Hepatocyte growth factor, a key tumor-promoting factor in the tumor microenvironment

The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner. Fibroblasts also confer resistance to anti-cancer therapy through HGF-induced epithelial mesenchymal transition (EMT) and activation of pro-survival signaling pathways such as ERK and AKT in tumor cells. Constitutive HGF/MET signaling in cancer cells is associated with increased tumor aggressiveness and predicts poor outcome in cancer patients. Due to its role in tumor progression and therapeutic resistance, both HGF and MET have emerged as valid therapeutic targets. Several inhibitors of MET and HGF are currently being tested in clinical trials. Preclinical data provide a strong indication that inhibitors of HGF/MET signaling overcome both primary and acquired resistance to EGFR, HER2, and BRAF targeting agents. These findings support the notion that co-targeting of cancer cells and stromal cells is required to prevent therapeutic resistance and to increase the overall survival rate of cancer patients. HGF dependence has emerged as a hallmark of therapeutic resistance, suggesting that inhibitors of biological activity of HGF should be included into therapeutic regimens of cancer patients

Protein Design is a Key Factor for Subunit-subunit Association

Fundamental questions about the role of the quaternary structures are addressed using a statistical mechanics off-lattice model of a dimer protein. The model, in spite of its simplicity, captures key features of the monomer-monomer interactions revealed by atomic force experiments. Force curves during association and dissociation are characterized by sudden jumps followed by smooth behavior and form hysteresis loops. Furthermore, the process is reversible in a finite range of temperature stabilizing the dimer. It is shown that in the interface between the two monomeric subunits the design procedure naturally favors those amino acids whose mutual interaction is stronger. Furthermore it is shown that the width of the hysteresis loop increases as the design procedure improves, i.e. stabilizes more the dimer.Comment: submitted to "Proceedings of the National Academy of Sciences, USA

THE MANAGEMENT OF KNOWLEDGE WORKERS – KEY FACTOR OF SUCCES

The traditional companies are built on familiar bedrock of buildings, plants, and inventories. Competitive advantage is viewed in terms of scale and volume stemming from high-capacity use of machine-based factories. Such an approach fails to recognize how the leverage of knowledge is becoming a key to long-term success. Nowadays, organizations must recognize that power resides in the minds of their best people, who are diffused throughout the business and the organizations are becoming more dependent on people than ever before. The recruitment and the employment of knowledge workers are becoming very important issues from Romanian managers. The competitiveness is the only chance to deal with a very challenging market, especially after European integration. In this paper we present the results of a survey of the opinions of Romanian managers about the most effective strategies for recruitment, motivation and retention the knowledge workers. The study investigated two groups of managers: the first group included the managers who never were involved in activities related to human resources, and the second, the managers who have been involved. The managers from the first group chose theoretical the strategies they considered most effective; the managers for the second group indicated the strategies they applied.knowledge management, human resources management

Standardized Payment Procedures as Key Enabling Factor for Mobile Commerce

Companies are not going to invest into the development of innovative applications or services unless these can be charged for appropriately. Thus, the existence of standardized and widely accepted mobile payment procedures is crucial for successful business-to-customer mobile commerce. In this paper we reflect on the acceptance of mobile payment and examine the characteristics of current mobile payment procedures. The outcomes of the paper are a categorization of current mobile payment procedures with strategic, participation and operational criteria and, based on these results, the derivation of the five mobile payment standard types prepaid, mobile money, conventional settlement, premium rate number and dual-card. Finally, a prospect is given to possible further development of mobile payment procedures in the direction of an integrative universal mobile payment system (UMPS).

A key role for leukemia inhibitory factor in C26 cancer cachexia

Cachexia is an exacerbating event in many types of cancer that is strongly associated with a poor prognosis. We have identified cytokine, signaling, and transcription factors that are required for cachexia in the mouse C26 colon carcinoma model of cancer. C2C12 myotubes treated with conditioned medium from C26 cancer cells induced atrophy and activated a STAT-dependent reporter gene but not reporter genes dependent on SMAD, FOXO, C/EBP, NF-κB, or AP-1. Of the gp130 family members IL-11, IL-6, oncostatin M (OSM), and leukemia inhibitory factor (LIF), only OSM and LIF were sufficient to activate the STAT reporter in myotubes. LIF was elevated in C26 conditioned medium (CM), but IL-6, OSM, TNFα, and myostatin were not. A LIF-blocking antibody abolished C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and myotube atrophy but blocking antibodies to IL-6 or OSM did not. JAK2 inhibitors also blocked C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and atrophy in myotubes. LIF at levels found in the C26 CM was sufficient for STAT reporter activation and atrophy in myotubes. In vivo, an increase in serum LIF preceded the increase in IL-6 in mice with C26 tumors. Overexpression of a dominant negative Stat3Cβ-EGFP gene in myotubes and in mouse muscle blocked the atrophy caused by C26 CM or C26 tumors, respectively. Taken together, these data support an important role of LIF-JAK2-STAT3 in C26 cachexia and point to a therapeutic approach for at least some types of cancer cachexia.R01 AR060217 - NIAMS NIH HHS; UL1 TR000157 - NCATS NIH HHS; UL1-TR000157 - NCATS NIH HHShttp://www.jbc.org/content/290/32/19976.full.pdf?sid=936d126d-814b-4f54-961d-0e98caa31314Published versio

Communication: key factor in multidisciplinary system design

System design research often looks at ways to model the system that is developing. Many modelling techniques and model representations exist. Another aspect these models can be used for is to enable, facilitate and improve communication among the developers during the process. The young System Design Group at the faculty of Engineering Technology of the University of Twente, the Netherlands, aims at focusing on this communication aspect in system design.\ud In the paper, a few finished and running projects undertaken in close cooperation with industry are described concisely. From these projects three research themes are derived. These are: creation of high-level models, combining model representations and condense information. The paper ends with plans for future research

Key factor for hastening the strategic issue diagnosis process: a within organisational model

Previous research on Strategic Issue Diagnosis (SID) had focused on the complexity and novelty associated with the decision-making process in a turbulent environment. What had not been previously addressed in the extant literature is the requirement for speed inherent within the SID process, especially that is related to the gathering of information and facts through an organisation’s environmental scanning procedures. Since proactive management techniques, nimble processes, and systems that allow an organisation to be responsive and build rapid decision-making capabilities are important determinants of success in a turbulent environment, the element of speed associated with SID is an important factor. Our paper identifi es a series of propositions focusing att ention on elements of the environmental scanning processes and management hierarchies that are intended to counteract the recursiveness and redundancy inherent in SID systems and ultimately hasten the strategic decision-making process

MER Model of Integral Management: Culture as Enterprise’s Key Success Factor

Enterprise culture is judged by many acknowledged scientists and researchers now as a major determinant of any enterprise’s success. The present article shows the research cognitions on the impact of enterprise culture to the success of the enterprises observed.