bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Analysis of Rhomboid Proteases during
Toxoplasma
Invasion
Authors: Shen Bang , Buguliskis Jeffrey S. , Lee Tobie D. , Sibley L. David 
Published: October 2014

ABSTRACT

Host cell invasion by
Toxoplasma gondii
and other apicomplexan parasites requires transmembrane adhesins that mediate binding to receptors on the substrate and host cell to facilitate motility and invasion. Rhomboid proteases (ROMs) are thought to cleave adhesins within their transmembrane segments, thus allowing the parasite to disengage from receptors and completely enter the host cell. To examine the specific roles of individual ROMs during invasion, we generated single, double, and triple knockouts for the three ROMs expressed in
T. gondii
tachyzoites. Analysis of these mutants demonstrated that ROM4 is the primary protease involved in adhesin processing and host cell invasion, whereas ROM1 or ROM5 plays negligible roles in these processes. Deletion of ROM4 blocked the shedding of adhesins such as MIC2 (microneme protein 2), causing them to accumulate on the surface of extracellular parasites. Increased surface adhesins led to nonproductive attachment, altered gliding motility, impaired moving junction formation, and reduced invasion efficiency. Despite the importance of ROM4 for efficient invasion, mutants lacking all three ROMs were viable and MIC2 was still efficiently removed from the surface of invaded mutant parasites, implying the existence of ROM-independent mechanisms for adhesin removal during invasion. Collectively, these results suggest that although ROM processing of adhesins is not absolutely essential, it is important for efficient host cell invasion by
T. gondii
.

IMPORTANCE
Apicomplexan parasites such as
Toxoplasma gondii
express surface proteins that bind host cell receptors to aid invasion. Many of these adhesins are subject to cleavage by rhomboid proteases (ROMs) within their transmembrane segments during invasion. Previous studies have demonstrated the importance of adhesin cleavage for parasite invasion and proposed that the ROMs responsible for processing would be essential for parasite survival. In
T. gondii
, ROM5 was thought to be the critical ROM for adhesin shedding due to its robust protease activity
in vitro
and posterior localization on the parasite surface. Here, we knocked out all three ROMs in
T. gondii
tachyzoites and found that ROM4, but not ROM5, was key for adhesin cleavage. However, none of the ROMs individually or in combination was essential for cell entry, further emphasizing that essential pathways such as invasion typically rely on redundant pathways to ensure survival.
Capturing patient information at nursing shift changes: methodological evaluation of speech recognition and information extraction
Authors: Suominen Hanna , Johnson Maree , Zhou Liyuan , Sanchez Paula , Sirel Raul , Basilakis Jim , Hanlen Leif , Estival Dominique , Dawson Linda , Kelly Barbara 
Published: October 2014

AbstractObjective We study the use of speech recognition and information extraction to generate drafts of Australian nursing-handover documents.Methods Speech recognition correctness and clinicians’ preferences were evaluated using 15 recorder–microphone combinations, six documents, three speakers, Dragon Medical 11, and five survey/interview participants. Information extraction correctness evaluation used 260 documents, six-class classification for each word, two annotators, and the CRF++ conditional random field toolkit.Results A noise-cancelling lapel-microphone with a digital voice recorder gave the best correctness (79%). This microphone was also the most preferred option by all but one participant. Although the participants liked the small size of this recorder, their preference was for tablets that can also be used for document proofing and sign-off, among other tasks. Accented speech was harder to recognize than native language and a male speaker was detected better than a female speaker. Information extraction was excellent in filtering out irrelevant text (85% F1) and identifying text relevant to two classes (87% and 70% F1). Similarly to the annotators’ disagreements, there was confusion between the remaining three classes, which explains the modest 62% macro-averaged F1.Discussion We present evidence for the feasibility of speech recognition and information extraction to support clinicians’ in entering text and unlock its content for computerized decision-making and surveillance in healthcare.Conclusions The benefits of this automation include storing all information; making the drafts available and accessible almost instantly to everyone with authorized access; and avoiding information loss, delays, and misinterpretations inherent to using a ward clerk or transcription services.
‘Connecting the dots’: leveraging visual analytics to make sense of patient safety event reports
Authors: Ratwani Raj M , Fong Allan 
Published: October 2014

Abstract
An increasing number of healthcare providers are adopting patient safety event reporting systems, yet leveraging these data to improve safety remains a challenge, particularly with large datasets composed of thousands of event reports. A MedStar Health research team, with expertise in data analytics and human factors, developed intuitive visualization dashboards to facilitate data exploration and trend analysis. Dashboards were developed using an iterative design and development process that was end-user focused. A system level dashboard, representing data from multiple hospitals, and a hospital level dashboard were developed. The dashboards allowed users to directly manipulate the data, provided coordinated displays in different formats, and allowed users to quickly zoom in on specific variables of interest. Overall feedback was incredibly positive with nearly all users wanting to adopt the system immediately. Several improvements were suggested and are discussed. The success of this approach highlights the need for more intuitive data analysis tools.
Benchmarks for detecting ‘breakthroughs’ in clinical trials: empirical assessment of the probability of large treatment effects using kernel density estimation
Authors: Miladinovic Branko , Kumar Ambuj , Mhaskar Rahul , Djulbegovic Benjamin 
Published: October 2014

ObjectiveTo understand how often ‘breakthroughs,’ that is, treatments that significantly improve health outcomes, can be developed.DesignWe applied weighted adaptive kernel density estimation to construct the probability density function for observed treatment effects from five publicly funded cohorts and one privately funded group.Data Sources820 trials involving 1064 comparisons and enrolling 331 004 patients were conducted by five publicly funded cooperative groups. 40 cancer trials involving 50 comparisons and enrolling a total of 19 889 patients were conducted by GlaxoSmithKline.ResultsWe calculated that the probability of detecting treatment with large effects is 10% (5–25%), and that the probability of detecting treatment with very large treatment effects is 2% (0.3–10%). Researchers themselves judged that they discovered a new, breakthrough intervention in 16% of trials.ConclusionsWe propose these figures as the benchmarks against which future development of ‘breakthrough’ treatments should be measured.
Quality indicators for hip fracture patients: a scoping review protocol
Authors: Pitzul Kristen B , Munce Sarah E P , Perrier Laure , Beaupre Lauren , Morin Suzanne N , McGlasson Rhona , Jaglal Susan B 
Published: October 2014

IntroductionHip fractures are a significant cause of morbidity and mortality and care of hip fracture patients places a heavy burden on healthcare systems due to prolonged recovery time. Measuring quality of care delivered to hip fracture patients is important to help target efforts to improve care for patients and efficiency of the health system. The purpose of this study is to synthesise the evidence surrounding quality of care indicators for patients who have sustained a hip fracture. Using a scoping review methodology, the research question that will be addressed is: “What patient, institutional, and system-level indicators are currently in use or proposed for measuring quality of care across the continuum for individuals following a hip fracture?”.Methods and analysisWe will employ the methodological frameworks used by Arksey and O'Malley and Levacet al. The synthesis will be limited to quality of care indicators for individuals who suffered low trauma hip fracture. All English peer-reviewed studies published from the year 2000-most recent will be included. Literature search strategies will be developed using medical subject headings and text words related to hip fracture quality indicators and the search will be peer-reviewed. Numerous electronic databases will be searched. Two reviewers will independently screen titles and abstracts for inclusion, followed by screening of the full text of potentially relevant articles to determine final inclusion. Abstracted data will include study characteristics and indicator definitions.DisseminationTo improve quality of care for patients and create a more efficient healthcare system, mechanisms for the measurement of quality of care are required. The implementation of quality of care indicators enables stakeholders to target areas for improvement in service delivery. Knowledge translation activities will occur throughout the review with dissemination of the project goals and findings to local, national, and international stakeholders.
Improving the accuracy of operation coding in surgical discharge summaries
Authors: Martinou Eirini , Shouls Genevieve , Betambeau Nadine 
Published: October 2014

AbstractProcedural coding in surgical discharge summaries is extremely important; as well as communicating to healthcare staff which procedures have been performed, it also provides information that is used by the hospital’s coding department. The OPCS code (Office of Population, Censuses and Surveys Classification of Surgical Operations and Procedures) is used to generate the tariff that allows the hospital to be reimbursed for the procedure. We felt that the OPCS coding on discharge summaries was often incorrect within our breast and endocrine surgery department. A baseline measurement over two months demonstrated that 32% of operations had been incorrectly coded, resulting in an incorrect tariff being applied and an estimated loss to the Trust of £17,000.We developed a simple but specific OPCS coding table in collaboration with the clinical coding team and breast surgeons that summarised all operations performed within our department. This table was disseminated across the team, specifically to the junior doctors who most frequently complete the discharge summaries. Re-audit showed 100% of operations were accurately coded, demonstrating the effectiveness of the coding table. We suggest that specifically designed coding tables be introduced across each surgical department to ensure accurate OPCS codes are used to produce better quality surgical discharge summaries and to ensure correct reimbursement to the Trust.
Self-management of vaginal pessaries for pelvic organ prolapse
Authors: Kearney Rohna , Brown Claire 
Published: October 2014

AbstractTwo thirds of women opt to use a vaginal pessary initially to manage the symptoms of pelvic organ prolapse. In the UK most women attend a health care professional at least every six months to change the pessary. This represents a significant burden both economically to the health care system and personally for the woman. Annually there are more than 300 appointments for pessary changes at our hospital. We developed a programme to teach women to self-manage their pessaries with the aim of improving patient experience and reducing outpatient attendances to free up outpatient capacity for new referrals. A physiotherapist was recuited to deliver this programme involving a one to one training session supplemented with written materials and an online video. Women using pessaries were offered the option of self-management.Eighty-eight women aged between 29 to 84 years enrolled in the programme. Sixty-three women (73% of those enrolled) successfully continued with self-management at six months, creating 126 extra outpatient appointment capacity in one year alone. Women self-managing reported higher levels of convenience (94% vs 81%), accessibility (97% vs 73%), support (100% vs. 83%), and comfort (86% vs. 53%) than those attending the hospital for GP practice for pessary change.Self-management appears to be an acceptable option for many women using vaginal pessaries, with personal benefits to the women and economic benefits to the hospital and commissioners.
Myostatin Gene Inactivation Prevents Skeletal Muscle Wasting in Cancer
Authors: Gallot Yann S. , Durieux Anne-Cécile , Castells Josiane , Desgeorges Marine M. , Vernus Barbara , Plantureux Léa , Rémond Didier , Jahnke Vanessa E. , Lefai Etienne , Dardevet Dominique , Nemoz Georges , Schaeffer Laurent , Bonnieu Anne , Freyssenet Damien G. 
Published: October 2014

Abstract
Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in ApcMin/+ mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in ApcMin/+ mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. Cancer Res; 74(24); 7344–56. ©2014 AACR.
Cellular Factors Promoting Resistance to Effective Treatment of Glioma with Oncolytic Myxoma Virus
Authors: Zemp Franz J. , McKenzie Brienne A. , Lun Xueqing , Reilly Karlyne M. , McFadden Grant , Yong V. Wee , Forsyth Peter A. 
Published: October 2014

Abstract
Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation. Cancer Res; 74(24); 7260–73. ©2014 AACR.
Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases
Authors: Prudnikova Tatiana Y. , Rawat Sonali J. , Chernoff Jonathan 
Published: October 2014

AbstractRHO GTPases, members of the RAS superfamily of small GTPases, are adhesion and growth factor–activated molecular switches that play important roles in tumor development and progression. When activated, RHO-family GTPases such as RAC1, CDC42, and RHOA, transmit signals by recruiting a variety of effector proteins, including the protein kinases PAK, ACK, MLK, MRCK, and ROCK. Genetically induced loss of RHO function impedes transformation by a number of oncogenic stimuli, leading to an interest in developing small-molecule inhibitors that either target RHO GTPases directly, or that target their downstream protein kinase effectors. Although inhibitors of RHO GTPases and their downstream signaling kinases have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to facilitate pharmaceutical research and development and is a promising therapeutic strategy. Clin Cancer Res; 21(1); 24–29. ©2014 AACR.
Molecular Characterization of Choroid Plexus Tumors Reveals Novel Clinically Relevant Subgroups
Authors: Merino Diana M. , Shlien Adam , Villani Anita , Pienkowska Malgorzata , Mack Stephen , Ramaswamy Vijay , Shih David , Tatevossian Ruth , Novokmet Ana , Choufani Sanaa , Dvir Rina , Ben-Arush Myran , Harris Brent T. , Hwang Eugene I. , Lulla Rishi , Pfister Stefan M. , Achatz Maria Isabel , Jabado Nada , Finlay Jonathan L. , Weksberg Rosanna , Bouffet Eric , Hawkins Cynthia , Taylor Michael D. , Tabori Uri , Ellison David W. , Gilbertson Richard J. , Malkin David 
Published: October 2014

Abstract
Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.
Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.
Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.
Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.
MUC1 Promoter–Driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer
Authors: Tholey Renee M. , Lal Shruti , Jimbo Masaya , Burkhart Richard A. , Blanco Fernando F. , Cozzitorto Joseph A. , Eisenberg Josh D. , Jiang Wei , Iacobuzio-Donahue Christine A. , Witkiewicz Agnieszka K. , Glbert Melissa , Yeo Charles J. , Brody Jonathan R. , Sawicki Janet A. , Winter Jordan M. 
Published: October 2014

Abstract
Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoter-driven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter–driven luciferase and DTA constructs. MUC1-positive (+) cells had significantly elevated MUC1 mRNA expression compared with MUC1-negative (−) cells. Luciferase activity was significantly higher in MUC1+ cells when transfected with MUC1 promoter–driven luciferase and MUC1+ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter–driven DTA. IFNγ pretreatment enhanced MUC1 expression in MUC1− cells and induced sensitivity to MUC1–DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 IHC labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared with either antibody alone. Combining MUC1 with MSLN-targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter–driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression.
Implications: MUC1 expression in primary and metastatic lesions provides a rationale for the development of a systemic MUC1 promoter–driven DTA therapy that may be further enhanced by combination with other promoter-driven DTA constructs. Mol Cancer Res; 13(3); 439–48. ©2014 AACR.