bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury Pathways in Two Different Nonhuman Primate Species
Authors: Smits Saskia L. , van den Brand Judith M. A. , de Lang Anna , Leijten Lonneke M. E. , van IJcken Wilfred F. , van Amerongen Geert , Osterhaus Albert D. M. E. , Andeweg Arno C. , Haagmans Bart L. 
Published: February 2011

ABSTRACT
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), caused by influenza A virus H5N1 and severe acute respiratory syndrome coronavirus (SARS-CoV), supposedly depend on activation of the oxidative-stress machinery that is coupled with innate immunity, resulting in a strong proinflammatory host response. Inflammatory cytokines, such as interleukin 1β (IL-1β), IL-8, and IL-6, play a major role in mediating and amplifying ALI/ARDS by stimulating chemotaxis and activation of neutrophils. To obtain further insight into the pathogenesis of SARS-CoV-associated ALI, we compared SARS-CoV infections in two different nonhuman primate species, cynomolgus macaques and African green monkeys. Viral titers in the upper and lower respiratory tract were not significantly different in SARS-CoV-infected macaques and African green monkeys. Inflammatory cytokines that play a major role in mediating and amplifying ALI/ARDS or have neutrophil chemoattractant activity, such as IL-6, IL-8, CXCL1, and CXCL2, were, however, induced only in macaques. In contrast, other proinflammatory cytokines and chemokines, including osteopontin and CCL3, were upregulated in the lungs of African green monkeys to a significantly greater extent than in macaques. Because African green monkeys developed more severe ALI than macaques, with hyaline membrane formation, some of these differentially expressed proinflammatory genes may be critically involved in development of the observed pathological changes. Induction of distinct proinflammatory genes after SARS-CoV infection in different nonhuman primate species needs to be taken into account when analyzing outcomes of intervention strategies in these species.
Consistent Inhibition of HIV-1 Replication in CD4
+
T Cells by Acyclovir without Detection of Human Herpesviruses
Authors: McMahon Moira A. , Parsons Teresa L. , Shen Lin , Siliciano Janet D. , Siliciano Robert F. 
Published: February 2011

ABSTRACT

Acyclovir, a nucleoside analog, is thought to be specific for the human herpesviruses because it requires a virally encoded enzyme to phosphorylate it to acyclovir monophosphate. Recently, acyclovir triphosphate was shown to be a direct inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Here, we showed that acyclovir is an inhibitor of HIV-1 replication in CD4
+
T cells from cord blood that have undetectable levels of the eight human herpesviruses. Additionally, acyclovir phosphates were detected by reverse-phase-high performance liquid chromatography (RP-HPLC) and quantified in a primer extension assay from cord blood. The data support acyclovir as an inhibitor of HIV-1 replication in herpesvirus-negative cells.
The Unique Transmembrane Hairpin of Flavivirus Fusion Protein E Is Essential for Membrane Fusion
Authors: Fritz Richard , Blazevic Janja , Taucher Christian , Pangerl Karen , Heinz Franz X. , Stiasny Karin 
Published: February 2011

ABSTRACT
The fusion of enveloped viruses with cellular membranes is mediated by proteins that are anchored in the lipid bilayer of the virus and capable of triggered conformational changes necessary for driving fusion. The flavivirus envelope protein E is the only known viral fusion protein with a double membrane anchor, consisting of two antiparallel transmembrane helices (TM1 and TM2). TM1 functions as a stop-transfer sequence and TM2 as an internal signal sequence for the first nonstructural protein during polyprotein processing. The possible role of this peculiar C-terminal helical hairpin in membrane fusion has not been investigated so far. We addressed this question by studying TM mutants of tick-borne encephalitis virus (TBEV) recombinant subviral particles (RSPs), an established model system for flavivirus membrane fusion. The engineered mutations included the deletion of TM2, the replacement of both TM domains (TMDs) by those of the related Japanese encephalitis virus (JEV), and the use of chimeric TBEV-JEV membrane anchors. Using these mutant RSPs, we provide evidence that TM2 is not just a remnant of polyprotein processing but, together with TM1, plays an active role in fusion. None of the TM mutations, including the deletion of TM2, affected early steps of the fusion process, but TM interactions apparently contribute to the stability of the postfusion E trimer and the completion of the merger of the membranes. Our data provide evidence for both intratrimer and intertrimer interactions mediated by the TMDs of E and thus extend the existing models of flavivirus membrane fusion.
Vesicular Stomatitis Virus-Based H5N1 Avian Influenza Vaccines Induce Potent Cross-Clade Neutralizing Antibodies in Rhesus Macaques
Authors: Schwartz Jennifer A. , Buonocore Linda , Suguitan Amorsolo , Hunter Meredith , Marx Preston A. , Subbarao Kanta , Rose John K. 
Published: February 2011

ABSTRACT
We analyzed the ability of a vaccine vector based on vesicular stomatitis virus (VSV) to induce a neutralizing antibody (NAb) response to avian influenza viruses (AIVs) in rhesus macaques. Animals vaccinated with vectors expressing either strain A/Hong Kong/156/1997 or strain A/Vietnam/1203/2004 H5 hemagglutinin (HA) were able to generate robust NAb responses. The ability of the vectors to induce NAbs against homologous and heterologous AIVs after a single dose was dependent upon the HA antigen incorporated into the VSV vaccine. The vectors expressing strain A/Vietnam/1203/2004 H5 HA were superior to those expressing strain A/Hong Kong/156/1997 HA at inducing cross-clade NAbs.
Specific Regulation of the Chemokine Response to Viral Hemorrhagic Septicemia Virus at the Entry Site
Authors: Montero Jana , Garcia Jessica , Ordas M. Camino , Casanova Isabel , Gonzalez Antonia , Villena Alberto , Coll Julio , Tafalla Carolina 
Published: February 2011

ABSTRACT

The fin bases constitute the main portal of rhabdovirus entry into rainbow trout (
Oncorhynchus mykiss
), and replication in this first site strongly conditions the outcome of the infection. In this context, we studied the chemokine response elicited in this area in response to viral hemorrhagic septicemia virus (VHSV), a rhabdovirus. Among all the rainbow trout chemokine genes studied, only the transcription levels of CK10 and CK12 were significantly upregulated in response to VHSV. As the virus had previously been shown to elicit a much stronger chemokine response in internal organs, we compared the effect of VHSV on the gills, another mucosal site which does not constitute the main site of viral entry or rhabdoviral replication. In this case, a significantly stronger chemokine response was triggered, with CK1, CK3, CK9, and CK11 being upregulated in response to VHSV and CK10 and CK12 being down-modulated by the virus. We then conducted further experiments to understand how these different chemokine responses of mucosal tissues could correlate with their capacity to support VHSV replication. No viral replication was detected in the gills, while at the fin bases, only the skin and the muscle were actively supporting viral replication. Within the skin, viral replication took place in the dermis, while viral replication was blocked within epidermal cells at some point before protein translation. The different susceptibilities of the different skin layers to VHSV correlated with the effect that VHSV has on their capacity to secrete chemotactic factors. Altogether, these results suggest a VHSV interference mechanism on the early chemokine response at its active replication sites within mucosal tissues, a possible key process that may facilitate viral entry.
Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas
Authors: Sasaki Tsuyoshi , Tazawa Hiroshi , Hasei Jo , Kunisada Toshiyuki , Yoshida Aki , Hashimoto Yuuri , Yano Shuya , Yoshida Ryosuke , Uno Futoshi , Kagawa Shunsuke , Morimoto Yuki , Urata Yasuo , Ozaki Toshifumi , Fujiwara Toshiyoshi 
Published: February 2011

AbstractPurpose: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301–resistant sarcomas.Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non–CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301–resistant OUMS-27 and NMFH-1 cells.Conclusions: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas. Clin Cancer Res; 17(7); 1828–38. ©2011 AACR.
Rapid Diagnosis of Medulloblastoma Molecular Subgroups
Authors: Schwalbe Ed C. , Lindsey Janet C. , Straughton Debbie , Hogg Twala L. , Cole Michael , Megahed Hisham , Ryan Sarra L. , Lusher Meryl E. , Taylor Michael D. , Gilbertson Richard J. , Ellison David W. , Bailey Simon , Clifford Steven C. 
Published: February 2011

Abstract
Purpose: Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.
Experimental Design: Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics.
Results: WNT tumors [12% (21/173)] were diagnosed &gt;5 years of age (peak, 10 years), displayed classic histology, CTNNB1 mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (&lt;3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH-positive, but these relationships broke down in noninfants. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss.
Conclusions: Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease-risk stratification and delivery of targeted therapeutics. Clin Cancer Res; 17(7); 1883–94. ©2011 AACR.
Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer
Authors: Wu De-Wei , Liu Wen-Shan , Wang John , Chen Chih-Yi , Cheng Ya-Wen , Lee Huei 
Published: February 2011

Abstract
Purpose: DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21WAF1/CIP1 (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV-associated lung cancers.
Experimental Design: Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan–Meier analysis.
Results: Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at −1,080/−1,070, −695/−685, and −283/−273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I + II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer.
Conclusion: The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients. Clin Cancer Res; 17(7); 1895–905. ©2011 AACR.
Reduction of Ovarian and Oviductal Cancers in Calorie-Restricted Laying Chickens
Authors: Carver Donna K. , Barnes H. John , Anderson Kenneth E. , Petitte James N. , Whitaker Regina , Berchuck Andrew , Rodriguez Gustavo C. 
Published: February 2011

Abstract
Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie-restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie-restricted group. On the basis of histopathology, 45 (26.3%) birds in the full-fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie-restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC. Cancer Prev Res; 4(4); 562–7. ©2011 AACR.
Determining the width of the optimal space needed to accommodate the drivers of passenger vehicles using the analogy of anthropometric measurement dynamics and mechanical mechanisms
Authors: Klarin M M , Spasojević-Brkić V K , Sajfert Z D , Djordjević D B , Nikolić M S , Ćoćkalo D Z 
Published: February 2011

This paper discusses a new way of modelling the width of the space that accommodates the drivers of passenger vehicles. The fact that there is a more or less fixed zero point, which is the origin of the coordinates of the man-vehicle system makes it possible to determine the mechanical–mathematical co-dependence in this system more accurately. The space is determined by taking extreme pairs of the dimensions and a series of anthropometric measurements to which the vehicle needs to be adjusted as the measurement limits. These were determined by analysis which includes both the theory of mechanisms and vehicle mechanics. In this way the method of adapting the vehicle to accommodate a range from the 5th-percentile woman to the 95th-percentile man has finally been surpassed. The paper demonstrates a methodology for designing the interior space of a passenger vehicle based on the fact that, in a range of anthropometric measurements of equal total lengths, each measurement has segments of different lengths, because people with the same leg lengths have different upper-and lower-leg lengths. Therefore the interior space of the vehicle is designed to accommodate extreme measurements and to allow for limitations caused by movement and the physical laws derived from seeing the anthropometric measurement mechanism as a mechanical mechanism. The paper offers a design for the space behind the windscreen, the position of the steering wheel, and the position of the foot controls together with the total space which the driver occupies, primarily from the aspect of anthropometric limitations, concluding that the maximum width for accommodation of the driver at the lowest level of a seat along the x axis is 169 mm, and along the y axis is 1013 mm.
The role of vanin-1 and oxidative stress–related pathways in distinguishing acute and chronic pediatric ITP
Authors: Zhang Bing , Lo Clara , Shen Lei , Sood Ruchira , Jones Carol , Cusmano-Ozog Kristina , Park-Snyder Shaun , Wong Wendy , Jeng Michael , Cowan Tina , Engleman Edgar G. , Zehnder James L. 
Published: February 2011

Abstract
Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress–related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up-regulation of VNN1 and down-regulation of PPARγ, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP.
Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions
Authors: Quentin Samuel , Cuccuini Wendy , Ceccaldi Raphael , Nibourel Olivier , Pondarre Corinne , Pagès Marie-Pierre , Vasquez Nadia , Dubois d'Enghien Catherine , Larghero Jérôme , Peffault de Latour Régis , Rocha Vanderson , Dalle Jean-Hugues , Schneider Pascale , Michallet Mauricette , Michel Gérard , Baruchel André , Sigaux François , Gluckman Eliane , Leblanc Thierry , Stoppa-Lyonnet Dominique , Preudhomme Claude , Socié Gérard , Soulier Jean 
Published: February 2011

Abstract
Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), −7/7q (17.2%), and 11q− (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.
High-resolution kinetics of cytokine signaling in human CD34/CD117-positive cells in unfractionated bone marrow
Authors: Woost Philip G. , Solchaga Luis A. , Meyerson Howard J. , Shankey T. Vincent , Goolsby Charles L. , Jacobberger James W. 
Published: February 2011

Abstract
Cytokine-mediated phosphorylation of Erk (pErk), ribosomal S6 (pS6), and Stat5 (pStat5) in CD34+/CD117+ blast cells in normal bone marrow from 9 healthy adult donors were analyzed over 60 minutes. Treatment with stem cell factor (SCF), Flt3-ligand (FL), IL-3, and GM-CSF and measurement by multiparametric flow cytometry yielded distinctive, highly uniform phosphoprotein kinetic profiles despite a diverse sample population. The correlated responses for SCF- and FL-stimulated pErk and pS6 were similar. Half the population phosphorylated Erk in response to SCF between 0.9 and 1.2 minutes, and S6 phosphorylation followed approximately a minute later (t½pS6 rise = 2.2-2.7 minutes). The FL response was equally fast but more variable (t½pErk rise = 0.9-1.3 minutes; t½pS6 rise = 2.5-3.5 minutes). Stat5 was not activated in 97% of the cells by either cytokine. IL-3 and GM-CSF were similar to each other with half of blast cells phosphorylating Stat5 and 15% to 20% responding through Erk and S6. Limited comparison with leukemic blasts confirmed universal abnormal signaling in AML that is significantly different from normal bone marrow blasts. These differences included sustained signals, a larger fraction of responding cells, and amplification of phosphorylation levels for at least one phosphoprotein. These data support the eventual use of this approach for disease diagnosis and monitoring.