Circulating microRNA profiling in patients with advanced non-squamous NSCLC receiving bevacizumab/erlotinib followed by platinum-based chemotherapy at progression (SAKK 19/05).

OBJECTIVES Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression. MATERIALS AND METHODS Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNA's. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearman's rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints). RESULTS Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNA's were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNA's (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNA's, resulting in a HR of 0.66 (95%-CI 0.53-0.82). CONCLUSION Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.

Nuclear iASPP may facilitate prostate cancer progression

One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPP(Δ8/Δ8) mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression.

Career-choice readiness in adolescence: Developmental trajectories and individual differences

Developing career-choice readiness is an important task in adolescence, but current theory and research has provided a rather static view of the phenomenon. The present study investigated the development of career-choice readiness among a group of 325 Swiss students assessed four times every 5 months from seventh through eighth grade. A variable-centered approach applying latent curve modeling showed not only a linear increase of readiness over time but also significant inter-individual differences in the level and development of readiness. Higher levels were predicted by more self-esteem and generalized self-efficacy and fewer perceived barriers while increase in readiness was predicted by increase in occupational information. A person-centered approach applying latent class-growth analysis identified four distinct developmental trajectories: high-increasing (42%), high-decreasing (5%), moderate-increasing (42%), and constantly low (11%). Students with different trajectories showed significant differences in core self-evaluations, occupational knowledge, and barriers. The results suggest that environmental demands promote a developmental trend in readiness development that overrules individual differences for the majority of students. Individual differences affect the level of readiness to a greater extent than the process of its development. Career information seems pivotal for readiness increase.

Callings in career: A typological approach to essential and optional components

A sense of calling in career is supposed to have positive implications for individuals and organizations but current theoretical development is plagued with incongruent conceptualizations of what does or does not constitute a calling. The present study used cluster analysis to identify essential and optional components of a presence of calling among 407 German undergraduate students from different majors. Three types of calling merged: “negative career self-centered”, “pro-social religious”, and “positive varied work orientation”. All types could be described as vocational identity achieved (high commitment/high self-exploration), high in career confidence and career engagement. Not defining characteristics were centrality of work or religion, endorsement of specific work values, or positivity of core self-evaluations. The results suggest that callings entail intense self-exploration and might be beneficial because they correspond with identity achievement and promote career confidence and engagement while not necessarily having pro-social orientations. Suggestions for future research, theory and practice are suggested.

Engagement in adolescent career preparation: Social support, personality, and the development of choice decidedness and congruence

This longitudinal panel study investigated predictors and outcomes of active engagement in career preparation among 349 Swiss adolescents from the beginning to the end of eighth grade. Latent variable structural equation modeling was applied. The results showed that engagement in terms of self- and environmental-exploration and active career planning related positively to interindividual increases in career decidedness and choice congruence. More perceived social support, early goal decidedness, and particular personality traits predicted more engagement. Support and personality impacted outcomes only mediated through engagement. Early decidedness and congruence were significant predictors of their respective later levels. Implications for practice are presented.

Who seeks career counselling? A prospective study of personality and career variables among Swiss adolescents

This study investigated whether career adaptability, personality, attitude towards career counselling and some demographic variables predict the help seeking behaviour in career counselling among 330 Swiss adolescents in eighth grade. The results indicated that boys were less likely to seek help and that career related variables and attitude but not personality significantly predicted help-seeking. Specifically, help seeking related positively to undecidedness and positive perception of career counselling. Implications for school and career counsellors and suggestions for future research are presented.

Vocational Interests and Career Goals: Development and Relations to Personality and Middle Adolescence

Cross-sectional research implies a close relation of vocation interests, goals, and traits, yet little is known about their reciprocal development over time. This longitudinal study examined development of Things/People (T/P) and Data/Ideas (D/I) vocational interests and career goals in relation to Big Five personality traits among 292 Swiss adolescents with a cross-lagged panel design with two measurement points over 1 year from seventh to eighth grade. Interests and goals were significantly related within time and showed significant interactions across time. Traits related significantly and equally to interests and goals within time and predicted their development across time except for T/P goals. Goals and interests possessed incremental validity above traits in affecting each other. Implications include the need to account for dynamic processes in the development of goals and interests and their systematic relation to traits in theory and practice.

Positive Adolescent Career Development: The Role of Intrinsic and Extrinsic Work Values

This longitudinal study of 268 Swiss adolescents, spanning across 8th grade, investigated the relation of intrinsic and extrinsic work values to positive career development in deciding, planning, and exploring. Results showed that girls reported more intrinsic and fewer extrinsic work values compared with boys. Students with an immigration background reported more extrinsic values than did students of Swiss nationality. When gender, nationality, and scholastic achievement were controlled, more general work value endorsement was a significant predictor of an above-average increase in career development over the course of the school year. Endorsement of more intrinsic but not extrinsic work values was related to positive career development.

The role of chance events in the school-to-work transition: The influence of demographic, personality and career development variables

Chance events are considered important in career development, yet little empirical research is available on their predictors and consequences. The present study investigated socio-demographic (gender, nationality, school-type), personality (openness, locus of control) and career development variables (career decidedness, career planning) in relation to perceived chance events with a retrospective (N = 229, eleventh grade), and 1-year longitudinal prospective study (N = 245, eighth/ninth grade) among Swiss adolescents. The results showed that the majority of both groups reported a significant influence of chance events on their transition from compulsory school to vocational education or high school. Importance of chance events related to socio-demographics and personality but not career preparation. Career preparation and chance events predicted subjective career success in terms of wish correspondence and overall satisfaction with transition outcome among the younger cohort. Implications include the necessity to integrate both thorough career preparation and chance events in theory and counseling practice.

Swiss Adolescents' Career Aspirations: Influence of Context, Age, and Career Adaptability

This study investigated the content, realism, stability, and coherence of the career aspirations of 262 students in seventh grade in Switzerland (ages 13-15 years). The content analysis revealed that 82% of the participants named at least one realistic career aspiration, and aspirations showed clear resemblance to existing opportunities in the environment. Quantitative analyses confirmed the hypotheses that realism and stability of aspirations over a 10-month period could better be predicted by individual degree of career adaptability as measured by planfulness and exploration than by chronological age when grade level was controlled for. Coherence of aspirations was not related to age or adaptability. Students attending basic scholastic requirements school tracks reported more adaptability but not more realistic, stable, or coherent aspirations compared to students in advanced requirements tracks.

Adaptation of career goals to self and opportunities in early adolescence

Development of career goals that are adapted to self and opportunities is a central component of adolescent career preparation. The present longitudinal study (conducted throughout the eighth grade with three assessment points) investigated how 330 Swiss adolescents simultaneously adapt career goals to interests, scholastic achievement and environmental opportunities. Results demonstrated that students increasingly adapt their goals to the environment. Mean adaptation to environment related positively to degree of adaption to interests and achievement. Increased adaptation to environment over time related to increased adaptation to achievement but to decreased adaptation to interests. Gender, attended school type and nationality moderated adaptation processes. Structurally disadvantaged students (girls, lower requirements school track, immigrant students) reported more conflict in aligning adaptation to environment with adaptation to interests.

Career adaptability development in adolescence: Multiple prdictors and effect on sense of power and life satisfaction

This longitudinal panel study investigated predictors of career adaptability development and its effect on development of sense of power and experience of life satisfaction among 330 Swiss eighth graders. A multivariate measure of career adaptability consisting of career choice readiness, planning, exploration, and confidence was applied. Based on Motivational Systems Theory four groups of predictors were assessed: positive emotional disposition, goal decidedness, capability beliefs and social context beliefs. Influence of gender, age, immigration background, parental educational level, and college-bound or vocational education plans were also assessed. Perceived social support and positive emotional disposition, non-immigration background, and continuing to vocational education were single significant predictors of more career adaptability development over the school year. Supporting the connection of career adaptability and positive youth development, increase in career adaptability over time predicted increase in sense of power and experience of life satisfaction.

Hope in Adolescent Careers: Mediating Effects of Work Motivation on Career Outcomes in Swiss Apprentices

Being hopeful is critical for individuals who are engaged in vocational pursuits. However, the empirical research examining how and why hope is related to work and career outcomes remains sparse. We evaluate a model that proposes that dispositional hope affects job performance and turnover intentions through increased work motivation in terms of autonomous goals (reason to motivation), positive affective experience at work (energized to motivation), and occupational self-efficacy beliefs (can do motivation). The hypotheses were tested among 590 Swiss adolescents in vocational education and training using path analysis and multiple mediation analyses. The results revealed that hope was positively related to all three motivational states and supervisor-rated job performance and negatively related to turnover intentions. Positive affect mediated the effects of hope on turnover intentions and performance. Autonomous goals mediated the effects of hope on turnover intentions. These results support the importance of hope to employee well-being and organizational outcomes.