bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and Immunogenicity of a Novel Synthetic Antigen Based on the Ligand Domain of the Plasmodium vivax Duffy Binding Protein
Authors: Ntumngia Francis B. , Adams John H. 
Published: November 2011

ABSTRACT

The Duffy binding protein is considered a leading vaccine candidate against asexual blood-stage
Plasmodium vivax
. The interaction of
P. vivax
merozoites with human reticulocytes through Duffy binding protein (DBP) and its cognate receptor is vital for parasite infection. The ligand domain of DBP (DBPII) is polymorphic, showing a diversity characteristic of selective immune pressure that tends to compromise vaccine efficacy associated with strain-specific immunity. A previous study resolved that a polymorphic region of DBPII was a dominant B-cell epitope target of human inhibitory anti-DBP antibodies, which we refer to as the DEK epitope for the amino acids in the SalI allele. We hypothesized that the polymorphic residues, which are not functionally important for erythrocyte binding but flank the receptor binding motif of DBPII, comprise variant epitopes that tend to divert the immune response away from more conserved epitopes. In this study, we designed, expressed, and evaluated the immunogenicity of a novel artificial DBPII allele, termed DEKnull, having nonpolar amino acids in the naturally occurring polymorphic charged residues of the DEK epitope. The DEKnull antigen retained erythrocyte-binding activity and elicited antibodies to shared epitopes of SalI DBPII from which it was derived. Our results confirmed that removal of the dominant variant epitope in the DEKnull vaccine lowered immunogenicity of DBPII, but inhibitory anti-DBPII antibodies were elicited against shared neutralizing epitopes on SalI. Focusing immune responses toward more conserved DBP epitopes may avoid development of a strain-specific immunity and enhance functional inhibition against broader range of DBPII variants.
SRE1
Regulates Iron-Dependent and -Independent Pathways in the Fungal Pathogen Histoplasma capsulatum
Authors: Hwang Lena H. , Seth Erica , Gilmore Sarah A. , Sil Anita 
Published: November 2011

ABSTRACT

Regulation of iron acquisition genes is critical for microbial survival under both iron-limiting conditions (to acquire essential iron) and iron-replete conditions (to limit iron toxicity). In fungi, iron acquisition genes are repressed under iron-replete conditions by a conserved GATA transcriptional regulator. Here we investigate the role of this transcription factor, Sre1, in the cellular responses of the fungal pathogen
Histoplasma capsulatum
to iron. We showed that cells in which
SRE1
levels were diminished by RNA interference were unable to repress siderophore biosynthesis and utilization genes in the presence of abundant iron and thus produced siderophores even under iron-replete conditions. Mutation of a GATA-containing consensus site found in the promoters of these genes also resulted in inappropriate gene expression under iron-replete conditions. Microarray analysis comparing control and
SRE1
-depleted strains under conditions of iron limitation or abundance revealed both iron-responsive genes and Sre1-dependent genes, which comprised distinct but overlapping sets. Iron-responsive genes included those encoding putative oxidoreductases, metabolic and mitochondrial enzymes, superoxide dismutase, and nitrosative-stress-response genes; Sre1-dependent genes were of diverse functions. Genes regulated by iron levels and Sre1 included all of the siderophore biosynthesis genes, a gene involved in reductive iron acquisition, an iron-responsive transcription factor, and two catalases. Based on transcriptional profiling and phenotypic analyses, we conclude that Sre1 plays a critical role in the regulation of both traditional iron-responsive genes and iron-independent pathways such as regulation of cell morphology. These data highlight the evolving realization that the effect of Sre1 orthologs on fungal biology extends beyond the iron regulon.
Critical Role for Voltage-Dependent Anion Channel 2 in Infectious Bursal Disease Virus-Induced Apoptosis in Host Cells via Interaction with VP5
Authors: Li Zhonghua , Wang Yongqiang , Xue Yanfei , Li Xiaoqi , Cao Hong , Zheng Shijun J. 
Published: November 2011

ABSTRACT

Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive avian disease caused by IBD virus (IBDV). Although IBDV-induced host cell apoptosis has been established, the underlying molecular mechanism is still unclear. We report here that IBDV viral protein 5 (VP5) is a major apoptosis inducer in DF-1 cells by interacting with the voltage-dependent anion channel 2 (VDAC2) in the mitochondrion. We found that in DF-1 cells, VP5-induced apoptosis can be completely abolished by 4,4′-diisothiocyanatostibene-2,2′-disulfonic acid (DIDS), an inhibitor of VDAC. Furthermore, knockdown of VDAC2 by small interfering RNA markedly inhibits IBDV-induced apoptosis associated with decreased caspase-9 and -3 activation and cytochrome
c
release, leading to increased IBDV growth in host cells. Thus, VP5-induced apoptosis during IBDV infection is mediated by interacting with VDAC2, a protein that appears to restrict viral replication via induction of cell death.
Asthma in adolescent athletes
Authors: Carlsen Kai-Håkon , Hem Erlend , Stensrud Trine 
Published: November 2011

Athletes active in endurance sports are at an increased risk of acquiring asthma through their sports activities, especially so for cross-country skiers, biathlon skiers, swimmers and athletes of other endurance sports. Asthma may be present from early childhood or develop while in active sports. This article focuses on the physical activity and sports activities in children and adolescents. Exercise-induced asthma (EIA) is found in 8–10% of a normal child population of school age and in about 35% of children with current asthma.EIA is caused by the markedly increased ventilation during exercise, with increased heat and water loss through respiration, leading to bronchial constriction. The risk of developing asthma in the young athlete is related to the repeated daily training activity with increased epithelial damage of the airways, delayed repair due to the daily repetition of the training and increased airway mucosal inflammation. The increased environmental exposure through the sports activity to environmental agents, such as cold, dry air in skiers and chlorine compounds in swimmers, increases symptoms and signs of asthma and bronchial hyper-responsiveness, either worsening an existing asthma or leading to a novel disease in a previously healthy athlete.Several specific aspects of daily training life, environmental exposure, diagnostic procedures and aspects of treatment related to the regulations of medication use in sports need particular attention when addressing the adolescent athlete with respiratory symptoms.
External Validation of Diagnostic Models to Estimate the Risk of Malignancy in Adnexal Masses
Authors: Van Holsbeke Caroline , Van Calster Ben , Bourne Tom , Ajossa Silvia , Testa Antonia C. , Guerriero Stefano , Fruscio Robert , Lissoni Andrea Alberto , Czekierdowski Artur , Savelli Luca , Van Huffel Sabine , Valentin Lil , Timmerman Dirk 
Published: November 2011

AbstractPurpose: To externally validate and compare the performance of previously published diagnostic models developed to predict malignancy in adnexal masses.Experimental Design: We externally validated the diagnostic performance of 11 models developed by the International Ovarian Tumor Analysis (IOTA) group and 12 other (non-IOTA) models on 997 prospectively collected patients. The non-IOTA models included the original risk of malignancy index (RMI), three modified versions of the RMI, six logistic regression models, and two artificial neural networks. The ability of the models to discriminate between benign and malignant adnexal masses was expressed as the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and likelihood ratios (LR+, LR−).Results: Seven hundred and forty-two (74%) benign and 255 (26%) malignant masses were included. The IOTA models did better than the non-IOTA models (AUCs between 0.941 and 0.956 vs. 0.839 and 0.928). The difference in AUC between the best IOTA and the best non-IOTA model was 0.028 [95% confidence interval (CI), 0.011–0.044]. The AUC of the RMI was 0.911 (difference with the best IOTA model, 0.044; 95% CI, 0.024–0.064). The superior performance of the IOTA models was most pronounced in premenopausal patients but was also observed in postmenopausal patients. IOTA models were better able to detect stage I ovarian cancer.Conclusion: External validation shows that the IOTA models outperform other models, including the current reference test RMI, for discriminating between benign and malignant adnexal masses. Clin Cancer Res; 18(3); 815–25. ©2011 AACR.
MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias
Authors: Yu Jun , Li Ang , Hong Seung-Mo , Hruban Ralph H. , Goggins Michael 
Published: November 2011

Abstract
Purpose: MicroRNA (miRNA) alterations are likely to contribute to the development of pancreatic cancer and may serve as markers for the early detection of pancreatic neoplasia.
Experimental Design: To identify the miRNA alterations that arise during the development of pancreatic cancer, we determined the levels of 735 miRNAs in 34 pancreatic intraepithelial neoplasias (PanIN) and 15 normal pancreatic duct samples isolated by laser capture microdissection using TaqMan miRNA microarrays. Differential expression of selected miRNAs was confirmed by FISH analysis and by quantitative real-time reverse transcription PCR (qRT-PCR) analysis of selected candidate miRNAs in an independent set of PanIN and normal duct samples.
Results: We identified 107 aberrantly expressed miRNAs in different PanIN grades compared with normal pancreatic duct samples and 35 aberrantly expressed miRNAs in PanIN-3 lesions compared with normal pancreatic duct samples. These differentially expressed miRNAs included those that have been previously identified as differentially expressed in pancreatic ductal adenocarcinomas (PDAC; including miR-21, miR-200a/b/c, miR-216a/b, miR-217, miR-146a, miR-155, miR-182, miR-196b, miR-203, miR-222, miR-338-3p, miR-486-3p, etc.) as well as miRNAs not previously described as differentially expressed in these lesions (miR-125b, miR-296-5p, miR-183*, miR-603, miR-625/*, miR-708, etc.). miR-196b was the most selectively differentially expressed miRNA in PanIN-3 lesions.
Conclusions: Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers. Clin Cancer Res; 18(4); 981–92. ©2011 AACR.
Interleukin-17A Deficiency Accelerates Unstable Atherosclerotic Plaque Formation in Apolipoprotein E-Deficient Mice
Authors: Danzaki Keiko , Matsui Yutaka , Ikesue Masahiro , Ohta Daichi , Ito Koyu , Kanayama Masashi , Kurotaki Daisuke , Morimoto Junko , Iwakura Yoichiro , Yagita Hideo , Tsutsui Hiroyuki , Uede Toshimitsu 
Published: November 2011

Objective—
Interleukin(IL)-17A, an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial.

Methods and Results—

To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE
−/−
IL-17A
−/−
) mice. Mice were fed with high-fat diet (HFD) for either 8 or 16 weeks, both starting at ages of 6 to 8 weeks. We found that splenic CD4
+
T-cells produced high amounts of IL-17A in ApoE
−/−
mice after HFD feeding for 8 weeks. Atherosclerosis was significantly accelerated in HFD-fed ApoE
−/−
IL-17A
−/−
mice compared with ApoE
−/−
mice. Splenic CD4
+
T-cells of ApoE
−/−
IL-17A
−/−
mice after HFD feeding for 8 weeks, but not for 16 weeks, exhibited increased interferon gamma and decreased IL-5 production. Importantly, formation of vulnerable plaque as evidenced by reduced numbers of vascular smooth muscle cells and reduced type I collagen deposition in the plaque was detected in ApoE
−/−
IL-17A
−/−
mice after HFD feeding for 8 weeks.

Conclusion—

These results suggest that IL-17A regulates the early phase of atherosclerosis development after HFD feeding and plaque stability, at least partly if not all by modulating interferon gamma and IL-5 production from CD4
+
T-cells.
The Relationship between Jugular Bulb–Vestibular Aqueduct Dehiscence and Hearing Loss in Pediatric Patients
Authors: Kupfer Robbi A. , Hoesli Rebecca C. , Green Glenn E. , Thorne Marc C. 
Published: November 2011

ObjectiveTo determine the prevalence of jugular bulb and vestibular aqueduct dehiscence (JBVAD) in pediatric patients undergoing temporal bone computed tomography (CT) scans and to assess the relationship between JBVAD and hearing loss.Study DesignCross‐sectional study with chart review.SettingTertiary academic medical center.Subjects and MethodsAll patients 18 years of age or younger who had undergone temporal bone CT scans and audiometric testing between 2004 and 2009 were retrospectively reviewed. JBVAD was determined by blinded review of CT images. Hearing loss was determined by review of audiometric data and was correlated with imaging findings.ResultsCT images and audiometric data were available for review in 927 patients (1854 ears). Overall prevalence of JBVAD was 8.6%, with a prevalence of 6.6% in right ears and 3.6% in left ears. JBVAD was present in 8.3% and 7.1% of patients with and without sensorineural or mixed hearing loss, respectively (95% confidence interval [CI], ‐2.3% to 4.6%;P=. 51). Similarly, JBVAD was present in 5.5% of ears with and 4.6% of ears without sensorineural or mixed hearing loss (95% CI, ‐1.1% to 2.9%;P=. 37).ConclusionThe prevalence of JBVAD is 8.6% in pediatric patients undergoing temporal bone CT scans, 65% of which occur in the right ear. We were unable to identify any relationship between JBVAD and hearing loss. A major contribution to pediatric sensorineural hearing loss from JBVAD is therefore extremely unlikely.
Face, Content, and Construct Validity of a Low‐Cost Sinus Surgery Task Trainer
Authors: Steehler Matthew K. , Pfisterer Michael J. , Na Hana , Hesham Hosai N. , Pehlivanova Marieta , Malekzadeh Sonya 
Published: November 2011

ObjectiveTo assess the face, content, and construct validities of a low‐cost sinus surgery task trainer in acquisition of skills for endoscopic sinus surgery.Study DesignProspective validation study.SettingTertiary academic center.Subjects and MethodsAttending otolaryngologists, otolaryngology residents at various levels of training, and medical students performed nasal endoscopy and 5 specific tasks using this model. Face and content validities were assessed based on the attendings’ responses to a questionnaire evaluating the task trainer. Construct validity was determined by comparing novice to experienced performance using a validated checklist and globalized rating scale.ResultsA total of 77 subjects participated in the study. Attending otolaryngologists responded to a survey after completing the tasks. Eighty percent of evaluators rated the trainer as realistic and agreed that this model correlates with the essential skills needed for endoscopic sinus surgery, 90% felt this model provided adequate training and would increase resident competency, and 90% were interested in using the model to train residents. On the task trainer, experienced otolaryngologists and senior residents scored significantly higher than junior residents and medical students using the objective measures of the globalized rating scale and checklist.ConclusionThis study demonstrates face, content, and construct validity of the low‐cost sinus surgery task trainer. This model has the potential to be a valuable tool in endoscopic sinus surgery training for otolaryngology residents.
Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas
Authors: Jen Kuang-Yu , Song Ihn Young , Banta Karl Luke , Wu Di , Mao Jian-Hua , Balmain Allan 
Published: November 2011

Abstract
T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.
A novel lentiviral vector targets gene transfer into human hematopoietic stem cells in marrow from patients with bone marrow failure syndrome and in vivo in humanized mice
Authors: Frecha Cecilia , Costa Caroline , Nègre Didier , Amirache Fouzia , Trono Didier , Rio Paula , Bueren Juan , Cosset François-Loïc , Verhoeyen Els 
Published: November 2011

AbstractIn vivo lentiviral vector (LV)–mediated gene delivery would represent a great step forward in the field of gene therapy. Therefore, we have engineered a novel LV displaying SCF and a mutant cat endogenous retroviral glycoprotein, RDTR. These RDTR/SCF-LVs outperformed RDTR-LVs for transduction of human CD34+ cells (hCD34+). For in vivo gene therapy, these novel RDTR/SCF-displaying LVs can distinguish between the target hCD34+ cells of interest and nontarget cells. Indeed, they selectively targeted transduction to 30%-40% of the hCD34+ cells in cord blood mononuclear cells and in the unfractionated BM of healthy and Fanconi anemia donors, resulting in the correction of CD34+ cells in the patients. Moreover, RDTR/SCF-LVs targeted transduction to CD34+ cells with 95-fold selectivity compared with T cells in total cord blood. Remarkably, in vivo injection of the RDTR/SCF-LVs into the BM cavity of humanized mice resulted in the highly selective transduction of candidate hCD34+Lin− HSCs. In conclusion, this new LV will facilitate HSC-based gene therapy by directly targeting these primitive cells in BM aspirates or total cord blood. Most importantly, in the future, RDTR/SCF-LVs might completely obviate ex vivo handling and simplify gene therapy for many hematopoietic defects because of their applicability to direct in vivo inoculation.
CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules
Authors: Kliche Stefanie , Worbs Tim , Wang Xiaoqian , Degen Janine , Patzak Irene , Meineke Bernhard , Togni Mauro , Moser Markus , Reinhold Annegret , Kiefer Friedemann , Freund Christian , Förster Reinhold , Schraven Burkhart 
Published: November 2011

Abstract
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.
Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells
Authors: He Shan , Wang Jina , Kato Koji , Xie Fang , Varambally Sooryanarayana , Mineishi Shin , Kuick Rork , Mochizuki Kazuhiro , Liu Yongnian , Nieves Evelyn , Mani Ram-Shankar , Chinnaiyan Arul M. , Marquez Victor E. , Zhang Yi 
Published: November 2011

Abstract
Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell–mediated inflammatory disorders in a broad context.