A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma.

© 2014 Haider et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Improved usage of the repertoires of pancreatic ductal adenocarcinoma (PDAC) profiles is crucially needed to guide the development of predictive and prognostic tools that could inform the selection of treatment options

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity

<p>Abstract</p> <p>Background</p> <p>Titanium dioxide (TiO₂) nanomaterials have considerable beneficial uses as photocatalysts and solar cells. It has been established for many years that pigment-grade TiO₂(200 nm sphere) is relatively inert when internalized into a biological model system (in vivo or in vitro). For this reason, TiO₂nanomaterials are considered an attractive alternative in applications where biological exposures will occur. Unfortunately, metal oxides on the nanoscale (one dimension < 100 nm) may or may not exhibit the same toxic potential as the original material. A further complicating issue is the effect of modifying or engineering of the nanomaterial to be structurally and geometrically different from the original material.</p> <p>Results</p> <p>TiO₂nanospheres, short (< 5 μm) and long (> 15 μm) nanobelts were synthesized, characterized and tested for biological activity using primary murine alveolar macrophages and in vivo in mice. This study demonstrates that alteration of anatase TiO₂nanomaterial into a fibre structure of greater than 15 μm creates a highly toxic particle and initiates an inflammatory response by alveolar macrophages. These fibre-shaped nanomaterials induced inflammasome activation and release of inflammatory cytokines through a cathepsin B-mediated mechanism. Consequently, long TiO₂nanobelts interact with lung macrophages in a manner very similar to asbestos or silica.</p> <p>Conclusions</p> <p>These observations suggest that any modification of a nanomaterial, resulting in a wire, fibre, belt or tube, be tested for pathogenic potential. As this study demonstrates, toxicity and pathogenic potential change dramatically as the shape of the material is altered into one that a phagocytic cell has difficulty processing, resulting in lysosomal disruption.</p

A qualitative study to identify community structures for management of severe malaria: a basis for introducing rectal artesunate in the under five years children in Nakonde District of Zambia

BACKGROUND: Malaria is a serious illness among children aged 5 years and below in Zambia, which carries with it many adverse effects including anemia and high parasites exposure that lead to infant and childhood mortality. Due to poor accessibility to modern health facilities, malaria is normally managed at home using indigenous and cosmopolitan medicines. In view of problems and implications associated with management of severe malaria at home, rectal artesunate is being proposed as a first aid drug to slow down multiplication of parasites in children before accessing appropriate treatment. METHODS: A qualitative study using standardised in-depth and Focuss Group Discussions (FGDs) guides to collect information from four (4) villages in Nakonde district, was conducted between February and March 2004. The guides were administered on 29 key informants living in the community and those whose children were admitted in the health facility. Participants in the 12 FGDs came from the 4 participating villages. Participants and key informants were fathers, younger and older mothers including grandmothers and other influential people at household level. Others were traditional healers, headmen, village secretaries, tradtional birth attendants, church leaders and black smiths. FGDs and interview transcriptions were coded to identify common themes that were related to recognition, classification and naming of malaria illness, care-seeking behaviour and community treatment practices for severe malaria. RESULTS: Parental prior knowledge of the disease was important as the majority of informants (23 out of 29) and participants (69 out of 97) mentioned four combined symptoms that were used to recognise severe malaria. The symptoms were excessive body hotness, convulsions, vomiting yellow things and bulging of the fontanelle. On the other hand, all informants mentioned two or more of symptoms associated with severe malaria. In all 12 FGDs, participants reported that treatment of severe malaria commenced with the family and moved into the community as the illness progressed. Although treatment of severe diarrheal effects, were common among the winamwanga, no rectal medicines to treat severe malaria were identified. Apart from the anti-malarial fansidar, which was mentioned by 23 in IDIs and 40 in FGDs, participants and informants also frequently mentioned indigenous medicines provided by healers and other respectable herbalists for repelling evil spirits, once a child had severe malaria. Mothers were the important arms for administration of ant-malarial drugs in the villages. Referrals began with healers to CHWs, where no CHWs existed healers directly referred sick children to the health facility. CONCLUSION: Our findings showed that there is a precedent for rectal application of traditional medicine for childhood illness. Therefore rectal artesunate may be a well-received intervention in Nakonde District, provided effective sensitisation, to mothers and CHWs is given which will strengthen the health care delivery system at community level

Influences of Forest Structure, Climate and Species Composition on Tree Mortality across the Eastern US

Few studies have quantified regional variation in tree mortality, or explored whether species compositional changes or within-species variation are responsible for regional patterns, despite the fact that mortality has direct effects on the dynamics of woody biomass, species composition, stand structure, wood production and forest response to climate change. Using Bayesian analysis of over 430,000 tree records from a large eastern US forest database we characterised tree mortality as a function of climate, soils, species and size (stem diameter). We found (1) mortality is U-shaped vs. stem diameter for all 21 species examined; (2) mortality is hump-shaped vs. plot basal area for most species; (3) geographical variation in mortality is substantial, and correlated with several environmental factors; and (4) individual species vary substantially from the combined average in the nature and magnitude of their mortality responses to environmental variation. Regional variation in mortality is therefore the product of variation in species composition combined with highly varied mortality-environment correlations within species. The results imply that variation in mortality is a crucial part of variation in the forest carbon cycle, such that including this variation in models of the global carbon cycle could significantly narrow uncertainty in climate change predictions

Grid Cells, Place Cells, and Geodesic Generalization for Spatial Reinforcement Learning

Reinforcement learning (RL) provides an influential characterization of the brain's mechanisms for learning to make advantageous choices. An important problem, though, is how complex tasks can be represented in a way that enables efficient learning. We consider this problem through the lens of spatial navigation, examining how two of the brain's location representations—hippocampal place cells and entorhinal grid cells—are adapted to serve as basis functions for approximating value over space for RL. Although much previous work has focused on these systems' roles in combining upstream sensory cues to track location, revisiting these representations with a focus on how they support this downstream decision function offers complementary insights into their characteristics. Rather than localization, the key problem in learning is generalization between past and present situations, which may not match perfectly. Accordingly, although neural populations collectively offer a precise representation of position, our simulations of navigational tasks verify the suggestion that RL gains efficiency from the more diffuse tuning of individual neurons, which allows learning about rewards to generalize over longer distances given fewer training experiences. However, work on generalization in RL suggests the underlying representation should respect the environment's layout. In particular, although it is often assumed that neurons track location in Euclidean coordinates (that a place cell's activity declines “as the crow flies” away from its peak), the relevant metric for value is geodesic: the distance along a path, around any obstacles. We formalize this intuition and present simulations showing how Euclidean, but not geodesic, representations can interfere with RL by generalizing inappropriately across barriers. Our proposal that place and grid responses should be modulated by geodesic distances suggests novel predictions about how obstacles should affect spatial firing fields, which provides a new viewpoint on data concerning both spatial codes

Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation

This study was supported by the British Heart Foundation (PG 09/002/ 2642). AJR is funded by King’s College London British Heart Foundation Centre of Excellence and EI was supported by the Department of Health via National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Tomas’ NHF Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. BG was supported by a British Heart Foundation studentship (FS/10/009/28166) and DC by an Arthritis Research UK Fellowship (18103)

Tumour budding in oral squamous cell carcinoma : a meta-analysis

Background: Tumour budding has been reported as a promising prognostic marker in many cancers. This meta-analysis assessed the prognostic value of tumour budding in oral squamous cell carcinoma (OSCC). Methods: We searched OvidMedline, PubMed, Scopus and Web of Science for articles that studied tumour budding in OSCC. We used reporting recommendations for tumour marker (REMARK) criteria to evaluate the quality of studies eligible for meta-analysis. Results: A total of 16 studies evaluated the prognostic value of tumour budding in OSCC. The meta-analysis showed that tumour budding was significantly associated with lymph node metastasis (odds ratio = 7.08, 95% CI = 1.75-28.73), disease-free survival (hazard ratio = 1.83, 95% CI = 1.34-2.50) and overall survival (hazard ratio = 1.88, 95% CI = 1.25-2.82). Conclusions: Tumour budding is a simple and reliable prognostic marker for OSCC. Evaluation of tumour budding could facilitate personalised management of OSCC.Peer reviewe

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor <it>(VEGF-R</it>) and Transketolase-like-1 (<it>TKTL1</it>) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of <it>VEGFR-1</it>, <it>VEGFR-2 </it>and <it>TKTL1 </it>in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab.</p> <p>Methods</p> <p>Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR.</p> <p>Results</p> <p>Significantly higher expression of <it>VEGFR-1/2 </it>was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High <it>TKTL1 </it>expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers.</p> <p>Conclusion</p> <p>High <it>TKTL-1 </it>expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.</p

Sterol Intermediates of Cholesterol Biosynthesis Inhibit Hair Growth and Trigger an Innate Immune Response in Cicatricial Alopecia

Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders