bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survey of radiation belt energetic electron pitch angle distributions based on the Van Allen Probes MagEIS measurements
Authors: Shi Run , Summers Danny , Ni Binbin , Fennell Joseph F. , Blake J. Bernard , Spence Harlan E. , Reeves Geoffrey D. 
Published: December 2015

AbstractA statistical survey of electron pitch angle distributions (PADs) is performed based on the pitch angle‐resolved flux observations from the Magnetic Electron Ion Spectrometer (MagEIS) instrument on board the Van Allen Probes during the period from 1 October 2012 to 1 May 2015. By fitting the measured PADs to a sinnα form, where α is the local pitch angle and n is the power law index, we investigate the dependence of PADs on electron kinetic energy, magnetic local time (MLT), the geomagnetic Kp index, and L shell. The difference in electron PADs between the inner and outer belt is distinct. In the outer belt, the common averaged n values are less than 1.5, except for large values of the Kp index and high electron energies. The averaged n values vary considerably with MLT, with a peak in the afternoon sector and an increase with increasing L shell. In the inner belt, the averaged n values are much larger, with a common value greater than 2. The PADs show a slight dependence on MLT, with a weak maximum at noon. A distinct region with steep PADs lies in the outer edge of the inner belt where the electron flux is relatively low. The distance between the inner and outer belt and the intensity of the geomagnetic activity together determine the variation of PADs in the inner belt. Besides being dependent on electron energy, magnetic activity, and L shell, the results show a clear dependence on MLT, with higher n values on the dayside.
Ion heating by Alfvén waves associated with dipolarization in the magnetotail: Two‐dimensional global hybrid simulation
Authors: Guo Zhifang , Wu Mingyu , Du Aimin 
Published: December 2015

AbstractIn this paper, ion heating by Alfvén waves associated with dipolarization in the near‐Earth magnetotail is investigated by performing a two‐dimensional (2‐D) global‐scale hybrid simulation. In our simulation, the earthward propagating plasma flow is initialized by the E × B drift near the equatorial plane due to the existence of the dawn‐dusk convection electric field. When the earthward flow reaches the strong dipole field region, it is braked by the geomagnetic field and simultaneously leads to the pileup of the magnetic flux. This continuous pileup finally results in the formation of the large‐scale dipolarization. Dipolarization first appears around (x, z) = (−10.5, 0.3)RE (where RE is the radius of Earth) and subsequently spreads tailward. In the dipolarization region, Alfvén waves are excited and cause the scattering and heating of ions. The heating is mainly on the perpendicular direction. Therefore, the ion temperature anisotropy can be formed in the dipolarization region. Our work provides one possible mechanism for the ion heating and anisotropic distributions observed near the dipolarization region.
Rising and falling diapirs, shifting depocenters, and flap overturning in the Cretaceous Sopeira and Sant Gervàs subbasins (Ribagorça Basin, southern Pyrenees)
Authors: Saura Eduard , Ardèvol i Oró Lluís , Teixell Antonio , Vergés Jaume 
Published: December 2015

AbstractThe halokinetic structure of inverted salt‐related continental margins is frequently obliterated by compressional overprinting. The Cretaceous Sopeira and Sant Gervàs subbasins of the Ribagorça Basin (south central Pyrenees) show evidence of salt‐related extensional tectonics and diapiric growth along the Iberian Margin of the Mesozoic Pyrenean rift. We present an integrated field‐based tectonic‐sedimentary study to reconstruct the evolution of the Ribagorça Basin system previous to, and in the early stages of, the Pyrenean orogeny. The ~4 km thick Albian‐Cenomanian Sopeira minibasin infill thins toward the basin borders, especially toward the eastern, N‐S trending, Llastarri salt weld. The 90° tilt to the south of the Sopeira basin bottom records the growth of the buried north dipping Sopeira listric fault from Albian to Santonian times, when it evolved as an extensional rollover associated with the Aulet salt roller. The ~3 km thick Cenomanian‐Campanian succession filling the Sant Gervàs flap displays 130° bed fanning attitude from overturned Cenomanian carbonate platform strata to upright Campanian turbidite beds. The Sant Gervàs flap development since Cenomanian times was related to the fall of a large salt pillow after the main Soperia minibasin stage. Jurassic‐Campanian diachronous subsidence is also observed in the adjacent Montiberri, Faiada, and Tamurcia depocenters. Correlation with the Pedraforca, Cotiella, and Basque‐Cantabrian Basins along the southern Pyrenees suggests that a significant segment of the Iberian side of the Pyrenean rift experienced a gravity‐driven extension from Albian to late Santonian. The Ribagorça Basin provides an excellent field analogue for presently buried salt‐related structures of extended passive margins.
Protein Engineering: Applications to Therapeutic Proteins and Antibodies
Authors: Popplewell Andrew G. 
Published: December 2015

AbstractThe development of recombinant DNA methodology and genetic engineering from the late 1970s onwards opened up a range of possibilities for making specific changes to primary protein sequences. This chapter serves as an introduction to protein engineering, briefly explaining the basic concepts and methods before exemplifying with some success stories of applications to therapeutic proteins. The examples are somewhat biased toward therapeutic antibodies, in part because of the author's own area of expertise and also because antibodies are the leading class of biological drugs. The chapter also mentions the contribution to other non‐antibody approved biologics. Fast‐acting forms include insulin lispro, engineered by point mutation of two adjacent residues of the beta chain (proline (Pro‐28) to lysine (Lys) and Lys‐29 to Pro) to de‐stabilize dimerization of the B‐subunit facilitating rapid capillary absorption of active monomer.
Therapeutic Antibodies—Protein Engineering to InfluenceADME,PK, and Efficacy
Authors: Tachibana Tatsuhiko , Haraya Kenta , Iwayanagi Yuki , Igawa Tomoyuki 
Published: December 2015

AbstractThis chapter focuses on protein engineering strategies to reduce nonspecific uptake. One of those strategies tries to reduce the isoelectric point (pI) of the antibody by protein engineering, which can be an effective way to reduce nonspecific cellular uptake as well as improve various pharmacokinetic properties of the antibody. The authors have developed a technology to reduce target‐mediated clearance by adding a pH‐dependent antigen binding property to the therapeutic antibody, thereby increasing its chances of being recycled. For antibodies targeting soluble antigens, conventional antibodies still face significant drawbacks even if their pharmacokinetic profile is in the acceptable range. In some cases, higher concentrations of the therapeutic antibody are needed due to this accumulation of antigen, which may require substantially higher dose levels. The authors have also developed a technology to reduce antigen accumulation by optimized pH‐dependent antigen binding and increased affinity to neonatal Fc receptor (FcRn) or Fcγ receptors (FcγRs).
Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins
Authors: Lin Jiunn H. , Wang Weirong 
Published: December 2015

Abstract
Therapeutic proteins can only be injected by parenteral routes, including intravenous (IV) and subcutaneous (SC) injection. It is highly desirable for therapeutic proteins to be self‐administered SC, than by IV injection, by patient themselves, thus providing convenience for patients, and improving the quality of life and treatment adherence. Bioavailability of protein drugs after SC administration is quite variable ranging from 20% to 95%. One possible source of the variation in the bioavailability of protein drugs is the difference in presystemic catabolism of proteins in the interstitial space and/or during the transport in lymphatic vessels after SC administration. This chapter provides an overview of current knowledge of the processes of protein absorption after SC administration. In addition, the underlying mechanisms that govern the SC absorption as well as the factors that influence the SC absorption will also be discussed.
Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies
Authors: Joseph Sean B. , Prabhu Saileta , Boswell C. Andrew 
Published: December 2015

Abstract

This chapter first provides an overview of the biodistribution of antibodies including biological determinants and available technologies for measurement. Antibody biodistribution is governed by various molecular and physiological factors, many of which also affect systemic pharmacokinetic (PK) exposure. The chapter then discusses the molecular (e.g., antigen binding, Fc receptor binding, and physicochemical attributes) and physiological (e.g., tissue‐specific blood flow, vascular volume, and interstitial volume) properties that govern antibody biodistribution. It also presents technical considerations for
in vivo
studies (e.g., labeling techniques, time point selection, organ harvest strategies, dosing, and euthanasia techniques) and tissue analysis (e.g., gamma counting, scintillation counting, and imaging techniques). Finally, the chapter provides helpful tips for data interpretation including calculations and units, blood correction, derivation of interstitial concentrations, confirmation of receptor occupancy, explaining unexpectedly rapid clearance, and assisting in clinical dose selection.
Immunogenicity: Its Impact onADMEof Therapeutic Biologics
Authors: Kropshofer Harald , Richter Wolfgang F. 
Published: December 2015

AbstractThe immunogenicity of therapeutic biologics is an intensively studied feature shared by almost all biologics that have been developed. This chapter addresses essentially three aspects: which factors are key in initiating and orchestrating an anti‐drug antibody (ADA) response; the impact of ADA (both neutralizing and nonneutralizing) on the absorption, distribution, and clearance of biologics, such as monoclonal antibodies (mAbs) and other protein drugs; and how to deal with ADA responses in nonclinical and clinical studies in the establishment of a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The impact of ADA on absorption, distribution, and clearance are discussed mainly based on nonclinical data. To establish a causal relationship between unexpected PK/ PD profiles and unwanted immune responses, PK/PD sampling needs to be accompanied by sampling for immunogenicity/ ADA testing and vice versa‐in both nonclinical and clinical studies.
Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies
Authors: Cao Yanguang , Jusko William J. 
Published: December 2015

Abstract

Physiologically based pharmacokinetic (PBPK) models, with integrating the structural,
in silico
, and
in vitro
physicochemical data of drugs and the physiological and anatomical features of the body, provide a realistic characterization of the systemic disposition of drugs. Therapeutic monoclonal antibodies (mAbs), as the fastest growing class of new therapeutic molecules, hold great promise for the treatment of a variety of diseases. This chapter first presents the background and history of PBPK models, and then details the principles and methods of PBPK modelling for mAbs. A number of factors should be particularly considered for antibodies in developing PBPK models: distribution space, extravasation, lymphatic distribution, and specific target binding. Then, the chapter discusses the challenges in PBPK modelling, by considering the physiological parameters, extravasation mechanisms, and FcRn function. The chapter also highlights two situations where the minimal PBPK model enacts target‐mediated drug disposition (TMDD) in either plasma or interstitial space.
Tumor Effect‐Site Pharmacokinetics: Mechanisms and Impact on Efficacy
Authors: Thurber Greg M. 
Published: December 2015

AbstractBiologics, particularly monoclonal antibodies, form a rapidly growing field of cancer therapeutics. These molecules have exquisite specificity for their targets, thereby reducing off‐target effects. However, there are inherent challenges in managing the pharmacokinetics of biologics. In this chapter, focus on how mechanisms of distribution and efficacy play out at the site of action for cancer biologics: the tumor. The chapter first describes the distribution of antibodies and other macromolecules in tumors comprising the effects of tissue physiology, drug properties, and their interaction. A brief review of fluid transport in healthy and tumor tissues is followed by mechanisms that determine antibody distribution. The chapter details how this distribution ultimately impacts efficacy. It overviews cell‐killing mechanisms leading into a discussion on how particular delivery issues impact each of these strategies.
Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier
Authors: Fricker Gert , Mahringer Anne 
Published: December 2015

AbstractThe understanding of the morphology of the blood‐brain barrier (BBB), and the molecular and cellular mechanisms that determine its function is a prerequisite for successful delivery of macromolecules to the brain. This chapter reviews present knowledge about receptors in brain capillary endothelial cells (BCECs) and delivery systems, which can be used to move biologics across the barrier and have an impact on their therapeutic efficacy. These include: transferrin receptor, insulin receptor, low density lipoprotein (LDL) receptor, and leptin receptor. A "Trojan horse" approach might be useful to deliver macromolecular drugs to the CNS, by coupling the respective drug to an endogenous substrate or an antibody versus one of the receptors in the luminal membrane of the BBB. The colloidal carriers used for brain‐directed drug delivery are mainly polymeric nanoparticles, liposomes, or solid lipid nanoparticles. The microbubble/focused ultrasound approach significantly increases the cerebral content of erythropoietin by bettering vascular permeability.
Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics
Authors: Flandre Thierry , Taplin Sarah , Jones Stewart , Lloyd Peter 
Published: December 2015

AbstractThis chapter reviews a range of molecular pathology‐based techniques that are currently used in preclinical animal studies to assist in answering specific scientific questions related to target biology (expression) and biotherapeutic distribution (including off‐target binding). It also highlights the importance of using a combination of appropriate complementary technologies rather than a single technique. The chapter describes an integrated approach that combines pharmacokinetics (PKs), target expression, concentration, receptor occupancy, pathology, immunogenicity, and other relevant information within the same study to characterize and interpret the absorption, distribution, metabolism, and excretion (ADME) profile of a biotherapeutic. This integrated approach can also serve to maximize the information generated in a single study and can limit the number of animals used. Methods used to determine the biodistribution of a therapeutic protein‐based molecule in treated animals include wholebody autoradiography (WBA) and immunohistochemistry (IHC) using either chromagen or fluorescence‐based detection methods.
Labeling and Imaging Techniques for Quantification of Therapeutic Biologics
Authors: Jang Julie K. , Canter David , Hu Peisheng , Epstein Alan L. , Khawli Leslie A. 
Published: December 2015

AbstractThis chapter discusses considerations on the choice of different labels suitable for various detection and imaging methods. It describes labeling methods of protein therapeutics in terms of direct versus indirect methods and in terms of radiohalogens (e.g., radioiodine), trivalent cation radiometals (e.g., indium, copper, and zirconium), and fluorophores. The chapter provides a guide for scientists to find the optimal combination of labeling techniques and labels suitable for pharmaceutical application. The chapter also discusses the advantages and the limitations of the labeling method. It emphasises on the use of numerous imaging techniques for assessing the pharmacokinetics (PK) and biodistribution of biologic proteins, with a focus on positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) and a brief discussion of the role of optical imaging (OI) in this application. Biodistribution studies for biologics are routinely carried out using radioactive iodine isotopes.
Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of
PK
/
PD
Assessments
Authors: Hurst Susan , Yin Donghua 
Published: December 2015

Abstract

To compare the pharmacokinetic (PK) and/or pharmacodynamic (PD) properties between a proposed biosimilar product and the originator's product, the study(s) should be designed in a way that any difference in the properties could be sensitively detected. This chapter introduces the topic of biosimilarity with a focus on nonclinical and clinical aspects that incorporate PK/PD and immunogenicity considerations including regulatory requirements and study design considerations. The determination of biosimilarity is based on a head‐to‐ head comparison of the proposed biosimilar to the biotherapeutic reference product in terms of quality, safety, and efficacy. These aspects are determined via a hierarchical stepwise process that includes analytical/ biological studies, nonclinical
in vivo
studies, and clinical studies. The regulatory environment for biosimilars is currently evolving and must be constantly monitored by the biosimilar manufacturers as they work to develop the proposed biosimilar for the global market.
Review: The Critical Role of Clinical Pharmacology in the Development of Biologics
Authors: Zhao Liang , Wang Diane , Zhao Ping , Shang Elizabeth Y. , Wang Yaning , Sinha Vikram 
Published: December 2015

Abstract
Compared with small‐molecule drugs (SMDs), the development of biologics has become one of the fastest growing areas in research and drug development owing to advancement in biotechnology sciences such as recombinant protein technology. This chapter focuses on the clinical pharmacology aspects of biologics, including their basic pharmacokinetic (PK)/pharmacodynamic (PD) characteristics, first‐in‐human dose selection, model‐based dose determination, and trial design. It also discusses monoclonal antibodies, proteins, and peptides. Compared to SMDs, biologics have unique characteristics in absorption, distribution, metabolism, and elimination, which play a role in their use as therapeutic interventions and lead to significant differences in their development. Quantitative methods, such as mechanism‐based PK, physiologically‐based PK, PK/PD, and exposure‐response models, offer great benefit for biologics development. With the advancement of new quantitative tools, drug developers and researchers can gain powerful insight into designing the most effective therapeutic regimens.
Investigating the NonclinicalADMEandPK/PDof an Antibody–Drug Conjugate: A Case Study of Ado‐Trastuzumab Emtansine (T‐DM1)
Authors: Tibbitts Jay 
Published: December 2015

AbstractAntibody‐drug conjugates (ADCs) are a growing class of anticancer agents combining the targeting ability of an antibody with the potency of a cytotoxic agent. Ado‐trastuzumab emtansine (Kadcyla®, or Trastuzumab‐DM1 (T‐DM1)) is approved for the treatment of human epidermal growth factor receptor 2+ (HER2+) metastatic breast cancer and in development for other HER2+ indications. This chapter explores the pharmacokinetic/pharmacodynamic (PK/PD) and absorption, distribution, metabolism, and excretion (ADME) strategy and data for T‐DM1. In the course of the development of T‐DM1, a substantial body of information was generated describing the ADME characteristics of the ADC. The strategy was to develop a comprehensive understanding of the behavior of T‐DM1, including its PK/PD, distribution,in vivoandex vivostability, catabolic fate, and excretion. The foundation upon which PK and ADME evaluation is built is thorough and robust bioanalytical methods capable of determining the presence of key components of the molecule of interest.
Use of
PK
/
PD
Knowledge in Guiding Bispecific Biologics Research and Development
Authors: Baumann Andreas , Prabhu Saileta , Kanodia Jitendra 
Published: December 2015

Abstract
This chapter describes the different types of bispecific formats as well as the principles used to generate them, before elaborating on the biochemical and pharmacological properties including affinity, avidity, and pharmacokinetics (PK). In addition, assay strategies to measure these compounds and the use of pharmacokinetic/pharmacodynamic (PK/PD) modeling in the design and development of these complex molecules are also covered. Next, the chapter highlights some of the key properties of bispecific antibodies (bsAbs) that may be considered or leveraged while developing these novel and complex therapeutics. The overall PK behavior of the bsAb is strongly dependent on the format. BsAbs based on immunoglobulin G (IgG) may be preferred due to the favorable PK properties (e.g., long serum half‐life) as well as the option to modulate the effector functions. Finally, it presents three case studies to highlight some of the challenges in the research and development of bsAbs.
Synthesis of B/P/N Containing Flame‐Retardant Additives and UV Curable Hybrid Coating Applications
Authors: Ocakoĝlu Melike , Şen Ferhat , Kahraman Memet Vezir 
Published: December 2015

ABSTRACTThe aim of this study is to synthesize flame‐retardant additive by using B/P/N and to investigate this additive's performance in the ultraviolet (UV) curable system. Therefore, in the first stage, borate ester (triethanolamine borate, TEAB) was synthesized by the reaction of boric acid and triethanolamine. In the second stage, phosphate salt of borate ester (triethanolamine borate polyphosphoric acid, TEAB‐PPA) was synthesized by the reaction of borate ester (TEAB), which synthesized in the first stage and PPA. Thermal stability and flammability of the samples were evaluated by thermal gravimetric analysis, differential scanning calorimetry, and limiting oxygen index. The samples were characterized with the following analyses: Fourier transform infrared, nuclear magnetic resonance, UV transmittance, gel content, water absorption capacity, and stress–strain test. Hydrophilicity of the samples was determined by the contact angle measurements. Moreover, the surface morphology of the samples was investigated by a scanning electron microscopy–energy dispersive spectrometer mapping. The obtained results prove that boron, nitrogen, and phosphorus increased the flame retardancy property of the synthesized additive and suggest desired flame retardancy using various resins and different ratio of additives.
Synthesis of (+)‐trans‐Dihydrolycoricidine by an Organocatalytic Enantioselective Friedel–Crafts Reaction
Authors: Kato Masaru , Yasui Koji , Yamanaka Masahiro , Nagasawa Kazuo 
Published: December 2015

AbstractThe amaryllidaceae alkaloid (+)‐trans‐dihydrolycoricidine (1) was synthesized by asymmetric organocatalytic Friedel–Crafts reaction of sesamol with nitro‐olefin followed by an intramolecular Henry reaction for construction of the C ring system. Construction of the B ring was achieved by a microwave‐assisted palladium‐catalyzed CO insertion reaction. Finally, regio‐ and stereoselective introduction of the third hydroxyl group (at C3) on the C ring afforded 1.