bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor necrosis factor‐α and interleukin‐1β expression pathway induced by Streptococcus mutans in macrophage cell line RAW 264.7
Authors: Kim J.S. , Kim K.D. , Na H.S. , Jeong S.Y. , Park H.R. , Kim S. , Chung J. 
Published: February 2012

SummaryStreptococcus mutans, a major etiological agent of dental caries, frequently causes systemic disease, such as subacute bacterial endocarditis, if it enters the bloodstream. In this study, the production pathways of the proinflammatory cytokines, tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), induced by S. mutans in mouse macrophage were examined using a quantitative real‐time polymerase chain reaction and an enzyme‐linked immunosorbent assay. The S. mutans stimulated the expression of TNF‐α and IL‐1β mRNA at a multiplicity of infection of 1 : 100, which increased at 2 and 4 h, respectively, to 24 h. It also induced the production of high levels of the TNF‐α and IL‐1β proteins, which increased at 2 h and reached a peak at 4 and 24 h, respectively. Nuclear factor‐κB (NF‐κB) was activated and reached a maximum level 30 min after the S. mutans treatment. The expression of TNF‐α and IL‐1β mRNA and protein was suppressed by the treatment with pyrrolidine dithiocarbamate, an NF‐κB inhibitor. The S. mutans‐induced TNF‐α expression was suppressed by the presence of SB203580, a p38 mitogen‐activated protein (MAP) kinase inhibitor, or SP600125, a Jun N‐terminal kinase (JNK) MAP kinase inhibitor. On the other hand, IL‐1β expression was inhibited by extracellular signal‐regulated kinase (ERK)/p38/JNK MAP kinase inhibitor pretreatment. In addition, TNF‐α production was suppressed more in the Toll‐like receptor 2−/− (TLR2−/−) macrophages than in the TLR4−/− macrophages, whereas IL‐1β production was suppressed more in the TLR4−/− macrophages than in the TLR2−/− macrophages. These results show that S. mutans stimulates the production of TNF‐α and IL‐1β in the mouse macrophage cell line, RAW 264.7, by activating ERK/p38/JNK, and NF‐κB through TLR2 and TLR4, respectively.
Energy expenditure and insulin sensitivity evaluation in obese children affected by hepatosteatosis
Authors: Fintini D. , Pietrobattista A. , Morino G. , Cafiero G. , Calzolari A. , Turchetta A. , Brufani C. , Alisi A. , Giordano U. , Nobili V. 
Published: February 2012

SummaryObjectivesThe aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non‐alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA).MethodsForty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age‐ and pubertal stage‐matched, children were included.ResultsSedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg–1 d–1) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB.ConclusionsRegular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.
Association of Major Histocompatibility Complex Class 1 Chain-Related Gene A Dimorphism with Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Algerian Population
Authors: Raache Rachida , Belanteur Khadidja , Amroun Habiba , Benyahia Amel , Heniche Amel , Azzouz Malha , Mimouni Safia , Gervais Thibaud , Latinne Dominique , Boudiba Aissa , Attal Nabila , Abbadi Mohamed Cherif 
Published: February 2012

ABSTRACT
Major histocompatibility complex class I chain-related gene A (MICA-129) dimorphism was investigated in 73 autoimmune diabetes patients (type 1 diabetes and latent autoimmune diabetes in adults) and 75 controls from Algeria. Only MICA-129 Val allele and MICA-129 Val/Val genotype frequencies were higher among patients than in the control group. Statistical analysis of the estimated extended HLA-DR-DQ-MICA haplotypes shown that individual effects of MICA alleles on HLA-DQ2-DR3-MICA-129 Val/Val and HLA-DQ8-DR4-MICA-129 Val/Val haplotypes were significantly higher in patients than in the control groups. These preliminary data might suggest a relevant role of MICA-129 Val/Val single nucleotide polymorphism (weak/weak binders of NKG2D receptor) in the pathogenesis of T1D and LADA.
Rapid Detection of Ampicillin Resistance in Escherichia coli by Quantitative Mass Spectrometry
Authors: Grundt A. , Findeisen P. , Miethke T. , Jäger E. , Ahmad-Nejad P. , Neumaier M. 
Published: February 2012

ABSTRACT

Early targeted antimicrobial therapy helps decrease costs and prevents the spread of antimicrobial resistance, including in
Escherichia coli
, the most frequent Gram-negative bacterium that causes sepsis. Therefore, rapid susceptibility testing represents the major prerequisite for knowledge-based successful antimicrobial treatment. To accelerate testing for antibiotic susceptibility, we have developed a new mass spectrometry-based assay for antibiotic susceptibility testing (MAAST). For proof of principle, we present an ampicillin susceptibility test for
E. coli
with a turnaround time of 90 min upon growth detection.
Emergence of a
mutL
Mutation Causing Multilocus Sequence Typing–Pulsed-Field Gel Electrophoresis Discrepancy among Pseudomonas aeruginosa Isolates from a Cystic Fibrosis Patient
Authors: García-Castillo María , Máiz Luis , Morosini María-Isabel , Rodríguez-Baños Mercedes , Suarez Lucrecia , Fernández-Olmos Ana , Baquero Fernando , Cantón Rafael , del Campo Rosa 
Published: February 2012

ABSTRACT

A multilocus sequence type (MLST) shift (from ST242 to ST996) was detected in
Pseudomonas aeruginosa
isolates with a uniform pulsed-field gel electrophoresis (PFGE) pattern obtained from a chronically colonized patient. MLST mutational change involved the
mutL
gene with the consequent emergence of a hypermutable phenotype. This observation challenges the required neutrality of
mutL
as an appropriate marker in MLST and alerts researchers to the limitations of MLST-only-based population studies in chronic infections under constant antibiotic selective pressure.
Superior Induction of T Cell Responses to Conserved HIV-1 Regions by Electroporated Alphavirus Replicon DNA Compared to That with Conventional Plasmid DNA Vaccine
Authors: Knudsen Maria L. , Mbewe-Mvula Alice , Rosario Maximillian , Johansson Daniel X. , Kakoulidou Maria , Bridgeman Anne , Reyes-Sandoval Arturo , Nicosia Alfredo , Ljungberg Karl , Hanke Tomáš , Liljeström Peter 
Published: February 2012

ABSTRACT

Vaccination using “naked” DNA is a highly attractive strategy for induction of pathogen-specific immune responses; however, it has been only weakly immunogenic in humans. Previously, we constructed DNA-launched Semliki Forest virus replicons (DREP), which stimulate pattern recognition receptors and induce augmented immune responses. Also,
in vivo
electroporation was shown to enhance immune responses induced by conventional DNA vaccines. Here, we combine these two approaches and show that
in vivo
electroporation increases CD8
+
T cell responses induced by DREP and consequently decreases the DNA dose required to induce a response. The vaccines used in this study encode the multiclade HIV-1 T cell immunogen HIVconsv, which is currently being evaluated in clinical trials. Using intradermal delivery followed by electroporation, the DREP.HIVconsv DNA dose could be reduced to as low as 3.2 ng to elicit frequencies of HIV-1-specific CD8
+
T cells comparable to those induced by 1 μg of a conventional pTH.HIVconsv DNA vaccine, representing a 625-fold molar reduction in dose. Responses induced by both DREP.HIVconsv and pTH.HIVconsv were further increased by heterologous vaccine boosts employing modified vaccinia virus Ankara MVA.HIVconsv and attenuated chimpanzee adenovirus ChAdV63.HIVconsv. Using the same HIVconsv vaccines, the mouse observations were supported by an at least 20-fold-lower dose of DNA vaccine in rhesus macaques. These data point toward a strategy for overcoming the low immunogenicity of DNA vaccines in humans and strongly support further development of the DREP vaccine platform for clinical evaluation.
The Latent Membrane Protein 1 (LMP1) Oncogene of Epstein-Barr Virus Can Simultaneously Induce and Inhibit Apoptosis in B Cells
Authors: Pratt Zachary L. , Zhang Jingzhu , Sugden Bill 
Published: February 2012

ABSTRACTThe latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) regulates its own expression and the expression of human genes via its two functional moieties; the transmembrane domains of LMP1 are required to regulate its expression via the unfolded protein response (UPR) and autophagy in B cells, and the carboxy-terminal domain of LMP1 activates cellular signaling pathways that affect cellular proliferation and survival. An apparent anomaly in the complex regulation of the UPR and autophagy by LMP1 is that the induction of either pathway can lead to cellular death, yet neither EBV-infected B cells nor B cells expressing only LMP1 die. Thus, we sought to understand how B cells that express LMP1 survive. The transmembrane domains of LMP1 activated apoptosis in B cells, the apoptosis required the UPR, and the carboxy-terminal domain of LMP1 blocked this apoptosis. The expression of the mRNA ofBcl2a1, encoding an antiapoptotic homolog of BCL2, correlated directly with the expression of LMP1 in EBV-positive B-cell strains, and its expression inhibited the apoptosis induced by the transmembrane domains of LMP1. These findings illustrate how the carboxy-terminal domain of LMP1 supports survival of B cells in the presence of the deleterious effects of the complex regulation of this viral oncogene.
Hepatitis C Virus Induces CD81 and Claudin-1 Endocytosis
Authors: Farquhar Michelle J. , Hu Ke , Harris Helen J. , Davis Christopher , Brimacombe Claire L. , Fletcher Sarah J. , Baumert Thomas F. , Rappoport Joshua Z. , Balfe Peter , McKeating Jane A. 
Published: February 2012

ABSTRACT
Hepatitis C virus (HCV) leads to progressive liver disease and hepatocellular carcinoma. Current treatments are only partially effective, and new therapies targeting viral and host pathways are required. Virus entry into a host cell provides a conserved target for therapeutic intervention. Tetraspanin CD81, scavenger receptor class B member I, and the tight-junction proteins claudin-1 and occludin have been identified as essential entry receptors. Limited information is available on the role of receptor trafficking in HCV entry. We demonstrate here that anti-CD81 antibodies inhibit HCV infection at late times after virus internalization, suggesting a role for intracellular CD81 in HCV infection. Several tetraspanins have been reported to internalize via motifs in their C-terminal cytoplasmic domains; however, CD81 lacks such motifs, leading several laboratories to suggest a limited role for CD81 endocytosis in HCV entry. We demonstrate CD81 internalization via a clathrin- and dynamin-dependent process, independent of its cytoplasmic domain, suggesting a role for associated partner proteins in regulating CD81 trafficking. Live cell imaging demonstrates CD81 and claudin-1 coendocytosis and fusion with Rab5 expressing endosomes, supporting a role for this receptor complex in HCV internalization. Receptor-specific antibodies and HCV particles increase CD81 and claudin-1 endocytosis, supporting a model wherein HCV stimulates receptor trafficking to promote particle internalization.
Restoration of TLR3-Activated Myeloid Dendritic Cell Activity Leads to Improved Natural Killer Cell Function in Chronic Hepatitis B Virus Infection
Authors: Tjwa Eric T. T. L. , van Oord Gertine W. , Biesta Paula J. , Boonstra Andre , Janssen Harry L. A. , Woltman Andrea M. 
Published: February 2012

ABSTRACT

There is increasing evidence that the function of NK cells in patients with chronic hepatitis B (CHB) infection is impaired. The underlying mechanism for the impaired NK cell function is still unknown. Since myeloid dendritic cells (mDC) are potent inducers of NK cells, we investigated the functional interaction of mDC and NK cells in CHB and the influence of antiviral therapy. Blood BDCA1
+
mDC and NK cells were isolated from 16 healthy controls or 39 CHB patients at baseline and during 6 months of antiviral therapy. After activation of mDC with poly(I · C) and gamma interferon (IFN-γ), mDC were cocultured with NK cells. Phenotype and function were analyzed in detail by flow cytometry and enzyme-linked immunosorbent assay. Our findings demonstrate that on poly(I · C)/IFN-γ-stimulated mDC from CHB patients, the expression of costimulatory molecules was enhanced, while cytokine production was reduced. In cocultures of poly(I · C)/IFN-γ-stimulated mDC and NK cells obtained from CHB patients, reduced mDC-induced NK cell activation (i.e., CD69 expression) and IFN-γ production compared to those in healthy individuals was observed. Antiviral therapy normalized mDC activity, since decreased expression of CD80 and CD86 on DC and of HLA-E on NK cells was observed, while poly(I · C)/IFN-γ-induced cytokine production by mDC was enhanced. In parallel, successful antiviral therapy resulted in improved mDC-induced NK cell activation and IFN-γ production. These data demonstrate that CHB patients display a diminished functional interaction between poly(I · C)/IFN-γ activated mDC and NK cells due to impaired mDC function, which can be partially restored by antiviral therapy. Enhancing this reciprocal interaction could reinforce the innate and thus the adaptive T cell response, and this may be an important step in achieving effective antiviral immunity.
A qualitative study of manufacturers' submissions to the UK NICE single technology appraisal process
Authors: Kaltenthaler Eva C , Dickson Rumona , Boland Angela , Carroll Christopher , Fitzgerald Patrick , Papaioannou Diana , Akehurst Ronald 
Published: February 2012

ObjectivesAs part of the National Institute for Health and Clinical Excellence (NICE) Single Technology Appraisal (STA) process, manufacturers present submissions outlining the clinical and cost-effectiveness of new technologies. These submissions are critically appraised by Evidence Review Groups (ERGs), who produce a report, which forms part of the evidence considered by the NICE Appraisal Committees. The purpose of this research was first to identify common issues and concerns identified by the ERGs in their analyses of manufacturers' submissions (MS). The aim was then to use these as a basis to develop feedback for manufacturers.DesignA qualitative study using a content analysis approach to examine two sources of evidence, the first 30 ERG reports and 21 clarification letters associated with these STAs.SettingUK HTA programme.Primary and secondary outcome measuresCommon issues and concerns in MS.ResultsThere were positive comments regarding the quality of the MS, many of which were clearly written. The majority, however, were generally of poor quality and issues and concerns identified across the ERG reports and clarification letters included: criticisms related to the data being used especially data employed in the cost-effectiveness model, failure to perform a necessary analysis and poor reporting of processes used in the MS. Aspects of the decision problem were also often poorly or inadequately addressed by manufacturers. The majority of points raised for clarification related to the economic data analysis. Internal inconsistencies between the clinical and economic sections of the submission were frequently highlighted. These were used as the basis for the development of 12 suggestions for manufacturers.ConclusionsMuch can be done to improve the quality of MS in the NICE STA process. Suggestions include the need for clear and transparent reporting of methods and analyses.
Clustering of substance use and sexual risk behaviour in adolescence: analysis of two cohort studies
Authors: Jackson Caroline , Sweeting Helen , Haw Sally 
Published: February 2012

ObjectivesThe authors aimed to examine whether changes in health risk behaviour rates alter the relationships between behaviours during adolescence, by comparing clustering of risk behaviours at different time points.DesignComparison of two cohort studies, the Twenty-07 Study (‘earlier cohort’, surveyed in 1987 and 1990) and the 11-16/16+ Study (‘later cohort’, surveyed 1999 and 2003).SettingCentral Clydeside Conurbation around Glasgow City.ParticipantsYoung people who participated in the Twenty-07 and 11-16/16+ studies at ages 15 and 18–19.Primary and secondary outcomes measuresThe authors analysed data on risk behaviours in both early adolescence (started smoking prior to age 14, monthly drinking and ever used illicit drugs at age 15 and sexual intercourse prior to age 16) and late adolescence (age 18–19, current smoking, excessive drinking, ever used illicit drugs and multiple sexual partners) by gender and social class.ResultsDrinking, illicit drug use and risky sexual behaviour (but not smoking) increased between the earlier and later cohort, especially among girls. The authors found strong associations between substance use and sexual risk behaviour during early and late adolescence, with few differences between cohorts, or by gender or social class. Adjusted ORs for associations between each substance and sexual risk behaviour were around 2.00. The only significant between-cohort difference was a stronger association between female early adolescent smoking and early sexual initiation in the later cohort. Also, relationships between illicit drug use and both early sexual initiation and multiple sexual partners in late adolescence were significantly stronger among girls than boys in the later cohort.ConclusionsDespite changes in rates, relationships between adolescent risk behaviours remain strong, irrespective of gender and social class. This indicates a need for improved risk behaviour prevention in young people, perhaps through a holistic approach, that addresses the broad shared determinants of various risk behaviours.
Intracellular Tumor-Associated Antigens Represent Effective Targets for Passive Immunotherapy
Authors: Noguchi Takuro , Kato Takuma , Wang Linan , Maeda Yuka , Ikeda Hiroaki , Sato Eiichi , Knuth Alexander , Gnjatic Sacha , Ritter Gerd , Sakaguchi Shimon , Old Lloyd J. , Shiku Hiroshi , Nishikawa Hiroyoshi 
Published: February 2012

AbstractMonoclonal antibody (mAb) therapy against tumor antigens expressed on the tumor surface is associated with clinical benefit. However, many tumor antigens are intracellular molecules that generally would not be considered suitable targets for mAb therapy. In this study, we provide evidence challenging this view through an investigation of the efficacy of mAb directed against NY-ESO-1, a widely expressed immunogen in human tumors that is expressed intracellularly rather than on the surface of cells. On their own, NY-ESO-1 mAb could neither augment antigen-specific CD8+ T-cell induction nor cause tumor eradication. To facilitate mAb access to intracellular target molecules, we combined anti-NY-ESO-1 mAb with anticancer drugs to accentuate the release of intracellular NY-ESO-1 from dying tumor cells. Strikingly, combination therapy induced a strong antitumor effect that was accompanied by the development of NY-ESO-1–specific effector/memory CD8+ T cells that were not elicited by single treatments alone. The combinatorial effect was also associated with upregulation of maturation markers on dendritic cells, consistent with the organization of an effective antitumor T-cell response. Administration of Fc-depleted F(ab) mAb or combination treatment in Fcγ receptor–deficient host mice abolished the therapeutic effect. Together, our findings show that intracellular tumor antigens can be captured by mAbs and engaged in an efficient induction of CD8+ T-cell responses, greatly expanding the possible use of mAb for passive cancer immunotherapy. Cancer Res; 72(7); 1672–82. ©2012 AACR.
Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor–Induced Tyrosine Kinase Inhibitor Resistance in EGFR Mutant Lung Cancer
Authors: Wang Wei , Li Qi , Takeuchi Shinji , Yamada Tadaaki , Koizumi Hitomi , Nakamura Takahiro , Matsumoto Kunio , Mukaida Naofumi , Nishioka Yasuhiko , Sone Saburo , Nakagawa Takayuki , Uenaka Toshimitsu , Yano Seiji 
Published: February 2012

Abstract
Purpose: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI–resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs.
Experimental Design: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed.
Results: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.
Conclusions: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs. Clin Cancer Res; 18(6); 1663–71. ©2012 AACR.
Statistical Issues and Recommendations for Noninferiority Trials in Oncology: A Systematic Review
Authors: Tanaka Shiro , Kinjo Yousuke , Kataoka Yoshiki , Yoshimura Kenichi , Teramukai Satoshi 
Published: February 2012

Abstract
To provide an overview of noninferiority trials in oncology with a special emphasis on methodologic issues, we conducted a systematic review of randomized trials assessing noninferiority of antineoplastic treatments. We identified 72 articles, of which 65 were randomized phase III trials with a single control arm, 3 were factorial phase III trials, and 4 were randomized phase II trials. Forty-six were trials in lung, colorectal, or breast cancer. The quality of reporting was improved chronologically (P &lt; 0.01); the major deficiencies were claims of noninferiority when the results did not meet statistical criteria for noninferiority (7 articles) or when the noninferiority margin was not prespecified (5 articles). Four trials (6%) presented plans for switching from superiority to noninferiority. The analysis populations were intent to treat (ITT) in 52, per-protocol set (PPS) in 6, and both ITT and PPS in 11 trials. Noninferiority margins were set in 68 trials (94%); 1 trial used both of the conventional and effect retention methods, 17 trials used the conventional method, 5 trials used the effect retention method, and in 45 trials, the method was not specified. Some trials used margins that possibly were larger than the assured effects of the active controls. No trials explicitly took into consideration uncertainty in historical data. Two trials (3%) specified 2 values of margins. Our findings highlight critical deficiencies in design and reporting of noninferiority trials. Seven practical recommendations are presented. Clin Cancer Res; 18(7); 1837–47. ©2012 AACR.