A realistic two-lane traffic model for highway traffic

A two-lane extension of a recently proposed cellular automaton model for traffic flow is discussed. The analysis focuses on the reproduction of the lane usage inversion and the density dependence of the number of lane changes. It is shown that the single-lane dynamics can be extended to the two-lane case without changing the basic properties of the model which are known to be in good agreement with empirical single-vehicle data. Therefore it is possible to reproduce various empirically observed two-lane phenomena, like the synchronization of the lanes, without fine-tuning of the model parameters

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

CD34+cells augment endothelial cell differentiation of CD14+endothelial progenitor cells in vitro

Neovascularization by endothelial progenitor cells (EPC) for the treatment of ischaemic diseases has been a topic of intense research. The CD34+ cell is often designated as EPC, because it contributes to repair of ischaemic injuries through neovascularization. However, incorporation of CD34+ cells into the neovasculature is limited, suggesting another role which could be paracrine. CD14+ cells can also differentiate into endothelial cells and contribute to neovascularization. However, the low proliferative capacity of CD14+ cell-derived endothelial cells hampers their use as therapeutic cells. We made the assumption that an interaction between CD34+ and CD14+ cells augments endothelial differentiation of the CD14+ cells. In vitro, the influence of CD34+ cells on the endothelial differentiation capacity of CD14+ cells was investigated. Endothelial differentiation was analysed by expression of endothelial cell markers CD31, CD144, von Willebrand Factor and endothelial Nitric Oxide Synthase. Furthermore, we assessed proliferative capacity and endothelial cell function of the cells in culture. In monocultures, 63% of the CD14+-derived cells adopted an endothelial cell phenotype, whereas in CD34+/CD14+ co-cultures 95% of the cells showed endothelial cell differentiation. Proliferation increased up to 12% in the CD34+/CD14+ co-cultures compared to both monocultures. CD34-conditioned medium also increased endothelial differentiation of CD14+ cells. This effect was abrogated by hepatocyte growth factor neutralizing antibodies, but not by interleukin-8 and monocyte chemoattractant protein-1 neutralizing antibodies. We show that co-culturing of CD34+ and CD14+ cells results in a proliferating population of functional endothelial cells, which may be suitable for treatment of ischaemic diseases such as myocardial infarction

Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1α triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling. © 2008 by The American Society for Cell Biology.published_or_final_versio

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a ‘bi-lineage’ differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony-formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition

Induction of interleukin-8 preserves the angiogenic response in HIF-1 alpha-deficient colon cancer cells

authorHypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis^1, ^2, ^3, ^4. It represents an attractive therapeutic target^5, ^6 in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy^7. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis^8, ^9. In HIF-1_α knockdown DLD-1 colon cancer cells (DLD-1^HIF-kd), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1_α (DLD-1^HIF-wt). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1^HIF-kd but not DLD-1^HIF-wt cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-_KB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1^HIF-kd but not DLD-1^HIF-wt xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1α may be most effective when IL-8 is simultaneously targeted

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-B-induced IL-8 expression by sequestering NF-B within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3NF-BIL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.P 25599(VLID)183891

Differentiation Potential of Pancreatic Fibroblastoid Cells/Stellate Cells: Effects of Peroxisome Proliferator-Activated Receptor Gamma Ligands

Pancreatic stellate cells have been investigated mostly for their activation process, supposed to support the development of pancreatic disease. Few studies have been presented on reversal of the activation process in vitro. Thiazolidinediones (TZDs) have been used as antidiabetics and have now been reported to exert antifibrotic activity. We tested effects of natural and synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARγ) on human pancreatic fibroblastoid cells (hPFCs) in search for specificity of action. Ciglitazone, as a prototype of TZDs, was shown to have reversible growth inhibitory effects on human pancreatic fibroblastoid cells/stellate cells. Cells treated with ciglitazone for three days showed enhanced lipid content and induction of proteins involved in lipid metabolism. Collagen synthesis was reduced in hPFC. Interaction of PPARγ with DNA binding sites upon ligand binding was shown by gel shift analysis. These findings point toward a potential for adipocyte differentiation in human pancreatic fibroblastoid cells

Complications of fixed infrared emitters in computer-assisted total knee arthroplasties

<p>Abstract</p> <p>Background</p> <p>The first stage in the implant of a total knee arthroplasty with computer-assisted surgery is to fasten the emitters to the femur and the tibia. These trackers must be hard-fixed to the bone. The objectives of our study are to evaluate the technical problems and complications of these tracker-pins, the necessary time to fix them to the bone and the possible advantages of a new femoral-fixed tracker-pin.</p> <p>Methods</p> <p>Three hundred and sixty seven tracker-pins were used in one hundred and fifty one computer-assisted total knee replacements. A bicortical screw was used to fix the tracker to the tibia in all cases; in the femur, however, a bicortical tracker was used in 112 cases, while a new device (OrthoLock) with percutaneous fixation pins was employed in the remaining 39.</p> <p>Results</p> <p>Technical problems related to the fixing of the trackers appeared in nine cases (2.5%). The mean surgery time to fix the tracker pin to the tibia was 3 minutes (range 2–7), and 5 minutes in the case of the femoral pin (range: 4–11), although with the new tool it was only three minutes (range 2–4) (p < 0.001). No complications were observed with this new device.</p> <p>Conclusion</p> <p>The incidence of problems and complications with the fixing systems used in knee navigation is very small. The use of a new device with percutaneous pins facilitates the fixing of femoral trackers and decreases the time needed to place them.</p