bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteome Profiling of Cancer-Associated Fibroblasts Identifies Novel Proinflammatory Signatures and Prognostic Markers for Colorectal Cancer
Authors: Torres Sofia , Bartolomé Rubén A. , Mendes Marta , Barderas Rodrigo , Fernandez-Aceñero M. Jesús , Peláez-García Alberto , Peña Cristina , Lopez-Lucendo María , Villar-Vázquez Roi , de Herreros Antonio García , Bonilla Felix , Casal J. Ignacio 
Published: September 2013

Abstract
Purpose: Cancer-associated fibroblasts (CAF) are essential components of the stroma that play a critical role in cancer progression. This study aimed to identify novel CAFs markers that might contribute to the invasion and the prognosis of colorectal cancer.
Experimental Design: The azoxymethane/dextran sodium sulfate mouse model of sporadic colon cancer represents an adequate source for the isolation of CAFs and normal fibroblasts. By using the explants technique, we purified CAFs and normal fibroblasts from colon tissues. Whole-cell extracts and supernatants were subjected to in-depth quantitative proteomic analysis by tandem mass spectrometry. Further validations of upregulated proteins in CAFs were carried out by chemokine microarray and immunohistochemical analyses of mouse and human tissues.
Results: Using a fold-change of 1.4 or more, we found 132 and 125 differentially expressed proteins in whole-cell extracts and supernatants, respectively. We found CAFs-associated proinflammatory and desmoplastic signatures. The proinflammatory signature was composed of several cytokines. Among them, CCL2 and CCL8 caused an increase in migration and invasion of colorectal cancer KM12 cells. The desmoplastic signature was composed of 30 secreted proteins. In mouse and human samples, expression of LTBP2, CDH11, OLFML3, and, particularly, FSTL1 was significantly increased in the tumoral stroma, without significant expression in the cancer epithelial cells. The combination of CALU and CDH11 stromal expression showed a significant association with disease-free survival and poor prognosis.
Conclusion: We have identified LTBP2, CDH11, OLFML3, and FSTL1 as selective biomarkers of cancer stroma, and CALU and CDH11 as candidate stromal biomarkers of prognostic significance in colon cancer. Clin Cancer Res; 19(21); 6006–19. ©2013 AACR.
Axl Mediates Acquired Resistance of Head and Neck Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Erlotinib
Authors: Giles Keith M. , Kalinowski Felicity C. , Candy Patrick A. , Epis Michael R. , Zhang Priscilla M. , Redfern Andrew D. , Stuart Lisa M. , Goodall Gregory J. , Leedman Peter J. 
Published: September 2013

Abstract
Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial–mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. Mol Cancer Ther; 12(11); 2541–58. ©2013 AACR.
A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult
Authors: Goodwin Jonathan F. , Schiewer Matthew J. , Dean Jeffry L. , Schrecengost Randy S. , de Leeuw Renée , Han Sumin , Ma Teng , Den Robert B. , Dicker Adam P. , Feng Felix Y. , Knudsen Karen E. 
Published: September 2013

Abstract
Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR–DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance and establish a new node for therapeutic intervention in advanced disease.
Significance: The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease. Cancer Discov; 3(11); 1254–71. ©2013 AACR.
See related commentary by Bartek et al., p. 1222
This article is highlighted in the In This Issue feature, p. 1207
Trypsin causes platelet activation independently of known protease-activated receptors
Authors: Mao Yingying , Kunapuli Satya P. 
Published: September 2013

SummaryTo identify a physiological agonist of PAR3, we used PAR4 null murine platelets, which were known to express only PAR3. In this study, we tested several proteases and found that trypsin, but not heat-inactivated trypsin, activated PAR4 null murine platelets. Even at high concentrations, trypsin caused shape change without increasing intracellular calcium levels in PAR4 null murine platelets. Consistent with this result, the Gq inhibitor YM-254890 had no effect on trypsin-induced shape change. However, trypsin-induced platelet shape change was abolished by either p160ROCK inhibitor, Y27632 or H1152. Furthermore, trypsin caused phosphorylation of myosin light chain (Thr18), but not Akt or Erk. Surprisingly, trypsin caused a similar shape change in PAR4-desensitised PAR3 null murine platelets as in PAR4 null murine platelets, indicating that trypsin did not activate PAR3 to cause shape change. More interestingly, the Src family kinase (SFK) inhibitor PP2 abolished trypsin-induced, but not AYPGKF-induced, shape change. Hence, trypsin activated a novel signalling pathway through RhoA/p160ROCK and was regulated by SFKs. In conclusion, our study demonstrates a novel protease signalling pathway in platelets that is independent of PARs. This protease-induced novel signalling pathway regulates platelet shape change through SFKs and p160ROCK.
Questionable reversal of anticoagulation in the therapeutic management of cerebral haemorrhage associated with vitamin K antagonists
Authors: Huertas Nuria , Egido Jose A. , Muriel Alfonso , García Ana , Ruiz-Ares Gerardo , Díez-Tejedor Exuperio , Fuentes Blanca , de Leciñana Maria Alonso 
Published: September 2013

SummaryReversal of anticoagulation is recommended to correct the international normalised ratio (INR) for patients with intracranial haemorrhage (ICH) associated with vitamin K antagonists (VKA). However, the validity of such treatment is debated. We sought to identify, prospectively, the prognostic effect of VKA-ICH treatment in a cohort of patients (n=71; median age 78 years, range 20–89; 52% males). Data collated were: baseline characteristics, treatments, baseline and post-treatment INR, haematoma volume, and haematoma enlargement. Treatment effects and prognostic factor assessment were in relation to mortality and functional outcomes. On admission, the patients had a median score of 9 [p25; p75 of 5; 20] on the National Institute of Health Stroke Scale (NIHSS) and a mean INR of 2.7 (range: 0.9 – 10.8). Haematoma volume (34.6 cm3; SD: 24.9) correlated with NIHSS (r = 0.55; p<0.001) but not with INR. Anticoagulation reversal treatment was administered in 83% of patients. INR <1.5 was achieved in 60.7% of cases. Death or dependency at three months was 76%. Neither baseline INR, anticoagulation reversal nor haematoma enlargement were related to mortality or functional outcome. The only independent prognostic factor was clinical severity on admission. Baseline NIHSS predicted mortality (OR: 1.18; 95%CI: 1.09–1.27), independence (OR: 0.83; 95%CI: 0.74–0.94) and neurological recovery (NIHSS 0–1) (OR: 0.83; 95%CI: 0.73–0.95). The data indicate that VKA-ICH had a poor prognosis. Treatment and INR correction did not appear to affect outcomes.
Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair
Authors: Ye Lei , Zhang Pengyuan , Duval Sue , Su Liping , Xiong Qiang , Zhang Jianyi 
Published: September 2013

Background—
Thymosin β4 (Tβ4) has been shown to enhance the survival of cultured cardiomyocytes. Here, we investigated whether the cytoprotective effects of Tβ4 can increase the effectiveness of transplanted swine mesenchymal stem cells (sMSCs) for cardiac repair in a rat model of myocardial infarction (MI).

Methods and Results—

Under hypoxic conditions, cellular damage (lactate dehydrogenase leakage), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelingc cells), and caspase-8 activity were significantly lower, whereas B-cell lymphoma-extra large protein expression was significantly higher, in sMSCs cultured with Tβ4 (1 μg/mL) than in sMSCs cultured without Tβ4, and Tβ4 also increased sMSC proliferation. For in vivo experiments, animals were treated with basal medium (MI: n=6), a fibrin patch (Patch: n=6), a patch containing sMSCs (sMSC: n=9), or a patch containing sMSCs and Tβ4 (sMSC/Tβ4: n=11); Tβ4 was encapsulated in gelatin microspheres to extend Tβ4 delivery. Four weeks after treatment, echocardiographic assessments of left-ventricular ejection fraction and fractional shortening were significantly better (
P
<0.05) in sMSC/Tβ4 animals (left-ventricular ejection fraction=51.7±1.1%; fractional shortening=26.7±0.7%) than in animals from MI (39±3%; 19.5±1.7%) and Patch (43±1.4%; 21.6±0.9%) groups. Histological assessment of infarct wall thickness was significantly higher (
P
<0.05) in sMSC/Tβ4 animals (50%, [45%, 80%]) than in animals from MI (25%, [20%, 25%]) group. Measurements in sMSC (left-ventricular ejection fraction=45±2.6%; fractional shortening=22.9±1.6%; TH=43% [25%, 45%]), Patch, and MI animals were similar. Tβ4 administration also significantly increased vascular growth, the retention/survival of the transplanted sMSCs, and the recruitment of endogenous c-Kit
+
progenitor cells to the infarcted region.

Conclusions—
Extended-release Tβ4 administration improves the retention, survival, and regenerative potency of transplanted sMSCs after myocardial injury.
Mitral Valve Disease in Patients with Marfan Syndrome Undergoing Aortic Root Replacement
Authors: Kunkala Meghana R. , Schaff Hartzell V. , Li Zhuo , Volguina Irina , Dietz Harry C. , LeMaire Scott A. , Coselli Joseph S. , Connolly Heidi 
Published: September 2013

Background—
Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement.

Methods and Results—

We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade >2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve–sparing procedures; both groups had similar prevalences of MR grade >2 (
P
=0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade >2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31±10 months). Echocardiography performed 21±13 months postoperatively revealed MR >2 in only 3 patients (2%). One early death and 2 late deaths occurred.

Conclusions—
Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤2 would benefit from prophylactic MV intervention.
Stroke and Outcomes in Patients With Acute Type A Aortic Dissection
Authors: Bossone Eduardo , Corteville David C. , Harris Kevin M. , Suzuki Toru , Fattori Rossella , Hutchison Stuart , Ehrlich Marek P. , Pyeritz Reed E. , Steg Philippe Gabriel , Greason Kevin , Evangelista Arturo , Kline-Rogers Eva , Montgomery Daniel G. , Isselbacher Eric M. , Nienaber Christoph A. , Eagle Kim A. 
Published: September 2013

Background—
Stroke is a highly dreaded complication of type A acute aortic dissection (TAAAD). However, little data exist on its incidence and association with prognosis.

Methods and Results—

We evaluated 2202 patients with TAAAD (mean age 62±14 years, 1487 [67.5%] men) from the International Registry of Acute Aortic Dissection to determine the incidence and prognostic impact of stroke in TAAAD. Stroke was present at arrival in 132 (6.0%) patients with TAAAD. These patients were older (65±12 versus 62±15 years;
P
=0.002) and more likely to have hypertension (86% versus 71%;
P
=0.001) or atherosclerosis (29% versus 22%;
P
=0.04) than patients without stroke. Chest pain at arrival was less common in patients with stroke (70% versus 82%;
P
<0.001), and patients with stroke presented more often with syncope (44% versus 15%;
P
<0.001), shock (14% versus 7%;
P
=0.005), or pulse deficit (51% versus 29%;
P
≤0.001). Arch vessel involvement was more frequent among patients with stroke (68% versus 37%;
P
<0.001). They had less surgical management (74% versus 85%;
P
<0.001). Hospital stay was significantly longer in patients with stroke (median 17.9 versus 13.3 days;
P
<0.001). In-hospital complications, such as hypotension, coma, and malperfusion syndromes, and in-hospital mortality (adjusted odds ratio, 1.62; 95% confidence interval, 0.99–2.65) were higher among patients with stroke. Among hospital survivors, follow-up mortality was similar between groups (adjusted hazard ratio, 1.15; 95% confidence interval, 0.46–2.89).

Conclusions—
Stroke occurred in >1 of 20 patients with TAAAD and was associated with increased in-hospital morbidity but not long-term mortality. Whether aggressive early invasive interventions will reduce negative outcomes remains to be evaluated in future studies.
Sustained Release of Engineered Stromal Cell–Derived Factor 1-α From Injectable Hydrogels Effectively Recruits Endothelial Progenitor Cells and Preserves Ventricular Function After Myocardial Infarction
Authors: MacArthur John W. , Purcell Brendan P. , Shudo Yasuhiro , Cohen Jeffrey E. , Fairman Alex , Trubelja Alen , Patel Jay , Hsiao Philip , Yang Elaine , Lloyd Kelsey , Hiesinger William , Atluri Pavan , Burdick Jason A. , Woo Y. Joseph 
Published: September 2013

Background—
Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell–derived factor 1-α (engineered stromal cell–derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.

Methods and Results—
Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical–initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.

Conclusions—
We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.
Impact of Expeditious Management of Perioperative Myocardial Ischemia in Patients Undergoing Isolated Coronary Artery Bypass Surgery
Authors: Davierwala Piroze M. , Verevkin Alexander , Leontyev Sergey , Misfeld Martin , Borger Michael A. , Mohr Friedrich W. 
Published: September 2013

Background—
To analyze the effect of immediate treatment of perioperative myocardial ischemia (PMI) because of early graft failure or incomplete revascularization in patients undergoing coronary artery bypass grafting (CABG) surgery.

Methods and Results—

Between January 2004 and December 2010, 7461 patients underwent isolated CABG at our institution. All patients showing evidence of PMI (n=399; 5.3% of total) underwent emergent coronary angiography. A total of 900 grafts and 1061 distal anastomoses were examined. Two hundred fifty-five patients had 360 distal anastomoses compromised because of early graft failure or incomplete revascularization (ie, abnormal postoperative coronary angiogram). Revision CABG or percutaneous coronary intervention was performed in 130 (51.0%) and 34 (13.3%) patients with abnormal angiograms, respectively. Nonsurgical therapy was implemented in the remaining 91 patients (35.7%) with abnormal angiograms. One hundred forty-four patients had normal postoperative graft-related angiograms. In-hospital mortality was 7.3% and 2.9% in patients with and without PMI (
P
<0.001). In patients with PMI, in-hospital mortality was 9.4% and 3.5% in patients with abnormal and normal postoperative angiograms, respectively (
P
=0.03). Significant multivariable predictors of in-hospital mortality were hemodynamic deterioration, preangiography creatine kinase-MB isoenzyme rise >2× normal, and time interval between primary CABG and coronary angiography >30 hours. Five-year survival in patients without PMI (85.7±0.5%) was significantly better than those with PMI and abnormal angiograms (74.9±2.9%;
P
<0.001 log-rank). When in-hospital mortality was excluded, however, this difference in midterm survival disappeared (
P
=0.9).

Conclusions—
PMI is associated with increased in-hospital mortality in patients undergoing isolated CABG. Expeditious management of bypass graft failure results in similar midterm survival to nonischemic patients in hospital survivors.
Enhanced Survival of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes by the Combination of Cell Sheets With the Pedicled Omental Flap Technique in a Porcine Heart
Authors: Kawamura Masashi , Miyagawa Shigeru , Fukushima Satsuki , Saito Atsuhiro , Miki Kenji , Ito Emiko , Sougawa Nagako , Kawamura Takuji , Daimon Takashi , Shimizu Tatsuya , Okano Teruo , Toda Koichi , Sawa Yoshiki 
Published: September 2013

Background—
Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply.

Methods and Results—
Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide–labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T–positive cells surrounded by vascular-rich structures.

Conclusions—
The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.