Myofibroblast-Derived SFRP1 as Potential Inhibitor of Colorectal Carcinoma Field Effect

Epigenetic changes of stromal-epithelial interactions are of key importance in the regulation of colorectal carcinoma (CRC) cells and morphologically normal, but genetically and epigenetically altered epithelium in normal adjacent tumor (NAT) areas. Here we demonstrated retained protein expression of well-known Wnt inhibitor, secreted frizzled-related protein 1 (SFRP1) in stromal myofibroblasts and decreasing epithelial expression from NAT tissues towards the tumor. SFRP1 was unmethylated in laser microdissected myofibroblasts and partially hypermethylated in epithelial cells in these areas. In contrast, we found epigenetically silenced myofibroblast-derived SFRP1 in CRC stroma. Our results suggest that the myofibroblast-derived SFRP1 protein might be a paracrine inhibitor of epithelial proliferation in NAT areas and loss of this signal may support tumor proliferation in CRC

Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00109-006-0122-9 and is accessible for authorized users

Semi-automated quantification of left ventricular volumes and ejection fraction by real-time three-dimensional echocardiography

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown that real-time three-dimensional (3D) echocardiography (RT3DE) gives more accurate and reproducible left ventricular (LV) volume and ejection fraction (EF) measurements than traditional two-dimensional methods. A new semi-automated tool (4DLVQ) for volume measurements in RT3DE has been developed. We sought to evaluate the accuracy and repeatability of this method compared to a 3D echo standard.</p> <p>Methods</p> <p>LV end-diastolic volumes (EDV), end-systolic volumes (ESV), and EF measured using 4DLVQ were compared with a commercially available semi-automated analysis tool (TomTec 4D LV-Analysis ver. 2.2) in 35 patients. Repeated measurements were performed to investigate inter- and intra-observer variability.</p> <p>Results</p> <p>Average analysis time of the new tool was 141s, significantly shorter than 261s using TomTec (<it>p </it>< 0.001). Bland Altman analysis revealed high agreement of measured EDV, ESV, and EF compared to TomTec (<it>p </it>= <it>NS</it>), with bias and 95% limits of agreement of 2.1 ± 21 ml, -0.88 ± 17 ml, and 1.6 ± 11% for EDV, ESV, and EF respectively. Intra-observer variability of 4DLVQ vs. TomTec was 7.5 ± 6.2 ml vs. 7.7 ± 7.3 ml for EDV, 5.5 ± 5.6 ml vs. 5.0 ± 5.9 ml for ESV, and 3.0 ± 2.7% vs. 2.1 ± 2.0% for EF (<it>p </it>= <it>NS</it>). The inter-observer variability of 4DLVQ vs. TomTec was 9.0 ± 5.9 ml vs. 17 ± 6.3 ml for EDV (<it>p </it>< 0.05), 5.0 ± 3.6 ml vs. 12 ± 7.7 ml for ESV (<it>p </it>< 0.05), and 2.7 ± 2.8% vs. 3.0 ± 2.1% for EF (<it>p </it>= <it>NS</it>).</p> <p>Conclusion</p> <p>In conclusion, the new analysis tool gives rapid and reproducible measurements of LV volumes and EF, with good agreement compared to another RT3DE volume quantification tool.</p

A stem-group cnidarian described from the mid-Cambrian of China and its significance for cnidarian evolution

Palaeontological data of extinct groups often sheds light on the evolutionary sequences leading to extant groups, but has failed to resolve the basal metazoan phylogeny including the origin of the Cnidaria. Here we report the occurrence of a stem-group cnidarian, Cambroctoconus orientalis gen. et sp. nov., from the mid-Cambrian of China, which is a colonial organism with calcareous octagonal conical cup-shaped skeletons. It bears cnidarian features including longitudinal septa arranged in octoradial symmetry and colonial occurrence, but lacks a jelly-like mesenchyme. Such morphological characteristics suggest that the colonial occurrence with polyps of octoradial symmetry is the plesiomorphic condition of the Cnidaria and appeared earlier than the jelly-like mesenchyme during the course of evolution

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden

Integrating sustainable hunting in biodiversity protection in central Africa: Hot spots, weak spots, and strong spots

© 2014 Fa et al. Wild animals are a primary source of protein (bushmeat) for people living in or near tropical forests. Ideally, the effect of bushmeat harvests should be monitored closely by making regular estimates of offtake rate and size of stock available for exploitation. However, in practice, this is possible in very few situations because it requires both of these aspects to be readily measurable, and even in the best case, entails very considerable time and effort. As alternative, in this study, we use high-resolution, environmental favorability models for terrestrial mammals (N = 165) in Central Africa to map areas of high species richness (hot spots) and hunting susceptibility. Favorability models distinguish localities with environmental conditions that favor the species' existence from those with detrimental characteristics for its presence. We develop an index for assessing Potential Hunting Sustainability (PHS) of each species based on their ecological characteristics (population density, habitat breadth, rarity and vulnerability), weighted according to restrictive and permissive assumptions of how species' characteristics are combined. Species are classified into five main hunting sustainability classes using fuzzy logic. Using the accumulated favorability values of all species, and their PHS values, we finally identify weak spots, defined as high diversity regions of especial hunting vulnerability for wildlife, as well as strong spots, defined as high diversity areas of high hunting sustainability potential. Our study uses relatively simple models that employ easily obtainable data of a species' ecological characteristics to assess the impacts of hunting in tropical regions. It provides information for management by charting the geography of where species are more or less likely to be at risk of extinction from hunting. Copyright

Predicting range shifts of African apes under global change scenarios

Aim: Modelling African great ape distribution has until now focused on current or past conditions, while future scenarios remain scarcely explored. Using an ensemble forecasting approach, we predicted changes in taxon-specific distribution under future scenarios of climate, land use and human populations for (1) areas outside protected areas (PAs) only (assuming complete management effectiveness of PAs), (2) the entire study region and (3) interspecies range overlap. Location: Tropical Africa. Methods: We compiled occurrence data (n = 5,203) on African apes from the IUCN A.P.E.S. database and extracted relevant climate-, habitat- and human-related predictors representing current and future (2050) conditions to predict taxon-specific range change under a best- and a worst-case scenario, using ensemble forecasting. Results: The predictive performance of the models varied across taxa. Synergistic interactions between predictors are shaping African ape distribution, particularly human-related variables. On average across taxa, a range decline of 50% is expected outside PAs under the best scenario if no dispersal occurs (61% in worst scenario). Otherwise, an 85% range reduction is predicted to occur across study regions (94% worst). However, range gains are predicted outside PAs if dispersal occurs (52% best, 21% worst), with a slight increase in gains expected across study regions (66% best, 24% worst). Moreover, more than half of range losses and gains are predicted to occur outside PAs where interspecific ranges overlap. Main Conclusions: Massive range decline is expected by 2050, but range gain is uncertain as African apes will not be able to occupy these new areas immediately due to their limited dispersal capacity, migration lag and ecological constraints. Given that most future range changes are predicted outside PAs, Africa's current PA network is likely to be insufficient for preserving suitable habitats and maintaining connected ape populations. Thus, conservation planners urgently need to integrate land use planning and climate change mitigation measures at all decision-making levels both in range countries and abroad

Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme.

BACKGROUND: A decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non-CCALD patients identified by screening. RESULTS: It is estimated that screening 780,000 newborns annually will identify 18 (95%CI 12, 27) boys with X-ALD, of whom 10 (95% CI 6, 15) will develop CCALD. It is estimated that screening may detect 7 (95% CI 3, 12) children with other peroxisomal disorders who may also have arisen symptomatically. If results for girls are returned an additional 17 (95% CI 12, 25) cases of X-ALD will be identified. The programme is estimated to cost an additional £402,000 (95% CI £399-407,000) with savings in lifetime health, social care and education costs leading to an overall discounted cost saving of £3.04 (95% CI £5.69, £1.19) million per year. Patients with CCALD are estimated to gain 8.5 discounted QALYs each giving an overall programme benefit of 82 (95% CI 43, 139) QALYs. CONCLUSION: Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs

Classifying chimpanzee (Pan troglodytes) landscapes across large scale environmental gradients in Africa

Primates are sometimes categorized in terms of their habitat. Although such categorization can be over-simplistic, there are scientific benefits from the clarity and consistency that habitat categorization can bring. Chimpanzees (Pan troglodytes) inhabit various environments, but researchers often refer to ‘forest’ or ‘savanna’ chimpanzees. Despite the wide use of this forest-savanna distinction, clear definitions of these landscapes for chimpanzees, based on environmental variables at study sites or determined in relation to existing bioclimatic classifications, are lacking. The robustness of the forest-savanna distinction thus remains to be assessed. We review 43 chimpanzee study sites to assess how the landscape classifications of researchers fit with the environmental characteristics of study sites and with three bioclimatic classifications. We use scatterplots and Principal Components 15 Analysis to assess the distribution of chimpanzee field sites along gradients of environmental 16 variables (temperature, rainfall, precipitation seasonality, forest cover and satellite-derived 17 Hansen tree cover). This revealed an environmental continuum of chimpanzee study sites 18 from savanna to dense forest, with a rarely acknowledged forest mosaic category in between, 19 but with no natural separation into these three classes and inconsistencies with the bioclimatic 20 classifications assessed. The current forest–savanna dichotomy therefore masks a progression 21 of environmental adaptation for chimpanzees, and we propose that recognizing an additional, 22 intermediate ‘forest mosaic’ category is more meaningful than focusing on the ends of this 23 environmental gradient only. Future studies should acknowledge this habitat continuum, place their study sites on the forest–savanna gradient, and include detailed environmental data to support further attempts at quantification

Quantitative estimates of glacial refugia for chimpanzees ( Pan troglodytes ) since the Last Interglacial (120,000 BP)

Paleoclimate reconstructions have enhanced our understanding of how past climates have shaped present-day biodiversity. We hypothesize that the geographic extent of Pleistocene forest refugia and suitable habitat fluctuated significantly in time during the late Quaternary for chimpanzees (Pan troglodytes). Using bioclimatic variables representing monthly temperature and precipitation estimates, past human population density data, and an extensive database of georeferenced presence points, we built a model of changing habitat suitability for chimpanzees at fine spatio-temporal scales dating back to the Last Interglacial (120,000 BP). Our models cover a spatial resolution of 0.0467° (approximately 5.19 km2 grid cells) and a temporal resolution of between 1000 and 4000 years. Using our model, we mapped habitat stability over time using three approaches, comparing our modeled stability estimates to existing knowledge of Afrotropical refugia, as well as contemporary patterns of major keystone tropical food resources used by chimpanzees, figs (Moraceae), and palms (Arecacae). Results show habitat stability congruent with known glacial refugia across Africa, suggesting their extents may have been underestimated for chimpanzees, with potentially up to approximately 60,000 km2 of previously unrecognized glacial refugia. The refugia we highlight coincide with higher species richness for figs and palms. Our results provide spatio-temporally explicit insights into the role of refugia across the chimpanzee range, forming the empirical foundation for developing and testing hypotheses about behavioral, ecological, and genetic diversity with additional data. This methodology can be applied to other species and geographic areas when sufficient data are available