bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging characteristics of metastatic nodes and outcomes by HPV status in head and neck cancers
Authors: Fujita Akifumi , Buch Karen , Truong Minh Tam , Qureshi Muhammad M. , Mercier Gustavo , Jalisi Scharukh , Sugimoto Hideharu , Sakai Osamu
Published: September 2015

Objectives/Hypothesis

Although several imaging characteristics of human papillomavirus (HPV)‐related head and neck squamous cell carcinoma (HNSCC) have been reported, imaging features of nodal metastasis and influence to outcomes have not been well studied thus far. The purpose of the study was to investigate the imaging characteristics of nodal metastasis by HPV status in HNSCC and to clarify whether those findings influence the outcomes.

Study Design

Retrospective review.

Methods

Computed tomography and magnetic resonance imaging for initial staging on 139 patients of HNSCC with known HPV status were retrospectively reviewed. We investigated imaging characteristics of the nodal metastasis including the presence of extracapsular spread (ECS), and also investigated the influence of nodal metastasis characteristics to outcomes by HPV status. Two‐year actuarial control and survival rates were estimated using the Kaplan‐Meier product‐limit method (P < 0.05).

Results

Eighty‐eight patients with nodal metastasis were identified and outcome information was available for 78 patients. Nodal metastasis was significantly more common in HPV‐positive patients compared to HPV‐negative patients (75% vs. 54%, P = 0.009). HPV‐positive patients showed a higher prevalence of ECS compared to HPV‐negative patients (77% vs. 56%, P = 0.041). The prevalence of disease recurrence was more common in HPV‐negative patients (67% vs. 13%, P < 0.0001), and it was independent of the presence of ECS in nodal metastasis.

Conclusions

Nodal metastases were significantly more common in HPV‐positive HNSCC, whereas the prevalence of disease recurrence was greater in HPV‐negative HNSCC. Although ECS was noted in the majority of the HPV‐positive patients with nodal metastasis, rates of recurrence were lower compared to HPV‐negative patients.

Level of Evidence

4. Laryngoscope, 126:392–398, 2016
Perceptual separation of sensorineural hearing loss and auditory neuropathy spectrum disorder
Authors: Wang Shuo , Dong Ruijuan , Liu Dongxin , Wang Yuan , Mao Yitao , Zhang Hua , Zhang Luo , Xu Li
Published: September 2015

Objectives/Hypothesis

The present study aimed to examine whether the response patterns to the chimeric lexical tone tokens, combined with their pure tone audiometry (PTA) results, could separate listeners with sensorineural hearing loss (SNHL) from listeners with auditory neuropathy spectrum disorder (ANSD).

Study Design

Case‐control study.

Methods

Forty‐three SNHL subjects and 46 ANSD subjects participated in a Mandarin lexical tone perception test using original and chimeric tone tokens. Ten sets of monosyllables, with four tone patterns for each, were processed through a 16‐channel chimeric synthesizer in which a temporal envelope (E) from a monosyllabic word of one tone was paired with a fine structure (FS) from the same monosyllable of other tones.

Results

Significantly negative correlations were present between tone perception scores and PTA0.5–4 kHz for both SNHL (P < 0.001) and ANSD (P < 0.001) subjects. Overall, 72.4%, 66.4%, and 46.3% of the tone responses were consistent with FS for the SNHL subjects with mild, moderate, and severe degree of hearing loss, respectively; and 28.4%, 23.1%, and 22.7% were consistent with FS for the ANSD subjects, with the equivalent degree of hearing loss. Similarly, 17.6%, 24.2%, and 37.7% of the tone responses were consistent with E for the SNHL subjects with mild, moderate, and severe degree of hearing loss, respectively; and 45.5%, 44.3%, and 36.5% were consistent with E for the ANSD subjects.

Conclusion

Subjects with SNHL and ANSD may be separated by representing their FS‐ and E‐consistent tone responses as a function of their pure‐tone hearing thresholds.

Level of Evidence

3b. Laryngoscope, 126:1420–1425, 2016
Vascularized tissue transfer in head and neck surgery: Is intensive care unit–based management necessary?
Authors: Panwar Aru , Smith Russell , Lydiatt Daniel , Lindau Robert , Wieland Aaron , Richards Alan , Shostrom Valerie , Militsakh Oleg , Lydiatt William
Published: September 2015

Objectives/Hypothesis

To study the impact of a non–intensive care unit (ICU)–based postoperative management strategy on patient outcomes following vascularized free tissue transfer for head and neck surgical defects.

Study Design

Retrospective cohort study.

Methods

The patients consisted of two groups of adults who underwent vascularized free tissue transfer for head and neck reconstruction between July 2007 and June 2012, at an academic and a community‐based hospital. By protocol, the first group of patients had a planned admission to the intensive care unit. After creation of a designated head and neck surgical unit, the second group was cared for in a protocol driven, non‐ICU setting. Outcomes and costs were compared between the two patient groups.

Results

There was no adverse impact on flap survival, inpatient morbidity, or mortality with the implementation of postoperative care outside of an ICU. The patients who stayed in the ICU in the immediate postoperative period had a longer median length of hospital stay (ICU vs. non‐ICU, 8 days [interquartile range {IQR} = 7–11 days] vs. 7 days [IQR = 6–9.5 days], P = .001). Median hospital charges and cost of care for patients who received ICU‐based care (US$109,367 [IQR = US$88,112–US$130,833] and US$33,642 [IQR = US$28,143–US$43,196], respectively) were significantly higher than those for non‐ICU–based care (US$86,195 [IQR = US$71,208–US$101,199] and US$28,524 [IQR = US$22,611–US$33,226], P < .0001).

Conclusions

We demonstrate that care in a non–intensive care setting following vascularized free tissue transfer is safe, less costly, and decreases length of hospital stay compared to routine intensive care–based management.

Level of Evidence

2c. Laryngoscope, 126:73–79, 2016
Headless: The Role of Gender and Self‐Referencing in Consumer Response to Cropped Pictures of Decorative Models
Authors: Berg Hanna
Published: September 2015

Product pictures with “headless” decorative models, whose heads have been cropped out of the pictures, are often used in online retailing. This article reports findings from three experiments comparing attitudes for clothing displayed in pictures with cropped and uncropped male and female models, focusing on the moderating effects of consumer and model gender and the mediating effects of product self‐referencing. Results indicate that the effects on product attitudes are moderated by the gender of both models and consumers and mediated by self‐referencing. Pictures with uncropped male models result in more positive product attitudes, irrespective of consumer gender. For product pictures with female models, male consumer attitudes are also more positive for products displayed with uncropped models. In fact, attitudes are only more positive for clothing shown with cropped, “headless” models when both models and consumers are female. Implications of the findings for research and practitioners are discussed.
Synthesis of Amphiphilic Block Copolypept(o)ides by Bifunctional Initiators: Making PeptoMicelles Redox Sensitive
Authors: Holm Regina , Klinker Kristina , Weber Benjamin , Barz Matthias
Published: September 2015

In this work, the synthesis of polypeptoid‐block‐polypeptide copolymers (block copolypept(o)ides) based on bifunctional initiators is described, which introduces a distinct chemical entity at the connection between both blocks. With a view towards redox‐sensitive block copolypept(o)ides, a cystamine‐based initiator was used to synthesize polysarcosine macroinitiators with degrees of polymerization (Xn) between 100 and 200 displaying monomodal molecular weight distributions and dispersities (Đ) around 1.1 as determined by size exclusion chromatography. Block copolypept(o)ides with a poly(γ‐t‐butyloxycarbonyl‐l‐glutamate) (PGlu(OtBu)) block (Xn = 25 or 50) were synthesized by controlled N‐carboxyanhydride polymerization. Resulting block copolymers possess monomodal molecular weight distributions, dispersities around 1.2 and were applied to degradation studies. While block copolypept(o)ides are stable at 10 × 10−6 m, they degrade over time at GSH concentrations of 10 × 10−3 and 100 × 10−3 m. Furthermore, these disulfide‐containing block copolymers form PeptoMicelles, which degrade at intracellular GSH concentrations while remaining stable at extracellular GSH levels.

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The potential roles for adipose tissue in peripheral nerve regeneration
Authors: Walocko Frances M. , Khouri Roger K. , Urbanchek Melanie G. , Levi Benjamin , Cederna Paul S.
Published: September 2015

Introduction

This review summarizes current understanding about the role of adipose‐derived tissues in peripheral nerve regeneration and discusses potential advances that would translate this approach into the clinic.

Methods

We searched PubMed for in vivo, experimental studies on the regenerative effects of adipose‐derived tissues on peripheral nerve injuries. We summarized the methods and results for the 42 experiments.

Results

Adipose‐derived tissues enhanced peripheral nerve regeneration in 86% of the experiments. Ninety‐five percent evaluated purified, cultured, or differentiated adipose tissue. These approaches have regulatory and scaling burdens, restricting clinical usage. Only one experiment tested the ability of adipose tissue to enhance nerve regeneration in conjunction with nerve autografts, the clinical gold standard.

Conclusion

Scientific studies illustrate that adipose‐derived tissues enhance regeneration of peripheral nerves. Before this approach achieves clinical acceptance, fat processing must become automated and regulatory approval achieved. Animal studies using whole fat grafts are greatly needed for clinical translation. © 2015 Wiley Periodicals, Inc. Microsurgery 36:81–88, 2016.
Developmental robustness in the Caenorhabditis elegans embryo
Authors: Maduro Morris F.
Published: September 2015

Developmental robustness is the ability of an embryo to develop normally despite many sources of variation, from differences in the environment to stochastic cell‐to‐cell differences in gene expression. The nematode Caenorhabditis elegans exhibits an additional level of robustness: Unlike most other animals, the embryonic pattern of cell divisions is nearly identical from animal to animal. The endoderm (gut) lineage is an ideal model for studying such robustness as the juvenile gut has a simple anatomy, consisting of 20 cells that are derived from a single cell, E, and the gene regulatory network that controls E specification shares features with developmental regulatory networks in many other systems, including genetic redundancy, parallel pathways, and feed‐forward loops. Early studies were initially concerned with identifying the genes in the network, whereas recent work has focused on understanding how the endoderm produces a robust developmental output in the face of many sources of variation. Genetic control exists at three levels of endoderm development: Progenitor specification, cell divisions within the developing gut, and maintenance of gut differentiation. Recent findings show that specification genes regulate all three of these aspects of gut development, and that mutant embryos can experience a “partial” specification state in which some, but not all, E descendants adopt a gut fate. Ongoing studies using newer quantitative and genome‐wide methods promise further insights into how developmental gene‐regulatory networks buffer variation. Mol. Reprod. Dev. 82: 918–931, 2015. © 2015 Wiley Periodicals, Inc.
A Knowledge Translation Programme to Increase the Utilization of Thoracic Spine Mobilization and Manipulation for Patients with Neck Pain
Authors: Karas Steve , Westerheide Angela , Daniel Laura
Published: September 2015

Background

There is extensive evidence that mobilization and manipulation of the thoracic spine is associated with improved outcomes in patients with neck pain. However, these evidence‐based techniques are not always utilized. Successful knowledge translation programmes are needed to move the best available evidence to clinical practice. The purpose of the present research was to evaluate the effects of a structured knowledge translation programme on the frequency of manual therapy techniques performed by physical therapists on patients with neck pain.

Methods

Prior to our intervention, we assessed physical therapists’ use of thoracic spine intervention for the treatment of neck pain and their knowledge of the evidence. We delivered a multimodal knowledge translation programme and then reassessed their use and knowledge of the interventions.

Results

The majority of our physical therapists increased the use of thoracic spine techniques for their patients with neck pain. The increase was greater in those who used the techniques infrequently. Overall knowledge of the evidence appeared unchanged.

Discussion

Knowledge translation programmes are essential in ensuring clinical use of evidence‐based practice. Our programme results, although on a small scale and not statistically significant, showed a positive trend toward increased thoracic spine manual therapy use for neck pain. Copyright © 2015 John Wiley & Sons, Ltd.
An Investigation into the Scale and Impact of Self‐Reported Foot Problems Associated with Systemic Lupus Erythematosus: A Study Protocol and Survey Questionnaire Development
Authors: Williams Anita Ellen , Cherry Lindsey , Blake Alison , Alcacer‐Pitarch Begonya , Edwards Christopher , Hopkinson Neil , Vital Edward , Teh Lee‐Suan
Published: September 2015

Background

Systemic lupus erythematosus (SLE) can manifest with arthralgia and myalgia, and, in severe cases, disorganization of the joints and tendon rupture. Further, Raynaud's phenomenon and other circulatory problems such as vasculitis have been reported, and may be associated with loss of sensation and ulcers. Associated with impaired peripheral neurovascular function there is the potential for changes in tissue viability leading to thinning of the skin or callus formation. In addition, resistance to infections may be reduced, such as fungal infection of the skin and nails, bacterial infection associated with wounds and viral infections such as verruca. There is a dearth of evidence for the effects of SLE in the foot, the prevalence of foot problems in SLE and the impact of these on the individual. In addition, it is not known if people with SLE and foot problems have access to specialist care through foot health services. Hence, there is a need to investigate the scale of foot problems associated with SLE. In order to achieve this, a questionnaire needs to be developed in order to carry out a national survey in England.

Methods

The items required for the questionnaire were generated using a focus group, which comprised patient advisers with SLE, consultants who specialized in SLE, specialist rheumatology podiatrists and specialist rheumatology nurses. From this consensus approach to the item generation, the draft questionnaire was developed with agreement on themes, question format and overall structure. Additionally, the Manchester Pain and Disability Questionnaire was included in order to capture levels of pain and associated disability. An iterative process followed, with feedback from the focus group reducing the number of other items from 53, until the penultimate version of questionnaire was produced with 50 items. Following on from this, a process of cognitive debriefing was used with two people with SLE who were naïve to the questionnaire. Minor changes to two questions and the layout was required before a final version of the questionnaire was produced.

Discussion

The questionnaire will be used for a study which aims to identify the frequency of patients’ self‐reported foot problems, the impact of foot problems on their lives and the status of foot care provision. This will be achieved through a survey of people with SLE across six clinical sites and interviews with some people in order to explore their experience of foot problems. The results from the present study will provide the information required to inform further research. In addition, it could potentially inform the design and delivery of foot health information and services to this patient group. Copyright © 2015 John Wiley & Sons, Ltd.
Auf den chemischen Spuren des Histon‐Codes
Authors: Flis Julia , Giessmann Robert , Schnettler Fernández David
Published: September 2015

Modifikationen an den DNA‐verpackenden Histonproteinen können festlegen, wie die DNA abgelesen wird. Neue chemische und biochemische Synthesekonzepte helfen dabei, diesen Histon‐Code zu ergründen und so die Phänomene der Epigenetik zu verstehen.
Wie Chemie vor Hautkrebs schützt
Authors: Osterath Brigitte
Published: September 2015

In weiten Teilen der Welt wächst das Bewusstsein, dass zu viel Sonnenstrahlung töten kann. Umso gefragter sind gute Sonnencremes. Bei deren Weiterentwicklung geht es auch um bessere UV‐Filter — aber etwas anderes ist inzwischen fast noch wichtiger: die Formulierung.
Naturstoffsynthese: Sequenzielle C‐H‐Funktionalisierungen
Authors: Hempel Christian , Nachtsheim Boris J.
Published: September 2015

Übergangsmetallkatalysierte C‐H‐Funktionalisierungen machen komplexe Naturstoffe aus kommerziell erhältlichen Startmaterialien zugänglich. Kürzlich gezeigte Beispiele umfassen Strukturen mit heterocyclischem Grundgerüst.
Deutschland an der Schwelle zur Bioökonomie
Authors: Kroner Wolf G.
Published: September 2015

Technische Innovationen, Energiewende und Decarbonisierungspolitik schaffen Bedarf an biobasierten Produkten. Branchenquervernetzung und Businessplattformen helfen, ihn zu befriedigen.
Geruchsmoleküle in der Innenraumluft
Authors: Buschmann Hans‐Jürgen , Brandes Jörg
Published: September 2015

Um herauszufinden, welche Substanzen Baumaterialien und Einrichtungsgegenstände in Innenräume abgeben, sind oft große Luftvolumina zu untersuchen.
Applications of Microscopy in Additive Manufacturing
Authors: Weissmayer Lisa , Schubert Tim , Bernthaler Timo , Schneider Gerhard
Published: September 2015

Additive manufacturing (also known as 3D‐printing) is a new and promising method for the production of components in tool engineering. Its layer‐by‐layer build‐up process offers a number of new production possibilities. Of special interest is the high geometric and constructive freedom. It is possible to build up near net shape components with complex geometries and integrated functional properties, such as curved cooling channels in drills. Besides microstructural defects that significantly degrade the usage properties of components, the challenges faced in additive manufacturing are: the high level of dimensional accuracy required; surface quality; and the construction of complex tools with inner structures like cooling channels. Taking the example of additively manufactured indexable insert drills with curved cooling channels, we will show the suitability of microscopic methods for evaluating the quality of components produced in this way.
Layer Thickness Determination
Authors: Houta Faiza , Quinten Michael
Published: September 2015

For determination of film thickness with a reflectometer, the incident light is usually perpendicular to the film. Often, however, measuring heads are used that keep the aperture of the optical fiber constant or even microscopes are used to increase the lateral resolution in film thickness determination. Analogous to a fixed angle of incidence α the thickness determination is influenced in both cases. In contrast to a fixed angle now all angles between 0° and the aperture angle αapt are present for a measuring head or a microscope objective. We demonstrate here, how the aperture of the measuring head affects the thickness determination and give a quantitative estimation of the influence by assigning an effective angle of incidence αeff to a measuring head with aperture angle αapt.
Thermal Imaging Ensures Aircraft Turbine Quality
Authors: Sarfels Joachim , Liebelt Frank , Brockmann Matthias , Gierlings Sascha
Published: September 2015

Highest quality standards during the manufacturing process of engine components are indispensable for secure aviation. The research conducted at the RWTH Aachen University's machine tool laboratory focuses on temperature as the primary variable in the machining process. This is a complex process due to the high speeds and relatively thin chips. These chips have a minimum thickness of 15 micrometers, and required a fast, high‐resolution thermal imaging camera equipped with a macro lens.

The thermographic studies confirm some of the common theories but have also resulted in corrections to the theoretically expected distribution of temperatures, which has in turn lead important insights, which help imtoprove quality and workmanship. The machine tool lab researchers have been able to define process conditions that ensure the highest quality and productivity at the same time.
Micro‐Optics for Photolithography
Authors: Voelkel Reinhard
Published: September 2015

Photolithography is the engine that empowered semiconductor industry to reduce the minimum feature size of the components of a microchip from some 50 microns in the 1960s to below 14 nanometers today. Diffractive and refractive micro‐optical components play a decisive role in modern photolithography systems, e. g. for laser line width narrowing, laser beam shaping (customized illumination), as phase‐shift masks (PSM), for optical proximity correction (OPC), and for diffraction‐based overlay (DBO). Wafer‐based manufacturing of high‐quality micro‐optics and their importance for photolithography will be explained.
German Photonics Industry Shows Dynamic Growth in Core Areas
Authors: Bähren Mike , Löffler Annika , Hein Gerhard , Tober Ursula
Published: September 2015

Export share continued to grow — strengths in production engineering, medical technology and optical components further underlined and extended / light market also improved, in particular LEDs
Epoxidized castor oil toughened Diglycidyl Ether of Bisphenol A epoxy nanocomposites: structure and property relationships
Authors: Paluvai Nagarjuna Reddy , Mohanty Smita , Nayak Sanjay K.
Published: September 2015

The present study highlights the structure and property relationships of epoxidized castor oil (ECO) toughened Diglycidyl Ether of Bisphenol A (DGEBA) epoxy nanocomposites. Toughened epoxy systems have been prepared by an addition of 10–40 wt% ECO to the DGEBA epoxy resin. Nanocomposites were prepared by mixing small amounts of Cloisite 30B (C30B) clay and 3‐aminopropyltriethoxysilane to the DGEBA/ECO blends. The chemical structure of toughened systems was confirmed using proton nuclear magnetic resonance and fourier transform infrared spectroscopy. The triethylenetetraamine‐cured DGEBA/ECO/C30B (8:2:0.1) nanocomposites exhibited tensile strength (50 MPa), tensile modulus (1.7 GPa), flexural strength (120 MPa), flexural modulus (3.02 GPa), and elongation (19%). The fracture toughness (critical intensity factor,KIC) and fracture energy (critical energy release rate,GIC) of DGEBA/ECO/C30B (8:2:0.1) system found to be higher than the other systems (2.5 MPa.m1/2and 1.8 kJ/m2forKICandGIC, respectively). The thermal stability and heat of reaction of DGEBA/ECO blends increase with the addition of C30B clays that were analyzed using thermogravimetric analysis and differential scanning calorimetry. Rheological characterizations of uncured samples revealed a pronounced effect of the C30B clay on the DGEBA/ECO blend systems that exhibited a shear‐thickening behavior. On the other hand, the dynamic mechanical properties also revealed that the addition of C30B clays to the DGEBA/ECO blend a significant enhancements in viscoelastic and cross linking density behavior. Scanning electron microscope analysis was used to study the fractured morphology of DGEBA, DGEBA/ECO, and its nanocomposite systems. Copyright © 2015 John Wiley & Sons, Ltd.
Enhancement of photo‐conversion efficiency in Cu2ZnSn(S,Se)4 thin‐film solar cells by control of ZnS precursor‐layer thickness
Authors: Kim Gee Yeong , Son Dae‐Ho , Thi Thu Nguyen Trang , Yoon Seokhyun , Kwon Minsu , Jeon Chan‐Wook , Kim Dae‐Hwan , Kang Jin‐Kyu , Jo William
Published: September 2015

CZTSSe thin‐film absorbers were grown by stacked ZnS/SnS/Cu sputtering with compound targets, and the precursors were annealed in a furnace with a Se atmosphere. We controlled the thickness of the ZnS precursor layer for the CZTSSe thin films in order to reduce the secondary phases and to improve the performance of the devices. The optimal value of the ZnS precursor thickness was determined for the CZTSSe absorbers, and this configuration showed an efficiency of up to 9.1%. In this study, we investigated the depth profiles of the samples in order to determine the presence of secondary phases in the CZTSSe thin films by Raman spectroscopy and Kelvin probe force microscopy. Cu2SnSe3, ZnSe, and MoSe2 secondary phases appeared near the back contact, and the work function distribution of the CZTSSe thin‐film surface and the secondary phase distribution were different depending on the depths of the absorber layer. This phase characterization allows us to describe the effects that changes in the thickness of the ZnS precursor can have on the performance of the CZTSSe thin‐film solar cells. Although it is important to identify the phases, the effects of secondary phases and point defects are not yet fully understood, even in optimal devices. Therefore, phase identification that is based on the work function and the results obtained from the Raman spectra in terms of the depth profile are instrumental to improve the surface and interface of CZTSSe thin‐film solar cells. Copyright © 2015 John Wiley & Sons, Ltd.
Matrix‐isolation IR spectroscopy of R‐(+)‐3‐methylcyclopentanone in para‐hydrogen crystal
Authors: Al‐Basheer Watheq
Published: September 2015

High‐resolution infrared (IR) spectra of R‐(+)‐3‐methylcyclopentanone (R3MCP) in para‐hydrogen (pH2) crystal were recorded and compared with the corresponding IR spectra of R3MCP in Argon (Ar) isolation matrix as well as the IR spectra of the neat crystalline R3MCP at low deposition temperature of 4 ± 0.05 K. Moreover, IR spectra of R3MCP, hosted in pH2 crystal, were recorded using a high‐resolution Fourier transform IR spectrometer as a function of sample concentration and over the range 10–300 ppm. Furthermore, density functional theory calculations of simulated IR spectra for the optimized geometries of R3MCP equatorial‐methyl and axial‐methyl conformers are compared with experimental spectra for the purpose of investigating molecular conformation. Upon comparison between theoretical and experimental IR spectra, vibrational modes arising from equatorial and axial conformers have been successfully assigned and related to the individual conformer's structure. Copyright © 2015 John Wiley & Sons, Ltd.
Triage for Patients with Spinal Complaints: A Systematic Review of the Literature
Authors: McEvoy Claire , Wiles Louise , Bernhardsson Susanne , Grimmer Karen
Published: September 2015

Background and Purpose

The aim of this study is to provide a systematic overview of the past decade of literature on processes of triage for patients with spinal pain, outcomes measured and markers of effectiveness.

Methods

A systematic search of the literature with narrative synthesis of findings was conducted. Studies in English language of any design concerning spinal triage programmes for adults with acute or chronic spinal complaints were considered for inclusion. Electronic database searches were conducted in OVID, Medline, Embase, CINAHL, Health Source Nursing, Scopus and Web of Science. Additional references were sourced through pearling reference lists, and expert input. Findings were synthesized descriptively.

Results

Of 216 potentially relevant records, 21 papers (20 studies) were included. There was little commonality in triage activities/programmes and outcomes, although physiotherapists were common members of triage programmes. Positive outcomes were reported most commonly for wait times, with several studies also reporting high levels of patient and physician satisfaction. Outcomes such as surgical conversion rates and selection accuracy were less clear.

Discussion

Spinal triage programmes have the potential to improve efficiency of care for outpatients with spinal complaints. The evidence gaps in health outcomes, service models and cost effectiveness should be addressed by more robust prospective research designs. Copyright © 2015 John Wiley & Sons, Ltd.
Template‐based protein structure prediction in CASP11 and retrospect of I‐TASSER in the last decade
Authors: Yang Jianyi , Zhang Wenxuan , He Baoji , Walker Sara Elizabeth , Zhang Hongjiu , Govindarajoo Brandon , Virtanen Jouko , Xue Zhidong , Shen Hong‐Bin , Zhang Yang
Published: September 2015

We report the structure prediction results of a new composite pipeline for template‐based modeling (TBM) in the 11th CASP experiment. Starting from multiple structure templates identified by LOMETS based meta‐threading programs, the QUARK ab initio folding program is extended to generate initial full‐length models under strong constraints from template alignments. The final atomic models are then constructed by I‐TASSER based fragment reassembly simulations, followed by the fragment‐guided molecular dynamic simulation and the MQAP‐based model selection. It was found that the inclusion of QUARK‐TBM simulations as an intermediate modeling step could help improve the quality of the I‐TASSER models for both Easy and Hard TBM targets. Overall, the average TM‐score of the first I‐TASSER model is 12% higher than that of the best LOMETS templates, with the RMSD in the same threading‐aligned regions reduced from 5.8 to 4.7 Å. Nevertheless, there are nearly 18% of TBM domains with the templates deteriorated by the structure assembly pipeline, which may be attributed to the errors of secondary structure and domain orientation predictions that propagate through and degrade the procedures of template identification and final model selections. To examine the record of progress, we made a retrospective report of the I‐TASSER pipeline in the last five CASP experiments (CASP7‐11). The data show no clear progress of the LOMETS threading programs over PSI‐BLAST; but obvious progress on structural improvement relative to threading templates was witnessed in recent CASP experiments, which is probably attributed to the integration of the extended ab initio folding simulation with the threading assembly pipeline and the introduction of atomic‐level structure refinements following the reduced modeling simulations. Proteins 2016; 84(Suppl 1):233–246. © 2015 Wiley Periodicals, Inc.
Protein structure prediction using residue‐ and fragment‐environment potentials in CASP11
Authors: Kim Hyungrae , Kihara Daisuke
Published: September 2015

An accurate scoring function that can select near‐native structure models from a pool of alternative models is key for successful protein structure prediction. For the critical assessment of techniques for protein structure prediction (CASP) 11, we have built a protocol of protein structure prediction that has novel coarse‐grained scoring functions for selecting decoys as the heart of its pipeline. The score named PRESCO (Protein Residue Environment SCOre) developed recently by our group evaluates the native‐likeness of local structural environment of residues in a structure decoy considering positions and the depth of side‐chains of spatially neighboring residues. We also introduced a helix interaction potential as an additional scoring function for selecting decoys. The best models selected by PRESCO and the helix interaction potential underwent structure refinement, which includes side‐chain modeling and relaxation with a short molecular dynamics simulation. Our protocol was successful, achieving the top rank in the free modeling category with a significant margin of the accumulated Z‐score to the subsequent groups when the top 1 models were considered. Proteins 2016; 84(Suppl 1):105–117. © 2015 Wiley Periodicals, Inc.
Sucrose prevents protein fibrillation through compaction of the tertiary structure but hardly affects the secondary structure
Authors: Estrela Nídia , Franquelim Henri G. , Lopes Carlos , Tavares Evandro , Macedo Joana A. , Christiansen Gunna , Otzen Daniel E. , Melo Eduardo P.
Published: September 2015

Amyloid fibers, implicated in a wide range of diseases, are formed when proteins misfold and stick together in long rope‐like structures. As a natural mechanism, osmolytes can be used to modulate protein aggregation pathways with no interference with other cellular functions. The osmolyte sucrose delays fibrillation of the ribosomal protein S6 leading to softer and less shaped‐defined fibrils. The molecular mechanism used by sucrose to delay S6 fibrillation was studied based on the two‐state unfolding kinetics of the secondary and tertiary structures. It was concluded that the delay in S6 fibrillation results from stabilization and compaction of the slightly expanded tertiary native structure formed under fibrillation conditions. Interestingly, this compaction extends to almost all S6 tertiary structure but hardly affects its secondary structure. The part of the S6 tertiary structure that suffered more compaction by sucrose is known to be the first part to unfold, indicating that the native S6 has entered the unfolding pathway under fibrillation conditions. Proteins 2015; 83:2039–2051. © 2015 Wiley Periodicals, Inc.
Applicability of second‐generation upcyte® human hepatocytes for use in CYP inhibition and induction studies
Authors: Ramachandran Sarada D. , Vivarès Aurélie , Klieber Sylvie , Hewitt Nicola J. , Muenst Bernhard , Heinz Stefan , Walles Heike , Braspenning Joris
Published: September 2015

Human upcyte® hepatocytes are proliferating hepatocytes that retain many characteristics of primary human hepatocytes. We conducted a comprehensive evaluation of the application of second‐generation upcyte® hepatocytes from four donors for inhibition and induction assays using a selection of reference inhibitors and inducers. CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were reproducibly inhibited in a concentration‐dependent manner and the calculated IC50 values for each compound correctly classified them as potent inhibitors. Upcyte® hepatocytes were responsive to prototypical CYP1A2, CYP2B6, CYP2C9, and CYP3A4 inducers, confirming that they have functional AhR‐, CAR‐, and PXR‐mediated CYP regulation. A panel of 11 inducers classified as potent, moderate or noninducers of CYP3A4 and CYP2B6 were tested. There was a good fit of data from upcyte® hepatocytes to three different predictive models for CYP3A4 induction, namely the Relative Induction Score (RIS), AUCu/F2, and Cmax,u/Ind50. In addition, PXR (rifampicin) and CAR‐selective (carbamazepine and phenytoin) inducers of CYP3A4 and CYP2B6 induction, respectively, were demonstrated. In conclusion, these data support the use of second‐generation upcyte® hepatocytes for CYP inhibition and induction assays. Under the culture conditions used, these cells expressed CYP activities that were equivalent to or higher than those measured in primary human hepatocyte cultures, which could be inhibited or induced by prototypical CYP inhibitors and inducers, respectively. Moreover, they can be used to predict in vivo CYP3A4 induction potential using three prediction models. Bulk availability of cells from multiple donors makes upcyte® hepatocytes suitable for DDI screening, as well as more in‐depth mechanistic investigations.
Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin‐4 genes
Authors: Mizuguchi Hiroyuki , Nariai Yuki , Kato Shuhei , Nakano Tomohiro , Kanayama Tomoyo , Kashiwada Yoshiki , Nemoto Hisao , Kawazoe Kazuyoshi , Takaishi Yoshihisa , Kitamura Yoshiaki , Takeda Noriaki , Fukui Hiroyuki
Published: September 2015

Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)‐4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin‐derived antiallergic compound and investigate its mechanism of action. The H1R and IL‐4 mRNA levels were determined by real‐time quantitative RT‐PCR. To investigate the effects of maackiain in vivo, toluene‐2,4‐diisocyanate (TDI)‐sensitized rats were used as a nasal hypersensitivity animal model. We identified (−)‐maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL‐4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (−)‐Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr311 on PKCδ, which led to the suppression of H1R gene transcription. However, (−)‐maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI‐induced upregulations of H1R and IL‐4 gene expressions in TDI‐sensitized rats. These data suggest that (−)‐maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI‐sensitized allergy model rats through the inhibition of H1R and IL‐4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation.
In silico identified targeted inhibitors of P‐glycoprotein overcome multidrug resistance in human cancer cells in culture
Authors: Follit Courtney A. , Brewer Frances K. , Wise John G. , Vogel Pia D.
Published: September 2015

Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P‐glycoprotein (P‐gp). P‐gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P‐gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P‐gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P‐gp inhibitors for use as co‐therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716–726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug‐like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P‐gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P‐gp‐mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P‐gp inhibition are excellent leads for the development of co‐therapeutics for the treatment of multidrug resistances.
FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib‐mediated cytotoxicity
Authors: Ahmed Dilruba , de Verdier Petra J. , Ryk Charlotta , Lunqe Oscar , Stål Per , Flygare Jenny
Published: September 2015

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin‐V and PI and 4′,6‐diamidino‐2‐phenylindole‐staining of nuclei. In addition, signs of both caspase‐dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly‐ADP ribose polymerase‐cleavage as well as translocation of Apoptosis‐inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3‐II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.
Randomized pharmacokinetic and drug–drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects
Authors: Das Shampa , Li Jianguo , Armstrong Jon , Learoyd Maria , Edeki Timi
Published: September 2015

We assessed pharmacokinetic and safety profiles of ceftazidime–avibactam administered ± metronidazole, and whether drug–drug interactions exist between ceftazidime and avibactam, or ceftazidime‐avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime–avibactam (2000–500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime–avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime–avibactam over 4 days to assess drug–drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime–avibactam and metronidazole in subjects receiving ceftazidime–avibactam (2000–500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime–avibactam over 4 days. In all studies, subjects received a single‐dose on the first and final days, and multiple‐doses every 8 h on intervening days. Concentration‐time profiles for ceftazidime and avibactam administered as single‐ or multiple‐doses separately or together with/without metronidazole were similar. There was no evidence of time‐dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80–125%) indicating no drug–drug interaction between ceftazidime and avibactam, or ceftazidime–avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug–drug interaction between ceftazidime and avibactam, or ceftazidime–avibactam and metronidazole.
Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules
Authors: Harrell Andrew W. , Sychterz Caroline , Ho May Y. , Weber Andrew , Valko Klara , Negash Kitaw
Published: September 2015

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution.
Clearance of systemic hematologic tumors by venetoclax (Abt‐199) and navitoclax
Authors: Ackler Scott , Oleksijew Anatol , Chen Jun , Chyla Brenda J. , Clarin Jerry , Foster Kelly , McGonigal Thomas , Mishra Sasmita , Schlessinger Sally , Smith Morey L. , Tahir Stephen K. , Leverson Joel D. , Souers Andrew J. , Boghaert Erwin R. , Hickson Jonathan
Published: September 2015

The Bcl‐2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non‐Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl‐2 family inhibitors alone or in combination with standard‐of‐care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response.