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BACKGROUND: Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines.
METHODS: Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance.
RESULTS: In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P < 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P <0.001) were successfully validated.
CONCLUSIONS: Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.
Head and neck squamous cell carcinomas (HNSCCs) 11 represent the sixth most common cancer worldwide with a 5-year survival rate of about 65% (1). Early-stage disease is managed currently with a single-modality treatment (surgery or radiotherapy), while advanced stages are treated using combined therapy (surgical resection and adjuvant radiotherapy, radio-chemotherapy, or definitive radio-chemotherapy) (2). A multimodal therapeutic approach is frequently accompanied by substantial side effects (3). Patients with early stage tumors have an increased probability of full recovery, whereas patients with more advanced stages often develop locoregional and/or distant recurrences (4) with a median survival of less than 1 year (5).
HNSCCs display a heterogeneous tumor biology regarding risk of recurrence, progression, and individual tendency to metastasize. Owing to the heterogeneous course of the disease, there are no exact guidelines defining the therapeutic approach for each patient. Additional diagnostic tools for patient risk stratification are urgently needed to achieve an effective individual treatment, while avoiding overtreatment. A pretherapeutically tested blood-based biomarker might identify patients at a higher risk of tumor recurrence. These patients might potentially benefit from a more aggressive treatment, whereas patients with a better prognosis might benefit from a treatment with reduced toxicity. A biomarker-based, intensified clinical disease monitoring method could lead to early detection of recurrent or metastatic disease, allowing for the timely initiation of a consecutive treatment, i.e., surgery, radio-chemotherapy, chemotherapy, and therapies with tyrosine kinase inhibitors (TKIs) or therapeutic monoclonal antibodies (mAbs). Although TKIs (e.g., erlotinib and gefitinib) may cause major side effects and lack satisfactory efficacy (6), mAbs show promising results (7). Cetuximab has already received US Food and Drug Administration approval for locally advanced, recurrent, and metastatic HNSCCs. Immunotherapeutic treatment with the mAb pembrolizumab demonstrated an overall response rate of 18% in patients with advanced HNSCCs (8) and has very recently received FDA approval for the treatment of recurrent and metastatic HNSCCs. The early detection of recurrent or metastatic disease is of particular importance in the context of immunotherapies, since late or delayed responses occurring after treatment initiation have been described for immune checkpoint inhibitors [for review see (9)], thus requiring a sufficient remaining life expectancy to allow for the drug to be effective.
In addition to tumor recurrence, patients with an HNSCC are at high risk of developing a second primary malignancy. The cumulative incidence of a second cancer within 5 years after initial tumor diagnosis has been reported to be 17.9% (10). A blood-based pan-cancer test for the detection of other malignant processes besides HNSCC might allow for an early diagnosis when curative treatment is still an option.
Tumor-derived circulating cell-free DNA (ccfDNA) is a highly promising biomarker for the assessment of tumor progression and the evaluation of prognosis, diagnosis, and response to treatment (11–13). Tumor cells release ccfDNA into the bloodstream; however, the majority of ccfDNA is hematopoietic and usually not of cancerous origin (14). Tumor-specific DNA methylation allows for the discrimination of tumorous and nontumorous ccfDNA.
Septins are aberrantly expressed in several tumor entities (15). Septin 9 has been shown to play a critical role in mitotic cell division (16), inhibition of proliferation, tumor growth, and angiogenesis (15, 17). The septin 9 (SEPT9) 12 gene locus is hypermethylated in colorectal precursor lesions and carcinomas (18), and its methylation in ccfDNA has been proven to be a powerful biomarker for colorectal cancer screening (19) that has received FDA approval. Furthermore, SEPT9 DNA hypermethylation has been suggested as a biomarker for the diagnosis of HNSCCs (20).
Methylation of the short stature homeobox 2 (SHOX2) gene locus is a validated lung cancer biomarker (21–26). SHOX2 methylation has been previously shown to be associated with the amplification of the 3q25 gene locus, which is a frequent event in HNSCCs (27–29). Furthermore, SHOX2 and SEPT9 methylation in combination have been shown to be clinically useful diagnostic and prognostic biomarkers in pleural effusions and ascites (30, 31). The present study explores the value of quantitative SEPT9 and SHOX2 methylation levels in ccfDNA for the clinical management of HNSCC patients.
HNSCC patients (training cohort: n = 284, testing cohort: n = 141) and matched control patients with nonmalignant diseases (training cohort: n = 122, testing cohort: n = 102) treated between July 2012 and November 2014 (training cohort) and between December 2014 and July 2016 (testing cohort) at the Departments of Head and Neck Surgery (training and testing cohorts) and Oral and Maxillofacial Surgery (testing cohort) at the University Hospital of Bonn were prospectively enrolled.
The HNSCC cohort consisted of 3 groups: (a) patients suffering from primary squamous cell carcinoma (SCC) of the larynx, pharynx, mouth; (b) patients with locoregional tumor recurrence (lymph nodes or local tissue) of a previous HNSCC; and (c) HNSCC patients who were clinically followed up after treatment. Group 3 was included in the training cohort only. All HNSCC patients were free of other SCCs than HNSCCs for at least 3 years. All control patients were matched to HNSCC patients with respect to age, sex, and tobacco and alcohol consumption. All control patients had a cancer-free history of at least 3 years and no prior history of SCC. Blood samples were taken before treatment and longitudinally during clinical follow-up.
The study protocol was approved by the ethics committee of the University Hospital Bonn (vote no. 224/12). All patients provided written informed consent.
The following clinical end points/times-to-event were investigated: (a) death/overall survival; (b) development of a locoregional recurrence (local lymph nodes or local tissue)/locoregional recurrence–free survival; (c) development of distant metastasis/distant metastasis–free survival; and (d) development of a locoregional recurrence and/or distant metastasis/progression-free survival. Second primary cancers were considered as a secondary clinical end point.
Plasma was prepared from EDTA-stabilized blood and the ccfDNA was bisulfite converted and purified as described in detail in Supplemental Protocol 1 in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol63/issue7.
Methylation was determined using SHOX2/SEPT9/ACTB (actin beta) triplex quantitative PCR (qPCR) as previously described in detail (30). The qPCR target regions within the SHOX2 and SEPT9 genes are shown in online Supplemental Fig. 1. Water was used as a no-template control to check for cross-contamination and DNA carryover. Quantitative methylation levels from 6 (plasma, 10-μL template DNA for each replicate) and 3 (tissue, 20 ng quantified via UV spectrophotometry) qPCR replicates were calculated using the ΔΔCq method, and mean values were computed (24, 30). The analytical performance of the qPCR assay has previously been evaluated (30).
ANOVA, Kendall τ and Spearman's ρ rank correlations, t tests, and Wilcoxon-Mann–Whitney tests were performed to compare SHOX2 and SEPT9 methylation levels among cancer patients and between controls and cancer patients. Median methylation levels were reported including interquartile ranges (IQRs). The area under the curve (AUC) of the ROC was computed as a measure of test diagnostic accuracy. Cox proportional hazards (univariate and multivariate with backward elimination) and Kaplan–Meier analyses were conducted to investigate the time-to-events. P values refer to the log rank test and Wald test, respectively. Two-sided P values <0.05 were considered statistically significant.
SHOX2 and SEPT9 were found to be hypermethylated in HNSCC tissues compared to normal adjacent tissues (diagnostic accuracy: AUCSEPT9 = 0.89, 95% CI, 0.85–0.94; AUCSHOX2 = 0.98, 95% CI, 0.97–0.99; see online Supplemental Fig. 2 in Supplemental Results 1). Furthermore, matched tumor samples and pretherapeutic blood samples from 55 patients were analyzed. SHOX2 methylation in plasma correlated significantly with tissue methylation levels (Spearman ρ = 0.36, P = 0.007), and SEPT9 showed a trend toward higher methylation in plasma from patients with SEPT9 hypermethylated tumors (Spearman's ρ = 0.25, P = 0.067). Based on these results additional patients were recruited to build a training and a testing cohort.
A total of 284 HNSCC patients and 122 control patients with benign diseases were recruited for the training cohort. Baseline characteristics and distribution of clinicopathological data reflected a representative white cohort of HNSCC patients (see online Supplemental Tables 1 and 2, and Table 1).
Blood plasma samples of HNSCC patients before treatment were available in 48% (137/284) of patients. Matched control patients were tested to determine the basal level of sporadic methylation in plasma. Quantitative levels of tumorous ccfDNA indicated by hypermethylation of the SHOX2 and SEPT9 gene loci were significantly higher in HNSCC patients compared to control patients (Fig. 1A, AUCSEPT9 = 0.79, 95% CI, 0.74–0.85; AUCSHOX2 = 0.80, 95% CI, 0.75–0.85). The level of methylated ccfDNA was associated significantly with clinicopathological tumor and nodal category, vascular and lymphatic invasion, and tumor grading (Table 1; also see online Supplemental Table 2). A methylation cutoff value was introduced to dichotomize the quantitative methylation values (Fig. 1A). The cutoff was chosen based on the methylation levels in control patients, with 95% of controls showing methylation levels below the cutoff (specificity). Methylation levels below these cutoffs (SHOX2: 0.25%, SEPT9: 0.075%) were considered sporadic background methylation levels known to occur in blood from healthy individuals and patients with benign diseases (21–24). In agreement with previous studies and as expected from the analysis of tissues described above, sporadic background methylation was higher for the SHOX2 gene locus compared to the SEPT9 gene locus (19, 21–23, 30, 31). Based on this cutoff, 50% (SHOX2) and 57% (SEPT9) of HNSCC patients showed a positive test result (sensitivity), respectively. For diagnostic purposes, both biomarker levels were averaged (mean) to compute 1 value reflecting the overall concentration of tumorous ccfDNA better than a single biomarker. The mean methylation level [meanSHOX2/SEPT9 = (SHOX2 + SEPT9)/2] resulted in 59% sensitivity at 96% specificity based on the mean cutoff of 0.16% (Fig. 1A). A mean methylation level led to an increased diagnostic accuracy (AUCmeanSEPT9/SHOX2 = 0.83, 95% CI, 0.78–0.88; Fig. 1A). The advantage of combining both biomarkers is the increase of specificity from 95% to 96%. If reproducible in a larger cohort, a specificity increase from 95% to 96% would mean a 20% reduction of false-positive results from 5% to 4%. Furthermore, a single value facilitates the application of the 2 biomarkers for monitoring purposes.
Eight out of 137 HNSCC patients with available plasma samples before primary treatment were treated in a palliative manner and thus were excluded from survival analyses. Due to the different biological relevance of SHOX2 and SEPT9, survival analyses were performed separately for each biomarker without the use of meanSHOX2/SEPT9. In univariate Cox proportional hazards analysis of the remaining 129 cases, patients with positive SEPT9 and SHOX2 plasma levels were at a higher risk of death compared to negative patients [SEPT9: hazard ratio (HR) = 5.27, 95% CI, 2.03–13.68, P = 0.001; SHOX2: HR = 2.32, 95% CI, 1.12–4.83, P = 0.024]. This finding was confirmed in Kaplan–Meier analyses of overall survival as shown in Fig. 1B.
To avoid overly optimistic results from the introduction of a methylation cutoff for result dichotomization, univariate and multivariate Cox proportional hazards analyses were conducted using SHOX2 and SEPT9 DNA methylation levels in plasma as continuous variables. In univariate Cox proportional hazards analyses, increased SEPT9 methylation levels were prognostic for an adverse overall survival, a higher risk of locoregional tumor recurrence, and the development of distant metastases (see online Supplemental Table 3). In multivariate Cox proportional hazards analyses including established prognostic factors, SEPT9 methylation proved to be an independent prognostic factor after backward elimination (see online Supplemental Table 3). SHOX2 plasma methylation levels, in contrast, were not prognostic in multivariate analysis for any of the analyzed clinical end points (death: P = 0.78, distant metastases: P = 0.97; locoregional recurrence: P = 0.91).
Selected clinical performance characteristics were validated in the testing cohort, i.e., diagnostic accuracy (AUCs, sensitivity, and specificity), molecular staging (association with T category, N category, grade), and prognostic value. A total of 141 HNSCC patients and 102 control patients were recruited for the testing cohort. Baseline characteristics and distribution of clinicopathological data of the testing cohort were comparable to the training cohort (see online Supplemental Tables 4 and 5, and Table 2).
Seventy-four of 141 HNSCC patients (sensitivity: 52%) showed a meanSHOX2/SEPT9 plasma level above the cutoff (0.16% as defined in the training cohort) and were true positive, while 97 of 102 control patients (specificity: 95%) were true negative. MeanSHOX2/SEPT9 resulted in a diagnostic accuracy of AUC = 0.80 (95% CI, 0.75–0.86, Fig. 1C). The strong correlation of SHOX2 and SEPT9 plasma hypermethylation with the tumor and nodal category was corroborated in the testing cohort (P <0.001 each, Table 2). In addition, SHOX2 plasma hypermethylation was associated significantly with tumor grade (P = 0.001).
Four out of 141 HNSCC patients were treated in a palliative manner and thus were excluded from survival analyses. In univariate Cox proportional hazards analysis of the remaining 137 cases, patients with positive SEPT9 and SHOX2 plasma levels were at higher risk of death compared to methylation-negative patients (SEPT9: HR = 2.78, 95% CI, 11.16–6.67, P = 0.022; SHOX2: HR = 2.50, 95% CI, 1.12–5.60, P = 0.026, Fig. 1D). Accordingly, the results obtained in the training study were successfully validated in the testing cohort.
Owing to the increased sensitivity and specificity noted with tandem use of both biomarkers (meanSEPT9/SHOX2), their combination was tested for posttherapeutic disease monitoring longitudinally. Plasma methylation levels during patients' posttherapeutic follow-up examinations were available in 90% (257/284) of patients. Twenty-two percent (56/257) of these patients reached 1 or more of the investigated clinical end points during surveillance. Twelve percent (31/257) of patients died, 8% (20/257) developed distant metastases, and 11% (27/257) relapsed locoregionally. Distant and/or locoregional progression of HNSCCs was diagnosed in 17% (43/257) of patients. Furthermore, 5% (12/257) of patients developed a second primary tumor (4 lung cancers, 3 HNSCCs, 2 colorectal cancers, 1 gastric, 1 esophageal, and 1 pancreatic cancer). Seven of these 12 patients (58%) did not have a recurrence of the HNSCC. Thirteen percent (38/284) of patients had a HNSCC-specific tumor progression in the absence of a second primary tumor.
Plasma methylation levels of 671 blood samples from all 257 monitored patients were analyzed. Sixty-four (10%) blood samples were above the selected cutpoint and therefore positive. According to 96% specificity, approximately 3 of these 64 positive samples could be expected to be false-positive results. Altogether, 16% (42/257) of patients showed 1 or more positive results. Of these patients, 62% (26/42) had a single positive result, 31% (13/42) had 2 positive blood samples, and 7% (3/42) of patients had more than 2 positive results. Online Supplemental Table 6 shows the results from the last negative and the first positive blood samples from all patients who reached 1 or more of the clinical end points during disease monitoring. All patients (n = 16) with more than 1 positive test result reached 1 or more of the clinical end points. Of patients with only 1 positive test result, 92% (24/26) suffered from a disease progression or a second cancer and/or died within 1 year after the first positive blood test, which is in line with the specificity of the test. Deceased patients had a positive biomarker testing in 18/31 (58%) cases. The test positivity occurred a mean of 213 (range: 30–488) days before death. However, 7 patients (see online Supplemental Table 6) showed high methylation levels in plasma before death without any diagnosed tumor recurrence or second primary cancer. Methylation levels in plasma above the cutoff were found in 47% (18/38) of patients with a locoregional or a distant tumor recurrence in the absence of a second primary tumor. Of these patients, 78% (14/18) had a positive test result a mean of 105 (range 8–377) days before the clinicopathological verification of the tumor progression. The tumor recurrence of the other 4 patients (4/18) was diagnosed on the day of treatment, as patients were not available for testing beforehand. In detail, 43% (6/14) developed a locoregional recurrence, 43% (6/14) a distant recurrence, and 14% (2/14) both. Two patients who developed a second primary cancer in the absence of a HNSCC-specific tumor recurrence (n = 7) showed a suspicious increase in biomarker levels 112 days (ductal pancreatic adenocarcinoma) and 343 days (esophageal cancer) before the clinicopathological diagnosis of the second cancer. Monitoring results from 8 selected cases are described in detail in online Supplemental Results 2.
Previously, the therapeutic approach for HNSCC patients has mainly relied on clinical staging parameters. However, there are no validated guidelines defining the exact treatment of HNSCCs. Powerful biomarkers are therefore urgently needed to enable precise and reliable diagnosis, treatment, and prognosis, particularly in the context of novel therapeutic options, e.g., immunotherapies.
The aggressiveness of adjuvant treatment has been controversial and a topic of frequent discussions. Novel prognostic factors besides clinical tumor staging might improve risk stratification and lead to more personalized therapy. SHOX2 and SEPT9 proved to be powerful prognostic and molecular staging biomarkers for identifying patients at higher risk of tumor recurrence. Consequently, patients with high methylation levels before therapy would benefit from a more aggressive first-line therapy and should receive more intensified posttherapeutic disease monitoring. Of note, in contrast to strong prognostic parameters, i.e., pathologic tumor and nodal category, SEPT9 and SHOX2 methylation in blood are accessible before a surgical resection of the tumor, thus providing a chance to adapt first-line treatment in accordance with the prognosis of the patient. Currently, neoadjuvant immunotherapies are under investigation and might represent an option for patients who are unlikely to benefit from a surgery with curative intent.
Following treatment, the timely detection of disease recurrence or metastases is of particular importance. The rapid development of novel immunotherapies, in particular, implies treatment options even for patients with an advanced or metastatic disease (8). However, immunotherapies require a minimal remaining life expectancy to be effective. Accordingly, the earlier detection of an incurable disease is likely to increase the quality-adjusted lifespan of these patients. Just as with the treatment of HNSCCs, there are no validated guidelines defining the intervals and the exact procedure of posttherapeutic follow-up examinations. To evaluate the impact of SHOX2 and SEPT9 in posttherapeutic monitoring, biomarker levels in blood plasma were investigated longitudinally during follow-up examinations. The sensitivity of the biomarkers for the detection of tumor recurrences was only slightly lower compared to the sensitivity of the detection of the primary HNSCCs. In test-positive patients with tumor recurrences, suspicious biomarker levels were found significantly earlier compared to the common clinical practice. However, shorter time intervals between biomarker testing during follow-up care could lead to an even higher efficiency of such a test. In this study cohort, 7 patients showed high methylation levels in plasma before death without any diagnosed tumor recurrence or development of a second primary cancer. Owing to the high specificity of the biomarkers (95%–96%), it can be speculated that an occult tumor progression was present in these cases. Unfortunately, body-imaging examinations that could have clarified the status of these patients were not feasible. Several patients with a posttherapeutic positive blood sample were retested over time. Those with positive results in consecutively taken blood samples proved to suffer from disease progression in all cases, whereas only 92% of patients with only 1 positive test result had a proven tumor recurrence. Accordingly, the retesting of a positive blood sample using a second blood sample is likely to increase the specificity of the monitoring test. The performance of the monitoring test might further be improved by individualizing the algorithm for the results interpretation based on the analysis of the tumor tissue or based on the inclusion of the pretherapeutic blood test result. Patients whose tumor or pretherapeutic blood sample is positive for only either SEPT9 or SHOX2 might benefit from a monitoring test that considers only the positive biomarker for the interpretation of the result.
SHOX2 and SEPT9 DNA hypermethylation additionally has been linked to other cancers associated with alcohol and tobacco consumption (i.e., tumors of the lung, colon, stomach, liver, biliary tract, and pancreas) (18, 19, 22, 30–32) and could therefore be a promising biomarker candidate for the detection of occult second primary cancers during disease monitoring of HNSCCs. Furthermore, these biomarkers might be a potential diagnostic tool for the management of malignant diseases other than HNSCCs, as they appear to be nonspecific regarding tumor-site and organ.
The use of ccfDNA for cancer screening purposes is controversial. This study indicates that neither of these biomarkers is well suited for HNSCC screening owing to 3 major shortcomings. (a) Even a relatively high specificity of 95%–96% results in a positive predictive value (PPV) that is too low leading to additional effort and costs for validation of patients with positive screening results. (b) The sensitivity of the investigated biomarkers is higher for advanced tumor stages compared with early stage cancers. Accordingly, small and clinically occult tumors that would have the highest chance of cure are likely to be missed. (c) The group of individuals with a high-risk profile of developing HNSCCs (main risk factors: alcohol consumption and smoking) usually do not exhibit health-conscious behavior and therefore would probably not participate in a screening program. The latter limitation, however, is a general problem regarding HNSCC patients and is not related to the clinical performance of a biomarker.
In conclusion, this study demonstrates that quantitative SEPT9 and SHOX2 DNA methylation levels in ccfDNA from blood plasma are clinically valuable biomarkers for diagnosis, molecular staging, prognosis (risk-stratification), and posttherapeutic monitoring of HNSCC patients. However, overdiagnosis is a common problem in clinical oncology and needs to be avoided (33). Accordingly, a multicenter, randomized, prospective, and interventional study is being currently planned that will investigate whether the application of such biomarkers leads to an improved survival with a high quality of life or to a reduction of costs.
↵† Andreas Schröck and Annette Leisse contributed equally to the work, and both should be considered as first authors.
↵‡ Glen Kristiansen and Dimo Dietrich are joint senior authors on this work.
↵11 Nonstandard abbreviations:
- head and neck squamous cell carcinoma;
- TKIs,
- tyrosine-kinase inhibitors;
- mAb,
- monoclonal antibody;
- Food and Drug Administration;
- ccfDNA,
- circulating cell-free DNA;
- squamous cell carcinoma;
- qPCR,
- quantitative PCR;
- interquartile range;
- area under the curve;
- hazard ratio;
- positive predictive value.
↵12 Human genes:
- short stature homeobox 2;
- septin 9;
- actin beta.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: G. Kristiansen, Roche and Astella.
Research Funding: The University Hospital Bonn.
Expert Testimony: None declared.
Patents: None declared.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, and final approval of manuscript.
- Received for publication December 14, 2016.
- Accepted for publication March 21, 2017.
- © 2017 American Association for Clinical Chemistry


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|re gag of the month
|Page 1 of 4
|Mark Turner [ Wed Feb 25, 2009 7:50 pm ]
|Post subject:
|re gag of the month
hi all firstly i will appologise to anyone finds this gag rude
picture the scene
John wayne ,charles bronson, lee marvin all sat round a camp fire way out west. bragging who is the hardest cowboy
charles bronson says , im so hard i fought a grizzly bear and killed it with my bare hands ,
thats nothing lee marvin said laughing, i fought two crocodiles at the same time and riped out their eyes and killed them with my bare hands,
they both turned to john wayne who was just sat there grinning ,,,,,,,
poking the fire,,,,,,,,,,,,,,,, with is dick ,,,,,,,,,,,,
|dannycovin [ Wed Feb 25, 2009 8:02 pm ]
|Post subject:
So he had a good poker hand ....doh!!!
|john whittam [ Wed Feb 25, 2009 8:07 pm ]
|Post subject:
That sounds like somthing Cris mills would do
|dannycovin [ Wed Feb 25, 2009 10:51 pm ]
|Post subject:
Are you refering to his unusual pool playing method while heavily influenced by happy juice
|Covin [ Wed Feb 25, 2009 11:41 pm ]
|Post subject:
Jeez I've not heard that one for years Still a real classic though and good to hear it again
Was it Chubby Brown who first did that gag back in the 80's
|dannycovin [ Thu Feb 26, 2009 3:42 pm ]
|Post subject:
haha retro gags they are all here
|Covin [ Thu Feb 26, 2009 8:33 pm ]
|Post subject:
I remember the one Chubby Brown did about his Son while watching an episode of Star Trek.....
Son..... Dad, Dad... I wish I could be shot into space.
Chubby Brown.... If I hadn't have been pissed son, you would have been
|no covin yet [ Mon Mar 02, 2009 10:05 pm ]
|Post subject:
A man gets pulled over on the motorway for speeding
The police man says "I just need a few details from you,your name please?"
man says- "John Brown"
police man-"and youre occupation?"
man- "im a rectum stretcher"
policeman- "what exactly is that"
man says- "well first i put a finger in a rectum,then two,then work all the way to a fist and stretch the arse till its six foot!"
policeman says- "what the hell do you do with a six foot arsehole??"
to which the man replies-"give it a uniform and a speedgun..."
|Covin [ Mon Mar 02, 2009 10:47 pm ]
|Post subject:
I like it Mike
|dannycovin [ Tue Mar 03, 2009 1:24 am ]
|Post subject:
Thats a good one
|no covin yet [ Fri Apr 17, 2009 7:31 pm ]
|Post subject:
The Pope was having a shower. Although he is very strict about the celibacy rules, he occasionally felt the need to exercise the right wrist, and this was one of these occasions.
Just as he reached the Papal climax he saw a photographer taking a picture of the holy seed flying through the air.
"Hold on a minute," said the Pope. "You can't do that. You'll destroy the reputation of the Catholic Church."
"This picture is my lottery win," said the photographer. "I'll be financially secure for the rest of my life."
So, the Pope offered to buy the camera off the photographer, and after lots of negotiation, they eventually arrived at a figure of two million quid.
The Pope then dried himself off, and headed off with his new camera.
He met his housekeeper, who spotted the camera. "That looks like a really good camera, "she said, "how much did it cost you?"
"Two million quid" replied the Pope.
"TWO MILLION QUID!" said the housekeeper.............
"They must have seen you coming"
|Mark Turner [ Fri Apr 17, 2009 8:46 pm ]
|Post subject:
|re post
tis a cracker
|Page 1 of 4
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subset: commoncrawl


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3 Colombia Tours We're Drooling Over
An Andean oasis, Carribean escape, and so much more, Colombia is full of hidden gems waiting to be explored. So we put together our 3 favorite Colombia tours for every type of traveler. Get ready to fall for Colombia's charms.
Intrepid Tours
Explore the best of Colombia from old world Cartagena to Guachaca's sparkling coastlines with Intrepid's 10 day small group tour. Wander through one of Colombia's prettiest towns, colonial Barichara, take in mountain views on the Camino Real, and jump in crystal clear water on a hike through Tayrona National Park. Sample delicious street food and dine in one of the country's coolest restaurants in a women's prison that helps female inmates. On this perfect Colombia tour, you'll explore jungle, coast, and city, and see why the South American country is one of the hottest travel destinations. For more information on this and other Intrepid tours click here.
Why we're drooling over Backroads' Colombia tour? Hike through bamboo and vibrant flowers in the Cocora Valley, float on a tube down a crystal clear river, and dine at a sustainable coffee farm. Our absolute favorite part of the tour has to be walking along ancient trails to meet with the indigenous Wiwa community, an experience unavailable to the average traveler. Now you get why we're obsessed, right? During this 7 day excursion, an expert guide will take you to some of the country's most beautiful spots like Tayrona national park, Cartagena, Salento, Pereira, and Bogota. Plus, you'll be doing a lot of walking, so eat as much bandeja paisa as your heart desires. We know you're going to love Backroads' Colombia Walking and Hiking Tour.
Explorations by Collette
Ready to fall in love with Colombia? We're warning you, after 10 days on Exploration's Experience Colombia tour, you will never want to leave. This journey will take you to Medellin's famous murals, the Cocora Valley's coffee farms, Cartagena's colorful streets, and much more. Indulge your senses at the Paloquemao market, get an adrenaline rush in a 4x4 jeep ride through valleys, and experience Colombian dancing first hand. Choose to hike or ride horseback through the Cocora Valley's mountain views, before sitting down for a locally sourced picnic lunch. For more information on this and other Explorations by Collette tours click here: Explorations by Collette.
Happy Travels!
Have you taken a Colombia tour before or is this on your bucket list? Let us know in the comments or tag us on social! @shetravelswellco


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Shepparton United vs Shepparton match reportBy Liam Nash
Shepparton United's cup was left overflowing with goals on Sunday after a dominant 4-1 victory against Shepparton at Vibert Reserve in the Bendigo Amateur Soccer League.
Everything seemed to fall into place for the Blues during the Shepparton derby, the only hitch being a late consolation goal for the Reds.
However, United coach Roven Shaholli said the contest was a much tighter affair than the score suggested.
''I rate them (Shepparton) very highly, they were dangerous down the wings and in the midfield,'' Shaholli mentioned.
''It was a long time coming, we have been doing things in patches, but everything fell together on Sunday.
''I was really proud of the boys.''
United sharpshooter Ermal Marku began with a bang, rifling the ball home from the spot in the ninth minute to give the Blues the ascendancy.
Marku was at it again just before half-time, finishing a slick move down the flank to put the spirits in the United dressing room at an all time high during the break.
''We recharged the batteries at half-time and everyone seemed to let loose,'' he said.
''All the boys were getting around each other.''
Defensive general Ardit Gavri joined the party with a goal shortly after the restart and Evan Rawluk got off the mark for United to add a fourth with 15 minutes remaining in the match.
Yannik Klein's late strike proved to be the only resistance from Shepparton and while it could not keep the clean sheet, Shaholli was confident United was a force to be reckoned with.
''We have given every side we have played a scare so far,'' he said.
''Our consistency is improving, which is very important, I think all the boys realise that when everyone pulls their weight it becomes much easier.''
United will host Colts on Sunday and Shaholli was expecting the same level of performance out of his side.
''We will take every game as it comes,'' he said.
''There are a few things we will need to work on at training on Wednesday, we can always improve.''


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Psychotherapy Services
One-on-one therapy with individuals of all ages. Although sometimes the therapist or client will request that they have guests attend some sessions (a child(ren), parent(s), partner(s)…) therapy are focused on helping the individual resolve a variety of problems and/or challenges utilizing a variety of therapeutic interventions and theoretical orientations. Such problems and challenges could include grief and loss, trauma, mood disorders, self-esteem, anger, anxiety, abuse, school issues, autism, parenting, depression, attention deficits, dyslexia, friendships, coping, or processing the effects of childhood trauma on adolescents or adults.
Therapy in which the whole family participates in sessions in order to resolve problems and meet challenges. Some problems and challenges include: transitional difficulties (change in family dynamic from new job, new family member(s), the loss of a family member(s), divorce, remarriage, young adult, or aging parents), siblings, filial work, reintegration, parenting, or others.
Some clients seeking a gender therapist are looking for either a letter of support so that they may begin hormone replacement therapy (HRT) and/or gender affirming surgeries. Some clients seeking a gender therapist are looking to begin sessions to explore, learn, transition, or process their questioning or confirmed gender. And some clients are looking for both. Some clients seeking a gender therapist are looking for individual, partner, or family therapy. Clients seeking a gender therapist can be of any age.
People who identify as Lesbian, Gay, Bisexual, Transgender, Intersex, Questioning and/or Queer, Asexual can have therapeutic needs related to their sexual and/or gender identity. These can include identity formation and development, coming out, relationship difficulties, internalized shame and doubt, religious internationalism, cultural and family processing, minority stress, and trauma. Sometimes clients are not seeking therapy specific to their sexual and/or gender identity but are still needing therapy from a therapist who is affirming and knowledgeable in these areas.


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In addition to giving nutritional advice and coaching clients, I also enjoy cooking and being able to use my creativity in the kitchen. I regularly post healthy and delicious recipes on Instagram & Facebook. At the bottom of my homepage are my Instagram photos; if you click on the photos you will also see the recipe.
I also like to make fresh soups, carrot-banana bread with oatmeal or healthy chocolate brownies on the weekend. I strive to do everything with as little sugar as possible and I regularly choose for example banana, avocado or coconut oil to prepare things with. And occasionally I also use butter for an extra delicious taste.
I used to like to help in the kitchen. And I still enjoy trying out recipes and cooking for friends or family. That's why I think it's important to provide my clients with fun recipes and good tips that they can use. In this way I try to inspire people to cook healthier and that is sometimes quite a challenge. Yet I see that you can achieve a lot with a little creativity and motivation. And cooking must be fun and easy, especially for people with a busy job and children at home. If you make an appointment with me soon, I hope to inspire you too, because healthy cooking can be learned!


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anneliesemoffitt needed a new logo & brand identity pack design and created a contest on 99designs.
A winner was selected from 111 designs submitted by 14 freelance designers.
Prometheus Solutions
We are a new international education management company that delivers training, project management, and consultative services to help schools and organizations develop strong STEM (science, technology, engineering, math) programs in the MENA (Middle East and North Africa) region.
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Designers, we want our logo to communicate that we work with education, technology, and robotics.
We'd like for the logo to combine organic elements (see the scarab, round watch shape, or the man from the reference images) with elements that communicate technology, mechanics, or robotics (this could be seen in gears, circuits, etc, or font styles).
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This is a new installation on an old very spare Fujitsu Siemens Scenic T. Hmm, have to try that cernobl, will not have access to this comp until thurs. Click Here to receive this Complete Guide absolutely free. TechSpot Account Sign up for free , it takes 30 seconds. By joining our community you will have the ability to post topics, receive our newsletter, use the advanced search, subscribe to threads and access many other special features. Sign in to vote. I'm ready to give up and just buy a cheap graphics card, as the machine is to only be used in a guest bedroom for people to browse and check email when visiting.
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Ok, now for some reason the screen res sticks when this comp boots now, so I'm giving out answers now. Just out of curiosity, what nvidia card did you have problems with?
Today I grzphic tried to install the drivers yet again with the graphics controller enabled, still same result. Tuesday, September 8, 3: Tuesday, September 29, 7: There are also xorg configuration utilities that'll walk you through doing a new xorg. What do you mean by "mail your problem and it has been resolved; "?
Intel E Graphics Driver Install Installed drivers again per your instructions with the same result as all other attempts. Visit the following links: Sign up for freeit takes 30 seconds.
Driver download
Resources for IT Professionals. When the system is detecting new hardware it is installing Windows' generic graphics driver.
It drivers me nuts to have to change the screen res. Wednesday, September 9, 9: Friday, September 11, Tuesday, September 8, 7: From where u got the source file? Having a problem logging in?
graphics driver for E
When new hardware was detected I browsed to the Intel drivers to be sure the "correct" drivers were loading, Note that registered members see fewer ads, and ContentLink is completely disabled once you log in. Inteel have 2 versions: Windows 7 IT Pro. Do you have any other suggestions? Thanks everyone for your help with this.
Intel E Graphics Driver on XP Home SP3 – TechSpot Forums
Last edited by knudfl; at For more advanced trainees it can be a desktop reference, and a collection of the base knowledge needed to proceed with system and 828810e administration.
If you'd like to contribute content, let us know. Tuesday, September 8, Are you meaning "contact this email and your problem will be resolved"? Don't you think, it is time to tell, which distribution you are using?? TechSpot Account Sign up for free grahpic, it takes 30 seconds.
OK thank u joe You told u have compiled the grapic driver. Installation runs fine, reboot the computer, enable the graphics controller. The time now is I don't think you are installing the downloaded driver correctly if I understood your post correctly.
If you resort to XP repair option through setup cd; it will restore your windows installation to SP1 state, while preserving all the other applications you may have installed on it.


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Flames win against Sabres must be start of playoff push
Players, management aware there's no wiggle room in tight raceby Mike Zeisberger @Zeisberger / NHL.com Staff Writer
BUFFALO -- Dougie Hamilton didn't need to hear the entire question before providing his answer.
Hamilton and the Calgary Flames defeated the Buffalo Sabres 5-1 at KeyBank Center on Wednesday, a victory in which the visitors dominated every aspect of the game.
The win came one day after Flames starting goalie Mike Smith returned to practice for the first time in almost a month. Smith has been out since he sustained a lower-body injury in the final seconds of a 3-2 victory at the New York Islanders on Feb. 11.
[RELATED: Flames gain in wild card with win | Smith returns to practice with Flames]
With that information in mind, a Buffalo reporter wanted to know if there was any correlation between Smith's return to the ice and the Flames' subsequent impressive win. Even though Smith isn't ready to play yet, perhaps seeing him working out with his teammates might have given the Flames a lift.
Video: CGY@BUF: Giordano hammers home big point-drive
At least that was the premise presented to Hamilton by the reporter when the Flames defenseman met the media after the game.
The exchange went like this:
Reporter: "This may be subconscious, but this result comes after Mike Smith rejoins you guys on the ice. Do you think that …"
"No," responded Hamilton, not waiting for the reporter to finish.
Reporter: "But, well …"
"No," Hamilton repeated.
Hamilton's point: Smith's potential return isn't what is providing motivation for the Flames. Fighting for a berth in the Stanley Cup Playoffs is.
"Every game is must-win for us," Hamilton said. "That's the way we have to treat it every time we go out there."
Video: CGY@BUF: Hamilton extends lead on the power play
Aside from forward Johnny Gaudreau, Smith (23-16-6, 2.53 goals-against average, .921 save percentage) was generally considered to be Flames MVP up until the time of his injury by teammates and management.
"It was tough losing him, but every team in the League has players that get hurt," general manager Brad Treliving said. "We can't use that as an excuse.
"We have no excuses. I really like our team and when we play like we did tonight, we show what we're capable of. But we've just been too inconsistent, and that's the frustrating part.
"The bottom line is, there is no wiggle room left for us."
One of the most perplexing aspects to the Flames' roller-coaster season for Treliving has been their struggles at Scotiabank Saddledome, where Calgary has gone 14-15-4. On the other hand, the Flames have flourished on the road (19-10-6).
"Our bugaboo all season has been our play at home," Treliving said. "I can't understand it or explain it, but that's in the past.
"Right now, our focus is clear. We have to build on our momentum. That's the main goal at this point."
Flames coach Glen Gulutzan stressed that same point during the second intermission. With his players holding a 5-0 lead, Gulutzan told his them the one-sided score line was something to build on moving forward.
"We need traction," Gulutzan said. "I stressed to our guys between periods that if we get this game, even as the coach who's not on the ice, you get more confident going into your next game.
"We all know when our team gets confident, they can get on a real good run. We've done it before. We did it last year. We've done it this year. Every little step is a big step for us."
Video: CGY@BUF: Bennett cleans up big rebound, opens scoring
The victory gave the Flames (33-25-10) 76 points. The Los Angeles Kings (36-25-5) hold the second wild card into the Stanley Cup Playoffs from the Western Conference with 77 points, the same amount as the Colorado Avalanche (35-24-7).
Flames fans are desperately hoping Smith will be back soon to help Calgary in the dogfight for a playoff berth, but Treliving refused to put a set timetable on his return.
"It's a weird injury and we certainly don't want to see it regress," Treliving said. "But I will say that it's positive that he's on the trip with us and he's felt good out on the ice for a couple of days.
"If he can string together a few days without any setbacks, it definitely will be encouraging."
In the meantime, the Flames will continue to rely on backup David Rittich, who was awarded by his teammates the ceremonial fireman's hat for player of the game. What would have been Rittich's first NHL shutout was spoiled by Sabres defenseman Casey Nelson with 18 seconds remaining in the third period.
"I don't care about that, I just care about the win," Rittich said. "Look how close the standings are. We need every point we can get."
Video: CGY@BUF: Rittich stops bids from O'Reilly, Reinhart
The win Wednesday started a four-game stretch for the Flames against teams who aren't in playoff position. They'll play their next game at the Ottawa Senators on Friday (7:30 p.m. ET; TSN5, RDS, SNW, NHL.TV), before returning home to play the Islanders on Sunday and the rival Edmonton Oilers on March 13.
In Hamilton's opinion, the Flames must take advantage of those opponents, whether Smith returns in time or not.
"We should win those games," he said. "If we want to make the playoffs, that's what we have to do."


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Understanding Sam Shepard investigates the notoriously complex and confusing dramatic world of Sam Shepard, one of America's most prolific, thoughtful, and challenging contemporary playwrights. During his nearly fifty-year career as a writer, actor, director, and producer, Shepard has consistently focused his work on the ever-changing American cultural landscape. James A. Crank's comprehensive study of Shepard offers scholars and students of the dramatist a means of understanding Shephard's frequent experimentation with language, setting, characters, and theme.
Beginning with a brief biography of Shepard, Crank shows how experiences in Shepard's life eventually resonate in his work by exploring the major themes, unique style, and history of Shepard's productions. Focusing first on Shepard's early plays, which showcase highly experimental, frenetic explorations of fractured worlds, Crank discusses how the techniques from these works evolve and translate into the major works in his "family trilogy": Curse of the Starving Class, the Pulitzer Prize–winning Buried Child, and True West. Shepard often uses elements from his past—his relationship with his father, his struggle for control within the family, and the breakdown of the suburban American dream—as major starting points in his plays.
Shepard is a recipient of a Pulitzer Prize for Drama, eleven Obie Awards, and a Chicago Tribune Literary Prize for Lifetime Achievement. Augmented with an extensive bibliography, Understanding Sam Shepard is an ideal point of entrance into complex and compelling dramas of this acclaimed playwright.
It seems that the more you write, the harder it gets, because you're not so easily fooled by yourself anymore, wrote Sam Shepard.
Even so, writing becomes more and more interesting as you go along, and it starts to open up some of its secrets. One thing I'm sure of, though. That I'll never get to the bottom of it.¹ In writing about his process of composition, dramatist Sam Shepard expressed the central ideas of his plays: exposing secrets, opening up hidden spaces to understand one's identity, and searching endlessly for satisfying conclusions. His plays investigate complicated worlds that seem to deepen with each new performance. For the uninitiated, his work may appear dense and rough: characters in his plays may speak, act, or move spontaneously and illogically. Shepard's language, including his copious stage directions, can seem stylized and needlessly complex; his dialogue is alternately lyrical and elaborate without context or exposition; and his realistic characters frequently interact unexpectedly and inexplicably with imaginary figures. Consequently he may frustrate readers more used to linear plots and realistic characters. Sam Shepard is, in short, a difficult playwright to understand.
But scholars, students, directors, actors, and dramaturges who approach the man and his work thoughtfully discover an incredibly rewarding and focused vision, one that has enthralled audiences and critics alike since his plays first exploded onto stages in New York during the 1960s. During his nearly fifty-year career, Sam Shepard's work has consistently documented the ever-changing cultural landscape of America: from its obsessions with rock 'n' roll and a mythic West to the realities of its class consciousness and broken families. He frequently challenges Americans' self-perceptions by exposing lies and secrets inherent in them, and his plays reexamine solved mysteries of the theatrical world—language, form, myth, narration, spectator, character—and defy audiences' expectations by violating their conventions.
Now, nearly a half century after the premiere of his first play, Sam Shepard still remains at the forefront of the American theatrical scene as one of our most prolific, thoughtful, and challenging living playwrights. Shepard has written nearly fifty plays while thriving as an actor, director, and producer for the stage, television, and cinema. Theater critics have proclaimed him
the most ruthlessly experimental and uncompromising American playwright and
the greatest American playwright of his generation. His plays articulate America's anxieties and fears during very specific historical and cultural moments. Yet, like the works of the great American playwrights before him, Shepard's plays find new audiences in successive generations. They are admired by scholars and actors alike. Literary critics admire the structure of his works, and some of the finest stage and screen actors, including John Malkovich, Gary Sinise, and Kathy Bates, have been eager to play parts in them because the emotional evolution of his characters provides opportunities for experimentation.
Although watching a Sam Shepard play is engaging, reading his plays for the first time may prove daunting. Because Shepard is clearly influenced by the theater of the absurd dramatists (such as Pirandello, Beckett, and Ionesco), his work can seem dense and incomprehensible to first-time readers without an understanding of absurdist techniques. This study introduces scholars, students, and directors to the challenging issues taken up in Shepard's plays, including experiments with language, setting, and characters. One key to understanding the works of Sam Shepard is his life. To a greater degree than those of most other American dramatists of his generation, his plays are largely autobiographical. Consequently information about his life facilitates understanding of his art. Because many of his plays focus on the American family, understanding Shepard's early family life becomes even more important in unlocking the mystery of his craft.
Samuel Shepard Rogers III was born in Fort Sheridan, Illinois, in 1943 to U.S. Army Air Force pilot Samuel Shepard Rogers II and Jane Elaine Shepard. Shepard remembers the town as
a real fort, where army mothers had their babies while the men were stationed abroad. Their time in Illinois was short, however, because the family moved often throughout the United States—to South Dakota, Utah, and Florida. Eventually the family settled on an American base in Guam. Shepard's memories of his time there revolve around his discovery that language has political import and can have the potentiality for violence: "There were a lot of Japanese on the island, who had been forced back into living in the caves, and they would come down and steal clothes off the clothes-lines, and food and stuff. All the women were issued army Lugers, and I remember my mother shooting at them. At that time everyone referred to Oriental people or Philippino [sic] people as gooks, and it wasn't until the Vietnam War that I realized that gook was a derogatory term—it had just been part of the army jargon, all the kids called them gooks, too."² The turbulence of his life abroad with his father gave way to a more normal calm when his family settled in Pasadena, a suburb that in some ways resembled a small town but stood in the shadow of Los Angeles, the largest city in the American West.
There Shepard would come to find one of his great muses: the interior world of the white, middle-class American family. Shepard remarked that Pasadena was
not all that rich, but very proud of the municipal swimming plunge and the ice-skating rink, and all that small-town-America-type stuff. The young Sam Shepard (known as
Steve to family and friends) lived in Pasadena from ages five to eleven. At home his father bordered on being a despot. Shepard recalls his being
very strict, … very aware of the need for discipline, so-called, and the boy felt his creativity threatened often by his father.
It was really like being jailed, he once said of his father's demanding rules.³ As he moved into his teenage years, he and his father constantly butted heads in power struggles in front of the whole family. Sam's sister, remembering their relationship, said they were
like two pit bulls vying to see who was the alpha dog:
You put two virile men in a room and they're going to test each other.⁴ Ruthless struggles for power within the family would later appear in Shepard's plays where characters fight for some measure of autonomy within suffocating family structures.
Eventually Shepard's family moved from the picturesque, sleepy town to a much more rugged life on an avocado ranch in Duarte, California, fifteen miles from their old address. The move suited Sam, who felt more at ease in the country and away from the stuffy suburban atmosphere of Pasadena:
I really liked being in contact with animals and the whole agricultural thing. … It was a funny community, divided into three very distinct social groups. There were the very wealthy people, who had ranches up in the mountains with white-faced Hereford cattle roaming around, and swimming-pools and Cadillacs. And then you'd get these very straight middle-class communities, people who sold encyclopedias and stuff like that. Shepard was amazed at the division between the middle class and the working poor, who were mostly black or Mexican and who, like the
gooks of Guam, were segregated from the rest of the community:
It was the first place where I understood what it meant to be born on the wrong side of the tracks, because the railroad tracks cut right down through the middle of this place: and below the tracks were the blacks and Mexicans.⁵
Sam was a good student at school, though he admitted to experimenting with Benzedrine and hanging out with the wrong crowd. Despite his bravado he had a deep love for animals and considered becoming a veterinarian. Outside school he was a member of the 4-H club, and a ram he raised placed first in the Los Angeles County Fair. Although his adolescence was far from ideal, he would come to reminisce fondly about his
pastoral years in Duarte and would use the settings and characters from his boyhood and adolescence in plays such as Curse of the Starving Class, The Tooth of Crime, and The Unseen Hand. He would also plumb the depths of his power struggles with his father to create some of the most compelling moments in his oeuvre.
During his time at the small junior college Mount San Antonio in Walnut, California, he first began experimenting with the theater. He acted in the school's productions of Harvey and The Skin of Our Teeth and even wrote his first play,
a sort of Tennessee Williams imitation, about some girl who got raped in a barn and her father getting mad at her or something.⁶ Shortly after his first experiment writing a play, Shepard got involved as an actor in the Bishop's Company Repertory Players, with whom he toured the East Coast putting on one-night productions of plays in churches. In the traveling company, Shepard learned a valuable lesson that he would come back to throughout his career:
Anybody can make theater. You don't need to be affiliated with anybody. You just make it with a bunch of people.⁷ Shepard followed his new passion for theater all the way to New York City, where he tried unsuccessfully to become a professional actor. There he found himself involved with a
really exciting music scene. The world I was living in was the most interesting thing to me, and I thought the best thing I could do maybe would be to write about it, so I started writing plays.⁸
In 1964, while working at the nightclub Village Gate, Shepard wrote the first of his plays ever to be produced. The play owed a debt to experimental theater, to the theater of the absurd, and to an early exposure to the works of Samuel Beckett, which had changed his writing style. When he first encountered the playwright's Waiting for Godot, he said it was
like nothing I'd ever read before. … And I thought, what's this guy talking about, what is this?⁹ From the influence of Beckett's aesthetic, Shepard wrote the short, semi-absurdist one-act Cowboys, so titled because he and his close friend Charles
used to run around the streets playing cowboys in New York. We'd both had the experience of growing up in California, in that special kind of environment, and between the two of us there was a kind of camaraderie, in the midst of all these people who were going to work and riding the buses. Cowboys became a powerful meditation on youth, innocence, and the incessant need for adventure—things to which the young Sam Shepard, as a new immigrant from California, could easily relate. Because of his roots in the West, he was also acutely aware of the cowboy's mythic hold on the American popular imagination:
Cowboys are really interesting to me—these guys, most of them really young, about 16 or 17, who decided they didn't want to have anything to do with the East Coast, with that way of life, and took on this immense country, and didn't have any real rules.¹⁰ As a stranger in a far away land without rules, Shepard felt a deep connection with the image of the cowboy.
The idea that anyone would perform his plays initially frightened Shepard, but when the headwaiter at the Village Gate nightclub told him that he was looking for fresh material for a new venture he called Theatre Genesis, Sam showed him the draft of his play about cowboys. During rehearsals for Cowboys, Shepard decided to add another short one-act play, The Rock Garden, to the evening's bill. Despite some early, negative reviews, critic Michael Smith of the Village Voice validated Shepard's decision to move to New York; Smith wrote that Shepard explored new territory for the American dramatist,
an area between ritual and naturalism, where character transcends psychology, fantasy breaks down literalism, and the patterns of ordinariness have their own lives. His is a gestalt theater which evokes the existence behind behavior.¹¹ The high praise from one of the most influential critics in New York won Shepard instant credibility and fame.
Following the modest success of his two one-acts, Sam Shepard began writing plays at a feverish pace and often wrote countless plays in a week's time.
I used to write very fast, he admitted to an interviewer.
The stuff would just come out, and I wasn't really trying to shape it or make it into any big thing. … I would have like a picture, and just start from there. A picture of a guy in a bathtub, or of two guys on stage with a sign blinking—you know, things like that.¹² Shepard's prolific period happened to coincide with the emergence of the
off-off-Broadway movement of the early 1960s in the wake of which small, avant-garde plays were capturing the imagination of audiences. The more intimate productions provided an alternative to the huge, expansive Broadway pieces running at the time. Shepard remembers the movement as full of possibilities: "On the Lower East Side there was a special sort of culture developing. … I mean nobody knew what was happening, but there was a sense that something was going on."¹³ Because he wrote so many compelling plays in such a short period, some of which were running simultaneously, he quickly found a place beside LeRoi Jones, Edward Albee, and Lanford Wilson, the major American playwrights at that time.
Shepard's plays in the mid-1960s drew enthusiastic crowds and impressed critics. Up to Thursday, Dog, Rocking Chair, Three and Melons, 4-H Club, Chicago, Icarus's Mother, and Red Cross all opened during the first part of the decade. The latter three earned him his first Obie awards. The one-acts shared the same stripped-down aesthetic and nonnaturalistic expression that would come to be recognized as hallmarks of his early work. One critic noted the difference between a conventional play, where
the characters stay pretty much the same over the time span of the play, which could be two days or twenty years, and Shepard's early, experimental plays, where characters frequently shift personalities from one monologue to the next. And the language they speak is specific, too. Each character engages in
purposefully banal dialogue to stitch together images, actions, and comically/poetically extended monologues which puncture the surface of the theatrical event.¹⁴ Each early one-act contains a heightened expressionistic style that draws upon his experiences, from his childhood and adolescence to his more recent move across the country to live in abject poverty surrounded by bohemians and artists. Shepard later explained why his early writing draws so much from his past: the plays
come from all kinds of things, they come from the country, they come from that particular sort of temporary society that you find in Southern California, where nothing is permanent, where everything could be knocked down and it wouldn't be missed, and the feeling of impermanence that comes from that—that you don't belong to any particular culture[,] … the more distant you are from [where you grew up], the more the implications of what you grew up with start to emerge.¹⁵ Shepard's short, early one-acts were also heavily influenced by his new friendship with Joe Chaikin, the founding father of the experimental Open Theater, whose repertory cast included Shepard's then girlfriend Joyce Aaron. Chaikin's group sought to explore
techniques for performing nonnaturalistic material, the Brechtian plays and verse dramas that irresistibly attract the avant-garde.¹⁶ Chaikin and Shepard's friendship flourished because of their shared interest in the avant-garde.
Shepard later admitted that he found it difficult
to remain with a certain attachment to his early, experimental plays:
I write plays before I get to another kind of play, and each play may be a sort of evolution to something else. I always feel like leaving behind rather than hanging on to them.¹⁷ Shepard's evolution manifested itself in the form of his first full-length piece, entitled La Turista (1966), which was performed at the famous American Place Theater. The play explored cultural myths about America and Mexico and contained a subtle satire on the persistence of stereotypes about indigenous people. After it was performed, Shepard's interest shifted from the obsessions he indulged in the early one-acts to a visceral aesthetic highly influenced by American rock 'n' roll music. Biographer Don Shewey has argued that Sam Shepard's next eight plays—Shaved Splits, The Unseen Hand, Operation Sidewinder, The Holy Ghostly, Black Dog Beast Bait, Mad Dog Blues, Cowboy Mouth, and The Tooth of Crime—all
recall the poetically evocative but inscrutable names of famous rock bands and albums from the sixties.¹⁸ In addition to his duties as a playwright, Shepard performed in several 1960s rock 'n' roll bands, including the locally famous Holy Modal Rounders, for whom he was the drummer. He joined the band in the recording studio and on their West Coast tour.
In 1970 Shepard married O-Lan Johnson, whom he had met through Theatre Genesis. A few months later their son Jesse Shepard was born. The relationship between Shepard and O-Lan was rocky from the beginning. Shortly after their marriage, Shepard began a brief, torrid affair with rock star Patti Smith. Their affair would become mythologized in the play Cowboy Mouth, a collaborative piece written by Shepard and Smith. Cowboy Mouth combines elements of documentary and mythology into a highly subjective look at the strange relationship between Smith and Shepard: in it both authors explore emotional responses


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Vasilisa the Wise - Giclee Print
Vasilisa the Wise - Giclee Print
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USA orders are shipped with tracking numbers and insurance. To inquire about international insurance/tracking options, please email firstname.lastname@example.com
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Lost teeth need to be replaced, or the results can be severe. Chewing and general health can be affected. The appearance of the front teeth and the smile can deteriorate. Teeth adjacent to spaces may drift and tilt into them. Teeth in the opposite jaw, over the space, can grow longer because there is no opposite tooth to bite against, and keep it in place. The bite can be affected, and the front teeth can be forced forward.
The methods of replacing teeth are determined by the position of the gap, its size and the presence or absence of adjoining teeth. The procedures to be described are bridges, dentures and implants.
New No. 45, Old Velachery Road, Little Mount, Saidapet, Chennai-600015.
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Install the WordSolver Android App!
4 Definitions of Grub
The definition of grub, the meaning of the word Grub:
Is grub a scrabble word? Yes!
- n. - Informal terms for a meal
- n. - A soft thick wormlike larva of certain beetles and other insects
- v. - Ask for and get free; be a parasite
- v. - Search about busily
Grub is worth 7 points in Scrabble, and 10 points in Words with Friends
There are 4 letters in grub: B G R U
1 Anagram of Grub
Words that can be created with an extra letter added to grub:
6 words found using the letters in "Grub"
4 Letter Words
3 Letter Words


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Latest News on Madebygoogle
Showing of 0 - 10 from 16 results
Madebygoogle - Total results - 16
Oct 10, 2018
Google Pixel 3 continues to capitalise on software, sticks with single rear cameraAnd that's a good thing!
Oct 10, 2018
Google quietly launches new Chromecast adding 1080p 60 fps video streaming supportThe new Chromecast comes with a SoC that is 15% faster when compared to the chip on the 2015 model.
Oct 09, 2018
Google Home Hub announced with a 7-inch display, stereo speakers for $145Google Home Hub is a 7-inch tablet-like display mounted on a smart speaker with Google Assistant.
Oct 09, 2018
Google Pixel 3, XL available from 1 November starting from Rs 71,000; Pixel Stand also announcedGoogle is offering two storage variants for both the devices with 4 GB RAM and 64/128 GB variants.
Oct 09, 2018
Google Pixel 3 event highlights: Pixel 3 launched at Rs 71,000, XL at Rs 83,000Devices will be available for pre-order from 11 October, to ship 1 November.
Oct 09, 2018
Google Pixel 3 and Pixel 3 XL expected to launch in India on 22 October: ReportGoogle India is yet to put out an official word on when the two phones will go on sale.
Oct 09, 2018
Google Pixel 3/3 XL alleged to come with a 5.5-inch, 6.3-inch display respectivelyGoogle Pixel 3 and 3 XL are said to come in three colour variants: Clearly White, Just Black and Not Pink.
Oct 07, 2018
Google's first Chrome OS-running Pixel Slate tablet leaked ahead of launchThe renders reveal the Pixel Slate from all sides and also shows the accessories compatible with it.
Sep 07, 2018
Pixel 3 expected to launch on 9 October at 'Made by Google' event in New YorkThe 'Made by Google' event is expected to mainly launch a Pixel 3 and Pixel 3 XL.
Dec 12, 2017
Google Home Max smart home speakers available in the US for $399, just in time for ChristmasArray


text:
He got diarrhea and was not eating and was getting weaker. As a result one of the other trekkers decided to carry his pack for him." This man went on to complete the trek with the help he received. "Many times it brings out the best in people and you get a real sense of what people are capable of," says.
The new methods allow for more hairs in each skin graft to be placed between existing hairs, promoting greater hair density, says Reed. At the same time, more precise instrumentation permits surgeons to work faster with less worry about tissue injury. This has turned hair transplants one of the most tedious and labor intensive of cosmetic surgery procedures into minor day surgery.
To ensure that the oil gets changed regularly, take your prized possession to a certified dealer. However, if you keen on DIY projects, you can do it yourself with an oil wrench and extractor pump. Inspect the Engine Before Sailing Before you go on a cruise, ensure to check the engine for issues.
Your brand is the foundation for your communication to your market. It impacts everything from building a customer base to attracting potential investors or other sources of startup capital. It's a magnet to attract your ideal customers. The Columbus school board is considering an increase for its superintendent, James Hyre, and the Cleveland board is searching for a new superintendent. Mom's Club theft: Year in jail WAUSEON, Ohio (AP) The former treasurer of a school mother's club, who was convicted of taking more than from the club's funds, has been sentenced to one year in prison. Bonnie Kemp, 33, who was treasurer of the Swanton Mothers' Club from 1982 to 1984, was sentenced Monday in Fulton County Common Pleas Court.
It doesn't mean they hate one another; it's kind of like how black people are allowed to say "government cheese" in a joke. However, if an editor cuts off the music track right after one girl says "bitch" and splices in footage of the other girl looking surprised, oh shit. Things just got real..
4. For example, there are meet ups for bar hoping nights, barbeques, fitness and nature walks and Sunday afternoon meet ups in the local park. These organised group events offer a great chance to socialise with women, and you're always in a group scenario thus taking the pressure off you to talk to the same person the whole time..
"My whole life growing up I just kinda always said 'why me, Why me, why didn't my dad want to be around?" he said in an interview with CNN's Rachel Nichols. "I feel like I'm a pretty cool kid, I'm a good kid, why wouldn't he want to be around for me?' And as I got older, when I had my own family, I started to think the reason he wasn't there is the reason why I became so strong mentally, so loving to my mother. I am who I am today because he wasn't there, because I use it as motivation.


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- $49,900 price
- 18042661 mls id
- Square Feet: 10,890 sqft
Lake Diane waterfront Lot 8 of Lakeshore Estates. Are you ready to build your dream home? With an excellent view and located on a bay with 120' m/l of water frontage this location can't be beat. Situated on small unpaved cul-de-sac for limited drive by traffic but just off pavement of West Diane Dr. Perfect for a walk out basement. -build your lake getaway here. Connect to the central sewer system when you build. Lake Diane is a 400 acre all sports lake. (1011)
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Great Value for a Merry Lake Waterfront Lot! Central Sewer System is available to hook up when building your Cottage or Dream Home! Lot has a few mature trees, over growth and needs cleared. Will support a walk out basement as high elevation. Located to the East side of the lot is an undeveloped...
Lots & Land
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3 Access lots at 400 ac. all sports Lake Diane are manicured and ready for you to build. 2 Large mature shade trees and a few pines are thriving. Paved county maintained road for easy access ( road assessment paid ). Connect to the central sewer system when you build. Great location approx. 1 HR....
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Listing Agent: Linda Greek
Updated: 17th October, 2019 7:08 AM.
14704 E Lakeshore Dr Camden, MI


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Party Planning
Okay, first things first.
La Fete de La Reine. The people who have shown interest in coming are hemming and hawing because they have no place to go afterwards. So! I am now having a dinner party. 7 to midnight. (I'm turning 37. I can't stay up much past midnight.) The following people are coming:
Eva (if you have to go somewhere else I understand)
Sister Staceypatrick
Father Patrick O'Stacey
Fresh's friend Martin who has no nickname, but we can think one up after a few drinks
The following people have not replied:
Crabby & Mr. Krabs - are you going to the Big House?
Mikael and Markus - pu-lease! You're practically like neighbours!
JB (I haven't met you technically, but I'm willing to let you come if Maria will vouch for you or you put down a security deposit)
Brett and Amber- seriously you're invited
Merv - you too
Clara and Jer - come on!
Lilly and Joe
Radmila and Clive
Benjamin - you probably don't read this anymore, I'll e-mail you
Chip - come home! All is forgiven!
Okay, That's all for now.
Please inform me of any food allergies. bring some good wine and don't pet the cats. Seriously. They look cute, but don't do it.
Maps will be e-mailed so ensure your VIP status by e-mailing screamforicequeenATgmailDOTcom.
More stories later. Business before pleasure!
Oh yeah, it's on December 31st.
No need for presents, although I do enjoy a good mix cd if you feel inspired.
Wednesday, December 21, 2005
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Douglas Adams was right about giant currency . Marie Curie " I have no dress except the one I wear every day. If you are going to...
Photo Essay: Things That Make Me Smile FROGGY LOST TOOTH MR. GRUMPY THE SIAMESE FIGHTING FISH YES MASTER FROGWARTS CASTLE
In Roman Holiday , there is a Vespa and no Cats are Harmed So I changed the blog template to a gas flame from a stove. I thought maybe I ...
The Amazing Kay Anderson, Your Friend! Found her on Kijiji. This woman is so multi-talented, she will rid you of snakes, perform for your ...


text: November 17, 2018 from 12pm to 4pm – Central Baptist Church, 8 Ward Road, Dundee DD1 1LX. This will be an interactive event of prayer and worship including seminars and participation. After two decades of church planting and mission leadership in Thailand, David and Sandra MacMillan from… Organized by Douglas Craig, WEC Scotland | Type: mission, world, wec, prayer, worship, networking, fellowship, challenge, wingspan, wing, span, growing, enjoyment, thailand, dundee, scotland


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Jess Fishlock: Wales and Reign FC midfielder out until January with torn ACL
- From the section Wales
Wales midfielder Jess Fishlock has been ruled out until at least January 2020 after suffering a serious knee injury.
The 32-year-old suffered a torn ACL playing for Reign FC against Utah Royals in the National Women's Soccer League.
She will undergo surgery on Monday.
"When you get injured it's a terrible feeling anyway, but when you get injured and you've been playing well it's a sucker punch." said Fishlock.
"But with regards to my rehab and with regards to coming back, I'm not worried at all. I'll be back early next year."
Fishlock, who won the Women's Champions League in May on loan with French club Lyon, told BBC Radio Wales Breakfast: "It's just my ACL.
"My other ligaments are fine, the rest of my cartilage is fine, so it's a really straight forward in and out kind of job.
"I'll only be on crutches for two weeks and then I'll be walking."
Wales' record cap holder will miss the first four games of Wales' Uefa Women's European Championship qualifiers.
Wales begin their campaign away to the Faroe Islands on 29 August, before playing Northern Ireland home and away either side of a fixture in Belarus.
Wales coach Jayne Ludlow said: "She'll be a huge miss for us, but what we have to do as a squad is make sure we do her proud.
"For the next few months that she won't be involved we have to step up, we have to perform to the levels that she'd expect us to perform at.
"It's going to be an opportunity for someone else to step in and make a claim for a place for the short term, maybe for the longer term.
"Jess will know that as a high-level competitor and that's what she would want from her Welsh team-mates."


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