bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of CD45−/CD31+/CD105+ Circulating Cells in the Peripheral Blood of Patients with Gynecologic Malignancies
Authors: Yu Hyun-Kyung , Lee Ho-Jeong , Choi Ha-Na , Ahn Jin-Hyung , Choi Ji-Young , Song Haeng-Seok , Lee Ki-Heon , Yoon Yeup , Yi Lee S. H. , Kim Jang-Seong , Kim Sun Jin , Kim Tae Jin 
Published: August 2013

AbstractPurpose: Circulating endothelial cells (CEC) have been widely used as a prognostic biomarker and regarded as a promising strategy for monitoring the response to treatment in several cancers. However, the presence and biologic roles of CECs have remained controversial for decades because technical standards for the identification and quantification of CECs have not been established. Here, we hypothesized that CECs detected by flow cytometry might be monocytes rather than endothelial cells.Experimental Design: The frequency of representative CEC subsets (i.e., CD45−/CD31+, CD45−/CD31+/CD146+, CD45−/CD31+/CD105+) was analyzed in the peripheral blood of patients with gynecologic cancer (n = 56) and healthy volunteers (n = 44). CD45−/CD31+ cells, which are components of CECs, were isolated and the expression of various markers (CD146, CD105, vWF, and CD144 for endothelial cells; CD68 and CD14 for monocytes) was examined by immunocytochemistry.Results: CD45−/CD31+/CD105+ cells were significantly increased in the peripheral blood of patients with cancer, whereas evaluation of CD45−/CD31+/CD146+ cells was not possible both in patients with cancer and healthy controls due to the limited resolution of the flow cytometry. Immunocytochemistry analyses showed that these CD45−/CD31+/CD105+ cells did not express vWF and CD146 but rather CD144. Furthermore, CD45−/CD31+/CD105+ cells uniformly expressed the monocyte-specific markers CD14 and CD68. These results suggest that CD45−/CD31+/CD105+ cells carry the characteristics of monocytes rather than endothelial cells.Conclusions: Our data indicate that CD45−/CD31+/CD105+ circulating cells, which are significantly increased in the peripheral blood of patients with gynecologic cancer, are monocytes rather than endothelial cells. Further investigation is required to determine the biologic significance of their presence and function in relation with angiogenesis. Clin Cancer Res; 19(19); 5340–50. ©2013 AACR.
Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo
Authors: Renshaw Jane , Taylor Kathryn R. , Bishop Ryan , Valenti Melanie , De Haven Brandon Alexis , Gowan Sharon , Eccles Suzanne A. , Ruddle Ruth R. , Johnson Louise D. , Raynaud Florence I. , Selfe Joanna L. , Thway Khin , Pietsch Torsten , Pearson Andrew D. , Shipley Janet 
Published: August 2013

Abstract
Purpose: To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths.
Experimental Design: The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110α short hairpin RNA–mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110α knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations.
Results: PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110α knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP–ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug–drug interaction with both combinations.
Conclusions: Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor. Clin Cancer Res; 19(21); 5940–51. ©2013 AACR.
Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study
Authors: Ang Joo Ern , Gourley Charlie , Powell C. Bethan , High Hilda , Shapira-Frommer Ronnie , Castonguay Vincent , De Greve Jacques , Atkinson Tina , Yap Timothy A. , Sandhu Shahneen , Banerjee Susana , Chen Lee-May , Friedlander Michael L. , Kaufman Bella , Oza Amit M. , Matulonis Ursula , Barber Louise J. , Kozarewa Iwanka , Fenwick Kerry , Assiotis Ioannis , Campbell James , Chen Lina , de Bono Johann S. , Gore Martin E. , Lord Christopher J. , Ashworth Alan , Kaye Stan B. 
Published: August 2013

Abstract
Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.
Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.
Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].
Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.
The Winning Formulation: The Development of Paclitaxel in Pancreatic Cancer
Authors: Ma Wen Wee , Hidalgo Manuel 
Published: August 2013

Abstract
Paclitaxel has wide application in anticancer therapy but was never considered an efficacious agent in pancreatic cancer. A review of the experience with the Cremaphor formulation hinted at paclitaxel's activity in pancreatic cancer, but the early development was hampered by significant toxicities such as neutropenia and infection at clinically tolerable doses. However, such efficacy was confirmed in the recently completed phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), in which the addition of nab-paclitaxel to gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer. Several other Cremaphor-free formulations of paclitaxel had also been evaluated in pancreatic cancer, and the reasons for the success of the albumin nanoparticulate are examined here. In the era of biologic and molecularly targeted agents, the success of nab-paclitaxel in recalcitrant pancreatic cancer is a timely reminder of the importance and relevance of pharmacology and novel drug delivery technology in the development of anticancer drugs. Clin Cancer Res; 19(20); 5572–9. ©2013 AACR.
Cetuximab Reverses the Warburg Effect by Inhibiting HIF-1–Regulated LDH-A
Authors: Lu Haiquan , Li Xinqun , Luo Zhongguang , Liu Jie , Fan Zhen 
Published: August 2013

Abstract
Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an EGF receptor–blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of EGF receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an HIF-1α downregulation–dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell-cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response. Mol Cancer Ther; 12(10); 2187–99. ©2013 AACR.
Targeting the Wnt Pathway in Synovial Sarcoma Models
Authors: Barham Whitney , Frump Andrea L. , Sherrill Taylor P. , Garcia Christina B. , Saito-Diaz Kenyi , VanSaun Michael N. , Fingleton Barbara , Gleaves Linda , Orton Darren , Capecchi Mario R. , Blackwell Timothy S. , Lee Ethan , Yull Fiona , Eid Josiane E. 
Published: August 2013

Abstract
Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT–SSX (SS18–SSX), drives sarcoma initiation and development. The exact mechanism of SYT–SSX oncogenic function remains unknown. In an SYT–SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT–SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT–SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.
Significance: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. Cancer Discov; 3(11); 1286–1301. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 1207
Longitudinal Determinants of Left Ventricular Mass and Geometry
Authors: Gidding Samuel S. , Liu Kiang , Colangelo Laura A. , Cook Nakela L. , Goff David C. , Glasser Stephen P. , Gardin Julius M. , Lima Joao A.C. 
Published: August 2013

Background—
The purpose of this study was to identify determinants of 20-year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods and Results—

We studied 2426 black and white men and women (54.7% white) aged 43 to 55 years with cardiovascular risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, sex, race, body mass index, change in body mass index, mean arterial blood pressure, change in mean blood pressure, heart rate, change in heart rate, tobacco use, presence of diabetes mellitus, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased, whereas prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m
2.7
were year 5 LVM, year 5 and change in body mass index, year 5 and change in mean arterial pressure, year 5 and change in heart rate, baseline diabetes mellitus, and year 5 tobacco and alcohol use (overall
r
2
=0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in body mass index, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes mellitus (overall
r
2
=0.11).

Conclusions—
Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult cardiovascular risk traits and change in these traits predicted change in LV mass/geometry.
Features of Coronary Plaque in Patients With Metabolic Syndrome and Diabetes Mellitus Assessed by 3-Vessel Optical Coherence Tomography
Authors: Yonetsu Taishi , Kato Koji , Uemura Shiro , Kim Byeong-Keuk , Jang Yangsoo , Kang Soo-Jin , Park Seung-Jung , Lee Stephen , Kim Soo-Joong , Jia Haibo , Vergallo Rocco , Abtahian Farhad , Tian Jinwei , Hu Sining , Yeh Robert W. , Sakhuja Rahul , McNulty Iris , Lee Hang , Zhang Shaosong , Yu Bo , Kakuta Tsunekazu , Jang Ik-Kyung 
Published: August 2013

Background—
The pathophysiological basis for the association between metabolic syndrome (MetS) and coronary artery disease is not well understood. We sought to characterize coronary plaques in patients with MetS by using optical coherence tomography.

Methods and Results—

We identified 451 coronary plaques from 171 subjects who underwent optical coherence tomographic imaging in 3 coronary arteries. Subjects were divided into 3 groups: diabetes mellitus (DM, n=77), MetS (n=35), and a control group (C group, n=59) without DM or MetS. Optical coherence tomographic analysis included the presence of lipid-rich plaque, maximum lipid arc, lipid-core length, lipid index (LI), fibrous cap thickness, and thin-cap fibroatheroma. We defined LI as mean lipid arc multiplied by lipid-core length. Lipid-core length and LI were significantly greater in DM and MetS than in C group (lipid-core length: 7.7±4.0 and 7.0±3.8 versus 5.5±2.4 mm;
P
<0.001 and
P
=0.012, and LI: 1164±716 and 1086±693 versus 796±417 mm;
P
<0.001 and
P
=0.008). Maximum lipid arc was significantly greater in DM than in C group, whereas no significant difference was observed between MetS and C group (196±45°, 187±42° versus 176±52°;
P
=0.002 and
P
=0.182). Fibrous cap thickness and thin-cap fibroatheroma showed no significant difference among the 3 groups. In multivariate analysis, DM and MetS were independently associated with LI, whereas only acute coronary syndrome was the independent predictor for thin-cap fibroatheroma.

Conclusions—
Compared with control subjects, coronary plaques in MetS contain larger lipid. However, the MetS criteria used in this study could not distinguish the vulnerable features such as thin-cap fibroatheroma, suggesting the necessity of complementary information to identify patients at high risk for cardiovascular events.
Comparison of Bivalirudin and Radial Access Across a Spectrum of Preprocedural Risk of Bleeding in Percutaneous Coronary Intervention
Authors: Baklanov Dmitri V. , Kim Sunghee , Marso Steven P. , Subherwal Sumeet , Rao Sunil V. 
Published: August 2013

Background—
Bleeding is a common, noncardiac, preventable complication of percutaneous coronary intervention. We compared the relative safety of radial access and bivalirudin in percutaneous coronary intervention.

Methods and Results—

From CathPCI Registry, we determined the association between the site of arterial access, bivalirudin, and periprocedural bleeding rates in 501 017 patients. Radial access patients receiving heparin (radial group) were compared with those receiving bivalirudin (radial combination group). Femoral access patients who had bivalirudin and a vascular closure device served as a reference group (femoral group). An inverse probability weighting analysis incorporating propensity scores was used to compare groups. The overall rate of bleeding was 2.59%. It was 2.71% in the femoral group, 2.5% in the radial group, and 1.82% in the radial combination groups (
P
<0.001). When compared with femoral group, the adjusted odds ratio for bleeding was significantly lower for patients with radial combination group (odds ratio, 0.79; 95% confidence interval, 0.72–0.86), but not for radial group (odds ratio, 0.96; 95% confidence interval, 0.88–1.05), unless patients treated with IIb/IIIa were excluded (radial group-IIb/IIIa odds ratio, 0.84; 95% confidence interval, 0.75–0.94).The number needed to treat to prevent 1 bleeding event with radial combination group was 138, whereas the number needed to treat to prevent 1 bleeding event in high-bleeding risk patients was 68.

Conclusions—
In this observational analysis, the combination of bivalirudin and radial access was associated with reduced bleeding event rate. This benefit was present across the entire spectrum of preprocedural risk of bleeding, with or without exposure to IIb/IIIa inhibitors. These data support an adequately powered randomized trial comparing bleeding avoidance strategies.
Variation in the Use of 12‐Lead Electrocardiography for Patients With Chest Pain by Emergency Medical Services in North Carolina
Authors: Bush Montika , Glickman Lawrence T. , Fernandez Antonio R. , Garvey J. L. , Glickman Seth W. 
Published: August 2013

Background

Prehospital 12‐lead electrocardiography (
ECG
) is critical to timely
STEMI
care although its use remains inconsistent. Previous studies to identify reasons for failure to obtain a prehospital
ECG
have generally only focused on individual emergency medical service
(EMS)
systems in urban areas. Our study objective was to identify patient, geographic, and
EMS
agency‐related factors associated with failure to perform a prehospital
ECG
across a statewide geography.

Methods and Results

We analyzed data from the Prehospital Medical Information System (Pre
MIS
) in
N
orth
C
arolina from January 2008 to November 2010 for patients >30 years of age who used
EMS
and had a prehospital chief complaint of chest pain. Among 3.1 million
EMS
encounters, 134 350 patients met study criteria. From 2008–2010, 82 311 (61%) persons with chest pain received a prehospital
ECG
; utilization increased from 55% in 2008 to 65% in 2010 (trend
P
<0.001). Utilization by health referral region ranged from 22.9% to 74.2% and was lowest in rural areas. Men were more likely than women to have an
ECG
performed (63.0% vs 61.3%, adjusted
RR
1.02, 95%
CI
1.01 to 1.04). The certification‐level of the
EMS
provider (paramedic vsbasic/intermediate) and system‐level
ECG
equipment availability were the strongest predictors of
ECG
utilization. Persons in an ambulance with a certified paramedic were significantly more likely to receive a prehospital
ECG
than nonparamedics (
RR
2.15, 95%
CI
1.55, 2.99).

Conclusions

Across a large geographic area prehospital
ECG
use increased significantly, although important quality improvement opportunities remain. Increasing
ECG
availability and improving
EMS
certification and training levels are needed to improve overall care and reduce rural‐urban treatment differences.
Vascularization Pattern After Ischemic Stroke is Different in Control Versus Diabetic Rats
Authors: Prakash Roshini , Li Weiguo , Qu Zhi , Johnson Maribeth A. , Fagan Susan C. , Ergul Adviye 
Published: August 2013

Background and Purpose—
Pre-existing diabetes mellitus worsens brain functionality in ischemic stroke. We have previously shown that type 2 diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the poststroke period in diabetes mellitus, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes mellitus.

Methods—
Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes mellitus and diabetes mellitus plus metformin groups 14 days after ischemic reperfusion injury, as well as in respective sham controls. Three-dimensional reconstruction of the fluorescein isothiocyanate (FITC)-stained vasculature was achieved by confocal microscopy, and stereological parameters, including vascular volume and surface area, were measured. Astrogliosis was determined by glial fibrillary acidic protein staining. The relative rates of sensorimotor recovery, cognitive decline, and spontaneous activity were assessed.

Results—
Vascular density in the peri-infarct area was significantly reduced in diabetes mellitus, whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity were more pronounced in diabetic stroke compared with control stroke. Diabetes mellitus blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes.

Conclusions—
Diabetes mellitus impairs poststroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome.