose-dependent fashion, in both nonmalignant and malignant bladder tissue, whereas no significant difference in EGCG accumulation between normal and tumor tissue was seen. While the finding of EGCG accumulation in nonmalignant bladder urothelium suggests that our primary study objective was achieved, an important caveat is that a low rate of detectability of EGCG in tissue was observed, in that only 4 of 16 specimens from patients treated with EGCG (and 4 of 25 specimens overall) demonstrated detectable levels of EGCG. The reasons for this are not clear, but could be related to study logistics. In particular, the timing between the last dose of EGCG and surgery, with harvesting of tissue, certainly varies patient to patient, and is not easy to control as it depends on surgical scheduling, time for anesthesia induction, and the operation itself which depending on the patient and tumor type can vary in technical difficulty. One potential advantage in our study is that the vast majority of patients underwent TURBT, a shorter procedure in which viable tissue can be resected and almost immediately frozen/processed, as compared with radical cystectomy, a longer operation in which tissue is gradually devitalized as the specimen is removed. Indeed the half-life of EGCG was only determined to be 2–4 hours in phase I testing (14), whereas patients who undergo surgery are required to maintain NPO status (no dietary intake) from midnight prior to surgery and therefore tissue harvesting would occur a minimum of 8–10 hours following their last dose of Polyphenon E. Given these logistic limitations, perhaps it is remarkable that we were able to detect EGCG tissue accumulation and biologic activity in any of the patients, and with a statistically significant dose–response relationship as well. However, were tissue harvesting to have occurred within 2–4 hours subsequent to the last dose of EGCG, it is possible that we would have observed a higher rate of detectability of EGCG in tissue. The lower detectability of EGCG in tissue in this study, as compared with plasma, seems to suggest a more rapid clearance or metabolism of EGCG in tissue. Other means of more immediate tissue acquisition, that is, needle biopsy to circumvent logistical challenges with tissue acquisition, would not be in accordance with standard of care and therefore timing of tissue acquisition remains a limitation to consider in the design of future trials.
Even more encouraging than the observed evidence of dose-related tissue accumulation, was evidence of favorable biologic activity. Specifically, both PCNA and clusterin were downregulated in a statistically significant, dose-dependent manner in study participants taking Polyphenon E. Inhibition of bladder cancer cell growth by EGCG has been demonstrated in vitro in multiple studies (8), with downregulation of cyclin D1, cyclin-dependent kinase 4/6, and inhibition of Rb phosphorylation in association with G0–G1 cell-cycle arrest (10). Furthermore, a reduction in the activity of ornithine decarboxylase, an enzyme responsible for polyamine production with biological significance in bladder cancer, has been observed with EGCG (26–28). We evaluated PCNA expression in our study, as PCNA has been established as a marker of cellular proliferation by the Mukhtar laboratory, in that green tea polyphenols were found to inhibit PCNA expression with corresponding tumor formation in the TRAMP model of prostate cancer (11). Similarly, downregulation of clusterin by EGCG with induction of cellular apoptosis has been described in laboratory studies (12, 13). In other preclinical studies, induction and accumulation of the cell-cycle mediator p27 has also been associated with cell-cycle arrest mediated by EGCG induction of p27/Kip1 (29, 30). While our findings pertaining to p27 as a function of EGCG administration were not statistically significant, a nonsignificant reduction in p27 expression was observed. Taken together, the favorable biomarker changes observed in this study have been associated with anticarcinogenic effects in numerous studies across different tumor types including bladder cancer. While follow-up biologic studies of effect on growth and apoptosis are needed to further corroborate our observations, these EGCG dose-dependent tissue biomarker findings, coupled with similar dose-dependent tissue and plasma pharmacokinetic results, strongly support the potential bladder cancer preventive properties of Polyphenon E.
We also explored variability in the metabolism of EGCG according to polymorphisms in UGT and COMT. Our rationale for exploring pharmacogenomic relationship between EGCG and UGT and COMT polymorphisms is based on known population prevalent altered metabolic enzymatic activity. For instance, EGCG is extensively glucuronidated by UGT 1A1 to an active metabolite (-)-EGCG-4"-O-glucuronide (18). An increase in dinucleotide repeats within the TATA box results in reduced UGT1A1 enzyme activity (31). Therefore, individuals with variant UGT enzymes could potentially have altered metabolism, efficacy, and toxicity (19). However, significant differences in EGCG metabolism were not determined in our study in relation to either UGT or COMT polymorphisms.
We demonstrate in a phase II pilot study tissue accumulation of EGCG in nonmalignant bladder urothelium which follows both plasma and urine levels in a dose-dependent fashion. Furthermore, dose-dependent changes in the intermediate endpoint biomarkers, PCNA and clusterin, were observed consistent with potential chemopreventive efficacy. Acknowledging the limitations of this pilot study, we feel these findings indicate Polyphenon E administration results in definable tissue accumulation and more importantly desirable biologic activity which warrant further clinical studies assessing the effect of Polyphenon E on actual bladder tumor recurrence and progression.
Conception and design: J.R. Gee, K. Kim, H. Mukhtar, H.L. Parnes, H.H. Bailey
Development of methodology: J.R. Gee, K. Kim, J. Kolesar, H.H. Bailey
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.R. Gee, D.R. Saltzstein, J.M. Kolesar, W. Huang, B.W. Wollmer, T. Downs, H.H. Bailey
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.R. Gee, K. Kim, T.C. Havighurst, T. Downs, H.L. Parnes
Writing, review, and/or revision of the manuscript: J.R. Gee, D.R. Saltzstein, K. Kim, J.M. Kolesar, W. Huang, T.C. Havighurst, B.W. Wollmer, T. Downs
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): B.W. Wollmer, H.L. Parnes, H.H. Bailey
Study supervision: H.H. Bailey
Other (specify): M.G. House
This work was supported by National Institutes of Health National Cancer Institute-Division of Cancer Prevention Contract (#N01-CN-35153, to H.H. Bailey), NCI Cancer Center Support Grant (P30 CA014520, to H.H. Bailey), Early Phase Clinical Trial (N01 CN05014-69, to H.H. Bailey), Core Grant (4P30CA014520-42, to H.H. Bailey), and CTSA grant (UL1TR000427-10, M. Drezner).
Revision received July 29, 2016.
Accepted March 13, 2017.
American Cancer Society. Cancer facts & figures 2016. Atlanta, GA: American Cancer Society; 2016.
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Sabichi AL,
Grossman HB
. Chemoprevention of superficial bladder cancer. Crit Rev Oncol Hematol 2002;43:277–88.
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Shipley WU,
Garnick MB,
Russell PJ,
Richie JP
. Biology and management of bladder cancer. New Engl J Med 1990;322:1129–38.
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Mukhtar H
. Tea in chemoprevention of cancer: biological and experimental studies (review). Int J Oncol 1996;8:221–38.
. Tea consumption and cancer. World Rev Nutr Diet 1996;79:154–84.
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. Green tea in chemoprevention of cancer. Toxicol Sci 1999;52S:111–7.
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Afaq F,
Saleem M,
Ahmad N,
. Targeting multiple signaling pathways by green tea polyphenol (–)-epigallo-catechin-3-gallate. Cancer Res 2006;66:2500–5.
Kemberling JK,
Hampton JA,
Keck RW,
Gomez MA,
Selman SH
. Inhibition of bladder tumor growth by the green tea derivative epigallocatechin-3-gallate. J Urol 2003;170:773–6.
Sato D
. Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea. Int J Urol 1999;6:93–9.
Chen JJ,
Ye ZQ,
Koo MW
. Growth inhibition and cell cycle arrest effects of epigallocatechin gallate in the NBT-II bladder tumour cell line. BJU Int 2004;93:1082–6.
Gupta S,
Hastak K,
Lewin JS,
. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A 2001;98:10350–5.
Caporali A,
Davalli P,
Astancolle S,
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Brausi M,
Bettuzzi S,
The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis 2004;25:2217–24.
Miyake H,
Hara I,
Kamidono S,
Gleave ME
. Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. Clin Cancer Res 2001;7:4245–52.
Chow HH,
Cai Y,
Alberts DS,
Hakim I,
Dorr R,
Shahi F,
Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and Polyphenon E®. Cancer Epidemiol Biomarkers Prev 2001;10:53–8.
Hakim IA,
Crowell JA,
Brooks CA,
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and Polyphenon E® in healthy individuals. Clin Cancer Res 2003;9:3312–9.
Vining DR,
Ranger-Moore J,
Chew WM,
Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E® in healthy individuals. Clin Cancer Res 2005;11:4627–33.
Cordova CA,
Effects of repeated green tea catechin administration on human cytochrome P450 activity. Cancer Epidemiol Biomarkers Prev 2006;15:2473–6.
Meng X,
Li C,
Sang S,
Patten C,
Sheng S,
Glucuronides of tea catechins: enzymology of biosynthesis and biological activities. Drug Metab Dispos 2003;31:452–61.
Wu AH,
Tseng C,
Van Den Berg D,
Yu M
. Tea intake, COMT genotype, and breast cancer in Asian-American women. Cancer Res 2003;63:7526–29.
Huang W,
Hennrick K,
Drew S
. A colorful future of quantitative pathology: validation of Vectra technology using chromogenic multiplexed immunohistochemistry and prostate tissue microarrays. Hum Pathol 2013;44:29–38.
McLeod HL,
Sargent DJ,
Marsh S,
Green EM,
King CR,
Fuchs CS,
Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 2010;28:3227–33.
Ohno Y,
Aoki K,
Obata K,
Morrison AS
. Case-control study of urinary bladder cancer in metropolitan Nagoya. Natl Cancer Inst Monogr 1985;69:229–34.
Bushman JL
. Green tea and cancer in humans: a review of the literature. Nutr Cancer 1998;31:151–9.
Bianchi GD,
Cerhan JR,
Parker AS,
Putnam SD,
See WA,
Lynch CF,
Tea consumption and risk of bladder and kidney cancers in a population-based case-control study. Am J Epidemiol 2000;151:377–83.
Hueper WG
. Cancers of the urinary system. In: Occupational and environmental cancers of the urinary system. New Haven, CT: Yale University Press; 1969. p. 1–67.
Hu G,
Han C,
Chen J
. Inhibition of oncogene expression by green tea and (-)-epigallocatechin gallate in mice. Nutr Cancer 1995;24:203–9.
Bachrach U,
Wang YC
. Cancer therapy and prevention by green tea: role of ornithine decarboxylase. Amino Acids 2002;22:1–13.
Mohan RR,
Husain MM,
. Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase. Cancer Res 1999;59:2115–20.
Mitscher LA,
Jung M,
Shankel D,
Dou J-H,
Steele L,
Pillai SP
. Chemoprotection: a review of the potential therapeutic antioxidant properties of green tea and certain of its constituents. Med Res Rev 1997;17:327–65.
Nam S,
Smith DM,
Dou QP
. Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem 2001;276:13322–30.
Bosma PJ,
Chowdhury JR,
Bakker C,
Gantla S,
de Boer A,
Oostra BA,
The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995;333:1171–5.
You are going to email the following A Phase II Randomized, Double-blind, Presurgical Trial of Polyphenon E in Bladder Cancer Patients to Evaluate Pharmacodynamics and Bladder Tissue Biomarkers
Cancer Prev Res May 1 2017 (10) (5) 298-307; DOI: 10.1158/1940-6207.CAPR-16-0167


text:
HomeAudiobooksChildren's & Young Adult
Written by Lauren Oliver
Narrated by Sarah Drew
The second book in Lauren Oliver's remarkable New York Times bestselling trilogy about forbidden love, revolution, and the power to choose.
In this electrifying follow-up to Delirium, Lena is on a dangerous course that takes her through the unregulated Wilds and into the heart of a growing resistance movement. This riveting, brilliant novel crackles with the fire of fierce defiance, romance, and the sparks of a revolution about to ignite.
Publisher: HarperAudioReleased: Feb 28, 2012ISBN: 0062101994Format: audiobook
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redpajama_set_name: RedPajamaCommonCrawl


text:
Q: EntityExistsException Issue with Many-To-One, One-To-Many Bi-directional mapping with additional properties in Spring JPA I have a User Table and a Movie Table & Fav_Movie table which is primarily for joining User, Movie and have some additional fields.
    @Entity
    @Table(name = "User")
    @Getter
    @Setter
    @EqualsAndHashCode
    @ToString
    public class User implements Serializable {
      @Column(name = "id")
      private String id;
      // rest
      @OneToMany(mappedBy = "user", fetch = FetchType.LAZY, cascade = CascadeType.ALL)
      private List<FavMovie> favMovie = new ArrayList<>();
   }

   @Entity
   @Table(name = "Movies")
   @Getter
   @Setter
   @EqualsAndHashCode
   @ToString
   public class Movie implements Serializable {
      @Column(name = "id")
      private String id;
      // rest
     @OneToMany(mappedBy = "movie", fetch = FetchType.LAZY, cascade = CascadeType.ALL)
     private List<FavMovie> favMovie = new ArrayList<>();
   }

   public class FavMovie implements Serializable {
    @Id
    @ManyToOne(fetch=FetchType.LAZY, optional = false)
    @JoinColumn(name = "id")
    @NotFound(action = NotFoundAction.IGNORE)
    private User user;

    @Id
    @ManyToOne(fetch=FetchType.LAZY, optional = false)
    @JoinColumn(name = "id")
    @NotFound(action = NotFoundAction.IGNORE)
    private Movie movie;

}

@Service
public class UserServiceImpl implements UserService {
 public User updateUser(UpdateUserRequest updateUserRequest) {
       User user  = userRepository.findByIdAndActive(updateUserRequest.getId(), true);
        User newUser = null;
        if(isNull(user)){
            throw new UserException(Messages.USER_NOT_FOUND);
        }
        String[] ignoreProps = ModelUtils.getNullPropertyNames(updateUserRequest);
        FavMovie favMovie = null;
        BeanUtils.copyProperties(updateUserRequest, user, ignoreProps);
        if(!isNull(updateUserRequest.getMovieIds()) && !updateUserRequest.getMovieIds().isEmpty()) {
            List<Movie> movie = movieService.getMoviesByIds(updateUserRequest.getMovieIds());

            List<FavMovie> favMovie = new ArrayList<>();
            for (Movie movie : movies) {
                favMovie = new FavMovie(user, movie);
                favMovie.add(favMovie);
                user.addFavMovie(movie);
            }
        }
            return userRepository.save(user);
    }
}

I am getting the error: EntityExistsException

"message": "A different object with the same identifier value was
already associated with the session :
[com.xxx.user.db.FavMovie#com.xxx.user.db.FavMovie@17ad]; nested
exception is javax.persistence.EntityExistsException: A different
object with the same identifier value was already associated with the
session :

tried with removing & changing FetchType, Cascade, optional etc but without success.
I dont want to use @JoinTable, that doesnt fit my purpose.
can someone help me where i am going wrong?

redpajama_set_name: RedPajamaStackExchange


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text:
Q: How to send a local image instead of URL to Microsoft Computer Vision API using JAVA The question is how to load image file and pass it as object to Microsoft Computer Vision API, all the sample code in Microsoft website is reading image from url.
// This sample uses the Apache HTTP client library(org.apache.httpcomponents:httpclient:4.2.4)
// and the org.json library (org.json:json:20170516).
package com.mparnisari.test;

import java.awt.image.BufferedImage;
import java.io.File;
import java.net.URI;
import java.nio.file.Files;
import java.nio.file.Path;
import java.nio.file.Paths;

import javax.imageio.ImageIO;

import org.apache.http.HttpEntity;
import org.apache.http.HttpResponse;
import org.apache.http.client.HttpClient;
import org.apache.http.client.methods.HttpPost;
import org.apache.http.entity.ContentType;
import org.apache.http.entity.FileEntity;
import org.apache.http.entity.StringEntity;
import org.apache.http.client.utils.URIBuilder;
import org.apache.http.impl.client.DefaultHttpClient;
import org.apache.http.util.EntityUtils;
import org.json.JSONObject;

public class Main
{
    public static final String subscriptionKey = "MY-KEY-HERE";

    public static final String uriBase =
        "https://westcentralus.api.cognitive.microsoft.com/vision/v1.0/analyze";

    public static void main(String[] args)
    {
        HttpClient httpclient = new DefaultHttpClient();

        try
        {
            URIBuilder builder = new URIBuilder(uriBase);

            builder.setParameter("visualFeatures", "Categories,Description,Color");
            builder.setParameter("language", "en");

            URI uri = builder.build();
            HttpPost request = new HttpPost(uri);

            request.setHeader("Content-Type", "application/json");
            request.setHeader("Ocp-Apim-Subscription-Key", subscriptionKey);

            // Request body.
            BufferedImage image = null;
            File f = null;
            f = new File("C:\\Coffee.jpg"); //image file path
            image = ImageIO.read(f);

            File file = new File("C:\\Coffee.jpg");

            FileEntity reqEntityF =
                new FileEntity(file, ContentType.APPLICATION_OCTET_STREAM);

            request.setEntity(reqEntityF);

            HttpResponse response = httpclient.execute(request);
            HttpEntity entity = response.getEntity();

            if (entity != null)
            {
                // Format and display the JSON response.
                String jsonString = EntityUtils.toString(entity);
                JSONObject json = new JSONObject(jsonString);
                System.out.println("REST Response:\n");
                System.out.println(json.toString(2));
            }
        }
        catch (Exception e)
        {
            System.out.println(e.getMessage());
        }
    }
}

The output is:
REST Response:

{
  "code": "BadArgument",
  "requestId": "7ecf2198-1b7f-44d0-9cc2-e05e28791281",
  "message": "JSON format error."
}

As in other post in stackoverflow guide to use FileEntity to upload the image. But it is not working.
i think this part should somehow refactor to read image instead of a URL.
// Execute the REST API call and get the response entity.
HttpResponse response = httpclient.execute(request);
HttpEntity entity = response.getEntity();

Let me know what is best solution to solve this problem, because if its possible to pass the image from local to the API, it would be great to have a for loop to analyze an image set.

A: As @Jon said, you need to change the content-type header.
// Request headers.
request.setHeader("Content-Type", "application/octet-stream");

// Request body.
File file = new File(imagePath);
FileEntity reqEntity = new FileEntity(file);
request.setEntity(reqEntity);

A: Change
request.setHeader("Content-Type", "application/json");

To:
request.setHeader("Content-Type", "application/octet-stream");

and instead of using
StringEntity reqEntity = new StringEntity(url)

Use:
FileEntity reqEntity = new FileEntity(image, ContentType.APPLICATION_OCTET_STREAM);

after this changes just give the image path as a file
File image = new File("D:\\coffee3.jpg"); //image file path

and Microsoft computer vision api will send back the result as Json.

A: my version for Android (Java)
private static void doRequest(final String image){
    new AsyncTask<Void, Void, String>() {
        DataOutputStream request;
        HttpURLConnection connection;
        @Override
        protected String doInBackground(Void... voids) {
            try {
                URL url = new URL(requestUrl);
                boolean isUrl = image.contains("http");
                openConnection(url);
                setPostData(isUrl);
                setBody(image, isUrl);
                return getResponse();
            }catch (IOException e) {
                e.printStackTrace();
            }
            return null;
        }
            private void openConnection(URL url) throws IOException {
                connection = (HttpURLConnection) url.openConnection();
            }
            private void setPostData(boolean isUrl) throws ProtocolException {
                connection.setRequestMethod("POST");
                connection.setRequestProperty("details", "{string}");
                connection.setRequestProperty("Host", "westeurope.api.cognitive.microsoft.com");
                if(isUrl) {
                    connection.setRequestProperty("Content-Type", "application/json");
                }
                else {
                    connection.setRequestProperty("Content-Type", "application/octet-stream");
                }
                connection.setRequestProperty("Ocp-Apim-Subscription-Key", "yourKey");
            }
            private void setBody(String image, boolean isUrl) throws IOException {
                request = new DataOutputStream(connection.getOutputStream());
                if(isUrl){
                    request.writeBytes(urlBody(image));
                }
                else {
                    request.write(FileManager.getBytesFrom(image));
                }

            }
                private String urlBody(String image){
                    return  "{\"url\":\"" + image + "\"}";
                }
            private String getResponse() throws IOException{
                InputStream inputStream = connection.getInputStream();
                String response = inputStream2String(inputStream);
                return response;
            }
                private String inputStream2String(InputStream inputStream) throws IOException{
                    BufferedReader bufferedReader = bufferResult(inputStream);
                    return resultString(bufferedReader).toString();
                }
                    private StringBuilder resultString(BufferedReader bufferedReader) throws IOException {
                        StringBuilder stringBuilder = new StringBuilder();
                        String line;
                        while ((line = bufferedReader.readLine()) != null) {
                            stringBuilder.append(line);
                        }
                        return stringBuilder;
                    }
                    private BufferedReader bufferResult(InputStream inputStream){
                        InputStreamReader inputStreamReader = new InputStreamReader(inputStream);
                        return new BufferedReader(inputStreamReader);
                    }

        @Override
        protected void onPostExecute(String result) {
            //...
        }

    }.execute();
}


We are pleased to introduce a new addition to Inflexxion's Behavioral Health Product Suite: the Behavioral Health Index Multimedia Version (BHI-MV). The BHI-MV is an evidence-based, consumer self-administered assessment tool, proven to increase the effectiveness and performance of clinical teams in organizations providing behavioral health services.
© All Rights Reserved. Inflexxion, Inc.


text:
Last edited by Kagaktilar
Tuesday, May 5, 2020 | History
2 edition of Kaleidoscope found in the catalog.
Trudy Roe
evoloution : the story of metamorphosis of plant form through time : variation, change, perpetuation
by Trudy Roe
Published 2004 by Trudy Roe .
Statement Trudy Roe photography and design.
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Mar 27, · Learn how to create a kaleidoscope for summer STEAM. This STEAM activity for young kids encourages the sense of sight! We spent a fun morning designing and crafting our DIY kaleidoscope for kids. This kid's kaleidoscope uses every component of STEAM to create a cool, homemade science toy. HOW TO MAKE A SIMPLE KALEIDOSCOPE FOR KIDS! WHAT IS STEAM? This is Cozy Baker's newest book on kaleidoscopes. There are over color photographs of kaleidoscopes and their amazing interior images. There is a splash of the history of the kaleidoscope; including a reprint of the original patent, and the latest news on the therapeutic value of kaleidoscope. Profiles of many of the leading kaleidoscope artists is also included. Cozy Baker has been.
Our assortment of children's kaleidoscopes also includes kaleidoscope kits and books. Imagine making your own kaleidoscope! Now there is a really cool gift that is sure to delight. Our kids kaleidoscopes are available in a wide range of prices that will suit any budget. Stop dreading the arrival of another party invitation for your child. In just a few simple steps, you can create sticker mandalas worthy of framing! The books includes everything you need to make eight stunning Sticker Kaleidoscopes™, plus one of your own design.
Belgium and Luxembourg.
statistical account of Scotland drawn up from the communications of the ministers of the different parishes
Lectures by S. Lefschetz on algebraic geometry, 1936-[1938]...
Incr Tcl/Tk from the ground up
Sugums boat
Interlinear Greek-English New Testament With a Greek-English Lexicon and New Testament Synonyms King James Version
If fish could scream
The life of John Carter
English synonymes explained in alphabetical order with copius illustrations and examples drawn from the best writers
Lay Morals
study of laterite profiles in relation to bed rock in the Darling Range near Perth, W.A.
guide for executive selection.
The evidential argument from evil
Kaleidoscope by Trudy Roe Download PDF EPUB FB2
The Kaleidoscope Book mpcs.online is an on-line book about kaleidoscopes, the artists that make them, the galleries that sell them and the collectors that enjoy them.
Its purpose is to help regenerate the "Kaleidoscope Renaissance" by providing up-to-date information about kaleidoscopes. Jan 01, · The book does an absolute justice to its title- Kaleidoscope, things change with the blink Kaleidoscope book an eye.
Danielle Steele once again manages to take her readers by surprise. The book is full of unexpected twists and turns which leaves the readers breathless gasping for more /5.
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Kaleidoscope: Diverse YA Science Fiction and Fantasy Stories seeks to fill an underrepresented niche, specified right there in the title. When I was a young adult, I read some anthologies of short stories, but as far as I can remember, they were about cis, straight, white, able-bodied, neurotypical people.4/5().
Mar 08, · KALEIDOSCOPE is my first faery story and I really quite enjoyed it. Calliope thought she was just a normal human being living a normal life while crushing on her longtime best friend. But she has these strange urges to be near Kaleidoscope book forest.
One day, the urge becomes too 4/5. Apr 18, · Scope it out: Here's a one-of-a-kind book of kaleidoscopes, plus a kit that contains everything you need to build your own. From Carolyn Bennett―author of The Kids' Book of Kaleidoscopes, Kaleidoscopia.
is the comprehensive update and revision loaded with kaleidoscope history and science, experiments, and eco-friendly projects that give recycled materials a vibrant new life.5/5(2).
Kaleidoscope is a novel by American Danielle Steel, published by Delacorte Press (see in literature). It was adapted into the NBC television movie of the same name in starring Jaclyn Smith and Perry King. It is Steel's 22nd novel. Plot [ edit ]Author: Danielle Steel.
Happy Release Day, Kristen Ashley!. It's not often a book keeps me up all night because I'm so caught up in the story I just can't put it down, but Kaleidoscope has done that.
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Coined by its Scottish inventor David Brewster, "kaleidoscope" is derived from the Ancient Greek word καλός (kalos), "beautiful, beauty", εἶδος (eidos), "that which is seen: form, shape" and σκοπέω (skopeō), "to look to, to examine", hence "observation of beautiful forms.".
Arts and Crafts Supplies, Books and Fabrics available worldwide from Kaleidoscope. Wide range of fabrics and quilting products. Free UK wide delivery over £ 'Kaleidoscope' speaks to the fundamental values that drive innovative service: trust, authenticity, and genuine care.
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Aug 14, · Kaleidoscope Wonders Color Art for Everyone by Leisure Arts is a kaleidoscope inspired coloring book featuring mirrored and variegated adult coloring patterns with 24 artistic designs printed on one-side of high quality paper/5().
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Publishers Weekly has described Salina Yoon's books as clever, fresh, funny, and smart/5(22). The kaleidoscope book is an on-line book about scope artists, galleries, collectors and restorers.
It also has information about kaleidoscope care, events, groups, history, patents, parts, books. Jul 28, · The Paperback of the Kaleidoscope by Danielle Steel at Barnes & Noble.
FREE Shipping on $35 or more. B&N Outlet Membership Educators Gift Cards Stores & Events Help Im still in the middle of reading thid book and at times im bitting my nails then laughing my butt off then crying im only on page 80 but its still the best book ive ever read/5.
Fat Quarter Books (38) Foundation Pieced (85) Hexagons - English Paper Piecing (19) History Amish and s (76) Japanese Style (48) Japanese Text (62) Jelly Roll Books (63) Kaleidoscope 3D (14) Landscapes (23) Layer Cakes-Charms (21) Log Cabin (25) Miniature (28) Mixed Media and Textile Art (72) Modern Quilting (30) Out Of Print Books ( Apr 13, · Kaleidoscope: A Novel - Kindle edition by Danielle Steel.
Download it once and read it on your Kindle device, PC, phones or tablets. Use features like bookmarks, note taking and highlighting while reading Kaleidoscope: A Novel/5(). Kaleidoscope is a collection of science fiction, fantasy and alternate history stories by Harry Turtledove, first published in paperback by Ballantine Books in April It was later gathered together with his novel Noninterference and collection Earthgrip into the omnibus collection 3 X T, published in hardcover by Baen Books in The book contains thirteen short short stories and Author: Harry Turtledove.
Kaleidoscope Setting. Outer space, in the aftermath of a rocket explosion. Characters. Hollis, Barkley, Captain, Woode, Stone, Stimson, Applegate and Lespere - Astronaut flung into space by his rocket exploding.
Boy - Wishes on the shooting star that is Hollis' body re-entering Earth's atmosphere. Mother - Encourages her son to make that wish. (Download) NCERT Book For Class XII: Kaleidoscope (English) Need Study Materials for UPSC? Click Here. Kaleidoscope (English): Class 12th.
Table of Contents. SHORT STORIES – INTRODUCTION 1. I Sell my Dreams GABRIEL GARCIA MARQUEZ 2. Eveline JAMES JOYCE 3.
A Wedding in Brownsville ISAAC BASHEVIS SINGER 4. Tomorrow JOSEPH CONRAD.A wonderful array of collectible books and nostalgia, Kaleidoscope is a repository of popular culture.About Kaleidoscope.
When a beautiful young Frenchwoman and a brilliant American actor meet in wartime Paris, their love begins like a fairy tale but ends in tragedy. Suddenly orphaned, their three children are cruelly separated. Megan, the baby, adopted by a family of comfortable means, becomes a doctor in the rural Appalachia.
mpcs.online - Kaleidoscope book © 2020


The first people to use the name Aichesown were a family of Strathclyde- Britons who lived in the Scottish/English Borderlands. The name comes from when someone lived in Berwickshire.
This web page shows only a small excerpt of our Aichesown research.
Another 67 words (5 lines of text) covering the years 1408, 1563, 1552, 1558, 1580, 1634, 1621, 1628, 1580, 1634, 1000, 1611, 1638, 1629, 1685, 1657, 1657, 1655, 1701, 1695, 1699, 1695, 1688, 1748, 1727, 1748 and 1728 are included under the topic Early Aichesown History in all our PDF Extended History products and printed products wherever possible.
Surnames that evolved in Scotland in the Middle Ages often appear under many spelling variations. These are due to the practice of spelling according to sound in the era before dictionaries had standardized the English language. Aichesown has appeared as Acheson, Acherson, Atcherson, Aitcheson, Aitchison, Atcheson, Achison and many more.
Another 46 words (3 lines of text) are included under the topic Early Aichesown Notables in all our PDF Extended History products and printed products wherever possible.
Some of the Aichesown family moved to Ireland, but this topic is not covered in this excerpt.


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Hey! Made my own Black Market decal with a Vampire theme. Breakout & Octane has special symbols inside the decal. But the decal works for every car as shown in the video.
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text:
Q: How do I create an instance from a string that provides the class name? Recently I found a piece of code that creates an instance of TButton from a string: 'TButton' was used as a parameter.
See "Is there a way to instantiate a class by its name in Delphi?"
I am trying to save published properties of any object to an XML file (which works fine), and lately I want to recreate these objects from the XML file. In this file is written which class is supposed to be created (for example TButton) and then follows a list of properties, which should be loaded into this run-time-created object.
The example above shows the way how to do it, but it does not work for the class of my own. See code below:
  TTripple=class (TPersistent)
    FFont:TFont;
  public
    constructor Create;
    Destructor Destroy;override;
  published
    property Font:TFont read FFont write  FFont;
  end;
var
  Form1: TForm1;

implementation

{$R *.dfm}

constructor TTripple.Create;
  begin
  inherited;
  FFont:=TFont.Create;
  end;

destructor TTripple.Destroy;
  begin
  FFont.Free;
  inherited;
  end;

procedure TForm1.FormCreate(Sender: TObject);
begin
RegisterClasses([TButton, TForm, TTripple]);
end;

procedure TForm1.Button1Click(Sender: TObject);
var
  CRef : TPersistentClass;
  APer : TPersistent;
begin
 // CRef := GetClass('TButton');
  CRef := GetClass('TTripple');
  if CRef<>nil then
  begin
     APer := TPersistent(TPersistentClass(CRef).Create);
     ShowMessage(APer.ClassName);  // shows TTripple, what is correct
     if APer is TTripple then (APer as TTripple).Font.Color:=90;

     /// Here  I get error message, because TTriple was not created... ?!?!?!

  end;
end;

I can not get through. The TTripple object is perhaps created, but its constructor is not used.

A: The TRipple constructor isn't being called because it's not virtual.
When you're constructing an object from a class reference, the compiler doesn't know what the final class type is yet, so it can't assign the right constructor in code.  All it knows is that it's descending from TPersistent, so it writes out code to call the constructor for TPersistent, which is TObject.Create.  If you want to call the right constructor, you have to do it virtually.
There's already a virtual constructor defined for reading classes from a class name.  It's defined in TComponent.  Make TRipple descend from TComponent and override its virtual constructor (the one that takes an Owner as a parameter) and then your code will work.

A: You may not want to use TComponent, and there is another way of doing this.
add a reference to your class
TTrippleClass = class of TTripple;

Then your buttonclick becomes :
procedure TForm1.Button1Click(Sender: TObject);
var
  CRef : TTrippleClass;
  APer : TPersistent;
begin
  CRef := TTrippleClass(GetClass('TTripple'));
  if CRef<>nil then
  begin
    APer := TTripple(TTrippleClass(CRef).Create);
    ShowMessage(APer.ClassName);  // shows TTripple, what is correct
    if APer is TTripple then (APer as TTripple).Font.Color:=90;
  end;
end;

Now you may want to have more than one Tripple type then create an custom ancestor.
TCustomTripple = class(TPersistent)
public
  constructor Create;virtual;
end;

TCustomTrippleClass = class of TCustomTripple;

TTripple = class(TCustomTripple)
strict private
  fFont : TFont;
public
  constructor Create;override;
  destructor Destroy;override;
  property Font : TFont read fFont;
end;

constructor TCustomTripple.Create;
begin
  inherited Create;
end;

constructor TTripple.Create;
begin
  inherited;
  fFont := TFont.Create;
end;

destructor TTripple.Destroy;
begin
  fFont.Free;
  inherited;
end;

procedure TForm1.Button1Click(Sender: TObject);
var
  CRef : TCustomTrippleClass;
  APer : TCustomTripple;
begin
  CRef := TCustomTrippleClass(GetClass('TTripple'));
  if CRef<>nil then
  begin
    APer := TCustomTripple(TCustomTrippleClass(CRef).Create);
    ShowMessage(APer.ClassName);  // shows TTripple, what is correct
    if APer is TTripple then (APer as TTripple).Font.Color:=90;
  end;
end;


And, Gary S. Shea, "Financial Market Analysis Can Go Mad (in the search for irrational behaviour during the South Sea Bubble," June 2005.
Michael Bordo and Eugene N. White, "A Tale of Two Currencies: Revolutions: British and French Finance During the Napoleonic Wars," Journal of Economic History, 51:2 (June 1991), pp. 303-316. Bordo and White's Tale.
Barry Eichengreen, Globalizing Capital, ch. 2.
Discussion leaders: Seminar 1, Biplap Chavorborty; Seminar 2, Jingjing Wang.
Barry Eichengreen, Globalizing Capital, ch. 3.
Eugene White (1990), "The Stock Market Boom and Crash of 1929 Revisited," Journal of Economic Perspectives , 4 (Spring 1990), 67-84.
Charles Calomiris (1993), "Financial Factors in the Great Depression," Journal of Economic Perspectives , 7 (Spring 1993), 61-85.
The Bretton Woods Era: Historical Perspective Bretton Woods, R.I.P.
Barry Eichengreen, Globalizing Capital, ch. 4.
Michael Bordo, "The Bretton Woods International Monetary System: A Historical Overview," in Michael Bordo and Barry Eichengreen, eds., A Retrospective on the Bretton Woods System: Lessons for International Monetary Reform, Chicago : University of Chicago Press, 1993, pp. 3-98.
The New Global Finance Bretton Woods II or Post-Bretton Woods?
Barry Eichengreen, Globalizing Capital, ch. 5.
Michael P. Dooley, David Folkerts-Landau, Peter Garber, "An Essay on the Revived Bretton Woods System," NBER Working Paper 9971, September 2003.
After Deregulation, Re-Globalization What is to be done?
Barry Eichengreen, Globalizing Capital, ch. 6.
Larry Neal, "Lessons from History?" in The Origins and Development of Financial Markets and Institutions, ch. 15.


text:
Posts tagged "phil coulson"
On Fangirling or Every One Just Shut Up for a Second
I saw Captain America on Thursday. It was amazing. I loved it.
Afterwards, I was walking home with my friend, Joe, munching on my popcorn refill as we went over what everything in The Winter Soldier meant for our heroes on ABC's Agents of SHIELD because shit was going to go down. There is no SHIELD, only Hydra.
Every five steps, I'd say, "Sooooo good," to the point where everyone on Hollywood Blvd. thinks I have some sort of weird popcorn fetish.
Anyway, I could not wait until Tuesday. I wanted to know. I had to know. What was going to happen to Coulson? What was going to happen to a show centered on an organization that has just been destroyed internally? I'm so excited.
And, then I read a bad review for Tuesday's episode.
Mind, I don't make it a habit to read bad reviews just as I don't make it a habit to write them. Unfortunately, this bad review was deceivingly titled. I honestly thought I was going to find some viewership numbers, because I wanted to know if there was a Captain America bump for the show. Instead, I was treated to a rant about how the show isn't doing what it's supposed to do and is merely surviving on thin thread tie-ins to blockbuster films.
Seriously, stop. This is my serious face.
I am not going to say that Agents of SHIELD started out as strong as it could have. It started to lose me. Then, I saw episode 6, which I still will argue is one of the best episodes of the season. It finally pulled in the non-Clark Gregg/Ming-Na characters to give them a stronger arc and finally show what they are made of. I want to see more of the team dynamic. I want to see more of the relationships. This episode did that beautifully while illustrating what being a member of SHIELD means to Coulson's team.
But, even with my own questions and flagging confidence, Jeph Loeb put out one last call to the fans at PaleyFest.
Trust us.
And, I do.
Agents of SHIELD is not about the Avengers. It's not about Nick Fury. It's not about Maria Hill (though if they can pull her in, I would be ecstatic.)
Agents of SHIELD is about the non-superpowered in a world of people and organizations that are. It's about the grunts. It's about the people that don't get to know everything. It's about people with limitations in a world full of impossibilities.
At this moment in time, I think people are too focused on trying to make Agents of SHIELD what it isn't. It's not about pulling in all the superheroes not big enough to have their own movie. It's not about answering all the questions that were raised in the movies. No one is defined by what they aren't, they're defined by what they are.
Science fiction is an iceberg medium. You only get to see a little bit without being privy to the immensity of the whole. The Avenger-universe movies are a piece of that iceberg. The TV show is giving us a glimpse of a different side and every once in awhile gives us the wink-nudge reminder that it's still part of the same iceberg.
You can't be upset that you aren't seeing the whole iceberg.
If you want to choose to just watch the movies, go for it. But, for me, having the show is giving me a richer experience of the Marvel Cinematic Universe.
I love seeing glimpses of this iceberg. I love knowing that there's so much more out there. I have never been this much of a fangirl, getting so excited to see the rest of the season, conjecturing as to who is which Marvel character, squeeing over Easter eggs, and laughing out loud when Coulson says, "Booyah."
Maybe this is how all those Firefly fans felt…
April 9, 2014 | Categories: Observations, TV Nonsense | Tags: agent ward, Agents of SHIELD, avengers, coulson, deal with it, fan, fangirl, fitz, marvel, Marvel's SHIELD, melinda may, phil coulson, SHIELD, simmons, skye | Leave a comment
Agents of SHIELD Pilot Review? Analysis? Post about me watching it?
I unapologetically have no time to watch TV when it airs. So, it's rather surprising that I was able to watch Agents of SHIELD last night.
But, if you know me, perhaps not that surprising. Because I love Agent Coulson. I had a small twinge of jealousy during Avengers when he said there was a cellist in Portland. I nearly ripped my theatre seat out of the ground when Loki stabbed him in the back. I hung on through the movie, thinking, "No body, no death," the reality of action movies, but the movie ended.
And, seemingly, Coulson ended with it.
Now, as anyone knows, Coulson is back and as quippy as ever. And he comes bearing conspiracy.
The pilot episode explains Coulson's reappearance as Nick Fury faking our favorite agent's death to get the Avengers to work as a team. This hypothesis is icky. If Coulson's death was a fake, it's ultimately meaningless, considering everything that Coulson stands for. However, Maria Hill and Doc Shepard (Firefly guy) hang on Coulson's resurrection a little too long. So long, in fact, that we know there's something rotten in the state of Strategic Homeland Initiative, Enforcement and Logistics Division.
The general agreement is that Agent Phil Coulson of Agents of SHIELD is a life model decoy. I'm not placing my bets on that, but it's certainly possible.
Any way, the thing that I really wanted to talk about was the definition of heroism. io9.com posed this in their biggest unanswered questions about Agents of SHIELD:
Are all superheroes essentially psychotic?
This seems to be one major theme of the episode — Michael gets superpowers and uses them to help people, just like the Avengers. But he resists doing the whole "costumed hero" thing when Skye suggests it… until he starts to go insane due to the tech in his arm. Then he suddenly starts talking about being a hero, and his mean factory foreman being "the bad guy." And he tells the nice doctor lady that this is his origin story. So… is the whole idea of being called to heroism just a form of psychosis? Is it essentially sociopathic? At the end of the episode, though, Michael says "it matters who I am," and Agent Coulson turns that around into a thing where Michael's real chance for heroism is self-sacrifice — saving the people in the train station from his own spontaneous combustion. (And then luckily, it doesn't come to that, thanks to Fitzsimmons.)
This is an interesting idea and, while I won't bet on the true nature of the current Phil Coulson, I would wager that Agents of SHIELD will be addressing a lot of the stigma around heroism. The tagline, after all, is "Not all heroes are super."
Part of my love of Phil Coulson is this weird grey area he exists in. He's definitely a hero. In Avengers, he's the hero that the super-powered aspires to be. He faces a "god" because it's the right thing to do. At the same time, Coulson absolutely loves his job. Is he just following orders?
It's sort of a Yoda moment. Coulson is a person who DOES. He doesn't try. He's gets shit done. And that, above most else, is why I love him so.
Anyway, I would purpose some major unanswered questions of my own:
Will Phil Coulson be in the next Avengers movie?
You can't just ignore the fact that Coulson is back. While the Marvel cinematic universe just got a little bigger, it's still very insular. Coulson was the go-to guy on ALL the heroes. He was Thor's contact, the first man on the job when Tony Stark started suiting up, and even saved Pepper a few times in the first Iron Man film. Not to mention JARVIS could have out with the big secret within 20 seconds of half-assed hacking.
How will the heroes react to it?
They don't need Coulson anymore. But, if they stick with the cover story that Nick Fury is a liar, well, that's not real great for team cohesiveness.
Where are the super-powered?
A lot of people wanted the Michael character to be Luke Cage. And, that's not a bad tactic, introducing Marvel characters less likely to get their own movies into the television universe. However, my thought is that we won't see any super powers. We'll be seeing how people in a world with the superpowered deal with not having them. And, that's pretty much how the series has been billed. Maybe we'll get these characters later, but I doubt we'll see supers in the first season outside of artificial ones.
What does this mean for the cinematic universe?
In the comics, all of the Marvel heroes exist in the same universe. X-men, Avengers, Spider-man, they're all kicking it around in the same world. With 20th Century Fox holding on to X-men and Sony with the iron grip on Spider-man, who knows when these properties will be back together on-screen. Stop celebrating the Batman/Superman movie, give me Spider-man/Human Torch or Wolverine vs. Hulk. One can only hope that competing companies will play nice for the sake of Marvel's success. But realistically, Coulson might have to die again to make that happen.
September 25, 2013 | Categories: Generalities, Items of Interest, TV Nonsense | Tags: agent coulson, agent phil coulson, coulson, entertainment, phil coulson | Leave a comment


78 Baynard Cove Road, Sea Pines, Hilton Head • Homefinders Plus, Inc.
78 Baynard Cove is perfect for the family seeking a beach vacation on Hilton Head Island. The property comfortably accommodates 8 people and up to the 3 vehicles. This property's amenities include, heated pool, heated spa, screened -in porch, gas grill, and much more. The property is in exceptional condition, its less than 1 mile to the beach and in very close proximity to the bike path. The bike path is easily accessed at the end of the property's driveway. If you're interested in a leisurely bike ride or a relaxing jog, the path is just steps away.
The house has 4BR; 3BA. The kitchen was renovated in 2016. The renovation included cabinets, granite countertops and stainless steel appliances.
The kitchen is nicely stocked with all the essentials. There is plenty of room in the kitchen and there is a bar for serving apps or drinks.
The property is Wi-Fi friendly. The signal is good throughout the property.


text:
Q: Vue-router alias with fixed param I have this little router over here, and basically I want to have a default language for my site. This means that the same content should be seen if you access www.example.com/about and www.example.com/es/about
I thought an alias would be apropiate for this, however I'm getting a error when tryin to access /about.
[vue-router] missing param for aliased route with path "/:language/about": Expected "language" to be defined

This makes sense as the :language param is not set, is there any way I can implement what I want? Can I set a fixed :language param whenever the user hits the alias?
This is my router.

router = new Router({
  routes: [
    {
      path: '/:language/about',
      alias: '/about'
      component: About
    }
  ]
})

A: Using optional parameters (append ?) will solve this. You won't even need the alias:
router = new Router({
  routes: [
    {
      path: '/:language?/about',
      component: About
    }
  ]
})

A: The routes config sets an arbitrary language as the default, if none is provided in the url:
var routes = [
{
    path: '/:lang',
    component: WelcomeComponent,
    children: [
    {
        path: 'hello/:name',
        component: HelloComponent
    }
    ]
},
path: '*',
redirect: '/en'
]

set the lang from the url after each route, if the user makes a direct access to /:lang
router.afterEach((to, from) => {
    Vue.config.lang = to.params.lang
}

I'm pulling this from a forum post that I often reference. It also includes some logic for a language switcher component: https://forum.vuejs.org/t/dynamic-base-in-vue-router/1026/4


text:
Absolut readies new brand campaign
By David Rattray	 23 Sep 2009 10:09 am
Absolut is set to launch its biggest ever UK campaign to unveil the premium vodka's overarching new brand "manifesto".
The digital, cinema, broadcast and experiential activity aims to set out "who the brand is and what it stands for" and marks the first major local push for the vodka since Pernod Ricard bought the brand from Vin & Sprit last year.
Advertisements, created by TBWA, spell out the brand's values: "doing things differently leads to something exceptional".
For example, the word "differently" is woven in wheat and depicts the primary ingredient for the vodka, while "doing" is carved from a glacier to depict the purity of the water used in Absolut.
Mark Hamilton, head of marketing for vodkas at Pernod Ricard UK, says the campaign aims to spell out what the brand's long-term strapline "In an Absolute world" means.
Pernod Ricard has launched two event-themed campaigns this year. "Protest" coincided with the G20 summit in London, while "Hugs" coincided with the Budget and intended to present a world where people "give kindness not cash".
Rival Smirnoff recently launched a £15m global campaign moving away from the previous focus on purity of the brand in favour of a lifestyle positioning.
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text:
Czechoslovakia 1968: The Award Winning Documentary
Czechoslovakia 1968 is a short documentary film about 50 years of history of Czechoslovakia, composed entirely of sepia toned archival footage. It was produced in 1969 and it focuses primarily on "Prague Spring", also known as the Russian invasion of Czechoslovakia.
A virtually wordless visual history of Czechoslovakia from 1918 to 1968, it is a collection of images that are haunting in their beauty. Starting out watching, one cannot imagine the heartbreaking imagery of Soviet tanks entering the city to suppress the political and cultural liberalization of the time which dominate the last half of this film.
Residents of Prague are seen protesting and mobilizing their political strength against the Soviet troops.
This moving film short was produced by the United States Information Agency under the direction of Robert M. Fresco and Denis Sanders. It features the graphic design of Norman Gollin.
Czechoslovakia 1968 received the award for the Best Documentary Short Subject of 1969 at the 42nd Annual Ceremony of the Academy of Motion Picture Arts and Sciences, Hollywood and you can see the Oscar win speech here with Fred Astaire giving them their award.
It should be noted there are two rather unsung heroes of this remarkable film: the film editor, Marvin Walowitz, who had a long career in Hollywood, mostly as a feature film sound editor, and the composer of the evocative score, Charlie Bernstein.
This is a film that only came together in the cutting room, and Marvin's & Charlie's contributions are clearly enormous.
In 1997, this film was selected for preservation in the United States National Film Registry by the Library of Congress having been identified as "culturally, historically, or aesthetically significant".
An online review by Robert Reynolds states "The editing job done to put this together is excellent. It's a very effective piece which is most pertinent today given what's going on between Russia and the Ukraine. The scenes from 1938, showing Chamberlain, Hitler and the Germans taking over, with Hitler's insistence that he was acting to "protect" Germans living in the Sudetenland rings rather familiar for some reason. The more things change, the more they stay the same…"
You can watch the complete Oscar Award winning documentary below or support this site by purchasing your own copy on Amazon for your home library.
(Note: The film below is 14.35 minutes. The Amazon documentary is 17 minutes and elsewhere we read that the film is 22 minutes long.)
What happened in the world in 1968 must never get forgotten.
Sources: YouTube, Wikipedia, Internet Movie Database, Encyclopedia Britannica.
ENTERTAINMENT, History, Movies
Cinema, History | Traditions, Military
The Good Soldier Švejk in Color
Back in Time to Charles University Students of 1948
Timeless Czech Villages in the Banat Region of Romania
The 100-Year-Old Czech Fish Knife
The White Disease aka Bílá Nemoc


Melody Callaway and Dianne Cutri are nominees for the National Drowning Prevention Alliance's Lifesaver of the Year Award. Please visit NDPA's Facebook page to read all the entries at http://bit.ly/tSn7nF and give a thumbs up for your favorites. Check back in January when the top 10 finalists are announced.
The National Drowning Prevention Alliance is a volunteer-driven 501(c) 3 nonprofit organization founded in 2004. NDPA members are dedicated to preventing drowning for all age groups in all bodies of water through public education, advocacy and strategic partnerships. The public is invited to join by visiting www.ndpa.org.
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