The influence of different culture microenvironments on the generation of dendritic cells from non-small-cell lung cancer patients

This study extends the model developed in Williams and Seaman’s [Williams, J. J. and Seaman, A. E. (2010). Corporate Governance and Mindfulness: The Impact of Management Accounting Systems Change, The Journal of Applied Business Research, Vol. 26, No. 5, pp. 1-17] exploratory paper examining the moderating effects of management accounting systems (MAS) change on the corporate governance/mindfulness relationship for a Canadian sample of 124 top-level accounting professionals. Canonical correlation analysis was applied to the linkage of multiple cognitive processes of mindfulness (Weick and Sutcliffe, 2001; 2007) and the governance dimensions of performance and conformance specified by the International Federation of Accountants (2009), underpinned by the moderating effects of five different components of MAS change, which yielded 13 significant relationships. The latter were subsequently analyzed for important gestalts (i.e., patterns) in the overall relationship, and assessed within the context of aligning professional accounting practices involving systems changes to the IFAC (2009) governance framework. These findings appear to have implications for improved governance structures in practice as well as offering a rich foundation for future research

Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models

Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Inhibition of dendropoiesis by tumor derived and purified prostate specific antigen.

PURPOSE: Prostate specific antigen (PSA) is a serine protease produced by the prostate gland at high concentrations. Serum PSA may be significantly elevated in prostate cancer and benign prostatic diseases. It has recently become evident that, in addition to being a tissue and/or serum marker, PSA may also have biological effects. Despite the voluminous literature on this biomarker in the diagnosis of prostatic diseases relatively few reports have addressed the issue of the physiological function, biological role and immune effects of PSA in the context of prostate cancer development and progression. MATERIALS AND METHODS: Human dendritic cell (DC) cultures were generated from CD34+ hematopoietic precursors in the presence of PSA. The DC phenotype was assessed by flow cytometry and DC ability to induce T-cell proliferation was detected by allogeneic mixed lymphocyte reaction assay. DCs were also generated in co-cultures with LNCaP cells in the presence of antiPSA antibodies. The concentrations of PSA in cultures were determined by the AXSYM System (Abbott Laboratories, Wiesbaden, Germany). RESULTS: We noted that purified and LNCaP derived PSA inhibited the generation and maturation of DC (dendropoiesis) in vitro, which might have a crucial role in the induction and regulation of specific antitumor immune responses. The addition of active PSA to DC cultures significantly inhibited the generation and maturation of DC, as assessed by the levels of expression of CD83, CD80, CD86 and HLA DR. The ability of DC to induce T-cell proliferation, which depends on the expression of co-stimulatory and major histocompatibility complex molecules, was also suppressed in PSA treated DC cultures. CONCLUSIONS: The antidendropoietic effect of PSA in vitro suggests a new mechanism of prostate cancer induced immunosuppression and tumor escape, and provides novel evidence of the immunoregulatory properties of PSA

Inhibition of dendropoiesis by tumor derived and purified prostate specific antigen.

PURPOSE: Prostate specific antigen (PSA) is a serine protease produced by the prostate gland at high concentrations. Serum PSA may be significantly elevated in prostate cancer and benign prostatic diseases. It has recently become evident that, in addition to being a tissue and/or serum marker, PSA may also have biological effects. Despite the voluminous literature on this biomarker in the diagnosis of prostatic diseases relatively few reports have addressed the issue of the physiological function, biological role and immune effects of PSA in the context of prostate cancer development and progression. MATERIALS AND METHODS: Human dendritic cell (DC) cultures were generated from CD34+ hematopoietic precursors in the presence of PSA. The DC phenotype was assessed by flow cytometry and DC ability to induce T-cell proliferation was detected by allogeneic mixed lymphocyte reaction assay. DCs were also generated in co-cultures with LNCaP cells in the presence of antiPSA antibodies. The concentrations of PSA in cultures were determined by the AXSYM System (Abbott Laboratories, Wiesbaden, Germany). RESULTS: We noted that purified and LNCaP derived PSA inhibited the generation and maturation of DC (dendropoiesis) in vitro, which might have a crucial role in the induction and regulation of specific antitumor immune responses. The addition of active PSA to DC cultures significantly inhibited the generation and maturation of DC, as assessed by the levels of expression of CD83, CD80, CD86 and HLA DR. The ability of DC to induce T-cell proliferation, which depends on the expression of co-stimulatory and major histocompatibility complex molecules, was also suppressed in PSA treated DC cultures. CONCLUSIONS: The antidendropoietic effect of PSA in vitro suggests a new mechanism of prostate cancer induced immunosuppression and tumor escape, and provides novel evidence of the immunoregulatory properties of PSA

Early bronchodilator action of glycopyrronium versus tiotropium in moderate-to-severe COPD patients: a cross-over blinded randomized study (Symptoms and Pulmonary function in the moRnING)

Jose M Marin,1 Kai M Beeh,2 Andreas Clemens,3 Walter Castellani,4 Lennart Schaper,5 Dinesh Saralaya,6 Anthony Gunstone,7 Ricard Casamor,8 Konstantinos Kostikas,3 Maryam Aalamian-Mattheis3 1University Hospital Miguel Servet, IISAragón, CIBERES, Zaragoza, Spain; 2Insaf Respiratory Research Institute, Wiesbaden, Germany; 3Novartis Pharma AG, Basel, Switzerland; 4Hospital Piero Palagi, Fiorenze, Italy; 5Research Institute and Practice, Berlin-Brandenburg, Germany; 6Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK; 7Staploe Medical Center, Soham, Cambridge, UK; 8Novartis Farmaceutica SA, Barcelona, Spain Background: Morning symptoms associated with COPD have a negative impact on patients’ quality of life. Long-acting bronchodilators with rapid onset may relieve patients’ symptoms. In the Symptoms and Pulmonary function in the moRnING study, we prospectively compared the rapid onset bronchodilator profile of glycopyrronium (GLY) and tiotropium (TIO) during the first few hours after dosing in patients with moderate-to-severe COPD.Methods: Patients were randomized (1:1) to receive either once-daily GLY (50 µg) or TIO (18 µg) and corresponding placebos in a cross-over design for 28 days. The primary objective was to demonstrate the superiority of GLY versus TIO in area under the curve from 0 to 4 hours (AUC0-4h) forced expiratory volume in 1 second (FEV1) after the first dose. The secondary objective was to compare GLY versus TIO using the patient reported outcomes Morning COPD Symptoms Questionnaire 3 hours post-inhalation.Results: One-hundred and twenty-six patients were randomized (male 70.2%; mean age 65.7 years) and 108 patients completed the study. On Day 1, GLY resulted in significantly higher FEV1 AUC0-4h after the first dose versus TIO (treatment difference [Δ], 0.030 L, 95% confidence interval 0.004–0.056, P=0.025). Improvements in morning COPD symptoms from baseline at Days 1 and 28 were similar between GLY and TIO. Post hoc analysis of the FEV1 AUC0-4h by time point on Day 1 showed significant improvements in patients receiving GLY versus TIO at 5 minutes (Δ=0.029 L, P=0.015), 15 minutes (Δ=0.033 L, P=0.026), and 1 hour (Δ=0.044 L, P=0.014). Safety results were comparable between both treatments.Conclusion: The SPRING study demonstrates the superiority of GLY versus TIO in terms of superior bronchodilation in the first 4 hours after administration, thus extending the clinical data that support a faster onset of action of GLY versus TIO. Keywords: LAMA, glycopyrronium, tiotropium, lung function, fast onset, rapid onset, patient reported outcome, COP