bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding and Mitigation of Underwater Sound in the Arctic
Authors: Ward John M.
Published: December 2011

Every human activity in the offshore Arctic, or anywhere offshore for that matter, emits some level of sound into the marine environment. Depending on intensity, and to some extent frequency, underwater sound can be a nuisance or even physically harmful to marine life.

The indigenous people of the Arctic Coastal Plain in Alaska depend on subsistence hunting of marine mammals for food and as an intrinsic part of their culture. Many have expressed concern that underwater sound from oil and gas industry activities may alter the behavior of these animals and make subsistence hunts more difficult or even permanently deflect the animals away from traditional hunting grounds. Understanding underwater sound and developing effective mitigation measures is important for operating in the Arctic marine environment.

This paper presents a brief discussion of underwater sound, regulations governing underwater sound from oil and gas exploration activities, practical implication of those regulations and outlines Shell's research program aimed at understanding underwater sound emitted by drilling operations offshore Alaska. Also presented are the concepts being developed to mitigate that sound. Although the research has been directed specifically at Alaska it is broadly applicable to other Arctic regions.

Introduction

Shell's objective in Alaska is to find and develop commercial hydrocarbon resources in the Chukchi and Beaufort Outer Continental Shelf. As with all Shell ventures, the company maintains high operational and social performance standards that will bring, with exploration success, economic benefits and new opportunities to communities across Alaska and the Northwest. Since returning to Alaska in 2005 Shell has embarked on an extensive field data acquisition, R&D and technology maturation effort aimed at supporting exploration and future development. This paper focuses on Shell's R&D program for mitigating underwater sound.

Every human activity in the offshore Arctic, or anywhere offshore for that matter, emits some level of sound into the marine environment. Depending on intensity, and to some extent frequency, underwater sound can be a nuisance or even physically harmful to marine life. Marine sound has been an ongoing issue for offshore oil and gas activities, primarily for seismic operations but also for construction and pipelaying activities in sensitive areas such as offshore Sakhalin Island, Russia. In seismic operations the concern is possible hearing damage to marine mammals and fish that are too close to the air gun arrays used. In Sakhalin the concern is disturbance of feeding behaviors of the endangered Western Grey Whale. In both cases industry and regulators have developed mitigating procedures to ensure minimum impact on health and behavior of marine mammal species. This paper describes efforts Shell is making to mitigate effects of marine sound from floating drilling rigs in Alaska. While the primary focus is Alaska, the results of this work is broadly applicable to other Arctic regions.
Development of Countermeasures for Bioterrorism in the United States
Authors: Levine Gregory H. , Handwerker Jeffrey L.
Published: December 2011

This chapter focuses on one element of biodefense‐the development of medical countermeasures to be used in advance of, or in response to, a bioterrorist attack. Unlike other areas of medicine, for which private market forces are generally sufficient to spur private industry to develop and market useful products, there are few market incentives to develop and market vaccines, diagnostics, and therapeutics for biodefense purposes. The majority of this chapter discusses the laws, regulations, and actions taken to date in the United States to spur the development of diagnostic, prophylactic, and therapeutic agents for biodefense.
Pain Management Market Overview
Authors: Holdcroft Anita
Published: December 2011

This chapter provides a detailed overview of the worldwide pain management arena. A structured approach to the analgesic market has been to identify the frequency and type of pain, how it is managed (e.g., mechanism‐based and evidence‐based approaches), and what combinations of therapies are used, what the unfulfilled needs are for over‐the‐counter (OTC) and prescribers, and how to improve therapeutic strategies to achieve maximum benefit for patients.
High‐Throughput Screening for Small‐Molecule Drug Discovery
Authors: Parker C. , Zhang J.‐H.
Published: December 2011

The aim of this chapter will be to review some of the high‐throughput screening (HTS) processes in current drug discovery, including assay technologies and screening strategies, the steps taken in assay development and validation, the screening process, and commonly used quality control measures. Also highlighted in this chapter are the analysis of HTS data and some of the approaches used for data mining for finding lead series. Finally, the chapter will reviews some of the emerging trends occurring in the science of biomolecular screening.
Molecular Screening for Therapeutic Agents
Authors: Damoiseaux R.
Published: December 2011

This chapter will provide an introduction to molecular screening, its underlying concepts, work flows, and novel applications as a research tool and for target discovery. Molecular screening has changed from a very specialized tool that was primarily used in drug discovery to an indispensable tool for research. The integration of genomic and chemical screening data will lead to a better understanding of disease mechanisms and enable a more efficient drug discovery process.
Antibodies for Human Diseases
Authors: Yu Guo‐Liang , Ni Jian
Published: December 2011

Many years of research have resulted in the successful examples of immunotherapies for many diseases including cancers and inflammatory diseases. These new treatments are referred to as biological therapies‐such as monoclonal antibodies and vaccine therapies. The recent technological advances in monoclonal antibody (mAb) development have caused significant investment and interest in the pharmaceutical and biotech industry. Therefore, this chapter will highlight these new advances in the biological therapy arena.
PEGylation
Authors: Dhawan Sanju , Kapoor Deepak N. , Kapil Rishi , Kumar Manoj , Bansal Ankur
Published: December 2011

PEGylation involves the masking of the surface of proteins and peptides by covalent coupling with soluble PEG. It is a method for optimizing pharmacokinetic and pharmacodynamic properties of therapeutic small drug molecules such as peptides and proteins. Thus, this chapter will focus on PEGylation as the modification of the surface properties of proteins and peptide or nonpeptide molecules via covalent attachment using a chemical modifier, PEG, either alone or in combination with other moieties. PEGylation has been exploited to increase the half life (t1/2), solubility, stability and decrease of the immunogenicity, and toxicity of enzymes, proteins, peptides, and nonpeptide molecules.
Discovery of Vaccine Adjuvants
Authors: Sharp Fiona A. , Lavelle Ed C.
Published: December 2011

The field of vaccine adjuvants is going through a “golden age” at present due in part to the developments in immunology. After almost 100 years of largely empirical developments in adjuvant research and development largely due to a poor understanding of how adjuvants work, the field is now developing on a new more rational plane. This chapter will provide a concentrated review of the parenteral routes of vaccination with a discussion of the past, present, and future achievements in this arena.
Oral Delivery of Macromolecules for the Development of Therapeutic Agents
Authors: Lee Hye J. , Choi Chanmi
Published: December 2011

This review will provide an overview of the existing approaches, the recent advances that have been made in oral delivery as related to proteins, and some future directions to consider followed by reviewing factors affecting oral protein absorption. It is likely that effective oral formulations for peptides and proteins will remain highly compound specific, but the principal concept is to preserve protein integrity before it reaches systemic circulation.
Antibiotic Development
Authors: Bettiker Robert L. , Gallagher Jason C.
Published: December 2011

Two major aspects of locating a new chemical entity (NCE) with potential antibiotic properties are (1) a source of compounds to screen and (2) the screening process itself. Pharmacokinetics and dynamics of the potential drug are two more areas of concern in antibiotic development. Although there are innumerable other steps in antibiotic development, this chapter will focus on just a few examples of these four areas.
Antimicrobial Resistance in Biofilms: A Sticky Situation
Authors: Queck Shu Yeong , Otto Michael
Published: December 2011

The increased recognition of the impact that biofilm formation has in the clinical and industrial settings has led to an explosion in the field of biofilm research over the past two decades. These studies led to the generation of several hypotheses to account for the exceptional ability of biofilm populations to resist antimicrobial killings. In this review, the various mechanisms of antimicrobial resistance will be examined with a specific emphasis on the predominant pathogens involved in biofilm‐associated infections, that is, staphylococci, Pseudomonas aeruginosa, and the fungal pathogenCandida albicans.
Drotrecogin Alfa Activated (Recombinant Human Activated ProteinC, Xigris)
Authors: Suh Byungse , Samuel Rafik
Published: December 2011

Our understanding of the immunopathophysiology of sepsis has made extraordinary progress during the past several decades, although therapeutic advances during the similar period have been extremely slow. During the past decade several clinical trials demonstrated promising results showing reduced morbidity and mortality in sepsis, although some had mixed outcomes. These trials have supported four major approaches: (1) maintenance of good tissue oxygenation by aggressive management of fluid and blood transfusion, (2) intensive insulin therapy to maintain the euglycemia, (3) low‐dose corticosteroids, and (4) treatment with human recombinant activated protein C. These options will be briefly summarized in this chapter, but we will concentrate on the epidemiology, pathophysiology, and management of sepsis with emphasis on the use of drotrecogin alfa activated (DAA) in the management of sepsis.
Cardiovascular Disease: In‐Depth Look
Authors: Norgard Nicholas B. , Abu‐Fadel Mazen S.
Published: December 2011

Heart disease is responsible for more deaths than any other disease. Recent advances in pharmacotherapy have helped to lessen the burden of heart disease but new technology is needed to maintain our progress. There are numerous potential cardiovascular therapeutic targets in various stages of development for the treatment of coronary heart disease, heart failure, and arrhythmias. The focus of this chapter will be to explore the current and novel pharmacological therapies in development for the treatment of cardiovascular diseases.
Ezetimibe and Cholesterol Absorption
Authors: Oswald Stefan , Siegmund Werner
Published: December 2011

This chapter will focus on the discovery and development of ezetimibe, its pharmacological and pharmacokinetic properties, as well as its therapeutic implications. Furthermore, the molecular mechanisms of cholesterol absorption, whose understanding was completely revolutionized by ezetimibe‐associated research, and novel therapeutic approaches affecting this promising pharmacological mechanism will be highlighted.
Cardiology—In‐Depth Look: Kinases as Therapeutic Targets in the Heart
Authors: Mauer Karin , Exaire J. Emilio
Published: December 2011

Agents that target protein kinases have been used successfully in oncology, and several have been tested in cardiology with mixed results, suggesting that in the future selective protein kinase inhibitors may be used to treat cardiovascular disease. As this chapter will discuss, protein kinases are unraveling a new and exciting area of knowledge in cardiovascular disease. Developing new agents that selectively and safely inhibit protein kinases may provide a new therapeutic line of agents that may be used in ischemic heart disease, congestive heart failure, pulmonary and systemic hypertension, and arrhythmias.
Gastrointestinal Disorders: A Focus on Acid‐Suppressive Agents
Authors: Hemstreet Brian
Published: December 2011

Acid‐related disorders are prevalent in many countries. Research over the last century into the physiology of gastric acid secretion has yielded valuable insight into pathophysiology of many of these disorders. The discovery that histamine, gastrin, and acetylcholine all effect the production of gastric acid paved the way for the development of the H2RAs and PPIs. These agents have subsequently revolutionized the treatment of many acid‐related disorders in clinical practice.
New Drugs and Nutraceuticals in the Treatment of Osteoarthritis
Authors: Henrotin Y. , Reginster J.‐Y.
Published: December 2011

Osteoarthritis is a disease with a multifactorial etiology affecting all joint tissues and involving both biochemical and mechanical factors that act in synergy to degrade cartilage. Until now, OA treatments are limited to pain relief, even if some new drugs of the SYSADOA class have shown potential structure‐modifying effects. These drugs target cartilage as the endpoint of joint failure, underestimating the role played by subchondral bone and synovium in this process. However, recent studies emphasized the key role played by subchondral bone sclerosis and synovium inflammation in OA pathophysiology. Unfortunately, until now, there is no validated method for a reliable assessment of structural changes in these tissues, explaining that guidance documents edited by the official agencies and scientific societies are strictly focused on the assessment of cartilage changes.
Development of Anticytokine Agents for Rheumatoid Arthritis
Authors: Sherlock Jonathan , Buckley Christopher D. , Raza Karim
Published: December 2011

In this chapter, we will focus on cytokine‐based therapeutics. Not only are developments in the identification and targeting of cytokines vital, but the detailed pharmacology of the therapeutics themselves is of critical importance. The proof of concept demonstrated by the success of anti‐ tumor necrosis factor (TNF) agents, combined with the experimental ease with which cytokines can be investigated and manipulated, has opened the future of rheumatology to exciting new conceptual and therapeutic prospects.
Overview ofCNSNeuropharmaceuticals
Authors: Roxana‐Georgiana Tauser , Dan‐Stefan Antohe
Published: December 2011

The advances in the molecular neurosciences during “the decade of the brain” in conjunction with new genomic and proteomic sciences have radically changed the paradigm of central nervous system (CNS) drug design and development. The classical, chemistry‐based small‐molecule drug discovery has been broadened by the twenty‐first century biology‐driven paradigm of large‐molecule neuropharmaceuticals: peptides, recombinant proteins, monoclonal antibodies, antisense oligonucleotides, and gene therapy. As this chapter will discuss, however, despite this progress in the field of neuroproteomics and rational drug design strategies, there is still a high failure rate of the candidates in later stages of projects and consequently an unsatisfied demand for novel neurotherapeutic and neurodiagnostic medicines. Therefore, CNS drug discovery and CNS drug targeting must be merged early in the CNS drug development process in order to obtain neuropharmaceuticals active in the brain following systemic administration.
Thinking Outside the Box in Alzheimer Disease Treatment
Authors: Castellani Rudy J. , Marlatt Michael W. , Nunomura Akihiko , Moreira Paula I. , Lee Hyoung‐Gon , Casadesus Gemma , Zhu Xiongwei , Perry George , Smith Mark A.
Published: December 2011

Sporadic Alzheimer disease (AD) is a complex process that develops over decades and involves biochemical dysfunction in multiple arenas. While amyloid‐β and phosphorylated tau are attractive targets for therapy, both accumulate as late phenomena in the disease process, particularly in sporadic disease. The lack of specificity of plaques and tangles for AD, particularly in early and intermediate stages of the disease, and with advanced age, highlight the need to look beyond amyloid‐β and tau for early pathogenic factors and treatment. Moreover, as this chapter will discuss, the strides that have been made in lipid metabolism with statins, and in neuroprotection from anti‐infl ammatory treatment, as well as antiexcitotoxic and cholinergic treatment, emphasize the point that AD is complex and that any one strategy or construct may not be sufficient.
Aromatase Inhibitors for Breast Cancer
Authors: Hossain Akm , Abraham Jame
Published: December 2011

The continued evolution of endocrine therapy has contributed to many therapeutic options for patients with breast cancer. In 1998, Oxford overview demonstrated that the selective estrogen receptor modulator (SERM) tamoxifen (TM) was equally effective in pre ‐ and postmenopausal breast cancer patients. As this chapter will discuss, the development of aromatase inhibitors (AIs) added a new option in addition to SERMs for the treatment of breast cancer.
Evolution of Selective Estrogen and Androgen Receptor Modulators: Status of Current Therapy and New Drug Development
Authors: Wurz Gregory T. , DeGregorio Michael W.
Published: December 2011

Prior to the discovery of nonsteroidal selective estrogen and androgen receptor modulators (SERMs and SARMs), the only available treatment modalities for conditions such as menopausal symptoms and postmenopausal osteoporosis in women, and the symptoms associated with hypogonadism in men, were steroid based. As this chapter will discuss, recent clinical trial data have shown that the long‐term use of hormone replacement therapy in postmenopausal women is associated with an increased risk of breast cancer and may increase the risk of coronary heart disease and dementia, contrary to the results of previous observational studies. There are also concerns that androgen replacement therapy in hypogonadal men may pose a risk to prostate health, in addition to the difficulties inherent with the delivery of steroidal androgens. Thus, there is now great interest in developing nonsteroidal, orally bioavailable therapies, that is, SERMs and SARMs, that can provide the respective benefits of estrogens and androgens while minimizing their associated side effects.
Development of Therapeutic Agents: The Maternal–Fetal Perspective
Authors: Gedeon C. , Bournissen F. Garcia , Koren G.
Published: December 2011

Our objective in this chapter will be to present the state of relevant research and to stimulate interest in research efforts aimed at developing selective drugs for use in pregnancy. The hope is to explore therapeutic strategies that can either reduce unnecessary fetal exposure to drugs required by the mother or, in some instances, reduce maternal exposure to drugs destined for fetal treatment.
History of Antipsychotic Drug Development
Authors: Gollapudi Shankar S. , Radhakrishnan Rajan
Published: December 2011

Currently, there are several classes of antipsychotic drugs available to psychiatrists to treat schizophrenia. Recent studies have shown that taking antipsychotic medications consistently is crucial and necessary to manage the symptoms and to control the risks of relapse. This chapter will review the history of antipsychotics starting with the birth of typical antipsychotics developed over a half century ago, the current newer safer atypical agents for treatment of schizophrenia, and novel emerging therapies being developed in the new millennium.
Therapeutic Drug Development for Kidney Diseases
Authors: Rosner Mitchell H. , King Joshua , Monteleone Peter
Published: December 2011

This chapter will explore drug development across the spectrum of kidney disease. This ranges from acute kidney injury (AKI) to specific causes of chronic kidney disease (CKD) such as polycystic kidney disease. Drugs to effectively manage the complications of CKD are also discussed. Finally, in each section, common obstacles to drug development for this disease state are discussed.
Development of Therapeutic Agents: Methods and Approaches in the Development of Vaccines Against Protozoan Parasites
Authors: Ivory Catherine , Chadee Kris
Published: December 2011

Parasitic infections make up a large percent of diseases in tropical countries and pose a significant threat to human health worldwide. Parasites are complex pathogens associated with chronic disease, high reinfection rates, and host immune depression. Furthermore, parasitic infections, unlike most viral and bacterial infections, are more complex and chronic, requiring special consideration when developing therapeutic agents. As this chapter will discuss, designing strategies against parasitic infections demands that scientists address the multifactorial aspects of special pathogens. The challenge in developing therapeutic agents against parasites lies in the nature of the parasites and their close relationship with both human immunity and anthropogenic activities.
Toxicology
Authors: Duffus John H.
Published: December 2011

The main objective of toxicology is to prevent harmful effects of useful substances, including therapeutic agents. For new pharmaceutical agents, extensive toxicity and efficacy data are required, including data from volunteer studies in humans. Pharmaceutical agents, at appropriate dose levels, are expected to have a beneficial effect on patients. Other substances, in normal use, whatever their beneficial effects, should have no biological effects on people. This includes pesticides, which, when used as intended, should produce a biological effect in pests without any effect on humans. This chapter on toxicology will provide a basic overview of the current state of toxicological research.
Development of Phosphodiesterase 4 Inhibitors for Allergic and Nonallergic Inflammatory Diseases of the Airways
Authors: Giembycz Mark A.
Published: December 2011

The decision by the pharmaceutical industry to develop second‐generation PDE4 inhibitors for the treatment of allergic and nonallergic inflammatory diseases of the airways is based on a conceptually robust hypothesis that is supported by a wealth of preclinical data. Therefore, if shown to be potentially disease modifying in clinical trials, PDE4 inhibitors will offer physicians a novel class of drug to treat patients with inflammation that may be refractory to other drugs such as glucocorticoids. That said, as this chapter will discuss, further major refinements in the design and/or use of PDE4 inhibitors are still necessary to improve their therapeutic ratio if major clinical benefit is to be achieved.
In Situ Fully Light‐Driven Switching of Superhydrophobic Adhesion
Authors: Li Chao , Zhang Yuanyuan , Ju Jie , Cheng Futao , Liu Mingjie , Jiang Lei , Yu Yanlei
Published: December 2011

An in situ fully light‐driven switching of superhydrophobic adhesion is demonstrated based on simply spin‐coating a hydrophobic azo‐polymer on an optimized micro‐nanopost arrayed silicon substrate. Furthermore, the detailed designing principles are discussed, which might shed light on efficient exploitation of superhydrophobic liquid/solid interfaces for smart microfluidic control.
Losartan, a therapeutic candidate in congenital muscular dystrophy: Studies in the dy2J/dy2J Mouse
Authors: Elbaz Moran , Yanay Nurit , Aga‐Mizrachi Shlomit , Brunschwig Zivia , Kassis Ibaa , Ettinger Keren , Barak Vivian , Nevo Yoram
Published: December 2011

Objective:

Lamininα2‐deficient congenital muscular dystrophy type 1A (MDC1A) is a cureless disease associated with severe disability and shortened lifespan. Previous studies have shown reduced fibrosis and restored skeletal muscle remodeling following treatment with losartan, an angiotensin II type I receptor blocker. We therefore evaluated the effect of losartan treatment in the dy2J/dy2J mouse model of MDC1A.

Methods:

Homozygous dy2J/dy2J and control mice were treated with losartan or placebo for 12 weeks from 6 weeks of age. Outcome measures included hindlimb and forelimb muscle strength by Grip Strength Meter and quantitative muscle fibrosis parameters. Losartan's effects on transforming growth factor β (TGF‐β) and mitogen‐activated protein kinase (MAPK) signaling pathways were evaluated with Western blotting, immunofluorescence, and cytokine measurements.

Results:

Losartan treatment was associated with significant impressive improvement in muscle strength and amelioration of fibrosis. Administration of losartan inhibited TGF‐β signaling pathway, resulting in decreased serum TGF‐β1 level and reduced downstream phosphorylated (P) Smad2/3 proteins. Moreover, losartan activated Smad7 protein, a key negative regulator of TGF‐β signaling. In addition, losartan treatment inhibited the MAPK cascade as shown by decreased expression of P‐p38 MAPK, P‐c‐jun‐N‐terminal kinase, and P‐extracellular signal‐regulated kinases 1 and 2 in the treated mice.

Interpretation:

Losartan, a commonly prescribed US Food and Drug Administration‐approved medication for hypertension, demonstrated clinical improvement and amelioration of fibrosis in the dy2J/dy2J mouse model of MDC1A via TGF‐β and MAPK signaling pathways. The results of this study support pursuing a clinical trial of losartan treatment in children with MDC1A. ANN NEUROL 2012;
The effect of monomer structures on photopolymerization kinetics and volume shrinkage behavior for plasma display panel barrier rib
Authors: Zhang Wei , Dong HuaNan , Zhang Tao , Guo JinBao , Wei Jie
Published: December 2011

Barrier rib manufactured by the photosensitive paste is the function structure of plasma display panels (PDPs) which is used to maintain the discharge space between two glass plates. As the most promising option for barrier rib preparation, the photosensitive paste contains binder polymer, monomers, photoinitiator, and barrier rib powder etc., all of which influenced the performance of barrier rib. Among all these components, monomers play a very important role in the formation process and resolution of barrier rib during of these components. In this work, double‐bond conversion, curing speed, content, volume shrinkage, and the best mixed proportion of monomers were investigated by Fourier transform infrared spectroscopy, density measurements, analog computation and orthogonal test. It was found that the high aspect ratio barrier rib could be produced based on the optimizing additives of components in the photosensitive paste. The height of barrier rib of about 220 μm could further decline the energy consumption of PDP effectively. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Preparation and properties of polydimethylsiloxane (PDMS)/polytetramethyleneadipate glycol (PTAd)‐based waterborne polyurethane adhesives: Effect of PDMS molecular weight and content
Authors: Rahman Mohammad Mizanur , Hasneen Aleya , Kim Han‐Do , Lee Won Ki
Published: December 2011

Waterborne polyurethane (WBPU) dispersions were prepared by pre‐polymer process using siloxane polyol, namely polydimethylsiloxane (PDMS), and polyester polyol, namely poly(tetramethyleneadipate glycol) (PTAd), as a soft segment. Three different molecular weights (Mn = 550, 6000, 110,000) of PDMS and one fixed molecular weight of PTAd (Mn = 2000) was used during preparation of WBPU dispersions. This research aims to explore the potential use of PDMS in complementing WBPU by boosting flexibility, water resistance, and adhesive strength. The water swelling (%), tensile strength, and adhesive strength of WBPUs were investigated with respect to PDMS molecular weight and PDMS content (PDMS mol %). The water swelling (%) and tensile strength decreased with increasing PDMS molecular weight at a fixed PDMS content (mol %) in mixed polyol of WBPU films. By contrast, the peel adhesive strength peaked at 6.64 mol % and 4.43 mol % with molecular weight of PDMS at 550 and 6000, respectively, while it only decreased when the molecular weight of PDMS stood at 110,000. The adhesive strength was almost unaffected with optimum content (6.64 mol %) of lower PDMS molecular weight (Mn = 550) in mixed polyol‐based WBPU after immersing the adhesive bonded nylon fabrics in water for 48 h among all of the samples. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012
Nickel‐Catalyzed Cyclization of ortho‐Iodoketoximes and ortho‐Iodoketimines with Alkynes: Synthesis of Highly Substituted Isoquinolines and Isoquinolinium Salts
Authors: Shih Wei‐Chun , Teng Chu‐Chun , Parthasarathy Kanniyappan , Cheng Chien‐Hong
Published: December 2011

A convenient method for the synthesis of highly substituted isoquinolines and isoquinolinium salts by the nickel‐catalyzed cyclization of ortho‐haloketoximes and ‐ketimines, respectively, with alkynes is described. The reaction of ortho‐haloketoximes and various alkynes in the presence of [Ni(PPh3)2Br2] and zinc powder in a mixture of acetonitrile and tetrahydrofuran at 80 °C for 15 hours gave 1,3,4‐trisubstituted isoquinoline products in moderate to excellent yields and high regioselectivity. The corresponding isoquinoline N‐oxide was found to be the intermediate in the cyclization reaction pathway. In contrast, the reaction of ortho‐haloketimines and alkynes under similar catalytic conditions in tetrahydrofuran at 70 °C for two hours gave 1,2,3,4‐tetrasubstituted isoquinolinium salts in good to excellent yields.
Rationally selected single‐site mutants of the Thermoascus aurantiacus endoglucanase increase hydrolytic activity on cellulosic substrates
Authors: Srikrishnan Sneha , Randall Arlo , Baldi Pierre , Da Silva Nancy A.
Published: December 2011

Variants of the Thermoascus aurantiacus Eg1 enzyme with higher catalytic efficiency than wild‐type were obtained via site‐directed mutagenesis. Using a rational mutagenesis approach based on structural bioinformatics and evolutionary analysis, two positions (F16S and Y95F) were identified as priority sites for mutagenesis. The mutant and parent enzymes were expressed and secreted from Pichia pastoris and the single site mutants F16S and Y95F showed 1.7‐ and 4.0‐fold increases in kcat and 1.5‐ and 2.5‐fold improvements in hydrolytic activity on cellulosic substrates, respectively, while maintaining thermostability. Similar to the parent enzyme, the two variants were active between pH 4.0 and 8.0 and showed optimal activity at temperature 70°C at pH 5.0. The purified enzymes were active at 50°C for over 12 h and retained at least 80% of initial activity for 2 h at 70°C. In contrast to the improved hydrolysis seen with the single mutation enzymes, no improvement was observed with a third variant carrying a combination of both mutations, which instead showed a 60% reduction in catalytic efficiency. This work further demonstrates that non‐catalytic amino acid residues can be engineered to enhance catalytic efficiency in pretreatment enzymes of interest. Biotechnol. Bioeng. 2012; 109:1595–1599. © 2011 Wiley Periodicals, Inc.
The historical evolution of the understanding of the submandibular and sublingual salivary glands
Authors: Lydiatt Daniel D. , Bucher Gregory S.
Published: December 2011

The discovery of the major salivary glands was primarily a story of the establishment of the glands major excretory ducts. Occurring during the Renaissance: religious, political, and philosophical considerations played a role in defining the structure's function. We describe the history and background of these political, religious, and philosophical factors. Next, we present a translation of the original texts, describing the establishment of the submandibular and sublingual salivary glands. We place these translations into historical context and comment on their naming propriety. Initially we translate the works of the 15th century anatomists. Next, we look at the discovery and description of the submandibular gland's duct by Thomas Wharton (1614–1673) in his landmark book, Adenographia sive glandularum totius corporis descriptio (Adenographia or the description of the glands of the entire body) (1656). Next, the somewhat unexpected discovery of the duct of the parotid gland by Nicholas Stenson (1638–1686) and his publication, De glandulis oris et novis earundum vasis (On the glands of the mouth and their new ducts) (1661), done primarily for his discussion of the submandibular and sublingual gland anatomy. Finally we outline the description and discussion by Caspar Bartholin (1655–1738), in De ductu salivali, hactenus non descripto observatio anatomica (Anatomical observation of a salivary duct not hitherto described) (1685) of the origin of the complex drainage system of the sublingual gland. The honor of naming these glands rested with the discoverer of their ducts. All original works were published in Latin, and we have translated these texts to more fully understand the author's perspectives and historical context for a more interesting and complete story. Clin. Anat. 25:2–11, 2012. © 2011 Wiley Periodicals, Inc.
Cancer care challenges in developing countries
Authors: Price Adi J. , Ndom Paul , Atenguena Etienne , Mambou Nouemssi Jean Pierre , Ryder Robert W.
Published: December 2011

BACKGROUND:

Health systems in Sub‐Saharan Africa are not prepared for the rapid rise in cancer rates projected in the region over the next decades. More must be understood about the current state of cancer care in this region to target improvement efforts. Yaounde General Hospital (YGH) currently is the only site in Cameroon (population: 18.8 million) where adults can receive chemotherapy from trained medical oncologists. The experiences of patients at this facility represent a useful paradigm for describing cancer care in this region.

METHODS:

In July and August 2010, our multidisciplinary team conducted closed‐end interviews with 79 consecutive patients who had confirmed breast cancer, Kaposi sarcoma, or lymphoma.

RESULTS:

Thirty‐five percent of patients waited >6 months to speak to a health care provider after the first sign of their cancer. The delay between first consultation with a health care provider and receipt of a cancer diagnosis was >3 months for 47% of patients. The total delay from the first sign of cancer to receipt of the correct diagnosis was >6 months for 63% of patients. Twenty‐three percent of patients traveled for >7 hours to reach YGH, and 40% of patients interviewed spent >$200 on a single round of chemotherapy.

CONCLUSIONS:

Cancer patients experienced numerous geographic and health care system challenges, resulting in significant delays in receiving diagnosis and treatment, even for cancers highly amenable to early intervention. This unacceptable and unethical situation is likely explained by limited knowledge about cancer among patients and health care professionals, government neglect, poverty, and reliance on traditional healers. Cancer 2012;3627–3635. © 2011 American Cancer Society.
Improving prognosis of glioblastoma in the 21st century: Who has benefited most?
Authors: Lawrence Yaacov Richard , Mishra Mark V. , Werner‐Wasik Maria , Andrews David W. , Showalter Timothy N. , Glass Jon , Shen Xinglei , Symon Zvi , Dicker Adam P.
Published: December 2011

BACKGROUND:

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Temozolomide was rapidly incorporated into first‐line treatment following the publication of the pivotal European Organization for Research and Treatment of Cancer–National Cancer Institute of Canada phase 3 trial in 2005. However, in the trial, enrollment was limited to younger patients with good performance status. Therefore, this study performed a population‐based survival analysis of patients with newly diagnosed GBM covering the period before and after the introduction of temozolomide.

METHODS:

Survival statistics and clinical and demographic variables were extracted from the Survival, Epidemiology and End Results Database for patients diagnosed with GBM from 2001 to 2007. Mean regional income for each patient was also collected. Survival was analyzed using the Kaplan‐Meier method and proportional hazard models.

RESULTS:

A total of 13,003 adult patients diagnosed with a GBM were identified. Prognostic variables included age <70 years, use of radiation, gross total resection, and residence in a high‐income district (P < .001). Between 2001 and 2007, the median survival time increased from 7 to 9 months for the entire population. The 1‐year survival increased from 29% to 39%. Prognosis of patients aged 70 or more years did not improve over this time. Over the study period, the absolute disparity in 1‐year survival between low‐ and high‐income districts increased from 6.6% to 10.1%.

CONCLUSIONS:

There has been a stepwise improvement in the overall survival of patients with GBM between 2001 and 2007. This improvement has been confined to patients <70 years of age and has been most prominent among patients living in high‐income districts. Cancer 2012. © 2011 American Cancer Society.
Dynamic contrast‐enhanced magnetic resonance imaging as a prognostic factor in predicting event‐free and overall survival in pediatric patients with osteosarcoma
Authors: Guo Junyu , Reddick Wilburn E. , Glass John O. , Ji Qing , Billups Catherine A. , Wu Jianrong , Hoffer Fredric A. , Kaste Sue C. , Jenkins Jesse J. , Ortega Flores Ximena C. , Quintana Juan , Villarroel Milena , Daw Najat C.
Published: December 2011

BACKGROUND:

The objective of this study was to prospectively evaluate dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as an early imaging indicator of tumor histologic response to preoperative chemotherapy and as a possible prognostic factor for event‐free survival (EFS) and overall survival in pediatric patients with newly diagnosed, nonmetastatic osteosarcoma who were treated on a single, multi‐institutional phase 2 trial.

METHODS:

Three serial DCE‐MRI examinations at week 0 (before treatment), week 9, and week 12 (tumor resection) were performed in 69 patients with nonmetastatic osteosarcoma to monitor the response to preoperative chemotherapy. Four DCE‐MRI kinetic parameters (the influx volume transfer constant [Ktrans], the efflux rate constant [kep], the relative extravascular extracellular space [ve], and the relative vascular plasma space [vp]) and the corresponding differences (ΔKtrans, Δkep, Δve, and Δvp) of averaged kinetic parameters between the outer and inner halves of tumors were calculated to assess their associations with tumor histologic response, EFS, and overall survival.

RESULTS:

The parameters Ktrans, ve, vp, and kep decreased significantly from week 0 to week 9 and week 12. The parameters Ktrans, vp, and Δkep at week 9 were significantly different between responders and nonresponders (P = .046, P = .021, and P = .008, respectively). These 3 parameters were indicative of histologic response. The parameter Δve at week 0 was a significant prognostic factor for both EFS (P = .02) and overall survival (P = .03).

CONCLUSIONS:

DCE‐MRI was identified as a prognostic factor for EFS and overall survival before treatment on this trial and was indicative of a histologic response to neoadjuvant therapy. Further studies are needed to verify these findings with other treatment regimens and establish the potential role of DCE‐MRI in the development of risk‐adapted therapy for osteosarcoma. Cancer 2012. © 2011 American Cancer Society.
How does health literacy affect quality of life among men with newly diagnosed clinically localized prostate cancer?
Authors: Song Lixin , Mishel Merle , Bensen Jeannette T. , Chen Ronald C. , Knafl George J. , Blackard Bonny , Farnan Laura , Fontham Elizabeth , Su L. Joseph , Brennan Christine S. , Mohler James L. , Godley Paul A.
Published: December 2011

BACKGROUND:

Health literacy deficits affect half of the US overall patient population, especially the elderly, and are linked to poor health outcomes among noncancer patients. Yet little is known about how health literacy affects cancer populations. The authors examined the relation between health‐related quality of life (HRQOL) and health literacy among men with prostate cancer.

METHODS:

Data analysis included 1581 men with newly diagnosed clinically localized prostate cancer from a population‐based study, the North Carolina‐Louisiana Prostate Cancer Project (PCaP). Participants completed assessment of health literacy using Rapid Estimate of Adult Literacy in Medicine (REALM) and HRQOL using the Short Form‐12 General Health Survey (SF12). Bivariate and multivariate regression was used to determine the potential association between REALM and HRQOL, while controlling for sociodemographic and illness‐related variables.

RESULTS:

Higher health literacy level was significantly associated with better mental well‐being (SF12‐Mental Component Summary [MCS]; P < .001) and physical well‐being (SF12‐Physical Component Summary [PCS]; P < .001) in bivariate analyses. After controlling for sociodemographic (age, marital status, race, income, and education) and illness‐related factors (types of cancer treatment, tumor aggressiveness, and comorbidities), health literacy remained significantly associated with SF12‐MCS scores (P < .05) but not with SF12‐PCS scores.

CONCLUSIONS:

Among patients with newly diagnosed localized prostate cancer, those with low health literacy levels were more vulnerable to mental distress than those with higher health literacy levels, but physical well‐being was no different. These findings suggest that health literacy may be important in patients managing prostate cancer and the effects of treatment, and provide the hypothesis that supportive interventions targeting patients with lower health literacy may improve their HRQOL. Cancer 2012. © 2011 American Cancer Society.
Tuning the Release of Anticancer Drugs from Magnetic Iron Oxide/Mesoporous Silica Core/Shell Nanoparticles
Authors: Knežević Nikola Ž. , Slowing Igor I. , Lin Victor S.‐Y.
Published: December 2011

A series of core/shell, iron oxide nanoparticle embedded magnetic mesoporous silica nanoparticle materials with radial (MMSN‐r) and hexagonal (MMSN‐h) porous structures are synthesized and their capacity to load and release the anticancer drugs, 9‐aminoacridine (9AA) and camptothecin (CPT) are investigated. Although effective release of 9AA is observed for nonfunctionalized MMSN, its release from the phenylethyl‐functionalized hexagonal MMSN material (Ph‐MMSN‐h) was hindered. Conversely, the loading and release of CPT is promoted by the presence of the phenylethyl functionality inside the mesopores of MMSN, whereas very low release of CPT was observed from nonfunctionalized MMSN material. Controlled‐release properties of the drug‐loaded magnetic materials were confirmed by viability studies on Chinese hamster ovarian (CHO) cells, which revealed efficient cytotoxic activity of CPT‐loaded Ph‐MMSN‐h and 9AA‐loaded MMSN‐h materials. In addition, it was demonstrated that applying an external magnetic field to induce agitation of the drug leaded materials promoted the release of anticancer drugs from the magnetic materials. It is envisioned that the MMSN materials could be effectively applied for externally controlled, selective drug delivery to tumor tissues.
One‐Flask Tethered Ring Closing Metathesis–Electrocyclic Ring Opening for the Highly Stereoselective Synthesis of Conjugated Z/E‐Dienes
Authors: Schmidt Bernd , Kunz Oliver
Published: December 2011

A one‐flask reaction sequence comprising ring closing metathesis (RCM) of butenoates derived from allylic alcohols and a base‐mediated ring opening gives 2Z,4E‐configured dienoic acids in high yields and stereoselectivities. Application of the method to the synthesis of the natural product fusanolide A suggests that the originally published structure was erroneously assigned and should be revised.
Detection of PAX8–PPARG fusion transcripts in archival thyroid carcinoma samples by conventional RT‐PCR
Authors: Klemke Markus , Drieschner Norbert , Belge Gazanfer , Burchardt Käte , Junker Klaus , Bullerdiek Jörn
Published: December 2011

The t(2;3)(q13;p25) occurs in a subgroup of follicular‐patterned thyroid tumors and leads to a fusion of the genes encoding for the thyroid‐specific transcription factor paired box 8 (PAX8) and the peroxisome proliferator‐activated receptor gamma (PPARγ). Although initially discovered in follicular carcinomas (FTC), the fusion transcripts were also detected in a small fraction of follicular adenomas and rarely in follicular variants of papillary carcinomas (FV‐PTC). In most RT‐PCR based studies, fresh or snap‐frozen tissue samples were used. The aim of the present study was to develop a method for the detection of chimeric PAX8–PPARG transcripts in formalin‐fixed paraffin‐embedded (FFPE) thyroid tumor samples by conventional RT‐PCR. For this purpose, RNA from FFPE samples of 21 FTC, seven FV‐PTC, and one bone metastasis derived from an FTC was subjected to RT‐PCR with subsequent gel electrophoretic separation of the products. Fusion transcripts were detected in 2/21 primary FTC (9.5%) and in the bone metastasis, but they were undetectable in all seven FV‐PTC under investigation. The RT‐PCR approach described herein allows to detect all known variants of PAX8–PPARG fusion transcripts and is applicable to FFPE tissues. Thus, it can be used to screen archival thyroid tumor samples for the gene fusion. © 2011 Wiley Periodicals, Inc.
Transoral robotic biopsy of the tongue base: A novel paradigm in the evaluation of unknown primary tumors of the head and neck
Authors: Abuzeid Waleed M. , Bradford Carol R. , Divi Vasu
Published: December 2011

Background

Squamous cell carcinoma of the head and neck can present as a cervical metastasis from an unknown primary site. The standard diagnostic workup includes panendoscopy and directed biopsies but this will fail to identify a portion of unknown primary tumors.

Methods

Herein, we present a case report of a male patient with an unknown primary tumor in which the da Vinci surgical robot was used to evaluate the tongue base.

Results

Clinical evaluation, imaging, and panendoscopy with directed biopsies failed to detect the primary tumor site. Robot‐assisted biopsy of a broad area of the tongue base, incorporating submucosal tissue, identified the primary tumor with minimal postoperative morbidity.

Conclusion

Failure to localize an unknown primary tumor often results in widespread irradiation of the upper aerodigestive tract, inducing significant morbidity. Robot‐assisted biopsies of the tongue base may identify unknown primaries that would otherwise have been missed through standard directed biopsy techniques. © 2011 Wiley Periodicals, Inc. Head Neck, 2013
p16 expression as a surrogate marker for HPV‐related oropharyngeal carcinoma: A guide for interpretative relevance and consistency
Authors: El‐Naggar Adel K. , Westra William H.
Published: December 2011

Recent studies of oropharyngeal carcinoma have reported remarkable correlation between integrated human papillomavirus (HPV) viral detection and p16 protein overexpression in tumor cells. These findings led to calls for the substitution of p16 expression for the more demanding HPV testing in clinical practice. The rationale for such practice is largely driven by the simplicity, low cost, and the feasibility of the immunohistochemical (IHC) analysis. There are, however, several caveats that need to be fully considered. These include the subjective nature of IHC evaluation, the variable mechanisms of p16 expression in head and neck squamous cell carcinoma, and the lack of scoring and interpretive criteria. This perspective addresses the conceptual and practical issues associated with the p16 expression analysis and provides a broad outline for its application and evaluation in patients with oropharyngeal carcinoma. © 2011 Wiley Periodicals, Inc. Head Neck, 2012