Simulation of Blood Flow and Nanoparticle Transport in a Stenosed Carotid Bifurcation and Pseudo-Arteriole

Numerical simulation of flow through a realistic bifurcated carotid artery geometry with a stenosis has been conducted for comparison to experimental measurements. The behaviour of simplified therapeutic nanoparticles in relatively low concentration was observed using a discrete particle approach. The role of size (diameters from 500 nm to 50 nm) in determining particle residence time and the potential for both desirable and undesirable wall interactions was investigated. It was found that mean particle residence time reduced with decreasing particle diameter, and the percentage of particles experiencing one or more wall interactions increased simultaneously. Further simulations were conducted on a scaled-down version of the geometry which approximated the size and flow conditions of an arteriole with capillary branches, and in this instance the mean residence time increased with decreasing particle diameter, owing largely to the greater influence of Brownian motion. 33% of all 50 nm particles were involved in wall interactions, indicating that smaller particles would have a greater ability to target, for instance, cancerous tumours in such regions

Revealing the molecular signatures of host-pathogen interactions.

Advances in sequencing technology and genome-wide association studies are now revealing the complex interactions between hosts and pathogen through genomic variation signatures, which arise from evolutionary co-existence

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed. Cell Rep 2015 Jul 14; 12(2):272-285

A cost-effectiveness analysis evaluating endoscopic surveillance for gastric cancer for populations with low to intermediate risk

10.1371/journal.pone.0083959PLoS ONE812-POLN

Empirical evidence of the continuing improvement in cost efficiency of an endoscopic surveillance programme for gastric cancer in Singapore from 2004 to 2010

10.1186/1472-6963-13-139BMC Health Services Research131

Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study

BMC Gastroenterology97

CEACAM6 is upregulated by <i>Helicobacter pylori</i> CagA and is a biomarker for early gastric cancer

Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro. The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro, a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach

Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Burgers-Rott vortices with surface tension

A modified Lundgren’s model (the LABSRL model) accounting for the effect of surface tension is applied for the description of stationary bathtub vortices in a viscous liquid with a free surface. Laminar liquid flow through the circular bottom orifice is considered in a horizontally unbounded domain with the liquid being assumed to be undisturbed at infinity and approaching to a constant depth. An approximate analytical solution of the LABSRL model is obtained for small-dent vortices. Good agreement is achieved between the constructed analytical and numerical solutions for the same set of parameters