bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in Pyruvate Metabolism Detected by Magnetic Resonance Imaging Are Linked to DNA Damage and Serve as a Sensor of Temozolomide Response in Glioblastoma Cells
Authors: Park Ilwoo , Mukherjee Joydeep , Ito Motokazu , Chaumeil Myriam M. , Jalbert Llewellyn E. , Gaensler Karin , Ronen Sabrina M. , Nelson Sarah J. , Pieper Russell O. 
Published: October 2014

Abstract
Recent findings show that exposure to temozolomide (TMZ), a DNA-damaging drug used to treat glioblastoma (GBM), can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-(13)C]-pyruvate–based MRI was used to monitor temporal effects on pyruvate metabolism in parallel with DNA-damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ-induced increases in levels of the DNA-damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased PK activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by MRI methods as an early sensor of TMZ therapeutic response. Cancer Res; 74(23); 7115–24. ©2014 AACR.
Combined Genome and Transcriptome Analysis of Single Disseminated Cancer Cells from Bone Marrow of Prostate Cancer Patients Reveals Unexpected Transcriptomes
Authors: Gužvić Miodrag , Braun Bernhard , Ganzer Roman , Burger Maximilian , Nerlich Michael , Winkler Sebastian , Werner-Klein Melanie , Czyż Zbigniew T. , Polzer Bernhard , Klein Christoph A. 
Published: October 2014

Abstract
Bone is the most frequent site of metastasis in prostate cancer and patients with bone metastases are deemed incurable. Targeting prostate cancer cells that disseminated to the bone marrow before surgery and before metastatic outgrowth may therefore prevent lethal metastasis. This prompted us to directly analyze the transcriptome of disseminated cancer cells (DCC) isolated from patients with nonmetastatic (UICC stage M0) prostate cancer. We screened 105 bone marrow samples of patients with M0-stage prostate cancer and 18 bone marrow samples of patients without malignancy for the presence of EpCAM+ single cells. In total, we isolated 270 cells from both groups by micromanipulation and globally amplified their mRNA. We used targeted transcriptional profiling to unambiguously identify DCCs for subsequent in-depth analysis. Transcriptomes of all cells were examined for the expression of EPCAM, KRT8, KRT18, KRT19, KRT14, KRT6a, KRT5, KLK3 (PSA), MAGEA2, MAGEA4, PTPRC (CD45), CD33, CD34, CD19, GYPC, SCL4A1 (band 3), and HBA2. Using these transcripts, we found it impossible to reliably identify true DCCs. We then applied combined genome and transcriptome analysis of single cells and found that EpCAM+ cells from controls expressed transcripts thought to be epithelial-specific, whereas true DCCs may express hematopoietic transcripts. These results point to an unexpected transcriptome plasticity of epithelial cancer cells in bone marrow and question common transcriptional criteria to identify DCCs. Cancer Res; 74(24); 7383–94. ©2014 AACR.
ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors
Authors: Goetz Eva M. , Ghandi Mahmoud , Treacy Daniel J. , Wagle Nikhil , Garraway Levi A. 
Published: October 2014

Abstract
The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor–resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. Cancer Res; 74(23); 7079–89. ©2014 AACR.
Akt-Activated Endothelium Constitutes the Niche for Residual Disease and Resistance to Bevacizumab in Ovarian Cancer
Authors: Guerrouahen Bella S. , Pasquier Jennifer , Kaoud Nadine Abu , Maleki Mahtab , Beauchamp Marie-Claude , Yasmeen Amber , Ghiabi Pegah , Lis Raphael , Vidal Fabien , Saleh Ahmed , Gotlieb Walter H. , Rafii Shahin , Rafii Arash 
Published: October 2014

Abstract
Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapies, initial tumor response is often followed by relapse suggesting the existence of a tumor niche. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them, antiangiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of hematopoietic and endothelial progenitor cells into new blood vessels. Despite in vitro and in vivo successes, antivascular therapy with bevacizumab targeting VEGF-A has limited efficacy in ovarian cancer. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not yet well understood. Among them, tumor and stromal heterogeneity might determine the treatment outcomes. The present study investigates whether abnormalities in the tumor endothelium may contribute to treatment resistance to bevacizumab and promote a residual microscopic disease. Here, we showed that ovarian cancer cells activate Akt phosphorylation in endothelial cells inducing resistance to bevacizumab leading to an autocrine loop based on FGF2 secretion. Altogether, our results point out the role of an activated endothelium in the resistance to bevacizumab and in the constitution of a niche for a residual disease. Mol Cancer Ther; 13(12); 3123–36. ©2014 AACR.
miR-185 Suppresses Tumor Proliferation by Directly Targeting E2F6 and DNMT1 and Indirectly Upregulating BRCA1 in Triple-Negative Breast Cancer
Authors: Tang Hailin , Liu Peng , Yang Lu , Xie Xinhua , Ye Feng , Wu Minqing , Liu Xiaoping , Chen Bo , Zhang Lijuan , Xie Xiaoming 
Published: October 2014

Abstract
Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer (TNBC). Recent studies have demonstrated that microRNAs (miRNA) play vital roles in the development of TNBC. In this study, we found that miR-185 was strongly downregulated in TNBC tissues and cell lines and that its expression levels were associated with lymph node metastasis, clinical stage, overall survival, and relapse-free survival in TNBC. We also found that ectopic expression of miR-185 inhibited TNBC cell proliferation in vitro and in vivo. We further identified that miR-185 directly targeted DNMT1 and E2F6, which resulted in a marked increase in the expression of BRCA1 at the mRNA and protein levels in TNBC. Our data suggest that miR-185 functions as a tumor suppressor in TNBC development. It is a promising prognostic biomarker and potential therapeutic target for TNBC. Mol Cancer Ther; 13(12); 3185–97. ©2014 AACR.
Radioprotection of the Brain White Matter by Mn(III) N-Butoxyethylpyridylporphyrin–Based Superoxide Dismutase Mimic MnTnBuOE-2-PyP5+
Authors: Weitzel Douglas H. , Tovmasyan Artak , Ashcraft Kathleen A. , Rajic Zrinka , Weitner Tin , Liu Chunlei , Li Wei , Buckley Anne F. , Prasad Mark R. , Young Kenneth H. , Rodriguiz Ramona M. , Wetsel William C. , Peters Katherine B. , Spasojevic Ivan , Herndon James E. , Batinic-Haberle Ines , Dewhirst Mark W. 
Published: October 2014

Abstract
Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP5+(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP5+ before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP5+/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP5+/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP5+/RT. Our data demonstrate that MnTnBuOE-2-PyP5+ is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP5+ combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP5+ with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP5+ has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer. Mol Cancer Ther; 14(1); 70–79. ©2014 AACR.
Fibrin clot properties and haemostatic function in men and women with type 1 diabetes
Authors: Jörneskog Gun , Ågren Anna , Lins Per-Eric , Wallén Håkan , Antovic Aleksandra , Tehrani Sara 
Published: October 2014

SummaryThe increased risk of vascular complications in type 1 diabetes may in part be explained by changes in haemostatic function. In the present study, we investigated the fibrin clot properties in patients with type 1 diabetes in relation to sex and microvascular complications. The study included 236 patients (107 women) aged between 20–70 years and without any history of cardiovascular disease. Fibrin clot properties, assessed by determination of the permeability coefficient (Ks) and turbidimetric clotting and lysis assays, did not differ between men and women. Compared with men, women had worse glycaemic control as well as higher levels of prothrombin fragment 1+2 and peak thrombin generation in vitro, indicating increased thrombin generation both in vivo and in vitro. Subgroup analyses of patients younger than 30 years revealed less permeable fibrin clots and prolonged lysis time in females compared with age-matched men. Patients with microvascular complications had higher fibrinogen concentrations and denser and less permeable fibrin clots. Thus, we conclude that in vitro fibrin clot properties in patients with type 1 diabetes without cardiovascular disease are not different between the sexes, but associate with prevalence of microvascular complications. Tighter fibrin clot formation in younger women, as suggested by our results, may affect their future cardiovascular risk and should be investigated in a larger population.
Atrial fibrillation associated with increased risk of venous thromboembolism
Authors: Wang Chun-Cheng , Lin Cheng-Li , Wang Guei-Jane , Chang Chiz-Tzung , Sung Fung-Chang , Kao Chia-Hung 
Published: October 2014

SummaryWhether atrial fibrillation (AF) is associated with an increased risk of venous thromboembolism (VTE) remains controversial. From Longitudinal Health Insurance Database 2000 (LHID2000), we identified 11,458 patients newly diagnosed with AF. The comparison group comprised 45,637 patients without AF. Both cohorts were followed up to measure the incidence of deep-vein thrombosis (DVT) and pulmonary embolism (PE). Univariable and multivariable competing-risks regression model and Kaplan-Meier analyses with the use of Aelon-Johansen estimator were used to measure the differences of cumulative incidences of DVT and PE, respectively. The overall incidence rates (per 1,000 person-years) of DVT and PE between the AF group and non-AF groups were 2.69 vs 1.12 (crude hazard ratio [HR] = 1.92; 95 % confidence interval [CI] = 1.54-2.39), 1.55 vs 0.46 (crude HR = 2.68; 95 % CI = 1.97-3.64), respectively. The baseline demographics indicated that the members of the AF group demonstrated a significantly older age and higher proportions of comorbidities than non-AF group. After adjusting for age, sex, and comorbidities, the risks of DVT and PE remained significantly elevated in the AF group compared with the non-AF group (adjusted HR = 1.74; 95 %CI = 1.36-2.24, adjusted HR = 2.18; 95 %CI = 1.51-3.15, respectively). The Kaplan-Meier curve with the use of Aelon-Johansen estimator indicated that the cumulative incidences of DVT and PE were both more significantly elevated in the AF group than in the non-AF group after a long-term follow-up period (p<0.01). In conclusion, the presence of AF is associated with increased risk of VTE after a long-term follow-up period.
Separating the Mechanisms of Transient Responses to Stratospheric Ozone Depletion–Like Cooling in an Idealized Atmospheric Model
Authors: Yang Huang , Sun Lantao , Chen Gang 
Published: October 2014

Abstract
Previous studies have suggested that Southern Hemisphere (SH) summertime trends in the atmospheric circulation in the second half of the twentieth century are mainly driven by stratospheric ozone depletion in spring. Here, the authors show that the pattern and timing of observed trends, characterized by downward propagation of signals, can be approximately captured in an idealized atmospheric global circulation model (AGCM) by imposing ozone depletion–like radiative cooling.
It is further shown that the synoptic eddies dominantly contribute to the transient tropospheric response to polar stratospheric cooling. The authors examine three possible mechanisms on the downward influence of polar stratospheric cooling. The polar stratospheric cooling affects tropospheric synoptic eddies via (i) the direct influences on the lower-stratospheric synoptic eddies, (ii) the planetary wave–induced residual circulation, and (iii) the planetary eddy–synoptic eddy nonlinear interaction. It is argued that the planetary wave–induced residual circulation is not the dominant mechanism and that the planetary eddies and further nonlinear interaction with synoptic eddies are more likely the key to the downward influence of the ozone depletion–like cooling.
Evaluation of Historical and Future Cool Season Precipitation over the Eastern United States and Western Atlantic Storm Track Using CMIP5 Models
Authors: Lombardo Kelly , Colle Brian A. , Zhang Zhenhai 
Published: October 2014

Abstract
This study analyzed the contribution of cyclones to projected changes in cool season (1 November–31 March) precipitation over the eastern United States and western North Atlantic Ocean. First, global climate model simulations from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were compared to Global Precipitation Climatology Project (GPCP) and Climate Prediction Center (CPC) precipitation analyses for the period 1979–2004. The CMIP5 ensemble mean realistically reproduced the historical distribution of regional precipitation with no discernable effect because of model spatial resolution. Subsequently, the projected changes in precipitation on cyclone and noncyclone days under the representative concentration pathway 8.5 (RCP8.5) scenario were quantified. While precipitation on both types of days was projected to increase, the increase on noncyclone days (23%) was greater than the increase on cyclone days (12%). The increase in precipitation on cyclone days occurred despite a decrease in the number of cyclone days. This increase can be attributed primarily to a shift toward more frequent extreme precipitation events coupled with a decline in light precipitation events.
Turbulent Heat Fluxes above a Suburban Reservoir: A Case Study from Germany
Authors: Goldbach Anja , Kuttler Wilhelm 
Published: October 2014

Abstract
With the objective of quantifying turbulent sensible QH and latent QE heat fluxes above a suburban reservoir, a micrometeorological turbulence measurement campaign using the eddy covariance technique was carried out between June and November 2012 on the Baldeneysee, an artificial lake (2.64 km2 area with up to 4-m depth) located in Germany. The study was conducted at this site because there is little information on this type of lake and the findings are important for the local water management system. Sensible heat fluxes show a mean diurnal course with maximum positive values during the early morning hours (maximum = +31.3 W m−2) and negative values in the afternoon (minimum = −12.3 W m−2). During daytime, average QH/Q* ratios (where Q* is the radiation balance) are, in general, smaller than 0.20. Sensible heat fluxes are especially affected by the product of wind speed and water–air temperature difference, as well as the magnitude of global radiation. In contrast, mean hourly values of QE are, on average, positive over the whole day, with an absolute spread between +175.1 and −0.8 W m−2. During daytime in summer, 74% of the radiation balance is transferred via QE. The measurement values show that during two summer days, 3.72 and 2.84 mm day−1 of water could be evaporated, whereas during two measurement days in autumn, evaporation rates of only 1.36 and 0.94 mm day−1 were registered. The magnitude of QE is mainly affected by four main parameters: the product of wind speed and vapor pressure deficit, followed by the magnitude of global radiation and water temperature.
Vichy, un passé qui ne passe pas ?
Authors: Bragança Manuel 
Published: October 2014

Résumé La Seconde Guerre mondiale demeure très présente dans les mémoires des Français qui seraient plongés dans une « phase obsessionnelle » depuis le début des années 1970 selon l’historien Henry Rousso. Notre étude se propose de vérifier dans quelle mesure cela reste vrai de nos jours. Elle entend le faire non pas en se basant sur ses occurrences dans la presse ou dans les médias – ce qui, paradoxalement, pourrait ne faire ressortir que ce qui est du domaine de l’épidermique – mais indirectement, à travers les romans et, plus précisément, les best-sellers qui sont, selon de nombreux critiques, des miroirs privilégiés de l’inconscient collectif ou de l’imaginaire d’une époque que, en retour, ils contribuent à façonner. Nous distinguerons quatre phases depuis 1945. Or, les best-sellers contemporains, ceux de la quatrième et dernière phase, présentent nombre de caractéristiques communes qui suggèrent que ce passé difficile est bel et bien en train de passer.
Repair of Anomalous Aortic Origin of a Coronary Artery in 113 Patients
Authors: Poynter Jeffrey A. , Bondarenko Igor , Austin Erle H. , DeCampli William M. , Jacobs Jeffrey P. , Ziemer Gerhard , Kirshbom Paul M. , Tchervenkov Christo I. , Karamlou Tara , Blackstone Eugene H. , Walters Henry L. , Gaynor J. William , Mery Carlos M. , Pearl Jeffrey M. , Brothers Julie A. , Caldarone Christopher A. , Williams William G. , Jacobs Marshall L. , Mavroudis Constantine ,   The Congenital Heart Surgeons’ Society AAOCA Working Group, DeCampli William M. , Fiore Andrew C. , Huddleston Charles B. , Weinstein Samuel , Bondarenko Igor , Walters Henry L. , Moga Francis X. , Morales David L.S. , Blackstone Eugene H. , Jacobs Jeffrey P. , Kanter Kirk R. , Mavroudis Constantine , Poynter Jeffrey A. , Jacobs Marshall L. , Austin Erle H. , Tchervenkov Christo I. , Pearl Jeffrey M. , Gruber Peter J. , Mainwaring Richard D. , Mery Carlos M. , Brothers Julie A. , Gaynor J. William , Caldarone Christopher A. , McCrindle Brian W. , Wilder Travis J. , Williams William G. , Karamlou Tara , Ziemer Gerhard , St. Louis James D. , Ricci Marco , Kirshbom Paul M. 
Published: October 2014

Background: Anomalous aortic origin of a coronary artery (AAOCA) encompasses a wide morphologic spectrum, which has impeded consensus regarding indications for the diverse repair strategies. We constructed a profile of current surgical techniques and explore their application to morphologic variants. Methods: Patients <30 years old (n = 113) with isolated AAOCA who underwent operations at 29 Congenital Heart Surgeons Society (CHSS) institutions from 1998 to 2012 were identified from the CHSS AAOCA Registry. Operative findings were related to surgical techniques at index repairs by cross-tabulation. Results: Anomalous origin of the left main or left anterior descending coronary artery was present in 33 (29%) patients and of the right coronary artery in 78 (69%) patients; 2 arteries originated directly above the commissure between the left and right sinuses. There were 101 (89%) interarterial and intramural (IA/IM) arteries, 10 (9%) were interarterial but not intramural (IA/NIM) and 2 (2%) were neither interarterial nor intramural. Intramural arteries were unroofed in 100 (88%) operations, usually with intimal tacking after incision (n = 47) or excision (n = 25) of the common wall. Coronary reimplantation (n = 11), pulmonary artery relocation (n = 7; 5 for IA/NIM), simple ostioplasty (without unroofing; n = 3), coronary artery bypass grafting (n = 2), and ostial window (n = 1) were less common. In 37 (33%) operations, a valvar commissure was taken down; 33 were resuspended. Conclusion: Current surgical repair of AAOCA is individualized to morphology, particularly the presence of intramural and/or interarterial segments. This report is foundational for future planned CHSS studies that will examine interventional and noninterventional outcomes and ultimately guide management of AAOCA.