Recent developments and future trends of industrial agents

The agent technology provides a new way to design and engineer control solutions based on the decentralization of control over distributed structures, addressing the current requirements for modern control systems in industrial domains. This paper presents the current situation of the development and deployment of agent technology, discussing the initiatives and the current trends faced for a wider dissemination and industrial adoption, based on the work that is being carried out by the IEEE IES Technical Committee on Industrial Agents

Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways

As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1α, MIP-1β, and TNF-α by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions

Syk-Mediated Translocation of PI3Kδ to the Leading Edge Controls Lamellipodium Formation and Migration of Leukocytes

The non-receptor tyrosine kinase Syk is mainly expressed in the hematopoietic system and plays an essential role in β2 integrin-mediated leukocyte activation. To elucidate the signaling pathway downstream of Syk during β2 integrin (CD11/CD18)-mediated migration and extravasation of polymorphonuclear neutrophils (PMN), we generated neutrophil-like differentiated HL-60 (dHL-60) cells expressing a fluorescently tagged Syk mutant lacking the tyrosine residue at the position 323 (Syk-Tyr323) that is known to be required for the binding of the regulatory subunit p85 of the phosphatidylinositol 3-kinase (PI3K) class IA. Syk-Tyr323 was found to be critical for the enrichment of the catalytic subunit p110δ of PI3K class IA as well as for the generation of PI3K products at the leading edge of the majority of polarized cells. In accordance, the translocation of PI3K p110δ to the leading edge was diminished in Syk deficient murine PMN. Moreover, the expression of EGFP-Syk Y323F interfered with proper cell polarization and it impaired efficient migration of dHL-60 cells. In agreement with a major role of β2 integrins in the recruitment of phagocytic cells to sites of lesion, mice with a Syk-deficient hematopoietic system demonstrated impaired PMN infiltration into the wounded tissue that was associated with prolonged cutaneous wound healing. These data imply a novel role of Syk via PI3K p110δ signaling for β2 integrin-mediated migration which is a prerequisite for efficient PMN recruitment in vivo

Transcriptomic Analysis Comparing Tumor-Associated Neutrophils with Granulocytic Myeloid-Derived Suppressor Cells and Normal Neutrophils

The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naïve neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC)

Induction of Immune Mediators in Glioma and Prostate Cancer Cells by Non-Lethal Photodynamic Therapy

BACKGROUND: Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. METHODOLOGY/PRINCIPAL FINDINGS: Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. CONCLUSIONS: Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways

Apoptosis-Related Gene Expression Profiling in Hematopoietic Cell Fractions of MDS Patients

Contains fulltext : 168172.pdf (publisher's version ) (Open Access)Although the vast majority of patients with a myelodysplastic syndrome (MDS) suffer from cytopenias, the bone marrow is usually normocellular or hypercellular. Apoptosis of hematopoietic cells in the bone marrow has been implicated in this phenomenon. However, in MDS it remains only partially elucidated which genes are involved in this process and which hematopoietic cells are mainly affected. We employed sensitive real-time PCR technology to study 93 apoptosis-related genes and gene families in sorted immature CD34+ and the differentiating erythroid (CD71+) and monomyeloid (CD13/33+) bone marrow cells. Unsupervised cluster analysis of the expression signature readily distinguished the different cellular bone marrow fractions (CD34+, CD71+ and CD13/33+) from each other, but did not discriminate patients from healthy controls. When individual genes were regarded, several were found to be differentially expressed between patients and controls. Particularly, strong over-expression of BIK (BCL2-interacting killer) was observed in erythroid progenitor cells of low- and high-risk MDS patients (both p = 0.001) and TNFRSF4 (tumor necrosis factor receptor superfamily 4) was down-regulated in immature hematopoietic cells (p = 0.0023) of low-risk MDS patients compared to healthy bone marrow

Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy

Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma

<p>Abstract</p> <p>Background</p> <p>The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease.</p> <p>Methods</p> <p>We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR.</p> <p>Results</p> <p>Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma).</p> <p>Conclusions</p> <p>The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.</p

Sequestration and Scavenging of Iron in Infection

The proliferative capability of many invasive pathogens is limited by the bioavailability of iron. Pathogens have thus developed strategies to obtain iron from their host organisms. In turn, host defense strategies have evolved to sequester iron from invasive pathogens. This review explores the mechanisms employed by bacterial pathogens to gain access to host iron sources, the role of iron in bacterial virulence, and iron-related genes required for the establishment or maintenance of infection. Host defenses to limit iron availability for bacterial growth during the acute-phase response and the consequences of iron overload conditions on susceptibility to bacterial infection are also examined. The evidence summarized herein demonstrates the importance of iron bioavailability in influencing the risk of infection and the ability of the host to clear the pathogen

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients