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Aim: Since reliable response predictors to platinum-based chemotherapy in ovarian cancer (OC) are scarce, we characterize NCALD as a predictive biomarker. Materials & methods: NCALD mRNA (n = 100) and protein (n = 102) expression was analyzed in OC samples and associated with patient outcome. A stable OC cell line knockdown was generated and cellular response to platinum was explored. Results: High NCALD mRNA and protein expression was significantly associated with longer overall patient survival (p = 0.037/0.002). Knockdown experiments revealed a significant association between cisplatin sensitivity and NCALD expression. Conclusion: Low NCALD expression was associated with reduced sensitivity to platinum-based chemotherapy. NCALD may be a new biomarker candidate to identify patients who might benefit from platinum-based chemotherapy.

In the last few years, plastic has become an issue of current interest as tremendous ecological effects from plastic littering have become visible. Taking the role of consumers into account, activities comprising purchasing decisions and political engagement are expected to help prevent plastic pollution. The goal of this study was to examine antecedents of three potential plastic reduction activities: purchasing, activism, and policy support. Based on well-established psychological models of pro-environmental behaviour (i.e. theory of planned behaviour, norm activation model), an online survey (N = 648) was administered and analysed via structural equation modelling. Results revealed that personal norms were a relevant predictor of all three intentions. Whereas sufficiency orientation and collective efficacy predicted only activism intention and policy support intention, perceived behavioural control was the strongest predictor of purchasing intentions. Regarding behaviour, people with high activism intentions and sufficiency orientation were more likely to choose a plastic-free incentive instead of the conventional shopping voucher. This study highlights psychological antecedents of plastic reduction. An integrated model showed that rational cost–benefit considerations as well as morality serve as drivers of reducing plastic consumption. Implications for the promotion of plastic-free consumption are discussed.

Patient characteristics of the whole breast cancer cohort used for CX3CL1 expression analysis (n=250)

CX3CL1 mRNA expression is associated with improved recurrence-free, distant-metastasis free, and overall survival in human breast cancer.

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2+) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell–mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low–expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell–dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low–expressing cancers and render it a potential predictive biomarker to determine therapy responders.

Supplementary Data from DNA Methylation Markers Predict Outcome in Node-Positive, Estrogen Receptor-Positive Breast Cancer with Adjuvant Anthracycline-Based Chemotherapy

Supplementary Table S2 from Association of DNA Methylation of Phosphoserine Aminotransferase with Response to Endocrine Therapy in Patients with Recurrent Breast Cancer

To understand the biological basis of resistance to endocrine therapy is of utmost importance in patients with steroid hormone receptor–positive breast cancer. Not only will this allow us prediction of therapy success, it may also lead to novel therapies for patients resistant to current endocrine therapy. DNA methylation in the promoter regions of genes is a prominent epigenetic gene silencing mechanism that contributes to breast cancer biology. In the current study, we investigated whether promoter DNA methylation could be associated with resistance to endocrine therapy in patients with recurrent breast cancer. Using a microarray-based technology, the promoter DNA methylation status of 117 candidate genes was studied in a cohort of 200 steroid hormone receptor–positive tumors of patients who received the antiestrogen tamoxifen as first-line treatment for recurrent breast cancer. Of the genes analyzed, the promoter DNA methylation status of 10 genes was significantly associated with clinical outcome of tamoxifen therapy. The association of the promoter hypermethylation of the strongest marker, phosphoserine aminotransferase (PSAT1) with favorable clinical outcome was confirmed by an independent quantitative DNA methylation detection method. Furthermore, the extent of DNA methylation of PSAT1 was inversely associated with its expression at the mRNA level. Finally, also at the mRNA level, PSAT1 was a predictor of tamoxifen therapy response. Concluding, our work indicates that promoter hypermethylation and mRNA expression of PSAT1 are indicators of response to tamoxifen-based endocrine therapy in steroid hormone receptor–positive patients with recurrent breast cancer.

Contains fulltext : 290914.pdf (Publisher’s version ) (Open Access) BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m(2) (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

INTRODUCTION The current study examined whether and how severe injustice such as a school attack threatens the belief in a just world (BJW). METHOD We collected longitudinal data on the BJW from adolescents in China who witnessed random school attacks on the news (N = 227). RESULTS Change analyses provided evidence that the BJW increased after witnessing severe injustice. Furthermore, we tested for moderating effects of buffer variables, such as life satisfaction and perceived social support, on change in the BJW. Findings showed that these variables buffered the threat to the BJW after observing unfairness. DISCUSSION We discuss these results in the context of justice motive theory and suggest implications for future research and practical implications.

The use of journal impact factors and other metric indicators of research productivity, such as the h-index, has been heavily criticized for being invalid for the assessment of individual researchers and for fueling a detrimental “publish or perish” culture. Multiple initiatives call for developing alternatives to existing metrics that better reflect quality (instead of quantity) in research assessment. This report, written by a task force established by the German Psychological Society, proposes how responsible research assessment could be done in the field of psychology. We present four principles of responsible research assessment in hiring and promotion and suggest a two-phase assessment procedure that combines the objectivity and efficiency of indicators with a qualitative, discursive assessment of shortlisted candidates. The main aspects of our proposal are (a) to broaden the range of relevant research contributions to include published data sets and research software, along with research papers, and (b) to place greater emphasis on quality and rigor in research evaluation.

Based on the assumption that disclosing explicit populist radical-right (PRR) attitudes and voting intentions for PRR parties may be inhibited by a social desirability bias, this paper aims at developing a measure for implicit populist attitudes (IAT) and at assessing its explanatory power for the prediction of PRR party support. Using data from a German online survey (N = 898), the populism-IAT is tested against corresponding direct measures of populist attitudes and anti-immigrant attitudes to predict voting propensity for the German PRR party Alternative für Deutschland (AfD). Results reveal that social desirability concerns indeed restrict the likelihood of reporting a high propensity of PRR vote; however, direct measures turn out as best predictors for self-reported voting intentions. Inconsistencies between implicit and explicit attitudes may indicate sensitivity to social (un-)desirability perceptions, when attitudes are displayed on the implicit but not on the explicit level. We find such incongruencies for 9% of our respondents regarding populist attitudes, and for 21% regarding anti-immigrant attitudes, indicating that the latter are considered even more undesirable. In light of our findings, we discuss the potential explanatory power of implicit attitudes for less deliberate forms of political behavior and the assumption of populist and anti-immigrant attitudes still being regarded as socially undesirable in Germany.

Studies complementing the assessment of symptoms right before (t1), right after therapy (t2), and at follow-up (t3) with an assessment of symptoms preceding the waiting period without intervention (t0) have revealed substantial t0–t1 changes. We discuss this phenomenon based on our own data and address the following questions: does it make sense to compare symptoms at the beginning of therapy (t1) with symptoms at the end of therapy (t2) or at follow-up (t3)? Or does it make more sense to use t0 instead of t1? We argue for the latter alternative based on the following reasons. (1) Symptom descriptions at t0 are realistic. (2) Expecting therapy success mitigates symptom descriptions at t1. (3) Security signals emitted from the therapy context also mitigate symptoms, especially anxiety, at t1. (4) Regression toward the mean reduces the validity of single occasion assessments. Controlling for regression requires two occasions of measurement with a short time interval at t0 (t01 and t02). It follows from this reasoning that therapy success should be evaluated using the t02–t2 and t02–t3 intervals. Single case evaluations require reliable critical differences. This will be illustrated using a concrete example. The validity of treatment evaluation can be increased via the elimination of non-pathological symptom scores. A simplified calculation of cut-off scores can facilitate applied treatment evaluation. Unspecific t0–t1 changes do not challenge therapy effects according to t1–t2 changes. Rather, they are part of the whole therapy process.

According to the congruence hypothesis, job and study satisfaction will be higher when individual interests and the respective environment (both conceptualised according to Holland’s RIASEC model) are congruent. As our target group were teacher students, all participants who did not intend to become a teacher or did not meet other inclusion criteria (e.g., no missing data on relevant variables) were removed from the sample, resulting in a final sample of N = 1171. Teacher students completed questionnaires on their vocational interests and their satisfaction with course content. To obtain an assessment of the environment (study majors), N = 166 lecturers were asked to rate their courses with respect to Holland’s RIASEC model. As previous findings have indicated that conclusions are influenced by the congruence measure that is used, we applied two different approaches. First, we computed the profile correlation between the individual interest profile and the environmental profile for each individual to measure congruence. Profile correlation scores were then correlated with satisfaction with course content scores. This correlation was significant (r = .21, p

In Western samples, individuals differ systematically in the importance they assign to matters of justice and injustice, and dispositional Justice Sensitivity can be differentiated according to the perspectives of victim, observer, beneficiary, and perpetrator. In a cross-cultural comparison between the Philippines, Germany, and Australia ( N = 677 students), we investigated whether Justice Sensitivity can be equivalently described by these four perspectives, whether measurement instruments have invariant psychometric properties, and whether the psychological relevance of the Justice Sensitivity perspectives for cooperation behavior differs between these cultural contexts. The results of multigroup confirmatory factor analyses support weak measurement invariance and invariant associations between Justice Sensitivity perspectives and trust game decisions. Across cultures, victim sensitivity predicted reluctance to cooperate under threat of exploitation, and observer, beneficiary, and perpetrator sensitivities predicted cooperation under temptation. Our study extends insight into Justice Sensitivity to underresearched cultural contexts of urban and rural Philippines.

Zusammenfassung. In Studie 1 wurde die Validität des Fragebogens FEMOLA (Fragebogen zur Erfassung der Motivation für die Wahl des Lehramtsstudiums) durch Überprüfung der internen Struktur untersucht. Hierzu wurden anhand von Daten von N = 1467 Lehramtsstudierenden zwei in der Literatur vorgeschlagene Faktorenstrukturen verglichen, wobei sich zeigte, dass eine Lösung mit sieben Faktoren besser zu den Daten passte als die ursprünglich vorgeschlagene Lösung mit sechs Faktoren. Anschließend wurde die Messinvarianz über nach angestrebter Schulform gebildete Gruppen von Lehramtsstudierenden (Grundschule, Förderschule, Sekundarstufe I und Gymnasium) untersucht; hier konnte schwache Invarianz (gleiche Faktorladungen) festgestellt werden. In Studie 2 wurde anhand von Längsschnittdaten ( N = 442) untersucht, ob pädagogisches Wissen und selbst eingeschätzte Unterrichtskompetenz bei Lehramtsstudierenden anhand der Studienwahlmotivation und Zielorientierungen (Lernziele, Annäherungs- und Vermeidungs-Leistungsziele sowie Arbeitsvermeidung) vorhergesagt werden können. Dabei wurde mittels eines Strukturgleichungsmodells u.a. die Annahme geprüft, dass die Effekte der Studienwahlmotivation durch die Zielorientierungen vermittelt werden; der Einfluss von Intelligenz wurde kontrolliert. Erwartungskonform war die Studienwahl aus intrinsischer Motivation mit einer höheren Lernzielorientierung und einer niedrigeren Tendenz zur Arbeitsvermeidung verbunden; die Studienwahl aus extrinsischer Motivation hingegen mit höheren Ausprägungen von Annäherungs- und Vermeidungs-Leistungszielen sowie einer stärkeren Tendenz zur Arbeitsvermeidung. Die durch die Zielorientierungen vermittelten Pfade von den Studienwahlmotivations-Faktoren zu den Kriterien erwiesen sich jedoch weitgehend als nicht signifikant. Beide Kriterien waren zudem nur schwach miteinander korreliert und für Intelligenz ergab sich nur mit dem pädagogischen Wissen ein signifikanter Zusammenhang. Ursachen für diese Befunde und Abweichungen von vorliegenden Studien werden diskutiert.

Background: Clinical observations suggest that many patients with obsessive-compulsive disorder (OCD) suffer from severe feelings of guilt. These observations, which are consistent with psychoanalytic assumptions (overly strict super-ego), have rarely been subjected to systematic empirical investigation. Even cognitive approaches broach the issue of guilt as a facet of OCD only indirectly. The purpose of our research was to investigate whether more patients with OCD report feelings of guilt as compared to healthy controls. Patients and Method: One hundred individuals (34 males, 66 females) participated in our study. Fifty participants were OCD patients according to IDCL criteria and in stationary treatment. An additional sample of 50 participants consisted of healthy controls matched for age, gender, and job status. All participants were interviewed via Structured Clinical Interview for DSM-IV. Two scales measured proneness to guilt: (a) Trait Guilt Scale (TGS) and (b) Test of Self-Conscious Affect (TOSCA). A new guilt-inducing scenario-based test (SIT) including two scales (SIT 1, SIT 2) served the same purpose. The SIT was developed by the authors and uses scenarios derived from interviews with patients and experts. Finally, we assessed depression (Beck Depression Inventory; BDI) and obsessive compulsiveness (Yale-Brown Obsessive Compulsive Scale; Y-BOCS) in the OCD sample only. Results: Our data confirm stronger feelings of guilt among OCD patients as compared to matched controls. Patients and controls differed mostly on the TGS and the 2 SIT scales. TOSCA guilt scores did not differ reliably between patients and controls. Finally, as a side result, OCD patients reported elevated depression scores. Discussion: The results of this study suggest that feelings of guilt should receive more attention than previously in the treatment of OCD. OCD patients suffer not only from their compulsive cognitions and actions but also from feelings of guilt. Exposure therapy of OCD should be complemented by treatment components that specifically address feelings of guilt.

Hintergrund: Zwangspatient(inn)en leiden, wie klinische Beobachtungen zeigen, häufig unter starker Schuld, was sich auch mit frühen psychoanalytischen Annahmen (übermäßig hohes Über-Ich) deckt, bis heute aber nicht spezifisch empirisch untersucht wurde. Auch aktuelle kognitionspsychologische Ansätze fokussieren auf diese emotionale Seite des Zwangsgeschehens nur indirekt. Unser Anliegen be­stand daher in der Untersuchung, inwieweit Zwangspatient(inn)en ausgeprägteres Schulderleben aufweisen als Personen ohne Zwang. Patient(inn)en und Methode: 100 Proband(inn)en (34 männlich, 66 weiblich) nahmen an der Studie teil, davon 50 mit einer gesicherten, IDCL-bestätigten Diagnose Zwangsstörung während eines stationären Auf­enthalts, und 50 gematchte Proband(inn)en aus der Normalbevölkerung ohne Zwang. Alle Teilnehmenden erhielten eine Untersuchung mit dem Strukturierten klinischen Interview für DSM-IV (SKID); auch wurde die Depression (Beck Depression Inventory; BDI) erhoben. Mit den Patient(inn)en wurde sodann die Yale-Brown Obsessive Compulsive Scale (Y-BOCS) durchgeführt. Zu Schuld bearbeiteten alle Teilneh­menden 2 nichtklinische Instrumente: (a) Schuldinventar, Traitvariante, und (b) Test of Self-Conscious Affect (TOSCA). Darüber hinaus wurde für diese Studie der Schuldinduzie­rende Szenarien Test (SIT), basierend auf vorangegangenen Interviews mit Patient(inn)en und Expert(inn)en, entwickelt (2 Skalen) und von allen Proband(inn)en bearbeitet. Er­gebnisse: Die Annahme höheren Schulderlebens von Zwangspatient(inn)en wird durch die Daten gestützt. Sehr deutliche Unterschiede zwischen ihnen und den Kon­trollproband(inn)en fanden sich für Schuld (Trait) und die Skalen SIT 1 und SIT 2; der Schuldwert im TOSCA war dagegen unspezifisch. Als Nebenbefund sind hohe Depressions­werte bei den Zwangspatient(inn)en zu verzeichnen. Diskussion: Durch die Befunde wird nahegelegt, dass in der Behandlung von Patient(inn)en mit einer Zwangserkrankung stärker als bisher das Schulderleben thematisiert werden sollte. Die Patient(inn)en leiden neben ihren Zwangshandlungen und -gedanken stark darunter. Leitliniengerechte Behandlung via Expositionen sollte insofern ergänzt werden um spezifische Behandlungsabschnitte zu Schuld und ­Schuldverarbeitung.

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2+) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell–mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low–expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell–dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low–expressing cancers and render it a potential predictive biomarker to determine therapy responders.

Stereotypes influence teachers’ perception of and behaviour towards students, thus shaping students’ learning opportunities. The present study investigated how 315 Australian pre-service teachers’ ...

Background Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4–7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4–7-transfected (OV-KLK4–7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors. Methods With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues. Results We demonstrated that KLK4–7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4–7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7. Conclusion These findings imply that KLK4–7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4–7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

Gene expression of a variety of the 15 members of the KLK serine protease family is dysregulated in ovarian cancer. We aimed at determining the clinical relevance of KLK13 and KLK14 mRNA expression in tumor tissues of a homogeneous patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO stage III/IV). mRNA expression levels of KLK13 and KLK14 were assessed by quantitative PCR in tumor tissue of 91 patients and related with clinical factors and patients’ outcome. There was no significant association of KLK13 and KLK14 mRNA expression with the clinical factors ascitic fluid volume or residual tumor mass. In univariate Cox regression analysis, elevated KLK13 mRNA levels were significantly linked with shorter progression-free (PFS; hazard ratio [HR] = 1.97, P = 0.020) and overall survival (OS; HR = 1.81, P = 0.041). High KLK14 mRNA levels were significantly associated with prolonged PFS (HR = 0.44, P = 0.017) and showed a trend towards significance for OS (HR = 0.55, P = 0.070). In multivariable analysis, including the factors age, residual tumor mass, ascitic fluid volume, KLK13, and KLK14, both KLKs, apart from residual tumor mass, remained statistically independent predictive markers: patients with high KLK13 mRNA expression levels displayed a more than twofold increase risk for shorter PFS (HR = 2.14, P = 0.020) as well as OS (HR = 2.05, P = 0.028), whereas elevated KLK14 mRNA values were found to be significant for both, prolonged PFS (HR = 0.36, P = 0.007) and OS (HR = 0.46, P = 0.037). These results indicate that in advanced high-grade serous ovarian cancer KLK13 may become proficient for tumor-supporting functions, whereas KLK14 may have adopted tumor-suppressing activity.

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. Results: The cut-off for the PITX2 methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Conclusions: Early-stage lymph node-positive breast cancer patients with low PITX2 methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high PITX2 DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens.

This study investigated the relationship between teachers’ beliefs about gifted students’ characteristics compared to students with average-ability and the teachers’ motivation (i.e., enthusiasm, s...

Cathepsin B (CTSB) is a lysosomal cysteine protease that has been linked to the progression of breast cancer, for example by activation of other proteases and tumor-promoting cytokines, thereby supporting tumor invasion and metastasis. Previously, it was shown that CTSB cleaves and inactivates C-X-C motif chemokine receptor 3 (CXCR3) chemokines. As CXCR3 ligands have been demonstrated to induce proteases in cancer cells, the present study hypothesized that they may also affect CTSB in breast cancer cells. The results demonstrated that the human breast cancer tumor cell lines MCF-7 and MDA-MB-231 express the CXCR3 splice variants A and B and CTSB. Upon binding to CXCR3, the two chemokine ligands C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 trigger upregulation of CTSB in these breast cancer cells, whereas the CXCR3-B-specific ligand CXCL4 has no such effect, suggesting the involvement of CXCR3-A in the regulation of CTSB. In early-stage human breast cancer specimens (n=81), overexpression of CXCR3 is associated with statistically significant poorer overall survival, independent of lymph node status, tumor size and nuclear grading (hazard ratio=1.99; 95% confidence interval=1.00–3.97; P=0.050). In conclusion, the data from the current study propose a so far unknown mechanism by which breast cancer cells may exploit tumor-suppressive chemokines to enhance their invasiveness and reduce immune cell infiltration by the degradation of these chemokines. This mechanism may support the established unfavorable prognostic feature of CXCR3 expression in breast cancer.

Background: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown. Methods: One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3. Results: High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n=70, CXCL9: HR 0.41; P=0.006; CXCL10: HR 0.46; P=0.010) which was confirmed in an independent validation set (n=114; CXCL9: HR 0.60; P=0.019; CXCL10: HR 0.52; P=0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-κB activation and inhibited chemokine release. Conclusion: Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.

To tackle the plastic problem, the worldwide campaign &lsquo, Plastic Free July&rsquo, aims at encouraging people to reduce single-use plastics during the month of July. To get people started with new behavior patterns, so-called &lsquo, windows of opportunity&rsquo, &mdash, periods where people become open for new experiences&mdash, are expected to matter. Therefore, the current study evaluated if an arbitrary month that is framed as an opportunity for change can interrupt people in their daily routines and reduce plastic consumption. An online survey (n = 509) with repeated measures (n = 366) was conducted including one experimental and one control group. The experimental group was invited to reduce their single-use plastic consumption during July in line with the &lsquo, campaign. Results revealed that, in this action period, single-use plastic consumption was slightly but significantly lower in the experimental than in the control group, which did not receive any information about &lsquo, The campaign seemed to be more effective for participants with low pro-environmental identity. Path analysis revealed that plastic consumption (prior to the intervention) was significantly predicted by perceived difficulty, habits, and pro-environmental identity. Policy support was predicted by problem awareness, pro-environmental identity and perceived barriers. We conclude with recommendations for plastic-free purchase and policy support.

Significant evidence has accumulated that DNA-methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene can serve as a prognostic and predictive biomarker in breast cancer. PITX2 DNA-methylation data have been obtained so far from microarray and polymerase chain reaction (PCR)-based research tests. The availability of an analytically validated in vitro methylation-specific real-time PCR assay format (therascreen PITX2 RGQ PCR assay) intended for the determination of the percent methylation ratio (PMR) in the (PITX2) promoter 2 prompted us to investigate whether the clinical performance of these different assay systems generate comparable clinical outcome data. Mathematically converted microarray data of a previous breast cancer study (n = 204) into PMR values leads to a PITX2 cut-off value at PMR 14.73. Recalculation of the data to experimentally equivalent PMRs with the PCR PITX2 assay leads to a cut-off value at PMR 12 with the highest statistical significance. This cut-off predicts outcome of high-risk breast cancer patients to adjuvant anthracycline-based chemotherapy (n = 204; Hazard Ratio 2.48; p therascreen PITX2 RGQ PCR assay is an analytically validated test with high reliability and robustness and predicts outcome of high-risk breast cancer patients to anthracycline-based chemotherapy.

This article proposes an optical measurement of movement applied to data from video recordings of facial expressions of emotion. The approach offers a way to capture motion adapted from the film industry in which markers placed on the skin of the face can be tracked with a pattern-matching algorithm. The method records and postprocesses raw facial movement data (coordinates per frame) of distinctly placed markers and is intended for use in facial expression research (e.g., microexpressions) in laboratory settings. Due to the explicit use of specifically placed, artificial markers, the procedure offers the simultaneous measurement of several emotionally relevant markers in a (psychometrically) objective and artifact-free way, even for facial regions without natural landmarks (e.g., the cheeks). In addition, the proposed procedure is fully based on open-source software and is transparent at every step of data processing. Two worked examples demonstrate the practicability of the proposed procedure: In Study 1(N= 39), the participants were instructed to show the emotions happiness, sadness, disgust, and anger, and in Study 2 (N= 113), they were asked to present both a neutral face and the emotions happiness, disgust, and fear. Study 2 involved the simultaneous tracking of 14 markers for approximately 12 min per participant with a time resolution of 33 ms. The measured facial movements corresponded closely to the assumptions of established measurement instruments (EMFACS, FACSAID, Friesen & Ekman, 1983; Ekman & Hager, 2002). In addition, the measurement was found to be very precise with sub-second, sub-pixel, and sub-millimeter accuracy.

Background Elevated levels of intratumoral uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to identify patients who might particularly benefit from adjuvant chemotherapy. The clinical utility of ELISA-based protein analysis is, however, greatly limited by the requirement of fresh tumor tisssue. We have therefore evaluated in a large clinical trial patient cohort with long-follow-up whether immunohistochemical detection of uPA and PAI-1 in FFPE archived tumor samples is also able to identify women with poor prognosis. Patients and Methods 547 postmenopausal women with hormone receptor–positive, early breast cancer who had received at least 5 years of endocrine therapy in the prospectively designed ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. uPA and PAI-1 protein expression was evaluated by immunohistochemistry, and correlated with distant-disease free (DDFS) and overall survival (OS). Results Stromal co-expression of uPA and PAI-1 was detected in 166 of 276 (60%) evaluable tumor samples and was weakly associated with tumor size (p=0.012, Chi Square test) but not with age, nodal status, grading, or receptor status. Women with intratumoral uPA/PAI-1 expression were more likely to have a shorter DDFS in multivariate analysis (HR for relapse p=1.870; 95% CI 1.184-2.955; p=0.007 Cox regression analysis) and and OS (adjusted HR for death p=1.291; 95% CI 0.928-1.795; p=0.129) than women without. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DDFS (p Conclusions Stromal co-expression of uPA and PAI-1 in breast cancer samples predicts poor DDFS and OS in postmenopausal women with hormone-receptor positive early-stage breast cancer who receive endocrine therapy. Citation Format: Singer CF, Filipits M, Jahn S, Abete L, Jakesz R, Greil R, Bauernhofer T, Kwasny W, Seifert M, Fitzal F, Schmitt M, Moinfar F, Gnant M. Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-21.

miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or miR-221-depleted cells were employed for qRT-PCR and Western blots to show associations of uPAR with miR-221/-222. To substantiate direct targeting of miR-221/-222 within 3' UTR of the uPAR isoform 2, in silico analysesand in vitro assays were conducted. Significant associations between miR-221 and uPAR isoform 2 expressions were observed at the mRNA and protein levels in breast cancer cells representing TNBC. For the first time, the uPAR isoform 2 was demonstrated as direct target for miR-221/-222. Inhibition of miR-221 reduced uPAR protein expression and expression of the tumor cell invasion markers vimentin and RHOC. These results demonstrate a direct and positive regulation of the secreted uPAR isoform 2 by miR-221, increasing its protein expression, a prerequisite for malignancy, while the other uPAR isoforms (1, 3 and 4) are indirectly regulated through miR-10b and miR-221/-222. By targeting uPAR isoforms and/or miRNA-221/-222, the diagnosis and therapy of breast cancer, in particular in TNBC, could be significantly improved.

Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (

High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and the HER2 receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of the PITX2 (paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application of PITX2 as a predictive biomarker to personalize breast cancer management.

Following primary debulking surgery, the presence of a residual tumor mass is one of the most important prognostic factors in ovarian cancer. In a previous study, we established the OVSCORE, an algorithm to predict surgical outcome, based on the clinical factors of nuclear grading and ascitic fluid volume, plus the cancer biomarkers, kallikrein-related peptidases (KLKs), KLK6 and KLK13. In the present study, OVSCORE performance was tested in an independent ovarian cancer patient cohort consisting of 87 patients. The impact of KLKs, KLK5, 6, 7 and 13 and other clinical factors on patient prognosis and outcome was also evaluated. The OVSCORE proved to be a strong and statistically significant predictor of surgical success in terms of area under the receiver operating characteristic curve (ROC AUC, 0.777), as well as positive and negative predictive value in this independent study group. KLK6 and 13 individually did not show clinical relevance in this cohort, but two other KLKs, KLK5 and KLK7, were associated with advanced FIGO stage, higher nuclear grade and positive lymph node status. In the multivariate Cox regression analysis for overall survival (OS), KLK7 had a protective impact on OS. This study confirms the role of KLKs in ovarian cancer for surgical success and survival, and validates the novel OVSCORE algorithm in an independent collective. As a key clinical application, the OVSCORE could aid gynecological oncologists in identifying those ovarian cancer patients unlikely to benefit from radical surgery who could be candidates for alternative therapeutic approaches.

International guidelines recommend anthracycline-based chemotherapy for high-risk breast cancer patients as the standard-of-care, but not all patients do equally benefit from such a chemotherapy. The novel therascreen® PITX2 RGQ PCR assay is a quantitative in vitro methylation-specific real-time PCR test (qMSP), intended for the determination of the percent methylation ratio (PMR) in the pituitary homeobox 2 (PITX2) promoter 2 expressed by primary breast cancer tumor tissue (FFPE-material). After bisulfite exposure of extracted DNA to distinguish between methylated and non-methylated PITX2 DNA, the percent methylation ratio (PMR) of the PITX2 gene promoter 2 is quantified by qMSP. The PMR obtained does provide information to the treating physician about whether a patient is likely to respond to anthracycline-based chemotherapy. Data will be presented for 205 high-risk lymph node-positive, estrogen receptor-positive, HER2-negative breast cancer patients, treated with adjuvant anthracycline-based chemotherapy. The PITX2 pre-defined cut-off value of PMR = 12 demonstrated a statistically significant differentiation between low- and high-risk breast cancer patient for the primary endpoint DFS, also for patients treated with endocrine therapy in addition to anthracycline-based adjuvant therapy. High-risk lymph node-positive, estrogen-receptor-positive, HER2-negative breast cancer patients, with PITX2 methylation defined as low (PMR ≤ 12), are sufficiently treated with anthracycline-based chemotherapy, irrespective if treated with additional tamoxifen. High-risk lymph node-positive, estrogen receptor-positive, HER2-negative breast cancer patients with PITX2 methylation defined as high (PMR > 12) should avoid anthracycline-based chemotherapy. These patients are recommended to switch to other chemotherapy regimens, since with this PITX2-characteristics, the patient has a lower probability to respond to anthracycline-based chemotherapy.

Background. Tumor tissue-associated KLKs (kallikrein-related peptidases) are clinically important biomarkers that may allow prognosis of the cancer disease and/or prediction of response/failure of cancer patients to cancerdirected drugs. Regarding the female/male reproductive tract, remarkably, all of the fifteen KLKs are expressed in the normal prostate, breast, cervix uteri, and the testis, whereas the uterus/endometrium and the ovary are expressing a limited number of KLKs only. Conclusions. Most of the information regarding elevated expression of KLKs in tumor-affected organs is available for ovarian cancer; depicting them as valuable biomarkers in the cancerous phenotype. In contrast, for breast cancer, a series of KLKs was found to be downregulated. However, in breast cancer, KLK4 is elevated which is also true for ovarian and prostate cancer. In such cases, selective synthetic KLK inhibitors that aim at blocking the proteolytic activities of certain KLKs may serve as future candidate therapeutic drugs to interfere with tumor progression and metastasis.

In this target article, we argue that personality processes, personality structure, and personality development have to be understood and investigated in integrated ways in order to provide comprehensive responses to the key questions of personality psychology. The psychological processes and mechanisms that explain concrete behaviour in concrete situations should provide explanation for patterns of variation across situations and individuals, for development over time as well as for structures observed in intra–individual and inter–individual differences. Personality structures, defined as patterns of covariation in behaviour, including thoughts and feelings, are results of those processes in transaction with situational affordances and regularities. It cannot be presupposed that processes are organized in ways that directly correspond to the observed structure. Rather, it is an empirical question whether shared sets of processes are uniquely involved in shaping correlated behaviours, but not uncorrelated behaviours (what we term ‘correspondence’ throughout this paper), or whether more complex interactions of processes give rise to population–level patterns of covariation (termed ‘emergence’). The paper is organized in three parts, with part I providing the main arguments, part II reviewing some of the past approaches at (partial) integration, and part III outlining conclusions of how future personality psychology should progress towards complete integration. Working definitions for the central terms are provided in the appendix. Copyright © 2017 European Association of Personality Psychology

High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and theHER2receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of thePITX2(paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application ofPITX2as a predictive biomarker to personalize breast cancer management.

Replicability of findings is at the heart of any empirical science. The aim of this article is to move the current replicability debate in psychology towards concrete recommendations for improvement. We focus on research practices but also offer guidelines for reviewers, editors, journal management, teachers, granting institutions, and university promotion committees, highlighting some of the emerging and existing practical solutions that can facilitate implementation of these recommendations. The challenges for improving replicability in psychological science are systemic. Improvement can occur only if changes are made at many levels of practice, evaluation, and reward. Copyright © 2013 John Wiley & Sons, Ltd.

Background Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets. Methods Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174). Results Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis. Conclusions Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2663-9) contains supplementary material, which is available to authorized users.

Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients’ outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

Withdrawn by Author Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-02.

The increasing demand for personalized cancer therapy requires a strong, intense, and continuous collaboration between pre-clinical and clinical investigators. As a part of the EORTC Translational Research Divison, the EORTC PathoBiology Group (EORTC PBG), focuses on discovery and validation of cancer biomarkers, providing both scientific evidence as well as quality assurance. The clinically relevant target-identification and validation studies carried out in the last decades within the EORTC PBG represent a paradigm for EORTC studies in which laboratory investigations on human biologic material are used to support the development of drugs directed to defined target molecules. The experience acquired within the EORTC PBG with respect to standardization of cancer biomarker test kits and reagents, quality assessment/assurance of cancer biomarker determinations, development of standard operating procedures for assessment of these markers as well as instruction of methodologies and teaching of ethical issues represent a valuable contribution of the EORTC PBG to the onco-translational strategies of the EORTC.

Item does not contain fulltext The prognostic and/or predictive value of the cancer biomarkers, urokinase-type plasminogen activator (uPA) and its inhibitor (plasminogen activator inhibitor [PAI]-1), determined by ELISA in tumor-tissue extracts, was demonstrated for several cancer types in numerous clinically relevant retrospective or prospective studies, including a multicenter breast cancer therapy trial (Chemo-N0). Consequently, for the first time ever for any cancer biomarker for breast cancer, uPA and PAI-1 have reached the highest level of evidence, level-of-evidence-1. At present, two other breast cancer therapy trials, NNBC-3 and Plan B, also incorporating uPA and PAI-1 as treatment-assignment tools are in effect. Furthermore, small synthetic molecules targeting uPA are currently in Phase II clinical trials in patients afflicted with advanced cancer of the ovary, breast or pancreas. 01 november 2010