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The transfer of American management ideas was a central part of the Cold War struggle over ideologies. A key mediator was the European Recovery Program, which conveyed American influences to European management specialists. However, a direct influence was not always possible, as in Finland, which officially blocked assistance because of foreign policy considerations. Still, it was among the first countries to follow Harvard University’s lead in launching advanced management training. We examine how and why the focal actors adopted the American model of executive education, and how they managed to translate foreign ideas persuasively to the local business elite. The translation of executive education to Finland was a lengthy process that involved modification and readjustment of the original idea according to emerging needs. The Advanced Management Program became the core of the curriculum of Finland’s leading executive education institution and thus has influenced the emergence of new business culture.

Significance: An increasing number of pathogens are acquiring resistance to antibiotics. Efficient antimicrobial drug regimens are important even for the most advanced therapies, which range from cutting-edge invasive clinical protocols, such as robotic surgeries, to the treatment of harmless bacterial diseases and to minor scratches to the skin. Therefore, there is an urgent need to survey alternative antimicrobial drugs that can reinforce or replace existing antibiotics. Recent Advances: Bacterial proteins that are critical for energy metabolism, promising novel anticancer thiourea derivatives, and the use of synthetic molecules that increase the sensitivity of currently used antibiotics are among the recently discovered antimicrobial drugs. Critical Issues: In the development of new drugs, serious consideration should be given to the previous bacterial evolutionary selection caused by antibiotics, by the high proliferation rate of bacteria, and by the simple prokaryotic structure of bacteria. Future Directions: The survey of drug targets has mainly focused on bacterial proteins, although host signaling molecules involved in the treatment of various pathologies may have unknown antimicrobial characteristics. Recent data have suggested that small molecule inhibitors might enhance the effect of antibiotics, for example, by limiting bacterial entry into host cells. Phagocytosis, the mechanism by which host cells internalize pathogens through β-actin cytoskeletal rearrangement, induces calcium signaling, small GTPase activation, and phosphorylation of the phosphatidylinositol 3-kinase-serine/threonine-specific protein kinase B pathway. Antioxid. Redox Signal. 34, 486-503.

An elderly patient with head injury was registered to the emergency room. Because the patient arrived to the hospital unconscious, her cranial, cerebrovascular, and cardiac function was studied. The cardiac function measurements were (i) heart rate, (ii) blood pressure, (iii) oxygen saturation level, (iv) electrocardiogram (ECG), (v) coronary angiogram, (vi) chest computerized tomography (CT), and (vii) echocardiogram. The head damage was studied by cerebral CT and magnetic resonance imaging (MRI). The serum ischemia and inflammatory biomarkers were analysed. For the immediate treatment, the patient received cardiovascular system supporting medication. The cardiac diagnostic results were (i) the ECG suggested an elevation in the left ventricular systolic function, (ii) the blood test showed neutrophilia, increased creatine and increased troponin I kinase values, and (iii) the coronary angiogram and ECG analysis demonstrated a lack of a myocardial infarction but identified apical akinesia. The patient did not have previous symptoms of cardiovascular disease. The brain imaging demonstrated (iv) an acute ischemia in the left occipital area and (v) increased intracranial pressure. Brain MRI indicated (vi) aqueductal stenosis and (vii) multiple gliomatotic foci demonstrating hydrocephalus caused by gliomatosis cerebri. A chest CT indicated (viii) chronic obstructive pulmonary disease (COPD). One week later, the patient died because of cardiac arrest. The diagnosis was Takotsubo syndrome enforced by gliomatosis cerebri and COPD. To our knowledge, this is the first reported case in which the cardiac dysfunction of the patient is associated with gliomatosis cerebri‐derived hydrocephalus and increased intracranial pressure that together with COPD may have enhanced the negative clinical outcome.

Gradually, bacteria have acquired resistance to antibiotics, predicting a slow but certain return to the preantibiotic era that may bring communicable diseases back as the leading cause of death and, additionally, severely affect the health care system. Based on current development, after a few decades, we may lack functional antibiotics for clinical treatments, emphasizing an urgent need to have alternatives, such as new classes of antimicrobial drugs, improved germ-free protocols, elimination of any kind of contamination in the surgery room, improved robotic surgeries, and novel noninvasive interventions. This forum discusses recent advances in the field of microbial defense mechanisms. Antioxid. Redox Signal. 34, 439-441.

Significance: Reduction/oxidation (redox) balance could be defined as an even distribution of reduction and oxidation complementary processes and their reaction end products. There is a consensus that aberrant levels of reactive oxygen species (ROS), commonly observed in cancer, stimulate primary cell immortalization and progression of carcinogenesis. However, the mechanism how different ROS regulate redox balance is not completely understood. Recent Advances: In the current review, we have summarized the main signaling cascades inducing NADPH oxidase NOX1–5 and superoxide dismutase (SOD) 1–3 expression and their connection to cell proliferation, immortalization, transformation, and CD34+ cell differentiation in thyroid, colon, lung, breast, and hematological cancers. Critical Issues: Interestingly, many of the signaling pathways activating redox enzymes or mediating the effect of ROS are common, such as pathways initiated from G protein-coupled receptors and tyrosine kinase receptors involving protein kinase A, phospholipase C, calcium, and small GTPase signaling molecules. Future Directions: The clarification of interaction of signal transduction pathways could explain how cells regulate redox balance and may even provide means to inhibit the accumulation of harmful levels of ROS in human pathologies.

Opportunistic modification of the tumour microenvironment by cancer cells enhances tumour expansion and consequently eliminates tumour suppressor components. We studied the effect of fibroblasts on the circadian rhythm of growth and protein expression in colon cancer HCT116 cells and found diminished oscillation in the proliferation of HCT116 cells co-cultured with naive fibroblasts, compared with those co-cultured with tumour-associated fibroblasts (TAFs) or those cultured alone, suggesting that TAFs may have lost or gained factors that regulate circadian phenotypes. Based on the fibroblast paracrine factor analysis, we tested IL6, which diminished HCT116 cell growth oscillation, inhibited early phase cell proliferation, increased early phase expression of the differentiation markers CEA and CDX2, and decreased early phase ERK5 phosphorylation. In conclusion, our data demonstrate how the cancer education of naive fibroblasts influences the circadian parameters of neighbouring cancer cells and highlights a putative role for IL6 as a novel candidate for preoperative treatments.

Background: Phosphorylation of the intracellular domain of the EPHA2 receptor tyrosine kinase (RTK) on serine 897 (S897) has been demonstrated to mediate EPHA2 oncogenic activity. Here, we show that in thyroid cancer cells harboring driver oncogenes that signal through the extracellular regulated kinase (ERK1/2) signaling pathway [rearranged RET RTK (RET/PTC), KRAS(G12R), or BRAFV600E oncogenes], EPHA2 is robustly phosphorylated on S897. EPHA2 S897 is embedded in a consensus sequence for phosphorylation by the AGC family kinases, including p90RSK (ribosomal protein S6 kinase), a direct ERK1/2 target. Methods: We show that recombinant p90RSK phosphorylates in vitro EPHA2 S897 and that treatment with chemical inhibitors targeting p90RSK or other components of the ERK1/2 pathway blunts S897 phosphorylation. Results: RNA interference-mediated knockdown combined with rescue experiments demonstrated that EPHA2 S897 phosphorylation mediates thyroid cancer cell proliferation and motility. Conclusions: These findings point to EPHA2 S897 as a crucial mediator of the oncogenic activity of the ERK1/2 signaling cascade in thyroid cancer.

Left ventricular pseudoaneurysms (LVP) are false aneurysms caused by the rupture of left ventricular wall as a complication of myocardial infarction, cardiac surgery, congenital heart disease, and, more rarely endocarditis. It is a rare condition that initiates 3-14 days are myocardial infarction affecting 0.5% of the patients. The known risk factors to develop LVP are age, history of hypertension, deficiency of collateral circulation after myocardial infarction, and female gender. The current case report describes LVP in a 58-year old male patient with frontal acute myocardial infarction history. The patient was diagnosed using ECG, CINE-MRI, DE-IR analysis, and thorax-CT followed by urgent cardiac surgery. The diagnosis was an apical pseudoaneurysm caused by previous myocardial necrosis. The Immunohistochemistry suggested cardiac fibrosis. The patient was discharged asymptomatic for angina pectoris, dyspnea and palpitations, and prescribed warfarin against clotting, β blocker/vasodilator, furosemide diuretic, angiotensin receptor blocker, and proton pump inhibitor medication. After six months of follow up, the patient demonstrated the absence of preoperative symptoms.

This research investigates the cognitive barriers to the generation of collaborative innovations among supply chain members. The results of our case study show how different perceptions of relationships between supply chain members can hinder the generation of collaborative innovations despite a shared managerial cognitive basis regarding the potential benefits of collaboration, Thus, we argue that the generation of collaborative innovations is largely dependent on the nature of multiple (not dyadic) supply chain relationships and managers' perceptions about the potential of these relationships. Our results provide important implications to supply chain relationships and their role in the generation of collaborative innovations.

Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of malignancies. Inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review, we will discuss the molecular signaling, expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up.

The hedgehog (Hh) signaling pathway, which is almost completely silenced in normal adult tissues but highly activated in cancer, offers ideal drug targets for small molecule development. During the last few years, several studies have indicated that the Hh pathway plays a role in tumor development and maintenance, and novel drugs inhibiting Hh signaling have been discovered. Although results from clinical trials in patients harboring activating mutations of Hh have been promising, there are many controversies regarding the role of the pathway in tumors that demonstrate ligand over-expression without identified mutations. In this review, we focus on the function and expression of the Hh pathway in different tumors and discuss the targeting approaches tested in preclinical and clinical studies.

Sunitinib and sorafenib are broad-spectrum tyrosine kinase inhibitors (TKI) targeting, for example, VEGF1-3, PDGFRb, RET, FLT3, CD117 (c-KIT) and CSF-1R cell membrane receptors thus suppressing tumor angiogenesis and cancer cell growth. Recently it has been suggested that the kinases targeted by Sunitinib and/or Sorafenib regulate leukocyte transmigration, which might in part be responsible for the often-observed reduction in tumor-associated myeloid derived suppressor cells and regulatory T cells. The aim of the current study is to determine whether sunitinib or sorafenib inhibit leukocyte extravasation. Sunitinib, sorafenib, or vehicle treated animals did not show any difference in leukocyte trafficking either in peritonitis or in vivo homing experiments, although sunitinib treatment effectively inhibited growth of B16 melanoma tumors in WT, SCID and SCID beige mice. Inhibition of tumor growth was associated with an increased number of infiltrating CD11b+ cells in the tumor, while the numbers of CD8, Gr-1 and F4/80 expressing cells were unchanged. In conclusion, the findings suggest that despite multiple targets with a potential role in leukocyte extravasation, neither sunitinib nor sorafenib effectively inhibits this process in vivo. Thus, the observed specific effect on CD11b cells among tumor infiltrating leukocytes is most likely an indirect effect.

The Timeless (Tim) gene, originally identified in Drosophila melanogaster and subsequently in mammals, is involved in the molecular clockwork that drives 24h periodicity in physiology and behavior. The Tim protein is involved not only in circadian rhythmicity but also in embryonic development, cell cycle progression, DNA replication, and the DNA damage response (DDR). It is thus a multifaceted factor implicated in the maintenance of many cellular processes, tissue functions, and ultimately homeostasis of various organisms, from insects to humans. This review highlights the current knowledge of Tim functions, especially the most recent achievements, and illustrates the possible roles that this factor plays in the physiological preservation of health, as well as in the pathogenic mechanisms of related diseases.

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy., Highlights • Primary and metastatic colon cancer cells from the same patient show differential time-dependent metabolic profiles. • Perturbations of the circadian clock induce differential alterations at the transcriptome level including metabolic pathways. • Core-clock gene (BMAL1) knockdown affects metabolic activity of cancer cells and impinges on treatment response. An evolutionary conserved molecular clockwork allows organisms to adapt physiology and biological processes to the geophysical time by driving various cellular pathways including metabolism and the cell cycle. In addition to dramatic metabolic alterations, cancer cells show severe changes in the biological clock likely to affect tumor progression and treatment response. Increasing efforts have been made to elucidate the connection between the circadian clock circuitry, tumor progression and cancer-associated metabolic alterations, yet a more detailed knowledge of this interplay is still missing. In this study, we investigated distinctive time-related transcriptomic and metabolic features in a cellular model of colon cancer progression and patient samples. We show that a disrupted biological clock leads to altered temporal profiles of gene expression, metabolic reprogramming and changes in drug response, and identify the hexokinase HKDC1 as a crucial element in this connection. Our results provide novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and pave the way to a possible optimization of cancer treatment.

Extracellular superoxide dismutase (SOD3) is a secreted enzyme that uses superoxide anion as a substrate in a dismutase reaction that results in the formation of hydrogen peroxide. Both of these reactive oxygen species affect growth signaling in cells. Although SOD3 has growth-supporting characteristics, the expression ofSOD3is downregulated in epithelial cancer cells. In the current work, we studied the mechanisms regulatingSOD3expressionin vitrousing thyroid cell models representing different stages of thyroid cancer. We demonstrate that a low level of RAS activation increasesSOD3mRNA synthesis that then gradually decreases with increasing levels of RAS activation and the decreasing degree of differentiation of the cancer cells. Our data indicate thatSOD3regulation can be divided into two classes. The first class involves RAS–driven reversible regulation ofSOD3expression that can be mediated by the following mechanisms: RAS GTPase regulatory genes that are responsible forSOD3self-regulation; RAS-stimulated p38 MAPK activation; and RAS-activated increased expression of themir21microRNA, which inversely correlates withsod3mRNA expression. The second class involves permanent silencing ofSOD3mediated by epigenetic DNA methylation in cells that represent more advanced cancers. Therefore, the work suggests thatSOD3belongs to the group ofrasoncogene-silenced genes.

Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers.

Tumor stroma-secreted growth factors, cytokines, and reactive oxygen species (ROS) influence tumor development from early stages to the metastasis phase. Previous studies have demonstrated downregulation of ROS-producing extracellular superoxide dismutase (SOD3) in thyroid cancer cell lines although according to recent data, the expression of SOD3 at physiological levels stimulates normal and cancer cell proliferation. Therefore, to analyze the expression of SOD3 in tumor stroma, we characterized stromal cells from the thyroid. We report mutually exclusive desmoplasia and inflammation in papillary and follicular thyroid cancers and the presence of multipotent mesenchymal stem/stromal cells (MSCs) in non-carcinogenic thyroids and papillary thyroid cancer (PTC). The phenotypic and differentiation characteristics of Thyroid MSCs and PTC MSCs were comparable with bone marrow MSCs. A molecular level analysis showed increased FIBROBLAST ACTIVATING PROTEIN, COLLAGEN 1 TYPE A1, TENASCIN, and SOD3 expression in PTC MSCs compared to Thyroid MSCs, suggesting the presence of MSCs with a fibrotic fingerprint in papillary thyroid cancer tumors and the autocrine-paracrine conversion of SOD3 expression, which was enhanced by cancer cells. Stromal SOD3 had a stimulatory effect on cancer cell growth and an inhibitory effect on cancer cell migration, thus indicating that SOD3 might be a novel player in thyroid tumor stroma.

// Stefania Napolitano 1 , Giulia Martini 1 , Erika Martinelli 1 , Valentina Belli 1 , Alessia Parascandolo 2 , Mikko O. Laukkanen 2 , Vincenzo Sforza 1 , Floriana Morgillo 1 , Davide Ciardiello 1 , Fortunato Ciardiello 1 and Teresa Troiani 1 1 Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Universita degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy 2 IRCCS SDN, Via Gianturco, 80143 Naples, Italy Correspondence to: Teresa Troiani, email: tessy75@inwind.it Fortunato Ciardiello, email: fortunato.ciardiello@unina2.it Keywords: SYM004, cetuximab, acquired resistance, MET, metastatic colorectal cancer Received: December 05, 2016 Accepted: February 14, 2017 Published: June 27, 2017 ABSTRACT Purpose: Cetuximab and panitumumab have an effective therapeutic response in a subset of RAS Wild-Type (WT) metastatic colorectal cancers (mCRCs). Despite molecular-driven selection, all patients do not respond to epidermal growth factor receptor (EGFR) inhibitors and the onset of secondary resistance limits their clinical benefit. Experimental Design: We tested, in vitro and in vivo , the effect of SYM004, a 1:1 mixture of two recombinant human-mouse chimeric monoclonal antibodies (mAbs) directed against non-overlapping epitopes of the EGFR, on CRC models with acquired resistance to cetuximab. Results: SYM004 showed a potent growth inhibitory effect in CRC cell lines with acquired resistance to cetuximab and MET activation. SYM004 treatment determined a significant induction of apoptosis and a strong inhibition of MET, AKT and MAPK phosphorilation in these resistant models. The data may further suggest SYM004 -driven induced internalization and degradation of the antibody-receptor complex, which prevents cross-interaction between EGFR and MET even in the presence of TGFα. Moreover, in vivo xenograft studies demonstrated that SYM004 has stronger antitumor activity than cetuximab in CRC models. Importantly, in the current work we observed a response to therapy in all cetuximab resistant tumors mice treated with SYM004. More importantly, four out of seven mice continue to respond to SYM004 after 30 weeks of treatment underling the prolonged effect of the drug. Conclusion: These results suggest that the treatment with SYM004 could be a strategy to overcome acquired resistance to first generation of anti-EGFR therapies in mCRC as a result of MET activation.

In this paper, we argue that competitor-based thinking, that is, stepping into a rival’s shoes, may offer benefits to the strategy process beyond those previously documented in the competitive dyna...

The use of live cases in marketing teaching has been suggested as a way to provide students with interesting and relevant course work while collaborating on live case exercises also provides industry partners with valuable new ideas for innovation and development. When properly conducted, live cases can also be used for conducting research by the course instructors. Our study shows how these three distinct levels of teaching, industry collaboration, and research can be managed simultaneously to produce benefits for all parties by introducing and testing a novel framework to be used by marketing instructors in their course work.

The early atmosphere of the earth contained low concentration of oxygen, which then slowly initiated to increase approximately 2.5 billion years ago after development of photosynthetic organisms and reached life-supporting levels 500–1000 million years ago. According to the oxygenic theory of evolution even the most primitive organisms used oxidative-antioxidative mechanisms in energy production, hence underlining the importance of reactive oxygen species (ROS) in normal cellular functions [1]. In reduction-oxidation (redox) biology the balance of oxidants and antioxidants determines the normal cellular homeostasis that is altered in tissue injuries and pathological conditions. Therefore, ROS, or unbalanced production of ROS, are often a consequence of injury or pathological condition with corresponding impact on cellular signal transduction and damage to macromolecules. The focus of this special issue is to characterize signaling pathways involved in tissue pathogenesis. Such studies potentially result in drug targets that supplement targets observed in currently used screenings [2].

// Giancarlo Vecchio 1, 2, * , Alessia Parascandolo 3, * , Chiara Allocca 1 , Clara Ugolini 4 , Fulvio Basolo 5 , Marco Moracci 6, 7 , Andrea Strazzulli 6, 7 , Beatrice Cobucci-Ponzano 6 , Mikko O. Laukkanen 3 , Maria Domenica Castellone 8 , Nobuo Tsuchida 9 1 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita di Napoli Federico II, Via Sergio Pansini, 5, Naples, Italy 2 Istituto Superiore di Oncologia, Via Sergio Pansini, 5, Naples and Via Balbi 5, Genoa, Italy 3 IRCCS SDN, Naples, Italy 4 Dipartimento di Medicina di Laboratorio, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy 5 Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, University of Pisa, Italy 6 Institute of Biosciences and Bioresources (IBBR), National Research Council of Italy (CNR), Via P. Castellino, 111, Naples, Italy 7 Department of Biology, University of Naples “Federico II”, Complesso Universitario di Monte S. Angelo, Naples, Italy 8 Istituto di Endocrinologia ed Oncologia Sperimentale “G. Salvatore” (IEOS), CNR, Naples, Italy 9 Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Maria Domenica Castellone, email: mcastell@unina.it Nobuo Tsuchida, email: ntutid.eme@tmd.ac.jp Keywords: glycosylation, fucosidase, thyroid carcinoma, metastasis Received: November 24, 2016 Accepted: January 24, 2017 Published: February 23, 2017 ABSTRACT Glycans containing α-L-fucose participate in diverse interactions between cells and extracellular matrix. High glycan expression on cell surface is often associated with neoplastic progression. The lysosomal exoenzyme, α-L-fucosidase-1 (FUCA-1) removes fucose residues from glycans. The FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors. However, the role of FUCA-1 in tumor progression remains unclear. It is speculated that its inactivation perturbs glycosylation of proteins involved in cell adhesion and promotes cancer. FUCA-1 expression of various thyroid normal and cancer tissues assayed by immunohistochemical (IHC) staining was high in normal thyroids and papillary thyroid carcinomas (PTC), whereas it progressively decreased in poorly differentiated, metastatic and anaplastic thyroid carcinomas (ATC). FUCA-1 mRNA expression from tissue samples and cell lines and protein expression levels and enzyme activity in thyroid cancer cell lines paralleled those of IHC staining. Furthermore, ATC-derived 8505C cells adhesion to human E-selectin and HUVEC cells was inhibited by bovine α-L-fucosidase or Lewis antigens, thus pointing to an essential role of fucose residues in the adhesive phenotype of this cancer cell line. Finally, 8505C cells transfected with a FUCA-1 containing plasmid displayed a less invasive phenotype versus the parental 8505C. These results demonstrate that FUCA-1 is down-regulated in ATC compared to PTC and normal thyroid tissues and cell lines. As shown for other human cancers, the down-regulation of FUCA-1 correlates with increased aggressiveness of the cancer type. This is the first report indicating that the down-regulation of FUCA-1 is related to the increased aggressiveness of thyroid cancer.

Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level,in vivoSOD3 overexpression reduces superoxide anion (O2-) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction.

Packages are expected to carry ever more information in a limited space. One solution to this problem is automatic identification, i.e. adding elements to the package that can be linked to electronic information systems. The aim of this study was to find the best way to produce additional business for the value chain of packages via existing technologies for automatic identification. Automatic identification can give benefits in the form of cost savings, new business opportunities, additional value to existing business and increased customer loyalty to all players in the value chain. Available technologies are 2D bar codes, digital watermarks, image recognition, fibre matrix, radiofrequency identification tags and magnetic codes. Pilot tests and user studies showed that additional services offered via automatic identification should include detailed product data, recipes, nutrient needs and user instructions and should match user demand. Obstacles to use are costs, time consumption and complexity. In Japan, mobile barcodes are part of everyday life: well known to consumers and used on a flat-rate basis. From the beginning, the introduction was based on consumer needs, not on early profit. Today, it operates on a win–win principle, with benefits for all the players in the value chain, and several traditional printers have created completely new service concepts for their customers. Copyright © 2011 John Wiley & Sons, Ltd.

Extracellular superoxide dismutase (SOD3) gene therapy has been shown to attenuate tissue damages and to improve the recovery of the tissue injuries, but the cellular events delivering the therapeutic response of the enzyme are not well defined. In the current work, we overexpressed SOD3 in rat hindlimb ischemia model to study the signal transduction and injury healing following the sod3 gene transfer. The data suggest a novel sod3 gene transfer-derived signal transduction cascade through Ras-Mek-Erk mitogenic pathway leading to activation of AP1 and CRE transcription factors, increased vascular endothelial growth factor (VEGF)-A and cyclin D1 expression, increased cell proliferation, and consequently improved metabolic functionality of the injured tissue. Increased cell proliferation could explain the improved metabolic performance and the healing of the tissue damages after the sod3 gene transfer. The present data is a novel description of the molecular mechanism of SOD3-mediated recovery of tissue injury and suggests a new physiological role for SOD3 as a Ras regulatory molecule in signal transduction.

ObjectivesThis study examined whether local gene therapy with extracellular superoxide dismutase (EC-SOD) could inhibit in-stent restenosis in atherosclerotic Watanabe heritable hyperlipidemic rabbits.BackgroundStenting causes an acute increase in superoxide anion production and oxidative stress; EC-SOD is a major component of antioxidative defense in blood vessels and has powerful cardioprotective effects in ischemic myocardium.MethodsEndothelial denudation and stenting were done in 36 adult (15 to 18 months old) rabbits. Catheter-mediated intramural delivery of clinical good manufacturing practice-grade adenoviruses encoding rabbit EC-SOD were done simultaneously with stenting. Control animals received adenovirus-encoding nuclear-targeted β-galactosidase (AdLacZ). Circulating markers for oxidative stress (nonesterified 8-iso-prostaglandin F2alpha) were measured. Analysis of 6-day, 28-day, and 90-day vessel histology, radical production, oxidation-specific epitopes, and expression studies were performed.ResultsThe EC-SOD treatment reduced oxidant production in stented vessels compared with control vessels. Early systemic recovery of total SOD activity was observed in the treated rabbits. The EC-SOD significantly accelerated endothelial recovery (67.4% ± 10.8% vs. 24.2.1% ± 4.6% at 6 days, p < 0.05; 89.3% ± 3.7% vs. 45.1% ± 9.6% at 28 days, p < 0.05), and the beneficial effect involved increased proliferation of regenerating endothelium. The EC-SOD group showed a 61.3% lower (p < 0.05) neointimal formation at 28 days, with a similar, albeit nonsignificant trend at 90 days (1.20 ± 0.32 mm2vs. 1.88 ± 0.24 mm2, p = 0.06).ConclusionsThe results suggest a central pathogenetic role of oxidation sensitive signaling processes in endothelial recovery and developing in-stent restenosis in atherosclerotic vessels. Local therapy against oxidative stress represents a promising therapeutic strategy in stent-induced vascular injury.

The study of cancer biology has mainly focused on malignant epithelial cancer cells, although tumors also contain a stromal compartment, which is composed of stem cells, tumor-associated fibroblasts (TAFs), endothelial cells, immune cells, adipocytes, cytokines, and various types of macromolecules comprising the extracellular matrix (ECM). The tumor stroma develops gradually in response to the needs of epithelial cancer cells during malignant progression initiating from increased local vascular permeability and ending to remodeling of desmoplastic loosely vascularized stromal ECM. The constant bidirectional interaction of epithelial cancer cells with the surrounding microenvironment allows damaged stromal cell usage as a source of nutrients for cancer cells, maintains the stroma renewal thus resembling a wound that does not heal, and affects the characteristics of tumor mesenchymal stem/stromal cells (MSCs). Although MSCs have been shown to coordinate tumor cell growth, dormancy, migration, invasion, metastasis, and drug resistance, recently they have been successfully used in treatment of hematopoietic malignancies to enhance the effect of total body irradiation-hematopoietic stem cell transplantation therapy. Hence, targeting the stromal elements in combination with conventional chemotherapeutics and usage of MSCs to attenuate graft-versus-host disease may offer new strategies to overcome cancer treatment failure and relapse of the disease.

Background Thyroid-derived cell models are commonly used to investigate the characteristics of thyroid cancers. It is noteworthy that each in vitro single cell model system imitates only a few characteristics of thyroid cancer depending on e.g. source of cells or oncogene used to transform the cells. Methods In the current work we utilized rat thyroid cancer cell models to determine their clinical relevance in redox gene studies by comparing in vitro expression data to thyroid Oncomine microarray database. To survey the cell lines we analyzed mRNA expression of genes that produce superoxide anion (nox family), genes that catalyze destruction of superoxide anion to hydrogen peroxide (sod family), and genes that remove hydrogen peroxide from cellular environment (catalase, gpx family and prdx family). Results Based on the current results, rat thyroid PC Cl3, PC PTC1, PC E1A, or FRLT5 cell models can be used to study NOX2, NOX4, SOD2, SOD3, CATALASE, GPX1, GPX2, GPX5, PRDX2, and PRDX3 gene expression and function. Conclusions Redox gene expression in rat originated single cell model systems used to study human thyroid carcinogenesis corresponds only partly with human redox gene expression, which may be caused by differences in redox gene activation stimulus. The data suggest careful estimation of the data observed in rat thyroid in vitro models. Electronic supplementary material The online version of this article (doi:10.1186/s12935-015-0264-3) contains supplementary material, which is available to authorized users.

RET, BRAF and other protein kinases have been identified as major molecular players in thyroid cancer. To identify novel kinases required for the viability of thyroid carcinoma cells, we performed a RNA interference screening in the RET/PTC1(CCDC6-RET)-positive papillary thyroid cancer cell line TPC1 using a library of synthetic small interfering RNAs (siRNAs) targeting the human kinome and related proteins. We identified 14 hits whose silencing was able to significantly reduce the viability and the proliferation of TPC1 cells; most of them were active also in BRAF-mutant BCPAP (papillary thyroid cancer) and 8505C (anaplastic thyroid cancer) and in RAS-mutant CAL62 (anaplastic thyroid cancer) cells. These included members of EPH receptor tyrosine kinase family as well as SRC and MAPK (mitogen activated protein kinases) families. Importantly, silencing of the identified hits did not affect significantly the viability of Nthy-ori 3-1 (hereafter referred to as NTHY) cells derived from normal thyroid tissue, suggesting cancer cell specificity. The identified proteins are worth exploring as potential novel druggable thyroid cancer targets.

Mesenchymal stromal cells (MSCs) are able to influence the growth abilities of transformed cells. Here, we show that papillary thyroid cancer TPC1 and HEK 293T cells interact physically with human primary bone marrow-derived MSCs followed by evanescence of MSC cytoplasm. Interestingly, transformed cells were able to connect only to apoptotic MSCs that had lost their migration ability, whereas naïve MSCs avoided the direct contact. The interaction stimulated the proliferation of the cocultured transformed cells, activated mitogen and stress signaling, and increased resistance to cytotoxins. Consistent with in vitro data, the MSC interaction stimulated transformed cells had enhanced ability to grow and metastasize in vivo. The parental control cells showed mild tumorigenicity as compared to MSC interaction stimulated cells yielding measurable tumors in 31 days and 7 days, respectively. Our coculture model system describes how adjacent transformed cells absorb stromal cells thereby leading to the stroma-driven evolution of moderately carcinogenic cells to highly aggressive metastatic cells.

Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides that act as autocrine growth factors. Here, we show that SCLC tumor samples feature co-expression of Shh and BBS-cognate receptor (gastrin-releasing peptide receptor (GRPR)). We also demonstrate that BBS activates Gli in SCLC cells, which is crucial for BBS-mediated SCLC proliferation, because cyclopamine, an inhibitor of the Shh pathway, hampered the BBS-mediated effects. BBS binding to GRPR stimulated Gli through its downstream G?q and G?12/13 GTPases, and consistently, other G?q and G?13 coupled receptors (such as muscarinic receptor, m1, and thrombin receptor, PAR-1) and constitutively active G?qQL and G?12/13QL mutants stimulated Gli. By using cells null for G?q and G?12/13, we demonstrate that these G proteins are strictly necessary for Gli activation by BBS. Moreover, by using constitutively active Rho small G-protein (Rho QL) as well as its inhibitor, C3 toxin, we show that Rho mediates G-protein-coupled receptor (GPCR)-, G?q- and G?12/13-dependent Gli stimulation. At the molecular level, BBS caused a significant increase in Shh gene transcription and protein secretion that was dependent on BBS-induced GPCR/G?q-12/13/Rho mediated activation of nuclear factor ?B (NF?B), which can stimulate a NF-?B response element in the Shh gene promoter. Our data identify a novel molecular network acting in SCLC linking autocrine BBS and Shh circuitries and suggest Shh inhibitors as novel therapeutic strategies against this aggressive cancer type.Oncogene advance online publication, 21 April 2014; doi:10.1038/onc.2014.104.

Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors. In our analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34+ cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, we detected insertion into one locus, the Mds1/Evi1 region, a total of 14 times in 9 animals. Mds1/Evi1 integrations were observed stably long term, primarily in myeloid cells. We hypothesize that this over-representation likely results from an impact on the self-renewal and engraftment potential of CD34+ progenitor cells via insertional mutagenesis at this specific locus. There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia. Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis. (Blood. 2005;106:2530-2533)

Due to high frequency of side effects caused by high-dose total body irradiation (TBI) the nonmyeloablative regimen together with cytotoxic agents is currently used especially for elderly patients. However, immediate and long-term effects of low-dose irradiation used in allogeneic transplantation on stem cells is less well known. We have studied the effect of low-dose 3 Gy TBI on the number of hematopoietic stem cell (HSC) clones contributing simultaneously to granulocyte production in rhesus macaque. The number of clones after 3 Gy TBI decreased markedly by 2 to 3 weeks after 3 Gy TBI, followed by a period of clonal instability, and recovery to almost pre–3 Gy TBI clonal diversity. The clones accounting for this recovery contributed before 3 Gy TBI, suggesting the profound initial impact of TBI was on a pool of progenitor cells, whereas most of the more primitive HSCs remained unaffected and were able to again contribute to hematopoiesis after recovery. Clonal fluctuation may indirectly suggest the presence of short-term/long-term HSC populations in rhesus macaque bone marrow as reported in a mouse model. The results indicate that even low-dose irradiation affects hematopoietic clonal dynamics and have implications for design of conditioning regimens for transplantation purposes.

Adenovirus is a widely used vector in gene transfer experiments because it produces high transduction efficiency in vitro and in vivo by means of the coxsackie-adenovirus receptor (CAR) and major histocompatibility complex (MHC) class I alpha-2 domain. Adenoviral gene transfer efficiency has been reported to correlate with cellular CAR expression. We report here a simple method to increase adenoviral gene transfer efficiency in cells that do not express high levels of CAR: preincubation of adenovirus for 30-40 minutes at +37 degrees C significantly increased the transduction efficiency in vitro in CHO and BALB/3T3 cells, in which CAR is expressed at very low levels. Increased transduction efficiency of preincubated adenovirus was also detected in vivo in rat brain tissue. In addition, we found that adenoviruses were rapidly inactivated in human serum in a complement-independent manner, whereas fetal bovine serum (FBS) had hardly any effects on the viral infectivity. We conclude that preincubation of adenoviral vectors at +37 degrees C may substantially increase gene transfer efficiency in applications in which target cells do not express high levels of CAR.

Clinical and epidemiological studies have provided circumstantial evidence that oxidized low-density lipoprotein (LDL) and antioxidants are involved in the pathogenesis of atherosclerosis. Superoxide dismutases (SODs) have been shown in vitro to protect LDL from deleterious effects of superoxide anions. In the present study, we have used adenoviral gene transfer to determine effect of extracellular SOD (EC-SOD) on atherogenesis in LDL receptor -/- mice. Intravenous administration of EC-SOD adenovirus (2 x 10(9) plaque forming units) into tail vein targeted transgene mainly to liver and induced a 3.5- to sevenfold increase in plasma total SOD activity. EC-SOD was secreted into circulation for 2-3 weeks mostly in a truncated B-form, suggesting that endogenous proteolytic mechanisms control the level and distribution of the enzyme. Therapeutic potential was determined by measuring plasma resistance against copper oxidation and analyzing atherosclerotic lesion areas in aortas of LDL receptor -/- mice. Mice were kept on a cholesterol diet for 10 weeks before gene transfer and 3 or 6 weeks after the gene transfer. Results showed a tendency for a reduction in the overall lesion area after EC-SOD gene transfer as compared with LacZ transduced control mice, but the difference did not reach statistical significance. It is concluded that short-term overexpression of EC-SOD in vivo does not affect atherogenesis in LDL receptor -/- mice.

Extracellular superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme with an abundant mRNA expression in kidney and arterial wall. In order to study expression and antioxidative function of EC-SOD, we cloned the rabbit ec-sod cDNA and produced the recombinant protein in cell culture. In vitro studies did not show a direct relationship between the amounts of synthesized mRNA and secreted protein activity, suggesting post-transcriptional regulation. The antiatherogenic role of EC-SOD was studied by determining the effect of EC-SOD on the oxidation (ox) of low density lipoprotein (LDL), and subsequent degradation of oxLDL in RAW 264 macrophages in vitro. It was found that recombinant EC-SOD reduced both the degradation of LDL in RAW 264 macrophages by 28-36% and its electrophoretic mobility caused by endothelial cell-mediated oxidation. It is therefore suggested that EC-SOD can act as a protective enzyme against the development of atherosclerosis.

The Hedgehog (Hh) signal transduction pathway has been discovered as a central regulator of embryonic development, tissue maintenance and repair [1]. Moreover, several recent evidences have highlighted its key function in tumorigenesis [2]. In some familial cancers, such as basal cell carcinoma and medulloblastoma, Hh pathway activation represents the initial tumorigenic event, whereas in other human malignancies, including gastrointestinal, lung, brain, breast and prostate cancers, deregulation of Hh signaling occurs during tumor progression and participates in tumor maintenance. Clinical trials using molecular inhibitors targeting Hh pathway components, in particular the Smo receptor, have often yielded limited clinical benefits unless they are used for the treatment of tumors harboring defined genetic mutations inactivating tumor suppressors (e.g. Ptch receptor) or activating oncogenes (e.g. Smo receptor, Gli transcription factor, Shh ligand) within the Hh pathway. In these specific cases, promising results led to FDA approval of Vismodegig (GDC0449, Genentech), a Smo inhibitor, in the treatment of basal cell carcinoma and medulloblastoma [3]. Notwithstanding, several clinical studies using the same compound in tumors exhibiting Hh overactivity without identified Hh mutations have resulted in discouraging outcome and discontinuation of the trials because of lack of objective response [2]. These unexpected results have been related to drug resistance due to the presence of activating mutations or genetic alterations driving Hh signaling bypassing Smo function. These evidences emphasize the need for further characterization of Hh signaling in tumorigenesis and for a more precise identification of the interaction between Hh and other signaling pathways involved in tumor development and response to therapy. Small cell lung carcinoma (SCLC) is a very aggressive cancer with extremely poor prognosis, whose genetic events, such as oncogenic driver mutations, have not been defined yet. Classified as neuroendocrine tumors, SCLCs secrete factors of the bombesin (BN)/Gastrin-Releasing Peptide (GRP) family and express their cognate receptors activating an autocrine loop that increases proliferation and survival [4]. The positivity for this ligand/receptor pair is considered to be a marker of aggressiveness and unfavorable tumor outcome. Recent reports have described the Hh pathway as a key regulator of lung embryogenesis and SCLCs maintenance, although no mutations in Hh signal transduction pathway molecules have been identified, suggesting a ligand-dependent pathway activation [5, 6]. The ligand-dependent activation of Hh signaling can occur in an autocrine manner, where cancer cells express both the ligand and the receptor, or in a paracrine manner, where ligand produced from cancer cells is activating Hh signaling in tumor stroma or vice versa. To characterize Hh function in SCLC and to evaluate the therapeutic potential of Hh inhibitors in this cancer, we have investigated the possibility of a direct interaction between Hh and BN/GRPR signaling pathways. According to our initial observations, Cyclopamine, an inhibitor of Smo, attenuated BN induced cell proliferation. In support of these data, RNA interference for Sonic Hedgehog (Shh), upstream activator of Smo, reduced BN stimulated growth, matrigel spreading and soft agar colony formation [7]. Surprisingly, when testing the activation of Gli transcription factor upon BN stimulation, we revealed the existence of a direct crosstalk between the two pathways. In order to dissect the signaling molecular events mediating this interaction, we discovered that BN, through its G protein coupled receptor (GRPR) linked to Gαq/Gα12/13 large G proteins, and their downstream target, the Rho small GTPase, was able to stimulate NFkB-mediated transcription of Shh, thus initiating an autocrine signaling loop that links BN/GRPR pathway to production of Shh ligand, and the autocrine Hh signaling activation (Figure ​(Figure1,1, left panel) [7]. Our findings, besides shedding new light on the mechanisms of Hh signaling activation in SCLC, may suggest a more general application for other BN/GRPR positive tumors over-expressing Shh pathway, such as pancreatic cancer, neuroblastomas and glioblastomas. Interestingly, use of Hh inhibitors alone in these tumors has not reached positive results that may indicate existence of functional parallel pathways able to counteract the effect of the drug. Moreover, recent reports have highlighted a role for Hh signaling in tumor-stroma interactions, with production of Shh ligand from cancer cells and stimulation of Gli transcription factor in tumor microenvironment (myofibroblasts, endothelial cells, and CSC) [8]. In our study, we have investigated the existence of an autocrine ligand-dependent Hh signaling in SCLC. We certainly believe that it would be interesting to study also the paracrine activation of Hh signaling, which could have the double effect of stimulating proliferation and survival of stroma cells, leading to increased angiogenesis and metastasis and, at the same time, produce growth factors acting on cancer cells to sustain their proliferation, epithelial-to-mesenchymal transition (EMT), dissemination and survival (Figure ​(Figure1,1, right panel). Our data connecting BN/GRPR and the Hh signaling pathway may therefore provide valuable knowledge on the complex interaction between tumor cells and cancer microenvironment and may offer the scientific basis for developing novel therapeutic stategies that, by combining different anti-tumor approaches, could be more effective than single agent treatments. In this case, novel co-targeting strategies would target not only cancer cells but also other component of tumor microenvironment. Moreover, simultaneous targeting of BN/GRPR and Hh pathway could help in counteracting mechanisms of cell-autonomous and non-cell autonomous (stroma-dependent) resistance to targeted therapies.

The gene encoding chicken egg-white avidin (Avd) was amplified from chromosomal DNA, cloned and sequenced. The entire coding region of preavidin (pre-Avd) containing four exons was identified by comparing the Avd gene (1119 bp) with the cDNA. It had a high identity percentage (91–95%) with the previously isolated Avd-related genes 1–5 (Avrl–Avr5) . Interestingly, comparison of Avd with the Avr genes showed that the introns were better conserved (on average 97%) than the exons (90%). The Avd gene, as well as the cDNA, encodes a Gln residue at position 53 of the mature protein, which is in contrast to the previously determined amino-acid sequence.

BackgroundExtracellular superoxide dismutase (SOD3), which dismutates superoxide anion to hydrogen peroxide, has been shown to reduce the free radical stress derived apoptosis in tissue injuries. Since both superoxide anion and hydrogen peroxide have a marked impact on signal transduction pathways and could potentially explain a number of apoptosis and survival -related phenomena in different pathological conditions, we clarified the impact of SOD3 on Akt and Erk1/2 cell survival pathways in rat hind limb injury model.Methodology and principal findingsBased on our data, the hind limb ischemic rats treated with virally delivered sod3 have milder injury and less apoptosis than control animals that could be due to parallel activation of pro-proliferative and anti-apoptotic Erk1/2 and Akt pathways. The common downstream factor of both signaling pathways, the apoptosis related forkhead box protein O3a (FoxO3a), was phosphorylated and translocated to the cytoplasm in sod3 treated tissues and cell line. Additionally, we obtained increased mRNA production of elk-1, ets-1, and microRNA 21 (miR-21), whereas synthesis of bim mRNA was decreased in sod3 overexpressing tissues. We further showed that overexpression of sod3 modulated redox related gene expression by downregulating nox2 and inos when compared to injured control animals.Conclusions and significanceThe study shows the complexity of SOD3-derived effects on tissue injury recovery that are not limited to the reduction of superoxide anion caused cellular stress but highlights the impact of SOD3 related signal transduction on tissue functions and suggests an important role for SOD3 in attenuating cell stress effects in different pathological conditions.