Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life

Challenges in using land use and land cover data for global change studies

Land use and land cover data play a central role in climate change assessments. These data originate from different sources and inventory techniques. Each source of land use/cover data has its own domain of applicability and quality standards. Often data are selected without explicitly considering the suitability of the data for the specific application, the bias originating from data inventory and aggregation, and the effects of the uncertainty in the data on the results of the assessment. Uncertainties due to data selection and handling can be in the same order of magnitude as uncertainties related to the representation of the processes under investigation. While acknowledging the differences in data sources and the causes of inconsistencies, several methods have been developed to optimally extract information from the data and document the uncertainties. These methods include data integration, improved validation techniques and harmonization of classification systems. Based on the data needs of global change studies and the data availability, recommendations are formulated aimed at optimal use of current data and focused efforts for additional data collection. These include: improved documentation using classification systems for land use/cover data; careful selection of data given the specific application and the use of appropriate scaling and aggregation methods. In addition, the data availability may be improved by the combination of different data sources to optimize information content while collection of additional data must focus on validation of available data sets and improved coverage of regions and land cover types with a high level of uncertainty. Specific attention in data collection should be given to the representation of land management (systems) and mosaic landscape

Symptom burden in malignant and non-malignant disease on admission to a palliative care unit

Background There is increasing recognition that patients with non-malignant diseases have comparable physical and psychosocial symptom burden to patients with cancer. There is currently limited data directly comparing symptom burden between these patient groups. Objective To investigate differences in symptom burden between patients with malignant and non-malignant conditions admitted to a palliative care unit (PCU). Method A cross-sectional study involving 186 patients admitted to a PCU was undertaken. Patients were dichotomised into malignant or non-malignant disease categories. Symptom burden at admission was assessed using the Symptom Assessment Scale and Palliative Care Problem Severity Score. Group differences in symptoms were analysed using univariate and multivariate approaches. Results One hundred patients (53.8%) had cancer, with upper gastrointestinal the most common type (18.0%). Among the 86 patients with non-malignant disease, neurological conditions were most prevalent (40.7%). Patients admitted with non-malignant diseases were older, more functionally impaired and more likely to be deteriorating or terminal. A malignant diagnosis was associated with a higher likelihood of clinician-assessed pain, patient-assessed pain, fatigue, psychological/spiritual symptoms and other symptoms. However, when adjusted for confounders, disease category ceased to be a significant predictor of symptom burden. Younger patients experienced worse pain and patients in terminal phase experienced less symptom burden. Conclusion Symptom burden was similar between patients with malignant and non-malignant disease after adjustment for confounders. Further research is needed to understand the palliative care needs of patients with non-malignant disease