bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Adhesin Complex Protein (ACP) of Neisseria meningitidis Is a New Adhesin with Vaccine Potential
Authors: Hung Miao-Chiu , Heckels John E. , Christodoulides Myron 
Published: February 2013

ABSTRACT

The
acp
gene encoding the 13-kDa adhesin complex protein (ACP) from
Neisseria meningitidis
serogroup B strain MC58 was cloned and expressed in
Escherichia coli
, and the purified recombinant ACP (rACP) was used for immunization studies. Analysis of the ACP amino acid sequences from 13 meningococcal strains, isolated from patients and colonized individuals, and 178 strains in the Bacterial Isolate Genome Sequence (BIGS) database showed the presence of only three distinct sequence types (I, II, and III) with high similarity (>98%). Immunization of mice with type I rACP in detergent micelles and liposomes and in saline solution alone induced high levels of serum bactericidal activity (SBA; titers of 1/512) against the homologous strain MC58 and killed strains of heterologous sequence types II and III with similar SBA titers (1/128 to 1/512). Levels of expression of type I, II, or III ACP by different meningococcal strains were similar. ACP functioned as an adhesin, as demonstrated by reduced adherence of
acp
knockout (MC58 ΔACP) meningococci to human cells
in vitro
and the direct surface binding of rACP and by the ability of anti-rACP sera to inhibit adherence of wild-type bacteria. ACP also mediated the invasion of noncapsular meningococci into human epithelial cells, but it was not a particularly impressive invasin, as the internalized bacterial numbers were low. In summary, the newly identified ACP protein is an adhesin that induces cross-strain bactericidal activity and is therefore an attractive target antigen for incorporation into the next generation of serogroup B meningococcal vaccines.

IMPORTANCE
Infections caused by
Neisseria meningitidis
serogroup B are still significant causes of mortality and morbidity worldwide, and broadly protective vaccines of defined antigen composition are not yet licensed. Here, we describe the properties of the adhesin complex protein (ACP), which we demonstrate is a newly recognized molecule that is highly conserved and expressed to similar levels in meningococci and facilitates meningococcal interactions with human cells. We also report that a recombinant ACP protein vaccine induces murine antibodies that significantly kill meningococci expressing different ACP. Taken together, these properties demonstrate that ACP merits serious consideration as a component of a broadly protective vaccine against serogroup B meningococci.
Exposure to benzene and childhood leukaemia: a pilot case-control study
Authors: Lagorio Susanna , Ferrante Daniela , Ranucci Alessandra , Negri Sara , Sacco Paolo , Rondelli Roberto , Cannizzaro Santina , Torregrossa Maria Valeria , Cocco Pierluigi , Forastiere Francesco , Miligi Lucia , Bisanti Luigi , Magnani Corrado 
Published: February 2013

ObjectivesMain purposeTo evaluate the feasibility of a measurement-based assessment of benzene exposure in case-control studies of paediatric cancer;Additional aimsTo identify the sources of exposure variability; to assess the performance of two benzene biomarkers; to verify the occurrence of participation bias; to check whether exposures to benzene and to 50 Hz magnetic fields were correlated, and might exert reciprocal confounding effects.DesignPilot case-control study of childhood leukaemia and exposure to benzene assessed by repeated seasonal weekly measurements in breathing zone air samples and outside the children's dwellings, with concurrent determinations of cotinine,t-t-muconic acid (MA) and sulfo-phenylmercapturic acid (S-PMA) in urine.Participants108 cases and 194 controls were eligible for inclusion.ResultsFull-participation was obtained from 46 cases and 60 controls, with low dropout rates before four repeats (11% and 17%); an additional 23 cases and 80 controls allowed the collection of outdoor air samples only. The average benzene concentration in personal and outdoor air samples was 3 μg/m3(SD 1.45) and 2.7 μg/m3(SD 1.41), respectively. Personal exposure was strongly influenced by outdoor benzene concentrations, higher in the cold seasons than in warm seasons, and not affected by gender, age, area of residence or caseness. Urinary excretion of S-PMA and personal benzene exposure were well correlated. Outdoor benzene levels were lower among participant controls compared with non-participants, but did not differ between participant and non-participant cases; the direction of the bias was found to depend on the cut-point chosen to distinguish exposed and unexposed. Exposures to benzene and extremely low-frequency magnetic fields were positively correlated.ConclusionsRepeated individual measurements are needed to account for the seasonal variability in benzene exposure, and they have the additional advantage of increasing the study power. Measurement-based assessment of benzene exposure in studies of childhood leukaemia appears feasible, although it is financially and logistically demanding.
Reproducibility of tender point examination in chronic low back pain patients as measured by intrarater and inter-rater reliability and agreement: a validation study
Authors: Jensen Ole Kudsk , Callesen Jacob , Nielsen Merete Graakjaer , Ellingsen Torkell 
Published: February 2013

ObjectivesTo evaluate the reliability and agreement of digital tender point (TP) examination in chronic low back pain (LBP) patients.DesignCross-sectional study.SettingsHospital-based validation study.ParticipantsAmong sick-listed LBP patients referred from general practitioners for low back examination and return-to-work intervention, 43 and 39 patients, respectively (18 women, 46%) entered and completed the study.Main outcome measuresThe reliability was estimated by the intraclass correlation coefficient (ICC), and agreement was calculated for up to ±3 TPs. Furthermore, the smallest detectable difference was calculated.ResultsTP examination was performed twice by two consultants in rheumatology and rehabilitation at 20 min intervals and repeated 1 week later. Intrarater reliability in the more and less experienced rater was ICC 0.84 (95% CI 0.69 to 0.98) and 0.72 (95% CI 0.49 to 0.95), respectively. The figures for inter-rater reliability were intermediate between these figures. In more than 70% of the cases, the raters agreed within ±3 TPs in both men and women and between test days. The smallest detectable difference between raters was 5, and for the more and less experienced rater it was 4 and 6 TPs, respectively.ConclusionsThe reliability of digital TP examination ranged from acceptable to excellent, and agreement was good in both men and women. The smallest detectable differences varied from 4 to 6 TPs. Thus, TP examination in our hands was a reliable but not precise instrument. Digital TP examination may be useful in daily clinical practice, but regular use and training sessions are required to secure quality of testing.
Developing a smartphone ‘app’ for public health research: the example of measuring observed smoking in vehicles
Authors: Patel Vimal , Nowostawski Mariusz , Thomson George , Wilson Nick , Medlin Hamish 
Published: February 2013

BackgroundWe have developed manual methods to gather data on the point prevalence of observed smoking in road vehicles. To enable the widespread international collection of such data, we aimed to develop a smartphone application (app) for this work.MethodsWe developed specifications for an app that described the: (1) variables that could be collected; (2) transfer of data to an online repository; (3) user interface (including visual schematics) and (4) processes to ensure the data authenticity from distant observers. The app functionality was trialled in roadside situations and the app was made publicly available.ResultsThe smartphone app and its accompanying website were developed, tested and released over a period of 6 months. Users (n=18) who have registered themselves (and who met authentication criteria), have reported no significant problems with this application to date (observing 20 535 vehicles as of 5 July 2012). The framework, methodology and source code for this project are now freely available online and can be easily adapted for other research purposes. The prevalence of smoking in vehicles was observed in: Poland 2.7% (95% CI 2.3% to 3.1%); Australia 1.0% (95% CI 0.7% to 1.3%); New Zealand 2.9% (95% CI 2.6% to 3.2%)—similar to results using preapp methods in 2011 (3.2%, 95% CI 3.1% to 3.3%).ConclusionsThis project indicates that it can be practical and feasible for health researchers to work together with information science researchers and software developers to create smartphone apps for field research in public health. Such apps may be used to collect observational data more widely, effectively and easily than through traditional (non-electronic) methods.
Differences on the effect of heat waves on mortality by sociodemographic and urban landscape characteristics
Authors: Xu Yihan , Dadvand Payam , Barrera-Gómez Jose , Sartini Claudio , Marí-Dell'Olmo Marc , Borrell Carme , Medina-Ramón Mercè , Sunyer Jordi , Basagaña Xavier 
Published: February 2013

BackgroundMortality increases during heat waves have been reported worldwide. The magnitude of these increases can vary within regions according to sociodemographic and urban landscape characteristics. The objectives of this study were to explore this variation and its determinants, and to identify the most heat-vulnerable areas by mapping heat vulnerability.MethodsWe conducted a time-stratified case-crossover analysis using daily mortality in the Barcelona metropolitan area during the warm seasons of 1999–2006. Temperature data on the date of death were assigned to each individual, which were assigned to their census tract of residence. Eight census tract-level variables on socioeconomic or built environment characteristics were obtained from the census. Residence surrounding greenness was obtained from satellite data. The relative risk (RR) of mortality after three consecutive hot days (defined as those exceeding the 95th percentile of maximum temperature) was calculated via conditional logistic regression. Effect modification was examined by including interaction terms.ResultsAnalyses were based on 52 806 deaths. The effect of three consecutive hot days was a 30% increase in all-cause mortality (RR=1.30, 95% CI 1.24 to 1.38). Heterogeneity of this effect was observed across census tracts. The effect of heat on mortality was higher in the census tracts with a large percentage of old buildings (RR=1.21, 95% CI 1.00 to 1.46), manual workers (RR=1.25, 95% CI 0.96 to 1.64) and residents perceiving little surrounding greenness (RR=1.29, 95% CI 1.01 to 1.65). After three consecutive hot days, mortality doubled in the most heat-vulnerable census tracts.ConclusionsSociodemographic and urban landscape characteristics are associated to mortality risk during heat waves and are useful to build heat vulnerability maps.
Bezoar stones, magic, science and art
Authors: Barroso Maria Do Sameiro 
Published: February 2013

Abstract
Bezoars were introduced into Western medicine by Arabian doctors during the twelfth century. They were used as antidotes to arsenic, the poison used most commonly in European courts. The use of bezoars was widespread during the sixteenth century, and their value was ten times more than their weight in gold. These were rare and expensive items and many kings owned one or more specimens, some of which were mounted as pieces of jewelry. Sixteenth and seventeenth century physicians wrote extensively about them, describing their properties and use. ‘Oriental bezoars’ (mostly from Asian porcupines) were introduced at this time.

Difficulty in obtaining bezoars led to the production of numerous dangerous counterfeits containing highly toxic substances including cinnabar, quicksilver and antimony. Possibly for these reasons, their use declined at the end of the seventeenth century and from 1800 onwards, they were no longer used. In strict mineralogical terms, bezoars are not actually stones. However, the Flemish mineralogist and physician, Anselm Boetius de Boodt (1550–1632) included them in his work
Gemmarum et Lapidum Historia (History of Gems and Stones
,
1609
) and their study is an important chapter in the history of toxicology.
Methylation of the hTERT Promoter: A Novel Cancer Biomarker for Leptomeningeal Metastasis Detection in Cerebrospinal Fluids
Authors: Bougel Stéphanie , Lhermitte Benoit , Gallagher Gabrielle , de Flaugergues Jeanne-Chantal , Janzer Robert C. , Benhattar Jean 
Published: February 2013

Abstract
Purpose: The diagnosis of leptomeningeal metastases is usually confirmed by the finding of malignant cells by cytologic examination in the cerebrospinal fluid (CSF). More sensitive and specific cancer biomarkers may improve the detection of tumor cells in the CSF. Promoter methylation of the human telomerase reverse transcriptase (hTERT) gene characterizes most cancer cells. The aim of this study was to develop a sensitive method to detect hTERT methylation and to explore its use as a cancer biomarker in CSF.
Experimental Design: In 77 CSF specimens from 67 patients, hTERT promoter methylation was evaluated using real-time methylation-sensitive high-resolution melting (MS-HRM) and real-time TaqMan PCR and MS-HRM in a single-tube assay.
Results: Real-time MS-HRM assay was able to detect down to 1% hTERT-methylated DNA in a background of unmethylated DNA. PCR products were obtained from 90% (69/77) of CSF samples. No false positive hTERT was detected in the 21 non-neoplastic control cases, given to the method a specificity of 100%. The sensitivity of the real-time MS-HRM compared with the cytologic gold standard analysis was of 92% (11/12). Twenty-six CSFs from 22 patients with an hTERT-methylated primary tumor showed cytologic results suspicious for malignancy; in 17 (65%) of them, a diagnosis of leptomeningeal metastases could be confirmed by the hTERT methylation test.
Conclusion: The hTERT real-time MS-HRM approach is fast, specific, sensitive, and could therefore become a valuable tool for diagnosis of leptomeningeal metastases as an adjunct to the traditional examination of CSF. Clin Cancer Res; 19(8); 2216–23. ©2013 AACR.
Cetuximab-Activated Natural Killer and Dendritic Cells Collaborate to Trigger Tumor Antigen–Specific T-cell Immunity in Head and Neck Cancer Patients
Authors: Srivastava Raghvendra M. , Lee Steve C. , Andrade Filho Pedro A. , Lord Christopher A. , Jie Hyun-Bae , Davidson H. Carter , López-Albaitero Andrés , Gibson Sandra P. , Gooding William E. , Ferrone Soldano , Ferris Robert L. 
Published: February 2013

Abstract
Purpose: Tumor antigen–specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)–mediated cytotoxicity. However, the role of CD8+ CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging.
Experimental Design: FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)–specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry.
Results: FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR853–861–specific CD8+ T cells were found in cetuximab-treated patients with HNC (P &lt; 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR+ tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ–dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (TH1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell–induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3.
Conclusion: Cetuximab-activated NK cells promote DC maturation and CD8+ T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through “NK–DC cross-talk.” FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK–DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response. Clin Cancer Res; 19(7); 1858–72. ©2013 AACR.
Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy
Authors: Radhakrishnan Prakash , Bryant Vashti C. , Blowers Elizabeth C. , Rajule Rajkumar N. , Gautam Nagsen , Anwar Muhammad M. , Mohr Ashley M. , Grandgenett Paul M. , Bunt Stephanie K. , Arnst Jamie L. , Lele Subodh M. , Alnouti Yazen , Hollingsworth Michael A. , Natarajan Amarnath 
Published: February 2013

Abstract
Purpose: The presence of TNF-α in approximately 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. Inhibitor of IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways.
Experimental Design: Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197 on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth, and metastases in vivo.
Results: 13-197 inhibited the kinase activity of IKKβ in vitro and TNF-α–mediated NF-κB transcription in cells with low-μmol/L potency. 13-197 inhibited the phosphorylation of IκBα, S6K, and eIF4EBP, induced G1 arrest, and downregulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from lipopolysaccharide (LPS)-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity.
Conclusion: These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype a viable cancer therapeutic. Clin Cancer Res; 19(8); 2025–35. ©2013 AACR.
Clinical Correlates of Promoter Hypermethylation of Four Target Genes in Head and Neck Cancer: A Cooperative Group Correlative Study
Authors: Roh Jong-Lyel , Wang Xin Victoria , Manola Judith , Sidransky David , Forastiere Arlene A. , Koch Wayne M. 
Published: February 2013

AbstractPurpose: Promoter hypermethylation is a well-documented mechanism for tumor-specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16INK4a in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes.Experimental Design: Methylation was assessed by quantitative methylation-specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable. Clinical data including demographics, stage, risk factor exposure, treatment, and outcome were collected by ECOG and RTOG. Methylation status was also correlated with mutation of TP53 (previously reported) and human papilloma virus status.Results: Methylation results were available for 368 cases, 353 of which also have p53 mutation status. At least one methylation event was present in all tumors. In multivariate analysis of the entire cohort, methylation of p16 was associated with decreased survival (HR = 1.008; P = 0.045). However, in tumors with disruptive TP53 mutation (poor prognostic group), the additional presence of methylation of p16 was protective (P = 0.019 considering p16 methylation as a continuous variable).Conclusion: Methylation of tumor-related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events. Clin Cancer Res; 19(9); 2528–40. ©2013 AACR.
CD44 and OTP Are Strong Prognostic Markers for Pulmonary Carcinoids
Authors: Swarts Dorian R.A. , Henfling Mieke E.R. , Van Neste Leander , van Suylen Robert-Jan , Dingemans Anne-Marie C. , Dinjens Winand N.M. , Haesevoets Annick , Rudelius Martina , Thunnissen Erik , Volante Marco , Van Criekinge Wim , van Engeland Manon , Ramaekers Frans C.S. , Speel Ernst-Jan M. 
Published: February 2013

Abstract
Purpose: Pulmonary carcinoids are well-differentiated neuroendocrine tumors showing usually a favorable prognosis. However, there is a risk for late recurrence and/or distant metastasis. Because histologic classification in typical and atypical carcinoids is difficult and its reliability to predict disease outcome varies, we evaluated three genes as potential prognostic markers, that is, orthopedia homeobox (OTP), CD44, and rearranged during transfection (RET).
Experimental Design: These genes were analyzed in 56 frozen carcinoids by quantitative real-time PCR (qRT-PCR). RET was further studied by methylation and mutation analysis. Immunohistochemistry for CD44 and OTP protein expression was conducted on 292 carcinoids.
Results: Low mRNA expression levels of CD44 (P = 1.8e−5) and OTP (P = 0.00054), and high levels of RET (P = 0.025), were strongly associated with a low 20-year survival of carcinoid patients. High RET expression was not related to promoter hypomethylation or gene mutations. A direct link between gene expression and protein levels was confirmed for CD44 and OTP but not for RET. Within all carcinoids as well as atypical carcinoids, absence of CD44 protein was significantly associated with low 20-year survival (P = 0.00014 and 0.00013, respectively). The absence of nuclear OTP followed by complete loss of expression was also significantly associated with unfavorable disease outcome in all carcinoids (P = 5.2−6). Multivariate analyses revealed that age at diagnosis, histopathology, stage, and cytoplasmic OTP immunoreactivity were independent predictors of prognosis.
Conclusions: Our study indicates that CD44 and OTP are strong indicators of poor outcome. We therefore argue for implementation of these markers in routine diagnostics in addition to histopathology to improve subclassification of pulmonary carcinoids into prognostically relevant categories. Clin Cancer Res; 19(8); 2197–207. ©2013 AACR.