bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Seismic Analyses for the Wind Energy Industry
Authors: Hu Weifei , Pryor S. C. , Letson Frederick , Barthelmie R. J.
Published: July 2017

This paper proposes new seismic-based methods for use in the wind energy industry with a focus on wind turbine condition monitoring. Fourteen Streckeisen STS-2 Broadband seismometers and two three-dimensional (3D) sonic anemometers are deployed in/near an operating wind farm to collect the data used in these proof-of-principle analyses. The interquartile mean (IQM) value of power spectral density (PSD) of the seismic components in 10 min time series is used to characterize the spectral signatures (i.e., frequencies with enhanced variance) in ground vibrations deriving from vibrations of wind turbine subassemblies. A power spectral envelope approach is taken in which the probability density function (PDF) of seismic PSD is developed using seismic data collected under normal turbine operation. These power spectral envelopes clearly show the energy distribution of wind-turbine-induced ground vibrations over a wide frequency range. Singular PSD lying outside the power spectral envelopes can be easily identified and is used herein along with supervisory control and data acquisition (SCADA) data to diagnose the associated suboptimal turbine operating conditions. Illustrative examples are given herein for periods with yaw misalignment and excess tower acceleration. It is additionally shown that there is a strong association between drivetrain acceleration and seismic spectral power in a frequency band of 2.5–12.5 Hz. The long-term goal of the research is development of seismic-based condition monitoring (SBCM) for wind turbines. The primary advantages of SBCM are that the approach is low-cost, noninvasive, and versatile (i.e., one seismic sensor monitoring multiple turbine components).
Single-crystalline germanium nanomembrane photodetectors on foreign nanocavities
Authors: Xia Zhenyang , Song Haomin , Kim Munho , Zhou Ming , Chang Tzu-Hsuan , Liu Dong , Yin Xin , Xiong Kanglin , Mi Hongyi , Wang Xudong , Xia Fengnian , Yu Zongfu , Ma Zhenqiang (Jack) , Gan Qiaoqiang
Published: July 2017

High-yield, high throughput method creates nanomembrane photodetectors with unique optoelectronic properties.
A fourth Denisovan individual
Authors: Slon Viviane , Viola Bence , Renaud Gabriel , Gansauge Marie-Theres , Benazzi Stefano , Sawyer Susanna , Hublin Jean-Jacques , Shunkov Michael V. , Derevianko Anatoly P. , Kelso Janet , Prüfer Kay , Meyer Matthias , Pääbo Svante
Published: July 2017

DNA retrieved from a tooth discovered deep in Denisova Cave allows us to assign it to the Denisovans, a group of archaic hominins.
Comment on “Monkey vocal tracts are speech-ready”
Authors: Lieberman Philip
Published: July 2017

Charles Darwin was correct to wonder why humans have tongues and airways that can make us more susceptible to choking on food.
Solving protein structures using short-distance cross-linking constraints as a guide for discrete molecular dynamics simulations
Authors: Brodie Nicholas I. , Popov Konstantin I. , Petrotchenko Evgeniy V. , Dokholyan Nikolay V. , Borchers Christoph H.
Published: July 2017

Short-distance cross-linking constraints combined with discrete molecular dynamics enable rapid prediction of protein structures.
Imposed Environmental Stresses Facilitate Cell-Free Nanoparticle Formation by Deinococcus radiodurans
Authors: Chen Angela , Contreras Lydia M. , Keitz Benjamin K.
Published: July 2017

The biological synthesis of metal nanoparticles has been examined in a wide range of organisms, due to increased interest in green synthesis and environmental remediation applications involving heavy metal ion contamination.Deinococcus radioduransis particularly attractive for environmental remediation involving metal reduction, due to its high levels of resistance to radiation and other environmental stresses. However, few studies have thoroughly examined the relationships between environmental stresses and the resulting effects on nanoparticle biosynthesis. In this work, we demonstrate cell-free nanoparticle production and study the effects of metal stressor concentrations and identity, temperature, pH, and oxygenation on the production of extracellular silver nanoparticles byD. radioduransR1. We also report the synthesis of bimetallic silver and gold nanoparticles following the addition of a metal stressor (silver or gold), highlighting how production of these particles is enabled through the application of environmental stresses. Additionally, we found that both the morphology and size of monometallic and bimetallic nanoparticles were dependent on the environmental stresses imposed on the cells. The nanoparticles produced byD. radioduransexhibited antimicrobial activity comparable to that of pure silver nanoparticles and displayed catalytic activity comparable to that of pure gold nanoparticles. Overall, we demonstrate that biosynthesized nanoparticle properties can be partially controlled through the tuning of applied environmental stresses, and we provide insight into how their application may affect nanoparticle production inD. radioduransduring bioremediation.

IMPORTANCEBiosynthetic production of nanoparticles has recently gained prominence as a solution to rising concerns regarding increased bacterial resistance to antibiotics and a desire for environmentally friendly methods of bioremediation and chemical synthesis. To date, a range of organisms have been utilized for nanoparticle formation. The extremophileD. radiodurans, which can withstand significant environmental stresses and therefore is more robust for metal reduction applications, has yet to be exploited for this purpose. Thus, this work improves our understanding of the impact of environmental stresses on biogenic nanoparticle morphology and composition during metal reduction processes in this organism. This work also contributes to enhancing the controlled synthesis of nanoparticles with specific attributes and functions using biological systems.
Deficiency of RgpG Causes Major Defects in Cell Division and Biofilm Formation, and Deficiency of LytR-CpsA-Psr Family Proteins Leads to Accumulation of Cell Wall Antigens in Culture Medium by Streptococcus mutans
Authors: De Arpan , Liao Sumei , Bitoun Jacob P. , Roth Randy , Beatty Wandy L. , Wu Hui , Wen Zezhang T.
Published: July 2017

Streptococcus mutans
is known to possess rhamnose-glucose polysaccharide (RGP), a major cell wall antigen.
S. mutans
strains deficient in
rgpG
, encoding the first enzyme of the RGP biosynthesis pathway, were constructed by allelic exchange. The
rgpG
deficiency had no effect on growth rate but caused major defects in cell division and altered cell morphology. Unlike the coccoid wild type, the
rgpG
mutant existed primarily in chains of swollen, “squarish” dividing cells. Deficiency of
rgpG
also causes significant reduction in biofilm formation (
P
< 0.01). Double and triple mutants with deficiency in
brpA
and/or
psr
, genes coding for the LytR-CpsA-Psr family proteins BrpA and Psr, which were previously shown to play important roles in cell envelope biogenesis, were constructed using the
rgpG
mutant. There were no major differences in growth rates between the wild-type strain and the
rgpG brpA
and
rgpG psr
double mutants, but the growth rate of the
rgpG brpA psr
triple mutant was reduced drastically (
P
< 0.001). Under transmission electron microscopy, both double mutants resembled the
rgpG
mutant, while the triple mutant existed as giant cells with multiple asymmetric septa. When analyzed by immunoblotting, the
rgpG
mutant displayed major reductions in cell wall antigens compared to the wild type, while little or no signal was detected with the double and triple mutants and the
brpA
and
psr
single mutants. These results suggest that RgpG in
S. mutans
plays a critical role in cell division and biofilm formation and that BrpA and Psr may be responsible for attachment of cell wall antigens to the cell envelope.

IMPORTANCE
Streptococcus mutans
, a major etiological agent of human dental caries, produces rhamnose-glucose polysaccharide (RGP) as the major cell wall antigen. This study provides direct evidence that deficiency of RgpG, the first enzyme of the RGP biosynthesis pathway, caused major defects in cell division and morphology and reduced biofilm formation by
S. mutans
, indicative of a significant role of RGP in cell division and biofilm formation in
S. mutans
. These results are novel not only in
S. mutans
, but also other streptococci that produce RGP. This study also shows that the LytR-CpsA-Psr family proteins BrpA and Psr in
S. mutans
are involved in attachment of RGP and probably other cell wall glycopolymers to the peptidoglycan. In addition, the results also suggest that BrpA and Psr may play a direct role in cell division and biofilm formation in
S. mutans
. This study reveals new potential targets to develop anticaries therapeutics.
Genome-Scale Model and Omics Analysis of Metabolic Capacities of
Akkermansia muciniphila
Reveal a Preferential Mucin-Degrading Lifestyle
Authors: Ottman Noora , Davids Mark , Suarez-Diez Maria , Boeren Sjef , Schaap Peter J. , Martins dos Santos Vitor A. P. , Smidt Hauke , Belzer Clara , de Vos Willem M.
Published: July 2017

The composition and activity of the microbiota in the human gastrointestinal tract are primarily shaped by nutrients derived from either food or the host. Bacteria colonizing the mucus layer have evolved to use mucin as a carbon and energy source. One of the members of the mucosa-associated microbiota is
Akkermansia muciniphila
, which is capable of producing an extensive repertoire of mucin-degrading enzymes. To further study the substrate utilization abilities of
A. muciniphila
, we constructed a genome-scale metabolic model to test amino acid auxotrophy, vitamin biosynthesis, and sugar-degrading capacities. The model-supported predictions were validated by
in vitro
experiments, which showed
A. muciniphila
to be able to utilize the mucin-derived monosaccharides fucose, galactose, and
N
-acetylglucosamine. Growth was also observed on
N
-acetylgalactosamine, even though the metabolic model did not predict this. The uptake of these sugars, as well as the nonmucin sugar glucose, was enhanced in the presence of mucin, indicating that additional mucin-derived components are needed for optimal growth. An analysis of whole-transcriptome sequencing (RNA-Seq) comparing the gene expression of
A. muciniphila
grown on mucin with that of the same bacterium grown on glucose confirmed the activity of the genes involved in mucin degradation and revealed most of these to be upregulated in the presence of mucin. The transcriptional response was confirmed by a proteome analysis, altogether revealing a hierarchy in the use of sugars and reflecting the adaptation of
A. muciniphila
to the mucosal environment. In conclusion, these findings provide molecular insights into the lifestyle of
A. muciniphila
and further confirm its role as a mucin specialist in the gut.

IMPORTANCE
Akkermansia muciniphila
is among the most abundant mucosal bacteria in humans and in a wide range of other animals. Recently,
A. muciniphila
has attracted considerable attention because of its capacity to protect against diet-induced obesity in mouse models. However, the physiology of
A. muciniphila
has not been studied in detail. Hence, we constructed a genome-scale model and describe its validation by transcriptomic and proteomic approaches on bacterial cells grown on mucus and glucose, a nonmucus sugar. The results provide detailed molecular insight into the mucus-degrading lifestyle of
A. muciniphila
and further confirm the role of this mucin specialist in producing propionate and acetate under conditions of the intestinal tract.
Host Specificity of Flagellins from Segmented Filamentous Bacteria Affects Their Patterns of Interaction with Mouse Ileal Mucosal Proteins
Authors: Chen Huahai , Yin Yeshi , Wang Yanling , Wang Xin , Xiang Charlie
Published: July 2017

Segmented filamentous bacteria (SFB) are known modulators of the mammalian immune system. Currently, the technology for investigating SFB culture
in vitro
is immature, and as a result, the mechanisms of SFB colonization and immune regulation are not yet fully elucidated. In this study, we investigated the gene diversity and host specificity of SFB flagellin genes. The
fliC1
and
fliC2
genes are relatively conserved, while the
fliC3
and
fliC4
genes are more variable, especially at the central and C-terminal regions. Host specificity analysis demonstrated that the
fliC1
genes do not cluster together based on the host organism, whereas the
fliC3
and
fliC4
genes were host specific at the nucleotide and deduced amino acid levels. SFB flagellin protein expression in the ileum mucosa and cecal contents was detected by using fluorescence
in situ
hybridization (FISH) combined with immunohistochemical (IHC) analysis, immunoblotting, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Although the purified SFB FliC3 protein originating from both mouse and rat was able to activate Toll-like receptor 5 (TLR5)-linked NF-κB signaling, no host specificity was observed. Interestingly, the patterns of interaction with mouse ileum mucosal proteins were different for mouse FliC3 (mFliC3) and rat FliC3 (rFliC3). Gene Ontology (GO) and KEGG analyses indicated that more adherence-related proteins interacted with mFliC3, while more lysosome- and proteolysis-related proteins interacted with rFliC3.
In vitro
degradation experiments indicated that the stability of rFliC3 was lower than that of mFliC3 when they were incubated with mouse ileum mucosal proteins. In summary, the gene diversity and host specificity of SFB flagellin genes were investigated, and SFB flagellin expression was detected in gut samples.

IMPORTANCE
Since SFB genomes contain only one copy of each FliC gene, the diversity of FliC is representative of SFB strain diversity. Currently, little is known regarding the diversity and specificity of members of the group of SFB. The work presented herein demonstrates that select SFB strains, exhibiting unique FliC patterns, are present in a variety of mammalian hosts. SFB
fliC
genes were found to interact with a number of unique targets, providing further evidence for SFB host selection. Together, this work represents a major advancement in identifying SFB and delineating how members of the group of SFB interact with the host. Future examination of FliC genes will likely enhance our knowledge of intestinal colonization by the gut microbiota.
High Temporal and Spatial Variability of Atmospheric-Methane Oxidation in Alpine Glacier Forefield Soils
Authors: Chiri Eleonora , Nauer Philipp A. , Rainer Edda-Marie , Zeyer Josef , Schroth Martin H.
Published: July 2017

Glacier forefield soils can provide a substantial sink for atmospheric CH4, facilitated by aerobic methane-oxidizing bacteria (MOB). However, MOB activity, abundance, and community structure may be affected by soil age, MOB location in different forefield landforms, and temporal fluctuations in soil physical parameters. We assessed the spatial and temporal variability of atmospheric-CH4oxidation in an Alpine glacier forefield during the snow-free season of 2013. We quantified CH4flux in soils of increasing age and in different landforms (sandhill, terrace, and floodplain forms) by using soil gas profile and static flux chamber methods. To determine MOB abundance and community structure, we employedpmoAgene-based quantitative PCR and targeted amplicon sequencing. Uptake of CH4increased in magnitude and decreased in variability with increasing soil age. Sandhill soils exhibited CH4uptake rates ranging from −3.7 to −0.03 mg CH4m−2day−1. Floodplain and terrace soils exhibited lower uptake rates and even intermittent CH4emissions. Linear mixed-effects models indicated that soil age and landform were the dominating factors shaping CH4flux, followed by cumulative rainfall (weighted sum ≤4 days prior to sampling). Of 31 MOB operational taxonomic units retrieved, ∼30% were potentially novel, and ∼50% were affiliated with upland soil clusters gamma and alpha. The MOB community structures in floodplain and terrace soils were nearly identical but differed significantly from the highly variable sandhill soil communities. We concluded that soil age and landform modulate the soil CH4sink strength in glacier forefields and that recent rainfall affects its short-term variability. This should be taken into account when including this environment in future CH4inventories.

IMPORTANCEOxidation of methane (CH4) in well-drained, “upland” soils is an important mechanism for the removal of this potent greenhouse gas from the atmosphere. It is largely mediated by aerobic, methane-oxidizing bacteria (MOB). Whereas there is abundant information on atmospheric-CH4oxidation in mature upland soils, little is known about this important function in young, developing soils, such as those found in glacier forefields, where new sediments are continuously exposed to the atmosphere as a result of glacial retreat. In this field-based study, we investigated the spatial and temporal variability of atmospheric-CH4oxidation and associated MOB communities in Alpine glacier forefield soils, aiming at better understanding the factors that shape the sink for atmospheric CH4in this young soil ecosystem. This study contributes to the knowledge on the dynamics of atmospheric-CH4oxidation in developing upland soils and represents a further step toward the inclusion of Alpine glacier forefield soils in global CH4inventories.
Injury epidemiology of tennis players at the 2011–2016 Australian Open Grand Slam
Authors: Gescheit Danielle T , Cormack Stuart J , Duffield Rob , Kovalchik Stephanie , Wood Tim O , Omizzolo Melanie , Reid Machar
Published: July 2017

Aim

To examine the epidemiology and in-event treatment frequency of injury at the 2011–2016 Australian Open tournaments.

Methods

Injury incidence was defined as a medical consultation by a tournament physician and in-event treatment frequency as the mean total number of follow-up medical/physiotherapy consultations (2013–2016 tournaments only). Data were collated by sex, injury region and type and reported as frequencies per 10 000 game exposures. Incidence rate s± 95% CI and rate ratios were used to test effects for injury, sex and year.

Results

Female players experienced more injuries than male players (201.7 vs 148.6). The shoulder (5.1±1.1 injuries per year), foot (3.2±1.1), wrist (3.1±1.5) and knee (3.1±1.1) were the most commonly injured regions among females. Knee (3.5±1.6), ankle (2.3±1.3) and thigh (2.3±1.5) were the most prevalent male injuries. Upper arm injuries and in-event treatment frequency increased by ≥2.4 times in both sexes over the 5-year period. Muscle injuries were most frequent. There was a greater than twofold increase in men and women with stress fractures over the 5-year period. The torso region, including the neck, thoracic spine, trunk and abdominal, lumbar spine, hip and groin, pelvis/buttock, attracted high in-event treatment frequencies in both sexes.

Conclusion

Investigation of injury at the Australian Open suggests that females are more commonly injured than males. Upper and lower extremity injuries affected females while lower limb injuries were more prominent in males. There was an increasing rate of in-event treatments of upper limb and torso injuries as well as stress fractures during the observation period.
Erosion monitoring during core overtopping using a laboratory model with digital image correlation and X-ray microcomputed tomography
Authors: Dumberry Kevin , Duhaime François , Ethier Yannic A.
Published: July 2017

Core overtopping in embankment dams is an important phenomenon that may lead to contact erosion along the core–filter interface. This paper presents new experimental results regarding erosion mechanisms at the core–filter interface during core overtopping. The experimental results were obtained using a reduced-scale model with a variable upstream water level. Digital image correlation (DIC), microcomputed tomography (μCT), and sediment collection at the outlet were used to quantify erosion. Four experimental runs were conducted with a till core and different filters. Only one of the four filters satisfied the filter criteria that were applied. No contact erosion occurred during this test. For filters that did not respect the filter criteria, piping occurred within the core along the downstream slope when the water level reached the top of the core. As a result of the self-healing process within the core material, the erosion rate decayed with time as the hydraulic gradient increased. Results for DIC mainly reflected settlements within the filter due to erosion and a soil arching effect. The magnitude of the displacement vector obtained with DIC is directly proportional to the volume of till eroded. μCT showed that contact erosion occurred continuously.
Putative drivers of adrenocortical activity in captive African lesser bushbaby (Galago moholi)
Authors: Scheun J. , Bennett N.C. , Nowack J. , Laver P.N. , Ganswindt A.
Published: July 2017

In seasonal breeders, periods of reproductive activity often coincide with high levels of glucocorticoids. We studied seven male and seven female African lesser bushbabies (Galago moholi A. Smith, 1836) over two mating periods via noninvasive faecal hormone metabolite monitoring to investigate the relationship between reproductive and adrenocortical hormone activity. We used linear mixed-effect models to investigate the effect of physiological (endocrine) variables on faecal glucocorticoid metabolite concentrations. Our results indicate faecal androgen (males) and progestagen metabolite (females) concentrations as the variables best able to explain variability in faecal glucocorticoid metabolite concentrations. However, the models explained only a fraction (26% and 12%, respectively) of the observed variability and graphical analysis suggests a biologically relevant difference in faecal glucocorticoid metabolite concentrations between captive and free-ranging animals during nonreproductive periods. Thus, captivity may have affected glucocorticoid output in our focal animals, potentially weakening the expected relationship between reproductive activity and faecal glucocorticoid metabolite variability. Due to the ease of faecal and observational sample collection, a large number of studies monitoring adrenocortical activity in wildlife are conducted using only captive settings, with inferences unquestioned when applied to free-ranging scenarios. Our study cautions against this practice, as particular housing or management conditions may influence the pattern of adrenocortical activity.
Annelids shed light on the evolution of spiralian development
Authors: Seaver Elaine C.
Published: July 2017

Spiralian development is characterized by stereotypic cell geometry and spindle orientation in early cleavage stage embryos, as well as conservation of ultimate fates of descendent clones. Diverse taxa such as molluscs, annelids, flatworms, and nemerteans exhibit spiralian development, but it is a mystery how such a conserved developmental program gives rise to such diverse body plans. This review highlights examples of variation during early development among spiralians, emphasizing recent experimental studies in the annelid Capitella teleta Blake, Grassle and Eckelbarger, 2009. Intracellular fate mapping studies in C. teleta reveal that many of its cells’ fates are shared among spiralians, but it also has a novel origin for trunk mesoderm (3c and 3d micromeres). Studies have identified an inductive signal in spiralians that has “organizing activity” and that influences cell fates in the surrounding embryo. Capitella teleta also has an organizing activity; however, surprisingly, it is localized to a different cell, it signals at a different developmental stage, and likely utilizes a distinct molecular signaling pathway compared with that in molluscs. A model is presented to provide a mechanistic explanation of evolutionary changes in the cellular identity of the organizer. Detailed experimental investigations in spiralian embryos demonstrate variation in developmental features that may influence the evolution of novel forms.
Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells
Authors: Borriello Lucia , Nakata Rie , Sheard Michael A. , Fernandez G. Esteban , Sposto Richard , Malvar Jemily , Blavier Laurence , Shimada Hiroyuki , Asgharzadeh Shahab , Seeger Robert C. , DeClerck Yves A.
Published: July 2017

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1–expressing CAFs that share phenotypic and functional characteristics with bone marrow–derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1–positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142–57. ©2017 AACR.
Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade
Authors: Yang Dong , Sun Bin , Zhang Xiaohong , Cheng Daomei , Yu Xiaoping , Yan Lanzhen , Li Lei , An Sanqi , Jiang Hua , Lasorella Anna , Iavarone Antonio , Zhang Shu , Zou Fangdong , Zhao Xudong
Published: July 2017

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer. Cancer Res; 77(18); 4773–84. ©2017 AACR.
Resistance to the Antibody–Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity
Authors: Ríos-Luci Carla , García-Alonso Sara , Díaz-Rodríguez Elena , Nadal-Serrano Mercedes , Arribas Joaquín , Ocaña Alberto , Pandiella Atanasio
Published: July 2017

Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1–resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. Cancer Res; 77(17); 4639–51. ©2017 AACR.
SOX5/6/21 Prevent Oncogene-Driven Transformation of Brain Stem Cells
Authors: Kurtsdotter Idha , Topcic Danijal , Karlén Alexandra , Singla Bhumica , Hagey Daniel W. , Bergsland Maria , Siesjö Peter , Nistér Monica , Carlson Joseph W. , Lefebvre Veronique , Persson Oscar , Holmberg Johan , Muhr Jonas
Published: July 2017

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.
Atrioventricular Nodal Reentrant Tachycardia in Patients With Congenital Heart Disease
Authors: Papagiannis John , Beissel Daniel Joseph , Krause Ulrich , Cabrera Michel , Telishevska Marta , Seslar Stephen , Johnsrude Christopher , Anderson Charles , Tisma-Dupanovic Svjetlana , Connelly Diana , Avramidis Dimosthenis , Carter Christopher , Kornyei Laszlo , Law Ian , Von Bergen Nicholas , Janusek Jan , Silva Jennifer , Rosenthal Eric , Willcox Mark , Kubus Peter , Hessling Gabriele , Paul Thomas
Published: July 2017

Background—

The relationship of atrioventricular nodal reentrant tachycardia to congenital heart disease (CHD) and the outcome of catheter ablation in this population have not been studied adequately.

Methods and Results—

A multicenter retrospective study was performed on patients with CHD who had atrioventricular nodal reentrant tachycardia and were treated with catheter ablation. There were 109 patients (61 women), aged 22.1±13.4 years. The majority, 86 of 109 (79%), had CHD resulting in right heart pressure or volume overload. Patients were divided into 2 groups: group A (n=51) with complex CHD and group B (n=58) with simple CHD. There were no significant differences between groups in patients’ growth parameters, use of 3-dimensional imaging, and type of ablation (radiofrequency versus cryoablation). Procedure times (251±117 versus 174±94 minutes;
P
=0.0006) and fluoroscopy times (median 20.8 versus 16.6 minutes;
P
=0.037) were longer in group A versus group B. There were significant differences between groups in the acute success of ablation (82% versus 97%;
P
=0.04), risk of atrioventricular block (14 versus 0%;
P
=0.004), and need for chronic pacing (10% versus 0%;
P
=0.008). There was no permanent atrioventricular block in patients who underwent cryoablation. After 3.2±2.7 years of follow-up, long-term success was 86% in group A and 100% in group B (
P
=0.004).

Conclusions—

Atrioventricular nodal reentrant tachycardia can complicate the course of patients with CHD. This study demonstrates that the outcome of catheter ablation is favorable in patients with simple CHD. Patients with complex CHD have increased risk of procedural failure and atrioventricular block.
Stand-Alone Pulmonary Vein Isolation Versus Pulmonary Vein Isolation With Additional Substrate Modification as Index Ablation Procedures in Patients With Persistent and Long-Standing Persistent Atrial Fibrillation
Authors: Fink Thomas , Schlüter Michael , Heeger Christian-Hendrik , Lemes Christine , Maurer Tilman , Reissmann Bruno , Riedl Johannes , Rottner Laura , Santoro Francesco , Schmidt Boris , Wohlmuth Peter , Mathew Shibu , Sohns Christian , Ouyang Feifan , Metzner Andreas , Kuck Karl-Heinz
Published: July 2017

Background—

Pulmonary vein isolation (PVI) for persistent atrial fibrillation is associated with limited success rates and often requires multiple procedures to maintain stable sinus rhythm. In the prospective and randomized Alster-Lost-AF trial (Ablation at St. Georg Hospital for Long-Standing Persistent Atrial Fibrillation), we sought to assess, in patients with symptomatic persistent or long-standing persistent atrial fibrillation, the outcomes of initial ablative strategies comprising either stand-alone PVI (PVI-only approach) or a stepwise approach of PVI followed by complex fractionated atrial electrogram ablation and linear ablation (Substrate-modification approach).

Methods and Results—

Patients were randomized 1:1 to stand-alone PVI or PVI plus substrate modification. The primary study end point was freedom from recurrence of any atrial tachyarrhythmia, outside a 90-day blanking period, at 12 months. A total of 124 patients were enrolled, with 118 patients included in the analysis (61 in the PVI-only group, 57 in the Substrate-modification group). Atrial tachyarrhythmias recurred in 28 PVI-only group patients and 24 Substrate-modification group patients, for 1-year freedom from tachyarrhythmia recurrence after a single ablation procedure of 54% (95% confidence interval, 43%–68%) in the PVI-only and 57% (95% confidence interval, 46%–72%) in the Substrate-modification group (
P
=0.86). Twenty-four patients in the PVI-only group (39%) and 18 in the Substrate-modification group (32%) were without arrhythmia recurrence and off antiarrhythmic drug therapy at the end of the 12-month follow-up.

Conclusions—

In patients with persistent and long-standing persistent atrial fibrillation, no significant difference was observed in 12-month freedom from atrial tachyarrhythmias between an index ablative approach of stand-alone PVI and a stepwise approach of PVI plus complex fractionated atrial electrogram and linear ablation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00820625.
Tachycardia-Induced J-Wave Changes in Patients With and Without Idiopathic Ventricular Fibrillation
Authors: Aizawa Yoshiyasu , Takatsuki Seiji , Nishiyama Takahiko , Kimura Takehiro , Kohsaka Shun , Kaneko Yoshiaki , Inden Yasuya , Takahashi Naohiko , Nagase Satoshi , Aizawa Yoshifusa , Fukuda Keichi
Published: July 2017

Background—

To know the underlying mechanisms of J waves, the response to atrial pacing was studied in patients with idiopathic ventricular fibrillation (IVF) and patients with non-IVF.

Methods and Results—

In 8 patients with IVF, the J-wave amplitude was measured before, during, and after atrial pacing. All patients had episodes of ventricular fibrillation without structural heart disease. The responses of J waves were compared with those of the 17 non-IVF control subjects who revealed J waves but no history of cardiac arrest and underwent electrophysiological study. The IVF patients were younger than the non-IVF patients (28±10 versus 52±14 years, respectively;
P
=0.002) and had larger J waves with more extensive distribution. J waves decreased from 0.35±0.26 to 0.22±0.23 mV (
P
=0.025) when the RR intervals were shortened from 782±88 to 573±162 ms (
P
=0.001). A decrease (≥0.05 mV) in the J-wave amplitude was observed in 6 of the 8 patients. In addition, 1 patient showed a distinct reduction of J waves in the unipolar epicardial leads. In contrast, J waves were augmented in the 17 non-IVF subjects from 0.27±0.09 to 0.38±0.10 mV (
P
<0.001): augmented in 9 and unchanged in the 8 subjects. The different response patterns of J waves to rapid pacing suggest different mechanisms: early repolarization in IVF patients and conduction delay in non-IVF patients.

Conclusions—

The response to atrial pacing was different between the IVF and non-IVF patients, which suggests the presence of different mechanisms for the genesis of J waves.
Visual and Quantitative Assessment of Coronary Stenoses at Angiography Versus Fractional Flow Reserve
Authors: Adjedj Julien , Xaplanteris Panagiotis , Toth Gabor , Ferrara Angela , Pellicano Mariano , Ciccarelli Giovanni , Floré Vincent , Barbato Emanuele , De Bruyne Bernard
Published: July 2017

Background—

The correlation between angiographic assessment of coronary stenoses and fractional flow reserve (FFR) is weak. Whether and how risk factors impact the diagnostic accuracy of angiography is unknown. We sought to evaluate the diagnostic accuracy of angiography by visual estimate and by quantitative coronary angiography when compared with FFR and evaluate the influence of risk factors (RF) on this accuracy.

Methods and Results—

In 1382 coronary stenoses (1104 patients), percent diameter stenosis by visual estimation (DS
VE
) and by quantitative coronary angiography (DS
QCA
) was compared with FFR. Patients were divided into 4 subgroups, according to the presence of RFs, and the relationship between DS
VE
, DS
QCA
, and FFR was analyzed. Overall, DS
VE
was significantly higher than DS
QCA
(
P
<0.0001); nonetheless, when examined by strata of DS, DS
VE
was significantly smaller than DS
QCA
in mild stenoses, although the reverse held true for severe stenoses. Compared with FFR, a large scatter was observed for both DS
VE
and DS
QCA
. When using a dichotomous FFR value of 0.80, C statistic was significantly higher for DS
VE
than for DS
QCA
(0.712 versus 0.640, respectively;
P
<0.001). C statistics for DS
VE
decreased progressively as RFs accumulated (0.776 for ≤1 RF, 0.750 for 2 RFs, 0.713 for 3 RFs and 0.627 for ≥4 RFs;
P
=0.0053). In addition, in diabetics, the relationship between FFR and angiographic indices was particularly weak (C statistics: 0.524 for DS
VE
and 0.511 for DS
QCA
).

Conclusions—

Overall, DS
VE
has a better diagnostic accuracy than DS
QCA
to predict the functional significance of coronary stenosis. The predictive accuracy of angiography is moderate in patients with ≤1 RFs, but weakens as RFs accumulate, especially in diabetics.
Dynamic Edematous Response of the Human Heart to Myocardial Infarction
Authors: Fernández-Jiménez Rodrigo , Barreiro-Pérez Manuel , Martin-García Ana , Sánchez-González Javier , Agüero Jaume , Galán-Arriola Carlos , García-Prieto Jaime , Díaz-Pelaez Elena , Vara Pedro , Martinez Irene , Zamarro Ivan , Garde Beatriz , Sanz Javier , Fuster Valentin , Sánchez Pedro L. , Ibanez Borja
Published: July 2017

Background:

Clinical protocols aimed to characterize the post–myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment–elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model.

Methods:

A total of 16 patients with anterior ST-segment–elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment–elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements.

Results:

In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography.

Conclusions:

Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post–ST-segment–elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.
Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling
Authors: Amyere Mustapha , Revencu Nicole , Helaers Raphaël , Pairet Eleonore , Baselga Eulalia , Cordisco Maria , Chung Wendy , Dubois Josée , Lacour Jean-Philippe , Martorell Loreto , Mazereeuw-Hautier Juliette , Pyeritz Reed E. , Amor David J. , Bisdorff Annouk , Blei Francine , Bombei Hannah , Dompmartin Anne , Brooks David , Dupont Juliette , González-Enseñat Maria Antonia , Frieden Ilona , Gérard Marion , Kvarnung Malin , Hanson-Kahn Andrea Kwan , Hudgins Louanne , Léauté-Labrèze Christine , McCuaig Catherine , Metry Denise , Parent Philippe , Paul Carle , Petit Florence , Phan Alice , Quere Isabelle , Salhi Aicha , Turner Anne , Vabres Pierre , Vicente Asuncion , Wargon Orli , Watanabe Shoji , Weibel Lisa , Wilson Ashley , Willing Marcia , Mulliken John B. , Boon Laurence M. , Vikkula Miikka
Published: July 2017

Background:

Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified
RASA1
mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs.

Methods:

We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro.

Results:

We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in
EPHB4
in 5 families that cosegregated with CM-AVM. Overall, screening of
EPHB4
detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs.

Conclusions:

We found
EPHB4
mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics
RASA1
-related CM-AVM1 and also hereditary hemorrhagic telangiectasia.
RASA1
-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Evaluating the Impact and Cost-Effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke
Authors: Heller David J. , Coxson Pamela G. , Penko Joanne , Pletcher Mark J. , Goldman Lee , Odden Michelle C. , Kazi Dhruv S. , Bibbins-Domingo Kirsten
Published: July 2017

Background:

Statins are effective in the primary prevention of atherosclerotic cardiovascular disease. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline expands recommended statin use, but its cost-effectiveness has not been compared with other guidelines.

Methods:

We used the Cardiovascular Disease Policy Model to estimate the cost-effectiveness of the ACC/AHA guideline relative to current use, Adult Treatment Panel III guidelines, and universal statin use in all men 45 to 74 years of age and women 55 to 74 years of age over a 10-year horizon from 2016 to 2025. Sensitivity analyses varied costs, risks, and benefits. Main outcomes were incremental cost-effectiveness ratios and numbers needed to treat for 10 years per quality-adjusted life-year gained.

Results:

Each approach produces substantial benefits and net cost savings relative to the status quo. Full adherence to the Adult Treatment Panel III guideline would result in 8.8 million more statin users than the status quo, at a number needed to treat for 10 years per quality-adjusted life-year gained of 35. The ACC/AHA guideline would potentially result in up to 12.3 million more statin users than the Adult Treatment Panel III guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 68. Moderate-intensity statin use in all men 45 to 74 years of age and women 55 to 74 years of age would result in 28.9 million more statin users than the ACC/AHA guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 108. In all cases, benefits would be greater in men than women. Results vary moderately with different risk thresholds for instituting statins and statin toxicity estimates but depend greatly on the disutility caused by daily medication use (pill burden).

Conclusions:

At a population level, the ACC/AHA guideline for expanded statin use for primary prevention is projected to treat more people, to save more lives, and to cost less compared with Adult Treatment Panel III in both men and women. Whether individuals benefit from long-term statin use for primary prevention depends more on the disutility associated with pill burden than their degree of cardiovascular risk.