Prognostic impact of CD73 expression and its relationship to PD-L1 in patients with radically treated pancreatic cancer

Immune suppressing molecule CD73 is overexpressed in various cancers and associated with poor survival. Little is so far known about the predictive value of CD73 in pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the prognostic significance of CD73 in PDAC. The study material consisted of 110 radically treated patients for PDAC. Tissue microarray blocks were constructed and stained immunohistochemically using CD73 antibody. Staining intensity and numbers of stained tumour cells, inflammatory cells, stroma, and blood vessels were assessed. High-level CD73 expression in tumour cells was positively associated with PD-L1 expression, perineural invasion, and histopathological grade. CD73 positivity in tumour-infiltrating lymphocytes was significantly associated with lymph node metastasis. Lymphocytic CD73 positivity was also associated with staining positivity in both stroma and vascular structures. In addition, CD73 positivity in vascular structures and stroma were associated with each other. There were no significant associations between CD73 positive tumour cells and CD73 positivity in any other cell types. PD-L1 expression was associated with CD73 staining positivity in stroma (p = 0.007) and also with histopathological grade (p = 0.033) and T class (p = 0.016) of the primary tumour. CD73 positivity in tumour cells was significantly associated with poor disease-specific (p = 0.021) and overall survival (p = 0.016). In multivariate analysis, CD73 positivity in tumour cells was an independent negative prognostic factor together with histopathological grade, TNM stage, and low immune cell score. In conclusion, high CD73 expression in tumour cells is associated with poor survival in PDAC independently of the number of tumour-infiltrating lymphocytes or TNM stage

A vibrational circular dichroism implementation within a Slater-type-orbital based density functional framework and its application to hexa- and hepta-helicenes

We describe the implementation of the rotational strengths for vibrational circular dichroism (VCD) in the Slater-type orbital based Amsterdam Density Functional (ADF) package. We show that our implementation, which makes use of analytical derivative techniques and London atomic orbitals, yields origin independent rotational strengths. The basis set dependence in the particular case of Slater-type basis functions is also discussed. It turns out that the triple zeta STO basis sets with one set of polarization functions (TZP) are adequate for VCD calculations. The origin- dependence of the atomic axial tensors is checked by a distributed origin gauge implementation. The distributed and common origin gauge implementations yield virtually identical atomic axial tensors with the Slater-type basis sets employed here, proving that our implementation yields origin independent rotational strengths. We verify the implementation for a set of benchmark molecules, for which the dependence of the VCD spectra on the particular choice of the exchange–correlation functional is studied. The pure functionals BP86 and OLYP show a particularly good performance. Then, we apply this approach to study the VCD spectra of hexa- and hepta- helicenes. In particular we focus on relationships between the sign of the rotational strengths of the two helicenes

CD44 Expression in Oro-Pharyngeal Carcinoma Tissues and Cell Lines

Expression of CD44, a transmembrane hyaluronan-binding glycoprotein, is variably considered to have prognostic significance for different cancers, including oral squamous cell carcinoma. Although unclear at present, tissue-specific expression of particular isoforms of CD44 might underlie the different outcomes in currently available studies. We mined public transcriptomics databases for gene expression data on CD44, and analyzed normal, immortalized and tumour-derived human cell lines for splice variants of CD44 at both the transcript and protein levels. Bioinformatics readouts, from a total of more than 15,000 analyses, implied an increased CD44 expression in head and neck cancer, including increased expression levels relative to many normal and tumor tissue types. Also, meta-analysis of over 260 cell lines and over 4,000 tissue specimens of diverse origins indicated lower CD44 expression levels in cell lines compared to tissue. With minor exceptions, reverse transcribed polymerase chain reaction identified expression of the four main isoforms of CD44 in normal oral keratinocytes, transformed lines termed DT and HaCaT, and a series of paired primary and metastasis-derived cell lines from oral or pharyngeal carcinomas termed HN4/HN12, HN22/HN8 and HN30/HN31. Immunocytochemistry, Western blotting and flow cytometric assessments all confirmed the isoform expression pattern at the protein level. Overall, bioinformatic processing of large numbers of global gene expression analyses demonstrated elevated CD44 expression in head and neck cancer relative to other cancer types, and that the application of standard cell culture protocols might decrease CD44 expression. Additionally, the results show that the many variant CD44 exons are not fundamentally deregulated in a diverse range of cultured normal and transformed keratinocyte lines

Insights into SCP/TAPS Proteins of Liver Flukes Based on Large-Scale Bioinformatic Analyses of Sequence Datasets

Background: SCP/TAPS proteins of parasitic helminths have been proposed to play key roles in fundamental biological processes linked to the invasion of and establishment in their mammalian host animals, such as the transition from free-living to parasitic stages and the modulation of host immune responses. Despite the evidence that SCP/TAPS proteins of parasitic nematodes are involved in host-parasite interactions, there is a paucity of information on this protein family for parasitic trematodes of socio-economic importance.\ud \ud Methodology/Principal Findings: We conducted the first large-scale study of SCP/TAPS proteins of a range of parasitic trematodes of both human and veterinary importance (including the liver flukes Clonorchis sinensis, Opisthorchis viverrini, Fasciola hepatica and F. gigantica as well as the blood flukes Schistosoma mansoni, S. japonicum and S. haematobium). We mined all current transcriptomic and/or genomic sequence datasets from public databases, predicted secondary structures of full-length protein sequences, undertook systematic phylogenetic analyses and investigated the differential transcription of SCP/TAPS genes in O. viverrini and F. hepatica, with an emphasis on those that are up-regulated in the developmental stages infecting the mammalian host.\ud \ud Conclusions: This work, which sheds new light on SCP/TAPS proteins, guides future structural and functional explorations of key SCP/TAPS molecules associated with diseases caused by flatworms. Future fundamental investigations of these molecules in parasites and the integration of structural and functional data could lead to new approaches for the control of parasitic diseases

Governing shipping externalities : Baltic ports in the process of SOx emission reduction

This paper analyses the debate which has unfolded in the Baltic Sea Region regarding the reduction of sulphur content in vessel fuels, in order to illustrate how tightening environmental regulation challenges traditional forms of maritime governance. Using an interactive governance approach, this study reconstructs the process of sulphur emission reduction as a complex multi-stakeholder interaction in multiple contexts. The empirical investigation has drawn on documentary material from around the Baltic region, including Russia, and has applied the method of qualitative content analysis. The empirical study focuses on two interlinked questions: (1) How sulphur emission reduction policies are being anticipated by maritime industry, in particular by Baltic ports and (2) How port adaptation strategies are tied into Baltic local and energy contexts. Addressing these questions highlights the role of polycentricity in shipping governance and explains how the same universal international regulations can produce varying patterns of governance. The paper concludes that policy-making shall take an account of the fact that the globalized shipping industry is nevertheless locally and sectorally embedded.Peer reviewe

Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (n{discovery} = 52 654 and n_{replication} = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10^{−11}), HLA-DRB1/DRB5 rs660895 on Chr6p21 (p_{combined} = 1.5 × 10^{−10}) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (p_{combined} = 1.2 × 10^{−122}). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology