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A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyze the “ectodomain shedding” of a range of cell surface proteins including signaling and adhesion molecules. These “sheddases” are associated with the invasion and metastasis of a range of cancers. Increased serum and tumor tissue levels of copper are also observed in several cancers, although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models, whereas other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pretreatment of cells with cycloheximide and in a cell-free membrane system, indicating a posttranslational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect that could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process. Mol Cancer Res; 10(10); 1282–93. ©2012 AACR.

PDF file - 87K, The Jagged1 ectodomain generated in the presence of copper is smaller than constitutively-generated sJag

PDF file - 43K, Summary of catalytically active human ADAM family members tested as candidates for copper-enhanced shedding activity

PDF file - 101K, Copper-mediated Jagged1 shedding is accompanied by reciprocal decreases in cell-associated holoprotein only at higher, physiologically irrelevant, metal concentrations

There is evidence suggesting that the conceptualization and operationalization of Obsessive-Compulsive Personality Disorder (OCPD) is not satisfactory (Watters et al., 2019). In this study, we used an online sample (N = 1008) to investigate the construct validity of the PID-5 OCPD trait measure. Regression analyses supported our hypothesis that rigid perfectionism captured the core phenomenology of OCPD whereas restricted affectivity and intimacy avoidance were not conceptually related to the OCPD construct. Based on the biosocial theory for overcontrol (Lynch, 2018), we introduced anxiousness and workaholism to the PID-5 OCPD trait profile. In establishing the validity of the revised OCPD trait profile, we investigated, for the first time, the role of social interaction anxiety and maladaptive coping in OCPD. Our revised OCPD profile showed good validity and was characterized by marked social interaction anxiety and dysfunctional coping mechanisms. The findings may lead to a new conceptualization of OCPD which prioritizes deficits in social interaction and coping. We identify areas that need to be prioritized in the evaluation of OCPD by mental health professionals and offer avenues for new clinical research in the field.

Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.

Article first published online: August 26, 2021 Following the global outbreak of COVID-19 in March 2020, individuals report psychological distress associated with the “new normal”—social distancing, financial hardships, and increased responsibilities while working from home. Given the interpersonal nature of stress and coping responses between romantic partners, based on the systemic transactional model this study posits that perceived partner dyadic coping may be an important moderator between experiences of COVID-19 psychological distress and relationship quality. To examine these associations, self-report data from 14,020 people across 27 countries were collected during the early phases of the COVID-19 pandemic (March–July, 2020). It was hypothesized that higher symptoms of psychological distress would be reported post-COVID-19 compared to pre-COVID-19 restrictions (Hypothesis 1), reports of post-COVID-19 psychological distress would be negatively associated with relationship quality (Hypothesis 2), and perceived partner DC would moderate these associations (Hypothesis 3). While hypotheses were generally supported, results also showed interesting between-country variability. Limitations and future directions are presented.

12 Background: Penile squamous cell carcinoma (PSCC) is rare, representing 0.4-0.6% of all male malignancies in the global-north, as compared with 2-10% in the global-south. Overall survival (OS) dramatically decreases with increased lymph node metastases (LNM). Increased prevalence of pro-tumorigenic M2 CD163+ tumour associated macrophages (TAM) is associated with poor PSCC OS, whereas increased prevalence of the generic M1/2 CD68+ TAMs is associated with better PSCC OS. PDL-1 expression has been noted in 40-60% of PSCC primary lesions. However, there is a paucity of evidence on the overall tumour immune microenvironment (TME) within penile LNM disease. This study describes the relationship between PDL-1 expression and TAMs within the TME of the primary tumour and paired LNMs, with the goal of predicting the utility of PD-1 inhibitors in clinical trials in PSCC. Methods: The Ventana Discovery ULTRA platform was used to optimise a 7-marker multiplex immunofluorescence panel on whole FFPE sections of primary and LNM lesions. Multispectral images were captured using a Vectra 3 microscope. Single cell spatial analysis was performed using HALO software, with statistical analysis of data using R 4.2.1. Results: 52 cases with differing LN stages were identified: N0 (N=20); N1/N2 (N=21); N3 (N=11). Increased expression of PDL-1 was noted at the primary lesion invasive margin (IM) of N+, compared with N0 patients. High expression in inguinal LNMs (iLN+) and pelvic LNMs (pLN+) was also observed, with no expression detected in microscopically normal, tumour free LNs (LN-) in the N0 cohort. More CD163+ M2 TAMs were observed at the IM of N+ compared with N0. However, no significant difference was observed between the three LN groups. M1/2 CD68+ TAMs were more prevalent within pLN+ vs iLN+ or LN-. There was no significant difference in M1/2 CD68+ TAMs number at the IM. Conclusions: Our data highlights increased prevalence of M2 CD163+ TAMs within the IM is associated with LNM. Increased presence of CD68+ M1/2 TAMs in pLN+ may represent active inflammation at the leading microscopic edge of metastatic deposits. A significant difference in the expression of PDL-1 between localised and metastatic disease at both primary and LN location is noted. High PDL-1 expression at the IM of the primary lesion is associated with increased LNMs, where PDL-1 expression is significantly higher as compared to LN-. This study supports the rationale for the use of anti-PD-1/PDL-1 therapies in patients with LNM disease.

The term “phubbing” is a portmanteau of “phone” and “snubbing”, representing interruptions in face-to-face interactions due to smartphones acting as a distractor. Phubbing has previously been associated with several negative relational and personal outcomes (i.e., reduced relationship satisfaction, low mood, and increased interpersonal conflict). The present study explored the consequences of partner phubbing on phubbee’s (i.e., the recipient’s) daily reports of relationship satisfaction and personal well-being. To extend current phubbing literature, we assessed how phubbees responded to being phubbed (ignoring, resentment, curiosity, retaliation, conflict) and their motivations for engaging in any retaliatory behaviours. Participants (N = 75) completed a 10-day daily diary study, consisting of short baseline and daily measures (perceived partner phubbing, relationship satisfaction, depressed mood, anxious mood, self-esteem, anger/frustration, responses to phubbing, and, if applicable, motivations for retaliation). Results revealed phubbees reported lower relationship satisfaction and greater feelings of anger when daily perceived partner phubbing was high. Likewise, when perceived partner phubbing was high, phubbees reported greater curiosity, resentment, and retaliation. Revenge, need for support, and need for approval were all significant motivations for retaliation. Findings reinforced the emotional and behavioural impact of phubbing on the recipient.

Psychopathic personality traits are positively associated with externalising behaviours, and negatively associated with internalising behaviours. However, the contribution of different facets of psychopathy (boldness, meanness, disinhibition) in explaining externalising and internalising behaviours across genders are inconsistent. In this study, we explored gender differences in the assessment of, and relationships between, psychopathic personality traits, trait anxiety, social anxiety, depression, mental health, and aggressive behaviour in 822 students from a German University (586 women, 236 men; Mage = 22.27). Using a structural equation model, we found a positive relationship between aggressive behaviour and all three facets of psychopathy, a positive relationship between internalising behaviours and disinhibition, and a significant negative relationship between internalising behaviours and boldness. Despite gender differences in absolute levels of these variables, the overall pattern of the relationships between variables was consistent across genders. This indicates that symptom level differences across gender cannot be accounted for by variation in early developing personality traits like psychopathy.

Research that informs policies in regard to public health should be conducted with scientific rigour and integrity. The consequence of this can lead to policies being implemented incorrectly and can remain in place for many years before being reversed or amended. When understanding the effect screen time has on wellbeing, it suffers from the ‘many voices’ problem, whereby academic interest has resulted in a spike of research on the subject. However, high quality research has been diluted by the many studies which use methodologies that are quick and easy to implement. An example of this is online questionnaires that adopt rating scales or ask people to estimate the time they spend on their devices, to get a proxy of people’s engagement with their technologies. However, contemporary research shows that these in fact do not measure usage at all, but instead capture people’s perceptions, worries and appraisals towards their use. Of greater concern, our latest project shows that these measures generate misleading results when linking smartphone use to mental health. To elaborate, when measuring smartphone use directly via objective logs gathered from the device itself, findings showed a person’s daily smartphone pickups or screen time did not predict anxiety, depression, or stress symptoms. However, people’s concerns and worries about their smartphone use, measured via a ‘problematic smartphone use scale’, showed noteworthy effects on mental wellbeing. Alarmingly, many studies confound the latter as a measure of ‘smartphone use’ and conclusions derived from this misconception dominates much of the field. Overall, this makes it difficult to make concrete policy recommendations but can also incorrectly promote the agenda that increased smartphone screen time is a public health crisis. Unfortunately, the same pattern of ‘fast’ research has now become focal during the COVID-19 pandemic. Whereby, academics pursuing high impact research are adopting measures that may be inappropriate for their research question. Whilst some research is time-sensitive, research still requires careful and considerate thought, preferably from existing experts, as it takes time for any academic to become acquainted to a new field research. However, as with the case of screen time, research of higher quality is often not elevated beyond the sea of ‘quick and questionable’ research, which may have attractive conclusions and are rapidly promoted across mass media.

Supplemental Material, sj-pdf-1-spr-10.1177_02654075211034236 for Coping with global uncertainty: Perceptions of COVID-19 psychological distress, relationship quality, and dyadic coping for romantic partners across 27 countries by Ashley K. Randall, Gabriel Leon, Emanuele Basili, Tam��s Martos, Michael Boiger, Michela Baldi, Lauren Hocker, Kai Kline, Alessio Masturzi, Richmond Aryeetey, Eran Bar-Kalifa, Susan D. Boon, Luis Botella, Tom Burke, Katherine Carnelley, Alan Carr, Arobindu Dash, Mimi Fitriana, Stanley O. Gaines, Sarah Galdiolo, Hart Claire M, Susanna Joo, Barani Kanth, Evangelos Karademas, Gery Karantzas, Selina A. Landolt, Louise McHugh, Anne Milek, Eddie Murphy, Jean C. Natividade, Alda Portugal, ��lvaro Qui��ones, Ana Paula Relvas, Pingkan C. B. Rumondor, Petruta Rusu, Viola Sallay, Luis Angel Saul, David P. Schmitt, Laura Sels, Sultan Shujja, Laura K. Taylor, S. Burcu Ozguluk, Leslie Verhofstadt, Gyesook Yoo, Martina Zemp, Silvia Donato, Casey J. Totenhagen, Rahel L. van Eickels, Emmanuel Anongeba Anaba, Sarah Beauchemin-Roy, Anna Berry, Audrey Brassard, Susan Chesterman, Lizzie Ferguson, Gabriela Fonseca, Justine Gaugue, Marie Geonet, Neele Hermesch, Laura Knox, Marie-France Lafontaine, Nicholas Lawless, Amanda Londero-Santos, Sofia Major, Tiago A. Marot, Ellie Mullins, Pauldy C. J. Otermans, Pagani Ariela F, Miriam Parise, Roksana Parvin, Mallika De, Katherine P��loquin, B��rbara Rebelo, Francesca Righetti, Daniel Romano, Sara Salavati, Steven Samrock, Mary Serea, Chua Bee Seok, Luciana Sotero, Owen Stafford, Christoforos Thomadakis, Cigdem Topcu-Uzer, Carla Ugarte, Low Wah Yun, Petra Simon-Z��mbori, Ching Sin Siau, Diana-S��nziana Duca, Cornelia Filip, Hayoung Park, Sinead Wearen, Guy Bodenmann and Claudia Chiarolanza in Journal of Social and Personal Relationships

A growing number of self-report measures aim to define interactions with social media in a pathological behavior framework, often using terminology focused on identifying those who are 'addicted' to engaging with others online. Specifically, measures of 'social media addiction' focus on motivations for online social information seeking, which could relate to motivations for offline social information seeking. However, it could be the case that these same measures could reveal a pattern of friend addiction in general. This study develops the Offline-Friend Addiction Questionnaire (O-FAQ) by re-wording items from highly cited pathological social media use scales to reflect "spending time with friends". Our methodology for validation follows the current literature precedent in the development of social media 'addiction' scales. The O-FAQ had a three-factor solution in an exploratory sample of N = 807 and these factors were stable in a 4-week retest (r = .72 to .86) and was validated against personality traits, and risk-taking behavior, in conceptually plausible directions. Using the same polythetic classification techniques as pathological social media use studies, we were able to classify 69% of our sample as addicted to spending time with their friends. The discussion of our satirical research is a critical reflection on the role of measurement and human sociality in social media research. We question the extent to which connecting with others can be considered an 'addiction' and discuss issues concerning the validation of new 'addiction' measures without relevant medical constructs. Readers should approach our measure with a level of skepticism that should be afforded to current social media addiction measures.

Which aspects of psychopathic personality, if any, contribute to professional success? Previous research suggests that fearless dominance does so. Yet, it also suggests that self-centered impulsivity impairs professional success. Here, we address this differential pattern in a preregistered, multi-wave study involving a large, nationally representative sample (N = 2969 New Zealanders). We test the (a) replicability of prior findings using a new objective measure of professional success, and (b) stability of our findings across two annual assessments from 2011 and 2012. Fearless dominance is positively associated, but self-centered impulsivity is negatively associated, with subjective professional success. Controlling for age, gender, education level, and time in the current job does not alter these associations. Further, self-centered impulsivity and coldheartedness are negatively related with objective professional success. However, only the effect of coldheartedness remains after considering demographic variables. These relations hold for predicting subjective and objective professional success one year later. Together, aspects of psychopathic personality are linked negatively to objective professional success, a finding that challenges popular beliefs about the functional benefits of psychopathy in the workplace.

What is the role of the self in explaining the links between procedural fairness and organizational experience? In three experiments, we examined four self-related mechanisms: respect, certainty, self-esteem, and competence. We manipulated procedural fairness, introduced unfavorable personal or organizational outcomes, measured the putative mediators, and assessed organizational allure (attitude, identification, commitment). Across the three experiments, and a meta-review, exposure to procedural fairness (vs. unfairness) led to higher organizational allure via increased respect only. We obtained these result patterns regardless of whether unfavorable outcomes were personally or organizationally relevant, and regardless of the order in which procedural fairness and unfavorable outcomes were introduced. We consider implications of the findings.

253 Background: Perineural Invasion (PNI) is defined as malignant epithelial cell invasion of the perineural space and nerves. Despite widespread acknowledgement of the clinical significance of PNI as a PCa pathological finding associated with recurrence, increased risk of bone metastasis and poor survival, the molecular mechanism underlying this pathology is relatively unknown. The malignant epithelial cells within the PNI potentially provides a spatially defined “snapshot” of disease progression, as the cells switch to a more migrational phenotype associated with metastatic progression. Here we present the initial spatial PNI phenotypic characterisation in PCa. Methods: Archival FFPE blocks, with associated full clinical history, from patients who underwent a radical prostatectomy for prostate cancer were retrieved under research ethics REC#07/H1003/161+5 10_NOCL_02. Biomarkers EphA2, pEphA2s897, pMLC2, E-Cadherin, Vimentin, TOMM20, MTC01, NDUFB8, PTEN were assessed on 4µm serial sections stained using a multiplex TSA protocol, with S100, pan-cytokeratin and DAPI acting as landmarks, on a Ventana Discovery platform prior to scanning on a Versa 3 platform with Halo image analysis. Prostate zones were defined at 500µm intervals either side of the prostate capsule. Univariate and multivariate (hierarchical clustering, UMap clustering) expression analysis and correlation with clinic-pathological features was conducted within R. Results: The PNI epithelial cells within each spatial zone of the prostate are significantly different to each other (Kruskal-Wallis test p < 2.2x10−16 except for MTC01 p = 5.3x10−10). In comparison with the local tumour lesion, PNI epithelial cells localised within 1000µm of the prostate edge and outside the tumour lesion, have undergone a migrational switch, gaining features associated with an activated metastatic phenotype, with increased expression of amoeboid signalling (EphA2, pEphA2s897, pMLC2) and mitochondrial defects (loss of Complex I and IV, gain of mitochondrial mass (TOMM20)). Patients clustering by multivariate expression trends across the prostate regions showed 4 distinct patient groups, with PNI epithelial cells in patient group 1 & 2 displaying a more epithelial to mesenchymal (EMT) phenotype, especially in the first 1000µm inside the prostate organ. Conclusions: Cells within PNI close to the edge of the prostate have features consistent with a switch to migrational/metastatic activation in contrast to the more indolent cell type found deeper within the tumour. Further characterisation of this localised migrational upregulation will help in understanding the transition from a localised to a metastatic phenotype.

Background Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40–50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. Objective To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. Design, setting, and participants Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. Outcome measurements and statistical analysis Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). Results and limitations Serum LDH ≥450 U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650–0.864, p < 0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450 U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289–2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127–2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p = 0.043). Of the 14 patients with LDH ≥450 U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r = 0.667, p < 0.01), and other DNA repair genes. Conclusions Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. Patient summary The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.

In this chapter we examine the argument and evidence that a lack of empathy may lie at the core of narcissists’ chronic interpersonal inadequacies. Empathy is a key ingredient in facilitating smooth social interactions and maintaining interpersonal harmony. Empathy is linked with the promotion of prosocial and mitigation of antisocial behavior. We review the research showing that narcissism is inversely related to a whole host of empathy measures. This relationship pertains to both cognitive (e.g., understanding and considering another person’s viewpoint) and affective (e.g., vicariously experiencing another’s emotional state) forms of empathy. We argue that without taking another’s perspective and feeling their emotions, narcissists have no reason to curb their antisocial behavior or participate in prosocial acts. We delineate the negative consequences of narcissists’ low empathy for those around them and society at large. Such empirical evidence has determined low empathy to be a mechanism underlying narcissists’ displays of aggression, bullying, and criminality, as well as an increased propensity to engage in poor parenting practices and inability to maintain long-term relationships. On a positive note, we review the literature which suggests that narcissists are capable of being empathic. Thus change is possible. With this in mind, we discuss the ways in which narcissists’ low empathy may be mitigated.

The Fading Affect Bias (FAB) occurs when the affect associated with personal events fades differentially across time: Positive affect fades slower than negative affect. Three studies examined whether the magnitude of the FAB is moderated by narcissism. Results from Study 1 (diary method, N = 26) showed that low narcissism participants evidenced a large FAB, but high narcissism participants evidenced a reversed FAB. Results from Study 2 (retrospective recall method, N = 110) showed that low narcissism participants evinced a large FAB, and that the FAB diminished or dissipated as narcissism increased. Results from Study 3 (retrospective recall method, N = 83) showed that high narcissists evinced a FAB when they recalled achievement-themed autobiographical events, but evinced a reversed FAB when they recalled communal-themed events. These findings occurred independently of event rehearsal frequency. Results are discussed in terms of the idea that emotion regulation efforts may be disrupted in narcissists.

Background: Bone metastases in prostate cancer (CaP) result in CaP-related morbidity/mortality. The omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and lipophilic statins affect metastasis-like behaviour in CaP cells, regulating the critical metastatic step of CaP migration to the bone marrow stroma. Methods: Microscopic analysis and measurement of adhesion and invasion of CaP cells through bone marrow endothelial cells (BMEC) was undertaken with AA stimulation and/or simvastatin (SIM) treatment. Amoeboid characteristics of PC-3, PC3-GFP and DU-145 were analysed by western blotting and Rho assays. Results: The CaP cell lines PC-3, PC3-GFP and DU-145 share the ability to migrate across a BMEC layer. Specific amoeboid inhibition decreased transendothelial migration (TEM). AA stimulates amoeboid characteristics, driven by Rho signalling. Selective knock-down of components of the Rho pathway (RhoA, RhoC, Rho-associated protein kinase 1 (ROCK1) and ROCK2) showed that Rho signalling is crucial to TEM. Functions of these components were analysed, regarding adhesion to BMEC, migration in 2D and the induction of the amoeboid phenotype by AA. TEM was reduced by SIM treatment of PC3-GFP and DU-145, which inhibited Rho pathway signalling. Conclusions: AA-induced TEM is mediated by the induction of a Rho-driven amoeboid phenotype. Inhibition of this cell migratory process may be an important therapeutic target in high-risk CaP.

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy.

A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyze the “ectodomain shedding” of a range of cell surface proteins including signaling and adhesion molecules. These “sheddases” are associated with the invasion and metastasis of a range of cancers. Increased serum and tumor tissue levels of copper are also observed in several cancers, although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models, whereas other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pretreatment of cells with cycloheximide and in a cell-free membrane system, indicating a posttranslational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect that could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process. Mol Cancer Res; 10(10); 1282–93. ©2012 AACR.

Background: Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown. Methods: Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins. Results: Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μℳ) and rosuvastatin (5 μℳ), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93–77.04% P

Self-report studies often call for assessment of socially desirable responding. Many researchers use the Marlowe–Crowne Scale for its brief versions; however, this scale is outdated, and contemporary models of social desirability emphasize its multi-dimensional nature. The 40-item Balanced Inventory of Desirable Responding (BIDR) incorporates Self-Deceptive Enhancement (honest but overly positive responding) and Impression Management (bias toward pleasing others). However, its length limits its practicality. This article introduces the BIDR-16. In four studies, we shorten the BIDR from 40 items to 16 items, while retaining its two-factor structure, reliability, and validity. This short form will be invaluable to researchers wanting to assess social desirability when time is limited.

People self-enhance in a variety of ways. For example, they generally expect to perform better than others, to be in control of events, and to have a brighter future. Might they also self-enhance by expecting to receive positive feedback in social interactions? Across five studies, we found that they did. People’s desire for feedback correlated with how positive they expected it to be (Study 1), and their feedback expectations were more positive for themselves than for others (Study 2). People’s positive feedback expectations also covaried with trait tendencies to self-enhance (i.e., self-esteem and narcissism; Study 3) and with a direct situational manipulation of self-enhancement motivation (Study 4). Finally, people expected to receive positive feedback but did not consistently expect to receive self-verifying feedback (Study 5). These findings are consistent with social expectations being driven in part by the self-enhancement motive.

220 Background: There is a lack of biomarkers to predict docetaxel response. Here we assess the potential of pre-treatment LDH, associated to the mutational background of the primary biopsy taken prior to 1st line therapy with ADT, to predict docetaxel response in the castrate resistant setting. Methods: Clinical and associated primary biopsy targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) sets of retrospective progressive mCRPC patients (diagnosed 1996-2006) treated with docetaxel therapy were analyzed. LDH thresholds were determined and validated on the training and test sets respectively. Clinico-pathological associations with LDH were assessed using student t-test, Wilcoxon test and Chi-square test and predictive value of LDH determined by linear regression analysis for PSA and radiologic response. Time to event outcomes (PFS & OS) was evaluated by Kaplan-Meier. Meta-analysis of LDH association with DNA repair genes in the MSKCC and SU2C/PCF was conducted using cBioPortal Results: Using pre-docetaxel serum LDH of ≥450U/L as a prognostic threshold (AUC:0.75 (SD 0.054, 95% CI, 0.650–0.864, P < 0.001)) patients with LDH ≥450U/L were poorer PSA responders, with shorter PFS (213 vs 372 days, HR 1.876 (95% CI, 1.289-2.730)) and OS (362 vs 563 days, HR 1.630 (95% CI, 1.127-2.357)). LDH was also an independent surrogate marker for prediction of poor radiologic response and survival following docetaxel chemotherapy (P = 0.043). Genomic analysis showed that patients with LDH ≥450U/L (9/14 (64.3%)) have a higher tumour mutational burden (TMB) at the point of primary pre-ADT biopsy (mean, 46.2 vs 6.2 mutations/MB; p = 0.129) and that they were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2 and Fanconi’s anemia gene). Meta-analysis of the large MSKCC and the SU2C-PCF patient genomic databases confirmed the positive correlation between the LDH gene LDHA and PARP1 gene (r = 0.667, p < 0.01) expression and expression of other DNA repair genes. Conclusions: High pre-treatment serum LDH coupled with mutations in the DNA repair pathway in primary pre-ADT biopsy correlates with poor docetaxel response and overall survival in the castrate resistant state.

Background: Mutation within the adult human stem cell (SC) compartment has been proposed as a factor in the initiation and promotion of carcinogenesis. Isolation of these Cancer Stem Cells (CSCs) has proven difficult, limiting their subsequent phenotypic, functional and genetic characterisation. We have used the Hoechst 33342 dye efflux technique to isolate an epithelial side-population (SP) from Genito-Urinary (GU) cancers, which is enriched for cells with SC traits. Methods: With informed consent, samples were taken from primary tumours in patients undergoing surgery for Prostatic (CaP), invasive bladder Transitional Cell (TCC) and Renal Cell (RCC) Carcinomas. Single cell epithelial suspensions were extracted from these and incubated with Hoechst 33342. Hoechst SP/ Non-SP profiles were then generated by Flow Cytometry using standardised protocols. SP/ Non-SP cell cycle status was established by Hoechst 33342 and Pyronin Y staining. Immuno-cytochemistry staining was performed for markers suggested as stem-markers as well as lineage specific markers. Functionality was determined using colony-forming assays and long term monolayer culture. Results: A characteristic verapamil sensitive SP was isolated from all three urological malignancies and represented 0.57+/-0.11% (CaP), 0.52+/-0.49% (TCC) and 5.9+/-0.9% (RCC) of the total epithelial population. Cell cycle analysis showed that the SP had enhanced numbers of cells in G0 as compared to the total cell population (CaP 12.4%+/-3.2 versus 3.8%+/-1.0, RCC 23.2%+/-3.4 versus 1.8%+/-0.9 and TCC 28.5%+/-4.9 versus 4%+/-1.3). Immuno-cytochemistry demonstrated an increased expression of proliferative and putative stem markers within the SP fraction. Cultures confirmed significant enhancement of colony-forming ability and proliferative capacity of the SP fraction. Conclusions: A characteristic Side Population enriched for stem-like cells has been isolated from the three commonest urological malignancies. This provides strong evidence that Hoechst 33342 efflux is a conserved and unified mechanism in GU cancer.

Good theoretical definitions of psychological phenomena not only are rigorously formulated but also provide ample conceptual coverage. To assess the latter, we empirically surveyed everyday conceptions of modesty in a combined U.S./U.K. sample. In Study 1, participants freely generated multiple exemplars of modesty that judges subsequently sorted into superordinate categories. Exemplar frequency and priority served, respectively, as primary and secondary indices of category prototypicality that enabled central, peripheral, and marginal clusters to be identified. Follow-up studies then confirmed the ordinal prototypicality of these clusters with the aid of both explicit (Studies 2 and 3) and implicit (Study 3) methodologies. Modest people emerged centrally as humble, shy, solicitous, and not boastful and peripherally as honest, likeable, not arrogant, attention-avoiding, plain, and gracious. Everyday conceptions of modesty also spanned both mind and behavior, emphasized agreeableness and introversion, and predictably incorporated an element of humility.

Which people are most swayed by self-image motives and hence most likely to make consumer choices in line with those motives? This article contends that the answer is narcissists —individuals who see themselves, and who want others to see them, as special, superior, and entitled and who are prone to exhibitionism and vanity. This work hypothesizes that narcissists will, to validate their excessively positive self-views, strive to purchase the high-prestige products (i.e., expensive, exclusive, new, and flashy). In so doing, they will regulate their own esteem by increasing their apparent status and consequently earning others’ admiration and envy. This article also hypothesizes that narcissists will show greater interest in the symbolic than utilitarian value of products and will exhibit, even controlling for self-esteem, more pronounced self-enhancement phenomena such as endowment and self-signaling effects.

Interindividual-intergroup discontinuity is the tendency for relations between groups to be more competitive than relations between individuals. We examined whether the discontinuity effect arises in part because group members experience normative pressure to favor the ingroup (parochialism). Building on the notion that accountability enhances normative pressure, we hypothesized that the discontinuity effect would be larger when accountability is present (compared to absent). A prisoner's dilemma game experiment supported this prediction. Specifically, intergroup (compared to interindividual) interaction activated an injunctive ingroup-favoring norm, and accountability enhanced the influence of this norm on competitive behavior.

Objectives: We introduce biochemistry as a second dimension to Gleason grading, using Fourier transform infrared (FTIR) microspectroscopy. For the first time, we correlate FTIR spectra derived from prostate cancer (pCA) tissue with Gleason score and the clinical stage of the tumour at time of biopsy. Methods: Serial sections from paraffin-embedded pCA tissue were collected. One was stained with hematoxylin and eosin and Gleason scored; FTIR spectra were collected from malignant locations using a second unstained section. FTIR spectra, representing different Gleason grades, were used to construct a diagnostic classifier for pCA using linear discriminant analysis (LDA). This model was blind tested using 383 IR spectra from 36 biopsies. Results: Using a three-band Gleason criteria, we obtained sensitivity of ≥70% for the FTIR-LDA model to predict Gleason 7, with specificities of ≥81%. Using a threshold of Gleason/FTIR-LDA score of ≥8, we obtained a sensitivity and specificity of 71% and 67%, respectively, for the correlation with metastatic tumours using the FTIR-LDA system and 85% and 63%, respectively, for the correlation of metastatic tumours using the Gleason system. Conclusions: There is a correlation between tissue architecture using Gleason score with tissue biochemistry using FTIR-LDA. Both systems are similar in their performance in predicting metastatic behaviour in tumours from individual patients. © 2006 European Association of Urology.

Epidemiological studies have shown not only a relationship between the intake of dietary lipids and an increased risk of developing metastatic prostate cancer, but also the type of lipid intake that influences the risk of metastatic prostate cancer. The Omega-6 polyunsaturated fatty acid, Arachidonic acid, has been shown to enhance the proliferation of malignant prostate epithelial cells and increase the risk of advanced prostate cancer. However, its role in potentiating the migration of cancer cells is unknown. Here we show that arachidonic acid at concentrations ≤5 μM is a potent stimulator of malignant epithelial cellular invasion, which is able to restore invasion toward hydrocortisone-deprived adipocyte-free human bone marrow stroma completely. This observed invasion is mediated by the arachidonic acid metabolite prostaglandin E2 and is inhibited by the Omega-3 poly-unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid at a ratio of 1:2 Omega-3:Omega-6, and by the COX-2 inhibitor NS-398. These results identify a mechanism by which arachidonic acid may potentiate the risk of metastatic migration and secondary implantation in vivo, a risk which can be reduced with the uptake of Omega-3 poly-unsaturated fatty acids. © 2006 Cancer Research UK.

Synchrotron-based Fourier transform infrared (SR-FTIR) microspectroscopy has been applied to the study of dynamic cellular events. SR-FTIR microspectroscopy is a powerful bioanalytical technique for the simultaneous analysis of proteins, lipids and a variety of phosphorylated molecules within whole cells. In this study, SR-FTIR microspectroscopy was used in imaging mode to generate biospectroscopic chemical maps of formalin-fixed PC-3 prostate cancer cells, which had been preserved in the process of cell division (cytokinesis) and locomotion. The distribution and intensity profiles of IR signals corresponding to the amide I and 11 (protein) and/or v(as and s) (CH3), v(as and s) (CH2) (lipid) modes were found to be useful in understanding fundamental biochemical processes at the midbody of the cytokinetic cells and at the lamellipodium of motile cells. Furthermore, in both of these cellular systems we observed a distinct hemispherical distribution of the lipid ester (C=O) signal, which surrounded high phosphate signal. This feature was assigned to intracellular IR signals corresponding to membrane-rich organelles surrounding the cell nucleus. (c) 2005 Elsevier B.V. All rights reserved.

In 3 experiments, the authors investigated the role of social identity in fostering group loyalty, defined as staying when members can obtain better outcomes by leaving their group. In Experiment 1, high (vs. low) identifiers expressed a stronger desire to stay in the group in the presence of an attractive (vs. unattractive) exit option. Experiments 2 and 3 replicated this basic finding and tested several explanations. The results suggest that high identifiers' group loyalty is better explained by an extremely positive impression of their group membership (group perception) than by a justification of previous investments in the group (self-perception) or their adherence to a nonabandonment norm (norm perception). Hence, social identity seems to act as social glue. It provides stability in groups that would otherwise collapse.

This paper investigated the impact of leadership style on the stability of small social dilemma groups. In two experiments, group members were more likely to exit their group and take their resources elsewhere if they were supervised by an autocratic style leader than by a democratic or laissez-faire style leader. The destabilizing influence of autocratic leadership is due to the procedural rather than distributive aspects of this leadership style: More members exited their group under an autocratic style leader, relative to a democratic style leader, regardless of whether or not they received favorable personal outcomes from the leader. Hence, autocratic leadership is not a stable long-term solution to the problem of public goods in groups.

Background Prostate stem cells, responsible for the development, maturation, and function of the prostate, have been implicated in the aetiology of both benign prostate hyperplasia (BPH) and prostate cancer (CaP). However, research has been hampered by the lack of a definitive stem cell marker. We have adapted the protocol for differential Hoechst 33342 uptake by hemopoietic stem cells to enable isolation of putative stem cells from the prostate. Methods Prostate epithelial cells isolated from prostate tissue obtained from patients with BPH after transurethral resection of the prostate were stained with Hoechst 33342. The Hoechst 33342 Red/Blue flow cytometry profile was then determined. Hoechst 33342 and Pyronin Y staining was used to determined the cell cycle status. Results A verapamil-sensitive side population (SP) can be isolated from primary prostate tissue accounting for 1.38% ± 0.07% of prostate epithelial cells. Cell cycle analysis of this SP population revealed that the majority of SP cells are in either G0 (12.38 ± 0.31%) or G1 (63.19 ± 2.13%). Conclusions The Hoechst 33342 dye efflux protocol can be adapted for the isolation of a SP from primary prostate tissue. Cytometry Part A 54A:89–99, 2003. © 2003 Wiley-Liss, Inc.