bluuebunny/crossref_metadata_2025_split huggingface dataset:
Permeability and thermal cracking at pressure in Sioux Quartzite
Authors: Siddiqi Gunter , Evans Brian 
Published: February 2015

Abstract

We heated specimens of Sioux Quartzite to 683, 783 and 830 K at confining pressures (
P
c
) of 0.1, 100 and 200 MPa. Following the heat treatments, we measured the permeability under confining pressures that varied from 170 MPa to 60 MPa, with pore-fluid pressures of 10, 16 or 22 MPa, resulting in tests having effective pressures ranging from 36 to 160 MPa. When measured under those effective pressures, the permeability of samples with microstructures formed by cracking at 683–830 K and atmospheric pressure increased by a factor of 3–4. Scanning electron microscopy (SEM) shows that thermal cracking increases the number of long, narrow cracks, qualitatively explaining the increased sensitivity of permeability to low effective pressure. Fracture mechanics models suggest that confining pressures lower the stress intensity factors to well below the critical value for crack propagation, and the absence of many long cracks is consistent with that prediction. At
P
c
=200 MPa, thermal cracking during the heat treatment is suppressed. Although the heating experiments were performed on nominally dry samples, in samples heated at the highest temperatures SEM revealed microstructural features that are similar to those seen in crack healing experiments.
Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle
Authors: Vainshtein Anna , Tryon Liam D. , Pauly Marion , Hood David A. 
Published: February 2015

Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. Deletion of PGC-1α resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α. Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/ .
A Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in Resectable Non–Small Cell Lung Cancer
Authors: Owonikoko Taofeek K. , Ramalingam Suresh S. , Miller Daniel L. , Force Seth D. , Sica Gabriel L. , Mendel Jennifer , Chen Zhengjia , Rogatko Andre , Tighiouart Mourad , Harvey R. Donald , Kim Sungjin , Saba Nabil F. , Pickens Allan , Behera Madhusmita , Fu Robert W. , Rossi Michael R. , Auffermann William F. , Torres William E. , Bechara Rabih , Deng Xingming , Sun Shi-Yong , Fu Haian , Gal Anthony A. , Khuri Fadlo R. 
Published: February 2015

Abstract
Purpose: The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non–small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer.
Experimental Design: We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples.
Results: There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, −21%, −24%; P = 0.014), tumor size (10.1%, 5.8%, −11.6%; P = 0.047), and modulation of S6 (−36.1, −13.7, −77.0; P = 0.071) and pS6 (−41.25, −61.57, −47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity.
Conclusions: This “window-of-opportunity” study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC. Clin Cancer Res; 21(8); 1859–68. ©2015 AACR.
Notch Reporter Activity in Breast Cancer Cell Lines Identifies a Subset of Cells with Stem Cell Activity
Authors: D'Angelo Rosemarie C. , Ouzounova Maria , Davis April , Choi Daejin , Tchuenkam Stevie M. , Kim Gwangil , Luther Tahra , Quraishi Ahmed A. , Senbabaoglu Yasin , Conley Sarah J. , Clouthier Shawn G. , Hassan Khaled A. , Wicha Max S. , Korkaya Hasan 
Published: February 2015

Abstract
Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch+) or reduced activity (Notch−) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays, we investigated the role of the Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch+ cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch+ cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts, whereas Notch− cells failed to generate tumors. γ-Secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent, effectively targets these Notch+ cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our study revealed a molecular mechanism for the role of Notch-mediated regulation of breast CSCs and provided a compelling rationale for CSC-targeted therapeutics. Mol Cancer Ther; 14(3); 779–87. ©2015 AACR.
Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2
Authors: Soares Heloisa P. , Ming Ming , Mellon Michelle , Young Steven H. , Han Liang , Sinnet-Smith James , Rozengurt Enrique 
Published: February 2015

Abstract
The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser240/244), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr37/46), and mTORC2-mediated AKT phosphorylation at Ser473, in a concentration-dependent manner. Strikingly, BEZ235 markedly enhanced the MEK/ERK pathway in a dose-dependent manner. Maximal ERK overactivation coincided with complete inhibition of phosphorylation of AKT and 4E-BP1. ERK overactivation was induced by other PI3K/TOR-KIs, including PKI-587 and GDC-0980. The MEK inhibitors U126 or PD0325901 prevented ERK overactivation induced by PI3K/TOR-KIs. The combination of BEZ235 and PD0325901 caused a more pronounced inhibition of cell growth than that produced by each inhibitor individually. Mechanistic studies assessing PI3K activity in single PDAC cells indicate that PI3K/TOR-KIs act through a PI3K-independent pathway. Doses of PI3K/TOR-KIs that enhanced MEK/ERK activation coincided with those that inhibited mTORC2-mediated AKT phosphorylation on Ser473, suggesting a role of mTORC2. Knockdown of RICTOR via transfection of siRNA markedly attenuated the enhancing effect of BEZ235 on ERK phosphorylation. We propose that dual PI3K/mTOR inhibitors suppress a novel negative feedback loop mediated by mTORC2, thereby leading to enhanced MEK/ERK pathway activity in pancreatic cancer cells. Mol Cancer Ther; 14(4); 1014–23. ©2015 AACR.
The IGF-Trap: Novel Inhibitor of Carcinoma Growth and Metastasis
Authors: Wang Ni , Rayes Roni F. , Elahi Seyyed Mehdy , Lu Yifan , Hancock Mark A. , Massie Bernard , Rowe Gerald E. , Aomari Hafida , Hossain Sazzad , Durocher Yves , Pinard Maxime , Tabariès Sébastien , Siegel Peter M. , Brodt Pnina 
Published: February 2015

AbstractThe IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, and the compensatory function of, the insulin receptor system. Here, we report on the production, characterization, and biologic activity of a novel, IGF-targeting protein (the IGF-Trap) comprising a soluble form of hIGFIR and the Fc portion of hIgG1. The IGF-Trap has a high affinity for hIGFI and hIGFII but low affinity for insulin, as revealed by surface plasmon resonance. It efficiently blocked IGFIR signaling in several carcinoma cell types and inhibited tumor cell proliferation, migration, and invasion in vitro. In vivo, the IGF-Trap showed favorable pharmacokinetic properties and could suppress the growth of established breast carcinoma tumors when administered therapeutically into tumor-bearing mice, improving disease-free survival. Moreover, IGF-Trap treatment markedly reduced experimental liver metastasis of colon and lung carcinoma cells, increasing tumor cell apoptosis and reducing angiogenesis. Finally, when compared with an anti-IGFIR antibody or IGF-binding protein-1 that were used at similar or higher concentrations, the IGF-Trap showed superior therapeutic efficacy to both inhibitors. Taken together, we have developed a targeted therapeutic molecule with highly potent anticancer effects that could address limitations of current IGFIR-targeting agents. Mol Cancer Ther; 14(4); 982–93. ©2015 AACR.
Functional Genetic Screen Identifies Increased Sensitivity to WEE1 Inhibition in Cells with Defects in Fanconi Anemia and HR Pathways
Authors: Aarts Marieke , Bajrami Ilirjana , Herrera-Abreu Maria T. , Elliott Richard , Brough Rachel , Ashworth Alan , Lord Christopher J. , Turner Nicholas C. 
Published: February 2015

Abstract
WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition. Inhibition of kinases that regulate CDK activity, CHK1 and MYT1, synergized with WEE1 inhibition through both increased replication stress and forced mitotic entry of S-phase cells. Loss of multiple components of the Fanconi anemia (FA) and homologous recombination (HR) pathways, in particular DNA helicases, sensitized to WEE1 inhibition. Silencing of FA/HR genes resulted in excessive replication stress and nucleotide depletion following WEE1 inhibition, which ultimately led to increased unscheduled mitotic entry. Our results suggest that cancers with defects in FA and HR pathways may be targeted by WEE1 inhibition, providing a basis for a novel synthetic lethal strategy for cancers harboring FA/HR defects. Mol Cancer Ther; 14(4); 865–76. ©2015 AACR.
MAPK7 Regulates EMT Features and Modulates the Generation of CTCs
Authors: Javaid Sarah , Zhang Jianmin , Smolen Gromoslaw A. , Yu Min , Wittner Ben S. , Singh Anurag , Arora Kshitij S. , Madden Marissa W. , Desai Rushil , Zubrowski Matthew J. , Schott Benjamin J. , Ting David T. , Stott Shannon L. , Toner Mehmet , Maheswaran Shyamala , Shioda Toshi , Ramaswamy Sridhar , Haber Daniel A. 
Published: February 2015

Abstract
Epithelial-to-mesenchymal transition (EMT) has been implicated in models of tumor cell migration, invasion, and metastasis. In a search for candidate therapeutic targets to reverse this process, nontumorigenic MCF10A breast epithelial cells were infected with an arrayed lentiviral kinome shRNA library and screened for either suppression or enhancement of a 26-gene EMT RNA signature. No individual kinase gene knockdown was sufficient to induce EMT. In contrast, grouped epithelial markers were induced by knockdown of multiple kinases, including mitogen activated protein kinase 7 (MAPK7). In breast cancer cells, suppression of MAPK7 increased E-cadherin (CDH1) expression and inhibited cell migration. In an orthotopic mouse model, MAPK7 suppression reduced the generation of circulating tumor cells and the appearance of lung metastases. Together, these observations raise the possibility that targeting kinases that maintain mesenchymal cell properties in cancer cells, such as MAPK7, may lessen tumor invasiveness.
Implications: Suppression of MAPK7 induces epithelial markers, reduces generation of circulating tumor cells and appearance of lung metastases. Mol Cancer Res; 13(5); 934–43. ©2015 AACR.
Adenosine Receptor 2A Blockade Increases the Efficacy of Anti–PD-1 through Enhanced Antitumor T-cell Responses
Authors: Beavis Paul A. , Milenkovski Nicole , Henderson Melissa A. , John Liza B. , Allard Bertrand , Loi Sherene , Kershaw Michael H. , Stagg John , Darcy Phillip K. 
Published: February 2015

Abstract
Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti–PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti–PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti–PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8+ T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8+ T cells and, accordingly, increased growth inhibition of CD73+ tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti–PD-1 mAb in patients with cancer and that the efficacy of anti–PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti–PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer. Cancer Immunol Res; 3(5); 506–17. ©2015 AACR.
Early stent thrombosis with bivalirudin in patients undergoing percutaneous coronary intervention
Authors: Piccolo Raffaele , Biase Chiara De , D’Anna Carolina , Trimarco Bruno , Piscione Federico , Galasso Gennaro 
Published: February 2015

SummaryAlthough bivalirudin has been shown to reduce bleeding events in patients undergoing percutaneous coronary intervention, residual concerns remain about a possible higher risk of early (within 30 days) stent thrombosis (ST). Therefore, we performed a meta-analysis of randomised trials reporting ST events with bivalirudin compared to other antithrombotic therapies (heparins ± glycoprotein IIb/IIIa inhibitors). A systematic literature search of electronic resources was performed through May, 2014. The primary endpoint was definite early ST, according to Academic Research Consortium criteria. Secondary endpoints included: all-cause death, myocardial infarction and major bleeding. A total of 11 trials, including 16,415 patients, were accrued. Compared to other regimens, bivalirudin significantly increased the risk of early ST (odds ratio [OR]=1.80; 95 % confidence interval [CI], 1.28 2.52; p=0.0007) and reduced the risk of major bleeding (OR [95 %CI]=0.64 [0.51 0.82], p=0.0003), with a comparable risk of mortality or myocardial infarction. The higher risk of early ST was mainly attributable to acute (OR [95 % CI] =4.33 [2.33 8.05], p < 0.001) than subacute (OR [95 % CI] =0.89 [0.53 1.50], p =0.67) ST events (p for interaction < 0.001). Non-fatal myocardial infarction was the most common presentation (83 %) of early ST events, while death occurred infrequently (about 5 %). In conclusion, in patients undergoing PCI, bivalirudin compared to heparins is associated with a higher risk of early ST, which is mainly related to more frequent acute events. Further studies are required to evaluate alternative strategies to mitigate this risk, without hampering the benefits derived from the reduction in bleeding events with bivalirudin.
Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation
Authors: Krul Sébastien P.J. , Berger Wouter R. , Smit Nicoline W. , van Amersfoorth Shirley C.M. , Driessen Antoine H.G. , van Boven Wim Jan , Fiolet Jan W.T. , van Ginneken Antoni C.G. , van der Wal Allard C. , de Bakker Jacques M.T. , Coronel Ruben , de Groot Joris R. 
Published: February 2015

Background—
Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF.

Methods and Results—

Thirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with optical mapping. Longitudinal CV (CV
L
), transverse CV (CV
T
), and activation times (>2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CV
L
was 0.55±0.22 m/s, mean CV
T
was 0.25±0.15 m/s, and the mean activation time was 9.31±5.45 ms. The amount of fibrosis was unrelated to CV or patient characteristics. CV
L
was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77±0.22 versus 0.48±0.19 m/s;
P
=0.012), which were more frequently present in persistent patients with AF. CV
T
was not significantly different (
P
=0.47), but activation time was 14.93±4.12 versus 7.95±4.12 ms in patients with thick versus thin interstitial collagen strands, respectively (
P
=0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands (
P
=0.008). Myofibroblasts were not detected in the left atrial appendage.

Conclusions—

In patients with AF, thick interstitial collagen strands are associated with higher CV
L
and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.
Myocardial Adaptations to Recreational Marathon Training Among Middle-Aged Men
Authors: Zilinski Jodi L. , Contursi Miranda E. , Isaacs Stephanie K. , Deluca James R. , Lewis Gregory D. , Weiner Rory B. , Hutter Adolph M. , d’Hemecourt Pierre A. , Troyanos Christopher , Dyer K. Sophia , Baggish Aaron L. 
Published: February 2015

Background—
Myocardial adaptations to exercise have been well documented among competitive athletes. To what degree cardiac remodeling occurs among recreational exercisers is unknown. We sought to evaluate the effect of recreational marathon training on myocardial structure and function comprehensively.

Methods and Results—

Male runners (n=45; age, 48±7 years; 64% with ≥1 cardiovascular risk factor) participated in a structured marathon-training program. Echocardiography, cardiopulmonary exercise testing, and laboratory evaluation were performed pre and post training to quantify changes in myocardial structure and function, cardiorespiratory fitness, and traditional cardiac risk parameters. Completion of an 18-week running program (25±9 miles/wk) led to increased cardiorespiratory fitness (peak oxygen consumption, 44.6±5.2 versus 46.3±5.4 mL/kg per minute;
P
<0.001). In this setting, there was a significant structural cardiac remodeling characterized by dilation of the left ventricle (end-diastolic volume, 156±26 versus 172±28 mL,
P
<0.001), right ventricle (end-diastolic area=27.0±4.8 versus 28.6±4.3 cm
2
;
P
=0.02), and left atrium (end-diastolic volume, 65±19 versus 72±19;
P
=0.02). Functional adaptations included increases in both early (E′=12.4±2.5 versus 13.2±2.0 cm/s;
P
=0.007) and late (A′=11.5±1.9 versus 12.2±2.1 cm/s;
P
=0.02) left ventricular diastolic velocities. Myocardial remodeling was accompanied by beneficial changes in cardiovascular risk factors, including body mass index (27.0±2.7 versus 26.7±2.6 kg/m
2
;
P
<0.001), total cholesterol (199±33 versus 192±29 mg/dL;
P
=0.01), low-density lipoprotein (120±29 versus 114±26 mg/dL;
P
=0.01), and triglycerides (100±52 versus 85±36 mg/dL;
P
=0.02).

Conclusions—
Among middle-aged men, recreational marathon training is associated with biventricular dilation, enhanced left ventricular diastolic function, and favorable changes in nonmyocardial determinants of cardiovascular risk. Recreational marathon training may, therefore, serve as an effective strategy for decreasing incident cardiovascular disease.