bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 Study of AS1409, a Novel Antibody-Cytokine Fusion Protein, in Patients with Malignant Melanoma or Renal Cell Carcinoma
Authors: Rudman Sarah M. , Jameson Michael B. , McKeage Mark J. , Savage Philip , Jodrell Duncan I. , Harries Mark , Acton Gary , Erlandsson Fredrik , Spicer James F. 
Published: March 2011

AbstractPurpose: AS1409 is a fusion protein comprising a humanized antibody BC1 linked to interleukin-12 (IL-12). It is designed to deliver IL-12 to tumor-associated vasculature using an antibody targeting the ED-B variant of fibronectin.Experimental Design: We conducted a phase 1 trial of weekly infusional AS1409 in renal carcinoma and malignant melanoma patients. Safety, efficacy, markers of IL-12–mediated immune response, and pharmacokinetics were evaluated.Results: A total of 11 melanoma and 2 renal cell carcinoma patients were treated. Doses of 15 and 25 μg/kg were studied. Most drug-related adverse events were grade 2 or less, and included pyrexia, fatigue, chills, headache, vomiting, and transient liver function abnormalities. Three dose limiting toxicities of grade 3 fatigue and transaminase elevation were seen at 25 μg/kg. IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles. Antidrug antibody responses were seen in all patients, although bioassays indicate these do not neutralize AS1409 activity. Plasma half-life was 22 hours and not dose-dependent. Five patients received 6 cycles or more and a best response of at least stable disease was seen in 6 (46%) patients. Partial response was seen in a melanoma patient, and disease shrinkage associated with metabolic response was maintained beyond 12 months in another melanoma patient despite previous rapid progression.Conclusions: The maximum tolerated dose was established at 15 μg/kg weekly. AS1409 is well tolerated at this dose. Evidence of efficacy assessed by RECIST, functional imaging, and biomarker response warrants the planned further investigation using this dose and schedule in malignant melanoma. Clin Cancer Res; 17(7); 1998–2005. ©2011 AACR.
Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a
Authors: Lin Chuyong , Wu Zhiqiang , Lin Xi , Yu Chunping , Shi Tingting , Zeng Yong , Wang Xi , Li Jun , Song Libing 
Published: March 2011

Abstract
Purpose: Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotinllin-1 (FLOT1), a marker of lipid rafts, is involved in the progression of cancer, but the precise mechanism remains unclear. The aim of the present study was to examine the role of FLOT1 on the tumorigenesis of breast cancer cells and its clinical significance in progression of the disease.
Experimental Design: FLOT1 expression was analyzed in 212 paraffin-embedded, archived clinical breast cancer samples by using immunohistochemistry (IHC). The effect of FLOT1 on cell proliferation and tumorigenesis was examined in vitro and in vivo. Western blotting and luciferase reporter analyses were carried out to identify the effects of downregulating FLOT1 on expression of cell cycle regulators and transcriptional activity of FOXO3a.
Results: IHC analysis revealed high expression of FLOT1 in 129 of the 212 (60.8%) paraffin-embedded archived breast cancer specimens. The overall expression level of FLOT1 significantly correlated with clinical staging and poor patient survival of breast cancer. Strikingly, we found that silencing FLOT1 inhibited proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo, which was further shown to be mechanistically associated with suppression of Akt activity, enhanced transcriptional activity of FOXO3a, upregulation of cyclin-dependent kinase inhibitor p21Cip1 and p27Kip1, and downregulation of the CDK regulator cyclin D1.
Conclusions: FLOT1 plays an important role in promoting proliferation and tumorigenesis of human breast cancer and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 17(10); 3089–99. ©2011 AACR.
Activity of Sorafenib against Desmoid Tumor/Deep Fibromatosis
Authors: Gounder Mrinal M. , Lefkowitz Robert A. , Keohan Mary Louise , D'Adamo David R. , Hameed Meera , Antonescu Cristina R. , Singer Samuel , Stout Katherine , Ahn Linda , Maki Robert G. 
Published: March 2011

AbstractBackground: Desmoid tumors (deep fibromatoses) are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are associated with morbidity and occasionally mortality. Responses of desmoid patients to sorafenib on an expanded access program led us to review our experience.Methods: After Institutional Review Board (IRB) approval, we reviewed data for 26 patients with desmoid tumors treated with sorafenib. Sorafenib was administered at 400 mg oral daily and adjusted for toxicity.Results: Sorafenib was the first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2–29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. Twelve of 13 (92%) patients evaluated by MRI had &gt; 30% decrease in T2 signal intensity, an indirect metric for increased fibrosis and loss of cellularity. Eighty percent of patients with radiological benefit had extra-abdominal desmoids.Discussion: Sorafenib is active against desmoid tumors. A prospective, randomized clinical trial of sorafenib against other active agents is warranted. Loss of MRI T2 signal may be a useful surrogate for defining responses, but requires validation by examination of tumor pathology. Clin Cancer Res; 17(12); 4082–90. ©2011 AACR.
Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations
Authors: Galimi Francesco , Torti Davide , Sassi Francesco , Isella Claudio , Corà Davide , Gastaldi Stefania , Ribero Dario , Muratore Andrea , Massucco Paolo , Siatis Dimitrios , Paraluppi Gianluca , Gonella Federica , Maione Francesca , Pisacane Alberto , David Ezio , Torchio Bruno , Risio Mauro , Salizzoni Mauro , Capussotti Lorenzo , Perera Timothy , Medico Enzo , Di Renzo Maria Flavia , Comoglio Paolo M. , Trusolino Livio , Bertotti Andrea 
Published: March 2011

Abstract
Purpose: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease.
Experimental Design: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets.
Results: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer.
Conclusions: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation. Clin Cancer Res; 17(10); 3146–56. ©2011 AACR.
Nitrophorin 2, a factor IX(a)-directed anticoagulant, inhibits arterial thrombosis without impairing haemostasis
Authors: Mizurini Daniella M. , Francischetti Ivo M. B. , Andersen John F. , Monteiro Robson Q. 
Published: March 2011

SummaryNitrophorin 2 (NP2) is a 20 kDa lipocalin identified in the salivary gland of the blood sucking insect, Rhodnius prolixus. It functions as a potent inhibitor of the intrinsic pathway of coagulation upon binding to factor IX (FIX) or FIXa. Herein we have investigated the in vivo antithrombotic properties of NP2. Surface plasmon resonance assays demonstrated that NP2 binds to rat FIX and FIXa with high affinities (KD = 43 and 47 nM, respectively), and prolongs the aPTT without affecting the PT. In order to evaluate NP2 antithrombotic effects in vivo two distinct models of thrombosis in rats were carried out. In the rose Bengal/laser induced injury model of arterial thrombosis, NP2 increased the carotid artery occlusion time by ≈35 and ≈155%, at doses of 8 and 80 μg/kg, respectively. NP2 also inhibited thrombus formation in an arterio-venous shunt model, showing ≈60% reduction at 400 μg/kg (i.v. administration). The antithrombotic effect lasted for up to 48 hours after a single i.v. dose. Notably, effective doses of NP2 did not increase the blood loss as evaluated by tail-transection model. In conclusion, NP2 is a potent and long-lasting inhibitor of arterial thrombosis with minor effects on haemostasis. It might be regarded as a potential agent for the treatment of human cardiovascular diseases.
Discharge to a Skilled Nursing Facility and Subsequent Clinical Outcomes Among Older Patients Hospitalized for Heart Failure
Authors: Allen Larry A. , Hernandez Adrian F. , Peterson Eric D. , Curtis Lesley H. , Dai David , Masoudi Frederick A. , Bhatt Deepak L. , Heidenreich Paul A. , Fonarow Gregg C. 
Published: March 2011

Background—
Heart failure (HF) is the leading cause of hospitalization among older Americans. Subsequent discharge to skilled nursing facilities (SNF) is not well described.

Methods and Results—

We performed an observational analysis of Medicare beneficiaries ≥65 years of age, discharged alive to SNF or home after ≥3-day hospitalization for HF in 2005 and 2006 within the Get With The Guidelines–HF Program. Among 15 459 patients from 149 hospitals, 24.1% were discharged to an SNF, 22.3% to home with home health service, and 53.6% to home with self-care. SNF use varied significantly among hospitals (median, 10.2% versus 33.9% in low versus high tertiles), with rates highest in the Northeast. Patient factors associated with discharge to SNF included longer length of stay, advanced age, female sex, hypotension, higher ejection fraction, absence of ischemic heart disease, and a variety of comorbidities. Performance measures were modestly lower for patients discharged to SNF. Unadjusted absolute event rates were higher at 30 days (death, 14.4% versus 4.1%; rehospitalization, 27.0% versus 23.5%) and 1 year (death, 53.5% versus 29.1%; rehospitalization, 76.1% versus 72.2%) after discharge to SNF versus home, respectively (
P
<0.0001 for all). After adjustment for measured patient characteristics, discharge to SNF remained associated with increased death (hazard ratio, 1.76; 95% confidence interval, 1.66 to 1.87) and rehospitalization (hazard ratio, 1.08; 95% confidence interval, 1.03 to 1.14).

Conclusions—
Discharge to SNF is common among Medicare patients hospitalized for HF, and these patients face substantial risk for adverse events, with more than half dead within 1 year. These findings highlight the need to better characterize this unique patient population and understand the SNF care they receive.
Group psychosocial interventions for adults with schizophrenia and bipolar illness: The evidence base in the light of publications between 1986 and 2006
Authors: Segredou I. , Xenitidis K. , Panagiotopoulou M. , Bochtsou V. , Antoniadou O. , Livaditis M. 
Published: March 2011

Aim: The treatment of major mental disorders usually combines medical and psychosocial interventions. The present study reviews research pertaining to the efficacy of group psychosocial interventions for people with psychotic illness. Method: An electronic search was conducted through Medline and PsychINFO to identify articles relevant to group therapy for people with schizophrenia and bipolar affective disorder. Articles published in the English language, between January 1986 and May 2006, were considered. Studies were included if they had a control group and at least 20 participants. The search resulted in 23 articles concerning patients with schizophrenia and five concerning patients with bipolar affective disorder. Results and Conclusion: The therapeutic approach in the majority of the studies was along the lines of cognitive behaviour therapy and psychoeducation. All studies reported improvement in at least one parameter. Most of them report improvement in skills and overall functioning.
Pluralized life courses? An exploration of the life trajectories of individuals with psychiatric disorders
Authors: Müller Nicolas S. , Sapin Marlène , Jacques-Antoine Gauthier , Orita Alina , Widmer Eric D. 
Published: March 2011

Background: Most of the existing research relating to the life courses of people with psychiatric symptoms focuses on the occurrence and the impact of non-normative events on the onsets of crises; it usually disregards the more regular dimensions of life, such as work, family and intimate partnerships that may be related to the timing and seriousness of psychiatric problems. An additional reason for empirically addressing life trajectories of individuals with psychiatric problems relates to recent changes of family and occupational trajectories in relation to societal trends such as individualization and pluralization of life courses. Aim: This paper explores the life trajectories of 86 individuals under clinical supervision and proposes a typology of their occupational, co-residence and intimacy trajectories. The results are discussed in light of the life-course paradigm. Method: A multidimensional optimal matching analysis was performed on a sample of 86 individuals under clinical supervision to create a typology of trajectories. The influence of these trajectories on psychiatric disorders, evaluated using a SCL-90-R questionnaire, was then assessed using linear regression modelling. Results: The typologies of trajectories showed that the patients developed a diversity of life trajectories. Individuals who have developed a standard life course with few institutionalization periods reported more symptoms and distress than individuals with an institutionalized life trajectory. Conclusion: The results of this study stress that psychiatric patients are social actors who are influenced by society at large and its ongoing process of change. Therefore, it is essential to take into account the diversity of occupational and family trajectories when dealing with individuals in therapeutic settings.
Towards a perspective of system synchronization in water governance: a synthesis of empirical lessons and complexity theories
Authors: Teisman Geert R. , Edelenbos Jurian 
Published: March 2011

In this manuscript we conclude the special issue on Water Governance. We look back on the different contributions and discuss different interesting insights from the three contributions focusing on Wisconsin, California and Southern Ecuador. We place these insights into a new perspective on integration, i.e. system synchronization, which the authors consider to be an option for integration in complex governance systems, where nobody is in charge. Points for practitioners In this epilogue we have picked the fruits of the contributions to this symposium. We have come to another way of looking at the fragmentation—integration debate in public administration, i.e. system synchronization. By discussing different water cases from Wisconsin, California and Southern Ecuador, we have arrived at three principles of system synchronization: Synchronization means self-organization and variation; Synchronization means thinking and acting between self and the larger whole; Synchronization means operating on and beyond the boundaries of subsystems. These principles are needed to realize system synchronicity in which different subsystems largely hold their identity, but strive for coherence.
Financial Management Accountability Index (FMAI) in the Malaysian public sector: a way forward
Authors: Nur Barizah Abu Bakar  , Ismail Suhaiza 
Published: March 2011

The National Audit Department (NAD) of Malaysia has introduced the Financial Management Accountability Index (FMAI) within the framework of the audit rating system. This study shares the Malaysian experience in using FMAI as an accountability medium, evaluates the FMAI scores obtained by agencies, and proposes measures to enhance the usefulness of FMAI. The study uses secondary data as provided on the NAD website. Descriptive analyses were conducted in evaluating the rating scores across agencies. It was found that majority of the agencies have a ‘good’ financial management system, with Federal agencies performing better than their counterparts at the State level. It was also found that the overall rating system and FMAI suffer from lack of proper disclosure, consequently reducing their worthiness. There are still areas of improvement that need to be addressed by the NAD to enhance the value of the overall audit rating system. Points for practitioners The FMAI, which has been developed and used in Malaysia, is an important initiative that can be emulated by public managers in other governments, either in its current form or with modifications. It is particularly useful for benchmarking purposes. In the context of Malaysia, this research provides important insights for public policy-makers on how the usefulness of the audit rating system can be further increased.
How well can public service motivation connect with occupational intention?
Authors: Bangcheng Liu  , Chun Hui  , Jin Hu  , Wensheng Yang  , Xinli Yu  
Published: March 2011

Researchers have hypothesized that a person’s public service motivation (PSM) has a positive connection with occupational intention: the greater an individual’s PSM, the more likely he or she is to seek membership in a public organization. However, few empirical studies have tested this proposition. Based on a survey of 584 students from two prestigious universities in eastern China, this study explores how well PSM relates to students’ occupational intention. This study found that not all dimensions of PSM were consistently connected with occupational intention. The self-sacrifice dimension of PSM has a positive relationship with occupational intention, but the commitment to the public interests dimension does not. Moreover, the study found that female students who majored in social sciences and had relatives or parents in the public sector were more likely to choose employment in the public sector. The implications of this study and areas of future research are discussed. Points for practitioners Results of the study demonstrated that there was a significant relationship between PSM and occupational intention, but not all dimensions of PSM were consistently connected with occupational intention. The results identified several key implications: (1) For professionals in charge of recruiting and selecting public servants, PSM of a job seeker is a key criteria. (2) For job seekers, when they decide to enter public sector, the levels of their PSM should be considered. (3) Additionally, the background information on job seekers does matter to some extent when recruiting and selecting in public sector.
Deliberative governance in synergy with government: a case study of credible environmental improvements in the Dairy Gateway, USA
Authors: Metze Tamara A.P. 
Published: March 2011

This article examines a case of deliberative governance in the Dairy Gateway Project in the Northeast of Wisconsin, USA. In this project government, academic researchers, farmers and environmental organizations built cooperative voluntary networks to improve the quality of water, air and soil. They introduced dialogue, learning and stewardship as alternatives to governmental ‘command and control’. At three types of meetings a broader group of participants deliberated about the interpretation of these concepts. The study of these interpretative struggles in the form of boundary work demonstrates that participants considered dialogue and learning in networks a credible new way to cooperate, and that in most cases they accepted farmers as stewards of the land. However, they all wanted government to audit this stewardship. Hence, deliberative governance emerged in synergy with government. Point for practitioners Reflective conversations about boundary concepts, for example ‘stewardship’, can help to overcome environmental conflicts. This concept aligns incompatible discourses. When boundary concepts are introduced, participants in networks of, for example, farmers, environmentalists and governmental actors are challenged to think about new solutions. Moreover, they are encouraged to rethink the role of government. Deliberative settings, in which facilitators pay special attention to the quality of the conversations, enable this rethinking. In these conversations adversarial actors can empathically disagree. As a result, participants start negotiating credible solutions and establish what role government has to have.
Preparing Jordanian university services to implement a quality self-assessment methodology
Authors: Tarí Juan José , Madeleine Carolina 
Published: March 2011

The purpose of this article is to analyse the European Foundation for Quality Management (EFQM) self-assessment model in higher education institutions (HEIs) in Spain and in Jordan, and show what Jordanian HEIs have learnt from the Spanish experience. The article uses a case study methodology on eight administrative services provided by a public university in Spain and seven services provided by one public and one private university in Jordan. The findings show the steps that an administrative service may follow in order to apply the questionnaire approach to self-assessment in a successful manner. It provides lessons for decision-makers and managers from other public services in HEIs in Jordan, and other developing countries, who wish to perform an exercise in self-assessment using a questionnaire approach. Points for practitioners The article describes a practical methodology for assessing quality in public services in HEIs. It identifies the steps to implement this methodology in public services in a developed country (Spain) and in a developing country (Jordan) and the lessons learnt by the developing country. The article shows that the concept of quality awards can be adapted to different contexts, although there is a need for modification and careful implementation. The study provides lessons for decision-makers and managers from other public services in HEIs in Jordan, and other developing countries, who wish to perform an exercise in self-assessment using a questionnaire approach.