bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reservoirs of resistance: polymyxin resistance in veterinary‐associated companion animal isolates of Pseudomonas aeruginosa
Authors: Scott Andrea , Pottenger Sian , Timofte Dorina , Moore Matthew , Wright Laura , Kukavica‐Ibrulj Irena , Jeukens Julie , Levesque Roger C , Freschi Luca , Pinchbeck Gina L , Schmidt Vanessa M , McEwan Neil , Radford Alan D , Fothergill Joanne L 
Published: June 2019

BackgroundPseudomonas aeruginosa is an opportunistic pathogen and a major cause of infections. Widespread resistance in human infections are increasing the use of last resort antimicrobials such as polymyxins. However, these have been used for decades in veterinary medicine. Companion animals are an understudied source of antimicrobial resistant P. aeruginosa isolates. This study evaluated the susceptibility of P. aeruginosa veterinary isolates to polymyxins to determine whether the veterinary niche represents a potential reservoir of resistance genes for pathogenic bacteria in both animals and humans.Methods and resultsClinical P. aeruginosa isolates (n=24) from UK companion animals were compared for antimicrobial susceptibility to a panel of human‐associated isolates (n=37). Minimum inhibitory concentration (MIC) values for polymyxin B and colistin in the companion animals was significantly higher than in human isolates (P=0.033 and P=0.013, respectively). Genotyping revealed that the veterinary isolates were spread throughout the P. aeruginosa population, with shared array types from human infections such as keratitis and respiratory infections, suggesting the potential for zoonotic transmission. Whole genome sequencing revealed mutations in genes associated with polymyxin resistance and other antimicrobial resistance‐related genes.ConclusionThe high levels of resistance to polymyxin shown here, along with genetic similarities between some human and animal isolates, together suggest a need for sustained surveillance of this veterinary niche as a potential reservoir for resistant, clinically relevant bacteria in both animals and humans.
Using polar nitrogen-, sulphur- and oxygen-compound compositions from ultra-high resolution mass spectrometry for petroleum fluid assessment in the Eagle Ford Formation, Texas
Authors: Poetz S. , Kuske S. , Song Y. , Jweda J. , Michael E. , Horsfield B. 
Published: June 2019

Abstract
The potential of polar compound compositions from electrospray ionization ultra-high resolution mass spectrometry (FT-ICR-MS) to characterize petroleum fluids as well as petroleum system processes is shown in the example of the Eagle Ford Formation in Texas, USA. A set of six black oil and nine source-rock bitumen samples is investigated with respect to its organic nitrogen-, sulphur- and oxygen-compound inventory in order to assess maturity, depositional environment, lithofacies and retention and migration behaviour. Compared to conventional geochemical tools based on molecular parameters from gas chromatographic analyses, FT-ICR-MS enables a maturity assessment from immature to late mature stage, which is barely influenced by source or depositional environment. Due to the increased molecular mass and polarity range of its target compounds, FT-ICR-MS is the most convincing tool to describe the retention and fractionation of polar compounds in a petroleum system.
Antitumor Effects of Anti-Semaphorin 4D Antibody Unravel a Novel Proinvasive Mechanism of Vascular-Targeting Agents
Authors: Zuazo-Gaztelu Iratxe , Pàez-Ribes Marta , Carrasco Patricia , Martín Laura , Soler Adriana , Martínez-Lozano Mar , Pons Roser , Llena Judith , Palomero Luis , Graupera Mariona , Casanovas Oriol 
Published: June 2019

AbstractOne of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell–derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs.Significance:An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.See related commentary by Tamagnone and Franzolin, p. 5146
Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer
Authors: Tacconi Carlotta , Ungaro Federica , Correale Carmen , Arena Vincenzo , Massimino Luca , Detmar Michael , Spinelli Antonino , Carvello Michele , Mazzone Massimiliano , Oliveira Ana I. , Rubbino Federica , Garlatti Valentina , Spanò Salvatore , Lugli Enrico , Colombo Federico S. , Malesci Alberto , Peyrin-Biroulet Laurent , Vetrano Stefania , Danese Silvio , D’Alessio Silvia 
Published: June 2019

Abstract

Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human nonmetastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of colorectal cancer, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells and TAMs to synergistically inhibit antitumor immunity and promote primary colorectal cancer growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of nonmetastatic colorectal cancer.

Significance:
The prolymphangiogenic factor VEGFC is abundant in colorectal cancer and activates VEGFR3 present on cancer-associated macrophages and lymphatic vessels; activation of VEGFR3 signaling fosters cancer immune escape, resulting in enhanced tumor growth.
Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer
Authors: Acharya Sunil , Yao Jun , Li Ping , Zhang Chenyu , Lowery Frank J. , Zhang Qingling , Guo Hua , Qu Jingkun , Yang Fei , Wistuba Ignacio I. , Piwnica-Worms Helen , Sahin Aysegul A. , Yu Dihua 
Published: June 2019

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasis-promoting gene FSCN1 via NFκB activation. Activation of the SPHK1/NFκB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFκB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFκB, as promising therapeutic targets in TNBC.

Significance:
SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFκB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.
Transcriptomic Differences between Primary Colorectal Adenocarcinomas and Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes
Authors: Kamal Yasmin , Schmit Stephanie L. , Hoehn Hannah J. , Amos Christopher I. , Frost H. Robert 
Published: June 2019

Abstract

Approximately 20% of colorectal cancer patients with colorectal adenocarcinomas present with metastases at the time of diagnosis, and therapies that specially target these metastases are lacking. We present a novel approach for investigating transcriptomic differences between primary colorectal adenocarcinoma and distant metastases, which may help to identify primary tumors with high risk for future dissemination and to inform the development of metastasis-targeted therapies. To effectively compare the transcriptomes of primary colorectal adenocarcinoma and metastatic lesions at both the gene and pathway levels, we eliminated tissue specificity of the "host" organs where tumors are located and adjusted for confounders such as exposure to chemotherapy and radiation, and identified that metastases were characterized by reduced epithelial–mesenchymal transition (EMT) but increased MYC target and DNA-repair pathway activities. FBN2 and MMP3 were the most differentially expressed genes between primary tumors and metastases. The two subtypes of colorectal adenocarcinoma metastases that were identified, EMT inflammatory and proliferative, were distinct from the consensus molecular subtype (CMS) 3, suggesting subtype exclusivity. In summary, this study highlights transcriptomic differences between primary tumors and colorectal adenocarcinoma metastases and delineates pathways that are activated in metastases that could be targeted in colorectal adenocarcinoma patients with metastatic disease.

Significance:
These findings identify a colorectal adenocarcinoma metastasis-specific gene-expression signature that is free from potentially confounding background signals coming from treatment exposure and the normal host tissue that the metastasis is now situated within.
Individual- and Area-Level Socioeconomic Inequalities in Esophageal Cancer Survival in Shandong Province, China: A Multilevel Analysis
Authors: Kou Kou , Baade Peter D. , Gatton Michelle , Cramb Susanna M. , Sun Jiandong , Lu Zilong , Fu Zhentao , Chu Jie , Xu Aiqiang , Guo Xiaolei 
Published: June 2019

Abstract

Background:
China contributes to almost half of the esophageal cancer cases diagnosed globally each year. However, the prognosis information of this disease in this large population is scarce.

Methods:
Data on a population-based cohort consisting of residents of Shandong Province, China who were diagnosed with esophageal cancer during the period from 2005 to 2014 were analyzed. The cancer-specific survival rates were estimated using Kaplan–Meier analysis. Discrete-time multilevel mixed-effects survival models were used to investigate socioeconomic status (SES) disparities on esophageal cancer survival.

Results:
The unadjusted 1-, 3-, and 5-year cause-specific survival rates were 59.6% [95% confidence interval (CI), 59.2%–59.9%], 31.9% (95% CI, 31.5%–32.3%), and 23.6% (95% CI, 23.1%–24.0%), respectively. Patients of blue-collar occupations had higher risk of esophageal cancer–related death than those of white-collar occupations in the first 2 years after diagnosis. Rural patients had higher risk of death than urban patients in the first 3 years after diagnosis. The risks of esophageal cancer–related death among patients living in low/middle/high SES index counties were not different in the first 2 years after diagnosis. However, patients living in high SES index counties had better long-term survival (3–5 years postdiagnosis) than those living in middle or low SES index counties.

Conclusions:
Socioeconomic inequalities in esophageal cancer survival exist in this Chinese population. Higher individual- or area-level SES is associated with better short-term or long-term cancer survival.

Impact:
Elucidation of the relative roles of the SES factors on survival could guide interventions to reduce disparities in the prognosis of esophageal cancer.
Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance
Authors: Guillamón Concepción F. , Martínez-Sánchez María V. , Gimeno Lourdes , Campillo José A. , Server-Pastor Gerardo , Martínez-García Jerónimo , Martínez-Escribano Jorge , Torroba Amparo , Ferri Belén , Abellán Daniel J. , Legaz Isabel , López-Álvarez María R. , Moya-Quiles María R. , Muro Manuel , Minguela Alfredo 
Published: June 2019

Abstract
Therapies using NK cells (NKc) expanded/activated ex vivo or stimulated in vivo with new immunostimulatory agents offer alternative opportunities for patients with recurrent/refractory tumors, but relevant biomarkers to guide the selection of patients are required for optimum results. Overall survival of 249 solid cancer patients was evaluated in relation to the genetics and/or the expression on peripheral blood NKcs of inhibitory and activating killer-cell immunoglobulin-like receptors (iKIR and aKIR, respectively), HLA class I ligands, CD226 (also known as DNAM-1), and NKG2A. Compared with patients with higher expression, patients with low expression of CD226 on total NKcs showed shorter mean overall survival (60.7 vs. 98.0 months, P &lt; 0.001), which was further reduced in presence of telomeric aKIRs (KIR2DS1-DS5 and/or KIR3DS1, 31.6 vs. 96.8 months, P &lt; 0.001). KIR2DL2/S2+, KIR3DL1+, KIR2DL1+, and KIR2DL3+ NKc subsets in the presence of their cognate ligands primarily contributed to shortening patients’ overall survival by increasing the sensitivity to CD226 downmodulation in aKIR-rich telomeric genotypes. In patients with high tumor burden who died during the follow-up period, aKIR-rich telomeric genotypes were associated with: (i) specific downmodulation of CD226 on educated NKcs but not on CD8+ T cells or uneducated NKcs, (ii) lower expression of CD226 and higher expression of NKG2A on aKIR+ NKcs, and (iii) lower numbers of total CD56dim NKcs. The reduced expression of CD226 on NKcs with aKIR-rich genotypes may be a biomarker indicative of NKc hyporesponsiveness in patients that could benefit from new NKc immune-stimulatory therapies.
Contribution of the Lung to the Genesis of Cheyne‐Stokes Respiration in Heart Failure: Plant Gain Beyond Chemoreflex Gain and Circulation Time
Authors: Giannoni Alberto , Gentile Francesco , Navari Alessandro , Borrelli Chiara , Mirizzi Gianluca , Catapano Giosuè , Vergaro Giuseppe , Grotti Francesco , Betta Monica , Piepoli Massimo F. , Francis Darrel P. , Passino Claudio , Emdin Michele 
Published: June 2019

Background

The contribution of the lung or the plant gain (
PG
; ie, change in blood gases per unit change in ventilation) to Cheyne‐Stokes respiration (
CSR
) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated.

Methods and Results

Twenty patients with systolic heart failure (age, 72.4±6.4 years; left ventricular ejection fraction, 31.5±5.8%), 10 with relevant
CSR
(24‐hour apnea‐hypopnea index [
AHI
] ≥10 events/h) and 10 without (
AHI
<10 events/h) at 24‐hour cardiorespiratory monitoring underwent evaluation of chemoreflex gain (CG) to hypoxia (

) and hypercapnia (

) by rebreathing technique, lung‐to‐finger circulation time, and
PG
assessment through a visual system.
PG
test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95%
CI
, 0.91–0.99); the best‐fitting curve to express the
PG
was a hyperbola (
R
2
≥0.98). Patients with
CSR
showed increased
PG
,

(but not

), and lung‐to‐finger circulation time, compared with patients without
CSR
(all
P
<0.05).
PG
was the only predictor of the daytime
AHI
(
R
=0.56,
P
=0.01) and together with the

also predicted the nighttime
AHI
(
R
=0.81,
P
=0.0003) and the 24‐hour
AHI
(
R
=0.71,
P
=0.001). Lung‐to‐finger circulation time was the only predictor of
CSR
cycle length (
R
=0.82,
P
=0.00006).

Conclusions

PG is a powerful contributor of
CSR
and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure.
Severe Acute Stent Malapposition After Drug‐Eluting Stent Implantation: Effects on Long‐Term Clinical Outcomes
Authors: Lee Seung‐Yul , Im Eui , Hong Sung‐Jin , Ahn Chul‐Min , Kim Jung‐Sun , Kim Byeong‐Keuk , Ko Young‐Guk , Choi Donghoon , Jang Yangsoo , Hong Myeong‐Ki 
Published: June 2019

Background

The effects of severe acute stent malapposition (
ASM
) after drug‐eluting stent implantation on long‐term clinical outcomes are not clearly understood. We evaluated long‐term clinical outcomes of severe
ASM
using optical coherence tomography.

Methods and Results

We pooled patient‐ and lesion‐level data from 6 randomized studies. Five studies investigated follow‐up drug‐eluting stent strut coverage and one investigated
ASM
. In this data set, a total of 436 patients with 444 lesions underwent postintervention optical coherence tomography examination and these data were included in the analysis. Severe
ASM
was defined as lesions with ≥400 μm of maximum malapposed distance or ≥1 mm of maximum malapposed length. Composite events (cardiac death, target lesion–related myocardial infarction, target lesion revascularization, and stent thrombosis) were compared between patients with and without severe
ASM
. The postintervention optical coherence tomography findings indicated that 62 (14.2%) patients had lesions with ≥400 μm of maximum malapposed distance and 186 (42.7%) patients had lesions with ≥1 mm of maximum malapposed length. The 5‐year clinical follow‐up was completed in 371 (86.1%) of the eligible 431 patients. The cumulative rate of composite events was similar among the patients in each group during 5‐year follow‐up: 3.3% in patients with
ASM
≥400 μm of maximum malapposed distance versus 3.1% in those with no
ASM
or
ASM
<400 μm of maximum malapposed distance (
P
=0.89), and 1.2% in patients with
ASM
≥1 mm of maximum malapposed length versus 4.6% in those with no
ASM
or
ASM
<1 mm of maximum malapposed length (
P
=0.06).

Conclusions

During the 5‐year follow‐up,
ASM
severity was not associated with long‐term clinical outcomes in patients treated with drug‐eluting stents.
Tropical Cyclone Center Fix Using CYGNSS Winds
Authors: Mayers David , Ruf Christopher 
Published: June 2019

AbstractA new method is described for determining the center location of a tropical cyclone (TC) using wind speed measurements by the NASA Cyclone Global Navigation Satellite System (CYGNSS). CYGNSS measurements made during TC overpasses are used to constrain a parametric wind speed model in which storm center location is varied. The “MTrack” storm center location is selected to minimize the residual difference between model and measurement. Results of the MTrack center fix are compared to the National Hurricane Center (NHC) Best Track, the Automated Rotational Center Hurricane Eye Retrieval (ARCHER), and aircraft reconnaissance fixes for category 1–category 3 TCs during the 2017 and 2018 hurricane seasons. MTrack produces storm center locations at intermediate times between NHC fixes with a factor of 5.6 overall reduction in sensitivity to uncertainties in the NHC fixes between which it interpolates. The MTrack uncertainty is found to be larger in the cross-track direction than the along-track direction, although this behavior and the absolute accuracy of position estimates require further investigation.
Interactions between a Nocturnal MCS and the Stable Boundary Layer as Observed by an Airborne Compact Raman Lidar during PECAN
Authors: Lin Guo , Geerts Bart , Wang Zhien , Grasmick Coltin , Jing Xiaoqin , Yang Jing 
Published: June 2019

AbstractSmall-scale variations within the low-level outflow and inflow of an MCS can either support or deter the upscale growth and maintenance of the MCS. However, these small-scale variations, in particular in the thermodynamics (temperature and humidity), remain poorly understood, due to a lack of detailed measurements. The compact Raman lidar (CRL) deployed on the University of Wyoming King Air aircraft directly sampled temperature and water vapor profiles at unprecedented vertical and along-track resolutions along the southern margin of a series of mature nocturnal MCSs traveling along a frontal boundary on 1 July 2015 during the Plains Elevated Convection at Night (PECAN) campaign. Here, the capability of the airborne CRL to document interactions between the MCS inflow and outflow currents is illustrated. The CRL reveals the well-defined boundary of a cooler current. This is interpreted as the frontal boundary sharpened by convectively induced cold pools, in particular by the outflow boundary of the downstream MCS. In one CRL transect, the frontal/outflow boundary appeared as a distinct two-layer structure of moisture and aerosols formed by moist stable boundary layer air advected above the boundary. The second transect, one hour later, reveals a single sloping boundary. In both cases, the lofting of the moist stably stratified air over the boundary favors MCS maintenance, through enhanced elevated CAPE and reduced CIN. The CRL data are sufficiently resolved to reveal Kelvin–Helmholtz (KH) billows and the vertical structure of the outflow boundary, which in this case behaved as a density current rather than an undular bore.