bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enrolling in animal‐assisted therapy programmes
Authors: Coghlan Simon 
Published: April 2019

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Enrolling in animal‐assisted therapy programmes’, was submitted and is discussed by Simon Coghlan. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue.The series is being coordinated by Steven McCulloch, senior lecturer in human animal studies at the Centre for Animal Welfare, University of Winchester. It aims to provide a framework that will help practising veterinarians find solutions when facing similar dilemmas.
Improving the specific diagnosis of trematode, cestode and nematode infections by a multiplex single-tube real-time PCR assay
Authors: Wong Samson S Y , Poon Rosana W S , To Kelvin K W , Chan Jasper F W , Lu Gang , Xing Fanfan , Cheng Vincent C C , Yuen Kwok-Yung 
Published: April 2019

AimsHelminth infections are becoming uncommon in high-income countries and laboratory staff may lose expertise in their morphological identification, especially in histological sections where speciation of helminths is challenging. Commercially available molecular diagnostic panels for faecal specimens only offer tests for protozoa but not helminths. We aim to improve the identification accuracy of helminths using a multiplex PCR assay.MethodsWe designed three pairs of PCR primers and probes targeting multicopy genes for a multiplex single-tube real-time PCR assay which covers 16 trematode (28S rRNA gene), 24 cestode (cox1gene) and 33 nematode (cox1gene) species. Helminths (n=27) from faecal samples (n=10), fresh parasites (n=11), formalin-fixed specimens (n=4), cerebrospinal fluid (n=1) and bile (n=1) were examined morphologically and tested by PCR. Fifty stool samples negative for parasites by microscopy were also tested.ResultsThe PCR assay correctly identified the genera of all tested helminths. Agarose gel electrophoresis and sequencing of the purified PCR amplicons confirmed that the PCR products were of correct sizes with 100% correlation with the respective species. Sequencing of thecox1gene failed to identifyCapillariaspp. in one sample owing to the lack of corresponding sequences in GenBank. PCR and sequencing of the nematode 18S rRNA gene using consensus primers showed 100% homology withCapillariaspp. sequence. No positive PCR products were found in the negative stool samples.ConclusionsThe highly specific test correctly identified all helminths in our cohort. It is a useful adjunct to helminth identification in difficult situations such as histological sections.
Cigarette smoking quit ratios among adults in the USA with cannabis use and cannabis use disorders, 2002–2016
Authors: Weinberger Andrea H , Pacek Lauren R , Wall Melanie M , Gbedemah Misato , Lee Joun , Goodwin Renee D 
Published: April 2019

BackgroundThe prevalence of cigarette smoking is nearly three times higher among persons who use cannabis and have cannabis use disorders (CUDs), relative to those who do not. The current study examined cigarette quit ratios from 2002 to 2016 among US adults with and without cannabis use and CUDs.MethodsThe current study analysed US adults aged 18 years and older from the National Survey on Drug Use and Health, an annual cross-sectional study. Quit ratios (ie, proportion of former smokers among ever-smokers) were calculated annually from 2002 to 2016. Time trends in quit ratios by cannabis use/CUDs were tested using logistic regression.ResultsIn 2016, the quit ratios for people with any cannabis use (23%) and CUDs (15%) were less than half the quit ratios of those without cannabis use and CUDs (51% and 48%, respectively). After controlling for demographics and substance use disorders, the quit ratio did not change from 2002 to 2016 among persons with CUD, though it non-linearly increased among persons with cannabis use, without cannabis use and without CUDs. Quit ratios increased more rapidly among those who reported past-month cannabis use compared with those without past-month cannabis use.ConclusionsCigarette smoking quit ratios remain dramatically lower among people who use cannabis and have CUDs and quit ratios did not change significantly from 2002 to 2016 among those with CUDs. Public health and clinical attention are needed to increase quit ratios and reduce harmful cigarette smoking consequences for persons with cannabis use and CUDs.
First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity
Authors: Gan Hui K. , Millward Michael , Hua Ye , Qi Chuan , Sai Yang , Su Weiguo , Wang Jian , Zhang Lilin , Frigault Melanie M. , Morgan Shethah , Yang Liu , Lickliter Jason D. 
Published: April 2019

Abstract

Purpose:
Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).

Patients and Methods:
This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.

Results:
Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.

Conclusions:
The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial
Authors: Anandappa Gayathri , Lampis Andrea , Cunningham David , Khan Khurum H. , Kouvelakis Kyriakos , Vlachogiannis Georgios , Hedayat Somaieh , Tunariu Nina , Rao Sheela , Watkins David , Starling Naureen , Braconi Chiara , Darvish-Damavandi Mahnaz , Lote Hazel , Thomas Janet , Peckitt Clare , Kalaitzaki Ria , Khan Nasir , Fotiadis Nicos , Rugge Massimo , Begum Ruwaida , Rana Isma , Bryant Annette , Hahne Jens C. , Chau Ian , Fassan Matteo , Valeri Nicola 
Published: April 2019

Abstract

Purpose:
Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs.

Experimental Design:
miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination.

Results:
Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer).

Conclusions:
Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.
Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer
Authors: Won Elizabeth , Basunia Azfar , Chatila Walid K. , Hechtman Jaclyn F. , Chou Joanne F. , Ku Geoffrey Y. , Chalasani Sree B. , Boyar Michelle S. , Goldberg Zoe , Desai Avni M. , Tuvy Yaelle , Berger Michael F. , Tang Laura , Kelsen David P. , Schattner Mark , Ilson David H. , Capanu Marinela , Solit David B. , Schultz Nikolaus , Janjigian Yelena Y. 
Published: April 2019

Abstract

Purpose:
VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib.

Patients and Methods:
Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response.

Results:
The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months–NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019).

Conclusions:
Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.
A Novel Autocrine CXCL14/ACKR2 Axis: The Achilles' Heel of Cancer Metastasis?
Authors: Zhang Qian , Zhou Nianxin , Wang Wei , Zhou Shengtao 
Published: April 2019

Abstract
Cancer-associated fibroblasts (CAF) are essential for cancer hallmarks. While CAFs are molecularly heterogeneous, a CXCL14-expressing subset has been a critical player in the cancer context. In breast cancer, an autocrine fibroblast CXCL14/ACKR2 axis mediates epithelial-to-mesenchymal transition and endows metastatic traits, which offers novel therapeutic potential in the clinical setting.
See related article by Sjöberg et al., p. 3702
Tissue-Specific Oncogenic Activity of KRASA146T
Authors: Poulin Emily J. , Bera Asim K. , Lu Jia , Lin Yi-Jang , Strasser Samantha Dale , Paulo Joao A. , Huang Tannie Q. , Morales Carolina , Yan Wei , Cook Joshua , Nowak Jonathan A. , Brubaker Douglas K. , Joughin Brian A. , Johnson Christian W. , DeStefanis Rebecca A. , Ghazi Phaedra C. , Gondi Sudershan , Wales Thomas E. , Iacob Roxana E. , Bogdanova Lana , Gierut Jessica J. , Li Yina , Engen John R. , Perez-Mancera Pedro A. , Braun Benjamin S. , Gygi Steven P. , Lauffenburger Douglas A. , Westover Kenneth D. , Haigis Kevin M. 
Published: April 2019

Abstract

KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor–induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer.

Significance:
Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties.
See related commentary by Hobbs and Der, p. 696.
This article is highlighted in the In This Issue feature, p. 681
Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population
Authors: Alzahrani Talal , Nguyen Tran , Ryan Angela , Dwairy Ahmad , McCaffrey James , Yunus Raza , Forgione Joseph , Krepp Joseph , Nagy Christian , Mazhari Ramesh , Reiner Jonathan 
Published: April 2019

Background:
As of 2016, ≈1.4 million people in the United States identify as transgender. Despite their growing number and increasing specific medical needs, there has been a lack of research on cardiovascular disease (CVD) and CVD risk factors in this population. Recent studies have reported that the transgender population had a significantly higher rate of CVD risk factors without a significant increase in overall CVD morbidity and mortality. These studies are limited by their small sample sizes and their predominant focus on younger transgender populations. With a larger sample size and inclusion of broader age range, our study aims to provide insight into the association between being transgender and cardiovascular risk factors, as well as myocardial infarction.

Methods and Results:

The Behavioral Risk Factor Surveillance System data from 2014 to 2017 were used to evaluate the cross-sectional association between being transgender and the reported history of myocardial infarction and CVD risk factors. A logistic regression model was constructed to study the association between being transgender and myocardial infarction after adjusting for CVD risk factors including age, diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease, smoking, and exercise. Multivariable analysis revealed that transgender men had a >2-fold and 4-fold increase in the rate of myocardial infarction compared with cisgender men (odds ratio, 2.53; 95% CI, 1.14–5.63;
P
=0.02) and cisgender women (odds ratio, 4.90; 95% CI, 2.21–10.90;
P
<0.01), respectively. Conversely, transgender women had >2-fold increase in the rate of myocardial infarction compared with cisgender women (odds ratio, 2.56; 95% CI, 1.78–3.68;
P
<0.01) but did not have a significant increase in the rate of myocardial infarction compared with cisgender men.

Conclusions:
The transgender population had a higher reported history of myocardial infarction in comparison to the cisgender population, except for transgender women compared with cisgender men, even after adjusting for cardiovascular risk factors.
Loss of Super-Enhancer-Regulated circRNA Nfix Induces Cardiac Regeneration After Myocardial Infarction in Adult Mice
Authors: Huang Senlin , Li Xinzhong , Zheng Hao , Si Xiaoyun , Li Bing , Wei Guoquan , Li Chuling , Chen Yijin , Chen Yanmei , Liao Wangjun , Liao Yulin , Bin Jianping 
Published: April 2019

Background:
circRNAs (circular RNAs) are emerging as powerful regulators of cardiac development and disease, but their roles in cardiac regeneration are still unknown. This study used superenhancers to distinguish key circRNAs in the regulation of cardiac regeneration and explored the mechanisms underlying circRNA functions.

Methods:
We used integrated bioinformatics analysis of RNA sequencing data and superenhancer catalogs to identify superenhancer-associated circRNAs. Quantitative polymerase chain reactions and in situ hybridization were performed to determine the circRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of circRNAs in cardiomyocyte proliferation and cardiac repair after myocardial infarction. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays were used to determine the binding of Meis1 (Meis homeobox 1) on circNfix-associated superenhancers. RNA pulldown and luciferase reporter assays were used to study circRNA interactions with proteins and miRNAs (micro RNAs).

Results:
We identified a circRNA, Nfix circRNA (circNfix), that was regulated by a superenhancer and overexpressed in the adult heart in humans, rats, and mice. The transcription factor Meis1 bound to the superenhancer at the circNfix locus, and increased its expression. In vitro and in vivo, cardiomyocyte proliferation was increased by knockdown of circNfix, whereas it was inhibited by circNfix overexpression. Moreover, circNfix downregulation promoted cardiomyocyte proliferation and angiogenesis and inhibited cardiomyocyte apoptosis after myocardial infarction, attenuating cardiac dysfunction and improving the prognosis. Mechanistically, circNfix reinforced the interaction of Ybx1 (Y-box binding protein 1) with Nedd4l (an E3 ubiquitin ligase), and induced Ybx1 degradation through ubiquitination, repressing cyclin A2 and cyclin B1 expression. In addition, circNfix acted as a sponge for miR-214 to promote Gsk3β (glycogen synthase kinase 3 β) expression and repress β-catenin activity.

Conclusions:
Loss of superenhancer-regulated circNfix promotes cardiac regenerative repair and functional recovery after myocardial infarction by suppressing Ybx1 ubiquitin-dependent degradation and increasing miR-214 activity and thus may be a promising strategy for improving the prognosis after MI.
Association of Statin Use and Mortality After Transcatheter Aortic Valve Replacement
Authors: Peri‐Okonny Poghni A. , Liu Yangbo , Malaisrie S. Chris , Huded Chetan P. , Kapadia Samir , Thourani Vinod H. , Kodali Susheel K. , Webb John , McAndrew Thomas C. , Leon Martin B. , Cohen David J. , Arnold Suzanne V. 
Published: April 2019

Background
Statins may reduce mortality after transcatheter aortic valve replacement (TAVR) through prevention of atherosclerotic events or pleiotropic effects. However, the competing mortality risks in TAVR patients may dilute any positive effect of statins. We sought to understand the association of statin use with post‐TAVR mortality.

Methods and Results

We included high– or intermediate–surgical risk patients who underwent TAVR as a part of the PARTNER (Placement of Aortic Transcatheter Valves) II and Sapien 3 trials and registries. Outcomes included 2‐year all‐cause, cardiovascular, and noncardiovascular mortality. We used propensity score matching to generate matched pairs between those discharged on a statin and those not on a statin after TAVR. Bias was explored with falsification end points (urinary infection, hip fracture). Among 3956 patients who underwent TAVR, we matched 626 patients on a statin with 626 patients not on a statin at discharge. Among matched patients, statin use was associated with lower risk of all‐cause (hazard ratio [HR] 0.65, 95% CI 0.49‐0.87,
P
=0.001), cardiovascular (HR 0.66, 95% CI 0.46‐0.96,
P
=0.030), and noncardiovascular mortality (HR 0.64, 95% CI 0.44‐0.99,
P
=0.045) compared with no statin use. The survival curves diverged within 3 months and continued to separate over a median follow‐up of 2.1 years. The falsification end points were similar among groups (urinary infection,
P
=0.66; hip fracture,
P
=0.64).

Conclusions
In an observational, propensity‐matched analysis of TAVR patients, statin use was associated with lower rates of cardiovascular and noncardiovascular mortality compared with no statin use. Given the early emergence of the apparent protective effect of statins, this result may be driven either by pleiotropic effects or by residual confounding despite propensity‐matching methodology.
Nahum 2:14 Text-Critical Notes
Authors: Hartog Pieter B. 
Published: April 2019

Abstract
Two reading traditions are reflected in the ancient witnesses to Nahum 2:14, which can be referred to as ‘masculine’ (4Q169) and ‘feminine’ (MT, TJon, P), depending on the implied referent of the suffixes in this verse. It is argued in this contribution that the textual history of Nahum 2:14 and the origins of these two reading traditions can be explained from the relationship between the Hebrew words רכב and רב, which presumably go back to a common source *רכבכה. This can be taken as evidence that the masculine reading of Nahum 2:14 is the more original one, whereas the feminine reading is the outcome of textual corruption.
Phylogenetic analysis of exotic invasive species of the brine shrimp Artemia Leach, 1819 (Branchiopoda, Anostraca) in Al Wathba Wetland Reserve (U.A.E.; Abu Dhabi)
Authors: Saji Anitha , Eimanifar Amin , Soorae Pritpal S. , Al Dhaheri Shaikha , Li Weidong , Wang Pei-Zheng , Asem Alireza 
Published: April 2019

Abstract
The taxonomic identity of an unknown Artemia population inhabiting the Al Wathba Wetland Reserve in Abu Dhabi, U.A.E., was determined using phylogenetic analysis of the mitochondrial marker Cytochrome Oxidase Subunit 1 (COI). The results showed that the examined population belongs to an exotic invasive species, Artemia franciscana. Based on the distribution pattern of haplotypes, the studied population could possibly have originated from that inhabiting the Great Salt Lake (Utah, U.S.A.).