bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of success of quality improvement collaboratives: what does the literature show?
Authors: Hulscher Marlies E J L , Schouten Loes M T , Grol Richard P T M , Buchan Heather 
Published: August 2012

ContextThe apparent inconsistency between the widespread use of quality improvement collaboratives and the available evidence heightens the importance of thoroughly understanding the relative strength of the approach. More insight into factors influencing outcome would mean future collaboratives could be tailored in ways designed to increase their chances of success. This review describes potential determinants of team success and how they relate to effectiveness.MethodWe searched Medline, CINAHL, Embase, Cochrane, and PsycINFO databases from January 1995 to June 2006. The 1995–2006 search was updated in June 2009. Reference lists of included papers were reviewed to identify additional papers. We included papers that were written in English, contained data about the effectiveness of collaboratives, had a healthcare setting, met our definition for collaborative, and quantitatively assessed a relationship between any determinant and any effect parameter.FindingsOf 1367 abstracts identified, 23 papers (reporting on 26 collaboratives) provided information on potential determinants and their relationship with effectiveness. We categorised potential determinants of success using the definition for collaboratives as a template. Numerous potential determinants were tested, but only a few related to empirical effectiveness. Some aspects of teamwork and participation in specific collaborative activities enhanced short-term success. If teams remained intact and continued to gather data, chances of long-term success were higher. There is no empirical evidence of positive effects of leadership support, time and resources.ConclusionsThese outcomes provide guidance to organisers, participants and researchers of collaboratives. To advance knowledge in this area we propose a more systematic exploration of potential determinants by applying theory and practice-based knowledge and by performing methodologically sound studies that clearly set out to test such determinants.
Reciprocal peer review for quality improvement: an ethnographic case study of the Improving Lung Cancer Outcomes Project
Authors: Aveling Emma-Louise , Martin Graham , Jiménez García Senai , Martin Lisa , Herbert Georgia , Armstrong Natalie , Dixon-Woods Mary , Woolhouse Ian 
Published: August 2012

BackgroundPeer review offers a promising way of promoting improvement in health systems, but the optimal model is not yet clear. We aimed to describe a specific peer review model—reciprocal peer-to-peer review (RP2PR)—to identify the features that appeared to support optimal functioning.MethodsWe conducted an ethnographic study involving observations, interviews and documentary analysis of the Improving Lung Cancer Outcomes Project, which involved 30 paired multidisciplinary lung cancer teams participating in facilitated reciprocal site visits. Analysis was based on the constant comparative method.ResultsFundamental features of the model include multidisciplinary participation, a focus on discussion and observation of teams in action, rather than paperwork; facilitated reflection and discussion on data and observations; support to develop focused improvement plans. Five key features were identified as important in optimising this model: peers and pairing methods; minimising logistic burden; structure of visits; independent facilitation; and credibility of the process. Facilitated RP2PR was generally a positive experience for participants, but implementing improvement plans was challenging and required substantial support. RP2PR appears to be optimised when it is well organised; a safe environment for learning is created; credibility is maximised; implementation and impact are supported.DiscussionRP2PR is seen as credible and legitimate by lung cancer teams and can act as a powerful stimulus to produce focused quality improvement plans and to support implementation. Our findings have identified how RP2PR functioned and may be optimised to provide a constructive, open space for identifying opportunities for improvement and solutions.
Environmental Informatics
Authors: Frew James E. , Dozier Jeff 
Published: August 2012

Environmental informatics uses large multidimensional, complex datasets to study environmental problems, which can be both discrete and continuous in space or time. These datasets and their requisite metadata can be managed by queryable databases. Geospatial Web application programming interfaces (APIs) provide remote access to dynamic subsets of environmental information. Persistent identifiers make data citable. The storage-computing trade-off is now heavily skewed in favor of moving calculations to the data. Provenance metadata help determine a data object's reliability and trustworthiness. Rising atmospheric CO2, the Antarctic ozone hole, and Gulf Stream warm-core rings were all discovered by analyzing long-term datasets. Similar work continues on mapping evapotranspiration and snow water equivalent. In these “fourth paradigm” problems, data (especially data collected operationally) drive hypothesis formation. Making data available requires new discovery mechanisms and policies favoring data sharing. Cloud computing and array-friendly databases will help bring processing to the data. Ubiquitous location sensing and geotagging will help turn citizen scientists into environmental information collectors.
S-Nitrosylation of EGFR and Src Activates an Oncogenic Signaling Network in Human Basal-Like Breast Cancer
Authors: Switzer Christopher H. , Glynn Sharon A. , Cheng Robert Y.-S. , Ridnour Lisa A. , Green Jeffrey E. , Ambs Stefan , Wink David A. 
Published: August 2012

Abstract
Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor negative (ER−) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in epidermal growth factor receptor (EGFR) tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER− breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER− breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt, and β-catenin) and the loss of PP2A tumor suppressor activity. In addition, NO signaling increased cellular EMT, expression and activity of COX-2, and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell–like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients. Mol Cancer Res; 10(9); 1203–15. ©2012 AACR.
Biological Responses to TGF-β in the Mammary Epithelium Show a Complex Dependency on Smad3 Gene Dosage with Important Implications for Tumor Progression
Authors: Kohn Ethan A. , Yang Yu-an , Du Zhijun , Nagano Yoshiko , Van Schyndle Catherine M.H. , Herrmann Michelle A. , Heldman Madeleine , Chen Jin-Qiu , Stuelten Christina H. , Flanders Kathleen C. , Wakefield Lalage M. 
Published: August 2012

Abstract
TGF-β plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-β signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3+/− IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis. Mol Cancer Res; 10(10); 1389–99. ©2012 AACR.
Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma
Authors: Agrawal Nishant , Jiao Yuchen , Bettegowda Chetan , Hutfless Susan M. , Wang Yuxuan , David Stefan , Cheng Yulan , Twaddell William S. , Latt Nyan L. , Shin Eun J. , Wang Li-Dong , Wang Liang , Yang Wancai , Velculescu Victor E. , Vogelstein Bert , Papadopoulos Nickolas , Kinzler Kenneth W. , Meltzer Stephen J. 
Published: August 2012

Abstract
Esophageal cancer ranks sixth in cancer death. To explore its genetic origins, we conducted exomic sequencing on 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T&gt;C:G transversions in EACs, and C:G&gt;G:C transversions in ESCCs (P &lt; 0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett esophagus. These discoveries highlight key genetic differences between EACs and ESCCs and between American and Chinese ESCCs, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from Barrett esophagus.
Significance: This is the first genome-wide study of mutations in esophageal cancer. It identifies key genetic differences between EACs and ESCCs including general mutation spectra and NOTCH1 loss-of-function mutations specific to ESCCs, shows geographic disparities between North American and Chinese ESCCs, and shows that most mutations in EACs are already present in matched Barrett esophagus. Cancer Discov; 2(10); 899–905. ©2012 AACR.
Read the Commentary on this article by Collisson and Cho, p. 870.
This article is highlighted in the In This Issue feature, p. 857.
RAF/MEK Dependence of KRAS-Mutant Pancreatic Ductal Adenocarcinomas
Authors: Hanrahan Aphrothiti J. , Solit David B. 
Published: August 2012

Abstract
Summary: Studies using genetically engineered mouse models indicate that RAF activation is sufficient to induce pancreatic intraepithelial neoplasms, suggesting that mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor–based combination approaches may have clinical use in patients with pancreatic ductal adenocarcinomas. Cancer Discov; 2(8); 666–9. ©2012 AACR.
Commentary on Collisson et al., p. 685.
Discovery in Context: Leveraging Multidimensional Glioblastoma Datasets to Identify Targetable Regulatory Networks
Authors: Babic Ivan , Mischel Paul S. 
Published: August 2012

Abstract
Summary: The Cancer Genome Atlas (TCGA) promises to transform the treatment of patients with cancer by identifying new drug targets. However, extracting mechanistically insightful, therapeutically actionable information from complex multidimensional datasets remains a significant challenge. In this issue of Cancer Discovery, Genovese and colleagues apply a context-dependent modeling algorithm to the glioblastoma TCGA datasets and couple it with functional genetic screens and experimental validation to identify a novel, and potentially targetable, microRNA-mediated regulatory pathway. Cancer Discov; 2(8); 676–8. ©2012 AACR.
Commentary on Genovese et al., p. 736.
STATe-of-the-Art Approach: Using Oligonucleotide Decoys to Target the “Undruggable”
Authors: Koppikar Priya , Bromberg Jacqueline 
Published: August 2012

Abstract
Summary: Sen and colleagues have shown for the first time the clinical application of an oligonucleotide decoy targeting the oncogenic transcription factor STAT3 for the treatment of head and neck tumors. Intratumoral injection of decoy effectively reduced the activity of STAT3 as evidenced by a decrease in several of its transcriptional targets. However, its low bioavailability makes them unacceptable for systemic therapy. Cyclization of the STAT3 decoy markedly increased its half-life while preserving specificity and showed significant antitumor activity upon systemic delivery in preclinical models of head and neck cancer. These findings have broad therapeutic implications for the treatment of many malignancies. Cancer Discov; 2(8); 670–2. ©2012 AACR.
Commentary on Sen et al., p. 694.
Nanoparticle-Mediated Delivery of Pioglitazone Enhances Therapeutic Neovascularization in a Murine Model of Hindlimb Ischemia
Authors: Nagahama Ryoji , Matoba Tetsuya , Nakano Kaku , Kim-Mitsuyama Shokei , Sunagawa Kenji , Egashira Kensuke 
Published: August 2012

Objective—
Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator−activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model.

Methods and Results—
In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin–positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase–deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP.

Conclusion—
NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.
Elevated Protein Kinase C-δ Contributes to Aneurysm Pathogenesis Through Stimulation of Apoptosis and Inflammatory Signaling
Authors: Morgan Stephanie , Yamanouchi Dai , Harberg Calvin , Wang Qiwei , Keller Melissa , Si Yi , Burlingham William , Seedial Stephen , Lengfeld Justin , Liu Bo 
Published: August 2012

Objective—
Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals.

Methods and Results—

Mouse experimental AAA is induced by perivascular administration of CaCl
2
. Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ
–/–
mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ
–/–
aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ
–/–
mice restores inflammatory response and aneurysm development.

Conclusion—
PKCδ is an important signaling mediator for SMC apoptosis and inflammation in a mouse model of AAA. By stimulating monocyte chemoattractant protein-1 expression in aortic SMCs, upregulated PKCδ exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKCδ may serve as a potential therapeutic strategy for AAA.
Increased Epidermal Growth Factor–Like Ligands Are Associated With Elevated Vascular Nicotinamide Adenine Dinucleotide Phosphate Oxidase in a Primate Model of Atherosclerosis
Authors: Stanic Bojana , Pandey Deepesh , Fulton David J. , Miller Francis J. 
Published: August 2012

Objective—
To characterize the relationship between the expression of epidermal growth factor (EGF)-like ligands and vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activity in a primate model of atherosclerosis.

Methods and Results—
Adult male Cynomolgus monkeys were fed a normal or atherogenic (AS) diet for 45 months, after which animals from the AS group were placed on a normal diet for 8 months (regression). The expression of membrane-associated EGF-like ligands was increased in arteries from animals on the AS diet and normalized in the regression group. EGF-like ligands were distributed throughout atherosclerotic vessels but predominantly colocalized with macrophages. Consistent with ligand shedding, circulating heparin-bound EGF was elevated in the plasma of AS monkeys but not in those on regression diet. Atherosclerosis was associated with the activation of EGF receptor signaling. Expression of NADPH oxidase subunits Nox1 and Nox2 but not Nox4 or Nox5 was increased in arteries from monkeys on the AS diet and returned to normal with regression. Levels of Nox1 and Nox2 positively correlated with EGF-like ligands. In cultured monkey smooth muscle cells, treatment with EGF-like ligands increased Nox1 expression and activity.

Conclusion—
These data identify EGF-like ligands as potential modulators of atherogenesis, resulting in part from increased vascular NADPH oxidase activity.
Arterial Stiffness and Cerebral Small Vessel Disease
Authors: Poels Mariëlle M.F. , Zaccai Kèren , Verwoert Germaine C. , Vernooij Meike W. , Hofman Albert , van der Lugt Aad , Witteman Jacqueline C.M. , Breteler Monique M.B. , Mattace-Raso Francesco U.S. , Ikram M. Arfan 
Published: August 2012

Background and Purpose—
Aging and vascular risk factors contribute to arterial stiffening. Increased arterial stiffness exposes the small vessels in the brain to abnormal flow pulsations and, as such, may contribute to the pathogenesis of cerebral small vessel disease. In a population-based study, we investigated the association between arterial stiffness, as measured by aortic pulse wave velocity (aPWV), and small vessel disease.

Methods—
Overall, 1460 participants (mean age, 58.2 years) underwent aPWV measurement and brain MRI scanning. We calculated aPWV by measuring time differences and distances between pulse waves in the carotid and femoral arteries. Using automated MRI analysis, we obtained white matter lesion volumes. Infarcts and microbleeds were rated visually. We used linear and logistic regression models to associate aPWV with small vessel disease, adjusting for age, sex, mean arterial pressure, and heart rate and additionally for cardiovascular risk factors. Subsequently, we explored associations in strata of hypertension.

Results—
In the study group, higher aPWV was associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.07; 95% CI, 0.02–0.12) but not with lacunar infarcts or microbleeds. In persons with uncontrolled hypertension, higher aPWV was significantly associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.09; 95% CI, 0.00–0.18), deep or infratentorial microbleeds (OR, 2.13; 95% CI, 1.16–3.91), and to a lesser extent also with lacunar infarcts (OR, 1.63; 95% CI, 0.98–2.70). No such associations were present in persons with controlled hypertension or without hypertension.

Conclusions—
In our study, increased arterial stiffness is associated with a larger volume of white matter lesions.
Higher Prehospital Priority Level of Stroke Improves Thrombolysis Frequency and Time to Stroke Unit
Authors: Berglund Annika , Svensson Leif , Sjöstrand Christina , von Arbin Magnus , von Euler Mia , Wahlgren Nils , Engerström Lars , Höjeberg Bo , Käll Tor-Björn , Mjörnheim Susanna , Engqvist Ann 
Published: August 2012

Background and Purpose—
Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences.

Methods—
Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel.

Results—

During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (
P
<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (
P
<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention.

Conclusion—
This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.