Mononuclear Phagocyte Activation in Acute Pancreatitis: A Clinical and Experimental Study

The pathophysiology of the systemic illness seen in patients with acute pancreatitis is unknown but there are similarities with the systemic complications of sepsis, prompting the suggestion that similar endogenous mediators may be responsible. Central to this hypothesis is the role of activated mononuclear phagocytes. The long acting somatostatin analogue, octreotide (Sandostatin) has been shown to improve hepatic reticuloendothelial cell function, an effect which may be beneficial in acute pancreatitis by enhancing the clearance of endotoxin from portal blood and preventing systemic mononuclear phagocyte activation. This thesis addresses two main questions. Firstly the potential role of octreotide in the treatment of acute pancreatitis and secondly the role of mononuclear phagocyte activation in the pathophysiology of the systemic complications of acute pancreatitis. Octreotide in acute pancreatitis 58 patients with moderate or severe acute pancreatitis who were admitted to hospitals within the West of Scotland over an 18 month period were randomised to receive octreotide, 40mug/h by continuous intravenous infusion, or placebo in addition to standard supportive therapy. Patients were comparable in age, sex, aetiology and severity of disease on admission. There was no significant difference in the incidence of complications (53.6% octreotide group and 43.3% placebo group) or mortality (octreotide group 18%; placebo group 20%). The resuhs of this study indicate that octreotide is of little or no benefit in the treatment of acute pancreatitis. Mononuclear phagocyte activation in acute pancreatitis Monocytes were isolated from the peripheral blood of 28 patients with moderate or severe acute pancreatitis and the in-vitro secretion of these cytokines measured at intervals during the first week of illness. Sixteen patients (57%) developed systemic complications. Peak TNF? secretion was significantly higher in patients who developed systemic complications (median = 18.5ng/ml, IQR 5.5-28.5) than in those with an uncomplicated course (3.7ng/ml, 2.3-6.4, P<0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6; complicated: median = 48.9ng/ml, IQR 12-71, uncomplicated 16.3ng/ml, 9.9-24.8, P<0.05; IL-8, complicated; median = 754ng/ml, IQR 683-857, uncomplicated; median = 602ng/ml, 496-756, P<0.05). No significant difference in peak IL-1 secretion was observed between the two groups. This study demonstrates that the systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNFalpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease. The role of IL-1beta and proteolytic degradation of parathyroid hormone (PTH) in the pathophysiology of pancreatitis-associated hypocalcaemia was studied. Serum levels of PTH, calcium and albumin were measured daily for five days in 41 selected patients with moderate to severe acute pancreatitis. PTH was measured by means of a two-site immunoradiometric assay specific for the intact peptide. A rise in PTH levels was observed more commonly in patients with a complicated or fatal outcome than in those with an uncomplicated course (complicated; 87.5% of 16 patients, uncomplicated; 24% of 25 patients, P<0.001, Chi-square test). In the presence of hypocalcaemia, although PTH levels were variable, raised levels of PTH were found more frequently in the complicated group (complicated; 7 of 8, uncomplicated; 2 of 7, P=0.035, Fisher's exact test). This study confirms that an appropriate rise in PTH occurs in response to the hypocalcaemic stimulus in patients with acute pancreatitis, with no evidence of significant PTH degradation. There was a significant negative correlation between serum calcium levels and the secretion of IL-1beta by monocytes but this was mainly a consequence of the resuhs obtained from one patient with very low serum calcium associated with high monocyte IL-1beta secretion. Increased production of pro-inflammatory cytokines by monocytes and mononuclear phagocytes would be expected to result in neutrophil activation and therefore raised plasma levels of polymorphonuclear elastase (PMNE). Measurement of PMNE in acute pancreatitis may therefore be a simple method of assessing the degree of leucocyte activation which would allow the early identification of patients at risk of developing systemic complications

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

&lt;b&gt;Background&lt;/b&gt; Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0–300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p &lt; .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt; A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.&lt;p&gt;&lt;/p&gt

Volatile Analyzer for Lunar Polar Missions

One of the major questions remaining for the future exploration of the Moon by humans concerns the presence of volatiles on our nearest neighbor in space. Observational studies, and investigations involving returned lunar samples and using robotic spacecraft infer the existence of volatile compounds particularly water [1]. It seems very likely that a volatile component will be concentrated at the poles in circumstances where low-temperatures exist to provide cryogenic traps. However, the full inventory of species, their concentration and their origin and sources are unknown. Of particular importance is whether abundances are sufficient to act as a resource of consumables for future lunar expeditions especially if a long-term base involving humans is to be established. To address some of these issues requires a lander designed specifically for operation at a high-lunar latitude. A vital part of the payload needs to be a volatile analyzer such as the Gas Analysis Package specifically designed for identification quantification of volatile substances and collecting information which will allow the origin of these volatiles to be identified [1]. The equipment included, particularly the gas analyzer, must be capable of operation in the extreme environmental conditions to be encountered. No accurate information yet exists regarding volatile concentration even for sites closer to the lunar equator (because of contamination). In this respect it will be important to understand (and thus limit) contamination of the lunar surface by extraneous material contributed from a variety of sources. The only data for the concentrations of volatiles at the poles comes from orbiting spacecraft and whilst the levels at high latitudes may be greater than at the equator, the volatile analyzer package under consideration will be designed to operate at the highest specifications possible and in a way that does not compromise the data

Markov decision analysis of neoadjuvant treatment pathway versus surgery first pathway for resectable pancreatic cancer

Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is controversial. This study is unique in utilizing institutional data to offer Markov decision-analysis of overall treatment pathways for resectable PDAC. Methods: An advanced Markov decision analysis model was constructed and populated with data from a retrospective institutional database. Patients presenting with resectable PDAC from 2008-2012 were included in the SF arm. Those presenting with resectable PDAC from 2012-2016 and treated within NAT pathway populated the NAT arm. Model uncertainties were tested with one and two-way deterministic sensitivity analysis and probabilistic Monte Carlo sensitivity analysis set to 1000 cycles with variables altered between highest and lowest observed values. Results: NAT pathway gave an additional 0.58 QALMs (22.43 vs. 21.85 QALMs). Monte Carlo analysis reported indifference between treatment strategies. One-way deterministic sensitivity analysis showed that probability of resection in the SF pathway must be greater than 0.82, or below 0.72 in NAT pathway, and probability of receiving adjuvant therapy above 0.6 to alter pathway superiority. Two-way deterministic sensitivity analysis demonstrated treatment superiority depended on resection rate in each pathway and receiving adjuvant therapy in SF pathway. Markov cohort analysis demonstrated superiority of neoadjuvant pathway (Table). Conclusions: Optimal treatment pathway remains debatable on an intention-to-treat Markov decision analysis. Markov cohort analysis of treatment received demonstrated benefit with NAT pathway

A systematic review of methodological quality of model development studies predicting prognostic outcome for resectable pancreatic cancer

Objectives To assess the methodological quality of prognostic model development studies pertaining to post resection prognosis of pancreatic ductal adenocarcinoma (PDAC). Design/setting A narrative systematic review of international peer reviewed journals Data source Searches were conducted of: MEDLINE, Embase, PubMed, Cochrane database and Google Scholar for predictive modelling studies applied to the outcome of prognosis for patients with PDAC post resection. Predictive modelling studies in this context included prediction model development studies with and without external validation and external validation studies with model updating. Data was extracted following the Checklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) checklist. Primary and secondary outcome measures Primary outcomes were all components of the CHARMS checklist. Secondary outcomes included frequency of variables included across predictive models. Results 263 studies underwent full text review. 15 studies met the inclusion criteria. 3 studies underwent external validation. Multivariable Cox proportional hazard regression was the most commonly employed modelling method (n=13). 10 studies were based on single centre databases. Five used prospective databases, seven used retrospective databases and three used cancer data registry. The mean number of candidate predictors was 19.47 (range 7 to 50). The most commonly included variables were tumour grade (n=9), age (n=8), tumour stage (n=7) and tumour size (n=5). Mean sample size was 1367 (range 50 to 6400). 5 studies reached statistical power. None of the studies reported blinding of outcome measurement for predictor values. The most common form of presentation was nomograms (n=5) and prognostic scores (n=5) followed by prognostic calculators (n=3) and prognostic index (n=2). Conclusions Areas for improvement in future predictive model development have been highlighted relating to: general aspects of model development and reporting, applicability of models and sources of bias

A prognostic Bayesian network that makes personalized predictions of poor prognostic outcome post resection of pancreatic ductal adenocarcinoma

Background The narrative surrounding the management of potentially resectable pancreatic cancer is complex. Surgical resection is the only potentially curative treatment. However resection rates are low, the risk of operative morbidity and mortality are high, and survival outcomes remain poor. The aim of this study was to create a prognostic Bayesian network that pre-operatively makes personalized predictions of post-resection survival time of 12months or less and also performs post-operative prognostic updating. Methods A Bayesian network was created by synthesizing data from PubMed post-resection survival analysis studies through a two-stage weighting process. Input variables included: inflammatory markers, tumour factors, tumour markers, patient factors and, if applicable, response to neoadjuvant treatment for pre-operative predictions. Prognostic updating was performed by inclusion of post-operative input variables including: pathology results and adjuvant therapy. Results 77 studies (n = 31,214) were used to create the Bayesian network, which was validated against a prospectively maintained tertiary referral centre database (n = 387). For pre-operative predictions an Area Under the Curve (AUC) of 0.7 (P value: 0.001; 95% CI 0.589–0.801) was achieved accepting up to 4 missing data-points in the dataset. For prognostic updating an AUC 0.8 (P value: 0.000; 95% CI:0.710–0.870) was achieved when validated against a dataset with up to 6 missing pre-operative, and 0 missing post-operative data-points. This dropped to AUC: 0.7 (P value: 0.000; 95% CI:0.667–0.818) when the post-operative validation dataset had up to 2 missing data-points. Conclusion This Bayesian network is currently unique in the way it utilizes PubMed and patient level data to translate the existing empirical evidence surrounding potentially resectable pancreatic cancer to make personalized prognostic predictions. We believe such a tool is vital in facilitating better shared decision-making in clinical practice and could be further developed to offer a vehicle for delivering personalized precision medicine in the future

Displaced geostationary orbit design using hybrid sail propulsion

Because of an increase in the number of geostationary spacecraft and the limits imposed by east–west spacing requirements, the geostationary orbit is becoming congested. To increase its capacity, this paper proposes to create new geostationary slots by displacing the geostationary orbit either out of or in the equatorial plane by means of hybrid solar sail and solar electric propulsion. To minimize propellant consumption, optimal steering laws for the solar sail and solar-electric-propulsion thrust vectors are derived and the performance in terms of mission lifetime is assessed. For comparison, similar analyses are performed for conventional propulsion, including impulsive and pure solar electric propulsion. It is shown that hybrid sails outperform these propulsion techniques and that out-of-plane displacements outperform in-plane displacements. The out-of-plane case is therefore further investigated in a spacecraft mass budget to determine the payload mass capacity. Finally, two transfers that enable a further improvement of the performance of hybrid sails for the out-of-plane case are optimized using a direct pseudospectral method: a seasonal transit between orbits displaced above and below the equatorial plane and a transit to a parking orbit when geostationary coverage is not needed. Both transfers are shown to require only a modest propellant budget, outweighing the improvements they can establish

IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects

Faint young Sun paradox remains

The Sun was fainter when the Earth was young, but the climate was generally at least as warm as today; this is known as the `faint young Sun paradox'. Rosing et al. [1] claim that the paradox can be resolved by making the early Earth's clouds and surface less reflective. We show that, even with the strongest plausible assumptions, reducing cloud and surface albedos falls short by a factor of two of resolving the paradox. A temperate Archean climate cannot be reconciled with the low level of CO2 suggested by Rosing et al. [1]; a stronger greenhouse effect is needed.Comment: 3 pages, no figures. In press in Nature. v2 corrects typo in author list in original submissio

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease