bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homotypic Gap Junctional Communication Associated with Metastasis Suppression Increases with PKA Activity and Is Unaffected by PI3K Inhibition
Authors: Bodenstine Thomas M. , Vaidya Kedar S. , Ismail Aimen , Beck Benjamin H. , Cook Leah M. , Diers Anne R. , Landar Aimee , Welch Danny R. 
Published: November 2010

Abstract
Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosphorylation events play a key role in their trafficking and degradation. The metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor LY294002, and its structural analogue LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a connexin gene. In addition, while levels of connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both LY294002 and LY303511 increased the activity of protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor H89 decreased the LY294002/LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of LY294002 and LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic therapy. Cancer Res; 70(23); 10002–11. ©2010 AACR.
Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity
Authors: Wang Leanne X.J. , Westwood Jennifer A. , Moeller Maria , Duong Connie P.M. , Wei Wei-Zen , Malaterre Jordane , Trapani Joseph A. , Neeson Paul , Smyth Mark J. , Kershaw Michael H. , Darcy Phillip K. 
Published: November 2010

Abstract
Adoptive immunotherapy involving genetic modification of T cells with antigen-specific, chimeric, single-chain receptors is a promising approach for the treatment of cancer. To determine whether gene-modified T cells could induce antitumor effects without associated autoimmune pathology, we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumor in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissues. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2+ 24JK tumor following administration of anti-Her-2 T cells compared with control T cells. The incorporation of a lymphoablative step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 were both found to further enhance survival. The reduction in tumor growth was also correlated with localization of transferred T cells at the tumor site. Furthermore, an antigen-specific recall response could be induced in long-term surviving mice following rechallenge with Her-2+ tumor. Importantly, antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment of cancer. Cancer Res; 70(23); 9591–8. ©2010 AACR.
Preoperative Circulating Tumor Cell Detection Using the Isolation by Size of Epithelial Tumor Cell Method for Patients with Lung Cancer Is a New Prognostic Biomarker
Authors: Hofman Véronique , Bonnetaud Christelle , Ilie Marius I. , Vielh Philippe , Vignaud Jean Michel , Fléjou Jean François , Lantuejoul Sylvie , Piaton Eric , Mourad Nadine , Butori Catherine , Selva Eric , Poudenx Michel , Sibon Stéphanie , Kelhef Sabrina , Vénissac Nicolas , Jais Jean-Philippe , Mouroux Jérôme , Molina Thierry Jo , Hofman Paul 
Published: November 2010

AbstractPurpose: Pathologic TNM staging is currently the best prognostic factor for non-small cell lung carcinoma (NSCLC). However, even in early-stage NSCLC, the recurrence rates after surgery range from 25% to 50%. The preoperative detection of circulating tumor cells (CTC) could be useful to tailor new therapeutic strategies in NSCLC. We assessed the presence of CTC in NSCLC patients undergoing surgery, using cytologic analyses, after their isolation by size of epithelial tumor cells (ISET method). The presence and the number of CTCs were considered and correlated with clinicopathologic parameters including patient follow-up.Experimental Design: Of the 247 blood samples tested, 208 samples were from patients with resectable NSCLC and 39 from healthy subjects. The mean follow-up was 24 months. An image of detected cells with presumably nonhematologic features [initially defined as “circulating nonhematologic cells” (CNHC)] was recorded. The presence of CNHC was assessed blindly and independently by 10 cytopathologists, using cytologic criteria of malignancy on stained filters. The count of detected CNHCs was made for each filter.Results: One hundred two of 208 (49%) patients showed CNHCs corresponding to CNHC with malignant cytopathologic features in 76 of 208 (36%) cases. CNHCs were not detected in the control group. A level of 50 or more CNHCs corresponding to the third quartile was associated with shorter overall and disease-free-survival, independently of disease staging, and with a high risk of recurrence and death in early-stage I + II-resectable NSCLC.Conclusion: A high percentage of NSCLC patients show preoperative detection of CNHC by the ISET method. The presence and level of 50 or more CNHCs are associated with worse survival of patients with resectable NSCLC. Clin Cancer Res; 17(3); 505–13. ©2010 AACR.
Nutlin-3a Is a Potential Therapeutic for Ewing Sarcoma
Authors: Pishas Kathleen I. , Al-Ejeh Fares , Zinonos Irene , Kumar Raman , Evdokiou Andreas , Brown Michael P. , Callen David F. , Neilsen Paul M. 
Published: November 2010

Abstract
Purpose: Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist.
Experimental Design: The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated.
Results: Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4.
Conclusion: Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease. Clin Cancer Res; 17(3); 494–504. ©2010 AACR.
Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue
Authors: Iersel Thijs van , Stroissnig Heimo , Giesen Peter , Wemer Johan , Wilhelm-Ogunbiyi Karin 
Published: November 2010

SummarySolulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.
ABO blood group as a potential risk factor for venous thromboembolism in acutely injured patients
Authors: Muellner Sarah , Haut Elliott , Streiff Michael , Holcomb John , Cotton Bryan 
Published: November 2010

SummaryVenous thromboembolism (VTE) is a major health problem that results in a significant burden on hospitals and patients. VTE screening and prophylaxis protocols in trauma patients vary significantly among hospitals and providers. In addition, many patients develop VTE even in the absence of “high-risk” categories. Therefore, more research is needed to better understand and prevent VTE in these patients. ABO blood group has long been recognised as a risk factor for VTE, but its contribution to VTE risk in the trauma setting is poorly studied. This paper reviews the literature describing the link between ABO blood group and VTE risk and the implications for VTE screening and prophylaxis in trauma patients. The effect of ABO blood groups are genotype-dependent – in most populations the A1 allele and the B allele increase risk while A2, O1, and O2 decrease risk of VTE. ABO group is a major determinant of plasma von Willebrand factor (vWF) and factor VIII levels, thereby (partially) mediating the effects of ABO blood group on VTE susceptibility. In addition, ABH antigens alter plasma levels of vWF via clearance mechanisms, which are in turn mediated by ADAMTS13. ABO blood group is a risk factor for VTE that warrants further investigation in trauma patients.
Clopidogrel withdrawal: Is there a “rebound” phenomenon?
Authors: Sambu Nalyaka , Warner Timothy , Curzen Nick 
Published: November 2010

SummaryDual antiplatelet therapy with aspirin and clopidogrel is routinely indicated in patients with acute coronary syndromes and following percutaneous coronary intervention to reduce the risk of cardiovascular mortality and ischaemic events. Although clinical guidelines recommend aspirin lifelong and clopidogrel for between one and 12 months, depending upon the indication, the optimal duration of clopidogrel therapy actually remains contentious. Premature cessation of clopidogrel in patients receiving drug-eluting stents is a clear risk factor for stent thrombosis, but recent clinical studies have also demonstrated a link between “appropriate” cessation of clopidogrel and clustering of adverse clinical events. It has been suggested that this may be due to a “rebound” prothrombotic and/ or proinflammatory response associated with clopidogrel withdrawal. This review will examine the defini- tion and concept of a “rebound” phenomenon associated with clopidogrel cessation as well as the likely mechanisms behind this effect. Within the context of clinical event clustering after clopidogrel cessation, we will also discuss (i) the clinical importance of clopidogrel and the increasing uncertainty surrounding optimal duration of therapy, (ii) the antiplatelet and anti-inflammatory properties of clopidogrel and, in particular, its influence on arachidonic acid pathways traditionally thought to be mediated predominantly by aspirin and (iii) the role of newer, more potent antiplatelet agents and potential changes to anti-platelet therapy prescribing guidelines in the future.
The Immunity of International Organizations Before Domestic Courts: Recent trends
Authors: Ryngaert Cedric 
Published: November 2010

AbstractThis article addresses the international organizations' immunity defence before domestic courts, and its relationship with the organizations' internal dispute settlement mechanisms. The focus of the article lies primarily on private law disputes between international organizations and individuals, and on (employment) disputes between organizations and their staff in particular. It draws inductively on cases that have recently been decided or made available, and that draw attention to three main issues: 1. the legal nature of the immunity of international organizations, 2. the weighing of the individual's right to a remedy and the organization's immunity and, to a lesser extent, 3. the relationship between the immunity from jurisdiction and the immunity from enforcement.
Immunity of International Organizations in Post-conflict International Administrations
Authors: De Brabandere Eric 
Published: November 2010

AbstractThe role played by international organizations in international law has evolved in the past decades. However, the continued application of an absolute system of immunities to international organizations has often led to a perception of impunity, in particular when organizations are involved in the administrations of foreign territories. Even though absolute immunity has been described as an 'anachronism', this article argues that international organization immunity serves a useful and essential purpose. The grant of privileges and immunities to international organizations is indispensable to allow the organization to effectively and independently carry out its functions. The functional reflections that lie at the basis of the immunities system of international organizations still are extremely pertinent when organizations exercise administrative duties in place of a state. This articles thus claims that there is a need to maintain immunities in order to preserve institutional autonomy, even when the UN or another international organization has taken up administrative duties in a state or territory, and suggests that, instead of proposing a revision or abolition of the system of immunities, the focus should be placed on the establishment of effective alternative mechanisms to assess alleged violations of the international legal obligations of the organization.
Responsibility of a Member state of an International Organization: Where Will It End? Comments on Article 60 of the ILC Draft on the Responsibility of International Organizations
Authors: Paasivirta Esa 
Published: November 2010

AbstractThe paper addresses the issue of possible responsibility of a member state for acts of an international organization of which it is a member. This particular issue forms part of the on-going work of the International Law Commission of establishing rules for the responsibility of international organizations. The particular challenge is posed by possible “responsibility gaps”, i.e. situations where a state might avoid compliance with its own obligations by prompting the organization of which it is a member to act instead. The paper compares the ILC approach, approaching the issue by way of trying to establish general rules of responsibility (“secondary rules”) and the practice of the EU, which has addressed the issue by tailor-made solutions in the context of specific treaties (“primary rules”). The latter approach is more flexible as it allows individual solutions pertinent to particular circumstances and treaty regimes so as to ensure that either the organization itself or its member state is responsible, depending whichever is genuinely responsible. The paper concludes that the ILC work is progressing in the right direction as it narrows down the possibilities where a member state can be held responsible to cover only situations bordering abuse, rather than more open-ended standards for individual member state responsibility, which can open the door for unpredictable results.
Abuse of the Members: Questions concerning Draft Article 16 of the Draft Articles on Responsibility of International Organizations
Authors: Blokker Niels 
Published: November 2010

AbstractThis contribution discusses Article 16 (“Decisions, authorizations and recommendations addressed to member states and international organizations”) of the ILC draft articles on responsibility of international organizations, completed in first reading in 2009. According to Article 16, international organizations may incur international responsibility for their binding and non-binding decisions if certain conditions are fulfilled. The main rationale of this provision is that an international organization may not require its members to perform acts which the organization itself may not perform under its own obligations. The need to include this provision in the draft articles is not questioned. Five specific issues are addressed. The provision concerning authorizations may in the future turn out to be the most troublesome, in particular in relation to Security Council authorizations for the use of force.
Impact of Secondary Eyewall Heating on Tropical Cyclone Intensity Change*
Authors: Zhou Xiaqiong , Wang Bin , Ge Xuyang , Li Tim 
Published: November 2010

Abstract
The primary goal of this study is to explore the factors that might influence the intensity change of tropical cyclones (TCs) associated with secondary eyewall replacement. Concentric eyewall structures in TCs with and without large intensity weakening are compared using the Tropical Rainfall Measuring Mission (TRMM) 2A12 and 2A25 data. It is found that the secondary eyewalls with a stratiform-type heating profile show a marked weakening, while those TCs with a convective-type heating weaken insignificantly or even intensify. This observed feature is supported by a set of sensitivity numerical experiments performed with the Weather Research and Forecasting model. With more active convection, the latent heat released in the outer eyewall and moat region can better sustain storm intensity. The prevailing stratiform precipitation results in low equivalent potential temperature air in the moat and reduces the entropy of the boundary layer inflow to the inner eyewall through persistent downdrafts, leading to a large intensity fluctuation. Comparison of observations and numerical model results reveals that the model tends to overproduce convective precipitation in the outer eyewall and the moat. It is possible that the model underestimates the storm intensity changes associated with eyewall replacement events.
A Simple Methodology for Estimating Mean and Variability of Annual Runoff and Reservoir Yield under Present and Future Climates
Authors: McMahon Thomas A. , Peel Murray C. , Pegram Geoffrey G. S. , Smith Ian N. 
Published: November 2010

Abstract
Overlying the challenge of managing within natural hydroclimatic variability is the likely modification of runoff variability along with average runoff due to anthropogenic enhancement of greenhouse gas concentrations. In this paper analytical models are developed in which runoff mean and variability, the latter defined by the variance (or standard deviation) of annual runoff, are related to the variances and the covariance of annual precipitation and potential evapotranspiration, and the aridity index (mean annual potential evapotranspiration divided by mean annual precipitation). The method was validated using observed runoff data for 699 worldwide catchments. It was concluded that combining the Schreiber function, which relates the ratio of annual actual evapotranspiration to annual precipitation, with the analytical models provided satisfactory estimates of observed annual runoff mean and interannual variability. It was also concluded that estimates of annual runoff variability based on the simplified model of Koster and Suarez were unsatisfactory. By way of illustrating the new methodology, the approach was applied to projected annual values of precipitation from the Hadley Centre Global Environment Model version 1 (HadGEM) and it showed that considerable changes in reservoir yield are likely to occur if climate change projections of precipitation from HadGEM are realistic. Finally, further simplifications of the equations, based on the Schreiber function, are developed to estimate the mean and standard deviation of annual runoff that allow climate analysts to estimate the impact of potential climate changes on annual runoff characteristics and reservoir yield performance without having to resort to the calibration and application of a rainfall-runoff model or rely on the runoff output from general circulation models to examine such characteristics.
Lightning Activity in a Hail-Producing Storm Observed with Phased-Array Radar
Authors: Emersic C. , Heinselman P. L. , MacGorman D. R. , Bruning E. C. 
Published: November 2010

Abstract
This study examined lightning activity relative to the rapidly evolving kinematics of a hail-producing storm on 15 August 2006. Data were provided by the National Weather Radar Testbed Phased-Array Radar, the Oklahoma Lightning Mapping Array, and the National Lightning Detection Network.
This analysis is the first to compare the electrical characteristics of a hail-producing storm with the reflectivity and radial velocity structure at temporal resolutions of less than 1 min. Total flash rates increased to approximately 220 min−1 as the storm’s updraft first intensified, leveled off during its first mature stage, and then decreased for 2–3 min despite the simultaneous development of another updraft surge. This reduction in flash rate occurred as wet hail formed in the new updraft and was likely related to the wet growth; wet growth is not conducive to hydrometeor charging and probably contributed to the formation of a “lightning hole” without a mesocyclone. Total flash rates subsequently increased to approximately 450 min−1 as storm volume and inferred graupel volume increased, and then decreased as the storm dissipated.
The vertical charge structure in the storm initially formed a positive tripole (midlevel negative charge between upper and lower positive charges). The charge structure in the second updraft surge consisted of a negative charge above a deep midlevel positive charge, a reversal consistent with the effects of large liquid water contents on hydrometeor charge polarity in laboratory experiments.
Prior to the second updraft surge, the storm produced two cloud-to-ground flashes, both lowering the usual negative charge to ground. Shortly before hail likely reached ground, the storm produced four cloud-to-ground flashes, all lowering the positive charge. Episodes of high singlet VHF sources were observed at approximately 13–15 km during the initial formation and later intensification of the storm’s updraft.