TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis

Dynamic Modelling under Uncertainty: The Case of Trypanosoma brucei Energy Metabolism

Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Glycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies

Geriatric patients' expectations of their physicians: findings from a tertiary care hospital in Pakistan

<p>Abstract</p> <p>Background</p> <p>Geriatric health is a neglected and under-explored area internationally and in Pakistan. We aimed to ascertain the expectations of the geriatric patients from their physicians and the factors associated with patient satisfaction in this particular age bracket.</p> <p>Methods</p> <p>A cross-sectional survey was carried out at a tertiary care teaching hospital in Karachi, Pakistan. Data collection was carried out via face-to-face interviews based on structured, pre-tested questionnaires. All consenting individuals aged 65 years or above were recruited into the study. Convenience sampling was used to draw the sample. The data was analyzed using SPSS version 16. Geriatric patient's expectations from physicians were elicited using a set of 11 questions that were graded on a scale of 1-3 where 1 = not important, 2 = important, 3 = very important.</p> <p>Results</p> <p>Three hundred and eighty geriatric patients were interviewed. The response rate of this study was 89.8%. The mean age of the respondents was 73.4 ± 6.8 years. Two hundred and forty eight respondents (65.3%) were female. Diabetes mellitus (53.7%), hypertension (59.5%), arthritis (40.5%) and renal disease (32.1%) were common ailments among geriatric patients. More than 50% of the patients were visiting their physicians once every two to three months. Discussing treatment options and letting patients make the final decision (79.2%), prescribing minimum possible medications (84.5%), physician's holistic knowledge about the spectrum of care issues for geriatric patients (79.2%), being given a realistic but optimistic picture of future health by physicians (85.5%) were ranked as very important expectations by patients from their physicians. Cumulative household income (p = 0.005), most important health complaint (p = 0.01) and frequency of experiencing health complaint (p < 0.001) emerged as independent predictors of the satisfaction of geriatric patients from care provided by physicians.</p> <p>Conclusion</p> <p>We have documented the expectations of the geriatric patients from their physicians in a developing country. Physicians belonging to all disciplines should keep these expectations in mind during clinical encounters with geriatric patients.</p