bluuebunny/crossref_metadata_2025_split huggingface dataset:
p53 Binds to and Is Required for the Repression of Arf Tumor Suppressor by HDAC and Polycomb
Authors: Zeng Yaxue , Kotake Yojiro , Pei Xin-Hai , Smith Matthew D. , Xiong Yue 
Published: March 2011

Abstract
The expression of tumor suppressor Arf is tightly repressed during normal cell growth at a young age and is activated by oncogenic insults, and during aging, results in p53 activation and cell-cycle arrest to prevent hyperproliferation. The mechanisms of both transcriptional repression and activation of Arf are not understood. We show that p53 binds to and represses Arf expression and that this repression requires the function of both histone deacetylases (HDAC) and polycomb group (PcG) proteins. Inactivation of p53 leads to increased Arf transcription in both mouse embryonic fibroblasts (MEF) cultured in vitro and in tissues and organs of p53 null mice. Activation of endogenous p53 enhances Arf repression, and reintroduction of p53 back into p53 null MEFs restores Arf repression. Both DNA binding and transactivation activities of p53 are required for Arf repression. We show that p53 is required for both HDAC and PcG to repress Arf expression. Bindings of both HDAC and PcG to Arf are disrupted by inactivation of p53 and can be restored in p53 null MEFs by the reintroduction of wild-type, but not mutant, p53. These results indicate that p53 recruits both HDAC and PcG to Arf locus to repress its expression, and this repression constitutes a second feedback loop in p53 regulation. Cancer Res; 71(7); 2781–92. ©2011 AACR.
BRAFV600E and Microenvironment in Thyroid Cancer: A Functional Link to Drive Cancer Progression
Authors: Nucera Carmelo , Lawler Jack , Parangi Sareh 
Published: March 2011

Abstract
Papillary thyroid cancer (PTC) rates continue to increase in the United States and Europe, and, although most patients do well, some recur and die of their disease. Patients with PTC harboring the BRAFV600E mutation seem to display a more aggressive clinical behavior, but little is known about the role of this mutation in crucial processes in the tumor microenvironment, such as tumor adhesion, migration, invasion, and metastasis. The extracellular matrix (ECM) microenvironment is not merely a structural scaffold for the cellular elements of the epithelial and stromal microenvironment, but it also elicits a profound influence on cell behavior affecting viability, proliferation, adhesion, and motility. The effects of BRAFV600E on cell surface receptors (i.e., integrins) and ECM noncellular components [i.e., thrombospondin-1 (TSP-1) and fibronectin (FN)] seem to trigger different pathologic biological processes in a cell context–dependent manner. This review focuses on the recent progress in understanding the role of BRAFV600E in the regulation of some ECM noncellular components and trans-membrane receptors of the microenvironment in PTC in order to design novel targeted therapies directed at the BRAFV600E multifaceted signaling cascades. Some of these targeted therapeutics, such as ATP-competitive BRAFV600E inhibitors (i.e., orally bioavailable PLX4720 and PLX4032 compounds), are already under investigation. Cancer Res; 71(7); 2417–22. ©2011 AACR.
Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms
Authors: Holkova Beata , Perkins E. Brent , Ramakrishnan Viswanathan , Tombes Mary Beth , Shrader Ellen , Talreja Neha , Wellons Martha D. , Hogan Kevin T. , Roodman G. David , Coppola Domenico , Kang Loveleen , Dawson Jana , Stuart Robert K. , Peer Cody , Figg William D. , Kolla Sarah , Doyle Austin , Wright John , Sullivan Daniel M. , Roberts John D. , Grant Steven 
Published: March 2011

Abstract
Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma).
Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted.
Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results.
Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non–Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.
Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma
Authors: Abraham Jinu , Prajapati Suresh I. , Nishijo Koichi , Schaffer Beverly S. , Taniguchi Eri , Kilcoyne Aoife , McCleish Amanda T. , Nelon Laura D. , Giles Francis G. , Efstratiadis Argiris , LeGallo Robin D. , Nowak Brent M. , Rubin Brian P. , Malempati Suman , Keller Charles 
Published: March 2011

Abstract
Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance. Mol Cancer Ther; 10(4); 697–707. ©2011 AACR.
Fragmentation and connection of frames in collaborative water governance: a case study of river catchment management in Southern Ecuador
Authors: Dewulf Art , Mancero Monica , Cárdenas German , Sucozhañay Dolores 
Published: March 2011

In collaborative water governance, the variety of frames that actors bring to the discussion constitutes an important challenge. In this study, we analyse the fragmentation and connection of frames in collaborative water governance projects in the Paute catchment and its sub-catchment Tabacay in the Southern Andes of Ecuador. We rely on frame analysis of project documents, interviews and meeting recordings to analyse the initial stages of these projects. We discuss (1) the different roles of problem domain framing and issue framing in frame fragmentation; (2) the significance of scale framing to problem domain and issue framing; (3) the challenge of connecting expert frames with frames of other actors; and (4) the importance of face-to-face dialogue for connecting frames. Points for practitioners Professionals in public management and administration all over the world are increasingly involved in governance processes where they have to deal with a multitude of actors and perspectives. If their task involves setting up collaborative projects with other governmental agencies, civil society organizations and/or business actors, there is much to gain by paying close attention to how they themselves and other actors are framing both the problem domain and the issues involved. In processes of collaborative water governance, additional attention is required for how projects are framed with respect to water system scales and administrative scales, and for how technical framing of the issues connects to the frames and experiences of other actors.
MPC-Polymer Reduces Adherence and Biofilm Formation by Oral Bacteria
Authors: Hirota K. , Yumoto H. , Miyamoto K. , Yamamoto N. , Murakami K. , Hoshino Y. , Matsuo T. , Miyake Y. 
Published: March 2011

Oral biofilms such as dental plaque cause dental caries and periodontitis, as well as aspiration pneumonia and infectious endocarditis by translocation. Hence, the suppression of oral biofilm formation is an issue of considerable importance. Mechanical removal, disinfectants, inhibition of polysaccharide formation, and artificial sugar have been used for the reduction of oral biofilm. From the viewpoint of the inhibition of bacterial adherence, we investigated whether aqueous biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymer can reduce streptococcal colonization and biofilm formation. We examined the effects of MPC-polymer on streptococcal adherence to saliva-coated hydroxyapatite and oral epithelial cells, and the adherence of Fusobacterium nucleatum to streptococcal biofilm. MPC-polymer application markedly inhibited both the adherence and biofilm formation of Streptococcus mutans on saliva-coated hydroxyapatite and streptococcal adherence to oral epithelial cells, and reduced the adherence of F. nucleatum to streptococcal biofilms. A small-scale clinical trial revealed that mouthrinsing with MPC-polymer inhibited the increase of oral bacterial numbers, especially of S. mutans. These findings suggest that MPC-polymer is a potent inhibitor of bacterial adherence and biofilm development, and may be useful to prevent dental-plaque-related diseases. (UMIN Clinical Trial Registry UMIN000003471). Abbreviations: QOL, quality of life; MPC, 2-methacryloyloxyethyl phosphorylcholine; BHI, brain-heart infusion broth; PBS, phosphate-buffered saline; SEM, scanning electron microscopy; CFU, colony-forming unit.
Uncertainty shift in robust predictive control design for application in CAV air-conditioning systems
Authors: Huang Gongsheng , Chow Tin-Tai 
Published: March 2011

Constant-air-volume (CAV) air-conditioning systems consist mainly of two local processes: an air-handling process and a room temperature process. A robust model predictive control (RMPC) strategy was developed for CAV air-conditioning systems, which adopted two uncertain first-order plus time-delay models to describe the dynamics of the local processes and used a linear matrix inequality (LMI)-based optimisation technique to optimise the control law. This paper develops a new control design, which reformulates the prediction models by shifting the uncertainties of the first model into the second one, and then uses the reformulated prediction models in the RMPC strategy. This paper will show that compared with the original design, the new control design can enhance the feasibility of the optimisation of control law, reduce the computational burden of the optimisation and also remove the requirement of a sensor for supply air temperature in the original design. Practical applications: The new design method is a further development of a RMPC strategy presented in Xu et al.13 It inherits the benefits of the original control design for practical application, i.e. uncertainties and constraints can be dealt with simultaneously in the design and the robustness of the controlled system can be enhanced. The new design improves the optimisation feasibility, reduces the computational complexity and does not need to measure the supply air temperature. When the new design is adopted to replace the traditional PI control, there is no necessity to change the existent input structure of the PI control. Hence, the new design can be realised in practice easier than the original design.
Biomechanical evaluation of the Pulvertaft versus the ‘wrap around’ tendon suture technique
Authors: Fuchs S. P. , Walbeehm E. T. , Hovius S. E. R. 
Published: March 2011

The purpose of this study was to compare the biomechanical properties of a novel wrap around tendon repair method with those of the standard Pulvertaft technique used for tendon reconstructions. Seventy-two porcine extensor tendons were used to create 36 reconstructions in six sets of six repairs, each using one of the two surgical techniques with differing lengths of the reconstructions. All the reconstructions were tested in vitro by cyclic tensile loading, resulting in the time-zero strength. When only the size of the repair and the strength were compared, and length of the reconstruction was not taken in consideration, the ‘wrap around’ reconstructions were of similar strength but less bulky than the Pulvertaft repairs. In conclusion, the ‘wrap around’ technique gives a thinner reconstruction which is as strong as, or stronger than the Pulvertaft technique, depending on the amount of weaves.
Biomechanical Comparison of 2 Different Locking Plate Fixation Methods in Vancouver B1 Periprosthetic Femur Fractures
Authors: Pletka Joshua D. , Marsland Daniel , Belkoff Stephen M. , Mears Simon C. , Kates Stephen L. 
Published: March 2011

Locking plates are commonly used to treat fractures around a well-fixed femoral component. The optimal construct should provide sufficient fixation while minimizing soft-tissue dissection. The purpose of the current study was to determine whether plate length, working length, or bone mineral density affects survival of locking plate fixation for Vancouver type B1 periprosthetic hip fractures. A transverse osteotomy was created just distal to cemented femoral prostheses in 9 pairs of cadaveric femurs. Fractures were stabilized with long (20-hole) or short (12-hole) locking plates that were secured proximally with cables and screws and distally with screws only. Specimens were then cycled 10 000 times at 2500 N of axial force and 15 Nm of torque to simulate full weightbearing. A motion capture system was used to record fracture displacement during cycling. Failure occurred in 5 long and 3 short plates, with no significant differences found in the number of cycles to failure. For the specimens that survived, there were no significant differences found between long and short plates for displacement or rotation observed at the fracture site. A shorter working length was not associated with increased failure rate. Lower bone mineral density was significantly associated with failure ( P = .02). We concluded that long locked plates do not appear to offer a biomechanical advantage over short locking plates in terms of fixation survival, and that bone mineral density was a better predictor of failure than was the fixation construct type.
Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor
Authors: Redell Michele S. , Ruiz Marcos J. , Alonzo Todd A. , Gerbing Robert B. , Tweardy David J. 
Published: March 2011

AbstractAcute myeloid leukemia (AML) is an aggressive malignancy with a relapse rate approaching 50%, despite aggressive chemotherapy. New therapies for AML are targeted at signal transduction pathways known to support blast survival, such as the Stat3 pathway. Aberrant activation of Stat3 has been demonstrated in many different malignancies, including AML, and this finding is frequently associated with more aggressive disease. The objectives of this study were: (1) to characterize Stat3 signaling patterns in AML cells lines and primary pediatric samples; and (2) to test the efficacy and potency of a novel Stat3 inhibitor in inducing apoptosis in AML cells. We found that Stat3 was constitutively activated in 6 of 7 AML cell lines and 6 of 18 primary pediatric AML samples. Moreover, constitutively phosphorylated Stat3 was frequent in samples with normal karyotype but uncommon in samples with t(8;21). Most cell lines and primary samples responded to G-CSF stimulation, although the sensitivity and magnitude of the response varied dramatically. Our novel small-molecule Stat3 inhibitor, C188-9, inhibited G-CSF–induced Stat3 phosphorylation, induced apoptosis in AML cell lines and primary samples, and inhibited AML blast colony formation with potencies in the low micromolar range. Therefore, Stat3 inhibition may be a valuable strategy for targeted therapies for AML.
Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli–induced hemolytic uremic syndrome
Authors: Ståhl Anne-lie , Sartz Lisa , Karpman Diana 
Published: March 2011

AbstractHemolytic uremic syndrome (HUS) is commonly associated with Shiga toxin (Stx)–producing Escherichia coli O157:H7 infection. This study examined patient samples for complement activation on leukocyte-platelet complexes and microparticles, as well as donor samples for Stx and lipopolysaccharide (O157LPS)–induced complement activation on platelet-leukocyte complexes and microparticles. Results, analyzed by flow cytometry, showed that whole blood from a child with HUS had surface-bound C3 on 30% of platelet-monocyte complexes compared with 14% after recovery and 12% in pediatric controls. Plasma samples from 12 HUS patients were analyzed for the presence of microparticles derived from platelets, monocytes, and neutrophils. Acute-phase samples exhibited high levels of platelet microparticles and, to a lesser extent, monocyte microparticles, both bearing C3 and C9. Levels decreased significantly at recovery. Stx or O157LPS incubated with donor whole blood increased the population of platelet-monocyte and platelet-neutrophil complexes with surface-bound C3 and C9, an effect enhanced by costimulation with Stx and O157LPS. Both Stx and O157LPS induced the release of C3- and C9-bearing microparticles from platelets and monocytes. Released microparticles were phagocytosed by neutrophils. The presence of complement on platelet-leukocyte complexes and microparticles derived from these cells suggests a role in the inflammatory and thrombogenic events that occur during HUS.
Adenosine modifies the balance between membrane and soluble forms of Flt-1
Authors: Leonard Frederique , Devaux Yvan , Vausort Melanie , Ernens Isabelle , Rolland-Turner Magali , Wagner Daniel R 
Published: March 2011

ABSTRACTVEGFR-1 (or Flt-1) exists under a sFlt-1 or a mFlt-1 form. sFlt-1 is antiangiogenic, and mFlt-1 is proangiogenic. The cardioprotective nucleoside Ado is proangiogenic, but its effects on Flt-1 are unknown and were tested in this study. In primary human macrophages from healthy volunteers, Ado inhibited sFlt-1 expression induced by LPS (–43%, P=0.006), HS, and IL-1β but not hypoxia. This effect was also observed in macrophages from patients with acute MI (–33%, P&lt;0.001). It was reproduced by the A2A Ado receptor agonist CGS21680 and abrogated by the A2A antagonist SCH58261. Conversely, Ado increased mFlt-1 expression, thus switching sFlt-1 from the soluble toward the membrane form. This switch was also present in macrophages from acute MI patients (P&lt;0.001). Assessment of HIF-1α nuclear translocation and activation together with siRNA experiments suggested that the effect of Ado on Flt-1 involves HIF-1α. In conclusion, Ado down-regulates sFlt-1 and up-regulates mFlt-1 production, an effect that indicates that Ado may be used to stimulate angiogenesis in the heart.
Die Supply Chain als regelungstechnische Aufgabe
Authors: Beyer Jürgen 
Published: March 2011

Zusammenfassung
Die Anwendung regelungstechnischer Methoden in der Supply Chain verspricht neben dem Erkenntnisgewinn auch die Möglichkeit, deren dynamisches Verhalten gezielt zu beeinflussen. Hierzu wird ein zeitdiskretes stochastisches Prozessmodell im Zustandsraum formuliert, das eine einfache Behandlung von Totzeiten ermöglicht. Nach einer Analyse des Prozesses hinsichtlich Stabilitätseigenschaften und dem Übertragungsverhalten der Erwartungswerte und Kovarianzen wird ein Zustandsregler zur Festlegung des Bestellverhaltens entworfen. Dieser Ansatz erlaubt die Kontrolle der Mittelwerte und Streuungen aller internen Zustände der Supply Chain.
Kooperative Wegplanung für dynamisch konfigurierbare Transportmodule
Authors: Krühn Tobias , Heiserich Gerd 
Published: March 2011

Zusammenfassung
Kleinskalige multidirektionale Transportmodule sind in der Lage, durch dynamische Gruppenbildung eine Vielzahl unterschiedlicher Transportaufgaben zu erfüllen. Stückgüter können auf einer flächig angeordneten Modulmatrix entlang beliebiger Transportwege bewegt werden. Das in diesem Beitrag vorgestellte Verfahren zur kooperativen Wegplanung basiert auf einem vollständig dezentralen Ansatz, bei dem die einzelnen Elemente durch eine einfache Zustandsübergangsfunktion charakterisiert sind, aus der sich ein effizientes Verhalten des Gesamtsystems ergibt.
Effect of a Direct Thrombin Inhibitor Compared with Dalteparin and Unfractionated Heparin on Human Osteoblasts
Authors: Winkler Tobias , Perka Carsten , Matziolis Dörte , Matziolis Georg 
Published: March 2011

Purpose:Osteoporosis is a relevant problem after long term administration of unfractionated heparin (UFH) and low molecular weight heparin. Melagatran is a representative of a new group of direct thrombin inhibitors with comparable data in the prevention of thromboembolic events after orthopaedic surgery. The aim of ourin vitrostudy was to investigate the effect of a direct thrombin inhibitor compared with dalteparin and UFH on human osteoblasts.Materials and Methods:Melagatran, dalteparin and UFH were added to primary osteoblast cultures in their therapeutic range and two decimal powers below and above. Cell number, protein synthesis, mitochondrial and alkaline phosphatase activity and collagen type I synthesis were evaluated.Results:Melagatran showed the least influence on protein synthesis and cell proliferation with a reduction of cell number to 83.5 ± 9% (p = 0.027) of the control group only in the highest investigated concentration after 15 days of incubation.Mitochondrial and alkaline phosphatase activity and collagen type I synthesis in osteoblasts incubated with melagatran and dalteparin showed similar patterns. UFH showed the most pronounced influence on cellular metabolism.Conclusions:Melagatran showed less inhibitory in vitro effects on human osteoblasts than dalteparin or UFH. The presented study gives first hints that direct thrombin inhibitors may help prevent heparin-induced negative effects on bone metabolism.