bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracrine Receptor Activation by Microenvironment Triggers Bypass Survival Signals and ALK Inhibitor Resistance in EML4-ALK Lung Cancer Cells
Authors: Yamada Tadaaki , Takeuchi Shinji , Nakade Junya , Kita Kenji , Nakagawa Takayuki , Nanjo Shigeki , Nakamura Takahiro , Matsumoto Kunio , Soda Manabu , Mano Hiroyuki , Uenaka Toshimitsu , Yano Seiji 
Published: May 2012

Abstract
Purpose: Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells.
Experimental Design: We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo.
Results: EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGF receptor (EGFR) ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. Hepatocyte growth factor (HGF) activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs resensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively.
Conclusions: Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with ALK inhibitors. Clin Cancer Res; 18(13); 3592–602. ©2012 AACR.
A Phase II Pharmacodynamic Study of Preoperative Figitumumab in Patients with Localized Prostate Cancer
Authors: Chi Kim N. , Gleave Martin E. , Fazli Ladan , Goldenberg S. Larry , So Alan , Kollmannsberger Christian , Murray Nevin , Tinker Anna , Pollak Michael 
Published: May 2012

Abstract
Purpose: Activation of the insulin-like growth factor 1 receptor (IGF-IR) is implicated in prostate cancer development and progression. This study evaluated biologic and clinical effects of figitumumab, a fully human monoclonal IGF-IR antibody, in patients with localized prostate cancer.
Experimental Design: Eligible patients received figitumumab 20 mg/kg intravenously every 3 weeks for 3 cycles followed by prostatectomy. The primary endpoint was IGF-IR expression inhibition as assessed by immunohistochemistry.
Results: Sixteen patients were accrued. Median age was 63 years, median prostate-specific antigen (PSA) was 7.2 μg/L (range, 2.5–35), clinical stage was T1 in four patients and T2 in 12 patients, Gleason score ≤7 or &gt;7 in 15 and one patients. Two patients received only 1 cycle (patient choice and grade III hyperglycemia). A PSA decline from baseline of ≥25% and ≥50% occurred in 15 (94%) and 5 (31%) of patients. Mean figitumumab concentration was 350.4 μg/mL (range, 26.3–492.8) in plasma and 51.3 μg/g (range, 27.4–79.6) in prostate tissue. Compared with pretreatment biopsies, IGF-IR expression decreased in the prostatectomy specimens in 14 of 16 patients. The mean IGF-IR immunohistochemistry visual score was 2.1 (SD = 0.6) in biopsy and 1.1 (SD = 0.5) in prostatectomy specimens (P &lt; 0.0001). Androgen receptor expression was also decreased and there was a trend for a decrease in downstream IGF-IR signaling components.
Conclusions: Figitumumab is biologically active in prostate cancer. PSA declines in treatment-naive patients were observed, potentially mediated by IGF-IR effects on androgen receptor expression. These results support the clinical relevance of IGF-IR signaling in prostate cancer and justify further clinical trials. Clin Cancer Res; 18(12); 3407–13. ©2012 AACR.
Human Monoclonal Antibodies Targeting Nonoverlapping Epitopes on Insulin-like Growth Factor II as a Novel Type of Candidate Cancer Therapeutics
Authors: Chen Weizao , Feng Yang , Zhao Qi , Zhu Zhongyu , Dimitrov Dimiter S. 
Published: May 2012

AbstractSoluble ligands are important targets for therapy of cancers and other diseases. Therapeutic monoclonal antibodies (mAb) against such ligands block their interactions with corresponding receptors but do not enhance their removal from the circulation and can increase their half-lives because of the long half-lives of the antibodies. We have hypothesized that mAbs targeting two or more nonoverlapping epitopes on the same ligand could form oligomeric antibody–ligand complexes that can bind to cells expressing Fc gamma receptors (FcγRs) with high avidity leading to their fast and irreversible removal from the circulation. Insulin-like growth factor II (IGF-II) is an example of such ligands and an important target for human cancer therapy. We identified two mAbs, m610.27 and m630.3, which bound to nonoverlapping epitopes on IGF-II with nanomolar affinity, and generated a bispecific antibody, m660. m660 inhibited the interaction of human IGF-II (hIGF-II) with the human breast cancer cell line MCF-7, hIGF-II–mediated IGF receptor type I and insulin receptor phosphorylation, and cell growth. In the presence of hIGF-II, large complexes of m660 were formed that bound to FcγRII-expressing BJAB cells much more efficiently than the monospecific antibody–hIGF-II complexes and were presumably phagocytosed by phorbol 12-myristate 13-acetate–stimulated macrophage-like U937 cells. A mixture of m610.27 and m630.3 exhibited similar properties. To our knowledge, these mAbs are the first reported to target nonoverlapping epitopes on a cancer-related ligand and could represent a novel class of candidate therapeutics against cancers. This approach could also be used to irreversibly eliminate other disease-related soluble ligands. Mol Cancer Ther; 11(7); 1400–10. ©2012 AACR.
A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation
Authors: Mahajan Shailaja , Fender Anke , Meyer-Kirchrath Jutta , Kurt Muhammed , Barth Mareike , Sagban Tolga , Fischer Jens , Schrör Karsten , Hohlfeld Thomas , Rauch Bernhard 
Published: May 2012

SummaryThrombin exerts coagulation-independent effects on the proliferation and migration of vascular smooth muscle cells (SMC). Forkhead box-O (FoxO) transcription factors regulate cell proliferation, apoptosis and cell cycle arrest, but a possible functional interaction between thrombin and FoxO factors has not been identified to date. In human cultured vascular SMC, thrombin induced a time-dependent phosphorylation of FoxO1 and FoxO3 but not FoxO4. This effect was mimicked by an activating-peptide (AP) for protease-activated receptor (PAR)-1, and abolished by a PAR-1 antagonist (SCH79797). APs for other PARs were without effect. FoxO1 and FoxO3 phosphorylation were prevented by the PI3 kinase (PI3K) inhibitor LY294002 while inhibitors of ERK1/2 (PD98059) or p38MAPK (SB203580) were ineffective. LY294002 moreover prevented thrombin-stimulated SMC mitogenesis and proliferation. FoxO1 and FoxO3 siRNA augmented basal DNA synthesis and proliferation of SMC. Nuclear content of FoxO proteins decreased time-dependently in response to thrombin, coincided with suppressed expression of the cell cycle regulating genes p21CIP1 and p27kip1 by thrombin. FoxO1 siRNA reduced basal p21CIP1 while FoxO3 siRNA attenuated p27kip1 expression; thrombin did not show additive effects. LY294002 restored p21CIP1 and p27kip1 protein expression. Immunohistochemistry revealed that human native and failed saphenous vein grafts were characterised by the cytosolic presence of p-FoxO factors in co-localisation of p21CIP1 and p27kip1 with SMC. In conclusion, thrombin and FoxO factors functionally interact through PI3K/Akt-dependent FoxO phosphorylation leading to expression of cell cycle regulating genes and ultimately SMC proliferation. This may contribute to remodelling and failure of saphenous vein bypass grafts.
Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age
Authors: Charoin-Pannier Anne , McIntyre Christine , Zandt Hagen , Ciorciaro Cornelia , Winters Katie , Pepper Tom , Schmitt Christophe 
Published: May 2012

SummaryThis study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3–5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.
Manipulating Large-Scale Qualitative Meteorological Information for Drought Outlook
Authors: Ahn Kuk-Hyun , Kim Young-Oh , Ahn Sang Jin 
Published: May 2012

Abstract
Despite many strides made in the development of global circulation models as well as the expansive understanding of meteorological phenomena, many countries still lack sufficient meteorological information that can be conveniently utilized for a hydrologic outlook. This paper suggests a technique of processing the meteorological information, which is not only difficult to differentiate by reducing to a specific basin because of extensive data, but is also impossible to be led to a quantitative drought outlook because of its presentation in qualitative forms.
To assess the drought conditions, two indices were selected—the standardized precipitation index (SPI), which is a meteorological index, and the soil moisture index (SMI), an agricultural index. The long-range forecasts, provided by the Korea Meteorological Administration (KMA) to target the Korean peninsula, were used to predict these indices. As a means to convert the qualitative interval forecast into a quantitative probability forecast, previous data on temperature and precipitation were used to create a compatible probability distribution that was then divided into three intervals. Based on the interval forecast provided by the KMA, the forecast probability of corresponding intervals were differentiated and optimized for each study basin by modifying the probability adjustment coefficient. The quantified probability forecast established in this manner was applied to three basins in Korea, and was verified by applying the ranked probability skill score (RPSS). The results proved that accuracy was ensured in both SPI and SMI.
Improving High-Resolution Numerical Weather Simulations by Assimilating Data from an Unmanned Aerial System
Authors: Jonassen Marius O. , Ólafsson Haraldur , Ágústsson Hálfdán , Rögnvaldsson Ólafur , Reuder Joachim 
Published: May 2012

Abstract
In this study, it is demonstrated how temperature, humidity, and wind profile data from the lower troposphere obtained with a lightweight unmanned aerial system (UAS) can be used to improve high-resolution numerical weather simulations by four-dimensional data assimilation (FDDA). The combined UAS and FDDA system is applied to two case studies of northeasterly flow situations in southwest Iceland from the international Moso field campaign on 19 and 20 July 2009. Both situations were characterized by high diurnal boundary layer temperature variation leading to thermally driven flow, predominantly in the form of sea-breeze circulation along the coast. The data assimilation leads to an improvement in the simulation of the horizontal and vertical extension of the sea breeze as well as of the local background flow. Erroneously simulated fog over the Reykjanes peninsula on 19 July, which leads to a local temperature underestimation of 8 K, is also corrected by the data assimilation. Sensitivity experiments show that both the assimilation of wind data and temperature and humidity data are important for the assimilation results. UAS represents a novel instrument platform with a large potential within the atmospheric sciences. The presented method of using UAS data for assimilation into high-resolution numerical weather simulations is likely to have a wide range of future applications such as wind energy and improvements of targeted weather forecasts for search and rescue missions.
The significance of autoantibodies against β2-glycoprotein I
Authors: de Groot Philip G. , Urbanus Rolf T. 
Published: May 2012

AbstractThe antiphospholipid syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with a history of thrombosis and/or pregnancy morbidity, including fetal loss. APS is an autoimmune disease with a confusing name because the pathologic auto-antibodies are shown to be directed against the plasma protein β2-glycoprotein I and not against phospholipids. In fact, auto-antibodies that recognize phospholipids themselves are not associated with thrombosis but with infectious diseases. One of the intriguing questions is why autoantibodies against β2-glycoprotein I are so commonly found in both patients and the healthy. Several potential mechanisms have been suggested to explain the increased thrombotic risk in patients with these autoantibodies. In this overview, we will summarize our knowledge on the etiology of the autoantibodies, and we will discuss the evidence that identify autoantibodies against β2-glycoprotein I as the culprit of APS.
Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury
Authors: Medford Andrew RL , Douglas Samantha K , Godinho Sofia IH , Uppington Kay M , Armstrong Lynne , Gillespie Kathleen M , van Zyl Berendine , Tetley Terry D , Ibrahim Nassif BN , Millar Ann B 
Published: May 2012

Abstract

Background
The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.

Methods
VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.

Measurements and Main Results
VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).

Conclusion
These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.
Generation and analysis of a barcode-tagged insertion mutant library in the fission yeast Schizosaccharomyces pombe
Authors: Chen Bo-Ruei , Hale Devin C , Ciolek Peter J , Runge Kurt W 
Published: May 2012

Abstract

Background
Barcodes are unique DNA sequence tags that can be used to specifically label individual mutants. The barcode-tagged open reading frame (ORF) haploid deletion mutant collections in the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe allow for high-throughput mutant phenotyping because the relative growth of mutants in a population can be determined by monitoring the proportions of their associated barcodes. While these mutant collections have greatly facilitated genome-wide studies, mutations in essential genes are not present, and the roles of these genes are not as easily studied. To further support genome-scale research in S. pombe, we generated a barcode-tagged fission yeast insertion mutant library that has the potential of generating viable mutations in both essential and non-essential genes and can be easily analyzed using standard molecular biological techniques.

Results
An insertion vector containing a selectable ura4
+ marker and a random barcode was used to generate a collection of 10,000 fission yeast insertion mutants stored individually in 384-well plates and as six pools of mixed mutants. Individual barcodes are flanked by Sfi I recognition sites and can be oligomerized in a unique orientation to facilitate barcode sequencing. Independent genetic screens on a subset of mutants suggest that this library contains a diverse collection of single insertion mutations. We present several approaches to determine insertion sites.

Conclusions
This collection of S. pombe barcode-tagged insertion mutants is well-suited for genome-wide studies. Because insertion mutations may eliminate, reduce or alter the function of essential and non-essential genes, this library will contain strains with a wide range of phenotypes that can be assayed by their associated barcodes. The design of the barcodes in this library allows for barcode sequencing using next generation or standard benchtop cloning approaches.
The response and recovery of the Arabidopsis thalianatranscriptome to phosphate starvation
Authors: Woo Jongchan , MacPherson Cameron Ross , Liu Jun , Wang Huan , Kiba Takatoshi , Hannah Matthew A , Wang Xiu-Jie , Bajic Vladimir B , Chua Nam-Hai 
Published: May 2012

Abstract

Background
Over application of phosphate fertilizers in modern agriculture contaminates waterways and disrupts natural ecosystems. Nevertheless, this is a common practice among farmers, especially in developing countries as abundant fertilizers are believed to boost crop yields. The study of plant phosphate metabolism and its underlying genetic pathways is key to discovering methods of efficient fertilizer usage. The work presented here describes a genome-wide resource on the molecular dynamics underpinning the response and recovery in roots and shoots of Arabidopsis thaliana to phosphate-starvation.

Results
Genome-wide profiling by micro- and tiling-arrays (accessible from GEO: GSE34004) revealed minimal overlap between root and shoot transcriptomes suggesting two independent phosphate-starvation regulons. Novel gene expression patterns were detected for over 1000 candidates and were classified as either initial, persistent, or latent responders. Comparative analysis to AtGenExpress identified cohorts of genes co-regulated across multiple stimuli. The hormone ABA displayed a dominant role in regulating many phosphate-responsive candidates. Analysis of co-regulation enabled the determination of specific versus generic members of closely related gene families with respect to phosphate-starvation. Thus, among others, we showed that PHR1-regulated members of closely related phosphate-responsive families (PHT1;1, PHT1;7–9, SPX1-3, and PHO1;H1) display greater specificity to phosphate-starvation than their more generic counterparts.

Conclusion
Our results uncover much larger, staged responses to phosphate-starvation than previously described. To our knowledge, this work describes the most complete genome-wide data on plant nutrient stress to-date.
Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event
Authors: C Warren Fiona , R Abrams Keith , Golder Su , J Sutton Alex 
Published: May 2012

AbstractBackgroundAdverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention.MethodsUsing a collection of reviews identified previously, 166 references including a meta-analysis were selected for review. At least one of the primary outcomes in each review was an adverse or unintended event. The nature of the intervention, source of funding, number of individual meta-analyses performed, number of primary studies included in the review, and use of meta-analytic methods were all recorded. Specific areas of interest relating to the methods used included the choice of outcome metric, methods of dealing with sparse events, heterogeneity, publication bias and use of individual patient data.ResultsThe 166 included reviews were published between 1994 and 2006. Interventions included drugs and surgery among other interventions. Many of the references being reviewed included multiple meta-analyses with 44.6% (74/166) including more than ten. Randomised trials only were included in 42.2% of meta-analyses (70/166), observational studies only in 33.7% (56/166) and a mix of observational studies and trials in 15.7% (26/166). Sparse data, in the form of zero events in one or both arms where the outcome was a count of events, was found in 64 reviews of two-arm studies, of which 41 (64.1%) had zero events in both arms.ConclusionsMeta-analyses of adverse events data are common and useful in terms of increasing the power to detect an association with an intervention, especially when the events are infrequent. However, with regard to existing meta-analyses, a wide variety of different methods have been employed, often with no evident rationale for using a particular approach. More specifically, the approach to dealing with zero events varies, and guidelines on this issue would be desirable.