bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer
Authors: Labidi-Galy Sana Intidhar , Sisirak Vanja , Meeus Pierre , Gobert Michael , Treilleux Isabelle , Bajard Agathe , Combes Jean-Damien , Faget Julien , Mithieux François , Cassignol Alexandre , Tredan Olivier , Durand Isabelle , Ménétrier-Caux Christine , Caux Christophe , Blay Jean-Yves , Ray-Coquard Isabelle , Bendriss-Vermare Nathalie 
Published: June 2011

Abstract
In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123+BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. Cancer Res; 71(16); 5423–34. ©2011 AACR.
Histone Deacetylase Cytoplasmic Trapping by a Novel Fluorescent HDAC Inhibitor
Authors: Kong Yali , Jung Mira , Wang Kan , Grindrod Scott , Velena Alfredo , Lee Sung A. , Dakshanamurthy Sivanesan , Yang Yonghong , Miessau Matthew , Zheng Chaoyi , Dritschilo Anatoly , Brown Milton L. 
Published: June 2011

Abstract
Inhibitors of histone deacetylases (HDAC) are an important emerging class of drugs for the treatment of cancers. HDAC inhibitors are currently under evaluation in clinical trials as single agents and as sensitizers in combinations with chemotherapies and radiation therapy. Although these drugs have important effects on cancer cell growth and functions, the mechanisms underlying HDAC inhibitor activities remain to be fully defined. By using rational drug design, compound 2, a fluorescent class II HDAC targeting inhibitor, was synthesized and observed to accumulate in the cytoplasmic compartments of treated cells, but not in the nuclei. Furthermore, immunostaining of inhibitor exposed cells for HDAC4 showed accumulation of this enzyme in the cytoplasmic compartment with concomitant increased acetylation of tubulin and nuclear histones. These observations support a mechanism by which nuclear histone acetylation is increased as a result of HDAC4 trapping and sequestration in the cytoplasm after binding to compound 2. The HDAC inhibitor offers potential as a novel theranostic agent, combining diagnostic and therapeutic properties in the same molecule. Mol Cancer Ther; 10(9); 1591–9. ©2011 AACR.
Linear Chain PEGylated Recombinant Bacillus Thiaminolyticus Thiaminase I Enzyme Has Growth Inhibitory Activity against Lymphoid Leukemia Cell Lines
Authors: Daily Abigail , Liu Shuqian , Bae Younsoo , Bhatnagar Saloni , Moscow Jeffrey A. 
Published: June 2011

Abstract
Cancer cells acquire abnormalities in energy metabolism, collectively known as the Warburg effect, affecting substrate availability of thiamine-dependent enzymes. To investigate a strategy to exploit abnormal cancer-associated metabolism related to thiamine, we tested the cytotoxicity of native Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, in the NCI60 cell line drug cytotoxicity screening program and found that leukemia cell lines were among the most sensitive to thiaminase I. We obtained additional lymphoid leukemia cell lines and confirmed that native thiaminase I and linear chain PEGylated thiaminase I enzyme (LCPTE) have cytotoxic activity in these cell lines. In addition, the IC50 of 3 of the 5 leukemia cell lines (Reh, RS4, and Jurkat) were at least 1,000-fold more sensitive than Molt-4 cells, which in turn, were among the most sensitive in the NCI60 panel. The 3 LCPTE-sensitive leukemia cell lines were also sensitive to removal of thiamine from the medium, thus suggesting the mechanism of action of LCPTE involves extracellular thiamine starvation. Surprisingly, rapamycin showed a protective effect against LCPTE toxicity in the 3 LCPTE-sensitive cell lines but not in the other 2 cell lines, suggesting involvement of an mTOR-dependent pathway. Immunoblot analysis of the LCPTE-sensitive cell lines after LCPTE exposure revealed changes in mTOR pathway phosphorylation. Nude mice bearing RS4 leukemia xenografts showed both tumor growth delay and prolonged survival after a single dose of LCPTE. Therefore, disruption of thiamine-dependent metabolism may be a novel therapeutic approach to target altered energy metabolism in leukemia and other cancers. Mol Cancer Ther; 10(9); 1563–70. ©2011 AACR.
Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel
Authors: Frelinger III Andrew L. , Michelson Alan D. , Wiviott Stephen D. , Trenk Dietmar , Neumann Franz-Josef , Miller Debra L. , Jakubowski Joseph A. , Costigan Timothy M. , McCabe Carolyn H. , Antman Elliott M. , Braunwald Eugene 
Published: June 2011

SummaryIt was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18–24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18–24 h and 15 day reactivity to ADP (correlations 0.24–0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
Care Processes Associated With Quicker Door-In–Door-Out Times for Patients With ST-Elevation–Myocardial Infarction Requiring Transfer
Authors: Glickman Seth W. , Lytle Barbara L. , Ou Fang-Shu , Mears Greg , O'Brien Sean , Cairns Charles B. , Garvey J. Lee , Bohle David J. , Peterson Eric D. , Jollis James G. , Granger Christopher B. 
Published: June 2011

Background—
The ability to rapidly identify patients with ST-segment elevation–myocardial infarction (STEMI) at hospitals without percutaneous coronary intervention (PCI) and transfer them to hospitals with PCI capability is critical to STEMI regionalization efforts. Our objective was to assess the association of prehospital, emergency department (ED), and hospital processes of care implemented as part of a statewide STEMI regionalization program with door-in–door-out times at non-PCI hospitals.

Methods and Results—

Door-in–door-out times for 436 STEMI patients at 55 non-PCI hospitals were determined before (July 2005 to September 2005) and after (January 2007 to March 2007) a year-long implementation of standardized protocols as part of a statewide regionalization program (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments, RACE). The association of 8 system care processes (encompassing emergency medical services [EMS], ED, and hospital settings) with door-in–door-out times was determined using multivariable linear regression. Median door-in–door-out times improved significantly with the intervention (before: 97.0 minutes, interquartile range, 56.0 to 160.0 minutes; after: 58.0 minutes, interquartile range, 35.0 to 90.0 minutes;
P
<0.0001). Hospital, ED, and EMS care processes were each independently associated with shorter door-in–door-out times (−17.7 [95% confidence interval, −27.5 to −7.9]; −10.1 [95% confidence interval, −19.0 to −1.1], and −7.3 [95% confidence interval, −13.0 to −1.5] minutes for each additional hospital, ED, and EMS process, respectively). Combined, adoption of EMS processes was associated with the shortest median treatment times (44 versus 138 minutes for hospitals that adopted all EMS processes versus none).

Conclusions—
Prehospital, ED, and hospital processes of care were independently associated with shorter door-in–door-out times for STEMI patients requiring transfer. Adoption of several EMS processes was associated with the largest reduction in treatment times. These findings highlight the need for an integrated, system-based approach to improving STEMI care.
A Hydroclimatological Assessment of Regional Drought Vulnerability: A Case Study of Indiana Droughts
Authors: Charusombat Umarporn , Niyogi Dev 
Published: June 2011

Abstract
Characterizing and developing drought climatology continues to be a challenging problem. As decision makers seek guidance on water management strategies, there is a need for assessing the performance of drought indices. This requires the adaptation of appropriate drought indices that aid in monitoring droughts and hydrological vulnerability on a regional scale. This study aims to assist the process of developing a statewide water shortage and assessment plan (WSP) for the state of Indiana by conducting a focused hydroclimatological assessment of drought variability. Drought climatology was assessed using in situ observations and regional reanalysis data. A summary of precipitation and evaporation trends, estimated drought variability, worst-case drought scenarios, drought return period, and frequency and duration was undertaken, using multiple drought indices and streamflow analysis. Results indicated a regional and local variability in drought susceptibility. The worst-case (200-yr return period) prediction showed that Indiana has a 0.5% probability of receiving 45% of normal precipitation over a 12-month drought in any year. Consistent with other studies, the standardized precipitation index (SPI) was found to be appropriate for detecting short-term drought conditions over Indiana. This recommendation has now been incorporated in the 2009 Indiana water shortage plan. This study also highlights the difficulties in identifying past droughts from available climatic data, and the authors’ results suggest a persistent, high degree of uncertainty in making drought predictions using future climatic projections.
Modeling the Miocene Climatic Optimum. Part I: Land and Atmosphere*
Authors: Herold N. , Huber M. , Müller R. D. 
Published: June 2011

Abstract
This study presents results from the Community Climate System Model 3 (CCSM3) forced with early to middle Miocene (~20–14 Ma) vegetation, topography, bathymetry, and modern CO2. A decrease in the meridional temperature gradient of 6.5°C and an increase in global mean temperature of 1.5°C are modeled in comparison with a control simulation forced with modern boundary conditions. Seasonal poleward displacements of the subtropical jet streams and storm tracks compared to the control simulation are associated with changes in Hadley circulation and significant cooling of the polar stratosphere, consistent with previously predicted effects of global warming. Energy budget calculations indicate that reduced albedo and topography were responsible for Miocene warmth in the high-latitude Northern Hemisphere while a combination of increased ocean heat transport and reduced albedo was responsible for relative warmth in the high-latitude Southern Hemisphere, compared to the present. Model–data analysis suggests Miocene climate was significantly warmer and wetter than simulated here, consistent with previous uncoupled Miocene models and supports recent reconstructions of Miocene CO2 substantially higher than present.
Properties of Steady Geostrophic Turbulence with Isopycnal Outcropping
Authors: Roullet G. , McWilliams J. C. , Capet X. , Molemaker M. J. 
Published: June 2011

Abstract
High-resolution simulations of β-channel, zonal-jet, baroclinic turbulence with a three-dimensional quasigeostrophic (QG) model including surface potential vorticity (PV) are analyzed with emphasis on the competing role of interior and surface PV (associated with isopycnal outcropping). Two distinct regimes are considered: a Phillips case, where the PV gradient changes sign twice in the interior, and a Charney case, where the PV gradient changes sign in the interior and at the surface. The Phillips case is typical of the simplified turbulence test beds that have been widely used to investigate the effect of ocean eddies on ocean tracer distribution and fluxes. The Charney case shares many similarities with recent high-resolution primitive equation simulations. The main difference between the two regimes is indeed an energization of submesoscale turbulence near the surface. The energy cycle is analyzed in the (k, z) plane, where k is the horizontal wavenumber. In the two regimes, the large-scale buoyancy forcing is the primary source of mechanical energy. It sustains an energy cycle in which baroclinic instability converts more available potential energy (APE) to kinetic energy (KE) than the APE directly injected by the forcing. This is due to a conversion of KE to APE at the scale of arrest. All the KE is dissipated at the bottom at large scales, in the limit of infinite resolution and despite the submesoscales energizing in the Charney case. The eddy PV flux is largest at the scale of arrest in both cases. The eddy diffusivity is very smooth but highly nonuniform. The eddy-induced circulation acts to flatten the mean isopycnals in both cases.
High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation
Authors: Gökbuget Nicola , Basara Nadezda , Baurmann Herrad , Beck Joachim , Brüggemann Monika , Diedrich Helmut , Güldenzoph Björn , Hartung Gernot , Horst Heinz-August , Hüttmann Andreas , Kobbe Guido , Naumann Ralph , Ratei Richard , Reichle Albrecht , Serve Hubert , Stelljes Matthias , Viardot Andreas , Wattad Mohammed , Hoelzer Dieter 
Published: June 2011

Abstract
Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.
The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility
Authors: Wu Yu-Hsuan , Hu Tzu-Fang , Chen Yu-Chieh , Tsai Ya-Ni , Tsai Yuan-Hau , Cheng Cheng-Chung , Wang Hsei-Wei 
Published: June 2011

AbstractmiRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.
Silencing of RhoA nucleotide exchange factor, ARHGEF3, reveals its unexpected role in iron uptake
Authors: Serbanovic-Canic Jovana , Cvejic Ana , Soranzo Nicole , Stemple Derek L. , Ouwehand Willem H. , Freson Kathleen 
Published: June 2011

AbstractGenomewide association meta-analysis studies have identified > 100 independent genetic loci associated with blood cell indices, including volume and count of platelets and erythrocytes. Although several of these loci encode known regulators of hematopoiesis, the mechanism by which most sequence variants exert their effect on blood cell formation remains elusive. An example is the Rho guanine nucleotide exchange factor, ARHGEF3, which was previously implicated by genomewide association meta-analysis studies in bone cell biology. Here, we report on the unexpected role of ARHGEF3 in regulation of iron uptake and erythroid cell maturation. Although early erythroid differentiation progressed normally, silencing of arhgef3 in Danio rerio resulted in microcytic and hypochromic anemia. This was rescued by intracellular supplementation of iron, showing that arhgef3-depleted erythroid cells are fully capable of hemoglobinization. Disruption of the arhgef3 target, RhoA, also produced severe anemia, which was, again, corrected by iron injection. Moreover, silencing of ARHGEF3 in erythromyeloblastoid cells K562 showed that the uptake of transferrin was severely impaired. Taken together, this is the first study to provide evidence for ARHGEF3 being a regulator of transferrin uptake in erythroid cells, through activation of RHOA.
Unresolved orthology and peculiar coding sequence properties of lamprey genes: the KCNA gene family as test case
Authors: Qiu Huan , Hildebrand Falk , Kuraku Shigehiro , Meyer Axel 
Published: June 2011

AbstractBackgroundIn understanding the evolutionary process of vertebrates, cyclostomes (hagfishes and lamprey) occupy crucial positions. Resolving molecular phylogenetic relationships of cyclostome genes with gnathostomes (jawed vertebrates) genes is indispensable in deciphering both the species tree and gene trees. However, molecular phylogenetic analyses, especially those including lamprey genes, have produced highly discordant results between gene families. To efficiently scrutinize this problem using partial genome assemblies of early vertebrates, we focused on the potassium voltage-gated channel, shaker-related (KCNA) family, whose members are mostly single-exon.ResultsSeven sea lampreyKCNAgenes as well as six elephant shark genes were identified, and their orthologies to bony vertebrate subgroups were assessed. In contrast to robustly supported orthology of the elephant shark genes to gnathostome subgroups, clear orthology of any sea lamprey gene could not be established. Notably, sea lampreyKCNAsequences displayed unique codon usage pattern and amino acid composition, probably associated with exceptionally high GC-content in their coding regions. This lamprey-specific property of coding sequences was also observed generally for genes outside this gene family.ConclusionsOur results suggest that secondary modifications of sequence properties unique to the lamprey lineage may be one of the factors preventing robust orthology assessments of lamprey genes, which deserves further genome-wide validation. The lamprey lineage-specific alteration of protein-coding sequence properties needs to be taken into consideration in tackling the key questions about early vertebrate evolution.