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Aims: Inflammation has important roles in atherosclerosis. CD4+CD28null (CD28null) T cells are a specialized T lymphocyte subset that produce inflammatory cytokines and cytotoxic molecules. CD28null T cells expand preferentially in patients with acute coronary syndrome (ACS) rather than stable angina and are barely detectable in healthy subjects. Importantly, ACS patients with CD28null T-cell expansion have increased risk for recurrent acute coronary events and poor prognosis, compared to ACS patients in whom this cell subset does not expand. The mechanisms regulating CD28null T-cell expansion in ACS remain elusive. We therefore investigated the role of cytokines in CD28null T-cell expansion in ACS., Methods and Results: High-purity sorted CD4+ T cells from ACS patients were treated with a panel of cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL-15), and effects on the number, phenotype, and function of CD28null T cells were analysed and compared to the control counterpart CD28+ T-cell subset. IL-7- and IL-15-induced expansion of CD28null T cells from ACS patients, while inflammatory cytokines TNF-α, IL-1β, and IL-6 did not. The mechanisms underlying CD28null T-cell expansion by IL-7/IL-15 were preferential activation and proliferation of CD28null T cells compared to control CD28+ T cells. Additionally, IL-7/IL-15 markedly augmented CD28null T-cell cytotoxic function and interferon-γ production. Further mechanistic analyses revealed differences in baseline expression of component chains of IL-7/IL-15 receptors (CD127 and CD122) and increased baseline STAT5 phosphorylation in CD28null T cells from ACS patients compared to the control CD28+ T-cell subset. Notably, we demonstrate that CD28null T-cell expansion was significantly inhibited by Tofacitinib, a selective JAK1/JAK3 inhibitor that blocks IL-7/IL-15 signalling., Conclusion: Our novel data show that IL-7 and IL-15 drive the expansion and function of CD28null T cells from ACS patients suggesting that IL-7/IL-15 blockade may prevent expansion of these cells and improve patient outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The co-inhibitory receptor PD-1 is expressed in many tumors including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1, and particularly PD-L2, in the tumor-stromal cell interactions that cause a tumor-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analyzed by immunohistochemistry in situ in HNSCC tumor tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analyzed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumor cells and stroma in HNSCC tissue in situ . In vitro , basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9.

More than 150 years from the initial description of inflammation in atherosclerotic plaques, randomized clinical trials to test anti-inflammatory therapies in atherosclerosis have recently been initiated. Lymphocytes and macrophages are main participants in the inflammatory response in atherosclerosis. T lymphocytes operate mainly by exerting strong influences on the function of many cells in the immune system and beyond, and co-ordinating their interactions. Importantly, T lymphocytes are not a homogenous population, but include several subsets with specialized functions that can either promote or suppress inflammation. The interactions between these T-lymphocyte subsets have critical consequences on the course and outcome of inflammation. The complexity of the inflammatory response in atherosclerosis poses significant challenges on translating experimental findings into clinical therapies and makes the journey from bench to bedside an arduous one. Here, we summarize recent advances on the role of CD4(+) T cells in the inflammatory process in atherosclerosis and discuss potential therapies to modulate these lymphocytes that may provide future breakthroughs in the treatment of atherosclerosis., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The Reproducibility Project: Cancer Biology seeks to address growing concerns about the reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Systematic identification of genomic markers of drug sensitivity in cancer cells" by Garnett and colleagues, published in Nature in 2012 (Garnett et al., 2012). The experiments to be replicated are those reported in Figures 4C, 4E, 4F, and Supplemental Figures 16 and 20. Garnett and colleagues performed a high throughput screen assessing the effect of 130 drugs on 639 cancer-derived cell lines in order to identify novel interactions for possible therapeutic approaches. They then tested this approach by exploring in more detail a novel interaction they identified in which Ewing's sarcoma cell lines showed an increased sensitivity to PARP inhibitors (Figure 4C). Mesenchymal progenitor cells (MPCs) transformed with the signature EWS-FLI1 translocation, the hallmark of Ewing's sarcoma family tumors, exhibited increased sensitivity to the PARP inhibitor olaparib as compared to MPCs transformed with a different translocation (Figure 4E). Knockdown mediated by siRNA of EWS-FLI1 abrogated this sensitivity to olaparib (Figure 4F). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical treatment and there is therefore a need to develop predictive bomarkers for clinical use that allow the selection of patients who are likely to respond. MicroRNA (miRNA) expression profiling of a panel of HNSCC tumours with and without recurrent disease after surgery and radiotherapy detected miR-196a as one of the highest upregulated miRNAs in the poor prognostic group. To further study the role of miR-196a, its expression was determined in eight head and neck cancer cell lines. Overexpression of miR-196a in HNSCC cells, with low endogenous miR-196a expression, significantly increased cell proliferation, migration and invasion, and induced epithelial to mesenchymal transition. Conversely, miR-196a knockdown in cells with high endogenous expression levels significantly reduced oncogenic behaviour. Importantly, overexpression of miR-196a increased radioresistance of cells as measured by gamma H2AX staining and MTT survival assay. Annexin A1 (ANXA1), a known target of miR-196a, was found to be directly modulated by miR-196a as measured by luciferase assay and confirmed by Western blot analysis. ANXA1 knockdown in HNSCC exhibited similar phenotypic effects to miR-196a overexpression, suggesting the oncogenic effect of miR-196a may at least be partly regulated through suppression of ANXA1. In conclusion, this study identifies miR-196a as a potential important biomarker of prognosis and response of HNSCC to radiotherapy. Furthermore, our data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in HNSCC., (© 2014 UICC.)

Apoptin, the VP3 protein from chicken anaemia virus (CAV), induces tumour cell-specific cell death and represents a potential future anti-cancer therapeutic. In tumour but not in normal cells, Apoptin is phosphorylated and translocates to the nucleus, enabling its cytotoxic activity. Recently, the β isozyme of protein kinase C (PKCβ) was shown to phosphorylate Apoptin in multiple myeloma cell lines. However, the exact mechanism and nature of interaction between PKCβ and Apoptin remain unclear. Here we investigated the physical and functional link between PKCβ and CAV-Apoptin as well as with the recently identified Apoptin homologue derived from human Gyrovirus (HGyV). In contrast to HCT116 colorectal cancer cells the normal colon mucosa cell lines expressed low levels of PKCβI and showed reduced Apoptin activation, as evident by cytoplasmic localisation, decreased phosphorylation and lack of cytotoxic activity. Co-immunoprecipitation and proximity ligation assay studies identified binding of both CAV- and HGyV-Apoptin to PKCβI in HCT116 cells. Using Apoptin deletion constructs the N-terminal domain of Apoptin was found to be required for interacting with PKCβI. FRET-based PKC activity reporter assays by fluorescence lifetime imaging microscopy showed that expression of Apoptin in cancer cells but not in normal cells triggers a significant increase in PKC activity. Collectively, the results demonstrate a novel cancer specific interplay between Apoptin and PKCβI. Direct interaction between the two proteins leads to Apoptin-induced activation of PKC and consequently activated PKCβI mediates phosphorylation of Apoptin to promote its tumour-specific nuclear translocation and cytotoxic function.

The virus-derived protein Apoptin has the ability to induce p53-independent apoptosis in a variety of human cancer cells while leaving normal cells unharmed. It thus represents a potential anti-cancer therapeutic agent of the future but a proper understanding of Apoptin-induced signalling events is necessary prior to clinical application. The tumor-specific nuclear translocation and phosphorylation of Apoptin by a cellular kinase such as protein kinase C seem to be required for its function but otherwise the mode of tumor selectivity remains unknown. Apoptin has been shown to interact with several cellular proteins including Akt and the anaphase-promoting complex that regulate its activity and promote caspase-dependent apoptosis. This chapter summarizes the available data on tumor-specific pathways sensed by Apoptin and the mechanism of Apoptin-induced cell death.

Objective: Previous research has shown that a better therapeutic relationship (TR) predicts more positive attitudes towards antipsychotic medication, but did not address whether it is also linked with actual adherence. This study investigated whether the TR is associated with adherence to antipsychotics in patients with schizophrenia., Methods: 134 clinicians and 507 of their patients with schizophrenia or a related psychotic disorder participated in a European multi-centre study. A logistic regression model examined how the TR as rated by patients and by clinicians is associated with medication adherence, adjusting for clinician clustering and symptom severity., Results: Patient and clinician ratings of the TR were weakly inter-correlated (r(s) = 0.13, p = 0.004), but each was independently linked with better adherence. After adjusting for patient rated TR and symptom severity, each unit increase in clinician rated TR was associated with an increase of the odds ratio of good compliance by 65.9% (95% CI: 34.6% to 104.5%). After adjusting for clinician rated TR and symptom severity, for each unit increase in patient rated TR the odds ratio of good compliance was increased by 20.8% (95% CI: 4.4% to 39.8%)., Conclusions: A better TR is associated with better adherence to medication among patients with schizophrenia. Patients' and clinicians' perspectives of the TR are both important, but may reflect distinct aspects.

Background: The effectiveness of psychosocial interventions in community mental healthcare has been shown to depend on the setting in which they are implemented. Recently structured patient-clinician communication was found to be effective in a multi-centre trial in six European countries, the DIALOG trial. In the overall study, differences between centres were controlled for, not studied. Here, we test whether the effectiveness of structured patient-clinician communication varies between services in different countries, and explore setting characteristics associated with outcome., Methods: The study is part of the DIALOG trial, which included 507 patients with schizophrenia or related disorder, treated by 134 keyworkers. The keyworkers were allocated to intervention or treatment as usual., Results: Positive effects were found on quality of life (effect size 0.20: 95% CI 0.01-0.39) and treatment satisfaction (0.27: 0.06-0.47) in all centres, but reductions in unmet needs for care were only seen in two centres (-0.83 and -0.60), and in positive, negative and general symptoms in one (-0.87, -0.78, -0.87). The intervention was most effective in settings with patient populations with many unmet needs for care and high symptom levels., Conclusions: Psychosocial interventions in community mental healthcare may not be assumed to have uniform effectiveness across settings. Differences in patient population served and mental healthcare provided, should be studied for their influence on the effectiveness of the intervention. Structured patient-clinician communication has a uniform effect on quality of life and treatment satisfaction, but on unmet needs for care and symptom levels its effect differs between mental healthcare settings.

Background and Aims: As part of an RCT in six European sites, the direct mental health care cost for 422 patients with schizophrenia was analysed according to how total and medication costs differed across sites and which variables were likely to predict total or service-specific costs., Method: Service use was recorded continuously during a 12-month follow-up. Prescribed psychotropic medication was recorded at baseline and 12 months later. Service use data were transformed into EURO, log-transformed and analysed using linear regression models., Results: Although samples were homogeneous, large inter-site cost differences were found (annual means ranging from 2958 euro in Spain up to 36978 euro in Switzerland). Psychopharmacologic costs were much more constant across sites than costs for other services. Total costs were associated more with region or socio-demographic characteristics than with disorder related parameters., Conclusions: The findings confirm remarkable differences in direct costs of patients with schizophrenia across Europe. However, the relative stability of medication costs suggests a need to analyse mechanisms that influence service-specific costs for schizophrenia.

Background: Mental health interventions should demonstrate an effect on patients' functioning as well as his/her needs, in particular on unmet needs whose assessment depends on the perspective of either the patient or the clinician. However, individual met and unmet needs appear to change over time, qualitatively and quantitatively, raising questions about their sensitivity to change and about the association between level of needs and treatment., Methods: Data on baseline and follow-up need assessment in community mental health services in four European countries in the context of a cluster randomised trial on a novel mental health service intervention were used, which involved 102 clinicians with key worker roles and 320 patients with schizophrenia or related psychotic disorders. Need assessment was performed with the Camberwell assessment of needs short appraisal schedule (CANSAS) among patients as well as clinicians. Focus is the sensitivity to change in unmet needs over time as well as the concordance between patient and clinician ratings and their relationship with treatment condition., Results: At follow-up 294 patients (92%) had a full need assessment, while clinician rated needs were available for 302 patients (94%). Generally, the total number of met needs remained quite stable, but unmet needs decreased significantly over time, according to patients as well as to clinicians. Sensitivity to change of unmet needs is quite high: about two third of all unmet needs made a transition to no or met need, and more than half of all unmet needs at follow-up were new. Agreement between patient and clinician on unmet needs at baseline as well as follow-up was rather low, without any indication of a specific treatment effect., Conclusions: Individual unmet needs appear to be quite sensitive to change over time but as yet less suitable as outcome criterion of treatment or specific interventions.

Background: Patient-clinician communication is central to mental healthcare but neglected in research., Aims: To test a new computer-mediated intervention structuring patient-clinician dialogue (DIALOG) focusing on patients' quality of life and needs for care., Method: In a cluster randomised controlled trial, 134 keyworkers in six countries were allocated to DIALOG or treatment as usual; 507 people with schizophrenia or related disorders were included. Every 2 months for 1 year, clinicians asked patients to rate satisfaction with quality of life and treatment, and request additional or different support. Responses were fed back immediately in screen displays, compared with previous ratings and discussed. Primary outcome was subjective quality of life, and secondary outcomes were unmet needs and treatment satisfaction., Results: Of 507 patients, 56 were lost to follow-up and 451 were included in intention-to-treat analyses. Patients receiving the DIALOG intervention had better subjective quality of life, fewer unmet needs and higher treatment satisfaction after 12 months., Conclusions: Structuring patient-clinician dialogue to focus on patients' views positively influenced quality of life, needs for care and treatment satisfaction.

Outpatients with chronic mental illness living in therapeutic residential facilities in Mannheim, Germany (N=110) responded to an opinion poll to determine their voting preferences for the 2002 federal election to the Bundestag. The poll found that the outpatients were significantly more likely than the general population in Mannheim to prefer left-wing parties (78 percent compared with 56 percent). This finding is in contrast to earlier reports; however, it seems to better reflect common beliefs about the political preferences of this population. In conclusion, persons with chronic mental illness seem to prefer political parties that they believe will best serve their perceived specific interests.

Objective: Voting behaviour of chronic mentally ill patients should demonstrate that this group may act as a political interest group., Methods: Residents of therapeutic facilities for mentally ill patients were questioned on their voting behaviour after the Federal Election to the Bundestag in 1994, 1998 and 2002., Results: There was a stable preference for the parties from the "left wing", more than (2/3) of the study population voted for the Social Democrats or the Green party. It was important for 17.2 % of the clients that a party puts emphasis on the interests of the mentally ill., Conclusions: Chronic mentally ill patients show a different voting behaviour than the general population. Their voting decision is partially related to their specific interests, which could give them a lobby-like status. This should be taken into consideration in the future development and planning of mental health care systems.

Three issues characterise the background to the MECCA study: A) Throughout Europe, most patients with severe forms of psychotic disorders are cared for in the community. The challenge now is to make processes in community mental health care more effective. B) There are widespread calls to implement regular outcome measurement in routine settings. This, however, is more likely to happen, if it provides a direct benefit to clinicians and patients. C) Whilst user involvement is relatively easy to achieve on a political level, new mechanisms may have to be established to make the views of patients feed into individual treatment decisions. The MECCA study is a cluster randomised controlled trial following the same protocol in community mental health teams in six European countries. In the experimental group, patients' subjective quality of life, treatment satisfaction and wishes for different or additional help are assessed in key worker-patient meetings every two months and intended to inform the therapeutic dialogue and treatment decisions. The trial tests the hypothesis that the intervention--as compared to current best standard practice--will lead to a better outcome in terms of quality of life and other criteria in patients with psychotic disorders over a one year period. This more favourable outcome is assumed to be mediated through different treatment input based on more appropriate joint decisions or a more positive therapeutic relationship in line with a partnership model of care or both. Moreover, the study will hopefully reveal new insights into how therapeutic processes in community mental health care work and how they can be optimised.

This paper describes a standardized assessment-procedure for the so-called "Gemeindepsychiatrische Verbünde" in Germany (GPV-Documentation), which are regional combines of community-based mental health care services. It is the first procedure in Germany which puts data on psychiatric care offers, needs for care and service utilization of all sectors and services in community-based mental health care into standardized measures, thus making offers and care of these services comparable. The procedure can be applied to the daily routine of catchment areas. From a methodical point of view the GPV-Documentation keeps a functional approach to community-based mental health care, but additionally it enables services to describe their specific contribution to regional care separately from others. Annual follow-ups make the GPV-Documentation an ideal tool for planning purposes, care management and quality assurance. Cross-regional comparisons of standards of care are possible. The implementation will also enhance the quality of governmental health reports on the care of chronically mentally ill in Germany remarkably.

We conducted a study on alcohol consumption habits in the five therapeutic homes for the mentally ill in Mannheim. Through assessment by their case managers we obtained data from 136 residents. Frequent alcohol use is currently reported in 12.5%. This group of frequent alcohol users is characterized by a higher proportion of men, higher age at entry into the institution and a lower dosage of neuroleptic medication. No significant relation is found with regard to the age at onset of disease, the rehospitalisation rate and the general life satisfaction. Severe problems through alcohol use are seen only isolated but in all clients with an earlier diagnosis of alcohol abuse. According to our results alcohol abuse in therapeutic homes is reported less frequently than in other populations of chronic mentally ill clients. It might be suspected that mentally ill patients with additional alcohol problems are not adequately provided with housing in the complementary care system. Verification is needed whether through the development of specific offers this deficit can be regressed.

55 visitors from five recreation and social clubs for mentally ill clients have been described, related to some sociographic data including the number of times the club is frequented, the duration of membership in the club as well as the source of information. They were asked to give their opinions on the frequency and the duration of the meetings and the quality of the clubrooms, the care and the programmes. They give the reasons for attending the clubs and the resulting main effects. They make wishes and complaints about the clubs. The results of the questioning are compared to the description of tasks and aims of clubs as seen from the professional point of view in order to find conformities and/or differences. On the whole a consensus is to be seen. Differences can be ascertained, where the professional aim is mainly of therapeutic nature. Such a target does not meet the needs of the visitors. For them the social aspect is of main importance in a surrounding offering protection, acceptance, understanding and support.