Bortezomib sensitises TRAIL-resistant HPV-positive head and neck cancer cells to TRAIL through a caspase-dependent, E6-independent mechanism.

Human papillomavirus (HPV) is causative for a new and increasing form of head and neck squamous cell carcinomas (HNSCCs). Although localised HPV-positive cancers have a favourable response to radio-chemotherapy (RT/CT), the impact of HPV in advanced or metastatic HNSCC remains to be defined and targeted therapeutics need to be tested for cancers resistant to RT/CT. To this end, we investigated the sensitivity of HPV-positive and -negative HNSCC cell lines to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), which induces tumour cell-specific apoptosis in various cancer types. A clear correlation was observed between HPV positivity and resistance to TRAIL compared with HPV-negative head and neck cancer cell lines. All TRAIL-resistant HPV-positive cell lines tested were sensitised to TRAIL-induced cell death by treatment with bortezomib, a clinically approved proteasome inhibitor. Bortezomib-mediated sensitisation to TRAIL was associated with enhanced activation of caspase-8, -9 and -3, elevated membrane expression levels of TRAIL-R2, cytochrome c release and G2/M arrest. Knockdown of caspase-8 significantly blocked cell death induced by the combination therapy, whereas the BH3-only protein Bid was not required for induction of apoptosis. XIAP depletion increased the sensitivity of both HPV-positive and -negative cells to TRAIL alone or in combination with bortezomib. In contrast, restoration of p53 following E6 knockdown in HPV-positive cells had no effect on their sensitivity to either single or combination therapy, suggesting a p53-independent pathway for the observed response. In summary, bortezomib-mediated proteasome inhibition sensitises previously resistant HPV-positive HNSCC cells to TRAIL-induced cell death through a mechanism involving both the extrinsic and intrinsic pathways of apoptosis. The cooperative effect of these two targeted anticancer agents therefore represents a promising treatment strategy for RT/CT-resistant HPV-associated head and neck cancers.

Human Gyrovirus Apoptin shows a similar subcellular distribution pattern and apoptosis induction as the chicken anaemia virus derived VP3/Apoptin.

The chicken anaemia virus-derived protein Apoptin/VP3 (CAV-Apoptin) has the important ability to induce tumour-selective apoptosis in a variety of human cancer cells. Recently the first human Gyrovirus (HGyV) was isolated from a human skin swab. It shows significant structural and organisational resemblance to CAV and encodes a homologue of CAV-Apoptin/VP3. Using overlapping primers we constructed a synthetic human Gyrovirus Apoptin (HGyV-Apoptin) fused to green fluorescent protein in order to compare its apoptotic function in various human cancer cell lines to CAV-Apoptin. HGyV-Apoptin displayed a similar subcellular expression pattern as observed for CAV-Apoptin, marked by translocation to the nucleus of cancer cells, although it is predominantly located in the cytosol of normal human cells. Furthermore, expression of either HGyV-Apoptin or CAV-Apoptin in several cancer cell lines triggered apoptosis at comparable levels. These findings indicate a potential anti-cancer role for HGyV-Apoptin.

What works for whom in a computer-mediated communication intervention in community psychiatry? Moderators of outcome in a cluster randomized trial.

OBJECTIVE: An intervention to structure patient-key worker communication has been tested in a randomized controlled trial. The aim of this paper was to investigate effectiveness of the intervention in terms of moderators of effectiveness. METHOD: A total of 507 patients with schizophrenia were included. Moderators of effectiveness were investigated using two-way anovas. RESULTS: Patients with a better relationship with their key worker and a shorter duration of illness at baseline benefited more from the intervention in terms of quality of life. Patients who received the intervention who were in competitive employment or had a shorter duration of illness showed greater reduction of unmet needs. Older patients receiving the intervention had better treatment satisfaction. CONCLUSION: Outcome of the intervention was moderated by patient characteristics. Moreover, the moderating characteristics varied depending on the specific outcome. Evidence on moderators is very limited, even though, they are significant for understanding, targeting and implementing complex interventions.

[Quality assurance and documentation for community mental health services cooperative (GPV). A standardized procedure for regional health care documentation and planning]. / Qualitätssicherung und Dokumentation im Gemeindepsychiatrischen Verbund (GPV). Ein standardisiertes Verfahren für die regionale Versorgungsdokumentation und -steuerung.

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.

[Alcohol consumption and its significance in therapeutic residences for psychiatric patients]. / Alkoholkonsum und seine Bedeutung in therapeutischen Wohnheimen für psychisch Kranke.

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.

[Leisure and social contact clubs for psychiatric patients--an assessment of club members]. / Freizeit- und Kontaktclubs für psychisch kranke Menschen--Ein Meinungsbild von Clubbesuchern.

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.