bluuebunny/crossref_metadata_2025_split huggingface dataset:
PGC-1α Promotes the Growth of ErbB2/Neu–Induced Mammary Tumors by Regulating Nutrient Supply
Authors: Klimcakova Eva , Chénard Valérie , McGuirk Shawn , Germain David , Avizonis Daina , Muller William J. , St-Pierre Julie 
Published: January 2012

Abstract
Cancer cells display an increased reliance on glycolysis despite the presence of sufficient oxygen levels to support mitochondrial functions. In this study, we asked whether ameliorating mitochondrial functions in cancer cells might limit their proliferative capacity. Specifically, we increased mitochondrial metabolism in a murine cellular model of ErbB2/Neu–induced breast cancer by ectopically expressing the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), a master regulator of mitochondrial metabolism. As predicted, ErbB2/Neu cells ectopically expressing PGC-1α displayed an increased level of mitochondrial metabolism and reduced proliferative capacity in vitro, compared with controls. In contrast, ErbB2/Neu cells ectopically expressing PGC-1α formed larger tumors in vivo. These tumors exhibited increased concentrations of glucose and the angiogenic factor VEGF as well as higher expression of ErbB2/Neu compared with controls. We discovered that ErbB2/Neu levels were sensitive to nutrient availability, such that reduced glucose concentrations resulted in diminished ErbB2/Neu protein levels. Therefore, our data indicate that PGC-1α prevents the nutrient-mediated downregulation of ErbB2/Neu in tumors by increasing glucose supply. Mechanistic investigations revealed that the regulation of ErbB2/Neu levels by glucose was mediated by the unfolded protein response (UPR). Incubation of ErbB2/Neu–induced breast cancer cells in limited glucose concentrations or with drugs that activate the UPR led to significant reductions in ErbB2/Neu protein levels. Also, ErbB2/Neu–induced tumors ectopically expressing PGC-1α displayed lowered UPR activation compared with controls. Together, our findings uncover an unexpected link between PGC-1α–mediated nutrient availability, UPR, and ErbB2/Neu levels. Cancer Res; 72(6); 1538–46. ©2012 AACR.
Phase I Dose-Escalation Study of Intravenous Aflibercept in Combination with Docetaxel in Patients with Advanced Solid Tumors
Authors: Isambert Nicolas , Freyer Gilles , Zanetta Sylvie , You Benoît , Fumoleau Pierre , Falandry Claire , Favier Laure , Assadourian Sylvie , Soussan-Lazard Karen , Ziti-Ljajic Samira , Trillet-Lenoir Veronique 
Published: January 2012

Abstract
Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.
Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m2) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.
Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (&gt;3 months in 18 patients).
Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.
Jets and Topography: Jet Transitions and the Impact on Transport in the Antarctic Circumpolar Current
Authors: Thompson Andrew F. , Sallée Jean-Baptiste 
Published: January 2012

Abstract
The Southern Ocean’s Antarctic Circumpolar Current (ACC) naturally lends itself to interpretations using a zonally averaged framework. Yet, navigation around steep and complicated bathymetric obstacles suggests that local dynamics may be far removed from those described by zonally symmetric models. In this study, both observational and numerical results indicate that zonal asymmetries, in the form of topography, impact global flow structure and transport properties.
The conclusions are based on a suite of more than 1.5 million virtual drifter trajectories advected using a satellite altimetry–derived surface velocity field spanning 17 years. The focus is on sites of “cross front” transport as defined by movement across selected sea surface height contours that correspond to jets along most of the ACC. Cross-front exchange is localized in the lee of bathymetric features with more than 75% of crossing events occurring in regions corresponding to only 20% of the ACC’s zonal extent.
These observations motivate a series of numerical experiments using a two-layer quasigeostrophic model with simple, zonally asymmetric topography, which often produces transitions in the front structure along the channel. Significantly, regimes occur where the equilibrated number of coherent jets is a function of longitude and transport barriers are not periodic. Jet reorganization is carried out by eddy flux divergences acting to both accelerate and decelerate the mean flow of the jets. Eddy kinetic energy is amplified downstream of topography due to increased baroclinicity related to topographic steering. The combination of high eddy kinetic energy and recirculation features enhances particle exchange. These results stress the complications in developing consistent circumpolar definitions of the ACC fronts.
Pharmacokinetics and Pharmacodynamics of Figitumumab, a Monoclonal Antibody Targeting the Insulin‐Like Growth Factor 1 Receptor, in Healthy Participants
Authors: Yin Donghua , Sleight Barbara , Alvey Christine , Hansson Arne G. , Bello Akintunde 
Published: January 2012

AbstractThis study determined the pharmacokinetics (PK) of figitumumab and its effects on insulin‐like growth factor (IGF) axis‐related biomarkers, following a single intravenous dose (10 [n = 16] and 20 [n = 12] mg/kg) in healthy adults. Serial blood sampling for PK and biomarkers was conducted up to 84 days postdose. A dose increase from 10 to 20 mg/kg led to 1.9‐ and 2.4‐fold increases in mean Cmax and AUC∞, respectively. Median disposition half‐life was 21.1 and 27.8 days at 10 and 20 mg/kg, respectively. At 10 and 20 mg/kg, figitumumab increased total IGF‐1, free IGF‐1, IGF binding protein (IGFBP)–3, and insulin by 4.1‐ and 4.8‐, 8.3‐ and 12.1‐, 2.4‐ and 2.9‐, and 7.3‐ and 9.8‐fold, respectively; increases were sustained throughout the 84‐day period. There was a slight and transient elevation in IGF‐2. Mean plasma glucose increased by 18% and 16% at 10 and 20 mg/kg, respectively. Most treatment‐related adverse events were mild in severity; the most common included dry eye (n = 9) and ocular hyperemia (n = 9) in the 20‐mg/kg group. No antidrug antibodies were detected. Overall, figitumumab (10 or 20 mg/kg) demonstrated PK properties typical of IgG2 antibodies and produced substantial and sustained increases in IGF‐1 (total and free), IGFBP‐3, and insulin.
Endoscopic vs Transfacial Resection of Sinonasal Adenocarcinomas
Authors: Vergez Sebastien , Martin‐Dupont Nathalie , Lepage Benoit , De Bonnecaze Guillaume , Decotte Anne , Serrano Elie 
Published: January 2012

ObjectivesCompare the survival and the complication rates of 2 comparable groups of patients who underwent either endoscopic or transfacial resection of a sinonasal adenocarcinoma.Study DesignHistorical cohort study.SettingTertiary referral center.Subjects and MethodsTwenty‐four patients with sinonasal adenocarcinomas who recently underwent an endoscopy (the ENDO group, 1999‐2009) were compared with 24 patients who underwent a lateral rhinotomy procedure (the LR group, 1993‐2007). The present retrospective study included patients who would have had an endoscopic resection in 2011.ResultsThe groups were comparable in terms of age and sex (P =. 49), as well as tumor stages; 43 of the 48 patients had undergone postoperative radiotherapy. There were 13 T1‐T2 and 11 T3‐T4 tumors in the ENDO group compared with 12 T1‐T2 and 12 T3‐T4 tumors in the LR group (P =. 77). The mean length of follow‐up was 38 months for the ENDO group and 89 for the LR group. The overall survival and recurrence‐free rates were not significantly different (P =. 3 and P =. 87, respectively). The median duration of hospitalization was significantly shorter in the ENDO group than in the LR group (4 vs 8 days, P <. 0001). The rate of early complications was identical in both groups (12.5%).ConclusionThe endoscopic approach is a safe and effective treatment in selected sinonasal adenocarcinoma cases. The early oncological outcome and morbidity associated with the endoscopic approach were comparable with a transfacial approach. Hospitalization was significantly reduced by the endoscopic approach. Although the endoscopic approach is less invasive, it requires an optimal preoperative imaging protocol and an experienced surgical team.
Quantifying Osteotome Sharpness
Authors: Ransom Evan R. , Antunes Marcelo B. , Bloom Jason D. , Becker Daniel G. 
Published: January 2012

Objective(1) To develop a method for quantification of osteotome sharpness in a rhinoplasty model, using artificial bone; (2) to demonstrate changes in osteotome sharpness over multiple uses; and (3) to compare osteotomes from different manufacturers in terms of sharpness and cost.Study DesignProspective surgical model.SettingAcademic hospital and engineering research facility.MethodsOsteotomes were used to make 4‐cm cuts through 4‐mm wedges of artificial bone. Sharpness was assessed at baseline and following 1, 4, 7, and 10 uses by measuring the load required to cut a #2 Prolene suture. Changes in sharpness from baseline were measured over time, and comparison of manufacturers was performed using analysis of variance (ANOVA). Cost per use was computed for each osteotome.ResultsFive osteotomes were tested (Biomet, Black & Black, Miltex, NexEdge, Storz). At baseline, the Storz osteotome was sharpest (1.74 lb, P <. 001), followed by Miltex and Biomet (2.50 lb, 2.68 lb) and NexEdge and Black & Black (3.48 lb, 3.40 lb). All osteotomes except NexEdge (P =. 098) demonstrated significant decreases in sharpness over time (P =. 02 to P <. 001), although relative changes and absolute sharpness varied greatly. ANOVA demonstrated Storz to be significantly sharper at all time points (P <. 001). Storz and Miltex were superior in cost‐per‐use analysis.ConclusionSharp osteotomes are important in cosmetic and functional rhinoplasty. Instruments may appear the same but can be quite dissimilar in efficacy and cost. Indeed, relative efficacy has not been previously tested. Quantitative analysis performance and cost‐effectiveness analyses are reported here and can assist the surgeon in selection and maintenance of instruments.
Pretreatment with CO-releasing molecules suppresses hepcidin expression during inflammation and endoplasmic reticulum stress through inhibition of the STAT3 and CREBH pathways
Authors: Shin Da-Yong , Chung Jihwa , Joe Yeonsoo , Pae Hyun-Ock , Chang Ki Churl , Cho Gyeong Jae , Ryter Stefan W. , Chung Hun-Taeg 
Published: January 2012

AbstractThe circulating peptide hormone hepcidin maintains systemic iron homeostasis. Hepcidin production increases during inflammation and as a result of endoplasmic reticulum (ER) stress. Elevated hepcidin levels decrease dietary iron absorption and promote iron sequestration in reticuloendothelial macrophages. Furthermore, increased plasma hepcidin levels cause hypoferremia and the anemia associated with chronic diseases. The signal transduction pathways that regulate hepcidin during inflammation and ER stress include the IL-6–dependent STAT-3 pathway and the unfolded protein response–associated cyclic AMP response element-binding protein-H (CREBH) pathway, respectively. We show that carbon monoxide (CO) suppresses hepcidin expression elicited by IL-6– and ER-stress agents by inhibiting STAT-3 phosphorylation and CREBH maturation, respectively. The inhibitory effect of CO on IL-6–inducible hepcidin expression is dependent on the suppressor of cytokine signaling-3 (SOCS-3) protein. Induction of ER stress in mice resulted in increased hepatic and serum hepcidin. CO administration inhibited ER-stress–induced hepcidin expression in vivo. Furthermore, ER stress caused iron accumulation in splenic macrophages, which could be prevented by CO. Our findings suggest novel anti-inflammatory therapeutic applications for CO, as well as therapeutic targets for the amelioration of anemia in the hypoferremic condition associated with chronic inflammatory and metabolic diseases.
Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia
Authors: Kuramitsu Madoka , Sato-Otsubo Aiko , Morio Tomohiro , Takagi Masatoshi , Toki Tsutomu , Terui Kiminori , Wang RuNan , Kanno Hitoshi , Ohga Shouichi , Ohara Akira , Kojima Seiji , Kitoh Toshiyuki , Goi Kumiko , Kudo Kazuko , Matsubayashi Tadashi , Mizue Nobuo , Ozeki Michio , Masumi Atsuko , Momose Haruka , Takizawa Kazuya , Mizukami Takuo , Yamaguchi Kazunari , Ogawa Seishi , Ito Etsuro , Hamaguchi Isao 
Published: January 2012

AbstractFifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs). To identify new mutations, we investigated large deletions in the RP genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26. We developed an easy method based on quantitative-PCR in which the threshold cycle correlates to gene copy number. Using this approach, we were able to diagnose 7 of 27 Japanese patients (25.9%) possessing mutations that were not detected by sequencing. Among these large deletions, similar results were obtained with 6 of 7 patients screened with a single nucleotide polymorphism array. We found an extensive intragenic deletion in RPS19, including exons 1-3. We also found 1 proband with an RPL5 deletion, 1 patient with an RPL35A deletion, 3 with RPS17 deletions, and 1 with an RPS19 deletion. In particular, the large deletions in the RPL5 and RPS17 alleles are novel. All patients with a large deletion had a growth retardation phenotype. Our data suggest that large deletions in RP genes comprise a sizable fraction of DBA patients in Japan. In addition, our novel approach may become a useful tool for screening gene copy numbers of known DBA genes.
Microscale functional cytomics for studying hematologic cancers
Authors: Young Edmond W. K. , Pak Chorom , Kahl Brad S. , Yang David T. , Callander Natalie S. , Miyamoto Shigeki , Beebe David J. 
Published: January 2012

Abstract
An important problem in translational cancer research is our limited ability to functionally characterize behaviors of primary patient cancer cells and associated stromal cell types, and relate mechanistic understanding to therapy selection. Functional analyses of primary samples face at least 3 major challenges: limited availability of primary samples for testing, paucity of functional information extracted from samples, and lack of functional methods accessible to many researchers. We developed a microscale cell culture platform that overcomes these limitations, especially for hematologic cancers. A key feature of the platform is the ability to compartmentalize small populations of adherent and nonadherent cells in controlled microenvironments that can better reflect physiological conditions and enable cell-cell interaction studies. Custom image analysis was developed to measure cell viability and protein subcellular localizations in single cells to provide insights into heterogeneity of cellular responses. We validated our platform by assessing viability and nuclear translocations of NF-κB and STAT3 in multiple myeloma cells exposed to different conditions, including cocultured bone marrow stromal cells. We further assessed its utility by analyzing NF-κB activation in a primary chronic lymphocytic leukemia patient sample. Our platform can be applied to myriad biological questions, enabling high-content functional cytomics of primary hematologic malignancies.
Asthma and coagulation
Authors: de Boer J. Daan , Majoor Christof J. , van 't Veer Cornelis , Bel Elisabeth H. D. , van der Poll Tom 
Published: January 2012

AbstractAsthma is a chronic airway disease characterized by paroxysmal airflow obstruction evoked by irritative stimuli on a background of allergic lung inflammation. Currently, there is no cure for asthma, only symptomatic treatment. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and platelets in the pathophysiology of asthma has increased considerably. Asthma is associated with a procoagulant state in the bronchoalveolar space, further aggravated by impaired local activities of the anticoagulant protein C system and fibrinolysis. Protease-activated receptors have been implicated as the molecular link between coagulation and allergic inflammation in asthma. This review summarizes current knowledge of the impact of the disturbed hemostatic balance in the lungs on asthma severity and manifestations and identifies new possible targets for asthma treatment.
A metabolomic strategy defines the regulation of lipid content and global metabolism by Δ9 desaturases in Caenorhabditis elegans
Authors: Castro Cecilia , Sar Funda , Shaw W Robert , Mishima Masanori , Miska Eric A , Griffin Julian L 
Published: January 2012

Abstract

Background

Caenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity. C. elegans possess the full range of desaturases, including the Δ9 desaturases expressed by fat-5, fat-6 and fat-7. They regulate the biosynthesis of monounsaturated fatty acids, used for the synthesis of lipids including phospholipids, triglycerides and cholesteryl esters.

Results
Liquid chromatography mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to define the metabolome of all the possible knock-outs for the Δ9 desaturases, including for the first time intact lipids. Despite the genes having similar enzymatic roles, excellent discrimination was achievable for all single and viable double mutants highlighting the distinctive roles of fat-6 and fat-7, both expressing steroyl-CoA desaturases. The metabolomic changes extend to aqueous metabolites demonstrating the influence Δ9 desaturases have on regulating global metabolism and highlighting how comprehensive metabolomics is more discriminatory than classically used dyes for fat staining.

Conclusions
The propagation of metabolic changes across the network of metabolism demonstrates that modification of the Δ9 desaturases places C.elegans into a catabolic state compared with wildtype controls.
Risk factors associated with fatal pulmonary hemorrhage in locally advanced non-small cell lung cancer treated with chemoradiotherapy
Authors: Ito Masami , Niho Seiji , Nihei Keiji , Yoh Kiyotaka , Ohmatsu Hironobu , Ohe Yuichiro 
Published: January 2012

Abstract

Background
The purpose of this study was to identify the risk factors associated with fatal pulmonary hemorrhage (PH) in patients with locally advanced non-small cell lung cancer (NSCLC), treated with chemoradiotherapy.

Methods
The medical records of 583 patients with locally advanced NSCLC, who were treated with chemoradiotherapy between July 1992 and December 2009 were reviewed. Fatal PH was defined as PH leading to death within 24 h of its onset. Tumor cavitation size was defined by the cavitation diameter/tumor diameter ratio and was classified as minimum (< 0.25), minor (≥ 0.25, but < 0.5), and major (≥ 0.5).

Results
Of the 583 patients, 2.1% suffered a fatal PH. The numbers of patients with minimum, minor, and major cavitations were 13, 11, and 14, respectively. Among the 38 patients with tumor cavitation, all 3 patients who developed fatal PH had major cavitations. On multivariate analysis, the presence of baseline major cavitation (odds ratio, 17.878), and a squamous cell histology (odds ratio, 5.491) proved to be independent significant risk factors for fatal PH. Interestingly, all patients with fatal PH and baseline major cavitation were found to have tumors with squamous cell histology, and the occurrence of fatal PH in patients having both risk factors was 33.3%.

Conclusions
Patients at high risk of fatal PH could be identified using a combination of independent risk factors.
Enterovirus 71 viral capsid protein linear epitopes: Identification and characterization
Authors: Gao Fan , Wang Yi-Ping , Mao Qun-Ying , Yao Xin , Liu Shuang , Li Feng-Xiang , Zhu Feng-Cai , Yang Jing-Yu , Liang Zheng-Lun , Lu Feng-Min , Wang Jun-Zhi 
Published: January 2012

AbstractBackgroundTo characterize the human humoral immune response against enterovirus 71 (EV71) infection and map human epitopes on the viral capsid proteins.MethodsA series of 256 peptides spanning the capsid proteins (VP1, VP2, VP3) of BJ08 strain (genomic C4) were synthesized. An indirect enzyme-linked immunosorbent assay (ELISA) was carried out to detect anti-EV71 IgM and IgG in sera of infected children in acute or recovery phase. The partially overlapped peptides contained 12 amino acids and were coated in the plate as antigen (0.1 μg/μl). Sera from rabbits immunized with inactivated BJ08 virus were also used to screen the peptide panel.ResultsA total of 10 human anti-EV71 IgM epitopes (vp1-14 in VP1; vp2-6, 21, 40 and 50 in VP2 and vp3-10, 12, 15, 24 and 75 in VP3) were identified in acute phase sera. In contrast, only one anti-EV71 IgG epitope in VP1 (vp1-15) was identified in sera of recovery stage. Four rabbit anti-EV71 IgG epitopes (vp1-14, 31, 54 and 71) were identified and mapped to VP1.ConclusionThese data suggested that human IgM epitopes were mainly mapped to VP2 and VP3 with multi-epitope responses occurred at acute infection, while the only IgG epitope located on protein VP1 was activated in recovery phase sera. The dynamic changes of humoral immune response at different stages of infection may have public health significance in evaluation of EV71 vaccine immunogenicity and the clinical application of diagnostic reagents.