bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer Potential of Plasmids Conferring Extended-Spectrum-Cephalosporin Resistance in Escherichia coli from Poultry
Authors: Mo Solveig Sølverød , Sunde Marianne , Ilag Hanna Karin , Langsrud Solveig , Heir Even
Published: April 2017

Escherichia coli
strains resistant to extended-spectrum cephalosporins (ESC) are widely distributed in Norwegian broiler production, and the majority harbor transferable IncK or IncI1 plasmids carrying
bla
CMY-2
. Persistent occurrence in broiler farms may occur through the survival of ESC-resistant
E. coli
strains in the farm environment, or by transfer and maintenance of resistance plasmids within a population of environmental bacteria with high survival abilities. The aim of this study was to determine the transferability of two successful
bla
CMY-2
-carrying plasmids belonging to the incompatibility groups IncK and IncI1 into
E. coli
and
Serratia
species recipients. Initially, conjugative plasmid transfer from two
E. coli
donors to potential recipients was tested in an agar assay. Conjugation was further investigated for selected mating pairs in surface and planktonic assays at temperatures from 12°C to 37°C. Transfer of plasmids was observed on agar, in broth, and in biofilm at temperatures down to 25°C. The IncK plasmid was able to transfer into
Serratia marcescens
, and transconjugants were able to act as secondary plasmid donors to different
E. coli
and
Serratia
species recipients. All transconjugants displayed an AmpC phenotype corresponding to the acquisition of
bla
CMY-2
. In summary, the results indicate that the IncK plasmid may transfer between
E. coli
and
Serratia
spp. under conditions relevant for broiler production.

IMPORTANCE
Certain
bla
CMY-2
-carrying plasmids are successful and disseminated in European broiler production. Traditionally, plasmid transferability has been studied under conditions that are optimal for bacterial growth. Plasmid transfer has previously been reported between
E. coli
bacteria in biofilms at 37°C and in broth at temperatures ranging from 8 to 37°C. However, intergenus transfer of
bla
CMY-2
-carrying plasmids from
E. coli
to environmental bacteria in the food-processing chain has not been previously studied. We demonstrate that
bla
CMY-2
-carrying plasmids are capable of conjugative transfer between different poultry-associated bacterial genera under conditions relevant for broiler production. Transfer to
Serratia
spp. and to hosts with good biofilm-forming abilities and with the potential to act as secondary plasmid donors to new hosts might contribute to the persistence of these resistance plasmids. These results contribute to increased knowledge of factors affecting the persistence of ESC resistance in broiler production and can provide a basis for improvement of routines and preventive measures.
Day-to-Day Dynamics of Commensal Escherichia coli in Zimbabwean Cows Evidence Temporal Fluctuations within a Host-Specific Population Structure
Authors: Massot Méril , Couffignal Camille , Clermont Olivier , D'Humières Camille , Chatel Jérémie , Plault Nicolas , Andremont Antoine , Caron Alexandre , Mentré France , Denamur Erick
Published: April 2017

To get insights into the temporal pattern of commensalEscherichia colipopulations, we sampled the feces of four healthy cows from the same herd in the Hwange District of Zimbabwe daily over 25 days. The cows had not received antibiotic treatment during the previous 3 months. We performed viableE. colicounts and characterized the 326 isolates originating from the 98 stool samples at a clonal level, screened them forstxandeaegenes, and tested them for their antibiotic susceptibilities. We observed thatE. colicounts and dominant clones were different among cows, and very few clones were shared. No clone was shared by three or four cows. Clone richness and evenness were not different between cows. Within each host, the variability in theE. colicount was evidenced between days, and no clone was found to be dominant during the entire sampling period, suggesting the existence of clonal interference. Dominant clones tended to persist longer than subdominant ones and were mainly from phylogenetic groups A and B1. FiveE. coliclones were found to contain both thestx1andstx2genes, representing 6.3% of the studied isolates. All cows harbored at least one Shiga toxin-producingE. coli(STEC) strain. Resistance to tetracycline, penicillins, trimethoprim, and sulfonamides was rare and observed in three clones that were shed at low levels in two cows. This study highlights the fact that the commensalE. colipopulation, including the STEC population, is host specific, is highly dynamic over a short time frame, and rarely carries antibiotic resistance determinants in the absence of antibiotic treatment.

IMPORTANCEThe literature about the dynamics of commensalEscherichia colipopulations is very scarce. Over 25 days, we followed the totalE. colicounts daily and characterized the sampled clones in the feces of four cows from the same herd living in the Hwange District of Zimbabwe. This study deals with the day-to-day dynamics of both quantitative and qualitative aspects ofE. colicommensal populations, with a focus on both Shiga toxin-producingE. coliand antibiotic-resistantE. colistrains. We show that the structure of these commensal populations was highly specific to the host, even though the cows ate and roamed together, and was highly dynamic between days. Such data are of importance to understand the ecological forces that drive the dynamics of the emergence ofE. coliclones of particular interest within the gastrointestinal tract and their transmission between hosts.
Global-Scale Structure of the Eelgrass Microbiome
Authors: Fahimipour Ashkaan K. , Kardish Melissa R. , Lang Jenna M. , Green Jessica L. , Eisen Jonathan A. , Stachowicz John J.
Published: April 2017

Plant-associated microorganisms are essential for their hosts' survival and performance. Yet, most plant microbiome studies to date have focused on terrestrial species sampled across relatively small spatial scales. Here, we report the results of a global-scale analysis of microbial communities associated with leaf and root surfaces of the marine eelgrass
Zostera marina
throughout its range in the Northern Hemisphere. By contrasting host microbiomes with those of surrounding seawater and sediment, we uncovered the structure, composition, and variability of microbial communities associated with eelgrass. We also investigated hypotheses about the assembly of the eelgrass microbiome using a metabolic modeling approach. Our results reveal leaf communities displaying high variability and spatial turnover that mirror their adjacent coastal seawater microbiomes. By contrast, roots showed relatively low compositional turnover and were distinct from surrounding sediment communities, a result driven by the enrichment of predicted sulfur-oxidizing bacterial taxa on root surfaces. Predictions from metabolic modeling of enriched taxa were consistent with a habitat-filtering community assembly mechanism whereby similarity in resource use drives taxonomic cooccurrence patterns on belowground, but not aboveground, host tissues. Our work provides evidence for a core eelgrass root microbiome with putative functional roles and highlights potentially disparate processes influencing microbial community assembly on different plant compartments.

IMPORTANCE
Plants depend critically on their associated microbiome, yet the structure of microbial communities found on marine plants remains poorly understood in comparison to that for terrestrial species. Seagrasses are the only flowering plants that live entirely in marine environments. The return of terrestrial seagrass ancestors to oceans is among the most extreme habitat shifts documented in plants, making them an ideal testbed for the study of microbial symbioses with plants that experience relatively harsh abiotic conditions. In this study, we report the results of a global sampling effort to extensively characterize the structure of microbial communities associated with the widespread seagrass species
Zostera marina
, or eelgrass, across its geographic range. Our results reveal major differences in the structure and composition of above- versus belowground microbial communities on eelgrass surfaces, as well as their relationships with the environment and host.
Effect of Antimicrobial and Physical Treatments on Growth of Multispecies Staphylococcal Biofilms
Authors: Stewart Elizabeth J. , Payne David E. , Ma Tianhui Maria , VanEpps J. Scott , Boles Blaise R. , Younger John G. , Solomon Michael J.
Published: April 2017

The prevalence and structure of
Staphylococcus aureus
and
Staphylococcus epidermidis
within multispecies biofilms were found to depend sensitively on physical environment and antibiotic dosage. Although these species commonly infect similar sites, such as orthopedic implants, little is known about their behavior in multispecies communities, particularly in response to treatment. This research establishes that
S. aureus
is much more prevalent than
S. epidermidis
when simultaneously seeded and grown under unstressed conditions (pH 7, 37°C) in both laboratory and clinical strains. In multispecies communities,
S. epidermidis
is capable of growing a more confluent biofilm when the addition of
S. aureus
is delayed 4 to 6 h during 18 h of growth. Different vancomycin dosages generate various behaviors:
S. epidermidis
is more prevalent at a dose of 1.0 μg/ml vancomycin, but reduced growth of both species occurs at 1.9 μg/ml vancomycin. This variability is consistent with the different MICs of
S. aureus
and
S. epidermidis
. Growth at higher temperature (45°C) results in an environment where
S. aureus
forms porous biofilms. This porosity allows
S. epidermidis
to colonize more of the surface, resulting in detectable
S. epidermidis
biomass. Variations in pH result in increased prevalence of
S. epidermidis
at low pH (pH 5 and 6), while
S. aureus
remains dominant at high pH (pH 8 and 9). This work establishes the structural variability of multispecies staphylococcal biofilms as they undergo physical and antimicrobial treatments. It provides a basis for understanding the structure of these communities at infection sites and how treatments disrupt their multispecies behaviors.

IMPORTANCE
Staphylococcus aureus
and
Staphylococcus epidermidis
are two species of bacteria that are commonly responsible for biofilm infections on medical devices. Biofilms are structured communities of bacteria surrounded by polysaccharides, proteins, and DNA; bacteria are more resistant to antimicrobials as part of a biofilm than as individual cells. This work investigates the structure and prevalence of these two organisms when grown together in multispecies biofilms and shows shifts in the behavior of the polymicrobial community when grown in various concentrations of vancomycin (an antibiotic commonly used to treat staphylococcal infections), in a high-temperature environment (a condition previously shown to lead to cell disruption and death), and at low and high pH (a change that has been previously shown to soften the mechanical properties of staphylococcal biofilms). These shifts in community structure demonstrate the effect such treatments may have on multispecies staphylococcal infections.
Endoscopic advanced imaging of the respiratory tract: exploring probe-based confocal laser endomicroscopy in emphysema
Authors: Yserbyt J , Dooms C , Janssens W , Verleden G M
Published: April 2017

Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the ‘quiet zone’.

Trial registration number

Results, NCT01204970.
From optimized monovalent ligands to size-controlled dendrimers: an efficient strategy towards high-activity DC-SIGN antagonists
Authors: Ordanini Stefania , Goti Giulio , Bernardi Anna
Published: April 2017

This short review describes our work on the development of dendrimeric antagonists of DC-SIGN, a dendritic cells (DCs) receptor recognizing highly mannosylated structures and primarily involved in the recognition of viruses such as HIV. The structure of pseudo-di-mannoside and pseudo-tri-mannoside compounds was first finely modified to obtain DC-SIGN ligands that were more stable and selective than mannose. Their DC-SIGN affinity differences were amplified once presented on multivalent dendrimer-like scaffolds, including poly-alkyne terminated and phenylene-ethynylene rod-like ones. Libraries of mannosylated dendrimers were synthesized, improving their stability and maximizing their monodispersity. The effect of the dendrimers valency, structure, and size on DC-SIGN affinity and antiviral potency was investigated. Both the valency and the topology of the architectures were revealed as key parameters for activity optimization, together with the intrinsic affinity of the monovalent ligand. The stability, rigidity, and length of the scaffolds were also tuned. The design of geometrically adapted scaffolds afforded one of the most potent inhibitors of DC-SIGN mediated HIV infections to date. This monodispersed, not cytotoxic, and highly active compound was also tested with DCs; its internalization into endolysosomal compartments and its ability to induce the overexpression of signaling molecules makes it a good precursor to produce pathogen-entry inhibitors with immunomodulant properties.
New generation low-energy probes for ultralight axion and scalar dark matter
Authors: Stadnik Yevgeny V. , Flambaum Victor V.
Published: April 2017

We present a brief overview of a new generation of high-precision laboratory and astrophysical measurements to search for ultralight (sub-eV) axion, axion-like pseudoscalar and scalar dark matter (DM), which form either a coherently oscillating classical field or topological defects (solitons). In these new detection methods, the sought effects are linear in the interaction constant between DM and ordinary matter, which is in stark contrast to traditional searches for DM, where the sought effects are quadratic or higher order in the underlying interaction constants (which are extremely small).
Multi-Scale Homogenization of Transversal Waves in Periodic Composite Beams
Authors: Sun Xiangkun , Zhou Changwei , Ichchou Mohamed , Lainé Jean-Pierre , Zine Abdel-Malek
Published: April 2017

This paper deals with the deduction of new homogenized models for the flexural wave in bi-periodic beams. According to the homogenization theory, the long-wave assumption is used and the valid frequency range of homogenized models is limited to the first Bragg band gap. However, the classical homogenization method, whose idea is taking the component’s mean values as effective material properties, has limitations in mimicking the dispersive behavior and the real valid frequency range is far less than the limit. Thus, enriched homogenized models, derived by the multi-scale asymptotic homogenization method, are proposed to provide more accurate homogenization models with larger real valid frequency range. The new homogenized models are validated by investigating the dispersion relation in the infinite case and the frequency response function in the finite case. Wave finite element method (WFEM) are used to provide associated references. A parametric study is carried out in the infinite case while two different boundary conditions are considered in the finite case.
0D/3D-CdSe/Bi12TiO20 Pyramidal Heterostructure Photocatalysts for Enhanced Visible-Light Photocatalytic Activities
Authors: Wang Tao , Ma Changchang , Wu Dan , Liu Xinlin , Liu Yang , Wei Maobin , Liu Zhi , Huo Pengwei , Yan Yongsheng
Published: April 2017

In this paper, a novel heterostructure of 0D/3D-CdSe/Bi[Formula: see text]TiO[Formula: see text] pyramidal photocatalyst was synthesized and characterized. It exhibited significantly photocatalytic efficiency in photocatalytic degradation of the tetracycline than pure Bi[Formula: see text]TiO2 and CdSe and showed high stability. The enhanced photocatalytic activity might be attributed to the formation of heterostructure between CdSe QDs and 3D Bi[Formula: see text]TiO[Formula: see text], in which CdSe QDs served as electron trapper to improve the separation of photodegradation electron–hole pairs, and provided a number of active adsorption sites for the photogenerated of pollutants. The photocatalytic mechanism of 0D/3D-CdSe/Bi[Formula: see text]TiO[Formula: see text] pyramidal heterostructure was also proposed.
Nanomechanical Cantilever-Based Sensor: An Efficient Tool to Measure the Binding Between the Herbicide Mesotrione and 4-Hydroxyphenylpyruvate Dioxygenase
Authors: Rodrigues L. F. , Ierich J. C. M. , Andrade M. A. , Hausen M. A. , Leite F. L. , Moreau Alberto L. D. , Steffens Clarice
Published: April 2017

Nanomechanical biosensors based on atomic force microscopy (AFM) cantilevers have garnered considerable attention. AFM cantilevers are devices that can detect a target either via a surface functionalization process based on immobilization through molecular adsorption, or through the selective chemical binding of a specific molecule, transforming the device into a specific biosensor. In this study, we demonstrate that functionalized AFM cantilevers could be used, in a process involving self-assembling layers, to create a homogeneous surface layer of the widely used herbicide mesotrione. Controlled experiments to evaluate its detection were performed, and binding between mesotrione and its target molecule, 4-hydroxyphenylpyruvate dioxygenase (HPPD), was evaluated using deflection curves of functionalized cantilevers interacting with mesotrione. The cantilevers worked as nanomechanical sensors inside a fluid cell device, under different concentrations of HPPD diluted in PBS. After evaluating increasing concentrations of HPPD, the deflection curves showed a clear, dose-dependent pattern. The homogeneous dispersion of mesotrione on the cantilevers was assessed by confocal microscopy, and this corroborated the functionalization method. Thus, the results obtained by this functionalized cantilever presented a high efficiency in detecting binding between HPPD and mesotrione molecules at concentrations as low as 17[Formula: see text]ng mL[Formula: see text]. In this way, as a preliminary step for a future environmental contaminants nanosensor development, the described detection method showed a suitable capability for molecular recognition at the nanoscale.
A comprehensive analysis of myocardial substrate preference emphasizes the need for a synchronized fluxomic/metabolomic research design
Authors: Ragavan Mukundan , Kirpich Alexander , Fu Xiaorong , Burgess Shawn C. , McIntyre Lauren M. , Merritt Matthew E.
Published: April 2017

The heart oxidizes fatty acids, carbohydrates, and ketone bodies inside the tricarboxylic acid (TCA) cycle to generate the reducing equivalents needed for ATP production. Competition between these substrates makes it difficult to estimate the extent of pyruvate oxidation. Previously, hyperpolarized pyruvate detected propionate-mediated activation of carbohydrate oxidation, even in the presence of acetate. In this report, the optimal concentration of propionate for the activation of glucose oxidation was measured in mouse hearts perfused in Langendorff mode. This study was performed with a more physiologically relevant perfusate than the previous work. Increasing concentrations of propionate did not cause adverse effects on myocardial metabolism, as evidenced by unchanged O2consumption, TCA cycle flux, and developed pressures. Propionate at 1 mM was sufficient to achieve significant increases in pyruvate dehydrogenase flux (3×), and anaplerosis (6×), as measured by isotopomer analysis. These results further demonstrate the potential of propionate as an aid for the correct estimation of total carbohydrate oxidative capacity in the heart. However, liquid chromotography/mass spectroscopy-based metabolomics detected large changes (~30-fold) in malate and fumarate pool sizes. This observation leads to a key observation regarding mass balance in the TCA cycle; flux through a portion of the cycle can be drastically elevated without changing the O2consumption.
Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing
Authors: Halade Ganesh V. , Kain Vasundhara , Ingle Kevin A. , Prabhu Sumanth D.
Published: April 2017

The metabolic transformation of fatty acids to form oxylipids using 12/15-lipoxygenase (LOX) can promote either resolving or nonresolving inflammation. However, the mechanism of how 12/15-LOX interacts with polyunsaturated fatty acids (PUFA) in postmyocardial infarction (post-MI) healing is unclear. Here, we reported the role of 12/15-LOX in post-MI cardiac remodeling in a PUFA [10% (wt/wt), 22 kcal]-enriched environment. Wild-type (WT; C57BL/6J) and 12/15-LOX-null (12/15-LOX−/−) male mice of 8–12 wk of age were fed a PUFA-enriched diet for 1 mo and subjected to permanent coronary artery ligation. Post-MI mice were monitored for day 1 or until day 5 along with standard diet-fed MI controls. No-MI surgery mice served as naïve controls. PUFA-fed WT and 12/15-LOX−/−mice improved ejection fraction and reduced lung edema greater than WT mice at day 5 post-MI ( P < 0.05). Post-MI, neutrophil density was decreased in PUFA-fed WT and 12/15-LOX−/−mice at day 1 ( P < 0.05). Deletion of 12/15-LOX in mice led to increased cytochrome P-450-derived bioactive lipid mediator epoxyeicosatrienoic acids (EETs), i.e., 11,12-EpETrE and 14,15-EpETrE, which were further enhanced by acute PUFA intake post-MI. Macrophage density was decreased in WT + PUFA and 12/15-LOX−/−mice compared with their respective standard diet-fed WT controls at day 5 post-MI. 12/15-LOX−/−+ PUFA mice displayed an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers ( Ym-1, Mrc-1, and Arg-1, all P < 0.05) in the infarcted area. Furthermore, 12/15-LOX−/−mice, with or without PUFA, showed reduced collagen deposition at day 5 post-MI compared with WT mice. In conclusion, deletion of 12/15-LOX and short-term exposure of PUFA promoted leukocyte clearance, thereby limiting cardiac remodeling and promoting an effective resolution of inflammation.

NEW & NOTEWORTHY This study determined that 1) deletion of 12/15-lipoxygenase (LOX) promotes the generation of epoxyeicosatrienoic acids, the cytochrome P-450-derived metabolites in postmyocardial infarction (post-MI) healing; 2) acute exposure of fatty acids to 12/15-LOX−/−mice drives leukocyte (neutrophils and macrophages) clearance post-MI; and 3) metabolic transformation of fats is the significant contributor in leukocyte clearance to drive either resolving or nonresolving inflammation post-MI.
Angiotensin-(1–7) attenuates angiotensin II-induced cardiac hypertrophy via a Sirt3-dependent mechanism
Authors: Guo Lirong , Yin Ankang , Zhang Qi , Zhong Tiecheng , O’Rourke Stephen T. , Sun Chengwen
Published: April 2017

The objectives of the present study were to investigate the effect of ANG-(1–7) on the development of cardiac hypertrophy and to identify the intracellular mechanism underlying this action of ANG-(1–7). Blood pressure and heart rate were recorded using radiotelemetry before and after chronic subcutaneous infusion of control (PBS), ANG II, ANG-(1–7), or ANG II + ANG-(1–7) for 4 wk in normotensive rats. Chronic administration of ANG-(1–7) did not affect either basal blood pressure or the ANG II-induced elevation in blood pressure. However, ANG-(1–7) significantly attenuated ANG II-induced cardiac hypertrophy and perivascular fibrosis in these rats. These effects of ANG-(1–7) were confirmed in cultured cardiomyocytes, in which ANG-(1–7) significantly attenuated ANG II-induced increases in cell size. This protective effect of ANG-(1–7) was significantly attenuated by pretreatment with A779 (a Mas receptor antagonist) or Mito-TEMPO (a mitochondria-targeting superoxide scavenger) as well as blockade of Sirt3 (a deacetylation-acting protein) by viral vector-mediated overexpression of sirtuin (Sirt)3 short hairpin (sh)RNA. Western blot analysis demonstrated that treatment with ANG-(1–7) dramatically increased Sirt3 expression. In addition, ANG-(1–7) attenuated the ANG II-induced increase in mitochondrial ROS generation, an effect that was abolished by A779 or Sirt3 shRNA. Moreover, ANG-(1–7) increased FoxO3a deacetylation and SOD2 expression, and these effects were blocked by Sirt3 shRNA. In summary, the protective effects of ANG-(1–7) on ANG II-induced cardiac hypertrophy and increased mitochondrial ROS production are mediated by elevated SOD2 expression via stimulation of Sirt3-dependent deacetylation of FoxO3a in cardiomyocytes. Thus, activation of the ANG-(1–7)/Sirt3 signaling pathway could be a novel therapeutic strategy in the management of cardiac hypertrophy and associated complications.

NEW & NOTEWORTHY Chronic subcutaneous ANG-(1–7) has no effect on ANG II-induced elevations in blood pressure but significantly attenuates ANG II-induced cardiac hypertrophy and fibrosis by a mitochondrial ROS-dependent mechanism. This protective effect of ANG-(1–7) against the action of ANG II action is mediated by stimulation of sirtuin-3-mediated deacetylation of FoxO3a, which triggers SOD2 expression.
Vasculopathy in the setting of cardiorenal syndrome: roles of protein-bound uremic toxins
Authors: Guo Jingbin , Lu Lu , Hua Yue , Huang Kevin , Wang Ian , Huang Li , Fu Qiang , Chen Aihua , Chan Paul , Fan Huimin , Liu Zhong-Min , Wang Bing Hui
Published: April 2017

Chronic kidney disease (CKD) often leads to and accelerates the progression of cardiovascular disease (CVD), while CVD also causes kidney dysfunction. This bidirectional interaction leads to the development of a complex syndrome known as cardiorenal syndrome (CRS). CRS not only involves both the heart and the kidney but also the vascular system through a vast array of contributing factors. In addition to hemodynamic, neurohormonal, mechanical, and biochemical factors, nondialyzable protein-bound uremic toxins (PBUTs) are also key contributing factors that have been demonstrated through in vitro, in vivo, and clinical observations. PBUTs are ineffectively removed by hemodialysis because their complexes with albumins are larger than the pores of the dialysis membranes. PBUTs such as indoxyl sulfate and p-cresyl sulfate are key determinate and predictive factors for the progression of CVD in CKD patients. In CRS, both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) exhibit significant dysfunction that is associated with the progression of CVD. PBUTs influence proliferation, calcification, senescence, migration, inflammation, and oxidative stress in VSMCs and ECs through various mechanisms. These pathological changes lead to arterial remodeling, stiffness, and atherosclerosis and thus reduce heart perfusion and impair left ventricular function, aggravating CRS. There is limited literature about the effect of PBUT on the vascular system and their contribution to CRS. This review summarizes current knowledge on how PBUTs influence vasculature, clarifies the relationship between uremic toxin-related vascular disease and CRS, and highlights the potential therapeutic strategies of uremic vasculopathy in the setting of CRS.
Numerical Modelling of Building Vibrations due to Railway Traffic: Analysis of the Mitigation Capacity of a Wave Barrier
Authors: Ribes-Llario Fran , Marzal Silvia , Zamorano Clara , Real Julia
Published: April 2017

Transmission of train-induced vibrations to buildings located in the vicinity of the track is one of the main negative externalities of railway transport, since both human comfort and the adequate functioning of sensitive equipment may be compromised. In this paper, a 3D FEM model is presented and validated with data from a real track stretch near Barcelona, Spain. Furthermore, a case study is analyzed as an application of the model, in order to evaluate the propagation and transmission of vibrations induced by the passage of a suburban train to a nearby 3-storey building. As a main outcome, vertical vibrations in the foundation slab are found to be maximum in the corners, while horizontal vibrations keep constant along the edges. The propagation within the building structure is also studied, concluding that vibrations invariably increase in their propagation upwards the building. Moreover, the mitigation capacity of a wave barrier acting as a source isolation is assessed by comparing vibration levels registered in several points of the building structure with and without the barrier. In this regard, the wave barrier is found to effectively reduce vibration in both the soil and the structure.
Study on the Correlation of Vibration Properties and Crack Index in the Health Assessment of Tunnel Lining
Authors: Wu Xuezhen , Jiang Yujing , Masaya Kusaba , Taniguchi Tetsuya , Yamato Takahide
Published: April 2017

This paper examines the correlation of vibration properties and crack index of tunnel lining in evaluating risk of collapsing. The visual inspection method, which was widely used, was not reliable enough as the stability of tunnel lining was influenced by the voids and the cracks that were invisible. A new method for the health assessment of tunnel lining was proposed, which can evaluate the whole structural condition according to the vibration properties of tunnel lining. A series of field tests were conducted to evaluate the validity of this new method and to make a comparative analysis with the visual inspection test results. The resultant average spectrum (RAS) of tunnel lining was identified according to the acceleration data of ambient vibration test of Hidake Tunnel in Japan. The tunnel lining crack index (TCI) was also obtained by digital visual inspection test. The correlation between the vibration characteristics and the crack index of tunnel lining was confirmed. However, the voids and the cracks on the inside of the lining were neglected in visual inspection test, which could pose a serious threat to tunnel safety. The vibration measurements by seismometer are an effective way to evaluate the global stability of tunnel lining.
Learning Curve and Clinical Outcomes of Performing Surgery with the InterTan Intramedullary Nail in Treating Femoral Intertrochanteric Fractures
Authors: Li A-Bing , Zhang Wei-Jiang , Wang Ji-Qi , Zhao You-Ming , Guo Wei-Jun
Published: April 2017

Purpose. The purpose of this study is to evaluate the learning curve of performing surgery with the InterTan intramedullary nail in treating femoral intertrochanteric fractures, to provide valuable information and experience for surgeons who decide to learn a new procedure. Methods. We retrospectively analyzed data from 53 patients who underwent surgery using an InterTan intramedullary nail at our hospital between July 2012 and September 2015. The negative exponential curve-fit regression analysis was used to evaluate the learning curve. According to 90% learning milestone, patients were divided into two group, and the outcomes were compared. Results. The mean operative time was 69.28 (95% CI 64.57 to 74.00) minutes; with the accumulation of surgical experience, the operation time was gradually decreased. 90% of the potential improvement was expected after 18 cases. In terms of operative time, intraoperative blood loss, hospital stay, and Harris hip score significant differences were found between two groups (p=0.009, p=0.000, p=0.030, and p=0.002, resp.). Partial weight bearing time, fracture union time, tip apex distance, and the number of blood transfusions and complications were similar between two groups (p>0.5). Conclusion. This study demonstrated that the learning curve of performing surgery with the InterTan intramedullary nail is acceptable and 90% of the expert’s proficiency level is achieved at around 18 cases.
Vitamin D Modulates Hematological Parameters and Cell Migration into Peritoneal and Pulmonary Cavities in Alloxan-Diabetic Mice
Authors: Bella Leonardo M. , Fieri Isis , Tessaro Fernando H. G. , Nolasco Eduardo L. , Nunes Fernanda P. B. , Ferreira Sabrina S. , Azevedo Carolina B. , Martins Joilson O.
Published: April 2017

Background/Aims. The effects of cholecalciferol supplementation on the course of diabetes in humans and animals need to be better understood. Therefore, this study investigated the effect of short-term cholecalciferol supplementation on biochemical and hematological parameters in mice.Methods. Male diabetic (alloxan, 60 mg/kg i.v., 10 days) and nondiabetic mice were supplemented with cholecalciferol for seven days. The following parameters were determined: serum levels of 25-hydroxyvitamin D, phosphorus, calcium, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, red blood cell count, white blood cell count (WBC), hematocrit, hemoglobin, differential cell counts of peritoneal lavage (PeL), and bronchoalveolar lavage (BAL) fluids and morphological analysis of lung, kidney, and liver tissues.Results. Relative to controls, cholecalciferol supplementation increased serum levels of 25-hydroxyvitamin D, calcium, hemoglobin, hematocrit, and red blood cell counts and decreased leukocyte cell counts of PeL and BAL fluids in diabetic mice. Diabetic mice that were not treated with cholecalciferol had lower serum calcium and albumin levels and hemoglobin, WBC, and mononuclear blood cell counts and higher serum creatinine and urea levels than controls.Conclusion. Our results suggest that cholecalciferol supplementation improves the hematological parameters and reduces leukocyte migration into the PeL and BAL lavage of diabetic mice.
Analysis of Dynamic Coupling Characteristics of the Slope Reinforced by Sheet Pile Wall
Authors: Qu H. L. , Luo H. , Liu L. , Liu Y.
Published: April 2017

Large deformation of slope caused by earthquake can lead to the loss of stability of slope and its retaining structures. At present, there have been some research achievements about the slope reinforcement of stabilizing piles. However, due to the complexity of the structural system, the coupling relationship between soil and pile is still not well understood. Hence it is of great necessity to study its dynamic characteristics further. In view of this, a numerical model was established byFLAC3Din this paper, and the deformation and stress nephogram of sheet pile wall in peak ground motion acceleration (PGA) at 0.1 g, 0.2 g, and 0.4 g were obtained. Through the analysis, some conclusions were obtained. Firstly, based on the nephogram of motion characteristics and the positions of the slip surface and the retaining wall, the reinforced slope can be divided into 6 sections approximatively, namely, the sliding body parts of A, B, C, D, and E and the bedrock part F. Secondly, the deformation and stress distributions of slope reinforced by sheet pile wall were carefully studied. Based on the results of deformation calculation from time history analysis, the interaction force between structure and soil can be estimated by the difference of peak horizontal displacements, and the structure-soil coupling law under earthquake can be studied by this approach.
Phase I Study of Fenretinide Delivered Intravenously in Patients with Relapsed or Refractory Hematologic Malignancies: A California Cancer Consortium Trial
Authors: Mohrbacher Ann M. , Yang Allen S. , Groshen Susan , Kummar Shivaani , Gutierrez Martin E. , Kang Min H. , Tsao-Wei Denice , Reynolds C. Patrick , Newman Edward M. , Maurer Barry J.
Published: April 2017

Purpose: A phase I study was conducted to determine the MTD, dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies.

Experimental Design: Fenretinide (80–1,810 mg/m2/day) was administered by continuous infusion on days 1 to 5, in 21-day cycles, using an accelerated titration design.

Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1–7), were enrolled and received the test drug. Ninety-seven courses were completed. An MTD was reached at 1,280 mg/m2/day for 5 days. Course 1 DLTs included 6 patients with hypertriglyceridemia, 4 of whom were asymptomatic; 2 patients experienced DLT thrombocytopenia (asymptomatic). Of 11 patients with response-evaluable peripheral T-cell lymphomas, two had complete responses [CR, progression-free survival (PFS) 68+ months; unconfirmed CR, PFS 14+ months], two had unconfirmed partial responses (unconfirmed PR, PFS 5 months; unconfirmed PR, PFS 6 months), and five had stable disease (2–12 cycles). One patient with mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were approximately 10 mcg/mL (mid-20s μmol/L) at 640 mg/m2/day, approximately 14 mcg/mL (mid-30s μmol/L) at 905 mg/m2/day, and approximately 22 mcg/mL (mid-50s μmol/L) at 1,280 mg/m2/day.

Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced antitumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m2 on day 1, followed by 1,200 mg/m2 on days 2 to 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing. Clin Cancer Res; 23(16); 4550–5. ©2017 AACR.
Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer
Authors: Zou Min , Toivanen Roxanne , Mitrofanova Antonina , Floch Nicolas , Hayati Sheida , Sun Yanping , Le Magnen Clémentine , Chester Daniel , Mostaghel Elahe A. , Califano Andrea , Rubin Mark A. , Shen Michael M. , Abate-Shen Cory
Published: April 2017

Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.

Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736–49. ©2017 AACR.

See related commentary by Sinha and Nelson, p. 673.

This article is highlighted in the In This Issue feature, p. 653
Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC
Authors: Tumeh Paul C. , Hellmann Matthew D. , Hamid Omid , Tsai Katy K. , Loo Kimberly L. , Gubens Matthew A. , Rosenblum Michael , Harview Christina L. , Taube Janis M. , Handley Nathan , Khurana Neharika , Nosrati Adi , Krummel Matthew F. , Tucker Andrew , Sosa Eduardo V. , Sanchez Phillip J. , Banayan Nooriel , Osorio Juan C. , Nguyen-Kim Dan L. , Chang Jeremy , Shintaku I. Peter , Boasberg Peter D. , Taylor Emma J. , Munster Pamela N. , Algazi Alain P. , Chmielowski Bartosz , Dummer Reinhard , Grogan Tristan R. , Elashoff David , Hwang Jimmy , Goldinger Simone M. , Garon Edward B. , Pierce Robert H. , Daud Adil
Published: April 2017

We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis− group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417–24. ©2017 AACR.
Identification of an Oligopeptide Binding to Hepatocellular Carcinoma
Authors: Shimizu Akira , Maruta Fukuto , Akita Noriyuki , Miwa Shiro , Seymour Leonard W. , Kerr David J. , Parker Alan L. , Miyagawa Shinichi
Published: April 2017

Objectives: We carried out identification of a small peptide binding to human hepatocellular carcinoma (HCC) cells with the aim of applying the peptide for future HCC-targeted therapy or imaging. Methods: The biopanning technique using phage peptide display libraries was performed on HCC cells in vitro, and a phage clone expressing the HCC-binding peptide motif was selected. The binding activity of the selected phage was evaluated by plaque infection assay and immunofluorescence on cell lines. In addition, the binding activity of the peptide-expressing phage was investigated using HCC specimens derived from patients who had undergone hepatectomy for HCC. Results: A heptapetide, Thr-Thr-Pro-Arg-Asp-Ala-Tyr (TTPRDAY), was identified as a motif binding to HCC. TTPRDAY bound specifically to HCC cells in comparison with other cancer cells, and the binding to HCC cells was also confirmed by immunofluorescence. In addition, the synthesized TTPRDAY peptide showed binding activity and a non-mitogenic effect on HCC cells in vitro. TTPRDAY-presenting phage showed more significant binding to HCC cells derived from specimens obtained from actual patients than to non-cancerous liver tissue. Conclusion: The motif TTPRDAY, identified by the biopanning technique, shows significant binding to HCC cells.
The Pathology of Mueller Cells under Different Disease Conditions
Authors: Nishikawa Shimpei
Published: April 2017

The morphology and enzymes of Mueller cells were investigated in the developing retinas of Royal College of Surgeons (RCS) rats. Immunohistochemistry showed glutamine synthetase (GS) expression first on P10. It increased later in both normal and dystrophic retinas. Glial fibrillary acidic protein was not expressed in normal retinas, but Mueller cells of dystrophic retinas were stained on P35 and P100. The percentages of the area of Mueller cells in the outer nuclear layer in the macula, posterior pole, equator and periphery were 12.3 ± 2.7, 22.1 ± 4.5, 23.6 ± 1 and 26.7 ± 4.5%, respectively. In the foveal region, lower levels of GS and glutamate/aspartate transporter (GLAST) immunoreactivity were confirmed. Enzyme-linked immunosorbent assay and Western blot analyses revealed that the amounts of GS and GLAST in the foveal region were smaller than those in any other region. The role of Mueller cells in the preconditioned retinal ischemic rat was also investigated. Three and 7 days after ischemia, GS immunoreactivity recovered only in the preconditioned group. After 1 h of ischemia, the retinas showed increased GFAP immunoreactivity in the non-preconditioned group at 3 and 7 days. In the preconditioned group, only slight GFAP immunoreactivity was observed. These results suggest that the mechanism of preconditioned retinal ischemia may be related to Mueller cells in the retina.
Bronchoscopic Microsampling to Analyze the Epithelial Lining Fluid of Patients with Pulmonary Mycobacterium avium Complex Disease
Authors: Nishimura Tomoyasu , Hasegawa Naoki , Watanabe Masazumi , Takebayashi Toru , Tasaka Sadatomo , Ishizaka Akitoshi
Published: April 2017

Background: A new bronchoscopic microsampling (BMS) probe has recently been developed, which allows the minimally invasivecollection of epithelial lining fluid (ELF) simultaneously from multiple sites. While the number of immunocompetent patients with pulmonary Mycobacterium avium complex(MAC) disease is growing, the precise pathogenesis of the disease remains to be clarified. Objectives: This study aimed to measure biochemical markers in the ELF of patients with pulmonary MAC disease using BMS. Methods: We studied 8 healthy volunteers (controls) and 8 patients with pulmonary MAC disease. In the patients, ELF was collected from visibly abnormal (involved) and normal (uninvolved) sites using high-resolution computed tomography (HRCT). Results: The concentration of IFN-γ (means ± SEM) was significantly higher in patient ELF sampled from involved (26.62 ± 9.66 pg/ml) than from uninvolved sites (5.33 ± 1.44 pg/ml; p < 0.05) or from normal controls (<1.56 pg/ml; p < 0.05). In most patients, there was no difference in IFN-γ concentrations between the involved and uninvolved sites. The concentration of KL-6 in ELF was significantly higher in the involved (793 ± 108 U/ml) than in the uninvolved sites (192 ± 43 U/ml;p < 0.05) or in normal controls (186 ± 38 U/ml;p < 0.05). Conclusions: The specific inflammatory reaction caused by MAC infection might not be limited to sites that were visibly abnormal on HRCT. Although further improvement has to be considered, BMS may help to increase the understanding of the pathogenesis of various respiratory disorders.