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Research ArticleImmunologyOncology Free access | 10.1172/JCI91190
IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Mark Ayers,1 Jared Lunceford,1 Michael Nebozhyn,1 Erin Murphy,1 Andrey Loboda,1 David R. Kaufman,1 Andrew Albright,1 Jonathan D. Cheng,1 S. Peter Kang,1 Veena Shankaran,2 Sarina A. Piha-Paul,3 Jennifer Yearley,1 Tanguy Y. Seiwert,4 Antoni Ribas,5 and Terrill K. McClanahan1
1Merck & Co. Inc., Kenilworth, New Jersey, USA.
2University of Washington, Seattle, Washington, USA.
3University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4University of Chicago, Chicago, Illinois, USA.
5UCLA, Los Angeles, California, USA.
Address correspondence to: Terrill K. McClanahan, Profiling & Expression, Biologics Discovery, Merck Research Laboratories, 901 California Avenue, Palo Alto, California 94304, USA. Phone: 650.496.1129; E-mail: terri.mcclanahan2@merck.com.
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First published June 26, 2017 - More info
Published in Volume 127, Issue 8 on August 1, 2017
J Clin Invest. 2017;127(8):2930–2940. https://doi.org/10.1172/JCI91190.
Copyright © 2017, American Society for Clinical Investigation
First published June 26, 2017 - Version history
Received: October 12, 2016; Accepted: May 11, 2017
Gene expression profile predicts response to pembrolizumab
Author's Take
Anti-PD-1 therapy with inhibitors such as pembrolizumab has proven beneficial for multiple types of cancers. Not all patients respond to PD-1 blockade; therefore, strategies to better predict individual response to anti-PD-1 would be of great clinical benefit. In this episode, Terri McClanahan and Jared Lunceford discuss their work, which has led to the identification of a gene expression profile that correlates with clinical response to pembrolizimab. Importantly, the presence of this T cell-inflamed gene expression profile in patients prior to treatment was shown to be indicative of response in multiple cohorts and cancer types.
Programmed death-1–directed (PD-1–directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti–PD-1 therapies, including pembrolizumab. However, whether quantifying T cell–inflamed microenvironment is a useful pan-tumor determinant of PD-1–directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell–inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell–inflamed GEP contained IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell–inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.
Cancer cells have the ability to adapt to and avoid host immune checkpoints and surveillance as a means to promote their continued survival (1, 2). Although the exact molecular mechanisms of this adaptation are poorly understood, one of the key signaling pathways involves programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2 (3–5). Results of recent clinical studies with anti–PD-1 monoclonal antibodies in patients with cancer have validated the concept that targeting the host immune checkpoint mechanism via PD-1 receptor blockade produces durable antitumor responses, resulting in improved progression-free survival (PFS) and overall survival (OS) (6). However, only a subset of patients benefit from PD-1 blockade. Elucidation of the underlying immunologic characteristics of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from anti–PD-1 monotherapy and might reveal additional immunologic determinants that could be targeted in combination with PD-1 checkpoint blockade.
The mechanism by which the host immune system is capable of recognizing and eliminating dysplastic and neoplastic cells is the subject of ongoing investigation. Certain factors, such as exposure to ultraviolet radiation, smoking, and chronic viral infection, can damage critical genes involved in DNA replication and repair, resulting in abnormal cellular growth (7–9). In response, an orchestrated innate and adaptive antitumor immune response is initiated that may lead to the production of IFN-γ. IFN-γ is a key cytokine produced by activated T cells, as well as natural killer (NK) and NK T cells, in the tumor microenvironment, and it plays an important role in coordinating this process (10). However, the same IFN-γ signaling processes can ultimately induce feedback inhibition that compromises antitumor immunity (11). As part of this feedback loop, IFN-γ signaling enables the PD-1 signaling axis to become activated through direct upregulation of the ligands PD-L1 and PD-L2 in tumor, immune infiltrate, and stromal cells, which interact with PD-1 on tumor-infiltrating T cells to downregulate the cytotoxic response (12–14). In addition, IFN-γ can upregulate expression of other key immune suppressive molecules such as IDO1 within the tumor microenvironment (15). Tumor adaptation takes advantage of this delicate balance of positive and negative immune signaling factors, allowing the cancer to survive and progress.
Recently, increased PD-L1 expression on the surface of tumor cells has been identified as an important determinant of response to immune therapies targeting the PD-1 axis (16). PD-L1 expression on immune cells in the tumor microenvironment has also been associated with treatment responses to such agents (17). Although the assessment of PD-L1 expression on tumor and immune cells can be useful to predict clinical response to PD-1 checkpoint blockade, it offers only limited insight into the biology of the tumor-immune interface. In particular, PD-L1 expression might represent only a component of T cell–related biology that is relevant to a favorable tumor immune microenvironment. Newer genomic technologies can be used to evaluate complexities of tumor and host immune cell interactions within the tumor microenvironment, going beyond the measurement of single analytes such as PD-L1.
We specifically examined gene expression in the tumor microenvironment, using RNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue samples. Samples were obtained at baseline from patients undergoing treatment with pembrolizumab in clinical trials using multiple distinct tumor types. We report the rigorous, stepwise validation of the hypothesis that immune-related gene signatures can predict clinical response to PD-1 checkpoint blockade. Signatures related to IFN-γ signaling and activated T cell biology were initially delineated in a small pilot melanoma cohort, then confirmed and refined in a larger independent cohort of patients with melanoma. The cross-tumor predictive value of these signatures was demonstrated by testing in head and neck squamous cell carcinoma (HNSCC) and gastric cancer cohorts, followed by a modeling exercise to determine a final T cell–inflamed gene expression profile (GEP) and scoring algorithm that predicted response across 9 different cancer cohorts to arrive at a final signature, forming the basis of a clinical-grade assay for evaluation of clinical utility in select ongoing pembrolizumab clinical trials (18). The performance of this pan-tumor T cell–inflamed GEP compared favorably with that of immunohistochemistry (IHC) in an independent set of PD-L1–unselected patients with HNSCC and was shown to be robust despite any improvement using all genes on our profiling platform and all available data from the KEYNOTE-012 and KEYNOTE-028 clinical trials. Our data definitively confirm that a T cell–inflamed microenvironment, characterized by active IFN-γ signaling, cytotoxic effector molecules, antigen presentation, and T cell active cytokines, is a common feature of the biology of tumors that are responsive to PD-1 checkpoint blockade. Moreover, these data demonstrate that a focused set of genes can be used to identify this PD-1 checkpoint blockade–responsive biology and predict clinical response across a wide variety of tumor types.
IFN-γ–related gene expression signatures predict response to PD-1 checkpoint blockade in melanoma. To define immune-related gene expression signatures associated with response to pembrolizumab, a set of baseline biopsies from 19 patients with metastatic melanoma enrolled in the KEYNOTE-001 study (NCT01295827, ClinicalTrials.gov) was used as a pilot data set. Pembrolizumab responders (n = 8) and nonresponders (n = 11) were identified using Response Evaluation Criteria In Solid Tumors, version 1.1 (RECIST v1.1) by central radiographic imaging vendor. A 1-sided t test was applied to rank top genes associated with responders and nonresponders, using a custom panel of 680 tumor- and immune-related genes on the NanoString nCounter platform (NanoString Technologies Inc.) (Figure 1A and data not shown). It was apparent that many of the top-ranked genes were directly linked to IFN-γ signaling and showed correlation with the expression of IFN-γ. A 10-gene "preliminary IFN-γ" signature (IFNG, STAT1, CCR5, CXCL9, CXCL10, CXCL11, IDO1, PRF1, GZMA, and MHCII HLA-DRA) was constructed that was able to separate responders and nonresponders to anti–PD-1 therapy (pembrolizumab) among the 19 pilot data patients with melanoma (Figure 1B).
Gene signature development in melanoma samples. (A) Overall workflow for the development of immune-related gene signatures that predict response to anti–PD-1 therapy. (B) IFN-γ 10-gene signature evaluated in 19 patients with melanoma and association with response. (C) "Preliminary expanded immune" 28-gene signature with tight correlation to the IFN-γ 10-gene signature, validated in 62 patients with melanoma.
These findings were confirmed using expression data from an additional cohort of 62 patients with metastatic melanoma treated with pembrolizumab in KEYNOTE-001, of whom 51 were considered evaluable for objective response. Before unblinding of the clinical outcome information for these patients, genes from the preliminary IFN-γ signature were correlated with other genes on the custom 680-gene NanoString panel that had a nominal P value less than 0.05 for positive association with objective response and/or PFS on the initial set of 19 melanoma tumors. From these data, a larger expanded set of genes showing correlation with the preliminary IFN-γ signature was evident, and a 28-gene set, referred to as the "preliminary expanded immune" signature, was generated (Figure 1C). This 28-gene set encompassed genes related to cytolytic activity (e.g., granzyme A/B/K, PRF1), cytokines/chemokines for initiation of inflammation (CXCR6, CXCL9, CCL5, and CCR5), T cell markers (CD3D, CD3E, CD2, IL2RG [encoding IL-2Rγ]), NK cell activity (NKG7, HLA-E), antigen presentation (CIITA, HLA-DRA), and additional immunomodulatory factors (LAG3, IDO1, SLAMF6) (Figure 2 and Table 1). These 2 preliminary signatures were then tested using prespecified hypotheses for their association with clinical outcome following treatment with pembrolizumab. Nominal 1-sided P values less than 0.05 were observed for both signatures for best overall response (BOR) and PFS (Table 1), confirming their predictive value in metastatic melanoma. These data indicate that IFN-γ signaling and the associated biology of T cell cytolytic activity, antigen presentation, and chemokine production are important components of a PD-1 checkpoint blockade–responsive immune microenvironment in melanoma.
Box plots for the IFN-γ 10-gene and 28-gene expanded immune signatures and best overall response in 62 patients with melanoma with clinical outcomes under anti–PD-1 therapy.
Independent results evaluating correlation between the gene signatures and response in the validation set in 62 patients with melanoma with clinical outcomes under anti–PD-1 therapyA
Confirmatory testing and signature refinement across multiple cancer types demonstrates a common biology of responsiveness to PD-1 checkpoint blockade. Because activated Th1 and cytotoxic T cells are the likely direct effectors of checkpoint blockade–mediated tumor regression, we hypothesized that measures of this common biology would predict response to anti–PD-1 therapy regardless of tissue of origin. We therefore asked whether the biology of responsiveness to PD-1 checkpoint blockade that was observed in melanoma would extend to unrelated tumor types. After confirming that the 2 preliminary signatures in melanoma showed statistically significant associations with clinical outcome, both signatures were refined by removal of genes that did not reach a nominal 1-sided P value less than 0.05 for positive association with either objective response or PFS in the confirmatory set of 62 melanoma tumors, yielding refined "IFN-γ (6-gene)" and "expanded immune (18-gene)" signatures. Subsequently, as data from the KEYNOTE-012 (NCT01848834) study became available, these signatures were tested in biopsy specimens from pembrolizumab-treated patients with HNSCC or gastric cancer. RNA expression profiling data were available for tumors from 40 patients with HNSCC and were evaluable for objective response, with an objective response rate of 22.5%. There were 33 such patients with gastric cancer, with 22.2% responding. The refined signatures (Table 2) both showed statistically significant associations with improved clinical outcome at P < 0.05 for objective response and PFS for HNSCC (19) and at P < 0.10 and P < 0.05 for objective response and PFS, respectively, in gastric cancer (Figure 3, A and B, and Table 3). Receiver operating characteristics (ROCs) for response status over the range of the signature scores demonstrated the high discriminatory ability of the signatures (Figure 3, C and D). Areas under the ROC curves and their 95% CIs were 0.80 (0.61–0.95) for HNSCC (19) and 0.66 (0.47–0.83) for gastric cancer. To illustrate the potential clinical usefulness of these signatures to predict response to pembrolizumab, the Youden index–based cutoff values (20) for the IFN-γ 6-gene signature were determined and were similar for the 2 cancer types (1.882 HNSCC; 1.856 gastric). For HNSCC, the associated positive predictive value (PPV, response rate above the cutoff) was 40.0% and the negative predictive value (NPV, nonresponse rate below the cutoff) was 95.0% (19). For gastric cancer, the PPV and NPV were 45% and 92%, respectively. The percentage of patients with tumors above these cutoffs was 50% for HNSCC and 61% for gastric cancer. These results validate the observations in the melanoma cohort and point to a common gene expression pattern in pretreatment tumor biopsy specimens that predicts post-treatment clinical outcomes to anti–PD-1 therapy across multiple tumor types. Moreover, these results suggest a potential for a high discriminatory value of IFN-γ–related gene signatures, enriching response rates to pembrolizumab (i.e., increasing PPV) while preserving a high NPV. However, we note that any formal evaluation of clinical utility depends on cutoffs selected for implementation of a clinical-grade diagnostic device in developmental trials and is dependent on the goals of those trials.
Confirmatory testing and signature refinement across multiple cancer types. (A and B) Confirmatory analyses of the IFN-γ and expanded immune signature scores for the HNSCC (43 total patients) (A) and gastric cancer (33 patients) (B) cohorts of KEYNOTE-012. (C and D) ROC curves of sensitivity and specificity for the HNSCC (C) and gastric cancer (D) cohorts of KEYNOTE-012.
IFN-γ and expanded immune gene signatures
Correlation of signatures with BOR and PFS for HNSCC (43 total patients) and gastric cancer (33 patients) cohorts of KEYNOTE-012
Having achieved proof-of-concept that common sets of IFN-γ– and T cell–associated inflammatory genes can predict responsiveness to PD-1 blockade across different tumor types, we undertook a signature selection exercise with a larger and more diverse data set spanning 9 cancer types from pembrolizumab-treated patients in the KEYNOTE-012 (bladder, gastric, HNSCC, and triple-negative breast cancer) and KEYNOTE-028 (NCT02054806) (anal canal, biliary, colorectal, esophageal, and ovarian cancer) studies with a goal to identify a final pan-cancer predictive biomarker suitable for development as a diagnostic clinical test for use in pembrolizumab clinical trials. Penalized logistic regression was used to derive a final set of 18 genes, with weighting determined by the regression coefficients. Figure 4 shows a heatmap of unsupervised clustering of the data across 9 tumor types for these 18 genes, revealing the coordinated pattern of expression for many of the 18 genes in the T cell–inflamed GEP. All genes in the signature, except CD276, are positively associated with improved clinical outcome, as can be seen by the increased frequency of responders (denoted by "R" in Figure 4) in the region with generally larger expression levels of the genes. Across the set of patients in Figure 4, the Pearson correlation between the 18-gene score and the IFN-γ 6-gene signature score was 0.89. Within each cancer type, the area under the ROC curve was greater than 0.5, with an average area under the ROC curve of 0.75 across the 9 indications used to fit the model (data not shown). These data support the tumor type–independent applicability of a T cell–inflamed GEP that captures the biology of a T cell–inflamed microenvironment common to PD-1 checkpoint blockade responders.
Heatmap for the final 18-gene T cell–inflamed GEP for 216 tumors from patients in KEYNOTE-012 and KEYNOTE-028 considered evaluable for objective response. Rows represent patients and columns genes. Expression levels have been standardized (centered and scaled) within columns for visualization. The "R" on the right side indicates whether the patient was a responder (by central imaging vendor in KEYNOTE-012 and by investigator assessment in KEYNOTE-028). The rows and columns have been grouped using unsupervised clustering.
To further evaluate the predictive usefulness of the 18-gene T cell–inflamed GEP, a PD-L1–unselected cohort of 96 patients with HNSCC from KEYNOTE-012 who were not involved in prior testing or the training of the signature was used to validate its performance in comparison with PD-L1 IHC. The 1-sided P value for association between the score and objective response was less than 0.001. Figure 5A shows a heatmap of the expression pattern for the 18 genes in these 96 patients with HNSCC, and Figure 5B shows the ROC curve for the T cell–inflamed GEP and PD-L1 expression by IHC, in which percentage staining using the number of PD-L1–positive cells (tumor cells, macrophages, lymphocytes) over total tumor cells was used as the scoring system. The area under the ROC curve was 0.75 for the T cell–inflamed GEP and 0.65 for PD-L1 by IHC. Although the all-comers HNSCC cohort was not sized/powered for comparisons between areas under the ROC curves, a test comparing the areas under the ROC curves for equality had a 2-sided P value of 0.119. These results suggest that a multivariate approach using gene expression might offer benefits in sensitivity to detect responders to anti–PD-1 therapies.
Validation of the final 18-gene T cell–inflamed GEP. (A) Heatmap of 18-gene T cell–inflamed GEP in 96 PD-L1–unselected patients with HNSCC from KEYNOTE-012. Expression levels have been standardized (centered and scaled) within columns for visualization. The "R" on the right side indicates whether the patient was a responder (by central imaging vendor). The rows and columns have been grouped using unsupervised clustering. (B) ROC curves comparing final 18-gene score with expression of PD-L1 as measured by IHC on tumor and inflammatory cells for a cohort of 96 PD-L1–unselected patients with HNSCC from KEYNOTE-012 considered evaluable for objective response by central imaging vendor.
Subsequent to the derivation of the final 18-gene signature, as a cross-check on the performance of the signature, the original KEYNOTE-012 and partial KEYNOTE-028 data used to train the signature were augmented with data of patients with additional cancers from KEYNOTE-028, roughly doubling the size of the original training data set, and an additional cross-validation exercise was conducted. These pooled data were randomly divided multiple times into two-thirds training and one-third testing, with elastic net predictors trained in the two-thirds portion of the data and the resultant area under the ROC curve of the new predictor compared with that of the 18-gene T cell–inflamed GEP in the holdout one-third of the data. No evidence of improvement was found (data not shown).
GEPs suggest discrete biologies of nonresponse to PD-1 blockade. Across multiple tumor types, we observed a general pattern of a lack of objective response in patients whose tumors showed low expression levels across the genes, assumed to represent tumors without a T cell–inflamed phenotype. However, another category of nonresponders demonstrated clear evidence of IFN-γ and associated T cell inflammatory gene expression at baseline (Figure 6, A and B). Plotting the T cell–inflamed GEP compared with PFS yielded a similar observation (Figure 7). Patients whose tumors had scores less than –0.3 generally showed rapid disease progression, whereas a broad spectrum of progression times was observed for higher scores (Figure 7). These data suggest that the presence of a T cell–inflamed phenotype is necessary but not sufficient for clinical response to PD-1 checkpoint blockade. Moreover, these observations raise the possibility that distinct resistance mechanisms might be in play in tumors that lack T cell inflammation, compared with those that show evidence of an activated T cell infiltrate yet still show a lack of clinical response.
Relationship between increases in IFN-γ immune-related signature score and PFS in response to anti–PD-1 therapy for the HNSCC and gastric cancer cohorts of KEYNOTE-012. (A) Relationship in the HNSCC cohort (43 total patients). (B) Relationship in the gastric cancer cohort (33 patients). The cutoff associated with the Youden index is displayed in each figure.
PFS time versus T cell–inflamed GEP score in 244 patients from KEYNOTE-012 and KEYNOTE-028 for the 9 cancer cohorts used to determine the T cell–inflamed GEP.
Multigene immune signatures represent a robust means of capturing a complex, T cell–inflamed phenotype necessary for the clinical activity of PD-1–/PD-L1–directed monoclonal antibodies. In this proof-of-concept study, we assayed pretreatment tumor biopsy specimens, capturing broad measures of immune-related gene expression using a straightforward, sensitive, and quantitative method compatible with tissue-limiting FFPE clinical samples. Through a rigorous, multistep validation process, we derived an 18-gene T cell–inflamed GEP that predicted response to pembrolizumab across multiple solid tumors. Our results suggest that immune GEPs such as the 18-gene profile, when assayed on a platform such as the NanoString nCounter platform, can define tumor type–independent dimensions of the tumor microenvironment relevant to predicting clinical outcome for agents targeting the PD-1/PD-L1 signaling pathway. Moreover, our data showed that such signatures might perform favorably compared with PD-L1 IHC in PD-L1–unselected populations. The 18-gene profile has undergone analytical validation on the NanoString platform and is under development as a clinical-grade diagnostic device, employed in a set of ongoing pembrolizumab trials (18).
Gene expression signatures that predicted clinical response to PD-1 checkpoint blockade were identified and refined in a stepwise manner through a number of independent tumor cohorts representing 10 different tumor types. A set of predictive gene signatures was initially defined and evaluated in baseline tumor biopsy specimens in patients with metastatic melanoma undergoing treatment with pembrolizumab and was subsequently shown, via rigorous independent statistical testing, to be associated with improved clinical outcome for patients with HNSCC or gastric cancer after pembrolizumab therapy. Objective response and PFS times were used as the focal clinical endpoints in this testing given that the source trials were all single-arm studies. The prognostic relationship between these signatures and survival under standard of care (chemotherapy) is the subject of ongoing investigation, and a full understanding of the improvement in overall survival (OS) relative to nonimmunotherapies will require randomized studies; however, the association between immune signatures and durable objective responses to anti–PD-1 treatments, which are responses uncharacteristic of standard of care, is expected to translate into clear increases in expected survival for anti–PD-1 therapy compared with standard of care in patients whose tumors exhibit the T cell–inflamed phenotype.
The final 18-gene profile was derived through a cross-validated penalized regression modeling strategy in a large cohort of pembrolizumab-treated patients across 9 different tumor types. Although many of these patient cohorts had undergone enrichment for PD-L1 expression by pre-enrollment IHC screening, the predictive value of the signature was prospectively validated in a large, independent cohort of PD-L1–unselected patients with HNSCC. In this cohort, the area under the ROC curve for the T cell–inflamed GEP compared favorably with PD-L1 IHC (0.75 vs. 0.65). Although both PD-L1 and the T cell–inflamed GEP reflect IFN-γ–inducible biology, these results signify the more robust nature of an assay that simultaneously measures multiple microenvironmental features, rather than a single analyte. Likewise, these data provide a much higher level of statistical validation across multiple tumor types than has previously been reported for single genes associated with the IFN-γ signaling pathway and response to PD-1 blockade (17), indicating that integrated multigene signatures might represent more robust predictive biomarkers than single genes.
For clinical implementation, a cutoff on the T cell–inflamed GEP must be selected to identify the subgroup in which meaningful improvement in response can be demonstrated relative to standard of care. The bar for enrichment may be higher in the first-line than in the second- and third-line settings. The latter may not require extremely high PPV to demonstrate convincing activity of the drug in patients with advanced metastatic disease who have limited or no treatment options.
Inspection of the T cell–inflamed GEP suggests that a subset of tumors from diverse tissues of origin exhibit at baseline an ongoing adaptive Th1 and cytotoxic CD8+ T cell response, including IFN-γ signaling, cytolytic activity, antigen presentation, and T cell trafficking, as well as inhibitory mechanisms that are evident in T cell homeostasis (Figure 8). These data extend the observations of previous reports showing that CD8+ T lymphocytes and T cell active chemokines and T cell counterinhibitory molecules such as PD-1/PD-L1 and IDO1 are coregulated within tumors (4, 15, 21, 22) and confirm that response to anti–PD-1 blockade occurs primarily in patients with such a preexisting, intratumoral T cell adaptive immune response. Furthermore, these data indicate that the PD-1 pathway likely represents a common mechanism for restraining such antitumor responses through the IFN-γ–mediated induction of PD-L1 and PD-L2 expression. These correlative gene signatures represent a novel method for capturing the complexity of the dynamic immune response to a tumor by distinguishing between tumors with preexisting inflammatory components and noninflamed tumors, a classification that is likely to be of high clinical relevance (23, 24).
The T cell-inflamed gene expression signature highlights the complex biology of the host immune microenvironment.
The spectrum of genes associated with clinical response to PD-1 checkpoint blockade suggests a complex biology of immune cell homeostasis in anti–PD-1–responsive tumors. The production of IFN-γ by activated T cells, and perhaps other cells such as NK and NK T cells, activates a host of key downstream signaling molecules such as STAT1 and CMKLR1 in dendritic cells and macrophages. These cells in turn produce chemokines/chemoattractants, including CCL5 and CXCL9, which recruit additional CD8+ T cells. T cells upregulate activation-induced costimulatory receptors such as CD27 and produce an array of effector molecules, including IFN-γ, perforin, and granzymes. IFN-γ can induce upregulation of HLA molecules and other components of the immunoproteosome and antigen-presenting machinery such as PSMB10. However, IFN-γ also upregulates a host of checkpoint inhibitors, such as PD-L1 and PD-L2, on the surface of macrophages and dendritic and tumor cells. Other checkpoint molecules, such as IDO1, TIGIT, and LAG3, might also be homeostatically upregulated by T cell activation and IFN-γ signaling, and cooperate with PD-1 to restrain the antitumor immune response. The association of genes such as HLA-E and NKG7 with clinical response suggests that additional aspects of NK cell biology or noncanonical T cell antigen recognition might be involved in the T cell–inflamed microenvironment. Overall, the genes identified suggest that multiple immune cell types contribute to a T cell–inflamed but immune checkpoint–restrained tumor microenvironment that can be successfully modulated by PD-1 checkpoint blockade.
Furthermore, our data suggest that nonresponders to anti–PD-1 therapy fall into 2 broad categories: those who lack a preexisting antitumor immune response and those in whom an antitumor immune response has been generated, with associated infiltration of activated T cells into the tumor microenvironment. The reason for lack of clinical response in this subset of inflamed tumors is not clear, but it might be a result of effects of immunosuppressive pathways other than PD-1 within the tumor microenvironment, which could be T cell intrinsic or extrinsic. The observation that immunosuppressive molecules such as IDO1 and LAG3 are overexpressed in inflamed tumors suggests that increased anti–PD-1 efficacy in this class of tumors might be observed when combined with immune modulators targeting other suppressive pathways. For tumors lacking the inflamed phenotype, distinct strategies to stimulate a host immune response against the tumor may be necessary. Further work is needed to elucidate the discrete mechanisms that inhibit T cell trafficking to T cell–poor tumors, which might include tumor cell–intrinsic mechanisms (e.g., WNT/β-catenin pathway activation) (25), failure of T cell priming (amenable to reversal by tumor-specific vaccines, oncolytic viruses, or adoptive T cell therapy), or the activity of other cells in the tumor microenvironment, such as stromal cells (26) or vascular endothelial cells (27). Further studies using gene expression profiling might represent a powerful approach to dissecting the discrete biologies of resistance to PD-1 checkpoint blockade, potentially revealing new targets for converting anti–PD-1–resistant tumors to a state of responsiveness.
Quality assessment of clinical FFPE tissue specimens. The KEYNOTE-001, KEYNOTE-012, and KEYNOTE-028 trials were nonrandomized, open-label studies characterizing the safety, tolerability, and clinical activity of pembrolizumab in patients with locally advanced or metastatic cancers (KEYNOTE-001: melanoma, non–small cell lung cancer; KEYNOTE-012: HNSCC, gastric cancer, triple-negative breast cancer, bladder cancer; KEYNOTE-028: anal canal, biliary, colorectal, esophageal, and ovarian cancer). Pretreatment clinical specimens were collected as specified in the clinical protocols and consisted of FFPE blocks and/or cut tissue on slides. The melanoma cohort from KEYNOTE-001 and the HNSCC-expansion cohort of KEYNOTE-012 were all-comers cohorts (independent of PD-L1 expression), whereas the remaining cohorts from KEYNOTE-012 and all cohorts from KEYNOTE-028 were screened using an IHC assay for patients whose tumors were positive (≥1% of cells) for PD-L1 expression either in tumor cells or in inflammatory cells of the surrounding stroma. When only an FFPE block was available, sections were cut at 5 μm onto positively charged slides. One cut section from each tissue sample was routinely stained with H&E and coverslipped for assessment of sample quality. Each H&E-stained slide was reviewed by a pathologist to evaluate the adequacy of tumor representation, the quality of tissue preservation, and whether significant artifacts relating to fixation, processing, or prefixation tissue handling were present. Specimens containing no tumor tissue or very minimal tumor tissue were excluded from analysis. The number of slides needed for RNA isolation from any given tissue sample was based on a combination of sample size on the slide and the proportion of the sample that consisted of tumor tissue; typically, RNA was isolated from 2–4 slides per case.
A PD-L1 clinical trial assay (PD-L1 IHC 22C3 pharmDx assay; Agilent Technologies) was subsequently developed and approved as a PD-L1 IHC companion diagnostic for use in non–small cell lung cancer in the United States (28, 29). The approved assay was used to stain the 96 patient HNSCC samples under the staining protocol described in the instructions of the commercial assay. Staining was scored using the number of PD-L1–positive cells (tumor cells, macrophages, lymphocytes) over total tumor cells, expressed as a percentage.
RNA isolation and gene expression analysis. Total RNA was isolated from 5-μm-thick FFPE sections of tumors fixed on positively charged slides using the Ambion RecoverAll kit for RNA isolation from FFPE tissue (Thermo Fisher Scientific) following the manufacturer's protocols. RNA was quantified using the NanoDrop ND1000 spectrophotometer (Thermo Fisher Scientific). Gene expression analysis was conducted on the NanoString nCounter gene expression platform (NanoString Technologies). A custom code set consisting of a 680-gene panel related to T cell biology, immune regulation, and cellular markers of tumor-infiltrating lymphocytes and tumor-associated macrophages was used. Per sample, 50 ng of total RNA in a final volume of 5 μl was mixed with a 3′ biotinylated capture probe and a 5′ reporter probe tagged with a fluorescent barcode from the custom gene expression code set. Probes and target transcripts were hybridized overnight at 65°C for 12–16 hours per the manufacturer's recommendations. Hybridized samples were run on the NanoString nCounter preparation station using the high-sensitivity protocol, in which excess capture and reporter probes were removed and transcript-specific ternary complexes were immobilized on a streptavidin-coated cartridge. The samples were scanned at maximum scan resolution on the nCounter Digital Analyzer.
Quantile normalization. Gene expression data for each individual sample were normalized by quantile normalization. Gene counts collected from the NanoString scanner were used as input variables with a reference distribution generated using a pool of counts from all samples and 680 genes (excluding data from positive and negative control probes). After performance of quantile normalization, a log10 transformation was applied, and signature scores were calculated by averaging of the included genes for the IFN-γ (6-gene) and expanded immune (18-gene) signatures.
Housekeeping normalization. In anticipation of moving to a more limited set of genes that could serve as the basis of a focused clinical trial assay (a context not amenable to quantile normalization), a set of 11 genes showing low variance across a set of banked tumor samples from a variety of cancer types was identified and used to form a normalizing constant for each patient. The log10 count of each gene on the platform was normalized by subtracting of the arithmetic mean of the log10 counts of the housekeeping genes.
Statistics. Logistic regression modeling was used to conduct the hypothesis testing associated with best overall response (BOR), and a Cox model was used for testing of PFS and OS. PFS was defined as the time from the start of treatment to documented evidence of progressive disease or death. OS was defined as time from treatment initiation to death from any cause. For BOR, a responder was defined as a patient with "complete response" or "partial response" as determined by RECIST v1.1 criteria, assessed by central imaging vendor for melanoma and by investigator review for the HNSCC and gastric cohorts (centrally reviewed data were not as mature at the time of analysis). One-sided P values were calculated according to the hypothesized positive association between the immune signatures and improved clinical outcome under treatment. Calculation of the area under the ROC curve was used as a measure of discriminatory ability for the signature scores. The Youden index, a summary measure of the ROC curve (20), was used as an agnostic method for choosing an "optimal" cutoff on the signature scores to illustrate potential clinical usefulness. The NanoString platform was used as a discovery research assay rather than a clinical trial–grade assay.
Nominal P values were reported for signature testing. The gene signatures developed from the melanoma cohort were independently confirmed by prespecified hypothesis testing in 2 additional cancer types: HNSCC and gastric cancer. Afterward, a larger effort to define a focused gene signature and an optimal scoring for that signature was undertaken by combining of early versions of data from KEYNOTE-012 and KEYNOTE-028. A total of 220 patients with measurable disease by investigator and RNA expression profiling from KEYNOTE-012 (25 bladder, 40 HNSCC, 30 triple-negative breast cancer, and 33 gastric) and KEYNOTE-028 (19 anal canal, 13 biliary tract, 18 colorectal, 18 esophageal, and 24 ovarian) were available at the time and were used in an elastic net penalized regression model (30) for objective response to select a final set of genes and their weighting. Fivefold cross-validation was used to select the penalty parameters, and 10 different random partitions of the data into 5-folds were used. The average of the estimated penalties from these 10 cross-validation runs was used as the final set of penalty parameters to determine the final gene set and weights. The penalized regression models adjusted for cancer type, performance status, and the interaction between cancer type and performance status. The final values of the regression coefficients on the genes that were not zeroed out by the penalty terms were used as the weights in the computation of the T cell–inflamed GEP score for the resulting 18 genes, not to be confused with the 18 genes of the expanded immune signature. The score was computed as the weighted sum of the housekeeping normalized values of the 18 genes.
Study approval. The original studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and approved by relevant regulatory and independent ethics committees from each study's institution. All patients provided written informed consent before study entry.
MA participated in the concept, design, or planning of the study, acquired the data, and drafted the manuscript. JL analyzed the data, interpreted the results, and drafted the manuscript. MN analyzed the data and drafted the manuscript. EM acquired and analyzed the data. AL analyzed the data and interpreted the results. DRK analyzed the data, interpreted the results, and drafted the manuscript. AA acquired the data. JDC participated in the concept, design, or planning of the study, acquired the data, and interpreted the results. SPK acquired the data. VS interpreted the results. SAPP provided study materials and patients and interpreted the results. JY acquired the data. TYS provided study materials and patients, acquired the data, and interpreted the results. AR participated in the concept, design, or planning of the study, interpreted the results, and drafted the manuscript. TKM participated in the concept, design, or planning of the study, acquired and analyzed the data, interpreted the results, and drafted the manuscript. All authors critically reviewed iterations of the manuscript and approved the final draft for submission.
The authors thank Razvan Cristescu (Merck & Co. Inc.) for his contributions in the development of the manuscript, Robert Kastelein (Merck & Co. Inc.) for critical review of the manuscript, and Matthew Grzywacz and the ApotheCom oncology team (Yardley, Pennsylvania, USA) for assistance with manuscript editing (funded by Merck & Co. Inc.). Funding for this analysis was provided by Merck & Co. Inc.
Conflict of interest: M. Ayers, J. Lunceford, M. Nebozhyn, E. Murphy, A. Loboda, D.R. Kaufman, A. Albright, J.D. Cheng, S.P. Kang, J. Yearley, and T.K. McClanahan are employees of Merck & Co. Inc. S.P. Kang and T.K. McClanahan also disclose stock ownership in Merck & Co. Inc. M. Ayers, J. Lunceford, E. Murphy, A. Loboda, and T.K. McClanahan have a patent pending (system and methods for deriving gene signature biomarkers of response to PD-1 antagonists; PCT/US2015/064445), and S.P. Kang has a patent pending (MK-3475). V. Shankaran received a grant from Merck & Co. Inc. during the conduct of the study and has received grants from Amgen and Castle Biosciences. T.Y. Seiwert reports personal fees from Merck & Co. Inc. during the conduct of the study. A. Ribas has been a consultant for Merck & Co. Inc., with the honoraria paid to his institution.
Reference information: J Clin Invest. 2017;127(8):2930–2940.https://doi.org/10.1172/JCI91190.
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Version 1 (June 26, 2017): Electronic publication
Version 2 (August 1, 2017): Print issue publication


What are the best Madrid souvenirs to remind you of your great time in this city?
Well Madrid guide Spain cannot possibly answer that but it can give you an idea of whats available & where so that you can make an informed decision!
Your souvenir needs to provoke something in you & not simply the typical "Why on earth did I buy that?"
Although Madrid has a number of tacky tourist shops, almost exclusively stocked with items "Made in ..... anywhere but Spain", there are also a great deal of typical Spanish products available.
All you have to do is follow this guide!
Madrids souvenir shops are located within the central area of the city with the greatest concentration around the Puerta del Sol and Plaza Mayor. Within two minutes walk of each other you can be sure to find the mass produced bags, bulls, T-shirts and keyrings being sold at a premium after having been plastered with "MADRID" in some way. They're very affordable and would hardly cause a dent on your savings accounts, normally the quality is questionable but if you realise you have forgotten to get someone something these are the shops to visit in a hurry.
Official outlets: In the same manner as the world over, just about every Madrid attraction has a souvenir store or stall attached to it. Unfortunately they tend to have a limited range of items and all associated to their particular business. Whilst normally I would dismiss these as a "tacky" way of trying to get you put your hand in your pocket once more, Madrid galleries are an exception!
Art Galleries offer a number of high quality prints of the various paintings on display which, if framed, are as close as most of us will get to having the real thing on our living room wall. Available cheaply this is one Madrid souvenir you would not be ashamed to have on display.
Barrio La Latina - On Weekdays the narrow streets have a number of stores offering handmade Spanish craftwork. Here it is possible to see a huge variety of handmade paintings, woodwork and earthenware from all over Spain.
Plaza Mayor - There are two stores in the south west corner of the plaza offering typical Spanish handicrafts. In addition there is a small cluster of shops, in the alleys leading off the plaza, dealing almost wholly with Spanish cloth. A handmade fan or headware is the best bet here.
It is physically impossible to list all the possible souvenirs available in Madrid. Instead here is a list of uniquely Spanish / Madrid items that cannot be purchased elsewhere.
Toro - Miniture Spanish Bulls, They vary in quality from plastic injection molded bulls from Asia to elaborate pieces hand made from actual leather.
Abanico -Hand held fan, Elaborately decorated or carved from wood the variety is almost limitless. Available from a few euros to the hundreds of euros.
Miniture Monuments - Hand carved and painted of topics as diverse as the Puerta Alcala to the Real Madrid football stadium.
Football Souvenirs - Just about everything and anything is available with a Real Madrid crest on it. Either licensed products from the Real Madrid city centre club shop or unlicensed from the many stores and market stalls.
Bullfighting souvenirs- Have an advertising poster made with your name included as one of the three matadors (see here for why there are three matadors) or perhaps you want to go the whole hog and purchase a replica matadors jacket?
Art & Paintings - From the country that gave birth to Salvador Dali and Picasso there is a large selection of cheap scenes of everyday Spain in everything from Acryllic paint to cloth montages. Perhaps after a couple of Cañas (small beers) a portrait or carictature from one of the many artists in Plaza Mayor is your perfect personal momento?
Is there a Madrid souvenir you want to know about that is not listed? Contact us!
Swords - Trading on the reputation of Toledo Steel there are two stores in Plaza Mayor offering imitation Swords from Roman leginaires to Conan the barbarian.
Postage Stamps - A unique gift available from post offices (this year) or speciality shops in Calle Mayor. A gift and an investment!
Euros - Why not give money itself? In europe each country´s money has the same obverse with the reverse showing a design from the issuing country. A mint set of Spanish coins can be had for less than 12€. Available in Calle Mayor and Plaza Mayor.
Real Madrid Merchandise - Available from either the stadium itself or the down town store. Take the stadium tour (Paseo de Castellana) and there are discounts available in the stadium store.
After shopping for Madrid souvenirs isn´t it time you checked out Madrid shopping for you personally?


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Flagstaff Hill Sports Ground Sports Recreation and Facilities upgrade
We have been working in partnership with the Flagstaff Community Club, sporting clubs and local residents to plan for upgrades to the sports and recreation facilities at Flagstaff Hill Sports Ground.
During February and March 2020 we sought feedback on the proposed upgrade of the playground adjacent the oval, and the location of a proposed new unisex change room building. The initial concept plan proposed a new change room building location in the area of the existing playground near York Drive. This required the playground to be relocated further east towards York Drive. While there was some support for this proposal there were also concerns that warranted further consideration.
Since then we've been working further with key stakeholders to find a solution that works for everyone. Through this process, we have reached general agreement that relation of the planned changeroom facility to the area adjacent the existing clubroom building would be an improved outcome. This site will require the western-most practice cricket pitch to be removed.
The unanimous support for this option by key stakeholder representatives gives Council confidence that this revised plan will support the growth of sport and community use whilst minimising any negative the impact of the proposed development and activities.
We are continuing to work directly with club representatives to progress related projects including the renewal of the two remaining cricket practice nets and the playground for younger children next to the tennis courts. The revised changeroom location also means that the playground adjacent the oval can stay in its current location. This playground will be enhanced with new equipment designed for primary school aged children.
The work will be complemented with new paths, trees and landscaping to further enhance the Sports Grounds, and provide better access from York Drive.
INITIAL WORK HAS COMMENCED
If you're a regular user of the Sports Ground, you may have noticed that some early works have already been undertaken, including removal of a non-regulated tree, the existing junior playground equipment, some fencing and park furniture.
Further works scheduled for the coming months include:
demolition of the existing cricket nets and oval playground
installation of new service connections to York Drive, ahead of the changeroom, cricket net and playground projects
In addition to the projects listed above, Council is also working with the tennis club towards a complete rebuild of the two southern courts (the blue ones), and resealing of the remaining four courts.
We are aiming for the playground, cricket net and tennis court projects to be completed later this year, while the changeroom facility will be completed by Autumn 2021.
The updated concept plan provides an overview of these proposed works. We also have frequently asked questions available.
Stay tuned for more updates as these exciting projects for Flagstaff Hill progress!
If you have any further comments, we'd love to hear them. Please leave your feedback below.
Do you have any further feedback?
Consultation was held
25 February → 16 March 2020
Flagstaff Hill Sportsground Concept Plan September 2020.pdf (1.07 MB) (pdf)
Frequently Asked Questions Sept 2020.pdf (109 KB) (pdf)
Senior Urban Designer
Email mail@onkaparinga.sa.gov.au

redpajama_set_name: RedPajamaCommonCrawl


Recipe card templates are available in Word, Publisher, Corel Draw and InDesign formats in several colors and styles. The template can be printed one or two up on letter size paper or printed on pre-perfed postcard stock.
Five colors to choose from. Finished size is 4" x 6" and can be printed 3 up on 6" x 12.5" pre-perforated postcard stock.


twenty-four hours, mean solar day, sidereal day, time between sunrise and sunset, period from dawn to dark, solar day, nautical day, natural day, civil day, astronomical day, diurnal course, date.
daylight, daytime, broad daylight, full day, workday, working day, daylight hours, broadcast day, eight-hour day, union day; good, bad, hot, cold, damp, etc., day; sizzler*, scorcher*, good day for the races*.
holiday, celebration, festival; see anniversary, holiday 1.
era, time, heyday, prime; see age 3.
finish, quit, stop work, call it quits*; see end 1, stop 1, 2.
without thought for the future, sporadically, irresponsibly, heedlessly; see carelessly, irregularly.
"day." YourDictionary, n.d. Web. 15 April 2019. <https://thesaurus.yourdictionary.com/Day>.
The period during which someone or something exists.
"This may be the last great day," he said.
"It is the day of the Lord." said one.


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95bFM Extended Play
Manu Taylor
The early 1980s was one of the pivotal times in the acceptance of New Zealand music creativity. Amongst other things, one South Island town's artists circumvented the accepted ways of writing, recording and distributing their work, and became noticed around the world. The artists released on Flying Nun spearheaded a unique do-it-yourself ethos, resulting in a sound that is still emulated today.
Tall Dwarfs, 1981. Although not released on Flying Nun (it was on the Furtive label), their 1981 EP 3 Songs could be argued to have launched the Flying Nun series of EPs - Photo by Barbara Ward
In 2011, in anticipation of the 30th anniversary of Flying Nun, the opportunity arose to speak to many of the artists involved in some of the key tracks from the early days of the label. After Chris Knox's debilitating stroke, many were feeling their mortality, so a real effort was made to capture the stories before the opportunity was gone — or, like Chris, the players were unable to speak for themselves.
95bFM, as the only Auckland radio station that had embraced and got behind the work when it was released, was the perfect middle man to speak with the artists and get the true, unfiltered story without any label slant or usual media spin on the narrative.
The result was an extensive, long-form radio documentary series: Extended Play, with each 54 minute episode structured around the songs originally released as EPs.
The following year 95bFM made another series using the same framework, this time focused on the remarkable burst of young creativity in Auckland in the early years of the 1980s. Again, these were filmed using the same setup.
Who Killed Colonel Mustard, the 1982 Bored Games 12" EP, featured the classic Joe 90
Sensing a shift in how audiences were receiving and consuming their media, 95bFM filmed all of the interviews with the intention of allowing the stories to be told in the future in a different form. The idea of a short, easily-digestible video with the artists telling their own stories around their own music suits the short attention span of online audiences, and with a narrative based around the music will be easily accessible.
Blam Blam Blam's 1981 EP – later extended to a mini-LP as pictured – with a sleeve designed by 'Sauna Productions' aka Blam Blam Blam
Time moves on, and the footage that has been captured is as unique as the artists' voice on their work and circumstance.
The third release from The Clean, and their second 12-inch EP from June 1982. Great Sounds Great, Good Sounds Good, So-So Sounds So-So, Bad Sounds Bad, Rotten Sounds Rotten!! was not only an extended play release but its title was made to match.
Alms For Children were a North Shore band fronted by Gary Rodent whose sole EP was released on REM Records in 1981. They would later rename themsleves This Sporting Life and record for Flying Nun.
Online is the perfect home for these pieces: released as a weekly "broadcast", the stories will live on around the songs and add an authentic narrative to the music story as we know it.
Extended Play on Radio New Zealand National


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Home / Family Tree Premium Articles / How-Tos & Tutorials / Genealogy Records / Church Records / Genealogy Workbook: Church Records
Genealogy Workbook: Church Records
Sunny Jane Morton July 28, 2016 updated on October 3, 2017
Church records can reveal immigrant ancestors' origins, provide mystery parents' names, stand in for missing birth records and more. Our guide will help you find church registers, baptism and marriage records, and more.
In 1926, roughly half the US population belonged to one of about 230,000 religious congregations across the country. Some churchgoers also attended Sunday schools, church socials, service auxiliaries and revivals; and sent their children to church-sponsored schools.
Such vigorous worship communities often produced vigorous records. Among them were membership lists, baptismal registers, marriage records and lists of deaths and burials. Maiden names, ages or dates of birth, relatives' names and relationships, and prior or subsequent residences (including overseas birthplaces) may be sprinkled throughout these records.
Church records aren't always easy to find or access, but online resources make this task easier. Online sources may help you identify an ancestor's probable congregation. Web searches may lead you to sources of published or microfilmed versions and even digitized online records. This guide will get you started.
Types of church records
Before you set off in search of church records, consider when it's worth searching for them. Records pre-dating the Civil War are more likely to be written freeform in blank books or on loose sheets, often with scant detail. Baptisms and marriages are the life events most commonly found, with the date of the event, witnesses or godparents, officiant, and (for children's baptisms) names of parents. Deaths and/or burials were more likely recorded if the church had its own burial ground. Protestant faiths often created periodic roll calls of members or a master membership list with infrequent but valuable details like a spouse's name or death date noted.
In the later 1800s, churches began using registers pre-printed with columns. Details varied by faith, congregation and even the scribe. Many Protestant faiths kept membership ledger books with separate lists of ministers and church officers, baptisms (with parents' names for children), marriages (often with the couple's residences) and deaths (sometimes with burial information). The dates of these events, officiants and sometimes witnesses were recorded.
Members of many Protestant denominations who migrated received letters of transfer admitting them to the new church. Membership ledgers may have notations such as "admitted by letter," along with the previous city or church. When someone moved out, you may see "dismissed to" or "disposed of" with the destination and/or date. Rarely, letters of transfer survive in church administrative files.
Some Protestant faiths, such as Lutherans and Methodists, recorded more details than others. Baptist records are typically sparse. Record content also may vary based on beliefs or practices. For example, Quakers don't baptize; therefore, they don't have baptismal records. But records of Quaker marriages often include the names of everyone in attendance, the bride's and groom's residences and their parents' names and residences (or an indication the parents were deceased).
Catholic parishes (the term for a local congregation) didn't generally keep membership lists, but they did register
sacraments—often in Latin and sometimes, for churches with large immigrant memberships, in a foreign language. Most often you'll find records for:
Baptism, often performed within a day or two of birth, with the date, godparents, child's parents and the parents' birthplace. Later sacraments in that child's life also might be noted here, too, even if they occurred in another church.
Confirmation, often received as a young teen, recorded as a simple list of those who received it and the date. Use this record to confirm a family's residence at that time and participation in church life. More recent records may mention the place and date of baptism.
Catholic Baptismal Register
The columns shown are for last name, date of event, particulars of baptism and additional comments.
These records are in Latin; even Latin forms of names may be used. "Guilel" is an abbreviation of Gulielmus, Latin for William.
The translated baptismal record reads, "I, the undersigned, baptized Appoloniam Helaram, born 15 Ap[ril], of Jos[eph] Steinlein from place [blank] and Cath[erine] Gunther from place [blank], married. Godparents were Jos[eph] Steiner and Appolonia Gunther."
Comments include a note about Appolonia's marriage, specifying her spouse's name, the date and parish. Check that parish for records of the marriage and children's baptisms.
Citation for this record: St. Joseph's Church (Fremont, OH). "Diocese of Toledo, Ohio, Catholic Parish Records, 1796-2004." Digital images, Ancestry.com: accessed 19 April 2016. Original images from FamilySearch.org.
Marriage and possible banns (formal announcements), if they were read prior to the marriage. Look for the couple's name, parents' names, witnesses and officiant's name. More recent records may indicate baptismal place and date.
Extreme unction or last rites, performed for the dying. Look for notes about the dates of death and burial, burial place, and sometimes age at death.
Holy orders and taking of vows, for those who became priests or nuns. (Look for additional records in an archive for the religious order the person joined.)
Also look for denominational newspapers. Methodists published regional versions of the Christian Advocate (for example, the New York Christian Advocate or the Nashville Christian Advocate). Several Catholic dioceses published newspapers or newsletters, too. Many of these had limited runs in the late 1800s and included obituaries of members.
Identifying the right church
On the eve of the Revolutionary War, more than half of those in the English colonies were either Congregationalists (mostly in New England) or Anglicans (Church of England, dominant in the South). Others were Presbyterian, Dutch Reformed and in much smaller numbers, Quakers, Baptists, Catholics, Methodists and Jews. Spanish and French colonists were largely Catholic; a significant minority of French colonists were Huguenots.
That religious picture changed dramatically during the following century. Anglicans and Congregationalists lost government sponsorship and popularity. More experiential faiths took their place. By 1860, half the congregations in the US were Methodist and a quarter were Baptist. Another 10 percent were Catholic—a number that would grow as more Catholic immigrants arrived.
To determine what church might have records of your ancestors, make an informed guess based on these factors:
Family lore: Ask older relatives what churches family members attended throughout their lives. Check with distant cousins, too, especially those who still live near an ancestral hometown.
Records: An ancestor's faith or specific church might be specified (or at least hinted at) in nonreligious records. Watch for a religion or church mentioned in an obituary or associated with a burial place (keeping in mind that a churchyard burial may have represented the religious wishes of other relatives, not the deceased). Research the affiliation of ministers who married or buried your ancestors. Look up the meaning of symbols on tombstones. Look for biographical details in funeral programs, county histories and other documents.
Transitions: The religious choices of one generation don't always agree with the preceding one. Switching to a different faith might happen with marriage or migration away from relatives or to a place where the old faith didn't have a foothold. As you trace immigrant ancestors, be aware that some ethnic groups assimilated faster than others. Watch for a transitional generation whose more "American" naming patterns or dress are distinct from those of the previous generation. This may be a key time to look for clues pointing to an "Old World" religion.
Ethnic group: Immigrants often brought their country's dominant faiths. English were often Anglican (a denomination that became the Episcopal church in the United States); Scots-Irish, Presbyterian; and Scandinavians, Lutheran. Irish, Italians, Spanish, French and many Eastern Europeans often were Catholic. Germans had the most variety: Catholic, Lutheran, Reformed, Jewish and many smaller sects.
Conversely, members of many religious groups—English Quakers or French Huguenots, for example—came to the United States because they didn't agree with their national faith. Consult history books to learn the overall religious picture of your ancestor's ethnic or national group, including dissenting or "nonconformist" sects that migrated during that time period.
Immigrants from the same place and who shared a religion often settled together in America. Those initial religious cultures evolved with the changing times and residents. A region of the South that was primarily Anglican during one generation may have become mostly Methodist or Baptist within a few generations. Research local history to learn about these patterns.
The nearest reasonable option may have determined a family's place of worship. Many Congregationalists who went west from New England joined Presbyterian churches, which had a similar culture. Migrating German Lutherans may have joined ranks with local Reformed or similar German sects. City directories and neighborhood maps showing property ownership or local landmarks can help you identify the churches nearest your ancestors.
Some Catholic immigrants didn't attend the parish nearest their home. In the late 1800s and early 1900s, ethnic parishes served German, Irish, Italian, Slovak and other Catholics who wanted to worship in their own languages. Local histories or a Catholic diocesan archivist (see below) can tell you about local parishes that served your family's ethnicity.
Methodist Sunday School Register
On continuing pages, the year may appear in an abbreviated format, such as 81 for 1881.
Prob likely stands for "probationer," a probationary member. Look for these names with further information on a probationer's list in the register book.
This migration information is a clue to look for individuals in their new places.
If someone was "received into membership," look for his or her entries in the member list in elsewhere in the register book.
Notes such as "discontinued as unworthy" or "discontinued—drunkenness" reveal more than just whether a person was present at Sunday school.
Citation for this record: Calvary United Methodist Church (Keyport, NJ). "New Jersey, Calvary United Methodist Church Records, 1832-2003." Digital images, FamilySearch: accessed 19 April 2016.
Accessing church records
Once you've identified a possible ancestral church, it's time to start looking for its membership or sacramental records. These may exist in original manuscript, microfilmed, published and/or even digitized format.
Although Ancestry.com and FamilySearch have selected church records (including Quaker records on the former), for the most part, these records aren't online. But you can start your search with your favorite web browser. Search for the name of the church if you know it, along with the denomination, city and state. As desired, add terms such as records, baptisms or marriages to narrow search results.
Browse search results for websites of churches. Also watch for any mention of records in online manuscript finding aids, genealogy website databases, on microfilm or in published format at a library (more about these below).
If the local church exists and has a website, your search should bring it up. If you can't find one, search for the name of the denomination and the phrase "church locator." Most denominations have online tools to help you find their churches in specific locales.
Look for history information on the website to confirm that this church existed during your ancestor's life, was in the right place and, if applicable, matched your family's ethnicity. Most congregational websites don't mention whether they have old records, but it's worth browsing the site to see.
You should at least find contact information for the church office. Send a brief inquiry about membership or sacramental records for the time period in question and the procedure for ordering them. Ask whether they would direct you to records if they exist elsewhere. Be polite and patient. Church offices aren't obligated to fulfill genealogical requests. Mention your willingness to pay for a researcher's time or to make a donation to the church.
Your ancestor's congregation may have dissolved or merged with another one. In that case, conduct a web search for a denominational archive. Consult the toolkit on the previous page for a starter list. Some churches maintain a central archive or have archival collections at universities. Other churches have regional archives, such as Methodist conferences and Catholic dioceses. These may hold old records of congregations within their boundaries. Contact archivists about how to access historical records from the church and time period in question.
Tip: When requesting copies of records from churches and religious archives, be respectful and patient. Church offices aren't obligated to help genealogical researchers.
If the denomination itself doesn't seem to exist anymore, consult a denominational family tree like the ones at the Association of Religion Data Archives website. You'll learn important details. For example, Congregational churches now exist under the banner of the United Church of Christ. This may help you to locate existing successor churches or contact an appropriate denominational archive.
The Family History Library (FHL) in Salt Lake City has many church records on microfilm. On the FamilySearch website, click Search, then Catalog. Search by place: Start typing the town, city, county or state, then choose from the dropdown menu that appears. In your search results, click Church Records. You'll see a list of the FHL's church records holdings for that place; click each one for details on the type of record and time period covered.
Some church records end up in private archives, too. Watch web search results for online finding aids or record collection descriptions. Use Archive Grid, an online catalog listing millions of records, to search for archives near your ancestor's home. Also conduct a targeted search for published and/or microfilmed congregational records. Start with WorldCat, an online catalog with over 2 billion items in libraries worldwide. Enter the same types of search terms as previously described.
Besides membership and sacramental registers, archives' collections of church records may include church histories, denominational newspapers, administrative minutes, changes in membership status and occasionally members' significant life events. Separate records may cover women's or other service auxiliaries. Financial records, including itemized donation lists, also may mention your relatives.
If you find index-only versions of records, try to track down the originals. They'll expose any errors in the indexed information and provide additional information that wasn't in the index. Some Catholic sacramental records are considered confidential. Church records are released at the discretion of the record custodian, whether it's a local priest or diocesan archivist. If you can't get photocopies of a record, you might be able to at least receive a certificate with basic sacramental information transcribed onto it. Request that every piece of information on the record be provided, not just what the certificate has space for.
Chronicling America can help you identify denominational newspapers to research. Click on the site's US Newspaper Directory, 1690-Present to search for denominational titles. The Language, Ethnicity Press and Labor Press pulldown menus have options such as Anabaptist, Jewish and Catholic Labor Unions. Also try keyword searches like Catholic diocese or Lutheran. Click on a search result to look for microfilmed holdings you might borrow through interlibrary loan, or print holdings at libraries that may provide obituary searches.
Clues in church records
Church histories may have lists of members, substantial donors, churchyard burials or clergy. See whether mention is made of original church records still extant at that time. Scan the text to learn more about the religious community to which your family belonged. Other local or county histories may include historical sketches of the church, too.
Church records can solve several types of family history mysteries. They can provide evidence of vital events when government records conflict, weren't created, or are missing. For some times and places, church records may provide the most likely or even the only source to mention births, marriages and deaths.
Tip: Don't use a baptismal date as a surrogate for a birth date without evidence that it was an infant baptism.
They can resolve mysteries such as parents' names, a woman's maiden or married surname, the "illegitimate" circumstances of a child's birth, an immigrant's overseas birthplace, or a family's previous or subsequent residence. They even can help you reconstitute a family group with all siblings, including those who died young and would otherwise go unnoticed. They can tell you about women and minorities, who were underrepresented in other records of the day. Finally, church records may give you a better understanding of your ancestor's religious life and community.
When you come across records that require translation, try Google Translate for a single word or phrase. The FamilySearch wiki includes several foreign-language lists of common genealogical words. In the wiki search box, enter the name of the language and word list. Published genealogical guides for various ethnic or language groups may also include important genealogical words or phrases.
Click here to download our Church Record Extraction Form as a PDF.
Records begin: generally with establishment of an individual congregation
Jurisdiction where kept: individual churches' administrative offices; denominational archives; government, university and private libraries and archives
Key details: dates and places of birth, baptism, marriage, death and burial; sometimes names of family members, migration places and dates
Search terms: name of denomination, church and/or congregation; plus the place and records, baptisms or marriages
How to find in the FamilySearch catalog: Under Search, select Catalog. Enter the place in the Places search box, then look under the Church Records category.
Associated/substitute records: records of birth, marriage, death and burial
American Baptist Historical Society
Association of Religion Data Archives Denominational Trees
Catholic Diocese and Bishop Addresses
Catholic Parishes Online
Church of Jesus Christ of Latter-day Saints Church History Library
Congregational Library
Episcopal Church Archives
Evangelical Lutheran Church Archives
FamilySearch wiki
Huguenot Society of America
Methodist General Commission on Archives & History
Presbyterian Historical Society
Quaker: Friends Historical Library
Southern Baptist Historical Library & Archives
German Church Books: Beyond the Basics by Kenneth L Smith (Picton Press)
How to Find Your Family History in US Church Records by Sunny Jane Morton (Genealogical Publishing Co.)
Our Quaker Ancestors by Ellen Thomas Berry and David Allen Berry (Genealogical Publishing Co.)
A Religious History of the American People by Sydney E Ahlstrom (Yale University Press)
Researching American Religious Records by Kyle Betit & Beverly Whitaker CG (Heritage Productions)
A Survey of American Church Records, 4th Rev Ed. by E Kay Kirkham (Everton Brothers)
Tracing Your Huguenot Ancestors by Kathy Chater (Pen and Sword)
Understanding and Using Baptismal Records by John T. Humphrey (Humphrey Publications)
US Catholic Sources: A Diocesan Research Guide by Virginia Humling (Ancestry)
1. What genealogical problems might church records particularly help solve?
a. unidentified parents
b. missing maiden names
c. finding overseas birthplaces
2. What valuable information should a letter of transfer contain?
a. parents' names
b. birthplace
c. prior residence
d. marriage date
3. Which of the following national origins and religions do not typically match?
a. English and Anglican
b. Scots-Irish and Lutheran
c. French and Catholic
d. German and Lutheran
Exercise A: Using your preferred web browser, conduct a search with the terms Evangelical Lutheran Church Records. Click on the Ancestry.com database <search.ancestry.com/search/db.aspx?dbid=60722> that comes up in the search results.
Using the browse feature, find what three congregations' records are available for Dodge City, Kan.
Using an Ancestry.com subscription or visiting a library offering Ancestry Library Edition, click on Hope Church records, then image No. 3. According to the contents list, for what years are baptismal records available?
Page forward to the baptisms (image No. 17). In a separate window, open Google Translate. Enter the first two column headers, "Name der täuflings" and "Name der eltern" in the box on the left, one at a time. Choose German for the left box and English for the right. How do these phrases translate into English?
4. Write a citation for this record.
1 d 2c. 3 b. Exercise A 1 Christ the King, Hope and Messiah 2 1908-1944 3 "Name of the person to be baptized" and "name of parents" 4 Hope Church (Dodge City, KS). "Evangelical Lutheran Church of America, Records, 1875-1940." Digital images, Ancestry.com (http://www.ancestry.com). Original data: Evangelical Lutheran Church of America, Chicago, Illinois.
Free Web Content
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Researching Methodist Ancestors
This entry was posted in Church Records, September 2016 and tagged ancestors, ancestry, church records, family history, genealogy, genealogy research, genealogy search, religious records, vital records. Bookmark the permalink.
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text:
using System;
using System.Collections.ObjectModel;
using System.Threading.Tasks;
using Famoser.MassPass.Business.Content.Models;
using Famoser.MassPass.Business.Content.Models.Base;
using Famoser.MassPass.Business.Managers;
using Famoser.MassPass.Business.Models;
using Famoser.MassPass.Business.Repositories.Interfaces;

namespace Famoser.MassPass.Business.Repositories.Mocks
{
    public class ContentRepositoryMock : IContentRepository
    {
        public ObservableCollection<GroupedCollectionModel> GetGroupedCollectionModels()
        {
            CollectionManager.AddCollectionModel(GetCollectionModel());
            CollectionManager.AddCollectionModel(GetCollectionModel());
            CollectionManager.AddCollectionModel(GetCollectionModel());
            return CollectionManager.GroupedCollectionModels;
        }

        private Random _random = new Random();
        private CollectionModel GetCollectionModel()
        {
            return new CollectionModel(Guid.Empty)
            {
                ContentModels =
                {
                    GenerateContentModel(),
                    GenerateContentModel(),
                    GenerateContentModel(),
                    GenerateContentModel(),
                    GenerateContentModel(),
                }
            };
        }

        private BaseContentModel GenerateContentModel()
        {
            switch (_random.Next(0,2))
            {
                case 0:

                    return new NoteModel(Guid.Empty)
                    {
                        Description = "A pretty long description about this note, far too long to fit on one line",
                        Name = "My first Note!"
                    };
                case 1:
                    return new CreditCardModel(Guid.Empty)
                    {
                        Description = "BLKB Credit card",
                        Name = "BLKB Master card"
                    };
                default:
                    return new LoginModel(Guid.Empty)
                    {
                        Description = "facebook",
                        Name = "Login facebook.com"
                    };
            }
        }

        public Task<bool> SyncAsync()
        {
            throw new NotImplementedException();
        }

        public Task<bool> LoadValues(BaseContentModel model)
        {
            throw new NotImplementedException();
        }

        public Task<bool> FillHistory(BaseContentModel model)
        {
            throw new NotImplementedException();
        }

        public Task<bool> Save(BaseContentModel model)
        {
            throw new NotImplementedException();
        }
    }
}

redpajama_set_name: RedPajamaGithub


text:
NBA Scouts Weigh In On 'Polarizing' Eastern Michigan Star Emoni Bates
Sixers President Daryl Morey Hints At A Relatively Quiet NBA Trade Deadline
Wout Weghorst Has Shown Signs Of Promise – But There's Plenty More To Come For Him At Manchester United
Here's How Much It Would Cost Jim Dolan To Shut Off Alcohol At Madison Square Garden
Baseball Hall Of Fame Candidates Linked To PED Use Still Suffer In Voting Results
Facundo Pellistri To Remain At Manchester United For Rest Of Season
Shift Concept Racket Showcases Wilson's New Release Strategy
Why Are Arsenal And Chelsea Interested In Brighton Midfielder Moises Caicedo?
ForbesBusinessSportsMoney
For NCAA Football And Basketball Programs, Covid-19 Challenges Are Mounting Alongside Game Cancellations
Karen Weaver
I cover the intersection of college sports and higher education
Dec 1, 2020, 11:22am EST |
ASHEVILLE, NC - NOVEMBER 30: Indiana Hoosiers bench reacts after Indiana made a three point shot ... [+] against the Providence Friars during the second half of the first round of the Camping World Maui Invitational on November 30, 2020, at the Harrah's Cherokee Center in Asheville, NC. (Photo by Brian Spurlock/Icon Sportswire via Getty Images)
Icon Sportswire via Getty Images
It's December 1. In the last three months, colleges and universities have canceled or postponed more than 200 football and basketball games. What started as a trickle of games being rescheduled to open weekends has now morphed into weeks without football and basketball teams being allowed to practice. Now, a new concern has emerged: Will there be enough referees for the season?
The domino effect of lost games has exasperated athletic directors across the country. Not only have they had to worry about the impact on media revenues for the 2020-21 year, but the extraordinary expenses to get and keep athletes on the field have exceeded $3 million per school. Ohio State revealed it has budgeted $3.5 million for "Covid-19 testing, medical personal protective equipment and other supplies for the current fiscal year." The Pac-12 will lose almost $5 million for each game canceled because of Covid-19.
Basketball is already in rough shape. The idea to replicate the NBA bubble in Orlando fell apart when the teams and ESPN could not agree on the Covid-19 minimum protocols all would follow. The cancellation impacted ten ESPN events and more than 24 teams.
SEATTLE, WA - NOVEMBER 28: An ESPN banner is seen during a PAC12 football game between the Utah Utes ... [+] and the Washington Huskies on November 28, 2020, at Husky Stadium in Seattle, WA. (Photo by Jeff Halstead/Icon Sportswire via Getty Images)
Reports are that the minimum number of games needed to qualify for March Madness is 13; as we head into the "dark winter" of the pandemic, that could be somewhat optimistic. In the Big Ten, the chancellors and presidents agreed in October to a 21-day return-to-play protocol. Three weeks is a lifetime in college basketball, and with just 13 scholarship players permitted in men's basketball, the season could quickly spiral out of control if you layer multiple positive tests over the course of a week.
Why The Rock's Social Media Muscle Made Him Hollywood's Highest-Paid Actor
T.J. Holmes And Amy Robach To Part Ways With 'GMA3' After Relationship Investigation—Here's How They Got Here
LVMH's Patou Showed Fall '23 In Paris' La Samaritaine & The Chicest Of Grocery Carts
College athletic directors and conference commissioners should pay close attention to the Children's Hospital of Philadelphia's Covid-19 website, as nationally one in five Covid-19 tests was positive (19.2%). Considering how often college athletes are tested at the Power 5 level, the odds are strong that basketball teams could be left undermanned frequently throughout the season.
Another variable to playing games are the game officials. According to Athlete Veritas, the NCAA's Core Principles of Resocialization of College Basketball Committee just released extensive competition guidelines for college officials and referees to comply with, including:
Game officials are considered part of the Tier One grouping for testing and tracing. This means they are tested a minimum of three times per week, and schools and conferences are expected to bear the costs for these tests. Schools should have a plan in place to accommodate an official testing positive, such as having a replacement official ready.
Host institutions are urged to have alternative travel plans in place for officials in case of changing state by state (or county by county) guidelines. Officials should avoid rideshares and be mindful of wearing a mask and social distancing throughout their entire trip.
Before arriving on site, the NCAA schools are asked to discuss hosting pregame conferences virtually or at a location other than the locker room to manage social distancing. Watching games over the holiday weekend, venues have inserted lots of plexiglass, and spaced-out seating for table officials and team benches.
The NCAA has urged consideration for the creation of a "national dashboard" of basketball officials who are in compliance with Covid-19 protocols (or, in non-compliance). Officials would have to agree to join the database, and could then receive a daily health-related questionnaire. Assigners are "strongly advised" to have stand-by officiating crews for each game in case an entire crew of officials are sidelined the day of a game.
Finally, officials have been advised not to intervene physically if players become "entangled" or are fighting.
Pulling off a college basketball season will be enormously challenging. At this rate, college basketball will be lucky to break even with revenues and expenses. What happens to the rest of the department if the season operates at a deficit?
It's gonna be a long winter. And it's gonna be an even longer season.
Follow me on Twitter or LinkedIn. Check out my website or some of my other work here.


text:
3a9586b9-faeb-4e5f-9f37-2d9b34c2b273
Private schools to go back to the classroom
Sarah Lagan
Private schools, including Mount Saint Agnes Academy, are welcoming their students back physically, in time for their scheduled winter term start dates (Photograph Supplied)
Private school pupils will go back to their classrooms for the start of the new term, it was announced yesterday.
But public schoolchildren will be learning at home from today until at least January 12.
Pupils at Mount Saint Agnes Academy were back at their desks yesterday and Bermuda High School and Saltus Grammar School pupils will return today.
Warwick Academy and Somersfield Academy youngsters are scheduled to return to the classroom on January 11.
Kendaree Burgess, the chief executive of the Bermuda Chamber of Commerce, said the organisation had not received any complaints about the public schools shutdown from its members, but she understood that people might be frustrated.
She added: "From a business perspective, it is tricky managing staff who may be required to stay home.
"I would advise them to have a back up plan for that eventuality where possible."
The education ministry said earlier that the Education Emergency Measures Committee would meet this week to decide what would happen after January 12.
A spokeswoman said at the time: "The Department of Education has received feedback from parents and guardians of young children who may not have adequate childcare arrangements and cannot work from home during remote learning.
"Health Department guidelines and constraints now preclude the Department of Education from offering any programmes for children during this time.
"As a first resort, affected parents and guardians are urged to reach out to their family support network for assistance.
"The department is engaged in conversations with employer groups and are pleased that they too empathise with the plight of affected parents and guardians and are willing to be supportive within the confines of existing employment legislation and collective bargaining agreements.
"We urge affected parents to also approach their employers and discuss their specific challenges.
"Likewise, we would urge all employers to consider all options that would meet the needs of their employees at such a challenging time."
Berkeley students learn about the hijab
Minister praises trainee programme graduates
Envoy: increased data collection will ease Canada student visas
Shiver me timbers! Locals to take the plunge for charity
Published January 05, 2021 at 8:00 am (Updated January 04, 2021 at 8:28 pm)


text:
"""
    SALTS XBMC Addon
    Copyright (C) 2014 tknorris

    This program is free software: you can redistribute it and/or modify
    it under the terms of the GNU General Public License as published by
    the Free Software Foundation, either version 3 of the License, or
    (at your option) any later version.

    This program is distributed in the hope that it will be useful,
    but WITHOUT ANY WARRANTY; without even the implied warranty of
    MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
    GNU General Public License for more details.

    You should have received a copy of the GNU General Public License
    along with this program.  If not, see <http://www.gnu.org/licenses/>.
"""
import urlparse
import kodi
import dom_parser2
from salts_lib import scraper_utils
from salts_lib.constants import FORCE_NO_MATCH
from salts_lib.constants import QUALITIES
from salts_lib.constants import VIDEO_TYPES
import scraper

BASE_URL = 'http://watchmovies-online.is'

class Scraper(scraper.Scraper):
    base_url = BASE_URL

    def __init__(self, timeout=scraper.DEFAULT_TIMEOUT):
        self.timeout = timeout
        self.base_url = kodi.get_setting('%s-base_url' % (self.get_name()))

    @classmethod
    def provides(cls):
        return frozenset([VIDEO_TYPES.MOVIE])

    @classmethod
    def get_name(cls):
        return 'wmo.ch'

    def get_sources(self, video):
        hosters = []
        source_url = self.get_url(video)
        if not source_url or source_url == FORCE_NO_MATCH: return hosters
        url = scraper_utils.urljoin(self.base_url, source_url)
        html = self._http_get(url, cache_limit=.5)
        for _attrs, td in dom_parser2.parse_dom(html, 'td', {'class': 'tdhost'}):
            match = dom_parser2.parse_dom(td, 'a', req='href')
            if match:
                stream_url = match[0].attrs['href']
                host = urlparse.urlparse(stream_url).hostname
                quality = scraper_utils.get_quality(video, host, QUALITIES.HIGH)
                hoster = {'multi-part': False, 'host': host, 'class': self, 'url': stream_url, 'quality': quality, 'views': None, 'rating': None, 'direct': False}
                hosters.append(hoster)
        return hosters

    def search(self, video_type, title, year, season=''):  # @UnusedVariable
        results = []
        html = self._http_get(self.base_url, params={'s': title, 'search': ''}, cache_limit=8)
        for _attrs, item in dom_parser2.parse_dom(html, 'div', {'class': 'movie_poster'}):
            match = dom_parser2.parse_dom(item, 'a', req=['href', 'title'])
            if match:
                attrs = match[0].attrs
                match_title, match_year = scraper_utils.extra_year(attrs['title'])
                if not year or not match_year or year == match_year:
                    result = {'url': scraper_utils.pathify_url(attrs['href']), 'title': scraper_utils.cleanse_title(match_title), 'year': match_year}
                    results.append(result)

        return results