bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Snapshot of Invasive Serogroup B Meningococci in South Africa from 2005 to 2008
Authors: du Plessis Mignon , Moodley Chivonne , Mothibeli Kedibone M. , Fali Azola , Klugman Keith P. , von Gottberg Anne 
Published: May 2012

ABSTRACT

In South Africa, serogroup B meningococcal disease is sporadic. The aim of this study was to characterize serogroup B strains causing invasive meningococcal disease (IMD) in South Africa from 2005 to 2008. Isolates, collected through a national, laboratory-based surveillance program for IMD, were characterized by multilocus sequence typing (MLST). Two thousand two hundred thirty-four cases were reported, of which 1,447 had viable isolates. Intermediate resistance to penicillin was observed in 2.8% (41/1,447) of all strains. Serogroup B was the second most common serogroup (17%, 251/1,447) and increased from 14% (58/414) in 2005 to 25% (72/290) in 2008 (
P
< 0.001); however, incidence remained stable during the study period (average incidence, 0.13/100,000 population) (
P
= 0.54). Serogroup B was predominantly characterized by three clonal complexes, namely, ST-41/44/lineage 3, ST-32/ET-5, and the new complex ST-4240/6688, which accounted for 27% (65/242), 23% (55/242), and 16% (38/242) of isolates, respectively. ST-4240/6688 was more prevalent among young children (<5 years) than other clonal complexes (27/37 [73%] versus 108/196 [55%];
P
= 0.04). In the most densely populated province of South Africa, Gauteng, the prevalence of ST-32/ET-5 increased from 8% (2/24) in 2005 to 38% (9/24) in 2008 (
P
= 0.04). Capsular switching was observed in 8/242 (3%) strains. The newly assigned clonal complex ST-4240/6688 was more common in young children.
A Novel Extraction Method Combining Plasma with a Whole-Blood Fraction Shows Excellent Sensitivity and Reproducibility for Patients at High Risk for Invasive Aspergillosis
Authors: Springer Jan , Schloßnagel Hannes , Heinz Werner , Doedt Thomas , Soeller Rainer , Einsele Hermann , Loeffler Juergen 
Published: May 2012

ABSTRACT
Diagnosis of invasive aspergillosis (IA) is still a major problem in routine clinical practice. Early diagnosis is essential for a good patient prognosis. PCR is a highly sensitive method for the detection of nucleic acids and could play an important role in improving the diagnosis of fungal infections. Therefore, a novel DNA extraction method, ultraclean production (UCP), was developed allowing purification of both cellular and cell-free circulating fungal DNA. In this prospective study we evaluated the commercially available UCP extraction system and compared it to an in-house system. Sixty-three patients at high risk for IA were screened twice weekly, and DNA extracted by both methods was cross-analyzed, in triplicate, by two different real-time PCR assays. The negative predictive values were high for all methods (94.3 to 100%), qualifying them as screening methods, but the sensitivity and diagnostic odds ratios were higher using the UCP extraction method. Sensitivity ranged from 33.3 to 66.7% using the in-house extracts to 100% using the UCP extraction method. Most of the unclassified patients showed no positive PCR results; however, single-positive PCR replicates were observed in some cases. These can bear clinical relevance but should be interpreted with additional clinical and laboratory data. The PCR assays from the UCP extracts showed greater reproducibility than the in-house method for probable IA patients. The standardized UCP extraction method yielded superior results, with regard to sensitivity and reproducibility, than the in-house method. This was independent of the PCR assay used to detect fungal DNA in the sample extracts.
Identification of DNA Signatures Suitable for Use in Development of Real-Time PCR Assays by Whole-Genome Sequence Approaches: Use of Streptococcus pyogenes in a Pilot Study
Authors: Hung Guo-Chiuan , Nagamine Kenjiro , Li Bingjie , Lo Shyh-Ching 
Published: May 2012

ABSTRACT

A stepwise computational approach using three layers of publicly available software was found to effectively identify DNA signatures for
Streptococcus pyogenes
. PCR testing validated that 9 out of 15 signature-derived primer sets could detect as low as 5 fg of target DNA with high specificity. The selected signature-derived primer sets were successfully evaluated against all 23 clinical isolates. The approach is readily applicable for designing molecular assays for rapid detection and characterization of various pathogenic bacteria.
Accelerated Heterologous Adenovirus Prime-Boost SIV Vaccine in Neonatal Rhesus Monkeys
Authors: Liu Jinyan , Li Hualin , Iampietro M. Justin , Barouch Dan H. 
Published: May 2012

ABSTRACTA pediatric human immunodeficiency virus type 1 (HIV-1) vaccine would be desirable to protect infants against HIV-1 transmission from breast-feeding. Such a vaccine would need to induce protective immunity at mucosal surfaces in neonates as soon as possible after birth. Recombinant adenovirus (rAd) vectors have been shown to elicit potent systemic and mucosal virus-specific immune responses in adult nonhuman primates and humans, but these vectors have not previously been comprehensively studied in infants. In this study, we demonstrate that a single injection of rAd26 encoding simian immunodeficiency virus mac239 (SIVmac239) Gag on the day of birth elicited detectable Gag-specific cellular immune responses in rhesus monkeys, but these responses were transient and waned quickly. In contrast, an accelerated heterologous prime-boost regimen involving administration of rAd35 at birth and rAd26 at 4 weeks of life elicited potent and durable Gag-specific cellular and humoral immune responses in neonatal rhesus monkeys, including mucosal responses that remained detectable at 1 year of age. These results suggest the potential of an accelerated heterologous rAd prime-boost regimen as a candidate HIV-1 vaccine for newborns.
Structural Insight into African Horsesickness Virus Infection
Authors: Manole Violeta , Laurinmäki Pasi , Van Wyngaardt Wouter , Potgieter Christiaan A. , Wright Isabella M. , Venter Gert J. , van Dijk Alberdina A. , Sewell B. Trevor , Butcher Sarah J. 
Published: May 2012

ABSTRACT
African horsesickness (AHS) is a devastating disease of horses. The disease is caused by the double-stranded RNA-containing African horsesickness virus (AHSV). Using electron cryomicroscopy and three-dimensional image reconstruction, we determined the architecture of an AHSV serotype 4 (AHSV-4) reference strain. The structure revealed triple-layered AHS virions enclosing the segmented genome and transcriptase complex. The innermost protein layer contains 120 copies of VP3, with the viral polymerase, capping enzyme, and helicase attached to the inner surface of the VP3 layer on the 5-fold axis, surrounded by double-stranded RNA. VP7 trimers form a second, T=13 layer on top of VP3. Comparative analyses of the structures of bluetongue virus and AHSV-4 confirmed that VP5 trimers form globular domains and VP2 trimers form triskelions, on the virion surface. We also identified an AHSV-7 strain with a truncated VP2 protein (AHSV-7 tVP2) which outgrows AHSV-4 in culture. Comparison of AHSV-7 tVP2 to bluetongue virus and AHSV-4 allowed mapping of two domains in AHSV-4 VP2, and one in bluetongue virus VP2, that are important in infection. We also revealed a protein plugging the 5-fold vertices in AHSV-4. These results shed light on virus-host interactions in an economically important orbivirus to help the informed design of new vaccines.
Characterization of Hepatitis E Virus Recombinant ORF2 Proteins Expressed by Vaccinia Viruses
Authors: Jiménez de Oya Nereida , Escribano-Romero Estela , Blázquez Ana-Belén , Lorenzo María , Martín-Acebes Miguel A. , Blasco Rafael , Saiz Juan-Carlos 
Published: May 2012

ABSTRACT
Hepatitis E virus (HEV), an enterically transmitted pathogen, is one of the major causes of acute hepatitis in humans worldwide, being responsible for outbreaks and epidemics in regions with suboptimal sanitary conditions, in many of which it is endemic. In industrialized countries, hepatitis E is rarely reported, but recent studies have revealed quite high human seroprevalence rates and the possibility of porcine zoonotic transmission. There is currently no specific therapy or licensed vaccine against HEV infection, and little is known about its intracellular growth cycle, as until very recently no efficient cell culture system has been available. In the present study, vaccinia viruses have been used to express recombinant HEV ORF2 proteins, allowing the study of their glycosylation patterns and subcellular localization. Furthermore, the expressed proteins have been shown to be good antigens for diagnostic purposes and to elicit high and long-lasting specific anti-HEV titers of antibodies in mice that are passively transferred to the offspring by both transplacental and lactation routes.
Enhancement or Attenuation of Disease by Deletion of Genes from
Citrus Tristeza Virus
Authors: Tatineni Satyanarayana , Dawson William O. 
Published: May 2012

ABSTRACT

Stem pitting is a common virus-induced disease of perennial woody plants induced by a range of different viruses. The phenotype results from sporadic areas of the stem in which normal xylem and phloem development is prevented during growth of stems. These alterations interfere with carbohydrate transport, resulting in reduced plant growth and yield.
Citrus tristeza virus
(CTV), a phloem-limited closterovirus, induces economically important stem-pitting diseases of citrus. CTV has three nonconserved genes (p33, p18, and p13) that are not related to genes of other viruses and that are not required for systemic infection of some species of citrus, which allowed us to examine the effect of deletions of these genes on symptom phenotypes. In the most susceptible experimental host,
Citrus macrophylla
, the full-length virus causes only very mild stem-pitting symptoms. Surprisingly, we found that certain deletion combinations (p33 and p18 and/or p13) induced greatly increased stem-pitting symptoms, while other combinations (p13 or p13 plus p18) resulted in reduced stem pitting. These results suggest that the stem-pitting phenotype, which is one of more economically important disease phenotypes, can result not from a specific sequence or protein but from a balance between the expression of different viral genes. Unexpectedly, using green fluorescent protein-tagged full-length virus and deletion mutants (CTV9Δp33 and CTV9Δp33Δp18Δp13), the virus was found at pitted areas in abnormal locations outside the normal ring of phloem. Thus, increased stem pitting was associated not only with a prevention of xylem production but also with a proliferation of cells that supported viral replication, suggesting that at random areas of stems the virus can elicit changes in cellular differentiation and development.
Heart-type fatty acid binding protein as an early marker for myocardial infarction: systematic review and meta-analysis
Authors: Carroll Christopher , Al Khalaf Mohamad , Stevens John W , Leaviss Joanna , Goodacre Steve , Collinson Paul O , Wang Jenny 
Published: May 2012

BackgroundHeart-type fatty acid binding protein (H-FABP) has been proposed as an early biomarker of myocardial infarction (MI). The authors aimed to undertake a systematic review and meta-analysis to estimate the early sensitivity and specificity of quantitative and qualitative H-FABP assays.MethodsThe authors undertook a systematic search using electronic databases, citation lists and expert contacts to identify all diagnostic cohort studies of patients presenting with suspected acute coronary syndrome that compared H-FABP at presentation to a reference standard based on the Universal definition of MI. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Meta-analysis was conducted using Bayesian Markov chain Monte Carlo simulation.ResultsThe authors included eight studies of quantitative H-FABP and nine studies of qualitative H-FABP. The summary estimates of sensitivity and specificity were 81% (95% prediction interval 50% to 95%) and 80% (26% to 98%) respectively for the quantitative assays and 68% (11% to 97%) and 92% (20% to 100%) respectively for the qualitative assays. Four studies reported the sensitivity of troponin and H-FABP at presentation in which the combination was considered positive if either test was positive. The addition of H-FABP to troponin increased sensitivity from 42–75% to 76–97% but decreased specificity from 94–100% to 65–93%.ConclusionH-FABP has modest sensitivity and specificity for MI at presentation but estimates are subject to substantial uncertainty and primary data are subject to substantial heterogeneity. H-FABP may have a role alongside troponin in improving early sensitivity but comparison with high sensitivity troponin assays is required.
Deletion of the Endothelial Bmx Tyrosine Kinase Decreases Tumor Angiogenesis and Growth
Authors: Holopainen Tanja , Alpuche Vanessa López- , Zheng Wei , Heljasvaara Ritva , Jones Dennis , He Yun , Tvorogov Denis , D'Amico Gabriela , Wiener Zoltan , Andersson Leif C. , Pihlajaniemi Taina , Min Wang , Alitalo Kari 
Published: May 2012

Abstract
Bmx (Bone marrow kinase in chromosome X), also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene–deleted (−/−) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx−/− mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal–regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth. Cancer Res; 72(14); 3512–21. ©2012 AACR.
Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes
Authors: Calcinotto Arianna , Filipazzi Paola , Grioni Matteo , Iero Manuela , De Milito Angelo , Ricupito Alessia , Cova Agata , Canese Rossella , Jachetti Elena , Rossetti Monica , Huber Veronica , Parmiani Giorgio , Generoso Luca , Santinami Mario , Borghi Martina , Fais Stefano , Bellone Matteo , Rivoltini Licia 
Published: May 2012

AbstractStimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra–extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6–6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8+ T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal–regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA–bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell–based cancer treatments. Cancer Res; 72(11); 2746–56. ©2012 AACR.
Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes
Authors: Singh Mallika , Murriel Christopher L. , Johnson Leisa 
Published: May 2012

Abstract
The high failure rate of late-stage human clinical trials, particularly in oncology, predicates the need for improved translation of preclinical data from mouse tumor models into clinical predictions. Genetically engineered mouse models (GEMM) may fulfill this need, because they mimic spontaneous and autochthonous disease progression. Using oncogenic Kras-driven GEMMs of lung and pancreatic adenocarcinoma, we recently showed that these models can closely phenocopy human therapeutic responses to standard-of-care treatment regimens. Here we review the successful preclinical application of such GEMMs, as well as the potential for discovering predictive biomarkers and gaining mechanistic insights into clinical outcomes and drug resistance in human cancers. Cancer Res; 72(11); 2695–700. ©2012 AACR.
The Changing View of High-Grade Serous Ovarian Cancer
Authors: Berns Els M.J.J. , Bowtell David D. 
Published: May 2012

Abstract
The classification of epithelial ovarian cancer has been substantially revised, with an increased appreciation of the cellular origins and molecular aberrations of the different histotypes. Distinct patterns of signaling-pathway disruption are seen between and within histotypes. Large-scale genomic studies of high-grade serous cancer, the most common histotype, have identified novel molecular subtypes that are associated with distinct biology and clinical outcome. High-grade serous cancers are characterized by few driver point mutations but abundant DNA copy number aberrations. Inactivation of genes associated with DNA damage repair underlies responses to platinum and PARP inhibitors. Here we review these recent developments. Cancer Res; 72(11); 2701–4. ©2012 AACR.
NF-κB Hyperactivation in Tumor Tissues Allows Tumor-Selective Reprogramming of the Chemokine Microenvironment to Enhance the Recruitment of Cytolytic T Effector Cells
Authors: Muthuswamy Ravikumar , Berk Erik , Junecko Beth Fallert , Zeh Herbert J. , Zureikat Amer H. , Normolle Daniel , Luong The Minh , Reinhart Todd A. , Bartlett David L. , Kalinski Pawel 
Published: May 2012

Abstract
Tumor infiltration with effector CD8+ T cells (Teff) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of Teff for effective immunosurveillance. Colorectal tumors with reduced accumulation of Teff express low levels of Teff-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of Teff-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (Treg). The Teff-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce Teff-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract Teff cells and reduced ability to attract Treg cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance Teff entry into colon tumors. Cancer Res; 72(15); 3735–43. ©2012 AACR.
Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma
Authors: Janouskova Hana , Maglott Anne , Leger David Y. , Bossert Catherine , Noulet Fanny , Guerin Eric , Guenot Dominique , Pinel Sophie , Chastagner Pascal , Plenat François , Entz-Werle Natacha , Lehmann-Che Jacqueline , Godet Julien , Martin Sophie , Teisinger Jan , Dontenwill Monique 
Published: May 2012

Abstract
Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of α5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the α5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, α5β1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high α5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between α5β1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that α5β1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of α5β1 integrin. Cancer Res; 72(14); 3463–70. ©2012 AACR.
Numb Regulates Stability and Localization of the Mitotic Kinase PLK1 and Is Required for Transit through Mitosis
Authors: Schmit Travis L. , Nihal Minakshi , Ndiaye Mary , Setaluri Vijayasaradhi , Spiegelman Vladimir S. , Ahmad Nihal 
Published: May 2012

Abstract
Numb functions in progenitor cell fate determination and early development, but it is also expressed in postdevelopmental tissues and cancers where its role is unclear. In this study, we report that a targeted knockdown of Numb expression causes a G2–M arrest and reduced cell growth in human melanoma cells. Co-immunoprecipitation and colocalization studies showed that Numb interacts with the serine/threonine polo-like kinase Plk1 and Numb cycles in a cell-cycle–dependent fashion along with this mitotic regulator. Interestingly, Numb expression was required for Plk1 protein stability and localization to the spindle poles during mitosis. Reduction in Numb expression resulted in mislocalization of Plk1 at both metaphase and anaphase, leading to disorganized γ-tubulin recruitment in centrosomes. Together, our findings present a novel function for Numb during symmetric cell division. We suggest that dysregulation of Numb expression results in mislocalized Plk1 and poor centrosomal γ-tubulin recruitment, potentially contributing to mitotic errors, aneuploidy, and cancer development. Cancer Res; 72(15); 3864–72. ©2012 AACR.