bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental factors explain socioeconomic prevalence differences in myopia in 6-year-old children
Authors: Tideman J Willem L , Polling Jan Roelof , Hofman Albert , Jaddoe Vincent WV , Mackenbach Johan P , Klaver Caroline CW 
Published: June 2017

PurposeHigh myopia (≤−6 D) usually has its onset before 10 years of age and can lead to blinding complications later in life. We examined whether differences in myopia prevalences in socioeconomic risk groups could be explained by differences in lifestyle factors.MethodsA total of 5711 six-year-old children participating in the prospective population-based birth cohort study Generation R underwent a stepwise ophthalmic examination, which included visual acuity and objective cycloplegic refraction to identify children with myopia (≤−0.5D). Daily activities, ethnicity, factors representing family socioeconomic status and housing were ascertained by questionnaire. Risk assessments of myopia and mediation analyses were performed using logistic regression; attenuation of risks was calculated by bootstrapping.ResultsPrevalence of myopia was 2.4% (n=137). Myopic children spent more time indoors and less outdoors than non-myopic children (p<0.01), had lower vitamin D (p=0.01), had a higher body mass index and participated less in sports (p=0.03). Children of non-European descent (OR 2.60; 95% CI 1.84 to 3.68), low maternal education (OR 2.27; 95% CI 1.57 to 3.28) and low family income (OR 2.62; 95% CI 1.8 to 3.74) were more often myopic. Lifestyle factors explained the majority of the increased risk for ethnicity (82%; 95% CI 55 to 120), maternal education (69%; 95% CI 45 to 109) and family socioeconomic status (71%; 95% CI 46 to 104).ConclusionThis study found environmental factors to be strong risk factors for myopia already at the age of 6 years. The myopia prevalence differences in socioeconomic groups were greatly determined by differences in distribution of these environmental risk factors, highlighting the importance of lifestyle adjustments in young children developing myopia.
'Treated as a number, not treated as a person': a qualitative exploration of the perceived barriers to effective pain management of patients with chronic pain
Authors: Hadi Muhammad Abdul , Alldred David Phillip , Briggs Michelle , Marczewski Kathryn , Closs S José 
Published: June 2017

ObjectivesTo identify barriers to effective pain management encountered by patients with chronic pain within the UK’s National Health Service (NHS).DesignSecondary analysis of face-to-face, semistructured qualitative interviews using thematic analysis.SettingA community-based chronic pain clinic jointly managed by a nurse and pharmacist located in the North of England.ParticipantsNineteen adult (>18 years) patients with chronic pain discharged from a pain clinic, with the ability to understand and speak the English language.ResultsIn general, patients were highly disappointed with the quality of pain management services provided both within primary and secondary care, and consequently were willing to seek private medical care. Barriers to effective pain management were divided into two main themes: healthcare professional-related and health systems-related. Three subthemes emerged under healthcare professionals-related barriers, namely (1) healthcare professionals’ lack of interest and empathy, (2) general practitioners’ (GP) lack of specialised knowledge in pain management and (3) lack of communication between healthcare professionals. Three subthemes emerged under health system-related barriers: (1) long waiting time for appointments in secondary care, (2) short consultation times with GPs and (3) lack of an integrated multidisciplinary approach.ConclusionsThe patients expressed a clear desire for the improved provision and quality of chronic pain management services within the NHS to overcome barriers identified in this study. An integrated holistic approach based on a biopsychosocial model is required to effectively manage pain and improve patient satisfaction. Future research should explore the feasibility, effectiveness and cost-effectiveness of integrated care delivery models for chronic pain management within primary care.
Impact of age on the association between cardiac high-energy phosphate metabolism and cardiac power in women
Authors: Nathania Maria , Hollingsworth Kieren G , Bates Matthew , Eggett Christopher , Trenell Michael I , Velicki Lazar , Seferovic Petar M , MacGowan Guy A , Turnbull Doug M , Jakovljevic Djordje G 
Published: June 2017

ObjectiveDiminished cardiac high-energy phosphate metabolism (phosphocreatine-to-ATP (PCr:ATP) ratio) and cardiac power with age may play an important roles in development of cardiac dysfunction and heart failure. The study defines the impact of age on PCr:ATP ratio and cardiac power and their relationship.MethodsThirty-five healthy women (young≤50 years, n=20; and old≥60 years, n=15) underwent cardiac MRI with 31P spectroscopy to assess PCr:ATP ratio and performed maximal graded cardiopulmonary exercise testing with simultaneous gas-exchange and central haemodynamic measurements. Peak cardiac power output, as the best measure of pumping capability and performance of the heart, was calculated as the product of peak exercise cardiac output and mean arterial blood pressure.ResultsPCr:ATP ratio was significantly lower in old compared with young age group (1.92±0.48 vs 2.29±0.55, p=0.03), as were peak cardiac power output (3.35±0.73 vs 4.14±0.81W, p=0.01), diastolic function (ie, early-to-late diastolic filling ratio, 1.33±0.54 vs 3.07±1.84, p<0.01) and peak exercise oxygen consumption (1382.9±255.0 vs 1940.3±434.4 mL/min, p<0.01). Further analysis revealed that PCr:ATP ratio shows a significant positive relationship with early-to-late diastolic filling ratio (r=0.46, p=0.02), peak cardiac power output (r=0.44, p=0.02) and peak oxygen consumption (r=0.51, p=0.01).ConclusionsHigh-energy phosphate metabolism and peak power of the heart decline with age. Significant positive relationship between PCr:ATP ratio, early-to-late diastolic filling ratio and peak cardiac power output suggests that cardiac high-energy phosphate metabolism may be an important determinant of cardiac function and performance.
Mechanical constraints on kink band and thrust development in the Appalachian Plateau, USA
Authors: Gillespie Paul , Kampfer Günther 
Published: June 2017

Abstract
The internal deformation of the Appalachian Plateau décollement sheet has a distinctive style involving kink bands and thrusts. In areas where the décollement sheet is underlain by thin salt, the dominant structures are thrusts developed at shallow levels, underlain by a series of steep kink bands that terminate downwards at the Silurian salt décollement. Where the salt is thick, large asymmetrical anticlines developed with hinterland-verging kinks on their back-limbs that deformed the entire supra-salt sequence. In order to understand the constraints on deformation, we have used analytical mechanical modelling based on the maximum strength theorem. The simplified model consists of three layers: two are fluids and the third, intervening layer is a stratified competent material. The model is compressed horizontally and the predictions made are based on the kinematic approach of classical limit analysis. Two modes of deformation are investigated: the thrust and the kink band. The modelling shows that kink bands dominate deformation at large burial depth. At shallower depth and small regional bedding dip, the dominant mode is thrusting. In areas of open folding it is predicted that through-going hinterland-verging kink bands will form at a critical limb dip angle of about 10°.

Supplementary material:
Technical details of the mechanical theory behind this article are available at
https://doi.org/10.6084/m9.figshare.c.3799492
Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial–Mesenchymal Transition
Authors: Pang Bo , Wu Nan , Guan Rongwei , Pang Lin , Li Xinlei , Li Su , Tang Liudi , Guo Ying , Chen Jialei , Sun Donglin , Sun Haiming , Dai Jialin , Bai Jing , Ji Guohua , Liu Peng , Liu An , Wang Qiushi , Xiao Sheng , Fu Songbin , Jin Yan 
Published: June 2017

Abstract
Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis.
Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD.
Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P &lt; 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro. Further study found that RCC2 induced epithelial–mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9.
Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK–JNK signaling. Clin Cancer Res; 23(18); 5598–610. ©2017 AACR.
Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells
Authors: Jiang Ben-Yuan , Li Yang-Si , Guo Wei-Bang , Zhang Xu-Chao , Chen Zhi-Hong , Su Jian , Zhong Wen-Zhao , Yang Xue-Ning , Yang Jin-Ji , Shao Yang , Huang Biao , Liu Yan-Hui , Zhou Qing , Tu Hai-Yan , Chen Hua-Jun , Wang Zhen , Xu Chong-Rui , Wang Bin-Chao , Wu Shu-Yu , Gao Cun-Yi , Zhang Xian , Wu Yi-Long 
Published: June 2017

Abstract
Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases.
Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients.
Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs.
Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.
Expression and Therapeutic Potential of SOX9 in Chordoma
Authors: Chen Hua , Garbutt Cassandra C. , Spentzos Dimitrios , Choy Edwin , Hornicek Francis J. , Duan Zhenfeng 
Published: June 2017

Abstract
Purpose: Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma.
Experimental Design: SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescent assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound-healing assay and a Transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell-cycle arrest, as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by an MTT assay.
Results: Tissue microarray and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell-cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells.
Conclusions: Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma. Clin Cancer Res; 23(17); 5176–86. ©2017 AACR.
Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer
Authors: Asghar Uzma S. , Barr Alexis R. , Cutts Ros , Beaney Matthew , Babina Irina , Sampath Deepak , Giltnane Jennifer , Lacap Jennifer Arca , Crocker Lisa , Young Amy , Pearson Alex , Herrera-Abreu Maria Teresa , Bakal Chris , Turner Nicholas C. 
Published: June 2017

Abstract
Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes and investigated mechanisms of sensitivity.
Experimental Design: A panel of cell lines representative of TNBC was tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single-cell analysis in conjunction with time-lapse imaging.
Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro (P &lt; 0.001 LAR vs. basal-like) and in vivo in MDA-MB-453 LAR cell line xenografts. Single-cell analysis of CDK2 activity demonstrated differences in cell-cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell-cycle reentry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity after mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA-mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes.
Conclusions: Cell-cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC. Clin Cancer Res; 23(18); 5561–72. ©2017 AACR.
Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non–Small Cell Lung Cancer Using Next-Generation Sequencing
Authors: Jin Xiance , Chen Yanfan , Chen Hanbin , Fei Shaoran , Chen Didi , Cai Xiaona , Liu Linger , Lin Baochai , Su Huafang , Zhao Lihao , Su Meng , Pan Huanle , Shen Lanxiao , Xie Deyao , Xie Congying 
Published: June 2017

AbstractPurpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non–small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311–9. ©2017 AACR.
Tumor Metabolism in the Microenvironment of Nodal Metastasis in Oral Squamous Cell Carcinoma
Authors: Curry Joseph , Tassone Patrick , Gill Kurren , Tuluc Madalina , BarAd Voichita , Mollaee Mehri , Whitaker‐Menezes Diana , Rodeck Ulrich , Luginbuhl Adam , Cognetti David , Keane William , Martinez‐Outschoorn Ubaldo 
Published: June 2017

ObjectiveIn many cancers, including head and neck squamous cell carcinoma (HNSCC), different regions within a tumor have different metabolic phenotypes. Transfer of metabolites between compartments promotes tumor growth and aggressive behavior. Metabolic compartmentalization in HNSCC nodal metastases has not been studied, nor has its impact on extracapsular extension or clinical outcomes been determined.Study DesignRetrospective analysis based on immunohistochemistry staining.SettingTertiary care center.Subjects and MethodsPrimary tumors and nodal metastases from 34 surgically treated oral cavity HNSCC patients with extracapsular extension (ECE) were stained for monocarboyxlate transporter (MCT) 4, MCT1, translocase of outer mitochondrial membrane 20, and Ki‐67. Strength of staining was assessed using a computer‐assisted pathology algorithm. Immunohistochemistry (IHC) scores along with clinical factors were used to predict disease‐free survival (DFS).ResultsPatterns of IHC staining showed metabolic compartmentalization both at the primary tumor sites and in nodal metastases. MCT4 staining in the perinodal stroma was significantly higher in specimens with ECE greater than 1 mm (macro‐ECE, P =. 01). Patients with high perinodal MCT4 staining were compared with those with low perinodal MCT4 staining. On multivariate analysis, only high perinodal MCT4 staining had a significant impact on DFS (P =. 02); patients with high perinodal MCT4 had worse survival. DFS was not significantly worsened by advancing T stage, N stage, ECE extent, or perineural invasion.ConclusionOral HNSCC displays compartmentalized tumor metabolism at both primary and metastases. Greater cancer‐associated stromal conversion around ECE, denoted by high stromal MCT4, may be a biomarker for aggressive disease and worsened DFS.
Safety of Repeated‐Dose Intratympanic Injections with AM‐101 in Acute Inner Ear Tinnitus
Authors: Staecker Hinrich , Morelock Michael , Kramer Timothy , Chrbolka Pavel , Ahn Joong Ho , Meyer Thomas 
Published: June 2017

ObjectiveTo evaluate the safety and tolerability of repeated intratympanic administration of the gel‐formulated NMDA receptor antagonist AM‐101 in acute patients with inner ear tinnitus.Study DesignProspective, double‐blind, randomized, placebo‐controlled study.SettingSixty‐nine secondary and tertiary sites in North America, Europe, and Asia.Subjects and MethodsIn total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM‐101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques.ResultsThe treatment was well tolerated, with no intervention‐related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups (P =. 82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure‐related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous.ConclusionRepeated intratympanic injections of AM‐101 over a 3‐ to 5‐day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.
Tympanic Membrane and Ossicular‐Sparing Modified Lateral Temporal Bone Resection
Authors: Ghavami Yaser , Haidar Yarah M. , Maducdoc Marlon , Tjoa Tjoson , Moshtaghi Omid , Lin Harrison W. , Djalilian Hamid R. 
Published: June 2017

A modified lateral temporal bone resection (mLTBR) is a unique technique that spares the tympanic membrane (TM) and ossicles in select patients with squamous cell carcinoma (SCCa). The records of 5 patients with SCCa of the temporal bone with negative frozen‐section biopsy at the tympanic annulus were reviewed. The mean follow‐up time for the patients was 29.2 months. One patient received postoperative radiation due to cervical nodal extracapsular spread. All patients were recurrence free as of the most recent follow‐up (range, 8‐50 months). Postoperative audiometry demonstrated an average conductive hearing loss of 9 dB (range, 0‐17 dB). The mLTBR with sparing of the TM can be an effective alternative to the traditional lateral temporal bone resection (LTBR) with better hearing results for patients with SCCa involving the bony external auditory canal. In the short term, oncologic results of mLTBR appear equivalent to the LTBR. However, long‐term follow‐up is needed for >5‐year outcomes.