bluuebunny/crossref_metadata_2025_split huggingface dataset:
The rights and duties of immigrants in liberal societies
Authors: Higgins Peter W. 
Published: June 2018

AbstractWhat legal rights and duties immigrants should have is among the most ferociously debated topics in the politics of liberal societies today. However, as this article will show, there is remarkably little disagreement of great magnitude among political theorists and philosophers of immigration on the rights and duties of resident immigrants (even in contrast to the closely related philosophical discussion of justice in immigrant admissions). Specifically, this article will survey philosophical positions both on what legal rights immigrants (documented permanent residents, guest workers, and undocumented immigrants) ought to have (including to citizenship and against deportation) and on what liberal societies may justly do to require immigrants to integrate. This article will reveal that there is a substantial, growing gap between contemporary politics worldwide and what the moral norms of liberalism seem to entail concerning the rights and duties of immigrants.
Demographic change and long‐term growth in China: Past developments and the future challenge of aging
Authors: Hsu Minchung , Liao Pei‐Ju , Zhao Min 
Published: June 2018

AbstractThis paper explores the influence of demographic changes, particularly the sharp decline in fertility and the evolution of the population age structure, on economic development in China. A general equilibrium overlapping generations model with endogenous decisions on fertility, educational investment, and factor accumulation is employed for our analysis. The family support provided by children to the elderly, which is a component of traditional culture in Chinese society, is also considered. We find that technological changes matter most for growth. Demographic changes, on average, account for approximately 4% of the growth in China, while the effect is negative in the pre‐1980 period. With an extension to include population aging, we find that aging is not necessarily adverse to growth. This finding reflects the fact that a longer life expectancy requires more savings and makes educational investment in children more attractive, which accelerates physical capital and human capital accumulation. However, if the social norm of family support for aging parents is strict, aging will significantly increase the children's burden and crowd out physical and human capital accumulation.
Oral health care for patients with developmental disabilities: A survey of Michigan general dentists
Authors: Byrappagari Divesh , Jung Youngjin , Chen Kelvin 
Published: June 2018

AbstractAimsThe aim of this study to examine the level of access to dental care in Michigan for individuals with DD and explore the dentists’ practices, attitudes, and perceived barriers to providing care to this vulnerable population.Methods and resultsA survey was mailed to a random sample of 1250 general dental practitioners with an active license in the State of Michigan. The survey included questions related to dentists’ demographic information, opinion about willingness, barriers, and training needs associated with delivering care to children and adults with developmental disabilities. Descriptive statistics were computed and chi‐squared tests and logistic regression models analyzed the association between predictor and key outcome variables. Results show that most dentists treated individuals with developmental disabilities (80.3%). Respondents who indicated that they currently do not treat these patients identified behavior management of patient (67.9%), inadequate training and experiences (52.4%) and severity of patient's condition (41.7%) as the most common reasons for not providing care to individuals with developmental disabilities.ConclusionA majority of Michigan general dentists treat patients with developmental disabilities. Addressing barriers like training and improved reimbursements might help in increasing the number of dentists willing to treat patients with developmental disabilities.
Adoption of paediatric and neonatal pulse oximetry by 12 hospitals in Nigeria: a mixed-methods realist evaluation
Authors: Graham Hamish R , Bakare Ayobami A , Gray Amy , Ayede Adejumoke Idowu , Qazi Shamim , McPake Barbara , Izadnegahdar Rasa , Duke Trevor , Falade Adegoke G 
Published: June 2018

IntroductionPulse oximetry is a life-saving tool for identifying children with hypoxaemia and guiding oxygen therapy. This study aimed to evaluate the adoption of oximetry practices in 12 Nigerian hospitals and identify strategies to improve adoption.MethodsWe conducted a mixed-methods realist evaluation to understand how oximetry was adopted in 12 Nigerian hospitals and why it varied in different contexts. We collected quantitative data on oximetry use (from case notes) and user knowledge (pretraining/post-training tests). We collected qualitative data via focus groups with project nurses(n=12)and interviews with hospital staff (n=11). We used the quantitative data to describe the uptake of oximetry practices. We used mixed methods to explain how hospitals adopted oximetry and why it varied between contexts.ResultsBetween January 2014 and April 2017, 38 525 children (38% aged ≤28 days) were admitted to participating hospitals (23 401 pretraining; 15 124 post-training). Prior to our intervention, 3.3% of children and 2.5% of neonates had oximetry documented on admission. In the 18 months of intervention period, all hospitals improved oximetry practices, typically achieving oximetry coverage on >50% of admitted children after 2–3 months and >90% after 6–12 months. However, oximetry adoption varied in different contexts. We identified key mechanisms that influenced oximetry adoption in particular contexts.ConclusionPulse oximetry is a simple, life-saving clinical practice, but introducing it into routine clinical practice is challenging. By exploring how oximetry was adopted in different contexts, we identified strategies to enhance institutional adoption of oximetry, which will be relevant for scale-up of oximetry in hospitals globally.Trial registration numberACTRN12617000341325.
Study protocol of a 52-week Prospective Running INjury study in Gothenburg (SPRING)
Authors: Jungmalm Jonatan , Grau Stefan , Desai Pia , Karlsson Jon , Nielsen Rasmus Østergaard 
Published: June 2018

IntroductionIt is assumed that a running-related (overuse) injury occurs when a specific structure of the human body is exposed to a load that exceeds that structures’ load capacity. Therefore, monitoring training load is an important key to understanding the development of a running-related injury. Additionally, other distribution, magnitude and capacity-related factors should be considered when aiming to understand the causal chain of injury development. This paper presents a study protocol for a prospective cohort study that aims to add comprehensive information on the aetiology of running-related injuries and present a new approach for investigating changes in training load with regard to running-related injuries.Methods and analysisThis study focused on recreational runners, that is, runners exposed to a minimum weekly average of 15 km for at least 1 year. Participants will undergo baseline tests consisting of a clinical/anthropometrical examination and biomechanical measurements. Furthermore, participants will log all training sessions in a diary on a weekly basis for 1 year. The primary exposure variable is changes in training load. A medical practitioner will examine runners suffering from running-related pain and, if possible, make a clear diagnosis. Finally, additional time-varying exposure variables will be included in the main analysis, whereas the analysis for the secondary purpose is based on time-fixed baseline-related risk factors.Ethics and disseminationEthical approval (DNR: 712–15) for the study and its design was obtained from the Gothenburg regional ethical review board. The results of the study will be published in peer-reviewed journals.
The 7-day contraceptive hormone-free interval should be consigned to history
Authors: MacGregor E Anne , Guillebaud John 
Published: June 2018

AimThis review summarises the available data on the disadvantages of the 7-day contraceptive-free interval (CFI) of combined oral contraceptives (COCs), in contrast to shorter CFIs or continuous use – including flexible regimens – and provides recommendations for practice.MethodsRelevant papers were identified by Medline and PubMed. The final reference list was generated on the basis of relevance to the review, with priority given to systematic reviews and randomised controlled trials.ResultsThere is considerable inter- and intra-individual variation in the absorption and metabolism of COCs. Even with perfect use, the loss of endocrine suppression during the standard 7-day CFI allows follicular development with the risk of escape ovulation in a vulnerable minority. This risk increases in typical users whenever the CFI is prolonged: late restarts are a common reason for pill omissions. Shortening or eliminating the CFI improves contraceptive efficacy using the lowest doses available, without evidence to date of compromised safety.ConclusionsThere is no scientific evidence to support a 7-day CFI and it should be replaced either by a continuous flexible regimen, or extended regimens with a shortened CFI, prescribed first-line. In women preferring a monthly ‘bleed’, a 4-day CFI similarly provides a greater safety margin when pills are omitted.
Malignant melanoma with central nervous system involvement in a dog treated with surgery, radiotherapy and chemotherapy
Authors: Perez Lopez Pablo , Rasotto Roberta , Caine Abby , Cherubini Giunio Bruto 
Published: June 2018

A five‐year‐old female entire cocker spaniel was admitted for acute obtundation and non‐ambulatory tetraparesis. MRI of the brain revealed a mass lesion in the right olfactory and frontal lobe area and in the right frontal sinus. Transfrontal craniotomy was performed for surgical excision, with intraoperative application of cytarabine and methotrexate. At discharge, the dog was ambulatory with mild generalised ataxia. Histopathology and immunohistochemistry revealed a malignant melanoma. Lomustine was initiated. Six months after surgery the dog was readmitted for right exophthalmos, due to a right retrobulbar mass that was surgically excised. Histopathology confirmed melanoma, and a course of radiotherapy was added and lomustine restarted. The dog was euthanased after further 17 months for relapsing neurological signs secondary to recurrent CNS melanoma. This treatment of a melanoma with CNS involvement showed encouraging results, achieving a total survival time of 23 months.
Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients
Authors: Hompland Tord , Hole Knut Håkon , Ragnum Harald Bull , Aarnes Eva-Katrine , Vlatkovic Ljiljana , Lie A. Kathrine , Patzke Sebastian , Brennhovd Bjørn , Seierstad Therese , Lyng Heidi 
Published: June 2018

Abstract
The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo. Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice.
Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg. Cancer Res; 78(16); 4774–85. ©2018 AACR.
Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma
Authors: Hong Shiao-Ya , Kao Yu-Rung , Lee Te-Chang , Wu Cheng-Wen 
Published: June 2018

Abstract
CBLC (CBL proto-oncogene c) belongs to the CBL protein family, which has E3 ubiquitin ligase activity toward activated receptor tyrosine kinases. CBLC is frequently upregulated in non–small cell lung cancer (NSCLC), yet very little is known about the functions of CBLC in tumorigenesis. Here we show that CBLC is an epigenetically demethylated target and its expression can be upregulated in NSCLC after treatment with the DNA methylation inhibitor 5′-azacytidine. Depletion of CBLC significantly inhibited cell viability and clonogenicity in vitro and reduced tumor growth in a xenograft model. CBLC silencing further sensitized EGFR-mutated NSCLC cells to treatment with tyrosine kinase inhibitors. Conversely, ectopic expression of CBLC enhanced the activation of EGFR and downstream ERK1/2 signaling after ligand stimulation by competing with CBL for EGFR binding. Analysis of ubiquitin linkages on activated EGFR (aEGFR) revealed that CBLC ubiquitinated and positively regulated aEGFR stability through the conjugation of polyubiquitin by K6 and K11 linkages. This CBLC-mediated polyubiquitination promoted either preferential recycling of aEGFR back to the plasma membrane or trafficking to the cell nucleus. IHC analyses revealed a positive correlation between phospho-EGFR and CBLC in lung adenocarcinoma. In summary, we demonstrate a novel mechanism by which aEGFR escapes lysosomal degradation in a CBLC/ubiquitin-dependent manner to sustain its activation. Our work identifies CBLC as a potential diagnostic biomarker and also points to its utilization as a novel therapeutic target for NSCLC therapy.
Significance: This work demonstrates the role of CBLC expression as a diagnostic biomarker and potential therapeutic target in lung adenocarcinoma. Cancer Res; 78(17); 4984–96. ©2018 AACR.
Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer
Authors: Li Shuai , Liu Shengwu , Deng Jiehui , Akbay Esra A. , Hai Josephine , Ambrogio Chiara , Zhang Long , Zhou Fangyu , Jenkins Russell W. , Adeegbe Dennis O. , Gao Peng , Wang Xiaoen , Paweletz Cloud P. , Herter-Sprie Grit S. , Chen Ting , Gutiérrez-Quiceno Laura , Zhang Yanxi , Merlino Ashley A. , Quinn Max M. , Zeng Yu , Yu Xiaoting , Liu Yuting , Fan Lichao , Aguirre Andrew J. , Barbie David A. , Yi Xianghua , Wong Kwok-Kin 
Published: June 2018

Abstract
Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation–driven mouse models.
Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRASG12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition.
Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D. Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy.
Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRASG12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854–64. ©2018 AACR.
Molecular Analyses Support the Safety and Activity of Retroviral Replicating Vector Toca 511 in Patients
Authors: Hogan Daniel J. , Zhu Jay-Jiguang , Diago Oscar R. , Gammon Dawn , Haghighi Ali , Lu Guangrong , Das Asha , Gruber Harry E. , Jolly Douglas J. , Ostertag Derek 
Published: June 2018

Abstract
Purpose: Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-grade glioma, we have performed extensive molecular analyses of patient specimens to track vector fate.
Patients and Methods: Toca 511 and Toca FC (extended-release 5-fluorocytosine) have been administered to 127 high-grade glioma patients across three phase I studies. We measured Toca 511 RNA and DNA levels in available body fluids and tumor samples from patients to assess tumor specificity. We mapped Toca 511 integration sites and sequenced integrated Toca 511 genomes from patient samples with detectable virus. We measured Toca 511 levels in a diverse set of tissue samples from one patient.
Results: Integrated Toca 511 is commonly detected in tumor samples and is only transiently detected in blood in a small fraction of patients. There was no believable evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes. Toca 511 sequence profiles suggest most mutations are caused by APOBEC cytidine deaminases acting during reverse transcription. Tissue samples from a single whole-body autopsy affirm Toca 511 tumor selectivity.
Conclusions: Toca 511 and Toca FC treatment was not associated with inappropriate integration sites and clonal expansion. The vector is tumor-selective and persistent in patients who received Toca 511 injections. Clin Cancer Res; 24(19); 4680–93. ©2018 AACR.
Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant
Authors: Liu Chao , Guo Theresa , Xu Guorong , Sakai Akihiro , Ren Shuling , Fukusumi Takahito , Ando Mizuo , Sadat Sayed , Saito Yuki , Khan Zubair , Fisch Kathleen M. , Califano Joseph 
Published: June 2018

AbstractPurpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)–negative HNSCC.Experimental Design: RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays.Results: A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival.Conclusions: Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. Clin Cancer Res; 24(20); 5123–32. ©2018 AACR.
Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity
Authors: Roche Francis P. , Pietilä Ilkka , Kaito Hiroshi , Sjöström Elisabet O. , Sobotzki Nadine , Noguer Oriol , Skare Tor Persson , Essand Magnus , Wollscheid Bernd , Welsh Michael , Claesson-Welsh Lena 
Published: June 2018

Abstract
The plasma–protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction–decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG–treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961–72. ©2018 AACR.