Course and predictors of posttraumatic stress and depression longitudinal symptom profiles in refugees:A latent transition model

Exposure to potentially traumatic events and post-migration living difficulties (PMLDs) may explain the high rates of posttraumatic stress disorder (PTSD) and depression in resettled refugees. Latent class analyses (LCAs) in refugees have identified subgroups that differ in symptom profiles of PTSD and comorbid symptoms. However, knowledge on longitudinal symptom profiles in refugees is sparse. Examining longitudinal PTSD and depression symptom profiles could provide information on risk factors underlying worsening of symptoms post-resettlement. Self-rated PTSD (Posttraumatic Diagnostic Scale) and depression (Patient Health Questionnaire-9) symptoms were assessed among 613 refugees who had resettled in Australia up to two years previously (W1) and at 6 months follow-up (W2). PTSD and depression symptom profiles were identified using LCAs for W1 and W2 separately. Latent transition analysis was used to examine (predictors of) changes in symptom profiles, including gender, age, trauma exposure, and PMLDs. Four classes were identified that were consistent across timepoints: a No symptoms (W1 61%; W2 68%), Low PTSD/Moderate depression (W1 16%; W2 10%), Moderate PTSD/depression (W1 16%; W2 14%), and High symptoms class (W1 7%; W2 7%). Higher levels of problems with PMLDs, including being discrimination and family separation, predicted movements out of the No symptom class at W1 to classes with psychopathology at W2. To conclude, most participants did not develop PTSD or depression symptoms. The risk of developing these symptoms seems higher when problems with interpersonal PMLDs increased, pointing to the need for considering these stressors when addressing the mental health needs in this population

The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

INTRODUCTION: Loss of the cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in breast cancer. The decrease in p27 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S phase kinase protein 2 (Skp2). The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphoinositol 3' kinase (PI3K)/Akt pathway that down-regulates p27 levels in breast cancer. Rapamycin was found to stabilize p27 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression is unknown. METHODS: The expression of Skp2 mRNA and protein levels were examined in rapamycin-treated breast cancer cell lines. The effect of rapamycin on the degradation rate of Skp2 expression was examined in cycloheximide-treated cells and in relationship to the anaphase promoting complex/Cdh1 (APC\C) inhibitor Emi1. RESULTS: Rapamycin significantly decreased Skp2 mRNA and protein levels in a dose and time-dependent fashion, depending on the sensitivity of the cell line to rapamycin. The decrease in Skp2 levels in the different cell lines was followed by cell growth arrest at G1. In addition, rapamycin enhanced the degradation rate of Skp2 and down-regulated the expression of the APC\C inhibitor Emi1. CONCLUSION: These results suggest that Skp2, an important oncogene in the development and progression of breast cancer, may be a novel target for rapamycin treatment

Psycho-social factors associated with mental resilience in the Corona lockdown

The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p < 0.0001). The resilience factor PAS also partly mediated the positive association between perceived social support and resilience, and its association with resilience was in turn partly mediated by the ability to easily recover from stress (both p < 0.0001). In comparison with other resilience factors, good stress response recovery and positive appraisal specifically of the consequences of the Corona crisis were the strongest factors. Preregistered exploratory subgroup analyses (osf.io/thka9) showed that all tested resilience factors generalize across major socio-demographic categories. This research identifies modifiable protective factors that can be targeted by public mental health efforts in this and in future pandemics

Requirement of Podocalyxin in TGF-Beta Induced Epithelial Mesenchymal Transition

Epithelial mesenchymal transition (EMT) is characterized by the development of mesenchymal properties such as a fibroblast-like morphology with altered cytoskeletal organization and enhanced migratory potential. We report that the expression of podocalyxin (PODXL), a member of the CD34 family, is markedly increased during TGF-β induced EMT. PODXL is enriched on the leading edges of migrating A549 cells. Silencing of podocalyxin expression reduced cell ruffle formation, spreading, migration and affected the expression patterns of several proteins that normally change during EMT (e.g., vimentin, E-cadherin). Cytoskeletion assembly in EMT was also found to be dependent on the production of podocalyin. Compositional analysis of podocalyxin containing immunoprecipitates revealed that collagen type 1 was consistently associated with these isolates. Collagen type 1 was also found to co-localize with podocalyxin on the leading edges of migrating cells. The interactions with collagen may be a critical aspect of podocalyxin function. Podocalyxin is an important regulator of the EMT like process as it regulates the loss of epithelial features and the acquisition of a motile phenotype

HER2 expression as a potential marker for response to therapy targeted to the EGFR

Since human epidermal growth factor receptor 2 (HER2) is known to participate with the epidermal growth factor receptor (EGFR) in mitogenic signalling, we hypothesised that HER2 overexpression might indicate responsiveness to EGFR targeted therapies. MCF7 breast cancer cells transfected with the HER2 gene were subcloned to establish a set of genetically related cell lines expressing graded levels of HER2 by immunoblot analysis. The subcloned cell lines and parental MCF7 cells were characterised by their growth characteristics, and cell by cell patterns of EGFR, HER2 and HER3 expression as well as levels of phosphorylated mitogen-activated protein kinase (MAPK) and AKT by laser scanning cytometry (LSC). Growth inhibition assays were used to characterise response to EGFR targeted therapy, and to determine the relationship between therapeutic response and levels of tyrosine kinase expression. The levels of growth inhibition of AG1478 and of the AG1478-trastuzumab combinations were correlated with levels of HER2 expression among the different cell lines. Among EGFR, HER2 and HER3, HER2 overexpression was the best single predictive marker, but combinations of two markers provided additional predictive information

Regulation of ErbB2 Receptor Status by the Proteasomal DUB POH1

Understanding the factors, which control ErbB2 and EGF receptor (EGFR) status in cells is likely to inform future therapeutic approaches directed at these potent oncogenes. ErbB2 is resistant to stimulus-induced degradation and high levels of over-expression can inhibit EGF receptor down-regulation. We now show that for HeLa cells expressing similar numbers of EGFR and ErbB2, EGFR down-regulation is efficient and insensitive to reduction of ErbB2 levels. Deubiquitinating enzymes (DUBs) may extend protein half-lives by rescuing ubiquitinated substrates from proteasomal degradation or from ubiquitin-dependent lysosomal sorting. Using a siRNA library directed at the full complement of human DUBs, we identified POH1 (also known as Rpn11 or PSMD14), a component of the proteasome lid, as a critical DUB controlling the apparent ErbB2 levels. Moreover, the effects on ErbB2 levels can be reproduced by administration of proteasomal inhibitors such as epoxomicin used at maximally tolerated doses. However, the extent of this apparent loss and specificity for ErbB2 versus EGFR could not be accounted for by changes in transcription or degradation rate. Further investigation revealed that cell surface ErbB2 levels are only mildly affected by POH1 knock-down and that the apparent loss can at least partially be explained by the accumulation of higher molecular weight ubiquitinated forms of ErbB2 that are detectable with an extracellular but not intracellular domain directed antibody. We propose that POH1 may deubiquitinate ErbB2 and that this activity is not necessarily coupled to proteasomal degradation

Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer

Introduction: We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC xenografts hosted by immunodeficient mice. Methods: To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures. Results: PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells. Conclusions: These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC

Life Cycle Management of Infrastructures

By definition, life cycle management (LCM) is a framework “of concepts, techniques, and procedures to address environmental, economic, technological, and social aspects of products and organizations in order to achieve continuous ‘sustainable’ improvement from a life cycle perspective” (Hunkeler et al.\ua02001). Thus, LCM theoretically integrates all sustainability dimensions, and strives to provide a holistic perspective. It also assists in the efficient and effective use of constrained natural and financial resources to reduce negative impacts on society (Sonnemann and Leeuw\ua02006; Adibi et al.\ua02015). The LCM of infrastructures is the adaptation of product life cycle management (PLM) as techniques to the design, construction, and management of infrastructures. Infrastructure life cycle management requires accurate and extensive information that might be generated through different kinds of intelligent and connected information workflows, such as building information modeling (BIM)