bluuebunny/crossref_metadata_2025_split huggingface dataset:
QT prolongation in a child with thyroid storm
Authors: Albert Benjamin B , Eckersley Luke Gerard , Skinner Jonathan Robert , Jefferies Craig 
Published: April 2014

SummaryA 12-year-old girl presented with an acute confusional state and a 2-year history of weight loss, anxiety, agitation and recurrent fever. Thyroid function tests confirmed severe hyperthyroidism, and a diagnosis of thyroid storm was made (Burch and Wartofsky score=75). ECG showed a prolonged QTc interval of 506 ms. Acute treatment for thyroid storm consisted of Lugol's iodine, prednisolone, carbimazole and propranolol. She made a steady recovery and by 3 months her thyroid function had normalised; a repeat ECG showed a QTc within the normal range (430 ms). There was no relevant family history. This is a case of QTc prolongation with hyperthyroidism and normalisation with euthyroidism. It is not commonly recognised that hyperthyroidism in children may be associated with QTc prolongation. QTc measurement should be incorporated into management protocols for hyperthyroidism.
Measurement confounding affects the extent to which verbal IQ explains social gradients in mortality
Authors: Chapman Benjamin , Fiscella Kevin , Duberstein Paul , Kawachi Ichiro , Muennig Peter 
Published: April 2014

BackgroundIQ is thought to explain social gradients in mortality. IQ scores are based roughly equally on Verbal IQ (VIQ) and Performance IQ tests. VIQ tests, however, are suspected to confound true verbal ability with socioeconomic status (SES), raising the possibility that associations between SES and IQ scores might be overestimated. We examined, first, whether two of the most common types of VIQ tests exhibited differential item functioning (DIF) favouring persons of higher SES and/or majority race/ethnicity. Second, we assessed what impact, if any, this had on estimates of the extent to which VIQ explains social gradients in mortality.MethodsData from the General Social Survey-National Death Index cohort, a US population representative dataset, was used. Item response theory models queried social-factor DIF on the Thorndike Verbal Intelligence Scale and Wechsler Adult Intelligence Scales, Revised Similarities test. Cox models examined mortality associations among SES and VIQ scores corrected and uncorrected for DIF.ResultsWhen uncorrected for DIF, VIQ was correlated with income, education, occupational prestige and race, with correlation coefficients ranging between |0.12| and |0.43|. After correcting for DIF, correlations ranged from |0.06| to |0.16|. Uncorrected VIQ scores explained 11–40% of the Relative Index of Inequalities in mortality for social factors, while DIF-corrected scores explained 2–29%.ConclusionsTwo of the common forms of VIQ tests appear confound verbal intelligence with SES. Since these tests appear in most IQ batteries, circumspection may be warranted in estimating the amount of social inequalities in mortality attributable to IQ.
Updating uniformitarianism: stratigraphy as just a set of ‘frozen accidents’
Authors: Miall Andrew D. 
Published: April 2014

Abstract
It has long been understood that the stratigraphic record is fragmentary. Barrell was the first to clearly understand the importance of accommodation, and the episodic way in which accommodation is created and removed by geological processes. He demonstrated that typically only a fraction of geological time is represented by accumulated sediment. This point was repeated in influential books by D. Ager. A significant feature of the sedimentary record is the correlation between the duration of a sedimentary unit and its sedimentation rate. Sedimentation rates range over more than eleven orders of magnitude.
The durations of stratigraphic gaps, the distribution of layer thicknesses, and sedimentation rates have fractal-like properties, facilitating the integration of our knowledge of the processes of accommodation generation with data on varying sedimentation rates and the scales of hiatuses and processes operating over all time scales.

This paper proposes the definition of a suite of
Sedimentation Rate Scales
to encompass the range of time scales and processes in the stratigraphic record. Assignment of stratigraphic units to the appropriate scale should help to clarify preservation mechanisms, leading to more complete quantitative understanding of the geological preservation machine, and a more grounded approach than earlier treatments of stratigraphic completeness.
Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer
Authors: Wang Chen , Cicek Mine S. , Charbonneau Bridget , Kalli Kimberly R. , Armasu Sebastian M. , Larson Melissa C. , Konecny Gottfried E. , Winterhoff Boris , Fan Jian-Bing , Bibikova Marina , Chien Jeremy , Shridhar Viji , Block Matthew S. , Hartmann Lynn C. , Visscher Daniel W. , Cunningham Julie M. , Knutson Keith L. , Fridley Brooke L. , Goode Ellen L. 
Published: April 2014

Abstract
To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n = 168) and validation (n = 169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P = 2.9 × 10−3, HR = 0.52; 95% confidence interval (CI), 0.34–0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n = 104) and CD8 T-cell infiltration (n = 89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P = 7.6 × 10−5), and trans-regulation of genes in immune-related pathways (P = 1.6 × 10−32). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC. Cancer Res; 74(11); 3084–91. ©2014 AACR.
Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19
Authors: Zhou Mei , Wang Xueyan , Phung Van , Lindhout Darrin A. , Mondal Kalyani , Hsu Jer-Yuan , Yang Hong , Humphrey Mark , Ding Xunshan , Arora Taruna , Learned R. Marc , DePaoli Alex M. , Tian Hui , Ling Lei 
Published: April 2014

Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19–FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer. Cancer Res; 74(12); 3306–16. ©2014 AACR.
Pattern of CD14+ Follicular Dendritic Cells and PD1+ T Cells Independently Predicts Time to Transformation in Follicular Lymphoma
Authors: Smeltzer Jacob P. , Jones Jason M. , Ziesmer Steven C. , Grote Deanna M. , Xiu Bing , Ristow Kay M. , Yang Zhi Zhang , Nowakowski Grzegorz S. , Feldman Andrew L. , Cerhan James R. , Novak Anne J. , Ansell Stephen M. 
Published: April 2014

Abstract
Purpose: Transformation of follicular lymphoma is a critical event associated with a poor prognosis. The role of the tumor microenvironment in previous transformation studies has yielded conflicting results.
Experimental Design: To define cell subtypes associated with transformation, we examined tissue specimens at diagnosis from patients with follicular lymphoma that later transformed and, using immunohistochemistry (IHC), stained for CD68, CD11c, CD21, CXCL13, FOXP3, PD1, and CD14. Cell content and the pattern of expression were evaluated. Those identified as significantly associated with time to transformation (TTT) and overall survival (OS) were further characterized by flow cytometry and multicolor IHC.
Results: Of note, 58 patients were analyzed with median TTT of 4.7 years. The pattern of PD1+ and CD14+ cells rather than the quantity of cells was predictive of clinical outcomes. On multivariate analysis, including the follicular lymphoma international prognostic index score, CD14+ cells localized in the follicle were associated with a shorter TTT (HR, 3.0; P = 0.004). PD1+ cells with diffuse staining were associated with a shorter TTT (HR, 1.9; P = 0.045) and inferior OS (HR, 2.5; P = 0.012). Multicolor IHC and flow cytometry identified CD14+ cells as follicular dendritic cells (FDC), whereas PD1+ cells represented two separate populations, TFH and exhausted T cells.
Conclusion: These results identify the presence of PD1+ T cells and CD14+ FDC as independent predictors of transformation in follicular lymphoma. Clin Cancer Res; 20(11); 2862–72. ©2014 AACR.
Small-Molecule RA-9 Inhibits Proteasome-Associated DUBs and Ovarian Cancer In Vitro and In Vivo via Exacerbating Unfolded Protein Responses
Authors: Coughlin Kathleen , Anchoori Ravi , Iizuka Yoshie , Meints Joyce , MacNeill Lauren , Vogel Rachel Isaksson , Orlowski Robert Z. , Lee Michael K. , Roden Richard B.S. , Bazzaro Martina 
Published: April 2014

Abstract
Purpose: Ovarian cancer is the deadliest of the gynecologic malignancies. Carcinogenic progression is accompanied by upregulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUB) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian cancer.
Experimental Design: The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian cancer cell lines and primary cells. The anticancer activity of RA-9 and its mechanism of action were evaluated in multiple cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intraperitoneal ES-2 xenograft model of human ovarian cancer.
Results: Here, we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of apoptosis in ovarian cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an unfolded protein response as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival, and was well tolerated by the host.
Conclusions: Our preclinical studies support further evaluation of RA-9 as an ovarian cancer therapeutic. Clin Cancer Res; 20(12); 3174–86. ©2014 AACR.
Aggressive Variants of Castration-Resistant Prostate Cancer
Authors: Beltran Himisha , Tomlins Scott , Aparicio Ana , Arora Vivek , Rickman David , Ayala Gustavo , Huang Jiaoti , True Lawrence , Gleave Martin E. , Soule Howard , Logothetis Christopher , Rubin Mark A. 
Published: April 2014

Abstract
A subset of patients with advanced castration-resistant prostate cancer may eventually evolve into an androgen receptor (AR)–independent phenotype, with a clinical picture associated with the development of rapidly progressive disease involving visceral sites and hormone refractoriness, often in the setting of a low or modestly rising serum prostate-specific antigen level. Biopsies performed in such patients may vary, ranging from poorly differentiated carcinomas to mixed adenocarcinoma-small cell carcinomas to pure small cell carcinomas. These aggressive tumors often demonstrate low or absent AR protein expression and, in some cases, express markers of neuroendocrine differentiation. Because tumor morphology is not always predicted by clinical behavior, the terms “anaplastic prostate cancer” or “neuroendocrine prostate cancer” have been used descriptively to describe these rapidly growing clinical features. Patients meeting clinical criteria of anaplastic prostate cancer have been shown to predict for poor prognosis, and these patients may be considered for platinum-based chemotherapy treatment regimens. Therefore, understanding variants within the spectrum of advanced prostate cancer has important diagnostic and treatment implications. Clin Cancer Res; 20(11); 2846–50. ©2014 AACR.
Ganitumab (AMG 479) Inhibits IGF-II–Dependent Ovarian Cancer Growth and Potentiates Platinum-Based Chemotherapy
Authors: Beltran Pedro J. , Calzone Frank J. , Mitchell Petia , Chung Young-Ah , Cajulis Elaina , Moody Gordon , Belmontes Brian , Li Chi-Ming , Vonderfecht Steven , Velculescu Victor E. , Yang Guorong , Qi Jingwei , Slamon Dennis J. , Konecny Gottfried E. 
Published: April 2014

Abstract
Purpose: Insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF-IR. Here, we explore the therapeutic potential of ganitumab for the treatment of ovarian cancer.
Experimental Design: The effects of ganitumab were tested in vitro against a panel of 23 established ovarian cancer cell lines. The ability of ganitumab to inhibit IGF-I–, IGF-II–, and insulin-mediated signaling was examined in vitro and in tumor xenografts using ovarian cancer models displaying IGF-IR/PI3K/AKT pathway activation by two distinct mechanisms, PTEN loss and IGF-II overexpression. Drug interactions between ganitumab and cisplatin, carboplatin, or paclitaxel were studied in vitro and in vivo.
Results: In vitro, growth inhibition varied significantly among individual ovarian cancer cell lines. IGF-II mRNA and phospho–IGF-IR protein expression were quantitatively correlated with response to ganitumab, and PTEN mutations conferred resistance to ganitumab. Ganitumab potently inhibited baseline and IGF-I–, IGF-II–, and insulin-induced IGF-IR and IGF-IR/insulin hybrid receptor signaling in vitro and in vivo. Synergistic and additive drug interactions were seen for ganitumab and carboplatin or paclitaxel in vitro. Furthermore, ganitumab significantly increased the efficacy of cisplatin in ovarian cancer xenograft models in vivo.
Conclusions: These observations provide a biologic rationale to test ganitumab as a single agent or in combination with carboplatin/cisplatin and paclitaxel in patients with ovarian cancer. Moreover, assessment of tumor expression of IGF-II, phospho–IGF-IR, or PTEN status may help select patients with ovarian cancer who are most likely to benefit from ganitumab. Clin Cancer Res; 20(11); 2947–58. ©2014 AACR.
Association Study of the let-7 miRNA-Complementary Site Variant in the 3′ Untranslated Region of theKRASGene in Stage III Colon Cancer (NCCTG N0147 Clinical Trial)
Authors: Sha Dan , Lee Adam M. , Shi Qian , Alberts Steven R. , Sargent Daniel J. , Sinicrope Frank A. , Diasio Robert B. 
Published: April 2014

AbstractPurpose: A let-7 microRNA-complementary site (LCS6) polymorphism in the 3′ untranslated region of the KRAS gene has been shown to disrupt let-7 binding and upregulate KRAS expression. We evaluated the LCS6 genotype and its association with KRAS mutation status, clinicopathologic features, and disease-free survival (DFS) in patients with stage III colon cancer who enrolled in a phase III clinical trial (NCCTG N0147).Experimental Design: The LCS6 genotype was assayed by real-time PCR in DNA extracted from whole blood (n = 2,834) and compared with paired tumor tissue (n = 977). χ2 and two-sample t tests were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed associations between LCS6 status and DFS, respectively.Results: We identified 432 (15.2%) blood samples and 143 (14.6%) tumor samples heterozygous or homozygous for the LCS6 G-allele, and 2,402 of 2,834 (84.8%) blood samples and 834 of 977 (85.4%) tumor samples homozygous for the LCS6 T-allele. Genotype results were highly concordant (99.8%) in cases with paired blood and tumor tissue (n = 977). G-allele carriers were significantly more frequent in Caucasians versus other races (χ2 test, P &lt; 0.0001). The LCS6 genotype was not associated with KRAS mutation status, clinicopathologic features (all P &gt; 0.2), or DFS (log-rank P = 0.49; HR, 0.929; 95% confidence interval, 0.76–1.14), even after combining LCS6 genotype with KRAS mutation status.Conclusions: In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors. Clin Cancer Res; 20(12); 3319–27. ©2014 AACR.
The empirical assessment of agency accountability: a regime approach and an application to the German Bundesnetzagentur
Authors: Biela Jan , Papadopoulos Yannis 
Published: April 2014

Regulation has in many cases been delegated to independent agencies, which has led to the question of how democratic accountability of these agencies is ensured. There are few empirical approaches to agency accountability. We offer such an approach, resting upon three propositions. First, we scrutinize agency accountability both de jure (accountability is ensured by formal rights of accountability ‘fora’ to receive information and impose consequences) and de facto (the capability of fora to use these rights depends on resources and decision costs that affect the credibility of their sanctioning capacity). Second, accountability must be evaluated separately at political, operational and managerial levels. And third, at each level accountability is enacted by a system of several (partially) interdependent fora, forming together an accountability regime. The proposed framework is applied to the case of the German Bundesnetzagentur's accountability regime, which shows its suitability for empirical purposes. Points for practitioners Regulatory agencies are often considered as independent, yet accountable. This article provides a realistic framework for the study of accountability ‘regimes’ in which they are embedded. It emphasizes the need to identify the various actors (accountability fora) to which agencies are formally accountable (parliamentary committees, auditing bodies, courts, and so on) and to consider possible relationships between them. It argues that formal accountability ‘on paper’, as defined in official documents, does not fully account for de facto accountability, which depends on the resources possessed by the fora (mainly information-processing and decision-making capacities) and the credibility of their sanctioning capacities. The article applies this framework to the German Bundesnetzagentur.
Reference control in the narratives of adult sign language learners
Authors: Bel Aurora , Ortells Marta , Morgan Gary 
Published: April 2014

Aims and Objectives: Learning to control reference in narratives is a major step in becoming a speaker of a second language, including a signed language. Previous research describes the pragmatic and cognitive mechanisms that are used for reference control and it is clear that differences are apparent between first and second language speakers. However, some debate exists about the reasons for second language learners’ tendency for over-redundancy in reference forms especially in the use of pronouns. In this study we tested these proposed reasons for L2 differences. Methodology: Narratives by 11 native signers and 13 adult advanced-learners of Catalan sign language were analysed for person reference. Data: Analysis focused on forms for introduction, reintroduction and maintenance of characters. Findings: The results indicate both groups used reference forms according to information saliency principles in similar ways. Differences between the groups were in the use of pronominal signs, where the learners adopted an over-redundancy strategy in line with one hypothesis in the previous studies on second language acquisition in spoken languages. Significance: The results are discussed in terms of the vulnerable syntax–pragmatics interface in developing bilinguals
Aboriginal and Torres Strait Islander children in child protection: A sample from the Victorian Children’s Court
Authors: De Bortoli Lillian , Coles Jan , Dolan Mairead 
Published: April 2014

Summary This article reports on a comparison of Aboriginal and Torres Strait Islander (ATSI) and non-ATSI children involved in the child protection system sampled from the Victorian Children’s Court. Groups were compared in terms of demographic profile, the types and grounds for protection applications and the types of abuse proven in court. Findings Our results highlight similarities between ATSI and non-ATSI children in the child protection system, a finding that indicates similar children, regardless of background, are being found to be at increased risk of abuse. The over-representation of ATSI children in the sample indicates a continued social and economic disadvantage associated with this group, requiring ongoing public health preventive measures. Our study also highlighted the longer term involvement of ATSI children with child protection services before reaching court. This may be explained by differences in case management policies affecting ATSI children in the child protection system as well as the ongoing legacy of the Stolen Generation. Applications In addition to addressing underlying inequalities, advancing the ATSI people towards self-determination in child protection may reduce the over-representation and longer term involvement with the child protection system. Importantly, alternative approaches must be considered as the potential trauma associated with longer term child protection involvement is greater in children of ATSI background.