bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical reasoning in canine cervical hyperaesthesia: which presenting features are important?
Authors: Grapes Nicholas John , Packer Rowena Mary Anne , De Decker Steven 
Published: September 2020

BackgroundTo evaluate whether clinical features from the history, presentation, physical and neurological examination of dogs with cervical hyperaesthesia are statistically predictive of the underlying diagnosis.MethodsTwo hundred and ninety‐eight dogs presenting with cervical hyperaesthesia between January 2010 and October 2018 were investigated. Only neurologically normal dogs with cervical hyperaesthesia on examination were included, while those with concurrent neurological deficits including gait abnormalities and proprioceptive deficits were excluded. Univariate analysis of clinical variables was performed, and those associated with each diagnosis were retained for multivariable binary logistic regression models.ResultsNinety‐five per cent of cervical hyperaesthesia presentations were represented by eight conditions that included steroid‐responsive meningitis arteritis (SRMA; n=100), intervertebral disc extrusion (n=78), syringomyelia (SM; n=51), intervertebral disc protrusion (n=30), neoplasia (n=8), cervical spondylomyelopathy (n=7), immune‐mediated polyarthritis (n=5) and meningoencephalomyelitis of unknown aetiology (n=5). Younger age (P=0.003), pyrexia (P=0.003) and haematology abnormalities (P=0.03) comprising leucocytosis, neutrophilia or monocytosis were associated with a diagnosis of SRMA.ConclusionsEasy‐to‐recognise clinical features can be used to identify the most likely differential diagnosis in neurologically normal dogs with cervical hyperaesthesia, which may aid the decision making of veterinary surgeons evaluating dogs with this presentation.
Flexible Resistive Switching Memory Devices Based on Graphene Oxide Polymer Nanocomposite
Authors: Zhao Enming , Liu Shuangqiang , Liu Xiaodan , Wang Chen , Liu Guangyu , Xing Chuanxi 
Published: September 2020

Flexible resistive switching memory devices based on graphene oxide (GO) polymer nanocomposite were prepared on flexible substrate to research the influence of bending on resistive switching behavior. The devices showed evident response in resistive switching memory characteristics to flexible bending. The 2000 cycles flexible bending leads to the switch of resistive switching memory characteristic from write-once-read-many time memory (WORM) to static random access memory (SRAM). Both WORM and SRAM memory properties are all repeatable, and the threshold switching voltage also showed good consistency. The resistive switching mechanism is attributed to the formation of carbon-rich conductive filaments for nonvolatile WORM characteristics. The bending-induced micro-crack may be responsible for the partial broken of the electrical channels, and may lead to the volatile SRAM characteristics.
Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer
Authors: Azar Walid J. , Christie Elizabeth L. , Mitchell Chris , Liu David S. , Au-Yeung George , Bowtell David D.L. 
Published: September 2020

Abstract

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date.

Significance:
This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.
Radiomics Improves Cancer Screening and Early Detection
Authors: Gillies Robert J. , Schabath Matthew B. 
Published: September 2020

AbstractImaging is a key technology in the early detection of cancers, including X-ray mammography, low-dose CT for lung cancer, or optical imaging for skin, esophageal, or colorectal cancers. Historically, imaging information in early detection schema was assessed qualitatively. However, the last decade has seen increased development of computerized tools that convert images into quantitative mineable data (radiomics), and their subsequent analyses with artificial intelligence (AI). These tools are improving diagnostic accuracy of early lesions to define risk and classify malignant/aggressive from benign/indolent disease. The first section of this review will briefly describe the various imaging modalities and their use as primary or secondary screens in an early detection pipeline. The second section will describe specific use cases to illustrate the breadth of imaging modalities as well as the benefits of quantitative image analytics. These will include optical (skin cancer), X-ray CT (pancreatic and lung cancer), X-ray mammography (breast cancer), multiparametric MRI (breast and prostate cancer), PET (pancreatic cancer), and ultrasound elastography (liver cancer). Finally, we will discuss the inexorable improvements in radiomics to build more robust classifier models and the significant limitations to this development, including access to well-annotated databases, and biological descriptors of the imaged feature data.See all articles in this CEBP Focus section, “NCI Early Detection Research Network: Making Cancer Detection Possible.”
Prediagnostic Circulating Concentrations of Vitamin D Binding Protein and Survival among Patients with Colorectal Cancer
Authors: Yuan Chen , Song Mingyang , Zhang Yin , Wolpin Brian M. , Meyerhardt Jeffrey A. , Ogino Shuji , Hollis Bruce W. , Chan Andrew T. , Fuchs Charles S. , Wu Kana , Wang Molin , Smith-Warner Stephanie A. , Giovannucci Edward L. , Ng Kimmie 
Published: September 2020

Abstract

Background:
Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with improved survival among patients with colorectal cancer, but the relationships between circulating vitamin D binding protein (VDBP), and bioavailable or free 25(OH)D, and colorectal cancer survival remain unknown.

Methods:
We examined the associations between prediagnostic plasma levels of vitamin D–related markers and survival among 603 White participants diagnosed with colorectal cancer from two prospective U.S. cohorts. Plasma VDBP and total 25(OH)D were directly measured, while bioavailable and free 25(OH)D was calculated using a validated formula on the basis of total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards regression was used to estimate HRs for overall and colorectal cancer–specific mortality, with adjustment for other prognostic markers and potential confounders.

Results:
Higher VDBP levels were associated with improved overall (Ptrend = 0.001) and colorectal cancer–specific survival (Ptrend = 0.02). Compared with patients in the lowest quartile, those in the highest quartile of VDBP had a multivariate HR of 0.58 [95% confidence interval (CI), 0.41–0.80] for overall mortality and 0.58 (95% CI, 0.37–0.91) for colorectal cancer–specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, neither bioavailable nor free 25(OH)D levels were associated with overall or colorectal cancer–specific mortality (all Ptrend &gt; 0.15).

Conclusions:
Prediagnostic circulating concentrations of VDBP were positively associated with survival among patients with colorectal cancer.

Impact:
The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action.
Automated Quantitative Measures of Terminal Duct Lobular Unit Involution and Breast Cancer Risk
Authors: Kensler Kevin H. , Liu Emily Z.F. , Wetstein Suzanne C. , Onken Allison M. , Luffman Christina I. , Baker Gabrielle M. , Collins Laura C. , Schnitt Stuart J. , Bret-Mounet Vanessa C. , Veta Mitko , Pluim Josien P.W. , Liu Ying , Colditz Graham A. , Eliassen A. Heather , Hankinson Susan E. , Tamimi Rulla M. , Heng Yujing J. 
Published: September 2020

Abstract

Background:
Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk.

Methods:
We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case–control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes.

Results:
Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index (P &lt; 0.05). No measure was correlated with body size at ages 5–10 years, age at menarche, age at first birth, or breastfeeding history (P &gt; 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk.

Conclusions:
Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer.

Impact:
TDLU involution may not impact breast cancer risk as previously thought.
Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype
Authors: Jaiswal Ashvin R. , Liu Arthur J. , Pudakalakatti Shivanand , Dutta Prasanta , Jayaprakash Priyamvada , Bartkowiak Todd , Ager Casey R. , Wang Zhi-Qiang , Reuben Alexandre , Cooper Zachary A. , Ivan Cristina , Ju Zhenlin , Nwajei Felix , Wang Jing , Davies Michael A. , Davis R. Eric , Wargo Jennifer A. , Bhattacharya Pratip K. , Hong David S. , Curran Michael A. 
Published: September 2020

Abstract
Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a “hypermetabolic” phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.
Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas
Authors: Edwards Jarem , Ferguson Peter M. , Lo Serigne N. , Pires da Silva Inês , Colebatch Andrew J. , Lee Hansol , Saw Robyn P.M. , Thompson John F. , Menzies Alexander M. , Long Georgina V. , Newell Felicity , Pearson John V. , Waddell Nicola , Hayward Nicholas K. , Johansson Peter A. , Mann Graham J. , Scolyer Richard A. , Palendira Umaimainthan , Wilmott James S. 
Published: September 2020

Abstract
Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
Characteristics of Esophageal Injury in Ablation of Atrial Fibrillation Using a High-Power Short-Duration Setting
Authors: Kaneshiro Takashi , Kamioka Masashi , Hijioka Naoko , Yamada Shinya , Yokokawa Tetsuro , Misaka Tomofumi , Hikichi Takuto , Yoshihisa Akiomi , Takeishi Yasuchika 
Published: September 2020

Background:
The mechanism of esophageal thermal injury (ETI; esophageal mucosal injury and periesophageal nerve injury leading to gastric hypomotility) remains unknown when using a high-power short-duration (HP-SD) setting. This study sought to evaluate the characteristics of esophageal injuries in atrial fibrillation ablation using a HP-SD setting.

Methods:
After exclusion of 5 patients with their esophagus at the right portion of left atrium and 21 patients with additional ablations such as box isolation and low voltage area ablation in left atrium posterior wall, 271 consecutive patients (62±10 years, 56 women) who underwent pulmonary vein isolation by radiofrequency catheter ablation were analyzed. In the 101 patients, a HP-SD setting at 45 to 50 W with an Ablation Index module was used (HP-SD group). In the remaining 170 patients before introduction of the HP-SD setting, a conventional power setting of 20 to 30 W with contact force monitoring was used (conventional group). We performed esophagogastroduodenoscopy after pulmonary vein isolation in all patients and investigated the incidence and characteristics of ETI.

Results:

Although the incidence of ETI was significantly higher in the HP-SD group compared with the conventional group (37% versus 22%,
P
=0.011), the prevalence of esophageal lesions did not differ between the groups (7% versus 8%). Multivariate logistic regression analysis revealed that the use of the HP-SD setting (odds ratio, 6.09,
P
<0.001), and the parameters that suggest anatomic proximity surrounding the esophagus, were independent predictors of ETI. However, the majority of ETI in the HP-SD group was gastric hypomotility, and the thermal injury was limited to the shallow layer of the periesophageal wall using the HP-SD setting.

Conclusions:
Although the use of the HP-SD setting was a strong predictor of ETI, it could avoid deeper thermal injuries that reach the esophageal mucosal layer.
ILRUN
, a Human Plasma Lipid GWAS Locus, Regulates Lipoprotein Metabolism in Mice
Authors: Bi Xin , Kuwano Takashi , Lee Paul C. , Millar John S. , Li Li , Shen Yachen , Soccio Raymond E. , Hand Nicholas J. , Rader Daniel J. 
Published: September 2020

Rationale:

Single-nucleotide polymorphisms near the
ILRUN
(inflammation and lipid regulator with ubiquitin-associated–like and NBR1 [next to
BRCA1
gene 1 protein]-like domains) gene are genome-wide significantly associated with plasma lipid traits and coronary artery disease (CAD), but the biological basis of this association is unknown.

Objective:
To investigate the role of ILRUN in plasma lipid and lipoprotein metabolism.

Methods and Results:

ILRUN
encodes a protein that contains a ubiquitin-associated–like domain, suggesting that it may interact with ubiquitinylated proteins. We generated mice globally deficient for
Ilrun
and found they had significantly lower plasma cholesterol levels resulting from reduced liver lipoprotein production. Liver transcriptome analysis uncovered altered transcription of genes downstream of lipid-related transcription factors, particularly PPARα (peroxisome proliferator-activated receptor alpha), and livers from
Ilrun
-deficient mice had increased PPARα protein. Human ILRUN was shown to bind to ubiquitinylated proteins including PPARα, and the ubiquitin-associated–like domain of ILRUN was found to be required for its interaction with PPARα.

Conclusions:

These findings establish ILRUN as a novel regulator of lipid metabolism that promotes hepatic lipoprotein production. Our results also provide functional evidence that
ILRUN
may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in human.
Calcium‐Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling
Authors: Nagata Manabu , Minami Manabu , Yoshida Kazumichi , Yang Tao , Yamamoto Yu , Takayama Naoki , Ikedo Taichi , Hayashi Kosuke , Miyata Takeshi , Yokode Masayuki , Miyamoto Susumu 
Published: September 2020

Background
Carotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium‐binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression.

Methods and Results

Preoperative high‐resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E‐deficient mice fed a high‐fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of
S100A4
,
MMP2
, and
MMP9
.
S100A4
mRNA levels were positively correlated with those of
MMP2
,
MMP9
, and
MMP13
. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC‐derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of
Mmp2
,
Mmp9
, and
Mmp13
and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs.

Conclusions
S100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4‐positive VSMC‐derived cells are considered to play an important role in carotid expansive remodeling.
Factors Associated With Participation in the Chronic Disease Self-Management Program
Authors: Lin Amy M. , Vickrey Barbara G. , Barry Frances , Lee Martin L. , Ayala-Rivera Monica , Cheng Eric , Montoya Ana V. , Mojarro-Huang Elizabeth , Gomez Patricia , Castro Marissa , Corrales Marilyn , Sivers-Teixeira Theresa , Tran Jamie L. , Johnson Renee , Ediss Chris , Shaby Betty , Willis Phyllis , Sanossian Nerses , Mehta Bijal , Dutta Tara , Razmara Ali , Bryg Robert , Song Shlee , Towfighi Amytis 
Published: September 2020

Background and Purpose:
Self-management programs may improve quality of life and self-efficacy for stroke survivors, but participation is low. In a randomized controlled trial of a complex, multidisciplinary, team-based secondary stroke prevention intervention, we offered participants Chronic Disease Self-Management Program (CDSMP) workshops in addition to clinic visits and home visits. To enhance participation, workshops were facilitated by community health workers who were culturally and linguistically concordant with most participants and scheduled CDSMP sessions at convenient venues and times. Over time, we implemented additional strategies such as free transportation and financial incentives. In this study, we aimed to determine factors associated with CDSMP participation and attendance.

Methods:
From 2014 to 2018, 18 CDSMP workshop series were offered to 241 English and Spanish-speaking individuals (age ≥40 years) with recent stroke or transient ischemic attack. Zero-inflated Poisson regression was used to identify factors associated with participation and attendance (ie, number of sessions attended) in CDSMP. Missing values were imputed using multiple imputation methods.

Results:
Nearly one-third (29%) of intervention subjects participated in CDSMP. Moderate disability and more clinic/home visits were associated with participation. Participants with higher numbers of clinic and home visits (incidence rate ratio [IRR], 1.06 [95% CI, 1.01–1.12]), severe (IRR, 2.34 [95% CI, 1.65–3.31]), and moderately severe disability (IRR, 1.55 [95% CI, 1.07–2.23]), and who enrolled later in the study (IRR, 1.12 [95% CI, 1.08–1.16]) attended more sessions. Individuals with higher chaos scores attended fewer sessions (IRR, 0.97 [95% CI, 0.95–0.99]).

Conclusions:
Less than one-third of subjects enrolled in the SUCCEED (Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities) intervention participated in CDSMP; however, participation improved as transportation and financial barriers were addressed. Strategies to address social determinants of health contributing to chaos and engage individuals in healthcare may facilitate attendance.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01763203.