Long‐lasting cross‐presentation of tumor antigen in human DC

DC cross‐present exogenous antigens on MHC class I molecules, a process required for the onset of anti‐tumor immune responses. In order to study the cross‐presentation of tumor antigens by human DC, we compared the pathways of cross‐presentation of long peptides requiring internalization and intracellular processing with the direct presentation of short peptides, which does not require intracellular processing. We found that, after brief incubations with DC, short peptides were presented to CD8⁺ T cells with higher efficiencies than long peptides. After longer times of chase in the absence of peptide, however, the efficiency of presentation of the two types of peptides was reversed. After 2–3 days, DC pulsed with long peptides still activated T cells efficiently, while DC pulsed with short peptides failed to do so. Long‐lasting presentation of the long peptides was, at least in part, due to a stored persistent pool of antigen, which was still available for loading on MHC class I molecules after several days of chase. These results show that the use of long synthetic peptides allows the efficient, long‐lasting, presentation of tumor antigens, suggesting that long peptides represent an interesting approach for active anti‐tumor vaccination.     

Direct medical mental health care costs of schizophrenia in France,Germany and the United Kingdom – Findings from the European Schizophrenia Cohort (EuroSC)

ObjectivesTo quantify and compare the resource consumption and direct costs of medical mental health care of patients suffering from schizophrenia in France, Germany and the United Kingdom.MethodsIn the European Cohort Study of Schizophrenia, a naturalistic two-year follow-up study, patients were recruited in France (N = 288), Germany (N = 618), and the United Kingdom (N = 302). Data about the use of services and medication were collected. Unit cost data were obtained and transformed into United States Dollar Purchasing Power Parities (USD-PPP). Mean service use and costs were estimated using between-effects regression models.ResultsIn the French/German/UK sample estimated means for a six-month period were respectively 5.7, 7.5 and 6.4 inpatient days, and 11.0, 1.3, and 0.7 day-clinic days. After controlling for age, sex, number of former hospitalizations and psychopathology (CGI score), mean costs were 3700/2815/3352 USD-PPP.ConclusionsService use and estimated costs varied considerably between countries. The greatest differences were related to day-clinic use. The use of services was not consistently higher in one country than in the others. Estimated costs did not necessarily reflect the quantity of service use, since unit costs for individual types of service varied considerably between countries.     

Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer

Due to an unfavorable prognosis using the usual therapy, patients with anaplastic thyroid cancer (ATC) are in desperate need of new therapeutic strategies. The objective of this study was to evaluate the effects of MLN8054, an inhibitor of the Aurora serine/threonine kinases, on ATC cells in vitro and on ATC xenografts as a new therapeutic strategy for ATC. Three anaplastic (Hth74, C643, Kat4) and one follicular (FTC133) thyroid cancer cell lines were evaluated in vitro and Kat4 xenografts in vivo. The antiproliferative effect of MLN8054 (0.1-10 μM) on thyroid cancer cells was quantified by sulphorhodamine B-assay. The proapoptotic effect and the effects on the cell cycle were evaluated by flow cytometry after Annexin-V-FITC staining. Further Histone H3 phosphorylation was analysed. In vivo, antiproliferative and antiangiogenic effects were assessed by tumor volume and morphometric analysis following immunohistochemical staining (Ki-67, pHisH3, CD31). Treatment of the different TC cells with MLN8054 inhibited proliferation in a time- and dose-dependent manner, with IC(50) values between 0.1 and 10 μM. Administration of MLN8054 resulted in an increase of apoptotic cells, decreased Histone H3 phosphorylation and induced cell cycle arrest. In vivo, treatment of ATC by MLN8054 resulted in an up to 86% reduced tumor volume and 89% reduced tumor vascularity. In conclusion, our data demonstrated that Aurora kinase inhibition is effective in reducing cell growth and inducing apoptosis of ATC in vitro and tumor growth and vascularity in vivo. Controlled clinical studies on MLN8054 or comparable compounds would be worthwhile to evaluate its potential therapeutic value for treatment of ATC.     

Oral brush biopsy analysis by matrix assisted laser desorption/ionisation-time of flight mass spectrometry profiling--a pilot study

Oral squamous cell carcinomas (OSCCs) often present as advanced tumours requiring aggressive local and regional therapy and result in significant functional impairment. The objective is to develop pre-symptomatic screening detection of OSCC by a brush biopsy method which is less invasive than the conventional biopsy for histology. Given the molecular heterogeneity of oral cancer, it is unlikely that even a panel of tumour markers would provide accurate diagnosis. Therefore, approaches such as the matrix-assisted-laser-desorption/ionisation-time-of-flight-mass-spectrometry (MALDI-TOF-MS) allow several biomarkers or peptide profile patterns to be simultaneously assessed. Brush biopsies from 27 patients with histology-proven OSCCs plus 40 biopsies from 10 healthy controls were collected. MALDI-TOF-MS profiling was performed and additional statistical analysis of the data was used to classify the disease status according to the biological behaviour of the lesion. For classification a support vector machine algorithm was trained using spectra of brush biopsy samples to distinguish healthy control patients from patients with histology-proven OSCC. MALDI-TOF-MS was able to distinguish between healthy patients and OSCC patients with a sensitivity of 100% and specificity of 93%. In summary, MALDI-TOF-MS in combination with sophisticated bioinformatic methods can distinguish OSCC patients from non-cancer controls with excellent sensitivity and specificity. Further improvement and validation of this approach is necessary to determine its feasibility to assist the pre-symptomatic detection of head and neck cancer screening in routine daily practice.     

Combined therapy versus usual care for the treatment of depression in oncologic patients: a randomized controlled trial

Objective: To compare narrative therapy (NT) plus escitalopram versus escitalopram plus usual care on quality of life and depressive symptomatology of depressed patients with oncologic disease. Methods: A total of 72 subjects (mean age 54.6 years), predominantly female with non‐metastatic breast, lung and colon cancer and depressive disorder (DSM‐IV‐TR) were randomized to receive treatment with NT plus escitalopram (n=39) or escitalopram (10–20 mg QD) plus usual care (n=33). Main endpoints were improvement in dimensions of quality of life measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C‐30 and reduction of depressive symptoms using the Hospital Anxiety and Depression Scale at weeks 12 and 24. Results: The combined therapy group showed significantly greater improvement in all the functioning dimensions (p<0.01), pain scale (p=0.02), global health (p=0.02), and global quality of life (p=0.007) at weeks 12 and 24. There were no statistically significant differences in depressive symptomatology between the groups. From week 12 to week 24 study retention was higher in the combined treatment group (p=0.01). Conclusions: Brief NT in combination with escitalopram was superior to usual care and escitalopram in improving functioning dimensions of quality life. Copyright © 2010 John Wiley & Sons, Ltd.     

Mesenchymal stem cells and inorganic bovine bone mineral in sinus augmentation: comparison with augmentation by autologous bone in adult sheep

Our aim was to compare the osteogenic potential of mononuclear cells harvested from the iliac crest combined with bovine bone mineral (BBM) (experimental group) with that of autogenous cancellous bone alone (control group). We studied bilateral augmentations of the sinus floor in 6 adult sheep. BBM and mononuclear cells (MNC) were mixed and placed into one side and autogenous bone in the other side. Animals were killed after 8 and 16 weeks. Sites of augmentation were analysed radiographically and histologically. The mean (SD) augmentation volume was 3.0 (1.0) cm³ and 2.7 (0.3) cm³ after 8 and 16 weeks in the test group, and 2.8 (0.3) cm³ (8 weeks) and 2.8 (1.2) cm³ (16 weeks) in the control group, respectively. After 8 weeks, histomorphometric analysis showed 24 (3)% BBM, and 19 (11)% of newly formed bone in the test group. The control group had 20 (13%) of newly formed bone. Specimens after 16 weeks showed 29 (12%) of newly formed bone and 19 (3%) BBM in the test group. The amount of newly formed bone in the control group was 16 (6%). The results show that mononuclear cells, including mesenchymal stem cells, in combination with BBM as the biomaterial, have the potential to form bone.     

Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings

The aim of this study was to evaluate a possible role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (ONJ) and to discuss an etiological model. Bone samples from 35 patients with ONJ were analyzed. Control samples were taken from five patients with osteomyelitis (OM), ten patients with osteoradionecrosis, seven patients with osteoporosis and bisphosphonate medication without signs of ONJ, and six osteoporotic elderly patients. Samples were examined using scanning electron microscopy. In 54% of the bone samples of patients with ONJ, microcracks were seen. Inflammatory and connective tissue reactions within the microcracks were evident in 82% of the cases, indicating that these cracks were not artificial. In contrast, only 29% of samples from patients with oral bisphosphonate medication without ONJ, no sample from patients with OM, none of the osteoradionecrosis group, and only 17% from patients with osteoporosis showed microcracks. Statistically significant differences could be found between the ONJ group and the group after irradiation and the group with OM, respectively. The evidence of microcracks could be a first step in the pathogenesis of bisphosphonate-related ONJ. The accumulation of these microcracks leads to a situation that could be named “non-symptomatic ONJ”. Disruptions of the mucosal integrity may then allow bacterial invasion, leading to jawbone infection with exposed bone, fistulas, and pain. This state could be called “symptomatic ONJ”. Furthermore, an assumed local immunosuppression as indicated by various studies could explain the severe courses of therapy-resistant ONJ as regularly observed.