Cultivating Self-Transcendence Through Meditation Practice: A Test of the Role of Meta-Awareness, (Dis)identification and Non-Reactivity.

In this paper, we present a study comprising two distinct stages to examine the extent to which metacognitive processes of decentering facilitate the emergence of self-transcendence experiences in everyday life (i.e., the frequency of self-transcendent emotions, flow proneness, and adopting an interconnected identity). In the course of conducting this research, the first stage (N = 374) focused on assessing the structure and validity of the French version of the Metacognitive Processes of Decentering Scale (MPoD-t). Building on this, the second stage (N = 294) examined the potential relationship between meditative practices and psychological decentering processes (i.e., meta-awareness, (dis)identification with internal experiences, and (non)reactivity to thought content) and explored whether these mechanisms explain the association between meditative practices and the experience of self-transcendent states. Overall, the results demonstrated satisfactory psychometric properties of the French version of the MPoD and provided enhanced insights into the distinct mediating roles played by various decentering components in the manifestation of self-transcendence experiences in daily life. Indeed, the findings revealed that the relationship between practice and the occurrence of self-transcendent emotions or flow was mediated by the meta-awareness component, while the association between practice and the development of an interconnected identity was explained by the (dis)identification with internal experiences component. The implications of these findings are discussed.

The structure of the Symptom Checklist-90-Revised: Global distress, Somatization, Hostility, and Phobic Anxiety scales are reliable and robust across community and clinical samples from four European countries.

While the reliability of SCL-90-R subscales is often questioned, five relatively recent European studies have examined the factor structure of SCL-90-R using a bifactor model and concluded that most of these subscales are reliable. However, examination of their results shows that three subscales, Somatization, Hostility, and Phobic Anxiety, consistently had significantly higher reliability than the other six across clinical and community samples recruited in three very different European countries, Greece, Hungary, and the Netherlands. The objective of this study was to examine whether this "top-3″ would be found in a sample from a fourth European country, France. To do this, we had 696 university students (387 women, 56 %) complete the SCL-90-R and we examined the reliability of the scales of this questionnaire by testing a bifactor model using Exploratory Structural Equation Modeling (ESEM). Our results confirmed that, in our sample, the three scales presented a higher reliability than the other six scales. It therefore seems that there exists, at least in the European cultural area, a stable structure of the SCL-90-R comprising a global distress factor and three reliable and robust specific factors: Somatization, Hostility, and Phobic Anxiety.

A reliable instrument for making use of an overly neglected source of information on personality: The French adaptation of the Big Five Inventory-2 (Bfi-2) informant-report form.

OBJECTIVES: The assessment of personality traits is most often based on self-report. However, a growing body of research has shown that informant-report is a valuable and too often overlooked source of unique information. The aim of this study was to validate the French version of the informant-report form of the Big Five Inventory-2 (BFI-2) which assesses 15 facet traits in addition to the five major trait domains. METHODS: We asked 699 psychology and sports science and technology students to describe a person they knew well using the BFI-2 and obtained 661 valid records with demographic information. The data were analyzed using a bi-factor exploratory structural equation model with five bifactors corresponding to the Big Five domains, and three group factors (facets) each. RESULTS: This model had an excellent overall fit. Cronbach's alpha coefficients for the five domains were very satisfactory and the McDonald's omega coefficients were even better. The scales that measured the five major factors were therefore highly reliable, although Extraversion was somewhat less so. The scales measuring facets all had high reliability as measures of the whole formed by the major factor and the group factor. In addition, ten of them were reliable measures of their specific factor, and the remaining five appeared to be pure measures of the five domains. CONCLUSIONS: The informant-report form of the BFI-2 is a reliable instrument which is easy and quick to administer. These qualities should enable clinicians and researchers to exploit the much-neglected source of original information provided by informant-reports.

Diversity policy, social dominance, and intergroup relations: predicting prejudice in changing social and political contexts.

In contrast to authors of previous single-nation studies, we propose that supporting multiculturalism (MC) or assimilation (AS) is likely to have different effects in different countries, depending on the diversity policy in place in a particular country and the associated norms. A causal model of intergroup attitudes and behaviors, integrating both country-specific factors (attitudes and perceived norms related to a particular diversity policy) and general social-psychological determinants (social dominance orientation), was tested among participants from countries where the pro-diversity policy was independently classified as low, medium, or high (N = 1,232). Results showed that (a) anti-Muslim prejudice was significantly reduced when the pro-diversity policy was high; (b) countries differed strongly in perceived norms related to MC and AS, in ways consistent with the actual diversity policy in each country and regardless of participants' personal attitudes toward MC and AS; (c) as predicted, when these norms were salient, due to subtle priming, structural equation modeling with country included as a variable provided support for the proposed model, suggesting that the effect of country on prejudice can be successfully accounted by it; and (d) consistent with the claim that personal support for MC and AS played a different role in different countries, within-country mediation analyses provided evidence that personal attitudes toward AS mediated the effect of social dominance orientation on prejudice when pro-diversity policy was low, whereas personal attitudes toward MC was the mediator when pro-diversity policy was high. Thus, the critical variables shaping prejudice can vary across nations.

Cytoplasmic overexpression of CD95L in esophageal adenocarcinoma cells overcomes resistance to CD95-mediated apoptosis.

INTRODUCTION: The CD95/CD95L pathway plays a critical role in tissue homeostasis and immune system regulation; however, the function of this pathway in malignancy remains poorly understood. We hypothesized that CD95L expression in esophageal adenocarcinoma confers advantages to the neoplasm other than immune privilege. METHODS: CD95L expression was characterized in immortalized squamous esophagus (HET-1A) and Barrett esophagus (BAR-T) cells; adenocarcinoma cell lines FLO-1, SEG-1, and BIC-1, and MDA468 (- control); and KFL cells (+ control). Analyses included reverse transcription-polymerase chain reaction, immunoblots of whole cell and secretory vesicle lysates, FACScan analysis, laser scanning confocal microscopy of native proteins and fluorescent constructs, and assessment of apoptosis and ERK1/2 pathways. RESULTS: Cleaved, soluble CD95L is expressed at both the RNA and protein levels in these cell lines derived from esophageal adenocarcinoma and other human tissues. CD95L was neither trafficked to the cell membrane nor secreted into the media or within vesicles, rather the protein seems to be sequestered in the cytoplasm. CD95 and CD95L colocalize by immunofluorescence, but an interaction was not proven by immunoprecipitation. Overexpression of CD95L in the adenocarcinoma cell lines induced robust apoptosis and, under conditions of pan-caspase inhibition, resulted in activation of ERK signaling. CONCLUSIONS: CD95L localization in EA cells is inconsistent with the conference of immune privilege and is more consistent with a function that promotes tumor growth through alternative CD95 signaling. Reduced cell surface expression of CD95 affects cell sensitivity to extracellular apoptotic signals more significantly than alterations in downstream modulators of apoptosis.

Bile salts differentially sensitize esophageal squamous cells to CD95 (Fas/Apo-1 receptor) mediated apoptosis.

BACKGROUND: The role of nonacidic reflux contents on the pathophysiology of Barrett's esophagus remains poorly understood. We hypothesized that esophageal squamous epithelium differs from Barrett's columnar epithelium in response to bile salts with respect to subsequent changes in the cell surface expression of CD95 (Fas/Apo-1) and sensitivity to CD95-mediated apoptosis. METHODS: Immortalized esophageal squamous cells (HET-1A) and Barrett's esophagus cells (BAR-T), and esophageal adenocarcinoma cells (Flo-1) were treated with toxic and nontoxic bile salts at concentrations observed in gastroesophageal refluxate. CD95 cell-surface expression and apoptotic response to activating anti-CD95 antibody treatment was determined by FACScan analysis. RESULTS: Bile salt exposure resulted in a dose-dependent increase in CD95 cell-surface expression in HET-1A cells, but not BAR-T or Flo-1 cells. This response occurred rapidly, within a time-frame inconsistent with de novo protein synthesis and was blocked by protein kinase C (PKC) inhibition. Surprisingly, PKC inhibition in Flo-1 cells resulted in an increase in CD95 cell surface expression. Following bile salt exposure, a corresponding increase in the induction of CD95-mediated apoptosis was observed in HET-1A cells; PKC inhibition sensitized Flo-1 cells to apoptosis. CONCLUSIONS: Our findings suggest that esophageal squamous cells are sensitized to CD95-mediated apoptosis following bile salt exposure. This differential response, compared with columnar epithelial cells, could exert a selection pressure that contributes to the pathophysiology of Barrett's esophagus.

[Impact of oral health in the daily life of institutionalized and non institutionalized elder in the city of Recife (PE, Brazil)]. / Impacto da saúde bucal no cotidiano de idosos institucionalizados e não institucionalizados da cidade do Recife (PE, Brasil).

The objective of the study is to assess the influence of oral health in the daily routine of both institutionalized and non-institutionalized elders living in the city of Recife-PE, as well as to come to conclusions concerning the relevance level of oral health in both groups. In order to assess the perception of oral health, it was used the Geriatric Oral Health Assessment Index (GOHAI). The GOHAI levels, concerning the perception, were categorized in: low (≤ 50), average (51 to 60) and high (57 to 60). Oral health conditions were represented by the DMFT index (with cavity, lost and repaired teeth). It was observed that the percentage of elderly with a GOHAI not higher than 50 (low perception of oral health) was rather higher in the non-institutionalized group than in the institutionalized (92.2% x 64.9%). The average DMFT and the number of lost teeth were higher in the institutionalized group (96.01% x 87.87%). The perception of oral health was lower for more than half of the examined elderly population, but there being a meaningful difference between the two groups concerning the GOHAI, with lower levels for the non-institutionalized group. The result of the perception of oral health was compatible with the high number of decayed and lost teeth.

Hypoxia-mediated regulation of Cdc25A phosphatase by p21 and miR-21.

Hypoxia is a common feature of solid tumors and represents a critical factor in their progression and responsiveness to chemotherapy and radiotherapy. We now report that hypoxic exposure of colon cancer cells decreased the protein levels of the cell cycle-controlling phosphatase Cdc25A. Hypoxia decreased the mitotic population and caused S-phase arrest in these cells. Suppression of Cdc25A was phosphatase family member-specific, as a similar decrease was not observed with closely related Cdc25B or Cdc25C phosphatases. Pharmacological and genetic blockade of Chk1 and Chk2 failed to inhibit the hypoxia-mediated loss of Cdc25A, indicating this process was not regulated by a traditional ATM/ATR checkpoint response. In addition, hypoxia did not affect ectopically expressed Cdc25A levels suggesting independence from an increase in proteasomal degradation. Cdc25A mRNA levels also decreased in human colon cancer cells 24 hr after hypoxia supporting a mechanistic role for decreased Cdc25A expression or mRNA stability. The reduction in Cdc25A mRNA and protein was dependent on the cyclin-dependent kinase inhibitor p21 and miR-21, which were upregulated in HCT116 colon cancer cells during hypoxia. These results reveal previously unknown mechanisms for the transient suppression of Cdc25A, providing a coordinated and fundamental adaptive change that may be exploited by cancer cells conferring proliferative and survival advantages.

Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages.

The dual-specificity phosphatase 6 (Dusp6) functions as a feedback regulator of fibroblast growth factor (FGF) signaling to limit the activity of extracellular signal-regulated kinases (ERKs) 1 and 2. We have identified a small-molecule inhibitor of Dusp6-(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI)-using a transgenic zebrafish chemical screen. BCI treatment blocked Dusp6 activity and enhanced FGF target gene expression in zebrafish embryos. Docking simulations predicted an allosteric binding site for BCI within the phosphatase domain. In vitro studies supported a model in which BCI inhibits Dusp6 catalytic activation by ERK2 substrate binding. We used BCI treatment at varying developmental stages to uncover a temporal role for Dusp6 in restricting cardiac progenitors and controlling heart organ size. This study highlights the power of in vivo zebrafish chemical screens to identify new compounds targeting Dusp6, a component of the FGF signaling pathway that has eluded traditional high-throughput in vitro screens.

Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non small-cell lung cancer.

Many studies have suggested a role for the hepatocyte growth factor (HGF)/c-Met pathway in tumorigenesis. Some actions of HGF are believed to be mediated by cyclooxygenase-2 (COX-2), resulting in the production of prostaglandin E2 (PGE(2)). We examined four c-Met-positive non-small-cell lung cancer (NSCLC) cell lines for effects of HGF on COX-2. HGF increased COX-2 protein expression 3-fold over basal levels. Induction of COX-2 occurred through both the extracellular signal-regulated kinase 1/2 and p38 pathways. HGF treatment caused activation of the activator protein-1, CCAAT/enhancer-binding protein, and cAMP response element-binding protein transcription factors, and COX-2 induction was blocked by actinomycin D. The half-life of COX-2 mRNA was also increased by HGF. HGF stimulation resulted in a 4-fold increase in PGE(2) secretion, and treatment of NSCLC cells with exogenous PGE(2) significantly increased cell proliferation. The addition of PGE(2) to NSCLC cells also led to rapid phosphorylation of c-Met in the absence of HGF, which was blocked by epidermal growth factor receptor (EGFR) inhibition. EGFR ligands were released in response to PGE(2). This suggests that secretion of PGE(2) induced by HGF/c-Met pathway activation can further activate the c-Met pathway via EGFR in a reinforcing loop that is independent of HGF. HGF and PGE(2) each significantly stimulated invasion in NSCLC cells. Cells transiently transfected with c-Met antisense plasmid showed a significant decrease in HGF- or PGE(2)-induced invasion. PGE(2)-induced invasion was EGFR-dependent, confirming a link between PGE(2), EGFR, and c-Met. Targeting of both the HGF/c-Met and PGE(2) pathways with a neutralizing antibody to HGF and celecoxib resulted in enhanced anti-invasion effects in response to HGF.

Inhibition of c-Met as a therapeutic strategy for esophageal adenocarcinoma.

The hepatocyte growth factor (HGF) receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA), yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressing EA cell lines (Seg-1, Bic-1, and Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, and downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K)/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.

Novel benzofuran inhibitors of human mitogen-activated protein kinase phosphatase-1.

Protein tyrosine phosphatases have a central role in the maintenance of normal cellular functionality. For example, PTP1B has been implicated in insulin-resistance, obesity, and neoplasia. Mitogen-activated protein kinase phosphatase-1 (MKP-1 or DUSP1) dephosphorylates and inactivates mitogen-activated protein kinase (MAPK) substrates, such as p38, JNK, and Erk, and has been implicated in neoplasia. The lack of readily available selective small molecule inhibitors of MKP family members has severely limited interrogation of their biological role. Inspired by a previously identified inhibitor (NSC 357756) of MKP-3, we synthesized seven NSC 357756 congeners, which were evaluated for in vitro inhibition against several protein phosphatases. Remarkably, none displayed potent inhibition against MKP-3, including the desamino NSC 357756 analog NU-154. Interestingly, NU-154 inhibited human PTP1B in vitro with an IC(50) value of 24 +/- 1 microM and showed little inhibition against Cdc25B, MKP-1, and VHR phosphatases. NU-126 [2-((E)-2-(5-cyanobenzofuran-2-yl)vinyl)-1H-indole-6-carbonitrile] inhibited MKP-1 and VHR in vitro but was less active against human MKP-3, Cdc25B, and PTP1B. The inhibition of MKP-1 by NU-126 was independent of redox processes. The benzofuran substructure represents a new potential scaffold for further analog development and provides encouragement that more selective and potent inhibitors of MKP family members may be achievable.

Ad-IRF-1 induces apoptosis in esophageal adenocarcinoma.

The nuclear transcription factor interferon regulatory factor-1 (IRF-1) is a putative tumor suppressor, but the expression and function of IRF-1 in esophageal adenocarcinoma (EA) remain unknown. We hypothesized that IRF-1 expression was reduced or lost in EA and that restoration of IRF-1 would result in the apoptosis of EA cells in vitro and the inhibition of tumor growth in vivo. Three EA cell lines were used to examine IRF-1 expression, IFN-gamma responsiveness, and the effects of IRF-1 overexpression using a recombinant adenoviral vector (Ad-IRF-1). All three EA cell lines produced IRF-1 protein following IFN-gamma stimulation, although IFN-gamma did not induce cell death. In contrast, Ad-IRF-1 infection resulted in high levels of IRF-1 protein and triggered apoptosis in all three EA cell lines. Potential mechanisms for the differential response to IFN-gamma versus Ad-IRF-1--such as modulation of c-Met or extracellular regulated kinase signaling, or altered expression of IRF-2, Fas, or survivin--were investigated, but none of these mechanisms can account for this observation. In vivo administration of IRF-1 in a murine model of EA modestly inhibited tumor growth, but did not lead to tumor regression. Strategies aimed at increasing or restoring IRF-1 expression may have therapeutic benefits in EA.

Altered trafficking of Fas and subsequent resistance to Fas-mediated apoptosis occurs by a wild-type p53 independent mechanism in esophageal adenocarcinoma.

BACKGROUND: Decreased cell-surface expression of Fas (CD95) results in resistance to Fas-mediated apoptosis in esophageal adenocarcinoma (EA). Because p53 is known to increase transcription of Fas and also may induce trafficking of the protein to the plasma membrane, we investigated whether the loss of wild-type (wt)-p53 function accounts for our previous findings. MATERIALS AND METHODS: Surgical specimens of Barrett's Esophagus containing areas of dysplasia were immunostained for p53 and Fas protein expression. Three EA cell lines were transfected with a wt-p53 containing adenovirus to examine the effects of p53 overexpression. The p53 status of these EA cell lines was determined by sequence analysis. RESULTS: Regions of dysplasia where p53 protein accumulation was observed corresponded to areas of loss of Fas expression. Sequence analysis of the p53 coding sequence in three EA cell lines (Seg-1, Bic-1, and Flo-1) that retain Fas protein within the cytoplasm, demonstrated that Seg-1 contained wt-p53, but mutations were found in Flo-1 and Bic-1 cell lines. Adenoviral transduction of the cell lines with wt-p53 resulted in cell growth arrest in Seg-1 and Bic-1 and induced cell death in Flo-1, but did not result in an increase in Fas protein expression, cell-surface expression, or restoration of sensitivity to Fas-mediated apoptosis. CONCLUSIONS: These data suggest that decreased cell-surface expression of Fas and resistance to Fas-mediated apoptosis may occur independently of loss of wt p53 expression.

The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma.

The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted.