bluuebunny/crossref_metadata_2025_split huggingface dataset:
The value of aspartate aminotransferase and alanine aminotransferase in cardiovascular disease risk assessment
Authors: Weng Stephen F , Kai Joe , Guha Indra Neil , Qureshi Nadeem 
Published: August 2015

ObjectiveAspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio, reflecting liver disease severity, has been associated with increased risk of cardiovascular disease (CVD). The aim of this study was to evaluate whether the AST/ALT ratio improves established risk prediction tools in a primary care population.MethodsData were analysed from a prospective cohort of 29 316 UK primary care patients, aged 25–84 years with no history of CVD at baseline. Cox proportional hazards regression was used to derive 10-year multivariate risk models for the first occurrence of CVD based on two established risk prediction tools (Framingham and QRISK2), with and without including the AST/ALT ratio. Overall, model performance was assessed by discriminatory accuracy (AUC c-statistic).ResultsDuring a total follow-up of 120 462 person-years, 782 patients (59% men) experienced their first CVD event. Multivariate models showed that elevated AST/ALT ratios were significantly associated with CVD in men (Framingham: HR 1.37, 95% CI 1.05 to 1.79; QRISK2: HR 1.40, 95% CI 1.04 to 1.89) but not in women (Framingham: HR 1.06, 95% CI 0.78 to 1.43; QRISK2: HR 0.97, 95% CI 0.70 to 1.35). Including the AST/ALT ratio with all Framingham risk factors (AUC c-statistic: 0.72, 95% CI 0.71 to 0.74) or QRISK2 risk factors (AUC c-statistic: 0.73, 95% CI 0.71 to 0.74) resulted in no change in discrimination from the established risk prediction tools. Limiting analysis to those individuals with raised ALT showed that discrimination could improve by 5% and 4% with Framingham and QRISK2 risk factors, respectively.ConclusionsElevated AST/ALT ratio is significantly associated with increased risk of developing CVD in men but not women. However, the ratio does not confer any additional benefits over established CVD risk prediction tools in the general population, but may have clinical utility in certain subgroups.
Atherosclerotic aortic aneurysm in a steppe eagle (Aquila nipalensis)
Authors: Abou‐Zahr Tariq , Dutton Thomas Anthony George , Calvo Carrasco Daniel , Forbes Neil , Stidworthy Mark Frederick 
Published: August 2015

A 23‐year‐old female imprinted steppe eagle (Aquila nipalensis) was presented by a public falconry centre for postmortem examination following sudden death with no previous clinical signs. Postmortem examination revealed the presence of 150 ml of blood within the coelomic cavity, with a packed cell volume of 42% indicating an acute, internal haemorrhage as a presumptive cause of death. A well‐demarcated, solid, hard, ovoid, approximately 3 cm×2 cm (in cross section) mass was discovered within the body of the aorta adjacent to the ovary. Histological examination confirmed this to be an aortic aneurysm underlain by severe atherosclerosis with a transmural rupture.
ADAPT, a Novel Scaffold Protein-Based Probe for Radionuclide Imaging of Molecular Targets That Are Expressed in Disseminated Cancers
Authors: Garousi Javad , Lindbo Sarah , Nilvebrant Johan , Åstrand Mikael , Buijs Jos , Sandström Mattias , Honarvar Hadis , Orlova Anna , Tolmachev Vladimir , Hober Sophia 
Published: August 2015

Abstract
Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity Proteins (ADAPT), has been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high-affinity binders to various proteins. Furthermore, ABD was engineered to enable rapid purification, to eradicate its binding to albumin, and to enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, 111In for SPECT imaging and 68Ga for PET imaging. Pharmacologic studies in mice demonstrated that the fully engineered molecule 111In/68Ga-DOTA-(HE)3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET at 1 hour after infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for noninvasive in vivo imaging. Cancer Res; 75(20); 4364–71. ©2015 AACR.
Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs
Authors: Hunter Francis W. , Young Richard J. , Shalev Zvi , Vellanki Ravi N. , Wang Jingli , Gu Yongchuan , Joshi Naveen , Sreebhavan Sreevalsan , Weinreb Ilan , Goldstein David P. , Moffat Jason , Ketela Troy , Brown Kevin R. , Koritzinsky Marianne , Solomon Benjamin , Rischin Danny , Wilson William R. , Wouters Bradly G. 
Published: August 2015

Abstract
Hypoxia is a prevalent feature of many tumors contributing to disease progression and treatment resistance, and therefore constitutes an attractive therapeutic target. Several hypoxia-activated prodrugs (HAP) have been developed, including the phase III candidate TH-302 (evofosfamide) and the preclinical agent SN30000, which is an optimized analogue of the well-studied HAP tirapazamine. Experience with this therapeutic class highlights an urgent need to identify biomarkers of HAP sensitivity, including enzymes responsible for prodrug activation during hypoxia. Using genome-scale shRNA screens and a high-representation library enriched for oxidoreductases, we identified the flavoprotein P450 (cytochrome) oxidoreductase (POR) as the predominant determinant of sensitivity to SN30000 in three different genetic backgrounds. No other genes consistently modified SN30000 sensitivity, even within a POR-negative background. Knockdown or genetic knockout of POR reduced SN30000 reductive metabolism and clonogenic cell death and similarly reduced sensitivity to TH-302 under hypoxia. A retrospective evaluation of head and neck squamous cell carcinomas showed heterogeneous POR expression and suggested a possible relationship between human papillomavirus status and HAP sensitivity. Taken together, our study identifies POR as a potential predictive biomarker of HAP sensitivity that should be explored during the clinical development of SN30000, TH-302, and other hypoxia-directed agents. Cancer Res; 75(19); 4211–23. ©2015 AACR.
Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of HER2-Amplified Gastrointestinal Carcinomas
Authors: Leto Simonetta M. , Sassi Francesco , Catalano Irene , Torri Valter , Migliardi Giorgia , Zanella Eugenia R. , Throsby Mark , Bertotti Andrea , Trusolino Livio 
Published: August 2015

Abstract
Purpose: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities.
Experimental Design: The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays.
Results: Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib—or, importantly, monotherapy with afatinib—resulted in overt tumor shrinkage.
Conclusions: Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res; 21(24); 5519–31. ©2015 AACR.
Prognostic Significance of CD169+ Lymph Node Sinus Macrophages in Patients with Malignant Melanoma
Authors: Saito Yoichi , Ohnishi Koji , Miyashita Azusa , Nakahara Satoshi , Fujiwara Yukio , Horlad Hasita , Motoshima Takanobu , Fukushima Satoshi , Jinnin Masatoshi , Ihn Hironobu , Takeya Motohiro , Komohara Yoshihiro 
Published: August 2015

Abstract
CD169 (sialoadhesin) is a sialic acid receptor that is specifically expressed on macrophages, including lymph node sinus macrophages. Animal studies suggest that CD169+ macrophages in lymph nodes have properties in preventing cancers. In order to determine the significance of CD169+ macrophages in patients with malignant melanoma, we evaluated tissue samples from 93 patients to investigate CD169 expression in regional lymph nodes (RLN) and determine the relationship of this expression with overall survival and various clinicopathologic factors. Higher densities of CD169+ cells were significantly associated with longer overall survival (P = 0.001). A multivariate analysis showed that the density of CD169+ cells was an independent prognostic factor, with higher densities correlating with higher density of CD8+ cytotoxic T cells within tumor sites. High CD169 expression in macrophages could be stimulated by IFNα in vitro, and in RLNs, IFNα-producing macrophages and CD303+ plasmacytoid dendritic cells were identified surrounding CD169+ macrophages. These data suggest that IFNα-stimulated CD169+ macrophages in RLNs are closely involved in T-cell–mediated antitumor immunity and may be a useful marker for assessing the clinical prognosis and monitoring antitumor immunity in patients with malignant melanoma. Cancer Immunol Res; 3(12); 1356–63. ©2015 AACR.
HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade
Authors: Woods David M. , Sodré Andressa L. , Villagra Alejandro , Sarnaik Amod , Sotomayor Eduardo M. , Weber Jeffrey 
Published: August 2015

Abstract
Expression of PD-1 ligands by tumors and interaction with PD-1–expressing T cells in the tumor microenvironment can result in tolerance. Therapies targeting this coinhibitory axis have proven clinically successful in the treatment of metastatic melanoma, non–small cell lung cancer, and other malignancies. Therapeutic agents targeting the epigenetic regulatory family of histone deacetylases (HDAC) have shown clinical success in the treatment of some hematologic malignancies. Beyond direct tumor cell cytotoxicity, HDAC inhibitors have also been shown to alter the immunogenicity and enhance antitumor immune responses. Here, we show that class I HDAC inhibitors upregulated the expression of PD-L1 and, to a lesser degree, PD-L2 in melanomas. Evaluation of human and murine cell lines and patient tumors treated with a variety of HDAC inhibitors in vitro displayed upregulation of these ligands. This upregulation was robust and durable, with enhanced expression lasting past 96 hours. These results were validated in vivo in a B16F10 syngeneic murine model. Mechanistically, HDAC inhibitor treatment resulted in rapid upregulation of histone acetylation of the PD-L1 gene leading to enhanced and durable gene expression. The efficacy of combining HDAC inhibition with PD-1 blockade for treatment of melanoma was also explored in a murine B16F10 model. Mice receiving combination therapy had a slower tumor progression and increased survival compared with control and single-agent treatments. These results highlight the ability of epigenetic modifiers to augment immunotherapies, providing a rationale for combining HDAC inhibitors with PD-1 blockade. Cancer Immunol Res; 3(12); 1375–85. ©2015 AACR.
Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent
Authors: Johnson C. Bryce , Riesenberg Brian P. , May Bennett R. , Gilreath Stuart C. , Li Guangfu , Staveley-O'Carroll Kevin F. , Garrett-Mayer Elizabeth , Mehrotra Shikhar , Cole David J. , Rubinstein Mark P. 
Published: August 2015

AbstractAdoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8+ T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhanced IL7 responsiveness was conferred by elevated IL7Rα expression, which was critical for antitumor immunity. Elevated IL7Rα expression was achievable without IL12, as polyclonal CD8+ T cells activated with high T-cell receptor (TCR) stimulation depended on T-cell IL7Rα expression and host IL7 for maximal engraftment. Finally, IL12 conditioning during the activation of human CD8+ T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL7Rα expression. Our results demonstrate the importance of the donor IL7Rα/host IL7 axis for effector CD8+ T-cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment. Cancer Immunol Res; 3(12); 1364–74. ©2015 AACR.
Comparative Study of PWM Control and PI Control of Induction Motor
Authors: Singh Rohitash , Kr. Bajpai Saurabh , Sandhu Harinder Singh 
Published: August 2015

The induction motor is without doubt the most used electrical motor because of its unique characteristics. Most of its applications need fast and intelligent speed control system. This paper presents comparison of the intelligent and advanced speed control methods based on PWM technique and PI controller to achieve maximum torque and efficiency. Simulation is carried out in MATLAB environment and results are investigated for speed control of induction motor without any controller and with PI controller on full load condition.
Arrhythmia Termination Versus Elimination of Dormant Pulmonary Vein Conduction as a Procedural End Point of Catheter Ablation for Paroxysmal Atrial Fibrillation
Authors: Theis Cathrin , Konrad Torsten , Mollnau Hanke , Sonnenschein Sebastian , Kämpfner Denise , Potstawa Maik , Ocete Blanca Quesada , Bock Karsten , Himmrich Ewald , Münzel Thomas , Rostock Thomas 
Published: August 2015

Background—
Pulmonary vein isolation (PVI) is still associated with a substantial number of arrhythmia recurrences in paroxysmal atrial fibrillation (AF). This prospective, randomized study aimed to compare 2 different procedural strategies.

Methods and Results—

A total of 152 patients undergoing de novo ablation for paroxysmal AF were randomized to 2 different treatment arms. The procedure in group A consisted of PVI exclusively. In this group, all isolated PVs were challenged with adenosine to reveal and ablate dormant conduction. In group B, PVI was performed with the patient either in spontaneous or in induced AF. If AF did not terminate with PVI, ablation was continued by targeting extra-PV AF sources with the desired procedural end point of termination to sinus rhythm. Primary study end point was freedom from arrhythmia during 1-year follow-up. In group A, adenosine provoked dormant conduction in 31 (41%) patients with a mean of 1.6±0.8 transiently recovered PVs per patient. Termination of AF during PVI was observed in 31 (65%) patients, whereas AF persisted afterward in 17 (35%) patients. AF termination occurred in 13 (76%) patients by AF source ablation. After 1-year follow-up, significantly more group B patients were free of arrhythmia recurrences (87 versus 68%;
P
=0.006). During redo ablation, the rate of PV reconduction did not differ between both groups (group A: 55% versus group B: 61%;
P
=0.25).

Conclusions—
Elimination of extra-PV AF sources after PVI is superior to sole PV isolation with the adjunct of abolishing potential dormant conduction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02238392.
Prognostic Value of Coronary Computed Tomography (CT) Angiography and Coronary Artery Calcium Score Performed Before Revascularization
Authors: Fujimoto Shinichiro , Kondo Takeshi , Kumamaru Kanako K. , Shinozaki Tomohiro , Takamura Kazuhisa , Kawaguchi Yuko , Matsumori Rie , Hiki Makoto , Miyauchi Katsumi , Daida Hiroyuki , Rybicki Frank J. 
Published: August 2015

Background

Cardiac events after revascularization are equally attributable to recurrence at site of culprit lesions and development of nonculprit lesions. We evaluated the hypothesis that coronary computed tomography (
CT
) angiography and coronary artery calcium score (
CACS
) performed before revascularization predicts cardiac events after treatment.

Methods and Results

Among 2238 consecutive patients without known coronary artery disease who underwent coronary CT angiography and
CACS
, 359 patients underwent revascularization within 30 days after
CT
; in 337 of 359 (93.9%) follow‐up clinical information was available. In addition to known cardiac risk factors,
CT
findings were evaluated as predictors of cardiac events after revascularization:
CACS
and the presence of
CT
‐verified high‐risk plaque (
CT
‐
HRP
). Improvement of predictive accuracy by including
CT
findings was evaluated from a discrimination (Harrell's C‐statistics) standpoint. During the follow‐up period (median: 673, interquartile range: 47 to 1529 days), a total of 98 cardiac events occurred. Cox proportional hazard model revealed that age, diabetes, triglyceride,
CACS
, and nonculprit
CT
‐
HRP
were significant predictors of overall cardiac events. Although not statistically significant, discriminatory power was greater for the model with
CACS
(C‐stat: 63.2%) and the model with both
CACS
and
CT
‐
HRP
(65.8%) compared to the model including neither
CACS
nor
CT
‐
HRP
(60.7%).

Conclusions

High
CACS
and the presence of nonculprit
CT
‐
HRP
performed before revascularization are significant predictors of cardiac events after revascularization.
The Interpretation of práti … mucāte in R̥gveda 10,27,11c
Authors: Ittzés Máté 
Published: August 2015

The 3s middle subjunctive verb form práti … mucāte (RV 10,27,11c) has generally been interpreted as having an agentive-attingent and irreflexive meaning. Taking into account the usage of the active and the middle forms of práti moc- in the R̥gveda and other Vedic texts, the present article argues that this interpretation is incorrect and that the middle form in question has to be taken as having its usual indirect reflexive meaning (‘to assume, to take on’). This grammatical analysis calls for a little modification of Jamison’s (1996) interpretation of RV 10,27,11.
Tracheal and Crico-Tracheal Resection and Anastomosis for Malignancies Involving the Thyroid Gland and the Airway
Authors: Piazza Cesare , Del Bon Francesca , Barbieri Diego , Grazioli Paola , Paderno Alberto , Perotti Pietro , Lombardi Davide , Peretti Giorgio , Nicolai Piero 
Published: August 2015

Objectives: To evaluate outcomes in different malignancies involving the thyroid and infiltrating the airway submitted to tracheal (TRA) or crico-tracheal resection and anastomosis (CTRA). Methods: Retrospective charts review of 27 patients affected by thyroid malignancies involving the airway treated by TRA/CTRA in a single academic institution. Kaplan-Meier curves were used to evaluate the overall (OS) and disease-specific (DSS) survivals and local (LC) and loco-regional control (LRC). Impact on survival of age, comorbidities, previous radiotherapy, types of TRA/CTRA, Shin’s stage (II, III, IV), grading (well vs poorly differentiated), and length of airway resected was calculated by the log-rank test. Results: Overall survival and DSS at 3 and 5 years were 82.3% and 71.6%, respectively. Local control and LRC in the entire group were 82.3% at 3 and 5 years. Crico-tracheal resection and anastomosis involving the cricoid arch and plate (type C) and tumor differentiation significantly affected OS and DSS (both P < .001). Type C CTRA and tumor differentiation significantly impacted on LC ( P = .002 and P = .009, respectively). Conclusions: Grading and extension of CTRA to the cricoid plate are the most important factors for oncologic outcomes in thyroid malignancies infiltrating the airway. Except for poorly differentiated tumors, TRA/CTRA allows adequate LC even in advanced stage lesions involving the crico-tracheal junction.
Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery
Authors: Mair Eric A. , Moss Jonathan R. , Dohar Joseph E. , Antonelli Patrick J. , Bear Moraye , LeBel Carl 
Published: August 2015

Objective: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. Methods: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). Results: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control ( P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. Conclusions: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea.