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The side population (SP) of cancer cells is reportedly enriched with cancer stem cells (CSCs), however, the functional role and clinical relevance of CSC marker molecules upregulated in the SP of head and neck squamous carcinoma (HNSCC) cells are yet to be elucidated. Patients with clinical stage I/II (T1-2N0M0) tongue squamous cell carcinoma (TSCC) typically undergo partial glossectomy; however, development of delayed neck metastasis (DNM) tends to reduce their survival. In the present study, we aimed to determine the CSC markers in the SP of HNSCC cells along with their functions in cellular behaviors, and to clarify the association of these markers with DNM.
Flow cytometry was applied to isolate SP from main population (MP) in HNSCC cells. The expression of the CSC markers was examined by semi-quantitative RT-PCR and immunocytochemistry. In vitro proliferation, migration, and invasion assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Oct3/4 and Nanog were evaluated using surgical specimens from 50 patients with stage I/II TSCC.
SPs were isolated in all three cell lines examined. Expression levels of Oct3/4 and Nanog were higher in SP cells than MP cells. Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation. Univariate analysis showed that expression of Oct3/4 and Nanog, vascular and muscular invasion, and mode of invasion were significantly correlated with DNM. Multivariate logistic regression revealed that Oct3/4 expression (risk ratio = 14.78, p = 0.002) and vascular invasion (risk ratio = 12.93, p = 0.017) were independently predictive of DNM. Regarding the diagnostic performance, Oct3/4 showed the highest accuracy, sensitivity, and NPV of 82.0 %, 61.5 %, and 86.8 %, respectively, while vascular invasion showed the highest specificity and PPV of 94.6 % and 71.4 %, respectively.
These results suggest that Oct3/4 and Nanog represent probable CSC markers in HNSCC, which contribute to the development of DNM in part by enhancing cell motility and invasiveness. Moreover, along with vascular invasion, expression of Oct3/4 can be considered a potential predictor for selecting patients at high risk of developing DNM.
Recent studies have provided evidence to support the existence of 'cancer stem cells' (CSCs), a small subpopulation of cancer cells that possess stem cell-like capabilities for self-renewal and differentiation into multiple mature progeny, which leads to cellular heterogeneity [1–5]. Currently, CSCs are thought to contribute not only to tumor initiation and maintenance but also aggressive tumor behaviors such as chemoresistance, anti-apoptosis, and metastasis; thus, they may be responsible for tumor persistence and recurrence after treatment [1–3, 6–9]. To identify CSCs and corroborate the CSC hypothesis, stem cell-associated molecules have been employed as putative CSC markers; however, these cell surface markers cannot discriminate a pure CSC population. In a number of human malignancies, subpopulations that possess CSC-like properties have been isolated from fresh tumor tissues and permanent cell lines by cell-sorting using the putative CSC-specific markers currently available for this purpose, e.g., CD34, CD44, CD133, ALDH1, EpCAM, and CD271 [1, 7, 8, 10–15]. Since no CSC sorting marker is universal to all types of cancer, it is assumed that they are tumor type-specific depending on the 'niche', i.e., the microenvironment of each type of CSC . In head and neck squamous cell carcinoma (HNSCC), however, CSC-enriched populations have been isolated using CD24, CD44, CD133, ALDH1, or CD271 as sorting markers [17–25], suggesting that a single common CSC sorting marker may not exist even within identical types of tumor.
Side population (SP) of cancer cells, defined by their elevated capability to efflux the vital DNA-binding dye Hoechst 33342, has been shown to possess stem cell-like characteristics [26–28]. Enhanced multidrug resistance of SP cells is attributed to their overexpression of the various adenosine triphosphate (ATP)-binding cassette (ABC) transporter family members including ABCG2 (BCRP-1) [29–31]. SP cells in which other stemness-related genes are upregulated have also been identified in cell lines of various human cancers including HNSCC, one of which was our previous observation [32–41]. Hence, the SP phenotype has been suggested as a potentially universal CSC sorting marker, although it also has the limitation on accuracy for sorting pure CSC-like populations. Once the stemness-related molecules that are specifically upregulated in these populations are determined as true CSC-specific markers, assessing the expression of those biomarkers in primary tumor biopsies can provide valuable individual information on tumor pathobiology. As regards the difference in cellular behaviors between the SP and non-SP (i.e., main population: MP) cells, however, somewhat conflicting results have been shown so far. For instance, concerning the clonogenic ability: several studies reported that the SP cells possess higher clonogenicity than the MP cells [35–38], whereas others including our previous study found no such a difference between them [32, 33, 41], indicating certain difficulty in interpretation of the SP phenotype. Thus, the functional role of CSC-specific markers identified in SP of HNSCC cells, as well as their clinical significance in cancer progression, should be further investigated.
Neck lymph node metastasis has long been the most critical prognostic factor in patients with HNSCCs including oral squamous cell carcinoma (OSCC) [42–44]. Patients with clinical stage I and II (i.e., cT1-2N0M0) oral tongue squamous cell carcinoma (TSCC) usually undergo partial glossectomy alone as a primary treatment, followed by strict observation as a 'careful watching' policy. However, delayed neck metastasis (DNM) eventually develops in 14 to 48 % of these patients [45–49], which is apt to be accompanied by detrimental features such as extracapsular spread and multiple site involvement. As a result, patients who develop DNM tend towards worse survival rates than those who do not [46–48, 50]. Notwithstanding the importance of earlier detection of occult lymph node metastasis that inevitably results in DNM in the clinically N0 (cN0) neck, no diagnostic imaging techniques are currently capable of accurately identifying micrometastases. Although ultrasound, CT, MRI, and PET-CT are employed as standard modalities, the positive predictive value remains at 69–77 % and the false negative rate is as high as 25–32 % [51, 52]. Therefore, identification of a dependable predictor of DNM, along with the molecular mechanisms leading to DNM, is imperative.
Several previous studies have explored the clinicopathological parameters and molecular biomarkers that are predictive of DNM in stage I/II OSCC including TSCC, but the results determined by multivariate analysis are rather limited. Reliable studies in which logistic regression analysis was used showed that tumor thickness or depth is independently correlated with DNM [45, 48]; however, there is currently no consensus on the ideal method for measuring tumor thickness or depth, and an optimal cutoff value has yet to be determined for either measurement . Other studies where multivariate analysis was employed (including our previous report) revealed expressions of certain molecules in the primary tumor as independent predictors of DNM, including downregulation of E-cadherin and upregulation of SIP1 (ZEB2), Cyclin D1 (CCND1), and S100A2 [53–57]. However, the most reliable predictive molecular marker for DNM has yet to be agreed upon. In addition, whether the potential CSC-specific marker molecules are implicated in the development of DNM in OSCC has not been examined.
We conducted the present study to determine the potential CSC-specific marker molecules upregulated in SP cells of HNSCC, and to clarify the phenotypic characteristics in the behavior of SP cells. We also aimed to elucidate whether the expression of putative CSC-specific markers, as well as standard clinicopathological parameters, is predictive of DNM in stage I/II TSCC.
We used three cell lines established from human HNSCC (tongue SCCs): SCC4, SAS, and HSC4 from JCRB Cell Bank (Osaka, Japan). The cells were grown in a mixture of Dulbecco's modified Eagle's medium and Ham's F-12 (SCC4), or RPMI1640 (SAS and HSC4), supplemented with 10 % fetal bovine serum (FBS), 1 % Antibiotic-Antimycotic mixture stock solution (100X) (Nakarai Tesque, Kyoto, Japan) in a humidified incubator (37 °C, 5 % CO2).
To identify and isolate SP from MP, a single-cell suspension was incubated (106 cells/mL) in each growth medium containing 2 % FBS with Hoechst 33342 dye (Sigma-Aldrich) at 6 μg/mL for SCC4, 2 μg/mL for SAS, and 3 μg/mL for HSC4, at 37 °C for 60 min with intermittent mixing. The control cells were incubated in the presence of 20 μg/mL of reserpine (Daiichi-Sankyo, Tokyo, Japan), which is an inhibitor of the transporters responsible for exclusion of Hoechst 33342 dye. Following incubation, cells were washed and suspended in Hanks' Balanced Salt Solution (HBSS; Invitrogen) containing 2 % FBS. Propidium iodide (BD Biosciences) was added at 1 μg/mL to discriminate dead cells. Cell sorting was performed using the Epics XL-MCL™ Flow Cytometer (Beckman Coulter). The SPs were analyzed by their characteristic fluorescent profiles in dual-wavelength analysis, in which the Hoechst 33342 dye was excited with a UV laser at 350 nm, and fluorescence emission was measured using 450 DF10 (450/20 nm band-pass filter) and 675LP (675 nm long-pass edge filter) optical filters. The experiments for each cell line were performed at least three times independently. SP and MP cells were collected separately for further experiments.
Total RNA was isolated from the sorted SP and MP cells using an RNeasy Mini Kit (Qiagen). Reverse transcription was performed with SuperScript II Reverse Transcriptase (Invitrogen) and random primers (Takara Bio, Japan) according to the manufacturer's instructions. The following primers for potential CSC-specific markers were used: Oct3/4, Nanog , Sox2 , Bmi-1 , Notch-1, ABCG2, and GAPDH . The PCR products were visualized under UV-light and quantified by densitometric analysis using ImageJ (NIH, USA). The relative expression levels of the genes were compared after normalization using those of GAPDH as an endogenous control.
The sorted cells were attached to glass coverslips, washed extensively with phosphate-buffered saline (PBS), and then fixed with 4 % (w/v) paraformaldehyde (PFA) in PBS for 10 min at room temperature. After washing with PBS, the cells were permeabilized with 0.1 % Triton X-100 in PBS for 10 min at room temperature. Following another wash with PBS and blocking with 10 % (v/v) normal donkey serum in PBS for 1 h, the cells were incubated overnight at 4 °C with primary antibodies against Oct3/4 (1:200, R&D Systems) and Nanog (1:200, R&D Systems). Subsequently, the cells were washed extensively with PBS and then incubated with the secondary antibody conjugated to Alexa Fluor 568 (Molecular Probes) for 40 min at room temperature. The nuclei were visualized by staining with DAPI (Sigma-Aldrich). Cells incubated with fluorescein-conjugated secondary antibody in the absence of primary antibodies were used as negative controls. Fluorescent images of the cells were captured using a fluorescence microscope (DM 2500; Leica, USA).
To eliminate the non-specific effects of Hoechst 33342 dye on MP cells, both SP and MP cells were first cultured for 24 h after sorting to remove dead cells, and then the following in vitro experiments were conducted. Cell proliferation rates were assayed using the Cell Counting Kit-8 (Dojindo Laboratories, Japan) according to the manufacturer's instructions. Briefly, the sorted cells were plated at 500 cells per well in 96-well plates and cultured, and the assay was performed after 24, 48, and 72 h. The water-soluble tetrazolium salt WST-8 (10 μL) was added to each well and the plate was incubated for 2 h at 37 °C. Viable cells were quantified by measuring the absorbance at 450 nm using a microplate reader. The experiment was conducted three times, and run in triplicate each time.
To evaluate the migratory capacity of the cells, 24-well Transwell inserts (polycarbonate filters) with 8-μm pores (BD Biosciences) were used. To assess the invasiveness of the cells, Matrigel (50 μg/mL)-coated (50 μL/insert) 24-well Transwell inserts (BD Biosciences) were used. The sorted cells suspended in serum-free medium were plated onto the Transwell inserts at 2.5 × 104 cells per well. Medium containing 10 % FBS was added to the bottom of wells as a chemoattractant. The inserts for the migration and invasion assays were incubated for 24 h and 48 h, respectively, at 37 °C. The filters were removed, and then cells on the lower surface of the filters were fixed and stained with a Diff-Quick kit (Sysmex Corp., Japan) according to the manufacturer's instructions. The migratory and invasive capacities of the cells were quantified as total cell numbers counted in ten random fields for each insert under a light microscope at 200× magnification. Both assays were performed three times, and conducted in triplicate each time.
We reviewed the medical records of patients with stage I/II (T1–2N0M0) TSCC who underwent only partial glossectomy without preventive neck dissection or irradiation at the Department of Otorhinolaryngology–Head and Neck Surgery, Keio University Hospital (Tokyo, Japan), from 1996 to 2010. Patients who had been followed up for at least 3 years were considered as qualified for inclusion in the study. Patients who had multiple primary cancers in the head and neck region, who had undergone any preoperative or postoperative treatment, or who had developed a recurrence at the primary site were excluded. The study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients, and the experimental protocol and use of the clinical materials in the study were approved by the Institutional Ethics Review Board of the ethics committee of Keio University School of Medicine. Formalin-fixed and paraffin-embedded (FFPE) surgical specimens were obtained from the 50 patients eligible for the study. After the initial surgery, 13 patients (26 %) developed DNM within a year postoperatively, whereas 37 patients (74 %) showed no sign of metastasis.
The FFPE specimens of TSCC were sliced into 4-μm thick serial sections. Two pathologists who were blinded from the clinical information reviewed all slides from each patient stained with hematoxylin and eosin to assess histopathological characteristics such as differentiation (histological grade), vascular invasion, lymphatic invasion, perineural invasion, and muscular invasion. The depth of invasion was measured from the surface of the normal mucosa to the deepest border or edge of the tumor. The mode of invasion at the tumor-host border was also evaluated according to the modified classification criteria that consist of four categories: grade 1: well defined, pushing borderline; grade 2: less-marked borderline, with tumor infiltration in solid cords, bands, or strands; grade 3: no distinct borderline, margin containing small groups of infiltrating tumor cells; and grade 4: diffuse invasion of cordlike or diffuse tumor type [53–55]. Additionally, the shape of the tumor nest was assessed using the criteria applied to esophageal squamous cell carcinoma .
For each case, specimens serially sliced to a 4-μm thickness at the central or maximum cross section were selected. After deparaffinization and rehydration, the tissue sections were processed with antigen retrieval by boiling the slides in sodium citrate buffer (10 mmol/L, pH 6.0) for 10 min, followed by immersion in 0.3 % H2O2 in methanol for 10 min to quench endogenous peroxidase activity. Non-specific immunoglobulin-binding sites were then blocked with normal serum (Vectastain Elite ABC kit; Vector Laboratories) for 30 min. The sections were incubated with each of the following primary antibodies overnight at 4 °C: rabbit anti-Oct3/4 (1:50; Bioworld) or mouse anti-Nanog (1:10; Abnova). After washing with PBS, the sections were incubated with biotinylated anti-rabbit or mouse secondary antibody for 30 min, which was followed by washing and incubation with avidin-biotin complexes (Vector Laboratories) for 1 h. After a further PBS wash, peroxidase activity was visualized with a 3,3'-diaminobenzidine tetrahydrochloride plus H2O2 substrate solution (Vector Laboratories) and counterstained with hematoxylin. The sections were mounted with cover glass and evaluated under a microscope. Immunostaining was defined as positive if nuclear staining was distinctly observed in more than 3 % of the tumor cells.
The data repeatedly obtained in the in vitro assays are presented as mean ± standard deviation. Correlations between DNM and clinicopathological factors or immunohistochemical expression of the marker molecules (Oct3/4 and Nanog) were evaluated by using Fisher's exact test. The independent significance of significant variables from univariate analysis was further assessed with multivariate analysis in which a multiple logistic regression model with the stepwise selection method was applied. P values less than 0.05 were considered statistically significant. Accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and odds ratio of each probable risk factor in prediction of DNM were calculated using two by two contingency tables. All statistical analyses were conducted using SPSS Version 18.0.
We first examined the presence of SP in three HNSCC cell lines (SCC4, SAS, and HSC4) using Hoechst 33342 dye and flow cytometry that generates Hoechst blue-red fluorescent profiles. The SP gate was defined as the region with diminished Hoechst 33342 accumulation, which could be prevented by reserpine, an inhibitor of Hoechst 33342 transporter activity. As shown in Fig. 1a–c, the presence of SPs was confirmed in the SCC4 cells (10.2 %), the SAS cells (1.3 %), and the HSC4 cells (0.9 %), and was distinguished as a distinct tail from the MP on scatter plot graphs. In each cell line, the SP was obviously abolished in the presence of reserpine, indicating that each population was truly an SP (Fig. 1d–f).
We also investigated whether the SP cells preferentially express certain stem cell specific marker molecules. Using semi-quantitative RT-PCR analysis, we found that, in the SCC4 cells, mRNA expression levels of Oct3/4, Nanog, and ABCG2 genes in the SP cells were considerably higher than those in the MP cells, with 4.2-, 9.2-, and 2.5-fold increases observed respectively, whereas expression levels of Sox2, Notch1, and Bmi-1 genes were only moderately higher in the SP cells compared with the MP cells (<2.0-fold increase) (Fig. 2a and b). In the SAS cells, Oct3/4, Nanog, and ABCG2 genes in the SP cells showed moderately higher expression than those in the MP cells (1.5–2.0-fold increase), whereas no difference was observed between SP and MP cells in their expression of Sox2, Notch1, and Bmi-1 genes (Fig. 2a and b).
The expression of Oct3/4 and Nanog proteins in the SCC4 and SAS cells was evaluated by using immunofluorescent staining, as shown in Fig. 2c and d. In agreement with the results of semi-quantitative RT-PCR analysis, intranuclear staining for Oct3/4 and Nanog in the SP cells was enhanced markedly in the SCC4 cells and moderately in the SAS cells, whereas staining in the MP cells was negative for both cell lines.
To examine the difference in the growth activity between the SP and MP cells, we performed an in vitro cell proliferation assay on the SCC4 cells that exhibited the highest percentage of SP cells. OD values of absorbance were measured at 450 nm. The data of the SP and MP cells were separately presented as follows: the data on day 1 were defined as 1.0, and those on day 2 and 3 were defined as the fold increase in the respective OD values as compared to those measured on day 1. As shown in Fig. 3a, there was no significant difference in the proliferation activity between the SP and MP cells up to 72 h after sorting.
To evaluate any differences in the migratory and invasive capacities of SP and MP cells, we performed an in vitro migration assay and Matrigel invasion assay using the SCC4 cells. The numbers of migrated or invaded cells were determined, and the data were presented as the fold difference between the SP and MP cells. As shown in Fig. 3b and c, both migratory and invasion capacities of SP cells were higher than those of MP cells, with >1.7-fold increases being observed.
Of the 50 cases examined, positive immunohistochemical staining of Oct3/4 was shown in 12 cases (24.0 %) and Nanog in 10 cases (20.0 %). Fig. 4a and b displays representative cases with positive immunostaining of each of the marker molecules, which were sporadically observed in cancer cell nuclei. Immunopositive cells of either marker tended to be localized at the inside portion of the tumor cell clusters rather than at the border of clusters or the invasive front region.
The association between protein expression of Oct3/4 and Nanog was assessed by Fisher's exact test. As shown in Table 1, the expression of these two marker molecules was significantly correlated (p = 0.007).
To determine the predictive risk factors of DNM, the association between clinicopathological factors and DNM was examined in the 50 cases of stage I/II TSCC. As summarized in Table 2, univariate analysis revealed that mode of invasion for grades 3/4 (p = 0.036), vascular invasion (p = 0.009), and muscular invasion (p = 0.010) were significantly correlated with DNM. T classification tended to be associated with DNM, although this relationship was not statistically significant (p = 0.055). All other factors, such as age, differentiation, depth of invasion, nest shape, lymphatic invasion, and perineural invasion, were not correlated with DNM in this cohort.
The relationship between each immunohistochemical marker and DNM is also summarized in Table 2. The expression of both Oct3/4 (p = 0.001) and Nanog (p = 0.001) was significantly correlated with DNM.
A multiple logistic regression model was applied to further analyze the variables that were significantly correlated with DNM in the aforementioned univariate analyses. As shown in Table 3, positive expression of Oct3/4 (odds ratio = 14.781, p = 0.002) and vascular invasion (odds ratio = 12.934, p = 0.017) were found to be the independent risk factors affecting DNM in this series.
To evaluate the diagnostic performance of the probable risk factors (Oct3/4, Nanog, and vascular invasion) in prediction of DNM, accuracy, sensitivity, specificity, PPV, NPV, and odds ratio of each factor were calculated and presented in Table 4. Among the three factors evaluated, Oct3/4 showed the highest sensitivity of 61.5 % and the highest NPV of 86.8 %, while vascular invasion showed the highest specificity of 94.6 % and the highest PPV of 71.4 %. Oct3/4 and Nanog had the equal accuracy of 82.0 %.
The clinical role of CSC-specific molecular markers is not only the detection and isolation of the CSC-like population but also the prediction of aggressive tumor behavior, which is achieved by evaluating the density and/or spatial distribution of the CSCs. Additionally, they serve as ideal targets for the development of new therapeutic agents. Therefore, the identification of a more selective CSC-specific marker that defines the stem cell phenotype alone is desirable so that the clinical relevance of the marker's expression in each type of cancer can be assessed. In the present study, we successfully identified and isolated SP cells in all three HNSCC cell lines examined at proportions of 0.9 % to 10.2 %. This result is comparable with previous studies that examined other HNSCC cells, in which the proportion of the SP ranged from 0.02 % to 17.1 % [37-40]. Moreover, we found that the SP cells expressed notably higher levels of Oct3/4, Nanog, and ABCG2 than the MP cells, which is partially consistent with the findings of the aforementioned studies, especially with regard to Oct3/4  and ABCG2 [37, 38, 40]. In a previous study that examined the HSC-4 cells, we found comparable results concerning Oct3/4 and Nanog, but not ABCG2, with much lower proportion of the SP (0.37 %) than that shown in the present study (0.9 %) . In addition, although increased expression of Bmi-1 in the SP of HNSCC cells was also previously reported [37, 40], this was not observed in our cells. Such inconsistencies as mentioned above are thought to be attributable not only to differences in the baseline expression levels of genes among the examined cell lines but also to differences in the conditions of SP analysis, including factors such as Hoechst concentration, incubation time, a type of cell sorting machine, and the stringency of SP selection .
Both Oct3/4 (also termed as Oct3, Oct4, or POU5F1) and Nanog are known to play an essential role in the maintenance of self-renewal and pluripotency at an undifferentiated state, i.e., the fundamental features that define embryonic stem (ES) cells [63, 64]. In simple terms, Oct3/4 collaborates with Sox2 and Nanog to form a regulatory circuit that maintains ES cell pluripotency . Interestingly, Oct3/4 and Nanog are reportedly two of the four defined factors that give rise to the reprogramming of human somatic cells into germ-line-competent induced pluripotent stem (iPS) cells [65, 66]. In comparative analyses using a naive Bayes network methodology focused on self-renewal of both human and murine ES cells, Oct3/4 was ranked top among 17,342 genes evaluated in both networks and Nanog was ranked within the top 1 % in each network .
Oct3/4, which is a member of the Pit-Oct-Unc domain transcription factors family, is normally expressed in both adult and embryonic stem cells [68, 69]. Genomic profiling studies revealed that Oct3/4 regulates the transcription of a large number of its downstream target genes, either positively or negatively, to sustain the stemness of ES cells [70, 71]. Intriguingly, Oct3/4-mediated gene regulation in ES cells is unique because Oct3/4 expression levels must remain within an appropriate narrow range to maintain the undifferentiated state, and either up- or downregulation of Oct3/4 to levels outside this range triggers the differentiation of ES cells . Of the specific pathways downstream of Oct3/4, Tcl1 (T cell leukemia/lymphoma 1, a product of proto-oncogene) was found to be regulated transcriptionally by Oct3/4, and it is involved in the control of ES cell proliferation (but not differentiation) via enhancement of the kinase activity of Akt1 . Furthermore, Oct3/4 is reportedly essential for the survival and anti-apoptosis activity of murine ES cells in response to stress, with effects being mediated through the STAT3/survivin pathway . In addition, the potential functions of Oct3/4 expressed in malignant tumors have also been investigated. For example, the oncogenic potential of ES cells was shown to be directed by Oct3/4 in a dose-dependent manner; higher Oct3/4 expression increases the malignant potential of ES cell-derived tumors, whereas Oct3/4 inactivation induces regression of the malignant component . Moreover, Oct3/4 was revealed to maintain the survival of CSC-like cells of Lewis lung carcinoma 3LL cells and breast cancer MCF7 cells, partly by inhibiting apoptosis through the Oct4/Tcl1/Akt1 pathway . In hepatocellular carcinoma cells, Oct3/4 was shown to upregulate BIRC5 (survivin) and CCND1 expression by increasing their promoter activity, thereby promoting cell proliferation and resisting cell apoptosis . These findings suggest that expression of Oct3/4 contributes to the transformation of non-tumorigenic cells as well as the maintenance of the CSC-like and malignant properties of cancer cells.
Nanog, the variant homeobox transcriptional factor, was identified as one of the primary downstream targets of Oct3/4 by a functional cDNA screen in ES cells [76, 77]. Although Oct3/4 cannot maintain the undifferentiated state of ES cells without leukemia inhibitory factor (LIF) , overexpression of Nanog allows ES cells to remain undifferentiated and to self-renew independently of LIF/STAT3 signaling [77, 78]. Interestingly, while Oct3/4 is obviously required for Nanog to function, expression of Nanog itself can be sustained in the absence of Oct3/4 [76, 78]. Taken together, the aforementioned studies imply that the functions of Oct3/4 and/or Nanog aberrantly expressed in CSCs of human cancer may be implicated in the malignant behavior of cancer cells, including tumorigenicity and metastasis. However, the functional and clinical significance of these molecules in human cancers, including HNSCC, have remained largely unknown.
In our in vitro experiments, we found that proliferation rates were similar between SP and MP cells. This is in agreement with previous studies including those that examined HNSCC cells, where SP cells expressed higher levels of Oct3/4 and/or Bmi-1 than MP cells, while no difference was shown in proliferation rate between them [37, 38]. These results indicate that Oct3/4 and Nanog, which were expressed at markedly higher levels in SP cells than MP cells, have a negligible contribution to the proliferation of the individual HNSCC cells examined here. In contrast, we confirmed that SP cells were more capable of migration and invasion than MP cells. This result is similar to that of a previous study in which SP cells were shown to be more invasive than both non-SP cells and parental HNSCC cells; however, these SP cells expressed higher levels of Bmi-1, and Oct3/4 and Nanog expression were not examined . Other than in SP cells, increased migration and/or invasion capacities have also been observed in oral cancer stem-like cell populations enriched through sphere formation in serum-free cultivation, which showed high expression of Oct3/4, Nanog, and ABCG2 , as well as in CD44+ cell populations of HNSCC cells isolated by cell sorting . Therefore, in combination with previous studies, our findings suggest that certain CSC marker molecules including Oct3/4 and Nanog may contribute to the enhanced cell motility and invasiveness of HNSCC cells.
In the clinical specimens examined here, a significant positive correlation was found between Oct3/4 and Nanog in terms of their immunopositivity. This finding substantiates the notion that Oct3/4 transcriptionally regulates the expression of Nanog, and that the two collaborate to maintain stemness properties in ES cells [63, 71, 76, 77]. Although the percentage of Oct3/4- or Nanog-positive cells was no more than 10 % at the most, such a small population of potential CSC-specific marker-positive cells appears to match the basic concept of CSC.
More importantly, multivariate analysis of clinicopathological and immunohistochemical data demonstrated, for the first time, that expression of Oct3/4, as well as vascular invasion, are independently correlated with DNM in stage I/II TSCC following partial glossectomy. Hence, both Oct3/4 and vascular invasion can be considered dependable markers for prediction of DNM development, which was further supported by the favorable diagnostic performance as shown in Table 4, although their reliability requires further validation based on larger independent cohorts. Although, in our cohort, Nanog was excluded from the independent predictors of DNM at the final step of the logistic regression analysis, this seems rather reasonable because the significant correlation found in expression between Oct3/4 and Nanog inevitably means these two factors are confounding factors of each other. Therefore, we suggest that Nanog could be an alternative independent predictor of DNM where Oct3/4 cannot be evaluated. Taken together, these results imply that certain stemness properties of CSCs that exist in primary cancer cells are closely involved with the development of DNM. Regarding the association between DNM and vascular invasion, our result lends support to a significant correlation in a previous study, which was identical except that a smaller sample size was analyzed .
Apart from the association with DNM, our results regarding the clinical significance of Oct3/4 and Nanog expression are seemingly inconsistent with a previous study of OSCC, in which increased expressions of Oct3/4 and Nanog were correlated with advanced stage and worse overall survival, but not with lymph node metastasis at the time of diagnosis . However, such inconsistency could be attributable to the unequal distribution of the stage of the patients and/or to differences in the protocols for immunohistochemistry and criteria for positive staining. As a comprehensive molecular approach, gene expression profiling based on cDNA microarray is reportedly advantageous for discriminating between N0 and N+ patients, with clustering analysis of at least 100 to >1,500 metastasis-associated genes being employed [80, 81]. However, because these profiling strategies are technically complex and not currently cost-effective, they have not necessarily been incorporated into routine diagnosis.
Based on the results of our in vitro experiments, and those of previous studies, the existence of Oct3/4- and Nanog-expressing CSCs in cancer cells in primary lesions is presumed to contribute to development of DNM, at least in part, by enhancing the cell motility and invasiveness of these CSCs. Specifically, given the assumption that cancer cells have already migrated and invaded from the primary lesion into nearby lymphatic vessels, even in the early stage before complete resection of the primary tumor, we can speculate that the vast majority of these cells, which lack the stemness properties associated with Oct3/4 and Nanog expression (i.e., non-CSCs), cannot survive and establish lymph node metastasis, in part due to insufficient cell motility and invasiveness. In contrast, we can postulate that certain cells expressing Oct3/4 and Nanog (i.e., CSCs) can form metastatic lesions because of their enhanced migration and invasion abilities as well as their other stemness properties. However, further studies will be necessary to clarify the actual difference in behavior between the CSCs and non-CSCs during the processes required for metastasis in human cancer.
One of the crucial mechanisms that regulate cell motility is epithelial-to-mesenchymal transition (EMT), a morphogenetic change in epithelial cells associated with various phenotypic modulations, which include loss of epithelial features such as cell polarity and cell-to-cell contact, and acquisition of mesenchymal traits such as cell motility [82–84]. EMT and its reverse process, mesenchymal-to-epithelial transition (MET), are considered to be involved in embryonic development and a variety of pathological events such as wound healing, tissue fibrosis, and cancer progression including metastasis [82–84]. Recent studies have implicated EMT in the emergence of CSCs; for example, induction of EMT resulted in acquisition of stemness properties in immortalized mammary epithelial cells and, inversely, stem-like cells isolated from both mammary glands and carcinomas expressed a number of EMT markers . These findings support the concept of "migrating CSCs" that are assumed to be derived from "stationary CSCs" by undergoing transient EMT and are responsible for metastasis . Such an EMT-induced stem cell-like phenotype was presumed to be acquired through developmentally regulated signaling pathways that induce EMT, such as Wnt, Notch1, and Hedgehog, which also drive the stemness properties of both normal cells and CSCs . Intriguingly, a recent study showed that co-overexpression of Oct4 and Nanog in lung adenocarcinoma cells increased CSC-like properties and induced EMT by upregulating Slug and Snail expression, and thereby promoted tumorigenesis, drug resistance, and metastasis . Collectively, our results and those of previous studies suggest that enhancement of the CSC's stemness properties by Oct3/4 and Nanog expression may also contribute to cancer progression, including the development of DNM, together with the elevated cell motility associated with EMT. Additional studies are required to fully understand the mechanism by which Oct3/4 and Nanog regulate the malignant behaviors of CSCs, as well as to establish the optimal criteria for estimating the latent malignant potential of cancer at the early stage using CSC-related molecular markers.
In conclusion, the present study demonstrated that Oct3/4 and Nanog were markedly expressed in SP cells that had superior migration and invasion capabilities compared with MP cells. This suggests that these molecules represent probable CSC markers in HNSCC, and that they contribute to DNM in stage I/II TSCC at least in part by enhancing cell motility and invasiveness. Moreover, together with vascular invasion, the expression of Oct3/4 and/or Nanog in primary cancer cells can be considered a probable predictor for selecting the patients at high risk of DNM who would benefit from additional treatment. Further investigations to better elucidate the functional roles of CSCs in tumorigenesis and metastasis are needed, particularly for developing novel targeted therapies that could annihilate the CSCs for complete extermination of a wide variety of malignant tumors.
This study was supported by JSPS Grants-in-Aid for Scientific Research (C) to Y. Imanishi (No. 22591917, 25462692) and to M. Fujii (No. 24592614), and that for Young Scientists (B) to N. Habu (No. 23791933, 25861587), as well as by Keio Gijuku Academic Development Funds to Y. Imanishi. We thank Guangwei Sun, Akira Sonoda, Masato Fujioka, Hideki Mutai, and Kazunori Namba for their helpful technical advice. We also thank the Core Instrumentation Facility, Keio University School of Medicine, for technical assistance.
NH conceived of and designed the study, conducted the experiments, performed the data analysis, and drafted the manuscript. YI conceived of and designed the study, performed the data analysis, and drafted and finalized the manuscript. KS provided support for the experiments and performed the data analysis. KK and MS provided and reviewed the histopathological diagnosis of clinical specimens. RF, SS, KOt, YS, and YW provided support for the experiments and data analysis. HO, and TT contributed to the design of the study and data analysis. YT and MF conceived of and designed the study, and provided general support to the study. KOg provided comprehensive support throughout the study. All authors read and approved the final manuscript.


Disney announces new details about the Marvel Super Hero-packed after-hours event Disneyland After Dark: Heroes Assemble, coming up at Disney California Adventure later this month.
Even MORE Cars Fun When Lightning McQueen's Racing Academy Opens on March 31!
Lightning McQueen Racing Academy officially waves the green flag on March 31, and Disney has just revved up its engines even more with additional Cars-related experiences coming to Disney's Hollywood Studios!
Two new Marvel-themed Disneyland After Dark: Heroes Assemble events will be held at Disney California Adventure on April 30 and May 1. Here are the details!
Disneyland's Tomorrowland Terrace hosts the new "Get Your Ears On" Celebration Dance Party on weekend evenings. Guests have the opportunity to hit the dance floor with some of the Disney characters.
Disney Junior Dance Party! Comes to Hollywood Studios December 22!
Disney World's Hollywood Studios will debut a brand new offering for families tomorrow, December 22. The Disney Junior Dance Party! will take place in Animation Courtyard multiple times a day. Learn more about this new party and watch a video preview here!
Two new Disneyland After Dark events are scheduled for 2019: Sweethearts' Nite on February 7, and 90s Nite on March 7. The parties take place from 9:00 p.m. to 1:00 a.m., tickets are $99/person.
Disney Junior Dance Party at Hollywood Studios!
There's a brand-new dance party coming to Disney's Hollywood Studios this December! Which of your favorite characters can you expect to see? Read on to find out!
Booking is now open for a new, immersive Pixar character experience that's part of a pilot program that starts April 13, 2018, at Disney's Contemporary Resort. Each night, kids, ages 4-12, will be transported to a world full of excitement and adventure with their favorite characters from Disney-Pixar films.


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Wall Street Journal defends Ireland's low corporate tax
A Wall Street Journal editorial has attacked the European Union for trying to force Ireland to change its corpor...
BARRY J WHYTE
Jean-Claude Trichet, the president of the European Central Bank
A Wall Street Journal editorial has attacked the European Union for trying to force Ireland to change its corporate tax structure, warning that such a shift will hinder any future economic growth in Ireland.
In an article entitled 'Europe tries to beat the Republic into tax submission,' the Journal points out that Ireland's economic growth, at least in the beginning, was not 'an economic mirage.' Before the disastrous housing bubble, Ireland's GDP grew as a result of attracting multinational corporations to set up factories and headquarters in the country. This provided jobs in the country and, as a result, "Ireland's brightest young people no longer felt they had to flee to America."
The European Union in recent days has been hinting that if Ireland wants an EU bail-out, it will have to change its corporate tax structure. "It's a fact of life that after what has happened, Irleand will not continue as a low-tax country but rather it will become a normal tax country in the European context," according to EU Commission Ollie Rehn.
Last week, a group of German MEPs told Jean-Claude Trichet, the president of the EU bank, that Ireland's corporate tax rate would have nearly double for Ireland to get any EU assistance.
Werner Langen of the EPP said that Ireland was guilty of "massive competitive distortion on corporation tax," while Markus Ferber, also of the EPP, and Sven Giegold, of the Green group, said that if Ireland's economy continued to decline then it would be necessary "for the Irish Government to make concessions in tax policy in return."
The Journal, however, praised Ireland for "standing firm, with a spokesman for the finance ministry affirming on Friday that its 12.5% corporate tax rate remains 'a cornerstone' of Irish fiscal policy."
The editorial points out that Ireland's "progress has been real and dramatic" under the lower corporate tax rate and that this progress "remains a long way from being undone by the events of the past two years."
"Recovery will take time given the depth of the damage to Ireland's financial system," it continues. "But it will not be helped by a return to the habits of the 1970s and 1980s, when taxes frequently sucked up close to half of Ireland's output and the economy stagnated. Tax hikes, especially on capital and investment, might please the mandarins in Brussels who loath competition. But they risk sending the Irish economy into long-term decline."
Aran Woollen Mills launch new collection, knitwear inspired by Irish landscape
Irish company InflightFlix teams up with Aer Lingus for inflight entertainment
An Irish American expert's top five tips to land your dream career in 2023

redpajama_set_name: RedPajamaCommonCrawl


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Home Supply Chain Knorr-Bremse awarded contract to equip new Velaro trains for Siemens Mobility
Knorr-Bremse awarded contract to equip new Velaro trains for Siemens Mobility
By Danny Longhorn
Photo credit: Siemens Mobility
Knorr-Bremse has been awarded a contract by Siemens Mobility to equip 15 high-speed Velaro Egypt electric multiple units (EMUs) with braking systems and entrance systems. The work starts in Q4 2023 and extends to Q1 2026.
The order includes an option for the equipment of another 26 trainsets. In addition, Knorr-Bremse's Evac brand will supply sanitary systems for 34 Desiro HighCapacity regional passenger trains built by Siemens Mobility for the Egyptian market, including an option for another 60 sanitary systems.
Dr. Jürgen Wilder, Member of the Executive Board of Knorr-Bremse AG and responsible for the Rail Vehicle Systems division, said: "In recent years, Egypt has emerged as an ambitious, dynamic market for rail travel and transportation. The country has been investing in state-of-the-art infrastructure and railroads for some time, in the urban, regional and high-speed sectors.
"We're delighted to have been awarded this contract, which will allow us to install our technologies in a whole series of new Velaro high-speed trains on behalf of our partner Siemens Mobility. As a systems specialist, this will mean we can contribute to the further development of safe, available, eco-friendly mobility for the people of Egypt."
Knorr-Bremse will equip the 15 trainsets with braking and entrance systems between 2023 and 2026. The trains will run between Alexandria and other major Egyptian hubs, carrying millions of passengers each year at speeds of up to 230 km/h (155 mph).
The orders were placed with Knorr-Bremse in the first and second quarters of 2022.The braking systems will include all bogie equipment, axle-mounted and wheel brake calipers, steel discs and sintered pads, as well as brake control systems with integrated smart braking computers.
Compressed air will be supplied by enclosed Piston Supply Ecocompressors. The braking system as a whole will deliver safe, highly efficient braking performance in Egypt's hot, dusty and consequently rather challenging desert climate.
Similarly, Knorr-Bremse will supply service-proven, reliable and pressure-tight doors –including boarding aids –for the Velaro trains through the Group's global IFE brand, the world's leading supplier of rail vehicle entrance systems.
The doors will help keep passengers safe as they enter and exit from railcars, and contribute to reliable train connections.
In addition, Knorr-Bremse will be fitting 34 of Siemens Mobility's Desiro High Capacity regional trains with a total of 136 ultra-reliable toilet systems, including a new type of bidet function. Supplied by the company's Evac brand, the world's leading supplier of sanitary systems for trains, the new systems will help enhance passenger comfort while simultaneously improving train availability.
Knorr-Bremse has been an established supplier of systems for Siemens Mobility's Velaro platform for many years. Velaro trains operate in various configurations in a number of countries with well-developed rail networks, including Germany, the UK and Turkey.
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Community ResilienceCurrently selected
PHE Home > Preparedness > Planning > At-Risk, Behavioral Health...(ABC) > Community Resilience
Community Health Resilience (CHR) is the ability of a community to use its assets to strengthen public health and healthcare systems and to improve the community's physical, behavioral, and social health to withstand, adapt to, and recover from adversity.
Why is community resilience important?
Communities are increasingly complex, and so are the challenges they face. Human-caused and natural disasters are more frequent and costly. Factors like climate change, globalization, and increased urbanization can bring disaster related risks to greater numbers of people.
Addressing these threats calls for an approach that combines what we know about preparing for disasters with what we know about actions that strengthen communities every day. Community resilience focuses on enhancing the day-to-day health and wellbeing of communities to reduce the negative impacts of disasters.
How are community resilience and disaster preparedness related?
Developing community resilience benefits disaster planners and community members alike. Community resilience expands the traditional preparedness approach by encouraging actions that build preparedness while also promoting strong community systems and addressing the many factors that contribute to health.
Key preparedness activities—such as continuity of operations plans for organizations, reunification plans for families, and compiling disaster kits and resources—continue to be essential, recommended steps to take. A resilience approach adds features like building social connectedness and improving everyday health, wellness, and community systems.
How does health fit into community resilience?
Community resilience is the sustained ability of communities to withstand, adapt to, and recover from adversity.
Health—meaning physical, behavioral, social, and environmental health and wellbeing—is a big part of overall resilience. In many ways, health is a key foundation of resilience because almost everything we do to prepare for disaster and protect infrastructure is ultimately in the interest of preserving human health and welfare. The part of overall community resilience that involves health is called Community Health Resilience.
What makes a community healthy and resilient?
A resilient community is socially connected and has accessible health systems that are able to withstand disaster and foster community recovery. The community can take collective action after an adverse event because it has developed resources that reduce the impact of major disturbances and help protect people's health. Resilient communities promote individual and community physical, behavioral, and social health to strengthen their communities for daily, as well as extreme, challenges.
Strategies to build resilient communities:
Some considerations, adapted from the National Preparedness and Response Science Board's Community Health Resilience Recommendations1 are:
Strengthen—and promote access to—public health, healthcare, and social services: Strong day-to-day systems can be better leveraged to support health resilience during disasters and emergencies. In capable systems people know how to access care and are not limited by real or perceived barriers to services.
Promote health and wellness alongside disaster preparedness: Information and education that involve public health, behavioral health, emergency preparedness, and community health resilience interventions can help people face everyday challenges as well as major disruptions or disasters. Optimal levels of physical and psychological health and well-being within the population facilitate the community's rapid recovery.
Expand communication and collaboration: Build networks that include social services, behavioral health, community organizations, businesses, academia, at-risk individuals, and faith-based stakeholders in addition to traditional public health, healthcare, and emergency management partners.
Engage at-risk individuals and the programs that serve them: Engaging individuals with potential vulnerabilities to take an active part in protecting their health and aiding their community's resilience strengthens the community as a whole. Assist programs that serve at-risk individuals to develop robust disaster and continuity of operations plans.
Build social connectedness: People are more empowered to help one another after a major disturbance in communities in which members are regularly involved in each other's lives. Building social connectedness can be an important emergency preparedness action.
In what ways can I strengthen my individual health and resilience?
Individual health and resilience is important for community resilience because healthy, socially connected, prepared people make for stronger communities that are better able to withstand, manage, and recover from disasters. People should try to:
Live a healthy lifestyle and learn skills to manage stress.
Maintain connections to meaningful groups like families, places of worship and volunteer organizations.
Be informed, educated, and able to help neighbors, family, and friends.
Engage in community or neighborhood preparedness activities.
Create evacuation and family reunification plans.
Have a disaster kit and be able to shelter in place for 72 hours.
Take trainings like CPR, first aid, CERT, or psychological first aid.
NPRSB Community Health Resilience Recommendations
RAND Community Resilience
Community Health Resilience Initiative
1National Preparedness and Response Science Board (NPRSB) 2014. Community Health Resilience Recommendations
Contact ABC
This page last reviewed: June 09, 2015


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6th annual Winter 4×4 Jamboree starts Thursday, public invited to 'awesome' vendor show
HURRICANE – Off-road enthusiasts from across the country are anxiously awaiting the start of the sixth annual Winter 4×4 Jamboree, which ranges from world-class rock crawling, to easy, scenic, Southern Utah trails – and all of the proceeds are donated to land use and other groups.
The Jamboree, which runs Thursday
"This will be our biggest and most successful Jamboree,"
ATV Adventures: 2020 ATV Jamborees scheduled – June through November
With the number of ATV jamborees increasing in Utah, I could only include those scheduled for the first half of the year in last week's article. I maintain that jamborees...
Ogden Standard-Examiner 2020-01-16
ST. GEORGE — In case you missed it, here is your weekend recap of the top five most viewed stories published on St. George News from Saturday and Sunday, Dec. 28-29. See...
St George News 2019-12-30
You don't have to travel too far – but you can if you want – ...
ST. GEORGE — If you want to add an extra challenge to your ice fishing this winter, a tournament may be just the thing. Plus, you can help many of Utah fisheries and often...
St. George News Year in Review: Most read and notable stories of 2019
FEATURE — St. George News had a banner year in 2019, with our highest readership on record, reflective of both a rapidly growing region whose population is hungry for...
Parks director tells Hurricane City Council that half-marathon is out, esports is in
HURRICANE — After a year that saw 76% of voters in Hurricane reject a bond to build a new recreation center, the head of the city's recreation services painted a picture of both addition and subtraction for his department during the City Council's first meeting of the new year with three new members Thursday. Recreation and Leisure Director Bryce King presents the state of his...
ATV Adventures: Planning ATV adventures for 2020
2007 is the year I wrote my first article reviewing ATV jamborees to be held during the year. That year Utah hosted six events. Last year that number had grown to thirteen and the number keeps going up. A jamboree is a great way to learn about where to ride and to learn about the incredible diversity of scenery offered in the counties of Utah. There are too many events to get...
Ogden Standard-Examiner
From attainable housing to a bus route to Zion: A look at Washington County projects ...
ST. GEORGE — From transportation infrastructure and new buildings to the reconstruction of the shooting sports park and securing the Red Cliffs Desert Reserve, Washington County officials move into 2020 with a number of projects on their plate. Washington County Commissioner Victor Iverson shares what projects of note the county is working on in 2020, St. George. Utah, Jan. 13,...
Wintery night, warm memories conclude Gulf News Fun Drive
Al Ain: After an action-packed dune-bashing outing on Friday, hundreds of people enjoyed the carnival atmosphere of the desert camp during the Gulf News Overnighter Fun Drive in Al Ain region, before heading back home on Saturday in their four-wheel drives. Friday had marked the start of the 39th edition of the adventure, this year titled 'Gulf News Overnighter Fun Drive -...
Wintry night, warm memories conclude Gulf News Fun Drive
10 essential tips to ensure your participation in the 2020 Gulf News Overnighter Fun Drive is a roaring success!
While a sizeable number of vehicles on UAE roads are highly capable 4x4s that can take on the harshest of terrain, a good percentage of owners don't venture further than the sand parking lot, or at a push, the beach. But this weekend (17th-18th Jan), over 750 of these vehicles and approximately 2,000 participants will be put to the ultimate test as they participate in the 39th...


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I graduated this year with a philosophy B.A., and now I am cautiously considering grad school in philosophy. My professors think I have promise; for example, they have encouraged me to try to get a couple of my undergrad papers published. However, I know that, given the state of the philosophy job market, I would likely end up out of philosophy and underemployed if I pursue a PhD. Do I have a moral obligation to pursue a less risky but productive career?
I don't think that one has a moral obligation to pursue any particular career: one's obligation is to oneself, to pursue what one thinks will be a fulfilling, satisfying career, but what will count as fulfilling or satisfying is of course highly contingent on one's values, personality, etc.. Although you are quite right to note that the philosophy job market is quite tight at the moment, that is no reason not to pursue a philosophy PhD: after all, even if one were not to continue on in professional philosophy, the training one receives in a PhD program is highly portable and may thus be transferred to other professions. My recommendation is that you determine whether, if you were to pursue a PhD in philosophy but were not able to secure a job in the profession, you would still wish to pursue the PhD. If so, then you should apply to graduate school in philosophy; if not, then you should not apply to graduate school in philosophy. If you do apply to graduate school in philosophy, then you need to think...
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The media frenzy and general public outcry arising from the acquittal of Casey Anthony has raised a major ethical issue:- If "everybody believes" that Casey was the person who killed her her child, was the jury wrong in concerning itself with the legal technicalities, such as the absence of any substantial evidence linking Casey to the murder. She claimed that her father was implicated in the child's death, and the jury considered him as a completely unsatisfactory witness, and that seemed to have given rise to the "reasonable doubt" that the jury had, and which ultimately caused them to opt for acquittal.
I think that the issue raised by the Anthony case is more directly bound up with the philosophy of law than with ethics more generally. Indeed, the justification for the verdict seems to reflect the nature of American law in particular, which holds that in a criminal case, guilt must be established "beyond a reasonable doubt." In the Anthony case, the inability of the prosecution to establish the cause of death was an especially important factor in the jury's verdict. What's crucial in this context, is the standard of evidence required for a guilty verdict, which is set quite high in order to try to give the accused the 'benefit of the doubt'. Regardless of whether all the evidence seems to point towards Anthony's guilt, the jury was quite right strictly to insist that guilt be established "beyond a reasonable doubt": this insistence does not reflect a misplaced concern with legal technicalities, but rather a commitment to the letter of the standard of evidence in American criminal trials. Despite...
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Are philosophy conferences really hostile? I ask this because I was reading how there was a guy in a conference with his portable white board keeping score of who was winning. I also hear that you guys are vicious trying to pick arguments. Is this some type of philosopher bonding thing or are you guys really just hostile? hehe.
In my experience, among humanists, it is philosophers who ask the most pointed questions: although the questions posed by Anglo-American philosophers (things are different on the Continent, in my experience) are pointed, they are not necessarily hostile, and I have never heard of anyone keeping score so obviously! It is among many philosophers a point of pride that discussions are as focused and pointed as they are, although it is most surprising to other humanists (and in fact I have sometimes inadvertently ruffled feathers when I have raised questions in a talk given in another area of the humanities in a fashion that would be unremarkable in a philosophy conference or talk.) I myself have found that the level of hostility and tension in a conference or talk varies directly with the topic: while there are of course always exceptions, I have found that talks in the general area of metaphysics and epistemology are more tense than talks in subfields of the history of philosophy, ethics, or political...
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Is human nature the subject of philosophy, or of the empirical sciences?
I myself am inclined to think that both philosophy and (certain) empirical sciences--including psychology--investigate human nature, although they investigate it in different ways. For example--and oversimplifying--the genetic differences between human beings and other animals can be investigated by biology; philosophy, however, can investigate whether there is some ultimate, natural end that all human beings seek, a question that does not seem to me to admit of resolution by natural science but squarely to fall within the province of philosophy. (Aristotle, for example, claims that 'all men by nature desire to know': I do not think that this claim admits of empirical confirmation or disconfirmation.)
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What area of Philosophy currently has the most impact outside of philosophy? On things like neuroscience, literature, religion, maths etc.
I'll be very interested to see how other panelists respond to this question!! My first inclination is to respond that very few areas of philosophy--especially as it is practiced in the English-speaking world--impact areas outside of philosophy; if pressed, I would venture that although the influence of 'Continental' philosophy on literary interpretation and art history isn't anywhere near as great today as it was, say, even a decade, but especially two decades ago, it nevertheless continues to influence those fields to an extent unmatched by the influence of philosophy on any other fields of inquiry.
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Why is there a universe, rather than nothing at all? Is this a question that shall never be answered by science?
Why is there something rather than nothing seems to me to be a quintessential example of a metaphysical question, one that cannot be answered by scientific investigation. It is logically possible that science might come to explain how the universe came into existence--although the information necessary in order to answer this question may well be inaccessible to us, so that the question is practically unanswerable, but even if we had that information, the question of WHY the universe came into existence seems to call for an answer beyond causes investigated by science and thus to lead directly to metaphysics (and religion).
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A majority of feminists as I understand them argue that the per se enjoyment of the physical body and particularly the female form is a form of "objectification". I completely disagree because in my opinion the female form has aesthetic qualities that are not "object" like at all and are actually quite human and therefor the appreciation of the female form is not objectification. Are there feminists who agree with that stance?
Many philosophers committed to feminism are concerned with 'objectification', i.e., roughly, treating a person--often, as in this case and henceforth, a woman--as a thing in some way. While the concept of objectification is slippery, as noted in the Stanford Encyclopedia of Philosophy entry on the topic, from which I profited and which one can access by clicking here , the case you present is clear-cut. While there are senses of objectification that are akin to taking the female form as an object of aesthetic appreciation--such as the reduction of a person to her body or her appearance--the mere appreciation of the beauty of the female form in particular or of the human body in general does not seem to me, in and of itself, to constitute a form of objectification, and I would be surprised if it were indeed the case that the majority of feminists would consider the aesthetic appreciation of the human body to be a form of objectification. To be sure, if one rigorously and uniquely adopts an ...
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When I see myself through Freudian glasses, my behaviors, fears, and understanding suddenly make sense. I can see how I might have repressed certain feelings which, as an adult, have led me to behave neurotically; and I can see how cultures, in order to deal with social anxieties, create political institutions and cultivate their own forms of art. When I think of the world from a Freudian perspective, everything makes sense. When I read theorists like Adorno and Horkheimer, Freud makes even more sense. But we're told that modern neuroscience has largely done away with Freud's ideas, or at least revised them so drastically that we wouldn't recognize them as belonging to Freud. What do we then do with the body of literature that seemed to clarify so much of our behavior, now that scientists are telling us that it's based on a pseudoscience? In particular, I'm reading Hermann Hesse's novel Demian right now. It mirrors my own experiences of growing up, searching for meaning, and trying to overcome the...
The great poet W. H. Auden wrote, in "In Memory of Sigmund Freud": "If often he was wrong and, at times, absurd To us is no more a person Now but a whole climate of opinion." Freud's 'deepening' of the mind is now, I think--and rightly so--part of our 'folk psychology': that is, we understand each other at least in part in terms of categories derived from Freud. If the existence of the unconscious does not admit of 'scientific' confirmation--as its critics allege--or if those criticisms rest on overly narrow conceptions of what scientific confirmation amounts to--as its defenders allege--the fact is, as Auden's poem and considerable other work testifies, we live now in a post-Freudian age, and we now understand ourselves in terms of categories inherited from Freud. It has been claimed that Freud's categories have no more relevance to lived experience than the Greek gods, in response to which I simply ask you to consider whether the testimony of your own experience counts for or against the...
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Does certainty suggest or indicate truth?
5/9/11 (changed 5/9/11 ) Permalink
I presume that in asking whether certainty suggests or indicates truth, you mean whether an agent's certainty about some proposition is a mark of its being true. If this is correct, then in order to answer the question, one needs to get clear about the kind of certainty at issue. It certainly does not seem to be the case that an agent's psychological certainty , or confidence, in some proposition, is a mark of its truth, since one can be confident about the truth of some proposition that isn't true. If the proposition, by contrast, is certain--if, for example, the proposition is a necessary truth, or a proposition that is the object of what Descartes in the Meditations calls the 'natural light', or reason, and hence can be said to be metaphysically certain, then the certainty of the proposition would indeed be a mark of its truth. It seems to me, however, that the propositions that we, as epistemic agents, are most interested in aren't metaphysically certain--_pace_ Descartes, I fear that we...
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Dear Philosophers, I would like to ask whether there is any reasonable explanation why many after/today's philosophers rather refer to Descartes than to Leibniz. Although Descartes had influenced significantly new modern era in philosophical thinking, so did Leibniz. Moreover, Leibniz proved some imperfections in Descartes' metaphysics. I mean both of them deserve our attention, yet in my opinion Leibniz is somehow still in Descartes' shadow. Why is that? Thank you in advance for any tangible arguments or inspiring ideas. Kind regards, Pablo
There are many reasons why Descartes is taken as a reference point for early modern metaphysics and epistemology rather than Leibniz: I present a few. Descartes preceded Leibniz, and certain of Leibniz's philosophical innovations, and especially those in the philosophy of mind, were developed in response to Descartes, who continues to be referred to as 'the father of modern philosophy'. Many of Leibniz's most interesting philosophical works were not published during his lifetime--or even for many years after his death--and he wrote no single, magisterial statement of his views in metaphysics and epistemology like Descartes's Meditations , so it is somewhat more difficult to isolate Leibniz's views than it is to do so for Descartes. Although all professional philosophers are exposed to Descartes's Meditations --most likely, multiple times--over the course of their training, and may even teach the work itself, or at least parts of it, even if they are not specialists in the history of early modern...
Read more about Dear Philosophers,


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Judge bars enforcement of 'docs v. Glocks' law
MICHAEL PELTIER
TALLAHASSEE - Saying it was based on anecdotal information and unfounded conjecture, a federal judge has barred enforcement of a 2011 state law that restricted doctors from asking patients about guns in their houses.
U.S. District Judge Marcia Cooke ruled Friday that lawmakers had failed to make the case that gun owners were being unduly burdened by the law, which restricted doctors and other medical providers from asking questions about gun ownership during medical visits.
In a 25-page ruling, Cook permanently barred the state from enforcing the law, known officially as the Firearm Owners' Privacy Act.
Backed by the National Rifle Association and the United Sportsmen of Florida, the bill (HB 155) was approved by lawmakers and signed by Gov. Rick Scott in 2011. The bill easily passed both chambers along largely party line votes of 88-30 in the House and 27-10 in the Senate.
"What is curious about this law and what makes it different from so many other laws involving practitioners speech is that it aims to restrict a practitioners ability to provide truthful, non-misleading information to a patient," Cook wrote. "The purpose of preventive medicine is to discuss with a patient topics that, while perhaps not relevant to a patients medical safety at the time, inform the patient about general concerns that may arise in the future."
A coalition of groups including the Florida Pediatric Society and the Washington-based Brady Center to Prevent Gun Violence filed suit in federal court in Miami, raising a litany of concerns over patient-doctor relationships and First Amendment Rights.
Cooke issued a temporary injunction in September, saying at the time the group had a good chance of winning its case against the Florida Department of Health.
Critics of the bill, led by Florida pediatricians, said the law interfered with the doctor-patient relationship and muzzled health care practitioners from asking pertinent questions regarding safety issues in the home.
Queries regarding guns at home, physicians argued, are part of a routine battery of questions including whether the home has a swimming pool and whether dangerous chemicals are properly stored.
Supporters said a gun ownership was a private matter. They cited an Ocala case in which a physician dropped a patient after she refused to answer questions about whether the family had guns in the home.
Cooke said neither supporters of the bill nor their attorneys could provide more than anecdotal information proving that prohibiting physicians from asking such questions would result in widespread discrimination against gun owners. They also could not show that Second Amendment guarantees would be jeopardized, Cooke concluded.
"I do not disagree that the government has such an interest in protecting its citizens fundamental rights," Cooke wrote. "The Firearm Owners Privacy Act, however, simply does not interfere with the right to keep and bear arms. The states arguments rest on a legislative illusion."
Gun control advocates, who have accused lawmakers and Gov. Scott of pandering to the NRA and other politically active pro-gun groups, lauded Cooke's ruling on Monday.
"Guns kill eight children every day," said Dan Gross, president of the Brady Center. "The government cannot tell us or our doctors that we are prohibited from discussing the deadly risks posed by guns."
"We thank the court for recognizing that pediatricians need to maintain an open dialogue with our patients and work with parents in order to keep children safe," said Dr. Mobeen Rathore, Florida Pediatric Society president. "Discovering potential risks and providing education on how to prevent injury fulfills the patient-physician relationship."
The Department of Health has not determined if it will appeal the decision, but House sponsor Rep. Jason Brodeur, R-Sanford, said an appeal is likely.
"I expect the ruling to be appealed to the 11th Circuit (Court of Appeals in Atlanta,)" Brodeur said. "But that will depend on the wording of the ruling. I haven't read it yet so we'll have to see."
Barring any appeal, at least one key supporter said he thinks gun owner rights advocates and medical professionals can come to terms.
Lawmakers, for example, last year crafted a bill that had enough protections that the Florida Medical Association did not oppose it.
"It's an issue worth addressing next session," Sen. Joe Negron, R-Stuart, said Monday."I'm optimistic that we can allow the reasonable application of medicine and protect constitutional rights."


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Edo State, Bank of Industry, others brainstorm on access to finance for MSMEs
Advocacy Photo Brochure on Lowering age of Consent to Access HIV Testing and Services
Niger Delta Conflict Tracker (March – April 2019)
The Edo State Government and other stakeholders in the investment sector, including officials of the Bank of Industry (BoI) are finetuning modalities to ease access to finance for Small and Medium Enterprises (SMEs) in Edo State to boost productivity.
During a presentation on 'Sector Opportunities and Ease of Doing Business in Edo State,' Senior Special Assistant to the Edo State Governor on Investment Promotion, Mr Kelvin Uwaibi, said the state has immense opportunities for investment in the oil palm industry and automobile sales, as records show that the state records the second largest automobile sales in Nigeria.
Uwaibi noted that Edo ranks 8th in terms of ease of doing business in Nigeria and is largely becoming an investors' hub with the increasing reforms in the industrial sector.
He added that reforms in land management through the Edo Geographic Information System Agency (Edo-GIS) has improved access to land and the state intends to partner with development finance institutions to create more opportunities for SMEs.
EDITOR'S PICK: Chevron, Partners donate classroom block to Abia school
MADE Niger Delta, Others stimulate CBN, Boi to Mull Financing Window For Edo Creative Hub
PIND Foundation Set to Revive Cocoa Plantations, Productivity in Five Years
The discussion featured expert session focused on agriculture, skills development, Information, and Communication Technology (ICT) and entertainment.
Deputy General Manager on SME (South), BoI, Mr. Ayo Bajomo, said the major role of the bank is to support Nigeria's economy and industrialization by supporting medium and large scale industries.
Commissioner for Women Affairs and Social Development, Hon. (Mrs) Magdalene Ohenhen, in her closing remarks, said the ministry is also looking to partnering with organizations in creating opportunities for women.
She encouraged start-ups with creative ideas and solutions to take advantage of opportunities offered by BoI to expand their businesses.
Culled From – nationonline


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Battle of Britain London Monument – Lt.(FAA) G C McE Guthrie
Battle of Britain London Monument – Lt.(FAA) G C McE Guthrie THE BATTLE OF BRITAIN LONDON MONUMENT "Never in the field of human
Privacy Statement The Airmen's Stories – Lt.(FAA) G C McE Guthrie
Giles Connop McEacharn Guthrie was born on 21st March 1916, the son of Sir Connop Guthrie, 1st Baronet. He was educated at Eton and Magdalene College, Cambridge. He was the winner, with CWA Scott, of the Portsmouth – Johannesburg Air Race in 1936.
Guthrie joined the Fleet Air Arm in 1939 and was with 808 Squadron at Wick in July 1940, flying Fulmars on dockyard defence. He embarked with 808 in HMS Ark Royal on 22nd October 1940 and took part in operations in the Mediterranean in 1941, including Operation Tiger (a Malta relief convoy) on 8th May.
On 23rd July 1941 Guthrie shared in the destruction of a SM79, on the 25th he shared a Cant Z506B and a SM79 and damaged another SM79, on 27th September he shared a SM84 and on 17th October he shared another Cant Z506B.
He was awarded the DSC (gazetted 25th November 1941). Guthrie was made an OBE (gazetted 1st January 1946) and released from the Navy on 30th January 1946 as a Lieutenant Commander (A).
He succeeded to the baronetcy in 1945 and died on 31st December 1979.


text:
Climate Justice Unity March: April 22-29
Saturday at 9:00 a.m. — April 29 at 1:00 p.m.
Starting Point: Little Creek Camp near Millersburg, IA
The People's Climate Movement is gaining momentum for what should be a landmark day of action on April 29, marking the 100th day of the Trump Presidency. The major event is in Washington, DC, billed as "a march for climate, justice and jobs," but there also will be hundreds of related marches in cities across the U.S. and around the globe.
People's Climate Movement Rally: April 29 in Des Moines
In Iowa, the People's Climate Movement will rally at the Iowa State Capitol at 1:00 p.m. on Saturday, April 29. A broad coalition of groups is working to make this a statewide event involving thousands of concerned Iowans representing a broad range of perspectives.
(Click here to sign up to join the April 29 rally.)
To build momentum for the April 29 rally, Bold Iowa and partners including
– Indigenous Iowa
– Sage Sisters of Solidarity
– League of United Latin American Citizens (LULAC) – Council 307
– Creative Visions
– Iowa Farmers Union
– Iowa Physicians for Social Responsibility
– Great March for Climate Action
– La Reina Radio 1260 AM
are announcing an eight-day, 85-mile Climate Justice Unity March, starting on April 22 (Earth Day) and arriving at the State Capitol for the April 29 People's Climate Movement Rally.
Marchers will set out at 9:00 a.m. and walk roughly 10 – 12 miles per day. We are actively encouraging and inviting members of five key constituencies critical to the coalition needed to move us forward on climate, justice and jobs:
Farmers and rural landowners
Marchers will need to bring a tent, sleeping bag, air mattress and other personal gear. Bold will provide food, toilet facilities and showers for the marchers.
In addition to marching, every evening from 5:00 – 8:00 there will be a forum, dinner and music in each overnight town. These community events are as important as marching. As we work to build the strongest possible alliance to push-back against the failed policies of status-quo politicians at both the state and federal level, it's essential that we take time to listen to each other and embrace our common ground and destiny.
Some of these conversations may be challenging. But, as we work to build the strongest possible alliance to push-back against the failed policies of status-quo politicians at both the state and federal level, it's critically important that we take time to hear each other and embrace our common ground.
The Climate Justice Unity March provides a unique opportunity to bring many voices together through the dignified, disciplined commitment of marching, and through non-confrontational forums and meals that will build momentum for April 29 and forge new relationships essential to the work we must do going forward.
Click here to view the Climate Justice Unity March FAQ.


text:
Q: Helm values.yaml variables from kubernetes secret I'm trying to use kubernetes secret in different helm charts and is any universal way to do it? For example I have grafana and admin password in helm values.yaml, and I want to keep it in k8s secret and load it into values.yaml . Is it possible? Grafana have option like admin.existingSecret but I also want to do it with charts where they don't have that options. Is it possible to do it with
      valueFrom:
        secretKeyRef:
          name: mysecret
          key: WSO2_CLOUD_ORG_KEY

or with
envFromSecrets: ""

I tried to use it in values.yaml in elasticsearch exportet but it didn't work and I'm looking for any universal way to do it. I tried:
envFromSecrets: "secret"
es:
  uri: ${secret}

A:
I want to keep it in k8s secret and load it into values.yaml

No it's not possible however you can create a template in the chart so if the secret is missing it will create the one with value
Not sure which chart you are using but can checkout the
https://github.com/grafana/helm-charts/blob/main/charts/grafana/values.yaml#L342
values.yaml
# Administrator credentials when not using an existing secret (see below)
adminUser: admin
# adminPassword: strongpassword

if you want to use the existing secret you can mention it in this section along with the user key and password key ref.
# Use an existing secret for the admin user.
admin:
  ## Name of the secret. Can be templated.
  existingSecret: ""
  userKey: admin-user
  passwordKey: admin-password

redpajama_set_name: RedPajamaStackExchange


text:
Mayim Bialik est une actrice et productrice née le  à San Diego en Californie.

Elle devient célèbre pour avoir joué le rôle éponyme de la série Petite Fleur dans les années 1990. En parallèle elle joue plusieurs rôles au cinéma ainsi que dans plusieurs séries télévisées.

À la fin des années 2010, sa renommée devient internationale lorsqu'elle rejoint la distribution principale de la série à succès The Big Bang Theory dans le rôle d'Amy Farrah Fowler.

Depuis 2020, elle a sa propre série et joue le premier rôle de Kat dans la comédie a succès Call me Kat.

Biographie

Carrière

Elle commence sa carrière, très jeune, à la fin des années 1980, par des petits rôles dans des films comme The Facts of Life, La Belle et la Bête, ou encore dans le film d'horreur Pumpkinhead en 1988. Elle participe également à trois épisodes de MacGyver, dans lesquels elle incarne le personnage de Lisa Woodman. Elle joue aussi Bette Midler (enfant) dans Au fil de la vie, en 1988. Elle participe, enfin, à la vidéo de Michael Jackson qui illustre la chanson Liberian Girl. En 1990, elle est engagée pour les épisodes pilotes de Molloy (pour la Fox) et Petite Fleur (Blossom en VO) pour NBC. La série Molloy est d'abord lancée pour six épisodes tests, mais retirée de la programmation devant le succès de Blossom qui l'avait surpassée en audience dès sa deuxième semaine de diffusion. Blossom prospère jusqu'en 1995. Entre 1995 et 2005, l'actrice fait de la post-synchronisation pour des dessins animés, comme The Real Adventures of Jonny Quest et La Cour de récré.

Elle figure en 2005 à l'affiche de Kalamazoo?, et fait une apparition dans trois épisodes de la série Larry et son nombril, pour HBO comedy, dans lesquels elle joue Jodi Funkhouser, la fille lesbienne d'un ami de Larry David. Elle fait également une brève apparition dans Fat Actress, et dans un épisode de Saving Grace. Elle bénéficie, en revanche, d'un rôle plus pérenne dans la série Family's The Secret Life of the American Teenager produite par ABC, dans lequel elle incarne la conseillère d'orientation du lycée. Elle est invitée, en outre, dans un épisode de la sitcom 'Til Death (Pour le Meilleur et pour le Pire, produite par la Fox) dans lequel elle retrouve deux acteurs de Blossom, Jenna von Oÿ, qui avait joué le rôle de Six, la meilleure amie de Blossom, et Michael Stoyanov, qui incarnait Anthony, le frère aîné de Blossom.

Elle rejoint, en 2009, la série The Big Bang Theory qui achève sa troisième saison, pour incarner Amy Farrah Fowler. Elle fait sa première apparition dans l'épisode final de ladite saison, lors de sa rencontre avec le personnage de Sheldon Cooper, interprété par Jim Parsons. Amy Farrah Fowler est docteur en neurobiologie, ce qui coïncide avec la formation universitaire de Mayim Bialik, achevée deux années plus tôt avec un doctorat en neurosciences. Son rôle dans The Big Bang Theory lui vaut une nomination pour la  des  2012, dans la catégorie meilleure actrice dans un second rôle dans une série télévisée comique, en plus de la nomination, en  avec toute l'équipe de The Big Bang Theory, aux Screen Actors Guild Awards dans la catégorie meilleure distribution pour une série télévisée comique.

En 2021, elle est nommée animatrice de Jeopardy! pendant deux semaines en mai. Il a été étendu au tournoi collégial ABC aux heures de grande écoute et elle partage les tâches de la version syndiquée avec Ken Jennings à partir du 20 septembre 2021.

Vie privée

Mayim Bialik est l'arrière-petite nièce du poète Hayim Nahman Bialik. Elle fait ses études en Californie à la Walter Reed Junior High School (North Hollywood, dans la San Fernando Valley). À la fin du tournage de Blossom, bien qu'elle soit acceptée à la fois à Harvard et à Yale, elle préfère rester en Californie, près de ses parents, où elle rejoint l'université d'UCLA. En 2000, elle obtient son diplôme universitaire de premier degré (l'équivalent du baccalauréat universitaire) en neuroscience, et approfondit ses études dans ce domaine. Elle les interrompt en 2005, pour jouer dans des sitcoms, puis les reprend pour obtenir finalement son doctorat en 2007, au cours duquel elle soutient une thèse relative au syndrome de Prader-Willi.

Étant végane, elle publie un livre de recettes dédiées. Par ailleurs, elle est membre fondatrice de l'institut Shamayim V'Aretz, puis donne quelques conférences scientifiques, notamment à Bethlehem — en Pennsylvanie — dont on peut trouver de larges extraits sur YouTube. Le , elle publie un livre, intitulé : Beyond the Sling: A Real-Life Guide to Raising Confident, Loving Children the Attachment Parenting Way. Le , elle a un accident de voiture à Los Angeles, dans lequel elle manque de peu de perdre un doigt. Mais, elle rassure tout de suite ses fans, et reprend, dès le lendemain, le tournage dans The Big Bang Theory.

En 2002, elle devient la compagne de Michael Stone - qu'elle épouse le . Ils ont deux enfants : Miles Roosevelt Stone (né le ) et Frederick Heschel Stone (né le ). Ils se séparent en , puis divorcent en .

Filmographie

Cinéma
 1988 : Au fil de la vie (Beaches) de Garry Marshall : Cecilia 'CC' Carol Bloom (âgée de 11 ans)
 1989 : Pumpkinhead : Le Démon d'Halloween (Pumpkinhead) de Stan Winston : Wallace kid
 2006 : Kalamazoo? de David O'Malley : Maggie Goldman

Télévision
 1989 : Liberian Girl (clip) : Elle-même
 1989-1990 : MacGyver : Lisa Woodman
 (saison 5, épisode 4 "Cessez le feu")
 (saison 5, épisode 19 "Cœurs d'acier")
 (saison 6, épisode 4 "Le questionnaire")
 1991-1995 : Petite Fleur (Blossom) : Peneloppe « Petite Fleur » Russo (Blossom Russo)
 1994 : Nuits de Chine (Don't Drink the Water) : Susan Hollander
 2003 : Sept à la maison : Cathy (saison 7. Épisode 20)
 2005 : Katbot (série) : Paula (voix)
 2008 : Bones, saison 4 épisode 20 : L'amour a ses raisons
 2009-2013 : La Vie secrète d'une ado ordinaire
 2010 : Pour le meilleur et pour le pire, saison 4 épisode 7 :  Bialik
 2010-2019 : The Big Bang Theory : Amy Farrah Fowler (203 épisodes)
 2015 : Embarquement immédiat pour Noël : Stéphanie
2020-2022 : Call Me Kat : Kat <small> (44 épisodes)
 2021:  Jeopardy!:   Animatrice de jeu
 saison 37, épisodes 176-185
 saison 38-39, version syndiquée, alternance avec Ken Jennings (saison 38, 115 épisodes, saison 39 TBD)
 saison 38-39, championnat universitaire (à diffuser sur American Broadcasting Company, version réseau aux heures de grande écoute )

Notes et références

Liens externes

Actrice américaine de télévision
Naissance en décembre 1975
Naissance à San Diego
Étudiant de l'université de Californie à Los Angeles
Judaïsme orthodoxe

redpajama_set_name: RedPajamaWikipedia


text:
"""Exceptions of the PPP Core."""

from ppp_libmodule.exceptions import ClientError, BadGateway

redpajama_set_name: RedPajamaGithub


Why Release Michael Jackson's Xscape?
With any posthumous release you get a complicated situation. Questions such as: what has been tampered with, and how far removed from the original artist's intention is the release? Why release something deemed previously unacceptable? These questions are often asked and in the case of this new Jackson album it is worth examining and clarifying a few things.
Firstly, in the last day a few sites have gone all crazy claiming the title track of the album leaked. They are correct, but this big news is a sheep in wolf's skin. The apparent leak of Xscape is the original version that leaked over 10 years ago so it isn't news, but at least it keeps the album publicised without Sony having to do any work for it. Funnily enough this nicely brings me to the first point. Many commenters say 'Why release it now?'. Simply because it was intended to be released THEN. The track was left of the Invincible album and probably a good shout considering it might have been mixed up with some of the similar beat driven tracks on the album. It was probably tweaked and Jackson and the management intended for the song to be released sometime around 2003. The exact intentions are confusing, however on the Number Ones compilation a new song was included (One More Chance) and it was suggested that plans for a similar styled release to the History album was intended with some additional cuts being included that probably became the Ultimate Collection eventually. However when the song was leaked Jackson dropped the track from any subsequent release. To include a version on a new album (albeit in both original and 'reworked' form) is a good shout. He has intended to release it but only canned the plans once pesky internet file sharing sites spread the track around.
Similarly, other tracks suited to this new posthumous release were being continually worked on and had many notes to base changes on as well as intended plans. A set of songs was pinned to a wall in Jackson's bedroom when he died in 2009 which included many of the tracks that are rumoured to appear on the new album. Speculation suggests that 6 out of the 8 tracks have been leaked in some form and so whilst this album is a mixture of new and heard material, it'll be the first time many casual fans will have heard the tracks, as well as the version Jackson himself last worked on.
Should an artist have works released posthumously though? Honestly, it is a question that deserves to be asked. Who knows what could have changed under their guidance? Posthumous releases look like greedy cash grabs and that easily puts a lot of fans off and most posthumous releases are marginally mediocre oft not. So why release it at all? Because the demand still exists. People wish for more, if the management are greedy it is because fans are equally so. It has been a long standing tradition to re-release albums with additional cut and demo material simply as it is interesting. This sometimes amusing, engaging, human, and many other aspects make some demos a gem to listen to and some cut songs questionably better than some of those that made the album. In Jackson's case, Streetwalker from Bad 2001 Re-release was intended for the album only to be canned in the final stages instead for Another Part of Me. Quincy Jones apparently made that call, and in some eyes that is the correct call, in other eyes and mistake. It is the same reason why fans will debate track listings and try to come up with something that flows more consistently. Also with any album, a track may be left off despite it being a noticeably better track simply because it works against the rest of the album, it has no consistency or relevancy to the majority of the other tracks and in an album it is one of the biggest calls to make or break an album. These tracks often end up as B-Sides that help round out the album and add to the 'canon' of an artist's history.
Again some of these tracks have been leaked in some form over the years. Slave to the Rhythm was initially toyed with for the first posthumous Jackson release and a leaked version of the uptempo 'house' track that resulted from those sessions has been floating around for a while. Funnily enough, this version could even be the 'new' version for the record but I suspect it will be the Timbaland 'Orchestral' hip-hop style one. The original track has never been publicly leaked or heard yet.
The simple fact of the matter is this album will have the stigma about it that all posthumous releases has, and always will. They'll be looked at with a coy smirk and wince as fans wish to enjoy the new material but are stuck wondering, what if? Why wonder? Consider it a separate artist and review it based on that. No one person is the lead in orchestrating the perfect album release. If anything Thriller would have been noticeably worse in Jackson had got his way and included the soppy Carousel instead of Human Nature, a song that became a live show highlight. So a posthumous release can be looked upon in a similar manner, and the careful nature of this release suggests that Epic and the estate have a lot of faith in their decision. The reworked tracks have been highly lauded by critics so far, and the album can be ordered in a deluxe package that'll include the 'final' versions Jackson had worked on in his lifetime. This removes any doubt that these songs aren't his, and enables fans to hear what could have been and what can be in equal measure. The biggest criticism is the fact that so many of the rumoured songs have been leaked, but they probably leaked because they were continually evaluated by Jackson during his life and thus CD copies were continually made and shared, unfortunately some people get their hands on one and it eventually leaks.
It is amusing at the state of the internet and professionally run websites that they all rely upon churnalism. MTV I believe originally stated the title track had leaked yesterday, despite it being the leak from 10 years ago. And since then many other articles have appeared online all trying to excitingly reveal the news that fans and people with long term memories have known about for a while. It really shows the horribly poor nature and the fact they'd so publicly dig it up could discourage people as many articles fail to address the fact that the song is an unfinished work from 2001.