bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenesis and Immune Response of Crimean-Congo Hemorrhagic Fever Virus in a STAT-1 Knockout Mouse Model
Authors: Bente Dennis A. , Alimonti Judie B. , Shieh Wun-Ju , Camus Gaëlle , Ströher Ute , Zaki Sherif , Jones Steven M. 
Published: August 2010

ABSTRACT

Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes a severe hemorrhagic syndrome in humans but not in its vertebrate animal hosts. The pathogenesis of the disease is largely not understood due to the lack of an animal model. Laboratory animals typically show no overt signs of disease. Here, we describe a new small-animal model to study CCHFV pathogenesis that manifests clinical disease, similar to that seen in humans, without adaptation of the virus to the host. Our studies revealed that mice deficient in the STAT-1 signaling molecule were highly susceptible to infection, succumbing within 3 to 5 days. After CCHFV challenge, mice exhibited fever, leukopenia, thrombocytopenia, and highly elevated liver enzymes. Rapid viremic dissemination and extensive replication in visceral organs, mainly in liver and spleen, were associated with prominent histopathologic changes in these organs. Dramatically elevated proinflammatory cytokine levels were detected in the blood of the animals, suggestive of a cytokine storm. Immunologic analysis revealed delayed immune cell activation and intensive lymphocyte depletion. Furthermore, this study also demonstrated that ribavirin, a suggested treatment in human cases, protects mice from lethal CCHFV challenge. In conclusion, our data demonstrate that the interferon response is crucial in controlling CCHFV replication in this model, and this is the first study that offers an in-depth
in vivo
analysis of CCHFV pathophysiology. This new mouse model exhibits key features of fatal human CCHF, proves useful for the testing of therapeutic strategies, and can be used to study virus attenuation.
CD8
+
T Cell Recognition of Cryptic Epitopes Is a Ubiquitous Feature of AIDS Virus Infection
Authors: Maness Nicholas J. , Walsh Andrew D. , Piaskowski Shari M. , Furlott Jessica , Kolar Holly L. , Bean Alexander T. , Wilson Nancy A. , Watkins David I. 
Published: August 2010

ABSTRACT

Vaccines designed to elicit AIDS virus-specific CD8
+
T cells should engender broad responses. Emerging data indicate that alternate reading frames (ARFs) of both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) encode CD8
+
T cell epitopes, termed cryptic epitopes. Here, we show that SIV-specific CD8
+
T cells from SIV-infected rhesus macaques target 14 epitopes in eight ARFs during SIV infection. Animals recognized up to five epitopes, totaling nearly one-quarter of the anti-SIV responses. The epitopes were targeted by high-frequency responses as early as 2 weeks postinfection and in the chronic phase. Hence, previously overlooked ARF-encoded epitopes could be important components of AIDS vaccines.
Lambda Interferon Is the Predominant Interferon Induced by Influenza A Virus Infection
In Vivo
Authors: Jewell Nancy A. , Cline Troy , Mertz Sara E. , Smirnov Sergey V. , Flaño Emilio , Schindler Christian , Grieves Jessica L. , Durbin Russell K. , Kotenko Sergei V. , Durbin Joan E. 
Published: August 2010

ABSTRACT

The type I alpha/beta interferons (IFN-α/β) are known to play an important role in host defense against influenza A virus infection, but we have now discovered that the recently identified type III IFNs (IFN-λ) constitute the major response to intranasal infection with this virus. Type III IFNs were present at much higher levels than type I IFNs in the lungs of infected mice, and the enhanced susceptibility of STAT2
−/−
animals demonstrated that only signaling through the IFN-α/β or IFN-λ pathways was sufficient to mediate protection. This finding offers a possible explanation for the similar levels of antiviral protection found in wild-type (WT) mice and in animals lacking a functional type I IFN receptor (IFNAR
−/−
) but also argues that our current understanding of type III IFN induction is incomplete. While murine IFN-λ production is thought to depend on signaling through the type I IFN receptor, we demonstrate that intranasal influenza A virus infection leads to the robust type III IFN induction in the lungs of both WT and IFNAR
−/−
mice. This is consistent with previous studies showing that IFNAR-mediated protection is redundant for mucosal influenza virus infection and with data showing that the type III IFN receptor is expressed primarily by epithelial cells. However, the overlapping effects of these two cytokine families are limited by their differential receptor expression, with a requirement for IFN-α/β signaling in combating systemic disease.
Trends in blood lead levels in UK workers, 1995–2007
Authors: Morton Jackie , Cotton Richard , Cocker John , Warren Nicholas D 
Published: August 2010

ObjectivesThis study evaluated blood lead data (including zinc protoporphyrin (ZPP) and haemoglobin levels) collected at the UK's Health and Safety Laboratory (HSL) in order to determine temporal changes in occupational exposure to lead between 1995 and 2007.MethodsA total of 20 889 blood lead measurements and accompanying ZPP and haemoglobin results from 8810 workers at 972 companies from routine samples received by HSL over the period 1995–2007 were analysed. Time trends in blood lead levels for each industry sector were estimated using Bayesian mixed effects modelling.ResultsReductions in median blood levels over the period 1995–2007 were seen in every sector except for those samples forwarded by occupational health providers, and range from 1.6% per year for workers in the smelting industry to 12% per year for workers in pottery and glazing industries. An overall reduction of 3.1% per year across all industries was determined. The percentage of results above the current UK suspension limit of 60 μg/dl fell from 4.8% in 1995 to 0.6% in 2007. ZPP and blood lead exhibited a strong association, but no significant correlation was found between blood lead and haemoglobin.ConclusionsOccupational exposure to lead has fallen across UK industries in recent years, although it remains substantially above background levels. There is evidence that many workers are exposed to elevated lead levels over a long period of time and this deserves renewed consideration now that inorganic lead has been reclassified as a probable human carcinogen.
Cytogenotoxicity in uroepithelial cells of women exposed to mercury in a mining area
Authors: Soto-Ríos M Lourdes , Rothenberg Stephen , Gonsebatt M Eugenia , Talavera-Mendoza Oscar 
Published: August 2010

ObjectiveTo investigate biomarkers of cytogenotoxicity in women exposed to mercury in a mining area. Mercury has been associated with cytogenotoxicity in human and animal models but has not been considered carcinogenic in humans, even though genotoxic effects following exposure to inorganic mercury compounds have been observed.MethodsA cross-sectional study and micronucleus assay in uroepithelial cells were performed in 104 women (12–84 years of age). First urine void samples were taken to determine creatinine-adjusted mercury levels in urine (HgUCr), to isolate cells and to quantify cytogenetic damage.ResultsThe geometric average level for HgUCr was 4.9 μg/g (range, 0.4–85). In the generalised linear model, after controlling for other co-variables, we observed that for each 10 μg/g increase in HgUCr, the OR of developing a genotoxic effect was 2.37 (95% CI 1.79 to 2.84), while for cytotoxic damage in uroepithelial cells the OR was 1.34 (95% CI 1.10 to 1.79). These results suggest a possible association between cytogenotoxicity and HgUCr.ConclusionLiving in a mining area with exposure to inorganic mercury and having higher mercury levels in urine increased the risk of developing uroepithelial cytogenotoxicity.
THE MILNE SPACETIME AND THE HADRONIC RINDLER HORIZON
Authors: CULETU H. 
Published: August 2010

A direct relation between the time-dependent Milne geometry and the Rindler spacetime is shown. Milne's metric corresponds to the region beyond Rindler's event horizon (in the wedge t ≻ |x|). We point out that inside a Schwarzschild black hole and near its horizon, the metric may be Milne's flat metric. It was found that the shear tensor associated to a congruence of fluid particles of the RHIC expanding fireball has the same structure as that corresponding to the anisotropic fluid from the black hole interior, even though the latter geometry is curved.
Gene Expression Analysis Identifies Potential Biomarkers of Neurofibromatosis Type 1 Including Adrenomedullin
Authors: Hummel Trent R. , Jessen Walter J. , Miller Shyra J. , Kluwe Lan , Mautner Victor F. , Wallace Margaret R. , Lázaro Conxi , Page Grier P. , Worley Paul F. , Aronow Bruce J. , Schorry Elizabeth K. , Ratner Nancy 
Published: August 2010

Abstract
Purpose: Plexiform neurofibromas (pNF) are Schwann cell tumors found in a third of individuals with neurofibromatosis type 1 (NF1). pNF can undergo transformation to malignant peripheral nerve sheath tumors (MPNST). There are no identified serum biomarkers of pNF tumor burden or transformation to MPNST. Serum biomarkers would be useful to verify NF1 diagnosis, monitor tumor burden, and/or detect transformation.
Experimental Design: We used microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma Schwann cells, neurofibromas, and MPNST. We validated differential expression by quantitative reverse transcription-PCR, Western blotting, and ELISA assays in cell conditioned medium and control and NF1 patient sera.
Results: Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed as differentially expressed and elevated in serum of NF1 patients. ADM protein concentrati on was further elevated in serum of a small sampling of NF1 patients with MPNST. MPNST cell conditioned medium, containing ADM and hepatocyte growth factor, stimulated MPNST migration and endothelial cell proliferation.
Conclusions: Thus, microarray analysis identifies potential serum biomarkers for disease, and ADM is a serum biomarker of NF1. ADM serum levels do not seem to correlate with the presence of pNFs but may be a biomarker of transformation to MPNST. Clin Cancer Res; 16(20); 5048–57. ©2010 AACR.
A Phase I/II Trial Combining High-Dose Melphalan and Autologous Transplant with Bortezomib for Multiple Myeloma: A Dose- and Schedule-Finding Study
Authors: Lonial Sagar , Kaufman Jonathan , Tighiouart Mourad , Nooka Ajay , Langston Amelia A. , Heffner Leonard T. , Torre Claire , McMillan Stephanie , Renfroe Heather , Harvey R. Donald , Lechowicz Mary J. , Khoury H. Jean , Flowers Christopher R. , Waller Edmund K. 
Published: August 2010

Abstract
Purpose: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.
Experimental Design: Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m2) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.
Results: Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.
Conclusions: The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation. Clin Cancer Res; 16(20); 5079–86. ©2010 AACR.
Intramedullary Acromioclavicular Ligament Reconstruction Strengthens Isolated Coracoclavicular Ligament Reconstruction in Acromioclavicular Dislocations
Authors: Gonzalez-Lomas Guillem , Javidan Pooya , Lin Tony , Adamson Gregory J. , Limpisvasti Orr , Lee Thay Q. 
Published: August 2010

Background Techniques for reconstruction of the dislocated acromioclavicular (AC) joint abound. Most, however, do not address the injured AC ligaments and capsule. Evidence exists supporting the horizontal stabilizing effect of these ligaments on the AC joint. A novel AC and coracoclavicular (CC) reconstruction technique with an intramedullary free-tissue graft secured by suture buttons is low-profile, technically straightforward, and reproducible. Hypothesis A novel intramedullary AC reconstruction will strengthen an isolated free-tissue reconstruction of the CC ligaments. Study Design Controlled laboratory study. Methods Six cadaveric matched pair shoulders were tested with a custom testing system. Anterior-posterior and superior-inferior AC joint displacements (mm) were measured with AC joint compressions of 10 N, 20 N, and 30 N, and with translational loads of 10 N and 15 N. The same measurements were made after performing either a free-tissue tendon allograft CC reconstruction, or a free-tissue graft reconstruction of the CC and AC ligamentous complexes in the corresponding contralateral matched shoulder. The AC ligamentous complex was reconstructed with an intramedullary free-tissue graft secured by suture buttons. Load-to-failure testing was then performed on each construct. A paired t test was used for statistical analysis (P < .05). Results Mean anterior-posterior translation of the reconstruction of the CC and AC ligamentous complexes was 50% or less than that of the CC reconstruction in all loading conditions (P < .05). Mean superior-inferior translation did not differ among the groups. Overall load-to-failure testing did not differ between groups. Conclusion Intramedullary AC complex reconstruction utilizing free-tissue graft for reconstruction of both the CC and AC ligaments demonstrates significantly greater initial horizontal stability than a free tissue isolated CC reconstruction and is similar to intact specimens. Clinical Relevance This novel intramedullary AC ligament reconstruction may be considered when seeking to improve horizontal stability in an anatomical CC ligament reconstruction.
Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6
Authors: Uzawa Akiyuki , Mori Masahiro , Arai Kimihito , Sato Yasunori , Hayakawa Sei , Masuda Saeko , Taniguchi Junko , Kuwabara Satoshi 
Published: August 2010

Background: Neuromyelitis optica (NMO) is assumed to be immunologically distinct from multiple sclerosis (MS). Adequate studies about cytokines and chemokines in NMO have been lacking. Objective: To investigate the contribution of cytokines/chemokines in the pathogenesis of NMO. Methods: We measured 27 cytokines/chemokines and Th17 cell-associated cytokines in the cerebrospinal fluid (CSF) of 31 NMO, 29 MS and 18 other non-inflammatory neurological disorders patients. The serum levels of some cytokines/ chemokines were also measured. The correlations between clinical characteristics/laboratory findings and levels of cytokines/chemokines in NMO were examined. Results: The CSF levels of interleukin (IL)-1 receptor antagonist, IL-6, IL-8, IL-13 and granulocyte colony-stimulating factor were significantly increased in NMO, while IL-9, fibroblast growth factor-basic, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein-1-beta and tumor necrosis factor-alpha were increased in MS. IL-10 and interferon-gamma-inducible protein-10 were elevated in NMO and MS. In serum analyses, only the IL-6 level showed significant elevation in NMO. The CSF IL-6 level had a significant correlation with the CSF glial fibrillary acidic protein level and CSF cells, and a weak correlation with anti-aquaporin-4 antibody titers. Conclusions: Different immunological status and pathophysiologies exist between NMO and MS, and IL-6 may play important roles in the pathogenesis of NMO.
Tissue transglutaminase contributes to the all-trans-retinoic acid–induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia
Authors: Csomós Krisztián , Német István , Fésüs László , Balajthy Zoltán 
Published: August 2010

AbstractTreatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA) results in terminal differentiation of leukemic cells toward neutrophil granulocytes. Administration of ATRA leads to massive changes in gene expression, including down-regulation of cell proliferation–related genes and induction of genes involved in immune function. One of the most induced genes in APL NB4 cells is transglutaminase 2 (TG2). RNA interference–mediated stable silencing of TG2 in NB4 cells (TG2-KD NB4) coupled with whole genome microarray analysis revealed that TG2 is involved in the expression of a large number of ATRA-regulated genes. The affected genes participate in granulocyte functions, and their silencing lead to reduced adhesive, migratory, and phagocytic capacity of neutrophils and less superoxide production. The expression of genes related to cell-cycle control also changed, suggesting that TG2 regulates myeloid cell differentiation. CC chemokines CCL2, CCL3, CCL22, CCL24, and cytokines IL1B and IL8 involved in the development of differentiation syndrome are expressed at significantly lower level in TG2-KD NB4 than in wild-type NB4 cells upon ATRA treatment. Based on our results, we propose that reduced expression of TG2 in differentiating APL cells may suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of differentiation syndrome.
Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells
Authors: Gu Zhi-Min , Wu Ying-Li , Zhou Mei-Yi , Liu Chuan-Xu , Xu Han-Zhang , Yan Hua , Zhao Yong , Huang Ying , Sun Han-Dong , Chen Guo-Qiang 
Published: August 2010

AbstractAll-trans retinoic acid (ATRA), a natural ligand for the retinoic acid receptors (RARs), induces clinical remission in most acute promyelocytic leukemia (APL) patients through the induction of differentiation and/or eradication of leukemia-initiating cells. Here, we identify a novel natural ent-kaurene diterpenoid derived from Isodon pharicus leaves, called pharicin B, that can rapidly stabilize RAR-α protein in various acute myeloid leukemic (AML) cell lines and primary leukemic cells from AML patients, even in the presence of ATRA, which is known to induce the loss of RAR-α protein. Pharicin B also enhances ATRA-dependent the transcriptional activity of RAR-α protein in the promyelocytic leukemia–RARα–positive APL cell line NB4 cells. We also showed that pharicin B presents a synergistic or additive differentiation-enhancing effect when used in combination with ATRA in several AML cell lines and, especially, some primary leukemic cells from APL patients. In addition, pharicin B can overcome retinoid resistance in 2 of 3 NB4-derived ATRA-resistant subclones. These findings provide a good example for chemical biology–based investigations of pathophysiological and therapeutic significances of RAR-α and PML-RAR-α proteins. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients.
Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity
Authors: Vallelian Florence , Schaer Christian A. , Kaempfer Theresa , Gehrig Peter , Duerst Elena , Schoedon Gabriele , Schaer Dominik J. 
Published: August 2010

AbstractGlucocorticoids are used extensively to treat autoimmune hemolytic anemias. Some beneficial effects of glucocorticoid pulse therapy have also been reported in sickle cell disease and paroxysmal nocturnal hemoglobinuria. Based on established concepts of hemoglobin (Hb) toxicity and physiologic Hb scavenger systems, we evaluated whether glucocorticoids could support an adaptive response to extracellular Hb independently of their immunosuppressive activities. Using global proteome and transcriptome analysis with mass-spectrometry (isobaric tag for relative and absolute quantitation and liquid chromatography-mass spectrometry) and gene-array experiments, we found that glucocorticoid treatment in vitro and in patients on glucocorticoid-pulse therapy polarized monocytes into a M2/alternatively activated phenotype with high Hb-scavenger receptor (CD163) expression and enhanced Hb-clearance and detoxification capability. Monocytes concurrently exposed to the interactive activity of glucocorticoids and extracellular Hb were characterized by high expression of a group of antioxidant enzymes known to be regulated by the conserved oxidative response transcription factor nuclear factor E2-related factor. Further, suppressed transferrin receptor, together with high ferroportin expression, pointed to a shift in iron homeostasis directed toward an increased cellular export of heme-derived iron. Therefore, stimulating Hb-endocytosis by CD163 and enhancing antioxidative homeostasis and iron recycling may be an essential activity of glucocorticoids that helps alleviate the adverse effects of extracellular Hb.
Involvement of TIP60 acetyltransferase in intracellular Salmonellareplication
Authors: Wang Xueqin , Li Dongju , Qu Di , Zhou Daoguo 
Published: August 2010

Abstract

Background

Salmonella enterica is a facultative intracellular pathogen that replicates within a membrane-bound compartment termed Salmonella containing vacuole (SCV). The biogenesis of SCV requires Salmonella type III protein secretion/translocation system and their effector proteins which are translocated into host cells to exploit the vesicle trafficking pathways. SseF is one of these effectors required for SCV formation and Intracellular Salmonella replication through unknown mechanisms.

Results
In an attempt to identify host proteins that interact with SseF, we conduct a yeast two-hybrid screening of human cell cDNA library using SseF as the bait. We identified that TIP60, an acetyltransferase, interacts with SseF. We showed that the TIP60 acetylation activity was increased in the presence of SseF, and TIP60 was upregulated upon Salmonella infection. In addition, TIP60 is required for efficient intracellular Salmonella replication in macrophages.

Conclusion
Taken together, our data suggest that Salmonella may use SseF to exploit the host TIP60 acetyltransferase activity to promote efficient Salmonella replication inside host cells.