bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional health literacy and glycaemic control in older adults with type 2 diabetes: a cross-sectional study
Authors: Souza Jonas Gordilho , Apolinario Daniel , Magaldi Regina Miksian , Busse Alexandre Leopold , Campora Flavia , Jacob-Filho Wilson 
Published: February 2014

ObjectivesTo investigate the relationship between functional health literacy and glycaemic control in a sample of older patients with type 2 diabetes.DesignCross-sectional study.SettingA government-financed outpatient geriatric clinic in São Paulo, Brazil.Participants129 older patients with type 2 diabetes, a mean (SD) age of 75.9 (6.2) years, a mean glycosylated haemoglobin (HbA1c) of 7.2% (1.4), of which 14.7% had no formal education and 82.9% had less than a high-school diploma.MeasuresHbA1c was used as a measure of glycaemic control. Functional health literacy was assessed with the 18-item Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA-18), a validated instrument to evaluate pronunciation and comprehension of commonly used medical terms. Regression models were controlled for demographic data, depressive symptoms, diabetes duration, treatment regimen, diabetes knowledge and assistance for taking medications.ResultsFunctional health literacy below adequate was encountered in 56.6% of the sample. After controlling for potential confounding factors, patients with inadequate functional health literacy were more likely than patients with adequate functional health literacy to present poor glycaemic control (OR=4.76; 95% CI 1.36 to 16.63). In a fully adjusted linear regression model, lower functional health literacy (β=−0.42; p<0.001), longer diabetes duration (β=0.24; p=0.012) and lack of assistance for taking medications (β=0.23; p=0.014) were associated with higher levels of HbA1c. Contrary to our expectations, illiterate patients did not have poorer outcomes when compared with patients with adequate functional health literacy, raising the hypothesis that illiterate individuals are more likely to have their difficulties recognised and compensated. However, the small subsample of illiterate patients provided limited power to reject differences with small magnitude.ConclusionsPatients with inadequate functional health literacy presented with higher odds of poor glycaemic control. These findings reinforce the importance of addressing limited functional health literacy in clinical practice.
A Timanian foreland basin setting for the late Neoproterozoic–Early Palaeozoic cover sequences (Dividal Group) of northeastern Baltica
Authors: Andresen Arild , Agyei-Dwarko Nana Yaw , Kristoffersen Magnus , Hanken Nils-Martin 
Published: February 2014

Abstract

LA-ICP-MS U–Pb and Hf-isotope data on detrital zircons from the Ediacaran and Cambrian Dividal Group demonstrate that the autochthonous cover sequence above the Fennoscandian Shield in northernmost Scandinavia is not derived from an easterly Archaean and Palaeoproterozoic source within Baltica as commonly thought. Detrital zircon age populations on four samples from the Dividal Group are dominated by Mesoproterozoic zircons with relatively few Palaeoproterozoic and Archaean zircons. Two samples, from Altevann and Reisadalen have, in addition, a significant population of Ediacaran zircons (
c.
570–560 Ma), indicating a Timanian source area for most of the lower Cambrian Dividal Group sediments. The
176
Hf/
177
Hf isotope data show the Ediacaran zircons to be derived from two separate plutonic complexes within the Timanides. It is argued that the Dividal Group sediments were deposited in a foreland basin south and SW of the Timanide Orogen. Similarities with clastic zircon age populations from Cambrian deposits in Akkajaure, Ladoga/White Sea and St Petersburg areas indicate that this foreland basin possibly extended southward for at least 1000 km. A foreland basin setting for the Ediacaran and Cambrian deposits in Central and Southern Scandinavia can thus account for the enigmatic Neoproterozoic detrital zircons in these deposits.

Supplementary material:

Analytical LA-ICP-MS data on detrital zircons from Dividal Group samples AA12-1, AA12-2, AA11-29 and AA11-30 are available at
http://www.geolsoc.org.uk/SUP18731
.
Detection of Brain Tumor Cells in the Peripheral Blood by a Telomerase Promoter-Based Assay
Authors: MacArthur Kelly M. , Kao Gary D. , Chandrasekaran Sanjay , Alonso-Basanta Michelle , Chapman Christina , Lustig Robert A. , Wileyto E. Paul , Hahn Stephen M. , Dorsey Jay F. 
Published: February 2014

Abstract
Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer. Cancer Res; 74(8); 2152–9. ©2014 AACR.
Bioluminescent Imaging of HPV-Positive Oral Tumor Growth and Its Response to Image-Guided Radiotherapy
Authors: Zhong Rong , Pytynia Matt , Pelizzari Charles , Spiotto Michael 
Published: February 2014

Abstract
The treatment paradigms for head and neck squamous cell cancer (HNSCC) are changing due to the emergence of human papillomavirus (HPV)-associated tumors possessing distinct molecular profiles and responses to therapy. Although patients with HNSCCs are often treated with radiotherapy, preclinical models are limited by the ability to deliver precise radiation to orthotopic tumors and to monitor treatment responses accordingly. To better model this clinical scenario, we developed a novel autochthonous HPV-positive oral tumor model to track responses to small molecules and image-guided radiation. We used a tamoxifen-regulated Cre recombinase system to conditionally express the HPV oncogenes E6 and E7 as well as a luciferase reporter (iHPV-Luc) in the epithelial cells of transgenic mice. In the presence of activated Cre recombinase, luciferase activity, and by proxy, HPV oncogenes were induced to 11-fold higher levels. In triple transgenic mice containing the iHPV-Luc, K14-CreERtam, and LSL-Kras transgenes, tamoxifen treatment resulted in oral tumor development with increased bioluminescent activity within 6 days that reached a maximum of 74.8-fold higher bioluminescence compared with uninduced mice. Oral tumors expressed p16 and MCM7, two biomarkers associated with HPV-positive tumors. After treatment with rapamycin or image-guided radiotherapy, tumors regressed and possessed decreased bioluminescence. Thus, this novel system enables us to rapidly visualize HPV-positive tumor growth to model existing and new interventions using clinically relevant drugs and radiotherapy techniques. Cancer Res; 74(7); 2073–81. ©2014 AACR.
Molecular Biomarkers in Advanced Renal Cell Carcinoma
Authors: Maroto Pablo , Rini Brian 
Published: February 2014

AbstractThe availability of agents directly targeting tumorigenic and angiogenic pathways has significantly improved the outcomes of patients with advanced renal cell carcinoma (RCC) in recent years. However, all patients eventually become resistant and a substantial percentage experience immediate disease progression with first-line targeted therapy. In addition, patients have variable clinical benefit and/or tolerance to different agents, including drugs within the same class. Thus, the choice of therapy for an individual patient remains empiric at present. Upon this landscape, several molecular biomarkers have been investigated with the purpose of guiding therapy. This review discusses prognostic biomarkers correlating with the outcome of patients independent of therapy, and predictive biomarkers of treatment response, including circulating biomarkers (such as VEGF and VEGF-related proteins, cytokine and angiogenic factors, and lactate dehydrogenase), and tissue-based biomarkers (such as single-nucleotide polymorphisms). Many potential prognostic and predictive molecular biomarkers have now been identified in RCC, although none has yet entered into clinical practice, and all require prospective validation in appropriately designed randomized studies. In the near future, however, validated biomarkers may become integral to management strategies in RCC, enabling tailored treatment for individual patients to improve clinical outcomes. Clin Cancer Res; 20(8); 2060–71. ©2014 AACR.
DNA Topoisomerase III Alpha Regulates p53-Mediated Tumor Suppression
Authors: Hsieh Mei-Yi , Fan Jia-Rong , Chang Han-Wen , Chen Hsiang-Chin , Shen Tang-Long , Teng Shu-Chun , Yeh Yen-Hsiu , Li Tsai-Kun 
Published: February 2014

Abstract
Purpose: Human DNA topoisomerase III alpha (hTOP3α) is involved in DNA repair surveillance and cell-cycle checkpoints possibly through formatting complex with tumor suppressors. However, its role in cancer development remained unsolved.
Experimental Design: Coimmunoprecipitation, sucrose gradient, chromatin immunoprecipitation (ChIP), real time PCR, and immunoblotting analyses were performed to determine interactions of hTOP3α with p53. Paired cell lines with different hTOP3α levels were generated via ectopic expression and short hairpin RNA (shRNA)-mediated knockdown approaches. Cellular tumorigenic properties were analyzed using cell counting, colony formation, senescence, soft agar assays, and mouse xenograft models.
Results: The hTOP3α isozyme binds to p53 and cofractionizes with p53 in gradients differing from fractions containing hTOP3α and BLM. Knockdown of hTOP3α expression (sh-hTOP3α) caused a higher anchorage-independent growth of nontumorigenic RHEK-1 cells. Similarly, sh-hTOP3α and ectopic expression of hTOP3α in cancer cell lines caused increased and reduced tumorigenic abilities, respectively. Genetic and mutation experiments revealed that functional hTOP3α, p53, and p21 are required for this tumor-suppressive activity. Mechanism-wise, ChIP data revealed that hTOP3α binds to the p53 and p21 promoters and positively regulates their expression. Two proteins affect promoter recruitments of each other and collaborate in p21 expression. Moreover, sh-hTOP3α and sh-p53 in AGS cells caused a similar reduction in senescence and hTOP3α mRNA levels were lower in gastric and renal tumor samples.
Conclusion: We concluded that hTOP3α interacts with p53, regulates p53 and p21 expression, and contributes to the p53-mediated tumor suppression. Clin Cancer Res; 20(6); 1489–501. ©2014 AACR.
Maximizing Return on Socioeconomic Investment in Phase II Proof-of-Concept Trials
Authors: Chen Cong , Beckman Robert A. 
Published: February 2014

Abstract
Phase II proof-of-concept (POC) trials play a key role in oncology drug development, determining which therapeutic hypotheses will undergo definitive phase III testing according to predefined Go-No Go (GNG) criteria. The number of possible POC hypotheses likely far exceeds available public or private resources. We propose a design strategy for maximizing return on socioeconomic investment in phase II trials that obtains the greatest knowledge with the minimum patient exposure. We compare efficiency using the benefit–cost ratio, defined to be the risk-adjusted number of truly active drugs correctly identified for phase III development divided by the risk-adjusted total sample size in phase II and III development, for different POC trial sizes, powering schemes, and associated GNG criteria. It is most cost-effective to conduct small POC trials and set the corresponding GNG bars high, so that more POC trials can be conducted under socioeconomic constraints. If δ is the minimum treatment effect size of clinical interest in phase II, the study design with the highest benefit–cost ratio has approximately 5% type I error rate and approximately 20% type II error rate (80% power) for detecting an effect size of approximately 1.5δ. A Go decision to phase III is made when the observed effect size is close to δ. With the phenomenal expansion of our knowledge in molecular biology leading to an unprecedented number of new oncology drug targets, conducting more small POC trials and setting high GNG bars maximize the return on socioeconomic investment in phase II POC trials. Clin Cancer Res; 20(7); 1730–4. ©2014 AACR.
A Short Treatment with Galactomannan GM-CT-01 Corrects the Functions of Freshly Isolated Human Tumor–Infiltrating Lymphocytes
Authors: Demotte Nathalie , Bigirimana René , Wieërs Grégoire , Stroobant Vincent , Squifflet Jean-Luc , Carrasco Javier , Thielemans Kris , Baurain Jean-François , Van Der Smissen Patrick , Courtoy Pierre J. , van der Bruggen Pierre 
Published: February 2014

AbstractPurpose: Several galectins are released by tumor cells and macrophages and accumulate in the tumor microenvironment. Galectin-1 and -3 were found to bind to glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein–galectin lattices that could reduce the motility and therefore the functionality of surface molecules. In contrast to blood T cells, human TIL show defective IFN-γ secretion upon ex vivo stimulation. We have previously shown that extracellular galectin-3 participates in the impairment of TIL functions. Indeed, disruption of glycoprotein–galectin-3 lattices using anti-galectin-3 antibodies, or N-acetyllactosamine as a competing sugar, boosted cytokine secretion by TIL. Here we have tested a clinical grade galectin antagonist: GM-CT-01, a galactomannan obtained from guar gum reported to be safe in more than 50 patients with cancer.Experimental Design: TIL were isolated from human tumor ascites, treated for 2 to 20 hours with galectin antagonists and tested for function.Results: We found that GM-CT-01 boosts cytotoxicity of CD8+ TIL and their IFN-γ secretion in a dose-dependent manner. Treating TIL obtained from patients with various cancers, during a few hours, resulted in an increased IFN-γ secretion in up to 80% of the samples.Conclusions: These observations pave the way for investigating the potential benefit of this galectin antagonist in patients with cancer, alone or combined with cancer vaccination, in order to correct in vivo impaired functions of TIL. Clin Cancer Res; 20(7); 1823–33. ©2014 AACR.
T-cell Responses to Oncogenic Merkel Cell Polyomavirus Proteins Distinguish Patients with Merkel Cell Carcinoma from Healthy Donors
Authors: Lyngaa Rikke , Pedersen Natasja Wulff , Schrama David , Thrue Charlotte Albæk , Ibrani Dafina , Met Özcan , thor Straten Per , Nghiem Paul , Becker Jürgen C. , Hadrup Sine Reker 
Published: February 2014

Abstract
Purpose: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC.
Method: To overcome this limitation, we scanned the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers.
Results: In peripheral blood from 38 patients with MCC and 30 healthy donors, we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in patients with MCC, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells toward MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor-infiltrating lymphocytes further substantiated the relevance of the identified epitopes.
Conclusion: These T-cell epitopes represent ideal targets for antigen-specific immune therapy of MCC, and enable tracking and characterization of MCPyV-specific immune responses. Clin Cancer Res; 20(7); 1768–78. ©2014 AACR.
Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells
Authors: Happold Caroline , Roth Patrick , Silginer Manuela , Florea Ana-Maria , Lamszus Katrin , Frei Karl , Deenen Rene , Reifenberger Guido , Weller Michael 
Published: February 2014

Abstract
Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O6-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β–mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-β sensitization. Gene expression profiling following IFN-β treatment revealed strong upregulation of IFN-β–associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-β, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-β. Thus, IFN-β is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-β operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters. Mol Cancer Ther; 13(4); 948–61. ©2014 AACR.
Protein Biomarkers of New-Onset Cardiovascular Disease
Authors: Yin Xiaoyan , Subramanian Subha , Hwang Shih-Jen , O’Donnell Christopher J. , Fox Caroline S. , Courchesne Paul , Muntendam Pieter , Gordon Neal , Adourian Aram , Juhasz Peter , Larson Martin G. , Levy Daniel 
Published: February 2014

Objective—
Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk.

Approach and Results—

We used discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. Then, we measured 59 markers by targeted MS in 336 ASCVD case–control pairs. Associations with MI or ASCVD were tested in single-marker and multiple-marker analyses adjusted for established ASCVD risk factors. Twelve single markers from discovery MS were associated with MI incidence (at
P
<0.01), adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, cluster of differentiation 5 molecule [CD5] antigen-like, cell-surface glycoprotein mucin cell surface associated protein 18 [MUC-18], collagen-α 1 [XVIII] chain, salivary α-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (
P
<0.0001) and significantly improved its prediction compared with a model with clinical risk factors alone (C-statistic of 0.71 versus 0.84). Through targeted MS, 12 single proteins were predictors of ASCVD (at
P
<0.05) after adjusting for established risk factors. In multiple-marker analyses, 4 proteins in combination (α-1–acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like) predicted incident ASCVD (
P
<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 versus 0.73).

Conclusions—
Proteomics profiling identified single- and multiple-marker protein panels that are associated with new-onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.
Role of Endothelial Cell–Derived Angptl2 in Vascular Inflammation Leading to Endothelial Dysfunction and Atherosclerosis Progression
Authors: Horio Eiji , Kadomatsu Tsuyoshi , Miyata Keishi , Arai Yasumichi , Hosokawa Kentaro , Doi Yasufumi , Ninomiya Toshiharu , Horiguchi Haruki , Endo Motoyoshi , Tabata Mitsuhisa , Tazume Hirokazu , Tian Zhe , Takahashi Otowa , Terada Kazutoyo , Takeya Motohiro , Hao Hiroyuki , Hirose Nobuyoshi , Minami Takashi , Suda Toshio , Kiyohara Yutaka , Ogawa Hisao , Kaikita Koichi , Oike Yuichi 
Published: February 2014

Objective—
Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression.

Approach and Results—

Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice (
ApoE
−/−
/
Angptl2
−/−
) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely,
ApoE
−/−
mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (
ApoE
−/−
/Tie2-
Angptl2
Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-
Angptl2
Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely,
Angptl2
−/−
mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis.

Conclusions—
Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.