bluuebunny/crossref_metadata_2025 huggingface dataset:
Bullwhip Effect Analysis in a Supply Chain
Authors: Najafi Mehdi , Farahani Reza Zanjirani
Published: December 2011

In today’s world, all enterprises in a supply chain are attempting to increase both their and the supply chain’s efficiency and effectiveness. Therefore, identification and consideration of factors that prevent enterprises to attain their expected/desired levels of effectiveness are very important. Since bullwhip effect is one of these main factors, being aware of its reasons help enterprises decrease the severity of bullwhip effect by opting proper decisions. Now that forecasting method is one of the most important factors in increasing or decreasing the bullwhip effect, this chapter considers and compares the effects of various forecasting methods on the bullwhip effect. In fact, in this chapter, the effects of various forecasting methods, such as Moving Average, Exponential Smoothing, and Regression, in terms of their associated bullwhip effect, in a four echelon supply chain- including retailer, wholesaler, manufacturer, and supplier- are considered. Then, the bullwhip effect measure is utilized to compare the ineffectiveness of various forecasting methods. Owing to this, the authors generate two sets of demands in the two cases where the demand is constant (no trend) and has an increasing trend, respectively. Then, the chapter ranks the forecasting methods in these two cases and utilizes a statistical method to ascertain the significance of differences among the effects of various methods.
Integrated Methodology for Mapping and Monitoring Permafrost and Seasonally Frozen Ground
Authors: Walter G.R. , Stothoff S.A. , Necsoiu D.M. , Dinwiddie C.L.
Published: December 2011

Arctic regions have been determined to be particularly sensitive to a warming global climate both on the basis of climatic modeling and observation of dramatic changes in arctic landscapes and sea ice. As early as the 1990s, air temperatures in interior northwest Alaska were warming at a rate of 0.75 °C per decade. The resulting thawing of permafrost causes significant damage to buildings, roadways, and can lead to increased mass wasting (e.g., active layer detachments and thaw slumps) by melting the soil ice that " cements?? the grains together to resist soil movement, as well as ground subsidence. These climate-induced ground movements can threaten infrastructure, such as road, bridges, and pipelines, either by direct physical damage or indirectly, such as through changes in drainage patterns, increased risk of flooding and forest fires.

Because these geohazards often occur in remote locations with harsh weather conditions and limited access, and the precursor conditions for initiating them can occur gradually, methods for remotely monitoring changes in ground conditions and estimating ground failure risks have significant engineering and economic value. The research described in this paper addresses this need by developing techniques for detecting changes in permafrost and seasonally frozen soil terrains using satellite and airborne remote sensing data, and combining these data with mathematical models to estimate the risk of ground failures due to soil thawing. The methodology consists of combining multiple sources of satellite-acquired synthetic aperture radar (SAR) data with high resolution optical-band data and aerial photography to map frozen ground and associated changes in soil moisture, and to detect vertical and lateral ground movements.

The remote sensing data interpretations along with traditional soil and vegetation mapping are used to inform mathematical models of permafrost and frozen soil stability. These models are used to develop maps of the probability of ground movements associated with permafrost degradation and seasonally frozen soil under current and future climate conditions. The models and slope stability risk algorithm were applied to a portion of Kobuk Valley National Park, Alaska for which soil and vegetation land cover maps were available. The cryosphere model results suggest that the same relative change in active-layer thickness occurs across the landscape, but warmer locations experience a larger absolute change in active-layer thickness and may experience permafrost loss as a consequence. The slope failure risk algorithm indicates that the upland areas are most susceptible to slope failure, particularly south-facing slopes, but low-cohesion low-land soils and steep river banks are also susceptible to failure.
Wave Propagation at Marginal Ice Zone
Authors: Petrie F. , Rousse B. , Cholley J.M.
Published: December 2011

Moving in Artic and Sub-Artic regions imposes significant challenges on engineering aspects of offshore Oil & Gas fields development. These new developments have to be subjected to environment composed of level ice sheets, ice ridges, marginal ice zones and free sea.

Marginal ice zone means the transition between the free sea (no ice) and ice. It is accepted that waves damp out in heavy pack ice, but the relationship between the amount of wave damping with ice concentration and distance into the ice field is not fully understood, area requiring further research and development.

This paper presents the main results of the program "wave propagation in marginal ice zone" initiated through a French JIP in 2009. It identifies the state of practices and state of art on wave propagation at marginal ice zone. A comparison is presented between ice floe modelling technique, experimental results and theoretical values. Finally the wave tank experiments carried out in the BGO First basin are presented in detail for this program.

Introduction

The continuous interest of Total E&P and the engineering companies (Saipem, Technip, Doris, Entrepose) for the Artic and Sub-Artic regions has lead them to begin a R&D study on the topic "wave propagation at marginal ice zone" through a French JIP (ref 1). The objective of this JIP is to analyse wave propagation at marginal ice zone by means of model tests in BGO FIRST.

Firstly, this paper presents an overview of the knowledge on the marginal ice zone and the wave propagation. This preparatory work has lead to a reflection on the way to perform model tests to study the phenomena.

In addition, a number of challenges are developed in relation to the definition of the model tests, the physical model of ice floes, the selection of the parameters to be tested, their range, and the reliability of the experimentation performed in a limited space basin.

This paper will present the model tests setup and the test procedure, including the ice floe modelling and instrumentation. At the end, the results of the experimentation are presented and compared with some analytical calculations.
Ice Actions in ISO 19906 - Overview
Authors: Karna T. , Frederking R. , Shkhinek K.
Published: December 2011

Eighteen ice experts from nine countries were actively involved in the development of new guidelines for ice actions that are an essential part of the new standard ISO 19906. This paper provides an overview of the methods that are recommended for ice action determination.

This standard is based on the limit states design method. Therefore, guidelines are provided for ice actions in four different categories of limit states. Characteristic values of ice actions depend on the limit state concerned and also on the life-safety and consequence categories that are applicable to a structure.

As a general principle, design shall be carried out separately for global ice actions, local ice actions and for dynamic ice actions. Operational procedures may be used to reduce ice actions. Ice action scenarios need to be selected by taking account of the specific conditions in the ice regime for which a structure is designed.

Data from full scale measurements on instrumented structures were the basis for developing methods for calculating ice actions. These methods are recommended for the practical determination of design ice actions on offshore structures. Both probabilistic and deterministic methods can be used. For many action scenarios, it is useful to consider limit-stress, limit-energy and limit-force mechanisms as well as specific ice failure modes. ISO 19906 provides a variety of methods and formulas that consider these limiting mechanisms and ice failure modes for the determination of global ice actions. Three methods for determining local ice actions in different conditions are provided. Basic modes of dynamic ice actions are described and simple models are provided for vertical and conical structures.

1. Introduction

Several surveys of predicted ice actions have been carried out in recent years (Shkhinek et al. (1994); Croasdale (1994) and Timco and Croasdale (2006)). International experts were invited in these surveys to determine ice actions for a few basic scenarios. These studies have revealed little consensus and a wide spread in the predicted values of ice actions. This situation has been a good reason for the development of the new standard ISO 19906, which should significantly reduce the discrepancies in the prediction of ice actions.

The new guidelines of ice action determination are provided in the sub-clauses 8.2 and A.8.2 of the new standard. These clauses were written by an international group of eighteen experts from nine countries, as shown in Table 1. The resulting clause is the consensus of these experts.

It is well known that formulas on ice action can not be derived directly from first principles. Empirical factors that are obtained from experiments play a very central role in all ice load prediction. The new standard emphasizes the importance of full-scale data.
Arctic and Harsh Environment Pipeline Trenching Technologies and Challenges
Authors: Jukes Paul , Kenny Shawn , Panapitiya Upali , Jafri Syed , Eltaher Ayman
Published: December 2011

A primary challenge of Arctic and harsh environment offshore field development is the protection of subsea pipelines and flowlines on the seabed. Damage from ice either through direct contact or through soil movements/pressures acting on the pipeline from ice gouging is a serious risk. Trenching and burial of pipelines in Arctic and harsh environments such as the Beaufort Sea, Chukchi Sea and the Grand Banks are considered to be the primary means of preventing damage from ice. Trenching can provide adequate protection for pipelines in Arctic areas. This paper presents the challenges associated with trenching and burial of pipelines and flowlines in Arctic and harsh environments, and discusses the state-of-the-art trenching and dredging technologies. Future equipment developments required to meet functional specifications for working in Arctic and harsh environments is then presented. Furthermore, key areas surrounding the operability of trenching and associated equipment are also discussed. This paper shows that there are a number of challenges facing trenching pipelines in arctic regions, and there are limitations of current trenching and dredging equipments. A continued effort is required by the industry to overcome a number of key issues and challenges and promote productions in Arctic and harsh environment frontiers.

Introduction

The world demand for oil and gas is growing at an ever increasing rate and, as a result, there is a demand to explore new areas for more petroleum production. The arctic region is one of the remaining unexplored areas where such exploration still can be undertaken. According to the US Geological Survey estimates, the arctic region, mostly offshore, holds as much as 22% of the world's untapped reserve of hydrocarbons where much of the reserve is lying under seasonal or year-round sea ice. The exploitation of these remaining reserves, however, will depend upon meeting the technical challenges of design, construction, and operation of offshore installations. These general Arctic technical challenges have been previously presented [1].
Green Management - Enabling Arctic Exploration and Reducing its Environmental Impact
Authors: Backman Anders , Hedman Ulf , Rohlen Ake
Published: December 2011

Whilst there is, potentially, large volumes of hydrocarbons yet to find on the Arctic shelf, the exploration and production of Arctic oil and gas reserves can only be performed if operations are planned, approved and operated to the highest possible environmental standards.

Enabling offshore drilling and production will often require that the operation is protected from ice above the limits set for the operation. This is often referred to as "Ice Management".

The effectiveness of the "Ice Management" sets the limits of the offshore operation. The effectiveness of the "Ice Management" is also directly correlated to the environmental foot-print of the operation.

The ice conditions at the operation site, is provided by nature. It cannot be influenced. What can be influenced is how the operation is performed.

By timely breaking of only the required ice and by doing this in the most energy efficient way the objective of protection against dangerous ice and low environmental impact is achieved.

To do this requires software and hardware, software being people and the systems that supports their decisions and hardware being the icebreakers.

By operating "real-time" with "now-casting" of weather and ice conditions and using modern technology, it is possible to determine with reasonable accuracy which ice that need to be broken. With good communication and a good management structure the icebreaking resources can be directed to deal with the threatening ice.

By using vessels with efficient propulsion and icebreaking technology, ice can be efficiently broken and with as low environmental impact as possible.

Recent operations in the high Arctic, Greenland and the Beaufort Sea, has given valuable input on how this "Green Ice Management" can be achieved. By the use of modern simulation technology it possible to train, and illustrate, the efficiency ahead of the operation.

Environmental Impacts

When looking upon different impacts it is important to analyse from where they come.

Exhaust gas emissions

Exhaust gas emissions coming from a combustion process is a combination of different factors, the efficiency of the engine, the contents in the used fuel and the way the integrated systems are used by the operator.
3D Continuum Simulations To Determine Pipeline Strain Demand Due to Ice-Gouge Hazards
Authors: Lele S.P. , Hamilton J.M. , Panico M. , Arslan H. , Minnaar K.
Published: December 2011

Offshore Arctic pipelines must be designed to withstand unique loading conditions of seafloor gouging by drifting sea ice ridge keels and icebergs. Due to the high cost of offshore pipeline burial, determination of the required burial depth is a critical factor for economical designs. One of the components of burial depth is the distance the top-of-pipe must be placed below the design gouge depth to protect it from excessive stress/strain due to subgouge soil deformation. While industry has done much over the past two decades to understand the complex ice/soil/pipe interaction process, there remains considerable uncertainty in our ability to estimate pipe strain due to soil displacement below a gouging ice feature. This paper presents an advanced 3D continuum model for estimating strain demand as a possible alternative to the currently accepted methodology based on published empirical equations for subgouge deformation and pipe-soil spring models. Some of the important numerical simulation techniques employed include Eulerian mesh for the soil to model extreme material deformation, complex soil material models with material parameters determined from standard triaxial test data, and optimum mesh density in the pipe-soil contact region. These advanced models, which capture the ice gouging physics and coupled soil-pipe interaction more accurately, generally predict lower subgouge soil deformations and pipeline burial depths compared to the current industry methodology. Since the greater accuracy comes with a significant increase in computational intensity, guidance is provided for the practical implementation of such advanced models in the design process. The authors believe that advanced continuum models, once properly validated using centrifuge and large-scale field tests, can be used to determine reliable and potentially more economical pipeline burial depths.

Introduction

Offshore arctic regions may contain several types of ice features that are capable of scouring the sea floor, including icebergs, first year ice ridge keels, and multiyear ridge keels. The ice features are continuously moving under the action of environmental forces (e.g. wind and ocean currents) and, whenever their draft is larger than the local water depth, they scour the seabed producing the characteristic process of ice gouging. Figure 1 shows a schematic illustration of the ice-gouging process.
Well Architecture and Well Operating Procedures on Kharyaga Field, Russia
Authors: Boyer Yannick , Szakolczai Cyril
Published: December 2011

In 1995 Total signed a Production Sharing Agreement with the Russian Federation for the development and production of the Kharyaga oil field, situated 60km to the north of the Polar Circle in the Nenets Autonomous Okrug, and 140km away from the main base in Usinsk (Figure 1).

Kharyaga is the first project in Russia under PSA terms. It is a key operationnal project for Total in Russia to date. Total (40%) operates the project in partnership with the Norwegian Statoil (30%), the Russian Zarubezhneft (20%), and the Russian Nenets Oil Company (10%).

Total E&P Russie has developed knowledge and competences for drilling and completion activities in arctic conditions, during its operations on the onshore Kharyaga field.

The weather is particularly harsh at the rig site with a temperature far below 0°C from October to June. The average temperature is around −20°C and it can sometimes go down to −53°C in winter time, without considering the wind chill.

From the operations point of view, the Kharyaga field reservoirs are normally pressured or depleted reservoirs, at depths of up to 2850mTVD. It contains up to 1.2% H2S. Whilst the wells themselves are relatively low technology and at quite average depths, operating in such environment remains a challenge.

This paper reviews the various operational specifics such as equipment, procedures and best practices required to safely and efficiently drill onshore wells in arctic conditions.

HSE specifics for arctic

Kharyaga field working conditions

The general working conditions on the field could be summarized as follow:Low temperatures (absolute static minimum: −53°C),Strong wind, up to 38m/s,Huge temperature range from winter to summer, about 85°C amplitude,Rapid temperature changes, up to 20°C within 24 hours,Low atmospheric pressure with sudden changes,Low light level / polar night,Swampy area / mosquitoes in summer time,Outside work limitation in winter.
Global Warming and Globalisation - The North East Passage (NEP) as a Viable Shipping Alternative Between Europe and Asia
Authors: Westvik Morten H. , Kvamstad Beate , Holte Even A. , Winge Christian
Published: December 2011

Global warming and Globalisation represents both challenges and new opportunities in the 21st Century, and the Arctic is expected to become the new frontier within petroleum and mineral exploration activities and for shipping activities. With an economic and geopolitical shift towards Asia, a significant growth in standard of living coupled with population growth, it is projected that global trade in 2050 will increase by 50% from 2010. The majority of this growth is expected to take place in Asia. Looking specifically at maritime transportation, and projections for growth from 2005 till 2050, estimates point to 93.4% for Europe (including short sea freight); while the corresponding figure outside Europe is 148.2%. Today approximately 90% of global trade is transported on ships, representing a cargo volume of 32.7 billion ton-miles. In commercial terms this represents a value of US$380billion, equal to 5% of world trade.

The main objective for this paper is therefore to highlight both possibilities and challenges that will have direct impact on developing the North East Passage (NEP) as a commercially viable shipping alternative compared to the Suez Canal route. Thus, in order to highlight the different issues related to this context, key topics that will be addressed are in this paper are: Globalisation, Arctic petroleum and mineral exploration, Infrastructure, support and Incidents, Ships and logistics, Climate change and environmental issues and International regulation and management of the NEP.

1. Introduction

In 2008 global seaborne trade stood at 8.17 billion tons of goods loaded, dry cargo accounting for 66.3% of total volume (hereof; iron ore, coal, bauxite/alumina, phosphate making up 25.7% of total volume), and oil representing 33.7%. The majority of goods loaded were in developing nations which accounted for more than 60% global volumes, and Asia alone taking up 40% of all goods loaded (UNCTAD 2009). Approximately 90% of global trade today is transported on ships, representing a cargo volume of 32.7 billion ton-miles (UNCTAD 2009). Worth noting is that the average growth in merchandised trade from 1998 till 2008 was 12% per annum. Meanwhile the growth respectively for fuels were 18.2% and 20% for natural resources during the same period, with the major growth markets being in Asia (WTO 2010). Further, the largest importers of natural resources in the world in 2008 are: USA 15.2%, Japan 9.1%, China 8.6%, Germany 6%, South Korea 4.7%, France 3.9% and India 3.5%.
Design of a Floating Platform Hull for Arctic Conditions in the Barents Sea
Authors: Le Marechal Guillaume , Anslot Philippe , Mravak Zoran , Liferov Pavel , Le Guennec Stephane
Published: December 2011

The Shtokman Gas Condensate Field (SGCF) is located 610 km from Murmansk in the Barents Sea. The water depth at location is around 340 m. The offshore facilities of the SGCF Phase 1 development will include ice-resistant ship shape disconnectable turret moored floating platform (FP). The design of the hull has been driven to be inherently safe, to resist the environmental condition, and minimize risk of repair over the 50 years operating duration.

Introduction

The SGCF is located 610km from Murmansk in the Barents Sea, around 73º latitude North and 44º longitude East. The water depth at location is around 340 m and the reservoir is 2000 m below the mudline. The field reserves are estimated to be 3700 GSm3. The gas reservoir covers a geographical area of approximately 1 400 km2, and is approximately 48 km long by 35 km wide. The field will be developed in three phases, the expected daily production of each phase being around 70 million Sm3 per day. SDAG owned by Gazprom (51%), Total (25%) and Statoil (24%) will operate the development of the First Phase of the SGCF.

The area is a harsh Arctic environment that can be covered by sea ice and is also known for its icebergs and experiences long periods of darkness during the winter months. Facilities in this region can be exposed to very low ambient air temperatures (including wind chill), snow and icing that require winterisation measures to be taken.

The offshore development of Phase 1 of the Shtokman Gas Condensate Field development consists of the following main elements (see Fig. 1):The Floating Platform, including hull, mooring, accommodation, process (oil, gas, water as needed), gas export facilities (compression and metering) and associated control systems.The Subsea Production System (referred to as the SPS).The Umbilicals, Flowlines and Risers (UFR) to gather production from SPS and transport it to the Floating Platform and to connect the Floating Platform to pipeline to shore.The Export Trunklines.

After various conceptual initial studies, Shtokman Development AG has concluded to design the floating platform as a turret moored disconnectable and ice resistant ship shaped floating platform. The FP design operating life is 50 years. The present paper describes the main principles of design of the hull that form the frame for further optimization by contractors.
From Concept to the Clinics: Development of Cancer Therapeutics
Authors: Kaur Balveen , Lesinski Gregory B. , Chaudhary Abhik Ray
Published: December 2011

Development of a therapeutic agent is a long and laborious process commencing with the discovery of a “druggable target” underlying the pathology of a disease. After rigorous testing, optimization, and modification, the candidate agent is then carefully tested for toxicity in appropriate animal models to define a dose that can be safely administered to human patients without adverse effects. Once these preclinical studies have been performed, the experiemental drug moves into the clinical trials phases. Phase I clinical trials are typically dose escalation studies meant to evaluate the safety, adverse events, and maximum tolerated dose in human patients. Agents that appear to be reasonably safe then progress to phase II and eventually phase III studies to evaluate their efficacy prior to government approval and marketing. In this chapter we will discuss three recently approved agents that have been through this process and are now being tested in combination with other therapies and one experimental agent that is actively engaged in the developmental process.
Development and Application of Conformation‐Selective Integrin Antibodies
Authors: Astrof Nathan S. , Peer Dan , Shimaoka Motomu
Published: December 2011

Of the major classes of adhesion receptors, including the immunoglobrin domain superfamily (IgSF), the cadherins, and other transmembrane adhesion receptors (e.g., claudins and occludins), integrins are unique in achieving rapid and reversible (second time scale) upregulation from a basal, inactive state to a maximally adhesive state, upon cell stimulation. In past studies, we have suggested, and subsequently demonstrated, that it is possible to selectively target persistently activated integrin in a physiological background. In this chapter, we will describe how such antibodies are derived, their mechanism of action, and their potential therapeutic application.
Antiviral Market Overview
Authors: Arora Anita , Mendoza Natalia , Tyring Stephen K.
Published: December 2011

The past 15 years have seen significant progress in developing new antivirals. In 1990, there were just five drugs licensed as antiviral agents, whereas now there are approximately 40 drugs in the antiviral market repertoire, most being for the treatment of the human immunodeficiency virus (HIV). Over the years, one of the main attributes sought in a new antiviral is the capacity to treat patients who have developed resistance to existing treatments, and numerous compounds are investigated in such advanced‐stage patients. The main need for antiviral agents, past, present, and likely in the future continues to be in the world's poorest countries. This chapter will provide a thorough overview of the antiviral market.
Accelerator Mass Spectrometry and Positron Emission Tomography in Human Microdosing
Authors: Cheng Zhengdong
Published: December 2011

Human microdosing study is one type of exploratory phase I investigation supported by both U.S. and European regulatory agencies. Very small subpharmacologic doses of a drug are used in humans to obtain an early assessment of pharmacokinetic properties in humans. This has the potential of reducing the number of preclinical animal studies, essential for conducting early clinical human studies, differentiating between good and bad candidate drugs early, and speeding up the early phases of drug development. Human microdosing, as will be outlined in this chapter, is a newly established and still evolving concept, around which knowledge is beginning to accumulate.
Locoregional Chemoradiotherapy of Cancer Using Hydrogel
Authors: Yang David J. , Azhdarinia Ali , Kurihara Hiroaki , Bryant Jerry , Kim E. Edmund
Published: December 2011

In this chapter, we will demonstrate that in situ hydrogel can be used for local‐regional delivery of chemotherapy and radiotherapy while reducing associated toxicities found with traditional delivery methods. In an attempt to incorporate well‐known slow‐release methodologies for drug delivery with radiotherapy, we highlight our own developed hydrogel that plays two roles in cancer treatment: (1) slow release of chemotherapeutic agents and (2) trapping of therapeutic radionuclides. The findings demonstrate the potential uses of image‐guided therapy in cancer treatment.
RNAi‐Mediated Therapeutics
Authors: Morral Núria , Witting Scott R.
Published: December 2011

The first RNA silencing mechanisms were discovered as part of an antiviral response believed to protect organisms from viral infection. It was later discovered that cells have the capacity to synthesize small RNAs known as microRNA (miRNA), which regulate hundreds of genes, coordinating complex developmental as well as physiological responses. Based on the fact that miRNA molecules modulate gene expression in all mammalian tissues, RNAi is being exploited as a system for the treatment of human diseases as well as to study gene function. This chapter will explore the current state of the field of RNAI‐mediated therapeutics.
Crystallography
Authors: Schwalbe Carl H.
Published: December 2011

This chapter will provide a general overview of what crystallography can contribute to drug discovery. A discussion of practical matters, covering the required features of the crystalline sample, the radiation source, and the detector will be given. Then the essentials of the underlying theory will be introduced so that the rationale for the steps in a crystal structure determination can be understood. Although crystallography is underpinned by mathematics, the treatment here will be as intuitive as possible with limited recourse to mathematics. The chapter will wrap up with specific examples of the use (and nonuse) of crystallography in drug discovery.
Anti‐Inflammatory Therapeutics
Authors: Chan Marion M. , Fong Dunne
Published: December 2011

The development of anti‐inflammatory therapeutics is an active area of pharmacological research. As we look forward to future discoveries, it also pays to look to the past for potentially useful but neglected therapeutic agents. One example is thalidomide, the drug that had caused a birth defect disaster. Another is cannabinoid, the molecule that has been associated with substance abuse. More targets for anti‐inflammatory therapeutics have been and will be discovered. In this chapter, we will provide two examples: SAHA and catecholamines.
Statins in the Reduction of Cardiovascular Events
Authors: Sachdeva Rajesh , Hughes Bradley , Mehta Jawahar L.
Published: December 2011

The major advances in coronary heart disease (CHD) diagnosis and treatment in the past half‐century include the detection of thrombosis or a mechanism of acute coronary syndromes that leads to heart attacks and discovery of major risk factors that leads to progression of atherosclerosis. Next was the role of aspirin in prevention. The most eradicable risk factor is smoking cessation in the prevention of CHD. Most modifiable risk factor is lipoprotein (LDL)‐cholesterol reduction that has been shown to cause regression of atherosclerosis and reduction in cardiac events. Statins play a major role in reducing LDL‐cholesterol, hence reducing cardiac events in every study. Statins not only have their effects through LDL‐cholesterol reduction, but have LDL‐cholesterol‐independent effects. The significance of the pleitropic effects is not well defined. Statins are, nonetheless, the only class of drugs that has been shown to consistently reduce CHD risk.
Neurotrophic Factors as Novel Therapeutic Targets
Authors: Skaper Stephen D.
Published: December 2011

It has long been hoped that the power of neurotrophic factors to regulate neuronal cell survival in the developing nervous system could be harnessed for the treatment of neurodegenerative disease. Preclinical data suggest that subcutaneous or intravenous administration of neurotrophic factors may be effective for the treatment of peripheral and central nervous system diseases. In spite of such encouraging experimental findings, clinical studies have proven largely disappointing. Not only have neurotrophic proteins failed to show a beneficial effect, but in some cases adverse side effects were noteworthy. As this chapter will discuss, therapeutic benefit may be dependent on the extent of neurodegeneration before therapy initiation, and although studies will be difficult, assessment of the effects of neurotrophic factors on the rate of progression over sufficiently long time frames may well be critical in determining their ultimate efficacy.
Oncology
Authors: Dudek Arkadiusz Z. , Powell Steven F.
Published: December 2011

This chapter will provide a basic understanding of the methods of anticancer drug research. This will be achieved by giving a background of where anticancer drug discovery has come from to where it is going. From natural products research to DNA microarrays, all facets of anticancer drug research will be explored. Additionally, the current classes of anticancer agents will be explained. Significant detail will be given to the newer agents that are being developed. Future directions will also be highlighted throughout the chapter. In the end, this chapter is designed to stimulate thought among researchers interested in anticancer drug discovery. With more insight into the treatment of such a devastating disease, we can hope to improve the quality of life for millions.
Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
Authors: Alam Muhammad Mansoor , Talpaz Moshe
Published: December 2011

As this chapter will discuss, the discovery of imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). It is a classic example of drug development based on the identification of a common molecular target involved in a signaling pathway. It was the first medication that inhibited a particular molecular target in the cell to treat a cancer type instead of as in earlier chemotherapy drugs that nonspecifically target rapid dividing cells. However, it is not considered curative. Furthermore, issues with imatinib resistance have emerged, which has led to the development of more targeted therapies to overcome resistance.
Radiopharmaceuticals and Medical Imaging: Development of Radioimmumoconjugates for Radioimmunoimaging and Radioimmunotherapy of Malignant Diseases
Authors: Niu Gang , Chen Xiaoyuan
Published: December 2011

Radioimmunopharmaceuticals or radioimmunoconjugates (RICs) are using antibody (Ab) or antibody derivatives as targeting carriers, taking advantage of the specific binding between antibody and antigen. In this chapter, we will discuss several aspects of RIC development and their application in radioimmunoimaging (RII) and radioimmunotherapy (RIT) for malignant diseases, including lymphoma, prostate cancer, colon cancer, and breast and ovarian cancers.
Targeting Chemokines and Angiogenesis in Rheumatoid Arthritis
Authors: Szekanecz Zoltán , Koch Alisa E.
Published: December 2011

In this chapter, we will briefly review the role of chemokines, chemokine receptors, and angiogenesis in the pathogenesis of arthritis. We will draw special attention to chemokines involved in neovascularization. Finally, we will describe studies on chemokine and angiogenesis targeting obtained in animal models of arthritis as well as in humans.
Personalized health care: From theory to practice
Authors: Snyderman Ralph
Published: December 2011

The practice of medicine stands at the threshold of a transformation from its current focus on the treatment of disease events to an emphasis on enhancing health, preventing disease and personalizing care to meet each individual's specific health needs. Personalized health care is a new and strategic approach that is driven by personalized health planning empowered by personalized medicine tools, which are facilitated by advances in science and technology. These tools improve the capability to predict health risks, to determine and quantify the dynamics of disease development, and to target therapeutic approaches to the needs of the individual. Personalized health care can be implemented today using currently available technologies and know‐how and thereby provide a market for the rational introduction of new personalized medicine tools. The need for early adoption of personalized health care stems from the necessity to reduce the egregious and wasteful burden of preventable chronic diseases, which is not effectively addressed by our current approach to care.
Different expression systems for production of recombinant proteins in Saccharomyces cerevisiae
Authors: Liu Zihe , Tyo Keith E.J. , Martínez José L. , Petranovic Dina , Nielsen Jens
Published: December 2011

Yeast Saccharomyces cerevisiae has become an attractive cell factory for production of commodity and speciality chemicals and proteins, such as industrial enzymes and pharmaceutical proteins. Here we evaluate most important expression factors for recombinant protein secretion: we chose two different proteins (insulin precursor (IP) and α‐amylase), two different expression vectors (POTud plasmid and CPOTud plasmid) and two kinds of leader sequences (the glycosylated alpha factor leader and a synthetic leader with no glycosylation sites). We used IP and α‐amylase as representatives of a simple protein and a multi‐domain protein, as well as a non‐glycosylated protein and a glycosylated protein, respectively. The genes coding for the two recombinant proteins were fused independently with two different leader sequences and were expressed using two different plasmid systems, resulting in eight different strains that were evaluated by batch fermentations. The secretion level (µmol/L) of IP was found to be higher than that of α‐amylase for all expression systems and we also found larger variation in IP production for the different vectors. We also found that there is a change in protein production kinetics during the diauxic shift, that is, the IP was produced at higher rate during the glucose uptake phase, whereas amylase was produced at a higher rate in the ethanol uptake phase. For comparison, we also refer to data from another study, (Tyo et al. submitted) in which we used the p426GPD plasmid (standard vector using URA3 as marker gene and pGPD1 as expression promoter). For the IP there is more than 10‐fold higher protein production with the CPOTud vector compared with the standard URA3‐based vector, and this vector system therefore represent a valuable resource for future studies and optimization of recombinant protein production in yeast. Biotechnol. Bioeng. 2012; 109:1259–1268. © 2011 Wiley Periodicals, Inc.
Monitoring On‐Chip Pictet–Spengler Reactions by Integrated Analytical Separation and Label‐Free Time‐Resolved Fluorescence
Authors: Ohla Stefan , Beyreiss Reinhild , Fritzsche Stefanie , Glaser Petra , Nagl Stefan , Stockhausen Kai , Schneider Christoph , Belder Detlev
Published: December 2011

High‐throughput screening for optimal reaction conditions and the search for efficient catalysts is of eminent importance in the development of chemical processes and for expanding the spectrum of synthetic methodologies in chemistry. In this context we report a novel approach for a microfluidic chemical laboratory integrating organic synthesis, separation and time‐resolved fluorescence detection on a single microchip. The feasibility of our integrated laboratory is demonstrated by monitoring the formation of tetrahydroisoquinoline derivatives by Pictet–Spengler condensation. After on‐chip reaction the products and residual starting material were separated enantioselectively on the same chip. On‐chip deep UV laser‐induced fluorescence detection with time‐correlated single photon counting was applied for compound assignment. The system was utilized to screen reaction conditions and various substrates for Pictet–Spengler reactions on‐chip. Finally, the microlab was successfully applied to investigate enantioselective reactions using BINOL‐based phosphoric acids as organocatalysts.
Metal‐Induced Specific and Nonspecific Oligonucleotide Folding Studied by FRET and Related Biophysical and Bioanalytical Implications
Authors: Kiy Mehmet Murat , Jacobi Zachary E. , Liu Juewen
Published: December 2011

Metal induced nucleic acid folding has been extensively studied with ribozymes, DNAzymes, tRNA and riboswitches. These RNA/DNA molecules usually have a high content of double‐stranded regions to support a rigid scaffold. On the other hand, such rigid structural features are not available for many in vitro selected or rationally designed DNA aptamers; they adopt flexible random coil structures in the absence of target molecules. Upon target binding, these aptamers adaptively fold into a compact structure with a reduced end‐to‐end distance, making fluorescence resonance energy transfer (FRET) a popular signaling mechanism. However, nonspecific folding induced by mono‐ or divalent metal ions can also reduce the end‐to‐end distance and thus lead to false positive results. In this study we used a FRET pair labeled HgII binding DNA and monitored metal‐induced folding in the presence of various cations. While nonspecific electrostatically mediated folding can be very significant, at each tested salt condition, HgII induced folding was still observed with a similar sensitivity. We also studied the biophysical meaning of the acceptor/donor fluorescence ratio that allowed us to explain the experimental observations. Potential solutions for this ionic strength problem have been discussed. For example, probes designed to signal the formation of double‐stranded DNA showed a lower dependency on ionic strength.
Effects of a Hydroxyl Substituent on the Reactivity of the 2,4,6‐Tridehydropyridinium Cation, an Aromatic σ,σ,σ‐Triradical
Authors: Jankiewicz Bartłomiej J. , Vinueza Nelson R. , Reece Jennifer N. , Lee Young C. , Williams Peggy , Nash John J. , Kenttämaa Hilkka I.
Published: December 2011

The reactivity of 3‐hydroxy‐2,4,6‐tridehydropyridinium cation was found to be drastically different from the reactivity of 2,4,6‐tridehydropyridinium cation. While the latter triradical reacts with tetrahydrofuran, dimethyl disulfide and ally iodide via three consecutive atom or group abstractions, the former triradical exhibits this behavior only with tetrahydrofuran. Only a single atom or group abstraction was observed for the 3‐hydroxy‐2,4,6‐tridehydropyridinium cation upon interaction with dimethyl disulfide and allyl iodide. This change in reactivity is caused by the hydroxyl group that strengthens the interactions between the two radical sites adjacent to it, thus reducing their reactivity. This explanation is supported by the observation of similar behavior for related biradicals.
Enantiomeric resolution of p‐toluenesulfonate of valine benzyl ester by preferential crystallizaion
Authors: Munegumi Toratane , Wakatsuki Aiko , Takahashi Yutaro
Published: December 2011

Preferential crystallization of amino acid derivatives by seeding a pure enantiomer into racemic amino acid solutions has been studied for many years. However, few examples of valine derivatives have been reported so far. Although there have been some reports using valine hydrogen chloride with preferential crystallization, it is difficult to obtain optical isomers for valine derivatives using preferential crystallization. In this study, repeated preferential crystallization of p‐toluenesulfonate valine benzyl ester with a 20% e.e. in 2‐propanol gave a 94% e.e. on sonication. Sonication accelerated crystallization rate, but there was not a big difference in e.e. between with and without sonication. However, this research demonstrates the first preferential crystallization of p‐toluenesulfonate of valine benzyl esters with an acceleration of crystallization using sonication. Chirality, 2012. © 2011 Wiley Periodicals, Inc.
Quality of life of patients after salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma
Authors: Chan Yu Wai , Chow Velda Ling Yu , Wei William Ignace
Published: December 2011

BACKGROUND:

The objective of this study was to examine the quality of life (QOL) of patients who underwent salvage nasopharyngectomy for residual or recurrent nasopharyngeal carcinoma and to justify the value of the procedure.

METHODS:

A self‐reported, health‐related QOL questionnaire was used to assess the QOL of patients after salvage nasopharyngectomy. The effects of potential complications after surgery also were evaluated.

RESULTS:

Between 2003 and 2011, 185 patients underwent salvage nasopharyngectomy using the maxillary swing approach. Curative resection was achieved in 80% of patients. There were no significant changes in mean global health system scores after surgery, except after palliative resection requiring postoperative adjuvant chemoradiation. Social functioning scores were the lowest of the 5 functioning scales in all patient groups. Palatal fistula significantly affected social eating and weight loss, and osteoradionecrosis caused more pain and nasal discharge, severely affecting the social life of patients.

CONCLUSIONS:

The QOL of patients after maxillary swing salvage nasopharyngectomy was good. The current results indicated that attention must be paid to the factors that adversely affect QOL after surgery, such as palliative resection, and complications like trismus, palatal fistula and osteoradionecrosis. Cancer 2012. © 2011 American Cancer Society.
Statin use and fatal prostate cancer
Authors: Marcella Stephen W. , David Alice , Ohman‐Strickland Pamela A. , Carson Jeffery , Rhoads George G.
Published: December 2011

BACKGROUND:

Statins are some of the most commonly prescribed medications in medical practice, and prostate cancer is the most common malignancy among men. Although there has been no consistent evidence that statins affect cancer incidence, including prostate cancer, several reports suggest they may decrease the rate of advanced prostate cancer. However, no study to date has specifically examined statin use and prostate cancer mortality. The authors conducted this population‐based case‐control investigation to examine this association.

METHODS:

This was a matched case‐control study. Cases were residents of New Jersey ages 55 to 79 years who died from prostate cancer between 1997 and 2000. The cases were matched individually to population‐based controls by 5‐year age group and race. Medication data were obtained identically for cases and controls from blinded medical chart review. Conditional logistic regression was used to adjust for confounders.

RESULTS:

In total, 718 cases were identified, and cooperation was obtained from 77% of their spouses (N = 553). After a review of medical records, 387 men were eligible, and 380 were matched to a control. The unadjusted odds ratio was 0.49 (95% confidence interval, 0.34‐0.70) and decreased to 0.37 (P < .0001) after adjusting for education, waist size, body mass index, comorbidities, and antihypertensive medication. There was little difference between lipophilic and hydrophilic statins, but more risk reduction was noted for high‐potency statins (73%; P < .0001) compared with low‐potency statins (31%; P = .32).

CONCLUSIONS:

Statin use was associated with substantial protection against prostate cancer death, adding to the epidemiologic evidence for an inhibitory effect on prostate cancer. Cancer 2012. © 2011 American Cancer Society.