bluuebunny/crossref_metadata_2025_split huggingface dataset:
Head-to-Head Comparison and Evaluation of 92 Plasma Protein Biomarkers for Early Detection of Colorectal Cancer in a True Screening Setting
Authors: Chen Hongda , Zucknick Manuela , Werner Simone , Knebel Phillip , Brenner Hermann 
Published: May 2015

Abstract
Purpose: Novel noninvasive blood-based screening tests are strongly desirable for early detection of colorectal cancer. We aimed to conduct a head-to-head comparison of the diagnostic performance of 92 plasma-based tumor-associated protein biomarkers for early detection of colorectal cancer in a true screening setting.
Experimental Design: Among all available 35 carriers of colorectal cancer and a representative sample of 54 men and women free of colorectal neoplasms recruited in a cohort of screening colonoscopy participants in 2005–2012 (N = 5,516), the plasma levels of 92 protein biomarkers were measured. ROC analyses were conducted to evaluate the diagnostic performance. A multimarker algorithm was developed through the Lasso logistic regression model and validated in an independent validation set. The .632+ bootstrap method was used to adjust for the potential overestimation of diagnostic performance.
Results: Seventeen protein markers were identified to show statistically significant differences in plasma levels between colorectal cancer cases and controls. The adjusted area under the ROC curves (AUC) of these 17 individual markers ranged from 0.55 to 0.70. An eight-marker classifier was constructed that increased the adjusted AUC to 0.77 [95% confidence interval (CI), 0.59–0.91]. When validating this algorithm in an independent validation set, the AUC was 0.76 (95% CI, 0.65–0.85), and sensitivities at cutoff levels yielding 80% and 90% specificities were 65% (95% CI, 41–80%) and 44% (95% CI, 24–72%), respectively.
Conclusions: The identified profile of protein biomarkers could contribute to the development of a powerful multimarker blood-based test for early detection of colorectal cancer. Clin Cancer Res; 21(14); 3318–26. ©2015 AACR.
Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions
Authors: Damelin Marc , Bankovich Alexander , Park Albert , Aguilar Jorge , Anderson Wade , Santaguida Marianne , Aujay Monette , Fong Sarah , Khandke Kiran , Pulito Virginia , Ernstoff Elana , Escarpe Paul , Bernstein Jeffrey , Pysz Marybeth , Zhong Wenyan , Upeslacis Erik , Lucas Judy , Lucas Justin , Nichols Timothy , Loving Kathryn , Foord Orit , Hampl Johannes , Stull Robert , Barletta Frank , Falahatpisheh Hadi , Sapra Puja , Gerber Hans-Peter , Dylla Scott J. 
Published: May 2015

Abstract
Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.
Experimental Design: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody–drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.
Results: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification.
Conclusions: These findings demonstrate the potential of PF-06647263 (anti–EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development. Clin Cancer Res; 21(18); 4165–73. ©2015 AACR.
When Cancer Fights Back: Multiple Myeloma, Proteasome Inhibition, and the Heat-Shock Response
Authors: Shah Shardule P. , Lonial Sagar , Boise Lawrence H. 
Published: May 2015

Abstract
Multiple myeloma is a plasma cell malignancy with an estimated 26,850 new cases and 11,240 deaths in 2015 in the United States. Two main classes of agents are the mainstays of therapy—proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Other new targets are emerging rapidly, including monoclonal antibodies and histone deacetylase (HDAC) inhibitors. These therapeutic options have greatly improved overall survival, but currently only 15% to 20% of patients experience long-term progression-free survival or are cured. Therefore, improvement in treatment options is needed. One potential means of improving clinical options is to target resistance mechanisms for current agents. For example, eliminating the cytoprotective heat-shock response that protects myeloma cells from proteasome inhibition may enhance PI-based therapies. The transcription factor heat-shock factor 1 (HSF1) is the master regulator of the heat-shock response. HSF1 is vital in the proteotoxic stress response, and its activation is controlled by posttranslational modifications (PTM). This review details the mechanisms of HSF1 regulation and discusses leveraging that regulation to enhance PI activity. Mol Cancer Res; 13(8); 1163–73. ©2015 AACR.
Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation
Authors: Van Allen Eliezer M. , Golay Hadrien G. , Liu Yan , Koyama Shohei , Wong Karrie , Taylor-Weiner Amaro , Giannakis Marios , Harden Maegan , Rojas-Rudilla Vanesa , Chevalier Aaron , Thai Tran , Lydon Christine , Mach Stacy , Avila Ada G. , Wong Joshua A. , Rabin Alexandra R. , Helmkamp Joshua , Sholl Lynette , Carter Scott L. , Oxnard Geoffrey , Janne Pasi , Getz Gad , Lindeman Neal , Hammerman Peter S. , Garraway Levi A. , Hodi F. Stephen , Rodig Scott J. , Dranoff Glenn , Wong Kwok-Kin , Barbie David A. 
Published: May 2015

Abstract
PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti–PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. Cancer Immunol Res; 3(8); 855–63. ©2015 AACR.
Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
Authors: Boyerinas Benjamin , Jochems Caroline , Fantini Massimo , Heery Christopher R. , Gulley James L. , Tsang Kwong Yok , Schlom Jeffrey 
Published: May 2015

Abstract
Several anti–PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti–PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti–PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti–PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. Cancer Immunol Res; 3(10); 1148–57. ©2015 AACR.
Soluble CD40L Is a Useful Marker to Predict Future Strokes in Patients With Minor Stroke and Transient Ischemic Attack
Authors: Li Jiejie , Wang Yilong , Lin Jinxi , Wang David , Wang Anxin , Zhao Xingquan , Liu Liping , Wang Chunxue , Wang Yongjun 
Published: May 2015

Background and Purpose—
Elevated soluble CD40 ligand (sCD40L) was shown to be related to cardiovascular events, but the role of sCD40L in predicting recurrent stroke remains unclear.

Methods—
Baseline sCD40L levels were measured in 3044 consecutive patients with acute minor stroke and transient ischemic attack, who had previously been enrolled in the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Cox proportional-hazards model was used to assess the association of sCD40L with recurrent stroke.

Results—

Patients in the top tertile of sCD40L levels had increased risk of recurrent stroke comparing with those in the bottom tertile, after adjusted for conventional confounding factors (hazard ratio, 1.49; 95% confidence interval, 1.11–2.00;
P
=0.008). The patients with elevated levels of both sCD40L and high-sensitive C-reactive protein also had increased risk of recurrent stroke (hazard ratio, 1.81; 95% confidence interval, 1.23–2.68;
P
=0.003).

Conclusions—
Elevated sCD40L levels independently predict recurrent stroke in patients with minor stroke and transient ischemic attack.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
The Influence of the Spectral Truncation on the Simulation of Waves in the Tropical Stratosphere
Authors: Krismer T. R. , Giorgetta M. A. , von Storch J. S. , Fast I. 
Published: May 2015

Abstract
Convectively triggered waves are the main driver of the tropical stratospheric circulation. In atmospheric models, the model’s resolution limits the length of the simulated wave spectrum. In this study, the authors compare the tropical tropospheric wave sources, their projection on the wave field in the lower stratosphere, and the circumstances of their upward propagation in the atmospheric model ECHAM6 with three spectral truncations of T63, T127, and T255. The model internally generates the quasi-biennial oscillation (QBO), which dominates the variability in the tropical stratosphere. This analysis focuses on two opposite phases of the QBO to account for the influence of the background wind field on the wave filtering. It is shown that, compared to the high-resolution model versions, the T63 version has less convective variability and less wave momentum in the lower stratosphere at wavenumbers larger than 20, well below the version’s truncation limit. In the low-resolution version, the upward propagation of the waves is further hindered by the highly active (relative to the high-resolution versions) horizontal diffusion scheme. However, even in the T255 version of ECHAM6, the convective variability is too small compared to TRMM observations at periods shorter than 2 days and wavelengths shorter than 1000 km. Hence, to model a realistic tropical wave activity, the convective parameterization of the model has to improve to increase the day-to-day precipitation variability.
Estimation of Finescale Rainfall Fields Using Broadcast TV Satellite Links and a 4DVAR Assimilation Method
Authors: Mercier François , Barthès Laurent , Mallet Cécile 
Published: May 2015

AbstractThis study proposes a method based on the use of a set of commercial satellite-to-Earth microwave links to rebuild finescale rainfall fields. Such microwave links exist all over the world and can be used to estimate the integrated rain attenuation over the links’ first 5–7 km with a very high temporal resolution (10 s in the present case). The retrieval algorithm makes use of a four-dimensional variational data assimilation (4DVAR) method involving a numerical advection scheme. The advection velocity is recovered from the observations or from radar rainfall fields at successive time steps.This technique has been successively applied to simulated 2D rain maps and to real data recorded in the autumn of 2013 during the Hydrological Cycle in the Mediterranean Experiment (HyMeX), with one sensor receiving microwave signals from four different satellites. The performance of this system is assessed and is compared to an operational Météo-France radar and a network of 10 rain gauges. Because of the limitations of the propagation model, this study is limited to the events with strong advective characteristics (four out of eight recorded events). For these events (only), the method produces rainfall fields that are highly correlated with the radar maps at spatial resolutions greater than . The point-scale results are also satisfactory for temporal resolutions greater than 10 min (mean correlation with rain gauge data equal to approximately 0.8, similar to the correlation between radar and rain gauge data).This method can also be adapted to the fusion of a rain gauge with microwave link measurements and, through the use of several sensors, it has the potential of being applied to larger areas.
The role of the induction of mild hypothermia in adult patient outcomes after cardiac arrest: Systematic review and meta-analysis of randomized controlled studies
Authors: Yu Tao , Longhini Federico , Wu Rongrong , Yao Weidong , Lu Weihua , Jin Xiaoju 
Published: May 2015

Objective To determine whether patients with return of spontaneous circulation (ROSC) following cardiac arrest who received mild hypothermia have improved mortality and neurological outcomes compared with those who do not receive mild hypothermia. Methods Online database searches were performed for English-language randomized controlled trials published before March 2014, comparing mild hypothermia (32–34℃) with normothermia or hypothermia other than mild hypothermia after cardiac arrest, in adults with ROSC. Data were independently extracted using a dedicated form. Mortality rates and neurological outcomes were recorded for the overall population and for in-hospital and prehospital mild hypothermia subgroups. Results Seven articles were identified for inclusion in the meta-analysis. Mild hypothermia demonstrated no significant beneficial effects in terms of overall mortality or neurological outcomes. In addition, no significant outcome differences were observed between the pre- and in-hospital subgroups. Conclusions On the basis of this limited data set, mild hypothermia does not improve mortality rates or neurological outcomes in patients with ROSC after cardiac arrest, regardless of the timing of the hypothermia. Larger trials need to be carried out to confirm these findings.
The quality of obtaining surgical informed consent
Authors: Joolaee Soodabeh , Faghanipour Somayeh , Hajibabaee Fatemeh 
Published: May 2015

Background: Informed consent goes beyond signing a form; it is a process of providing necessary information, helping patients make an informed decision, and actively participate in their treatment. Aim/objective: This study aimed to assess the quality of obtaining surgical informed consent in hospitals affiliated with Tehran University of Medical Sciences. Research design/participants/context: In a cross-sectional, descriptive-analytical study, 300 patients were chosen through stratified sampling from seven hospitals affiliated with Tehran University of Medical Sciences. Data were collected using a questionnaire developed by the researchers and analyzed using descriptive and analytical statistics on SPSS software. Ethical considerations: Ethical approval of this study was granted by Tehran University of Medical Sciences research ethics committee. Written informed consent for participation was obtained. The participants were reassured that their information will be used anonymously and their answers will not affect their treatment and care. Findings: The mean score of quality of acquisition of informed consent was 17.13 out of 35, indicating that the quality falls in the inappropriate category. The results indicate that 48% of the signatories do not even read the form before signing it. Among the 52% who did read the consent form, 61.3% mentioned varying degrees of incomprehensibility of the consent form and 94.2% mentioned the presence of incomprehensible technical, medical and legal vocabulary. Only 12% and 18% of respondents reported that they were not in hurry and they had no fear or anxiety, respectively, when signing the form. The quality of obtaining informed consent was higher in women, younger patients, patients with higher education, and those who had special surgeries. Discussion: This study shows a poor practice in obtaining surgical informed consent in Iran. It seems necessary to consider fundamental changes in the process of acquiring consent based on the temporal and local conditions of the patients.
Comparing Genomic Profiles of Women With and Without Fibromyalgia
Authors: Lukkahatai Nada , Walitt Brian , Espina Alexandra , Wang Dan , Saligan Leorey N. 
Published: May 2015

Background: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers. Methods: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups. Result: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS ( n = 29) and controls ( n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes ( p < .01). Conclusion: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings.
Characteristics of lesional and extra-lesional cortical grey matter in relapsing–remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study
Authors: Yaldizli Özgür , Pardini Matteo , Sethi Varun , Muhlert Nils , Liu Zheng , Tozer Daniel J , Samson Rebecca S , Wheeler-Kingshott Claudia AM , Yousry Tarek A , Miller David H , Chard Declan T 
Published: May 2015

Background: In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. Objective: To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. Methods: Seventy-two people with MS (46 relapsing–remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. Results: Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. Conclusion: Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability.
High-flow venous pouch aneurysm in the rabbit carotid artery: A model for large aneurysms
Authors: Krähenbühl Anna K , Gralla Jan , Abu-Isa Janine , Mordasini Pasquale , Widmer Hans R , Raabe Andreas , Reinert Michael 
Published: May 2015

Background and purpose Currently one of the most widely used models for the development of endovascular techniques and coiling devices for treatment of aneurysm is the elastase-induced aneurysm model in the rabbit carotid artery. Microsurgical techniques for creating an aneurysm with a venous pouch have also been established, although both techniques usually result in aneurysms less than 1 cm in diameter. We investigated whether an increase in blood flow toward the neck would produce larger aneurysms in a microsurgical venous pouch model. Materials and methods Microsurgical operations were performed on 11 New Zealand white rabbits. Both carotid arteries and the right jugular vein were dissected, and the right carotid artery was temporarily clipped followed by an arteriotomy. The left carotid artery was also clipped proximally, ligated distally, and sutured onto the proximal half of the arteriotomy in the right carotid artery. The venous graft was sutured onto the distal half of the arteriotomy. Digital subtraction angiography was also performed. Results Angiography showed patent anastomosed vessels and aneurysms in the seven surviving rabbits. Mean aneurysm measurements among surviving rabbits with patent vessels were: 13.9 mm length, 9.3 mm width, and neck diameter 4.7 mm. The resulting mean aspect ratio was 3.35 and the mean bottleneck ratio was 3.05. Conclusion A large venous graft and increased blood flow toward the base of the aneurysm seem to be key factors in the creation of large venous pouch aneurysms. These large aneurysms allow testing of endovascular devices designed for large and giant aneurysms.