Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment

Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer

Defence on demand: mechanisms behind optimal defence patterns

Background The optimal defence hypothesis (ODH) predicts that tissues that contribute most to a plant's fitness and have the highest probability of being attacked will be the parts best defended against biotic threats, including herbivores. In general, young sink tissues and reproductive structures show stronger induced defence responses after attack from pathogens and herbivores and contain higher basal levels of specialized defensive metabolites than other plant parts. However, the underlying physiological mechanisms responsible for these developmentally regulated defence patterns remain unknown. Scope This review summarizes current knowledge about optimal defence patterns in above- and below-ground plant tissues, including information on basal and induced defence metabolite accumulation, defensive structures and their regulation by jasmonic acid (JA). Physiological regulations underlying developmental differences of tissues with contrasting defence patterns are highlighted, with a special focus on the role of classical plant growth hormones, including auxins, cytokinins, gibberellins and brassinosteroids, and their interactions with the JA pathway. By synthesizing recent findings about the dual roles of these growth hormones in plant development and defence responses, this review aims to provide a framework for new discoveries on the molecular basis of patterns predicted by the ODH. Conclusions Almost four decades after its formulation, we are just beginning to understand the underlying molecular mechanisms responsible for the patterns of defence allocation predicted by the ODH. A requirement for future advances will be to understand how developmental and defence processes are integrated.

Collagen I modulates growth and gene expression in prostate cancer cells

Prostate cancer is the second leading cause of male cancer-related deaths in the United States. Interestingly, prostate cancer preferentially metastasizes to skeletal tissue. Once in the bone microenvironment, advanced prostate cancer becomes highly resistant to therapeutic modalities. Several factors, such as extracellular matrix (ECM) components, have been implicated in the spread and propagation of prostatic carcinoma. In these studies, we have utilized the PC3 cell line, derived from a human bone metastasis, to investigate the influence of the predominant bone ECM protein, type I collagen, on prostate cancer cell proliferation and gene expression. We have also initiated the design and production of ribozymes to specific gene targets that may influence prostate cancer bone metastasis. ^ Our results demonstrate that PC3 cells rapidly adhere and spread on collagen I to a greater degree than on fibronectin (FN) or poly-L-lysine (PLL). Flow cytometry analysis reveals the presence of the α1, α2 and α3 collagen binding integrin subunits. The use of antibody function blocking studies reveals that PC3 cells can utilize α2β 1 and α3β1 integrins to adhere to collagen I. Once plated on collagen I, the cells exhibit increased rates of proliferation compared with cells plated on FN or tissue culture plastic. Additionally, cells plated on collagen I show increased expression of proteins associated with progression through G1 phase of the cell cycle. Inhibitor studies point to a role for phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and p70 S6 kinase in collagen I-mediated PC3 cell proliferation and cyclin D1 expression. To further characterize the effect of type I collagen on prostate cancer bone metastasis, we utilized a cDNA microarray strategy to monitor type I collagen-mediated changes in gene expression. Results of this analysis revealed a gene expression profile reflecting the increased proliferation occurring on type I collagen. Microarray analysis also revealed differences in the expression of specific gene targets that may impact on prostate cancer metastasis to bone. ^ As a result of our studies on the interaction of prostate cancer cells and the skeletal ECM, we sought to develop novel molecular tools for future gene therapy of functional knockdown experiments. To this end, we developed a series of ribozymes directed against the α2 integrin and at osteopontin, a protein implicated in the metastasis of various cancers, including prostate. These ribozymes should facilitate the future study of the mechanism of prostate cancer cell proliferation, and disease progression occurring at sites of skeletal metastasis where a type I collagen-based environment predominates. ^ Together these studies demonstrate the involvement of bone ECM proteins on prostate cancer cell proliferation and suggest that they may play a significant role on the growth of prostate metastases once in the bone microenvironment. ^

The role of SRC family kinase activation in prostate cancer growth and lymph node metastasis

Aberrant expression and/or activation of Src Family of non-receptor protein tyrosine kinases (SFKs) occur frequently during progressive stages of multiple types of human malignancies, including prostate cancer. Two SFKs, Src and Lyn, are expressed and implicated in prostate cancer progression. Work in this dissertation investigated the specific roles of Src and Lyn in the prostate tumor progression, and the effects of SFK inhibition on prostate tumor growth and lymph node metastasis in pre-clinical mouse models. ^ Firstly, using a pharmacological inhibitor of SFKs in clinical trials, dasatinib, I demonstrated that SFK inhibition affects both cellular migration and proliferation in vitro. Systemic administration of dasatinib reduced primary tumor growth, as well as development of lymph node metastases, in both androgen-sensitive and -resistant orthotopic prostate cancer mouse models. Immunohistochemical analysis of the primary tumors revealed that dasatinib treatment decreased SFK phosphorylation but not expression, resulting in decreased cellular proliferation and increased apoptosis. For this analysis of immunohistochemical stained tissues, I developed a novel method of quantifying immunohistochemical stain intensity that greatly reduced the inherent bias in analyzing staining intensity. ^ To determine if Src and Lyn played overlapping or distinct roles in prostate cancer tumor growth and progression, Src expression alone was inhibited by small-interfering RNA. The resulting stable cell lines were decreased in migration, but not substantially affected in proliferation rates. In contrast, an analogous strategy targeting Lyn led to stable cell lines in which proliferation rates were significantly reduced. ^ Lastly, I tested the efficacy of a novel SFK inhibitor (KX2-391) targeting peptide substrate-binding domain, on prostate cancer growth and lymph node metastasis in vivo. I demonstrated that KX2-391 has similar effects as dasatinib, an ATP-competitive small molecular inhibitor, on both the primary tumor growth and development of lymph node metastasis in vivo, work that contributed to the first-in-man Phase I clinical trial of KX2-391. ^ In summary, studies in this dissertation provide the first demonstration that Src and Lyn activities affect different cellular functions required for prostate tumor growth and metastasis, and SFK inhibitors effectively reduce primary tumor growth and lymph node metastasis. Therefore, I conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer. ^

Experiment: Growth rates and percentages of normal versus malformed versus incomplete versus incomplete and malformed coccoliths

The coccolithophore Emiliania huxleyi (Lohmann) W. W. Hay et H. Mohler was cultured in natural seawater with the addition of either the microtubule-inhibitor colchicine, the actin-inhibitor cytochalasin B, or the photosynthesis inhibitor 3-(3,4 dichlorophenyl)-1,1-dimethyl-urea (DCMU). Additionally, E. huxleyi was cultured at different light intensities and temperatures. Growth rate was monitored, and coccolith morphology analyzed. While every treatment affected growth rate, the percentage of malformed coccoliths increased with colchicine, cytochalasin B, and at higher than optimal temperature. These results represent the first experimental evidence for the role of microtubules and actin microfilaments in coccolith morphogenesis.

Economic development capitalizing on brand agriculture : turning development strategy on its head

This paper explores the possibilities of two unique Japanese concepts - the One Village One Product Movement (OVOP) and Michino Eki (or Roadside Stations) - as potential tools for bridging the gap between cities and rural areas through community-driven development. From the viewpoint of spatial economics and endogenous growth theory, this paper considers both OVOP and Michino Eki as rural development strategies of a broader nature based on "brand agriculture." Here, brand agriculture represents a general strategy for community-based rural development that identifies, cultivates and fully utilizes local resources for the development of products or services unique to a certain "village." Selected examples of OVOP and Michino Eki from Japan and developing countries are introduced.

経済成長と貧困・雇用：Pro-Poor Growth論の系譜

開発途上国が長期的に貧困削減を実現していくためには、貧困削減に貢献する形で経済成長をすることが必要であり、貧困削減に親和的な経済成長がPro-Poor Growthと呼ばれている。現在までのところ、Pro-Poor Growth研究は、どの国のどの時期の経済成長が貧困削減に大きく貢献したかを問うものが多数を占めており、何がpro-poor growthをもたらすか、に着目した研究は少ない。その少ない研究の多くは農業や農村経済の役割に期待するものであるが、本稿では、既にある程度の貧困削減を遂げた東・東南アジアの経験に鑑み、低賃金の国において労働集約的製造業品を輸出することで貧困層の賃金や雇用機会を飛躍的に伸張させる可能性について考察した。バングラデシュ、カンボジアといった国々は既に縫製業がその役割を果たしており、これまでの東・東南アジアの貧困削減パターンが現在の東南アジアや南アジアの最貧国でも踏襲される可能性が十分にある。

Value Chain Dynamics and Growth of Local Firms:The Case of Motorcycle Industry in Vietnam

Vietnam’s burgeoning market for motorcycles has attracted global industry eaders,players from developing countries, and local firms. This has led to a dynamic evolution of value chains. This paper presents an explanation of the varieties of the growth patterns xperienced by the local suppliers, focusing on the roles of customer and local supplier strategies. Case studies showed that while the role of customers may be important, strategies of suppliers to improve the ompetitive edge in the production of otorcycle components and to diversify into other products account for important ariations of growth trajectories among local suppliers. Findings presented in this paper suggest the need to direct more attention to strategy that local firms use to boost their competitive edge in business.

Development strategy in Bihar through revitalizing the agricultural sector : a preliminary analysis

Based mainly on secondary data and partly on primary information obtained through field surveys in selected rural areas in Bihar in 2011, this paper firstly argues the critical importance of agricultural growth for overall economic development, and then reviews the sluggish growth of agriculture in Bihar in the past and examines the major reasons for this. The long-term negligence of agricultural research (especially development and diffusion endeavors for improved rice varieties suitable to the local conditions of Bihar) by the state government and some sort of ‘backwardness’ in tube-well irrigation technology can be pointed out as important constraints. There is, in particular, the ‘paradox’ in Bihar agriculture of why rice and wheat yields have remained so low in spite of the relatively well-developed irrigation by tube-wells. Finally, by showing the process of a rapid increase in autumn and winter rice yields during the 1990s in West Bengal, it is suggested that Bihar farmers and policy-makers should learn from the experience of West Bengal in order to get some hints for the development of the rice sector in Bihar.

Optimal Multiresolution 3D Level-Set Method for Liver Segmentation incorporating Local Curvature Constraints

Advanced liver surgery requires a precise pre-operative planning, where liver segmentation and remnant liver volume are key elements to avoid post-operative liver failure. In that context, level-set algorithms have achieved better results than others, especially with altered liver parenchyma or in cases with previous surgery. In order to improve functional liver parenchyma volume measurements, in this work we propose two strategies to enhance previous level-set algorithms: an optimal multi-resolution strategy with fine details correction and adaptive curvature, as well as an additional semiautomatic step imposing local curvature constraints. Results show more accurate segmentations, especially in elongated structures, detecting internal lesions and avoiding leakages to close structures

Content Delivery System for Optimal VoD Streaming

The demand of video contents has rapidly increased in the past years as a result of the wide deployment of IPTV and the variety of services offered by the network operators. One of the services that has especially become attractive to the customers is real-time video on demand (VoD) because it offers an immediate streaming of a large variety of video contents. The price that the operators have to pay for this convenience is the increased traffic in the networks, which are becoming more congested due to the higher demand for VoD contents and the increased quality of the videos. As a solution, in this paper we propose a hierarchical network system for VoD content delivery in managed networks, which implements redistribution algorithm and a redirection strategy for optimal content distribution within the network core and optimal streaming to the clients. The system monitors the state of the network and the behavior of the users to estimate the demand for the content items and to take the right decision on the appropriate number of replicas and their best positions in the network. The system's objectives are to distribute replicas of the content items in the network in a way that the most demanded contents will have replicas closer to the clients so that it will optimize the network utilization and will improve the users' experience. It also balances the load between the servers concentrating the traffic to the edges of the network.

A review of the potential of renewable energy sources for the State of Jammu and Kashmir (India)

The future economic development trajectory for India is likely to result in rapid and accelerated growth in energy demand, with expected shortages. Many of its current policies and strategies are aimed at the improvement and possible maximization of energy production from the renewable sector. It is also clear that while energy-conservation and energy-efficiency can make an important contribution in the national energy strategy, renewable energies will be essential to the solution and are likely to play an increasingly important role for the growth of grid power, providing energy access, reducing consumption of fossil fuels, and helping India pursue its low carbon progressive pathway. However, most of the states in India, like the northernmost State of Jammu and Kashmir (J&K), have experienced an energy crisis over a sustained period of time. As India intends to be one of the emerging powers of the 21st century, it has to embark upon with these pressing issues in a more sustainable manner and accordingly initiate various renewable energy projects within these states. This paper will provide a broad-spectrum view about the energy situation within J&K and will highlight the current policies along with future strategies for the optimal utilization of renewable energy resources.

Optimal and Long-Term Dynamic Transport Policy Design: Seeking Maximum Social Welfare through a Pricing Scheme.

This article presents an alternative approach to the decision-making process in transport strategy design. The study explores the possibility of integrating forecasting, assessment and optimization procedures in support of a decision-making process designed to reach the best achievable scenario through mobility policies. Long-term evaluation, as required by a dynamic system such as a city, is provided by a strategic Land-Use and Transport Interaction (LUTI) model. The social welfare achieved by implementing mobility LUTI model policies is measured through a cost-benefit analysis and maximized through an optimization process throughout the evaluation period. The method is tested by optimizing a pricing policy scheme in Madrid on a cordon toll in a context requiring system efficiency, social equity and environmental quality. The optimized scheme yields an appreciable increase in social surplus through a relatively low rate compared to other similar pricing toll schemes. The results highlight the different considerations regarding mobility impacts on the case study area, as well as the major contributors to social welfare surplus. This leads the authors to reconsider the cost-analysis approach, as defined in the study, as the best option for formulating sustainability measures.

A new method for the identification of old-growth trees in National Forest Inventories: Application to Pinus halepensis Mill. stands in Spain

Old-growth trees play a very important role in the maintenance of biodiversity in forests. However, no clear definition is yet available to help identify them since tree age is usually not recorded in National Forest Inventories. To develop and test a new method to identify old-growth trees using a species-specific threshold for tree diameter in National Forest Inventories. Different nonlinear mixed models for diameter ? age were generated using data from the Spanish Forest Inventory in order to identify the most appropriate one for Aleppo pine in its South-western distribution area. The asymptote of the optimal model indicates the threshold diameter for defining an old-growth tree. Additionally, five site index curves were examined to analyze the influence of site quality on these models.

Effect of solute and matric potential on growth rate of fungal species isolated from cheese

The effect of water potential ( J w ) on the growth of 15 fungal species isolated from cheeses was analysed. The species, identified mainly by analysis of DNA sequences, belonged to genera Penicillium , Geotrichum , Mucor , Aspergillus , Microascus and Talaromyces . Particularly, the effect of matric potential ( J m ), and ionic (NaCl) and non-ionic (glycerol) solute potentials ( J s ) on growth rate was studied. The response of strains was highly dependent on the type of J w . For J s , clear profiles for optimal, permissive and marginal conditions for growth were obtained, and differences in growth rate were achieved comparing NaCl and glycerol for most of the species. Conversely, a sustained growth was obtained for J m in all the strains, with the exception of Aspergillus pseudoglaucus , whose growth increased proportionally to the level of water stress. Our results might help to understand the impact of environmental factors on the ecophysiology and dynamics of fungal populations associated to cheeses.