MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets

Neutrophils: homing in on the myeloid mechanisms of metastasis

The metastasis cascade is complex and comprises several stages including local invasion into surrounding tissue, intravasation and survival of tumour cells in the circulation, and extravasation and colonisation of a distant site. It is increasingly clear that these processes are driven not only by signals within the tumour cells, but are also profoundly influenced by stromal cells and signals in the tumour microenvironment. Amongst the many cell types within the tumour microenvironment, immune cells such as lymphocytes, macrophages and neutrophils play a prominent role in tumour development and progression. Neutrophils, however, have only recently emerged as important players, particularly in metastasis. Here we review the current evidence suggesting a multi-faceted role for neutrophils in the metastatic cascade

Swapping in lattice-based cell migration models

Cell migration is frequently modelled using on-lattice agent-based models (ABMs) that employ the excluded volume interaction. However, cells are also capable of exhibiting more complex cell-cell interactions, such as adhesion, repulsion, pulling, pushing and swapping. Although the first four of these have already been incorporated into mathematical models for cell migration, swapping has not been well studied in this context. In this paper, we develop an ABM for cell movement in which an active agent can `swap' its position with another agent in its neighbourhood with a given swapping probability. We consider a two-species system for which we derive the corresponding macroscopic model and compare it with the average behaviour of the ABM. We see good agreement between the ABM and the macroscopic density. We also analyse the movement of agents at an individual level in the single-species as well as two-species scenarios to quantify the effects of swapping on an agent's motility.<br/

Zebrafish adult pigment stem cells are multipotent and form pigment cells by a progressive fate restriction process:Clonal analysis identifies shared origin of all pigment cell types

Skin pigment pattern formation is a paradigmatic example of pattern formation. In zebrafish, the adult body stripes are generated by coordinated rearrangement of three distinct pigment cell-types, black melanocytes, shiny iridophores and yellow xanthophores. A stem cell origin of melanocytes and iridophores has been proposed although the potency of those stem cells has remained unclear. Xanthophores, however, seemed to originate predominantly from proliferation of embryonic xanthophores. Now, data from Singh et al. shows that all three cell-types derive from shared stem cells, and that these cells generate peripheral neural cell-types too. Furthermore, clonal compositions are best explained by a progressive fate restriction model generating the individual cell-types. The numbers of adult pigment stem cells associated with the dorsal root ganglia remain low, but progenitor numbers increase significantly during larval development up to metamorphosis, likely via production of partially restricted progenitors on the spinal nerves.</p

Swapping in lattice-based cell migration models

Cell migration is frequently modelled using on-lattice agent-based models (ABMs) that employ the excluded volume interaction. However, cells are also capable of exhibiting more complex cell-cell interactions, such as adhesion, repulsion, pulling, pushing and swapping. Although the first four of these have already been incorporated into mathematical models for cell migration, swapping is an interaction that has not been well studied in this context. In this paper, we develop an ABM to describe cell movement where an active agent can `swap' its position with another agent in its neighbourhood with a given swapping probability. We consider single-species and two-species systems. In both cases, we derive the corresponding macroscopic model and compare it with the average behaviour of the ABM. We see good agreement between the ABM and the macroscopic density. We also derive an expression for the cell-level diffusion coefficient in terms of the swapping probability and cell density. We conclude by showing applications of swapping by using the ABM to represent cell movement with proliferation and cell-cell adhesion.Comment: 32 pages, 12 figures, articl

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

Aging and Endothelial Progenitor Cell Telomere Length in Healthy Men

BACKGROUND: Telomere length declines with age in mature endothelial cells and is thought to contribute to endothelial dysfunction and atherogenesis. Bone marrow-derived circulating endothelial progenitor cells (EPCs) are critical to vascular health as they contribute to both reendothelialization and neovascularization. We tested the hypothesis that EPC telomere length decreases with age in healthy adult humans. METHODS: Peripheral blood samples were collected from 40 healthy, non-obese, sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and 16 older (57-68 years). Putative EPCs were isolated from peripheral blood mononuclear cells and telomere length was determined using genomic DNA preparation and Southern hybridization techniques. RESULTS: EPC telomere length (base pairs) was approximately 20% (p=0.01) lower in the older (8492+523 bp) compared to the middle-aged (10,565+572 bp) and young (10,205+501 bp) men. Of note, there was no difference in EPC telomere length between the middle-aged and young men. CONCLUSIONS: These results demonstrate that EPC telomere length declines with age in healthy, sedentary men. Interestingly, telomere length was well preserved in the middle-aged compared to young men, suggesting that EPC telomere shortening occurs after the age of 55 years

Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses

AbstractThe intestinal epithelium is equipped with sensing receptor mechanisms that interact with luminal microorganisms and nutrients to regulate barrier function and gut immune responses, thereby maintaining intestinal homeostasis. Herein, we clarify the role of the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific Casr−/− mice. Epithelial CaSR deficiency diminished intestinal barrier function, altered microbiota composition, and skewed immune responses towards proinflammatory. Consequently, Casr−/− mice were significantly more prone to chemically induced intestinal inflammation resulting in colitis. Accordingly, CaSR represents a potential therapeutic target for autoinflammatory disorders, including inflammatory bowel diseases

The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration

Harmonized Landsat/Sentinel-2 Reflectance Products for Land Monitoring (Invited)

Many land applications require more frequent observations than can be obtained from a single 'Landsat class' sensor. Agricultural monitoring, inland water quality assessment, stand-scale phenology, and numerous other applications all require near-daily imagery at better than 1ha resolution. Thus the land science community has begun expressing a desire for a '30-meter MODIS' global monitoring capability. One cost-effective way to achieve this goal is via merging data from multiple, international observatories into a single virtual constellation. The Harmonized Landsat/Sentinel-2 (HLS) project has been working to generate a seamless surface reflectance product by combining observations from USGS/NASA Landsat-8 and ESA Sentinel-2. Harmonization in this context requires a series of radiometric and geometric transforms to create a single surface reflectance time series agnostic to sensor origin. Radiometric corrections include a common atmospheric correction using the Landsat-8 LaSRC/6S approach, a simple BRDF adjustment to constant solar and nadir view angle, and spectral bandpass adjustments to fit the Landsat-8 OLI reference. Data are then resampled to a consistent 30m UTM grid, using the Sentinel-2 global tile system. Cloud and shadow masking are also implemented. Quality assurance (QA) involves comparison of the output 30m HLS products with near-simultaneous MODIS nadir-adjusted observations. Prototoype HLS products have been processed for approximately 7% of the global land area using the NASA Earth Exchange (NEX) compute environment at NASA Ames, and can be downloaded from the HLS web site (https://hls.gsfc.nasa.gov). A wall-to-wall North America data set is being prepared for 2018. This talk will review the objectives and status of the HLS project, and illustrate applications of high-density optical time series data for agriculture and ecology. We also discuss lessons learned from HLS in the general context of implementing virtual constellations