Resection for pancreatic adenocarcinoma can be performed safely. The overall survival rate is determined by the radicality of resection. Patients deemed fit for surgery who have no radiological signs of distant metastasis should undergo surgical exploration. Resection should follow if there is a reasonable likelihood that an R0 resection can be obtained.

Background-Recent evidence indicates that stromal cell-derived factor-1␣ (SDF-1␣) is expressed in human atherosclerotic plaques, whereas high plasma levels are clinically associated with stable coronary artery disease. Herein, we investigate the involvement of SDF-1␣ in neointimal formation after vascular injury. Methods and Results-SDF-1␣ was detected by immunohistochemistry in carotid arteries of apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice at various stages of neointima formation after wire-induced injury. Double immunofluorescence revealed that SDF-1␣ staining was mostly confined to smooth muscle cells (SMCs). Furthermore, SDF-1␣ plasma levels peaked 1 day after vascular injury. Treatment of apoE Ϫ/Ϫ mice after carotid injury with a neutralizing SDF-1␣ monoclonal antibody for 3 weeks reduced neointimal lesion area by 44% (nϭ5, PϽ0.05) compared with isotype control. In SDF-1␣ antibody-treated apoE Ϫ/Ϫ mice, neointimal SMC content was decreased (21.7Ϯ2% versus 39.4Ϯ4%, nϭ5, Pϭ0.005), whereas the relative content of neointimal macrophages remained unchanged. As shown by flow cytometry, carotid injury resulted in a marked expansion of circulating Sca-1 ϩ lineage Ϫ progenitor cells (PBPCs) in the peripheral blood of apoE Ϫ/Ϫ mice after 1 day, which was mediated by SDF-1␣. Systemic injection of isolated PBPCs after vascular injury demonstrated their recruitment to neointimal lesions, where they can adopt an SMC-like phenotype. Conclusions-SDF-1␣ plays an instrumental role in neointimal formation after vascular injury in apoE

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Research on the regulation of transcription in mammals initially focused on the mechanism of transcriptional activation and ‘positive control’ of gene regulation. In contrast, transcriptional repression and ‘negative control’ of gene transcription was viewed rather as part of the ‘prokaryotic book of biology’. However, results obtained in recent years have shown convincingly that transcriptional repression mediated by repressor proteins is a common regulatory mechanism in mammals and may play a key role in many biological processes. In particular, the fact that human diseases, such as Rett and ICF syndromes as well as some human forms of cancer, are connected with the activities of human repressor proteins indicates that transcriptional repression and gene silencing is essential for maintenance of the cellular integrity of a multicellular organism. The wide range of diseases caused by aberration in transcriptional repression sheds light on the importance of understanding how mammalian transcriptional repressor proteins work.

Abstract-Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and "memory" T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-␣ and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell-derived factor (SDF)-1␣. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-B activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-B by adenoviral IB␣ in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-B-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.

The zinc finger protein RE-1-silencing transcription factor (REST) 1 is a transcriptional repressor that represses neuronal genes in nonneuronal tissues. Transfection experiments of neuroblastoma cells using a REST expression vector revealed that synapsin I promoter activity is controlled by REST. The biological activity of REST was further investigated using a battery of model promoters containing strong promoters/enhancers and REST binding sites. REST functioned as a transcriptional repressor when REST binding motifs derived from the genes encoding synapsin I, SCG10, ␣ 1 -glycine receptor, the ␤2-subunit of the neuronal nicotinic acetylcholine receptor, and the m4-subunit of the muscarinic acetylcholine receptor were present in the promoter region. No differences in the biological activity of these REST binding motifs tested were detected. Moreover, we found that REST functioned very effectively as a transcriptional repressor at a distance. Thus, REST represents a general transcriptional repressor that blocks transcription regardless of the location or orientation of its binding site relative to the enhancer and promoter. This biological activity could also be attributed to isolated domains of REST. Both repressor domains identified at the N and C termini of REST were transferable to a heterologous DNA binding domain and functioned from proximal and distal positions, similar to the REST protein. RE-1-silencing transcription factor (REST)1 , also known as neuron-restrictive silencer factor, functions as a transcriptional repressor of neuronal genes in nonneuronal tissues (1, 2). Target genes of REST are the genes encoding choline acetyltransferase, the type II sodium channel, SCG10, the m4 muscarinic acetylcholine receptor, and the adhesion proteins L1 and NgCAM (1-6). We have shown recently that the REST binding motif within the synapsin I promoter is responsible for restricting the expression of synapsin I to neuronal cells (7). Deletion of the REST binding site abolished neuron-specific expression of the reporter gene entirely, allowing constitutively acting elements of the promoter to direct expression in a nontissue specific manner.The REST binding motif termed the neural-restrictive silencer element (NRSE) was identified at various positions in those genes regulated by REST. NRSEs were found in the promoter region as shown for the synapsin I and the muscarinic acetylcholine receptor m4-subunit genes (7-9). In the SCG10 gene, an NRSE is located farther upstream at position Ϫ1472 to Ϫ1452 (10), whereas in the NgCAM gene, five NRSEs have been discovered within the first intron (3). Furthermore, genes encoding the ␣ 1 -glycine receptor and the ␤2-subunit of the neuronal nicotinic acetylcholine receptor contain NRSEs in the 5Ј-untranslated region downstream of the transcriptional start site (11,12). It has been proposed that REST switches its activity from repressing to activating transcription when REST binds to an NRSE located in the 5Ј-untranslated region or less than 50 base pairs upstream from the TATA bo...

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BackgroundHumans and other organisms are equipped with a set of responses that can prevent damage from exposure to a multitude of endogenous and environmental stressors. If these stress responses are overwhelmed, this can result in pathogenesis of diseases, which is reflected by an increased development of, e.g., pulmonary and cardiac diseases in humans exposed to chronic levels of environmental stress, including inhaled cigarette smoke (CS). Systems biology data sets (e.g., transcriptomics, phosphoproteomics, metabolomics) could enable comprehensive investigation of the biological impact of these stressors. However, detailed mechanistic networks are needed to determine which specific pathways are activated in response to different stressors and to drive the qualitative and eventually quantitative assessment of these data. A current limiting step in this process is the availability of detailed mechanistic networks that can be used as an analytical substrate.ResultsWe have built a detailed network model that captures the biology underlying the physiological cellular response to endogenous and exogenous stressors in non-diseased mammalian pulmonary and cardiovascular cells. The contents of the network model reflect several diverse areas of signaling, including oxidative stress, hypoxia, shear stress, endoplasmic reticulum stress, and xenobiotic stress, that are elicited in response to common pulmonary and cardiovascular stressors. We then tested the ability of the network model to identify the mechanisms that are activated in response to CS, a broad inducer of cellular stress. Using transcriptomic data from the lungs of mice exposed to CS, the network model identified a robust increase in the oxidative stress response, largely mediated by the anti-oxidant NRF2 pathways, consistent with previous reports on the impact of CS exposure in the mammalian lung.ConclusionsThe results presented here describe the construction of a cellular stress network model and its application towards the analysis of environmental stress using transcriptomic data. The proof-of-principle analysis described here, coupled with the future development of additional network models covering distinct areas of biology, will help to further clarify the integrated biological responses elicited by complex environmental stressors such as CS, in pulmonary and cardiovascular cells.