bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive Biomarkers of Sensitivity to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Breast Cancer Models
Authors: Diamond Jennifer R. , Eckhardt S. Gail , Tan Aik Choon , Newton Timothy P. , Selby Heather M. , Brunkow Kelsey L. , Kachaeva Maria I. , Varella-Garcia Marileila , Pitts Todd M. , Bray Mark R. , Fletcher Graham C. , Tentler John J. 
Published: November 2012

Abstract
Purpose: The Aurora kinases are a family of conserved serine-threonine kinases with key roles in mitotic cell division. As with other promising anticancer targets, patient selection strategies to identify a responsive subtype will likely be required for successful clinical development of Aurora kinase inhibitors. The purpose of this study was to evaluate the antitumor activity of the Aurora and angiogenic kinase inhibitor ENMD-2076 against preclinical models of breast cancer with identification of candidate predictive biomarkers.
Experimental Design: Twenty-nine breast cancer cell lines were exposed to ENMD-2076 and the effects on proliferation, apoptosis, and cell-cycle distribution were evaluated. In vitro activity was confirmed in MDA-MB-468 and MDA-MB-231 triple-negative breast cancer xenografts. Systematic gene expression analysis was used to identify up- and downregulated pathways in the sensitive and resistant cell lines, including within the triple-negative breast cancer subset.
Results: ENMD-2076 showed antiproliferative activity against breast cancer cell lines, with more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and proapoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression.
Conclusions: ENMD-2076 exhibited robust anticancer activity against models of triple-negative breast cancer and the candidate predictive biomarkers identified in this study may be useful in selecting patients for Aurora kinase inhibitors in the future. Clin Cancer Res; 19(1); 291–303. ©2012 AACR.
Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-Dose Cyclophosphamide in Children and Young Adults with Refractory/Recurrent Solid Tumors
Authors: Navid Fariba , Baker Sharyn D. , McCarville M. Beth , Stewart Clinton F. , Billups Catherine A. , Wu Jianrong , Davidoff Andrew M. , Spunt Sheri L. , Furman Wayne L. , McGregor Lisa M. , Hu Shuiying , Panetta John C. , Turner David , Fofana Demba , Reddick Wilburn E. , Leung Wing , Santana Victor M. 
Published: November 2012

Abstract
Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors.
Experimental Design: Sorafenib dose was escalated from 90 to 110 mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course.
Results: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1–23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (&gt;2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m2 at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019).
Conclusion: The recommended phase II doses are sorafenib, 90 mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation. Clin Cancer Res; 19(1); 236–46. ©2012 AACR.
Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts
Authors: Butler Anne M. , Yin Xiaoyan , Evans Daniel S. , Nalls Michael A. , Smith Erin N. , Tanaka Toshiko , Li Guo , Buxbaum Sarah G. , Whitsel Eric A. , Alonso Alvaro , Arking Dan E. , Benjamin Emelia J. , Berenson Gerald S. , Bis Josh C. , Chen Wei , Deo Rajat , Ellinor Patrick T. , Heckbert Susan R. , Heiss Gerardo , Hsueh Wen-Chi , Keating Brendan J. , Kerr Kathleen F. , Li Yun , Limacher Marian C. , Liu Yongmei , Lubitz Steven A. , Marciante Kristin D. , Mehra Reena , Meng Yan A. , Newman Anne B. , Newton-Cheh Christopher , North Kari E. , Palmer Cameron D. , Psaty Bruce M. , Quibrera P. Miguel , Redline Susan , Reiner Alex P. , Rotter Jerome I. , Schnabel Renate B. , Schork Nicholas J. , Singleton Andrew B. , Smith J. Gustav , Soliman Elsayed Z. , Srinivasan Sathanur R. , Zhang Zhu-ming , Zonderman Alan B. , Ferrucci Luigi , Murray Sarah S. , Evans Michele K. , Sotoodehnia Nona , Magnani Jared W. , Avery Christy L. 
Published: November 2012

Background—
The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

Methods and Results—

We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9–1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with
MEIS1, SCN5A, ARHGAP24, CAV1
, and
TBX5
to African American populations at the genome-wide significance level (
P
<5.0×10
−8
), we also identified a novel locus:
ITGA9
, located in a region previously implicated in
SCN5A
expression. The 3p21 region harboring
SCN5A
also contained 2 additional independent secondary signals influencing PR (
P
<5.0×10
−8
).

Conclusions—
This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
The relationship between the prescription of psychotropic drugs and suicide rates in older people in England and Wales
Authors: Shah Ajit , Zhinchin Galina , Zarate-Escudero Sofia , Somyaji Manjunath 
Published: November 2012

Background: Several studies have reported an inverse correlation between general population and elderly suicide rates and antidepressant prescribing rates. Correlations between general population and elderly suicide rates and prescribing rates of other psychotropic drugs have also been reported. All studies of elderly suicide rates have used data over a decade old. Methods: The relationship between elderly suicide rates and prescription rates of psychotropic drugs by the broad British National Formulary (BNF) categories, for individual psychotropic drug groups within the BNF categories (e.g. SSRIs), and for individual psychotropic drugs was examined over a 12-year period (1995–2006) using Spearman’s rank correlation. All data were ascertained from the archives of the National Statistics Office. Results: There was an absence of significant correlations between elderly suicides rates and rates of prescriptions of psychotropic drugs in the broad BNF categories, individual psychotropic drug groups and individual psychotropic drugs. Discussion: The findings may be due to methodological flaws. However, if they are genuine, then the following approaches require consideration to further reduce suicide rates: (1) development of strategies to ensure continued prescription of psychotropic drugs at the current level; (2) development of strategies to improve non-pharmacological measures, including improved mental health services provision for older people, improved assessment of suicide risk, increased availability of psychosocial interventions and restricting the availability of methods of suicide; and (3) development of strategies to implement improvement in distal risk (e.g. societal socio-economic status) and protective (e.g. societal educational attainment) factors for suicide at a societal level.
TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell–independent isotype switch in mice
Authors: Pihlgren Maria , Silva Alberto B. , Madani Rime , Giriens Valérie , Waeckerle-Men Ying , Fettelschoss Antonia , Hickman David T. , López-Deber María Pilar , Ndao Dorin Mlaki , Vukicevic Marija , Buccarello Anna Lucia , Gafner Valérie , Chuard Nathalie , Reis Pedro , Piorkowska Kasia , Pfeifer Andrea , Kündig Thomas M. , Muhs Andreas , Johansen Pål 
Published: November 2012

AbstractImmunoglobulin class switching from IgM to IgG in response to peptides is generally T cell–dependent and vaccination in T cell–deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell–independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.
Antibacterial effect of microvesicles released from human neutrophilic granulocytes
Authors: Timár Csaba I. , Lőrincz Ákos M. , Csépányi-Kömi Roland , Vályi-Nagy Anna , Nagy György , Buzás Edit I. , Iványi Zsolt , Kittel Ágnes , Powell David W. , McLeish Kenneth R. , Ligeti Erzsébet 
Published: November 2012

AbstractCell-derived vesicles represent a recently discovered mechanism for intercellular communication. We investigated their potential role in interaction of microbes with host organisms. We provide evidence that different stimuli induced isolated neutrophilic granulocytes to release microvesicles with different biologic properties. Only opsonized particles initiated the formation of microvesicles that were able to impair bacterial growth. The antibacterial effect of neutrophil-derived microvesicles was independent of production of toxic oxygen metabolites and opsonization or engulfment of the microbes, but depended on β2 integrin function, continuous actin remodeling, and on the glucose supply. Neutrophil-derived microvesicles were detected in the serum of healthy donors, and their number was significantly increased in the serum of bacteremic patients. We propose a new extracellular mechanism to restrict bacterial growth and dissemination.
Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis
Authors: Mendoza-Milla Criselda , Valero Jiménez Ana , Rangel Claudia , Lozano Alfredo , Morales Violeta , Becerril Carina , Chavira Roberto , Ruiz Víctor , Barrera Lourdes , Montaño Martha , Pardo Annie , Selman Moisés 
Published: November 2012

Idiopathic pulmonary fibrosis (IPF) is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone (DHEA), a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases.We quantified the plasma levels of DHEA and its sulfated form (DHEA-S) in 137 IPF patients and 58 controls and examined the effects of DHEA on human lung fibroblasts.Plasma DHEA/DHEA-S was significantly decreased in male IPF patients (median (range) DHEA: 4.4 (0.2–29.2)versus6.7 (2.1–15.2) ng·mL−1, p<0.01; DHEA-S: 47 (15.0–211)versus85.2 (37.6–247.0) μg·dL−1, p<0.001), while in females only DHEA-S was significantly decreased (32.6 (15.0–303.0)versus68.3 (16.4–171) μg·dL−1, p<0.001). DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins (Bax and cyclin-dependent kinase-inhibitor CDNK1A) and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis (c-IAP)1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-β1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration.These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in IPF patients and indicate that this molecule has multiple antifibrotic properties.
Surgical treatment of chronic thromboembolic pulmonary hypertension
Authors: Jenkins David P. , Madani Michael , Mayer Eckhard , Kerr Kim , Kim Nic , Klepetko Walter , Morsolini Marco , Dartevelle Philippe 
Published: November 2012

It is likely that chronic thromboembolic pulmonary hypertension (CTEPH) is more prevalent than currently recognised. Imaging studies are fundamental to decision making with respect to operability. All patients with suspected CTEPH should be referred to an experienced surgical centre. Currently, there is no risk scoring stratification system to guide operability assessment and it is predominantly based on surgical experience.The aim of pulmonary endarterectomy (PEA) is the removal of obstructive material to immediately reduce pulmonary vascular resistance. PEA affords the best chance of cure, but is difficult to perfect. Recognition and clearance of distal segmental and subsegmental disease is the main problem. The basic surgical techniques include: median sternotomy incision, cardiopulmonary bypass, arteriotomy incisions within pericardium, and a true endarterectomy with meticulous full distal dissection. Deep hypothermic circulatory arrest is recommended as the best means of reducing blood flow in the pulmonary artery to allow a clear field for dissection. In the recent PEACOG (PEA and COGnition) trial there was no evidence of cognitive impairment post-PEA.Reperfusion pulmonary oedema and residual pulmonary hypertension are unique post-operative complications post-PEA and are associated with increased mortality. However, in-hospital mortality is now <5% in experienced centres.
Barrier responses of human bronchial epithelial cells to grass pollen exposure
Authors: Blume Cornelia , Swindle Emily J. , Dennison Patrick , Jayasekera Nivenka P. , Dudley Sarah , Monk Phillip , Behrendt Heidrun , Schmidt-Weber Carsten B. , Holgate Stephen T. , Howarth Peter H. , Traidl-Hoffmann Claudia , Davies Donna E. 
Published: November 2012

The airway epithelium forms a physical, chemical and immunological barrier against inhaled environmental substances. In asthma, these barrier properties are thought to be abnormal. In this study, we analysed the effect of grass pollen on the physical and immunological barrier properties of differentiated human primary bronchial epithelial cells.Following exposure to Timothy grass (Phleum pratense) pollen extract, the integrity of the physical barrier was not impaired as monitored by measuring the transepithelial resistance and immunofluorescence staining of tight junction proteins. In contrast, pollen exposure affected the immunological barrier properties by modulating vectorial mediator release. CXC chemokine ligand (CXCL)8/interleukin (IL)-8 showed the greatest increase in response to pollen exposure with preferential release to the apical compartment. Inhibition of the extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways selectively blocked apical CXCL8/IL-8 releaseviaa post-transcriptional mechanism. Apical release of CC chemokine ligand (CCL)20/macrophage inflammatory protein-3α, CCL22/monocyte-derived chemokine and tumour necrosis factor-α was significantly increased only in severe asthma cultures, while CCL11/eotaxin-1 and CXCL10/interferon-γ-induced protein-10 were reduced in nonasthmatic cultures.The bronchial epithelial barrier modulates polarised release of mediators in response to pollen without direct effects on its physical barrier properties. The differential response of cells from normal and asthmatic donors suggests the potential for the bronchial epithelium to promote immune dysfunction in asthma.
Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey
Authors: Meyer Stephanie , McLaughlin Vallerie V. , Seyfarth Hans-Juergen , Bull Todd M. , Vizza Carmine D. , Gomberg-Maitland Mardi , Preston Ioana R. , Barberà Joan A. , Hassoun Paul M. , Halank Michael , Jaïs Xavier , Nickel Nils , Hoeper Marius M. , Humbert Marc 
Published: November 2012

We conducted an international, prospective, 3-year questionnaire-based survey among 11 pulmonary hypertension centres to assemble data from patients with pulmonary arterial hypertension (PAH) undergoing noncardiac and nonobstetric surgery.Data were collected between July 2007 and June 2010 from 114 patients with PAH (70% female, mean age 57 years) who underwent major surgery. At the time of surgery, 43% were in functional class III/IV. 82% of the interventions were performed under general anaesthesia and 18% under spinal anaesthesia. Major complications occurred in seven (6.1%) of the patients, of whom four died, resulting in an overall perioperative mortality rate of 3.5%. The mortality rate was 15% (two out of 13) in emergency procedures, compared with 2% (two out of 101) in nonemergency procedures (p=0.01). Risk factors for major complications were an elevated right atrial pressure (OR 1.1, 95% CI 1.0–1.3; p=0.01), a 6-min walking distance <399 m at the last preoperative assessment (OR 2.2, 95% CI 1.1–3.7; p=0.04), the perioperative use of vasopressors (OR 1.5, 95% CI 1.2–2.7; p=0.03) and the need for emergency surgery (OR 2.4, 95% CI 1.4–3.6; p=0.01).Major surgery in patients with PAH continues to be a high-risk procedure, particularly when emergency interventions are needed.
Low-dose plasmid DNA treatment increases plasma vasopressin and regulates blood pressure in experimental endotoxemia
Authors: Malardo Thiago , Batalhão Marcelo E , Panunto-Castelo Ademilson , Almeida Luciana P , Padilha Everton , Fontoura Isabela C , Silva Célio L , Carnio Evelin C , Coelho-Castelo Arlete AM 
Published: November 2012

Abstract

Background
Although plasmid DNA encoding an antigen from pathogens or tumor cells has been widely studied as vaccine, the use of plasmid vector (without insert) as therapeutic agent requires further investigation.

Results
Here, we showed that plasmid DNA (pcDNA3) at low doses inhibits the production of IL-6 and TNF-α by lipopolysaccharide (LPS)-stimulated macrophage cell line J774. These findings led us to evaluate whether plasmid DNA could act as an anti-inflammatory agent in a Wistar rat endotoxemia model. Rats injected simultaneously with 1.5 mg/kg of LPS and 10 or 20 μg of plasmid DNA had a remarkable attenuation of mean arterial blood pressure (MAP) drop at 2 hours after treatment when compared with rats injected with LPS only. The beneficial effect of the plasmid DNA on MAP was associated with decreased expression of IL-6 in liver and increased concentration of plasma vasopressin (AVP), a known vasoconstrictor that has been investigated in hemorrhagic shock management. No difference was observed in relation to nitric oxide (NO) production.

Conclusion
Our results demonstrate for the first time that plasmid DNA vector at low doses presents anti-inflammatory property and constitutes a novel approach with therapeutic potential in inflammatory diseases.
Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: Results of an open-label Phase I and a randomized, standard-of-care-controlled Phase I/II study
Authors: Nativ Ofer , Patel Bababhai , Shen Jessica , Batiller Jonathan , Horn Sara , Hart James C 
Published: November 2012

Abstract

Background
Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages.

Methods
We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level.

Results
Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled.

Conclusions
The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage.

Trial registration
Phase I/II trial, NCT00598130