bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measles Virus V Protein Inhibits NLRP3 Inflammasome-Mediated Interleukin-1β Secretion
Authors: Komune Noritaka , Ichinohe Takeshi , Ito Minako , Yanagi Yusuke 
Published: October 2011

ABSTRACT
Inflammasomes are cytosolic protein complexes that stimulate the activation of caspase-1, which in turn induces the secretion of the inflammatory cytokines Interleukin-1β (IL-1β) and IL-18. Recent studies have indicated that the inflammasome known as the NOD-like-receptor-family, pyrin domain-containing 3 (NLRP3) inflammasome recognizes several RNA viruses, including the influenza and encephalomyocarditis viruses, whereas the retinoic acid-inducible gene I (RIG-I) inflammasome may detect vesicular stomatitis virus. We demonstrate that measles virus (MV) infection induces caspase-1-dependent IL-1β secretion in the human macrophage-like cell line THP-1. Gene knockdown experiments indicated that IL-1β secretion in MV-infected THP-1 cells was mediated by the NLRP3 inflammasome but not the RIG-I inflammasome. MV produces the nonstructural V protein, which has been shown to antagonize host innate immune responses. The recombinant MV lacking the V protein induced more IL-1β than the parental virus. THP-1 cells stably expressing the V protein suppressed NLRP3 inflammasome-mediated IL-1β secretion. Furthermore, coimmunoprecipitation assays revealed that the V protein interacts with NLRP3 through its carboxyl-terminal domain. NLRP3 was located in cytoplasmic granular structures in THP-1 cells stably expressing the V protein, but upon inflammasome activation, NLRP3 was redistributed to the perinuclear region, where it colocalized with the V protein. These results indicate that the V protein of MV suppresses NLRP3 inflammasome-mediated IL-1β secretion by directly or indirectly interacting with NLRP3.
Functional Genomics Reveals an Essential and Specific Role for Stat1 in Protection of the Central Nervous System following Herpes Simplex Virus Corneal Infection
Authors: Pasieka Tracy Jo , Cilloniz Cristian , Carter Victoria S. , Rosato Pamela , Katze Michael G. , Leib David A. 
Published: October 2011

ABSTRACT

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1
−/−
) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1
−/−
mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1
−/−
mice). Through the use of functional genomics on the infected brain stems, we determined gene signatures that were representative of the three infection outcomes. We demonstrated a pathological signature in the brain stem of Stat1-deficient mice characterized by upregulation of transcripts encoding chemokine receptors, inflammatory markers, neutrophil chemoattractants, leukocyte adhesion proteins, and matrix metalloproteases. Additionally, there was a greater than 100-fold increase in the inflammatory markers interleukin 1β (IL-1β) and IL-6. Consistent with this gene signature, we demonstrated profound CNS inflammation with a concomitant lethal breach of the BBB. Taken together, our results indicated an essential role for normal Stat1-dependent signaling in mediating a nonpathological immune response to viral CNS infection.
Late Neogene volcanics and interbedded palaeosols near Mount Kenya
Authors: Mahaney W. C. , Barendregt René W. , Villeneuve Mike , Dostal Jaroslav , Hamilton T. S. , Milner Michael W. 
Published: October 2011

Abstract

Two lava flows with interbedded palaeosols outcrop
c.
40 km SW of Mount Kenya, near the Amboni River north of Mweiga, Kenya along the Nyeri/Thompson Falls Road, at 0°18′S; 37°48′E. These flows, overlain by loess, are principally trachyandesite and form the base of the Mount Kenya Volcanic Series which, in the early literature, is described as being of probable Miocene/Pliocene age. Here we report
39
Ar/
40
Ar dates (
c.
5.2–5.5 Ma) and reversed magnetizations which establish a Latest Miocene to Earliest Pliocene age for these flows. Weathering characteristics of palaeosols interbedded with the lavas indicate generally dry climatic conditions during the Late Miocene, punctuated with humid events during the Pliocene and Quaternary. These Late Miocene–Quaternary palaeosols depict a relatively long and complex weathering history, followed by loess deposition. The palaeosols appear to have been episodically deflated, initially in phase with the deposition of lavas when surfaces were devoid of vegetation and later during periods of climatic deterioration when wind systems intensified. Such weathering histories within palaeosol profiles are also documented on nearby Mount Kenya, where well-weathered lower palaeosol horizons developed on Matuyama-age tills are overlain by much younger less-weathered horizons developed on Brunhes-age loess. The geochronology of Late Miocene lavas reported here provides maximum ages for weathering histories of palaeosols formed in a xeric tropical highland climate.
Tectonosedimentary expressions of the evolution of the Fungurume foreland basin in the Lufilian Arc, Neoproterozoic–Lower Palaeozoic, Central Africa
Authors: Wendorff Marek 
Published: October 2011

Abstract

The Lufilian Arc is a part of the Neoproterozoic–Lower Palaeozoic Pan-African orogenic system within southern and central Africa. The succession of the Lufilian orogen, the Katanga Supergroup, contains large bodies of fragmental rocks recently interpreted as syntectonic conglomerates, which reveal the existence of two previously unrecognized basins and shed new light on tectonic evolution of the belt. Rifting between the Congo Craton in the north and the Kalahari Craton in the south at
c.
880 Ma resulted in the opening of two rift basins: the Roan rift and the succeeding Nguba rift. During post-735 Ma orogenesis, north-advancing nappes supplied detritus into the Fungurume foreland basin in the northern part of the Lufilian Arc. The coarse-clastic sequence of the Fungurume Group includes olistostromes that contain olistoliths of the pre-existing Katangan rocks, rest upon a syntectonic unconformity and are overridden by the Katangan nappes/thrust sheets. Strong tectonic deformations of strata within the olistoliths reflect their provenance from the orogenic source of the Katangan nappes. By contrast, the olistostrome matrix is essentially intact even when olistostrome occurs as a part of a tight fold. These structural relations suggest that nappe overthrusting and further deformation of the foreland occurred soon after deposition of the olistostrome sediments, and prior to their lithification.
Treatment of Hematologic Malignancies with Immunotoxins and Antibody-Drug Conjugates
Authors: FitzGerald David J. , Wayne Alan S. , Kreitman Robert J. , Pastan Ira 
Published: October 2011

AbstractTo enable antibodies to function as cytotoxic anticancer agents, they are modified either via attachment to protein toxins or highly potent, low-molecular-weight drugs. Such molecules, termed immunotoxins and antibody-drug conjugates, respectively, represent a second revolution in antibody-mediated cancer therapy. Thus, highly toxic compounds are delivered to the interior of cancer cells based on antibody specificity for cell-surface target antigens. Cancer Res; 71(20); 6300–9. ©2011 AACR.
Hepatitis B Virus Large Surface Antigen Promotes Liver Carcinogenesis by Activating the Src/PI3K/Akt Pathway
Authors: Liu Haiou , Xu Jiejie , Zhou Lei , Yun Xiaojing , Chen Lin , Wang Shanshan , Sun Linlin , Wen Yumei , Gu Jianxin 
Published: October 2011

Abstract
Of the three envelope glycoproteins encoded by hepatitis B virus (HBV) that are collectively referred to as HBV surface antigen (HBsAg), the large HBsAg (LHBs) glycoprotein is expressed preferentially in HBV-associated hepatocellular carcinoma. LHBs can act as an oncogene in transgenic mice, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of LHBs during HBV-associated hepatocarcinogenesis. LHBs increased tumor formation of hepatoma cells. Moreover, expression of LHBs but not other HBV envelope glycoproteins specifically promoted proliferation of hepatoma and hepatic cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal stimulation of PKCα/Raf1 signaling by LHBs. Proliferation induced by stable LHBs expression was associated with increased G1–S cell-cycle progression and apoptosis resistance mediated by Src kinase activation, as established in hepatocellular carcinoma clinical specimens. Importantly, LHBs-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that LHBs promotes tumorigenesis of hepatoma cells by triggering a PKCα/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis. Cancer Res; 71(24); 7547–57. ©2011 AACR.
A Let-7 MicroRNA SNP in the KRAS 3′UTR Is Prognostic in Early-Stage Colorectal Cancer
Authors: Smits Kim M. , Paranjape Trupti , Nallur Sunitha , Wouters Kim A.D. , Weijenberg Matty P. , Schouten Leo J. , van den Brandt Piet A. , Bosman Fred T. , Weidhaas Joanne B. , van Engeland Manon 
Published: October 2011

Abstract
Purpose: Colorectal cancer (CRC) is a common cause of death worldwide. Tumor-node-metastasis-system stage is currently used to guide therapy decisions but lacks precision. Prognostic biomarkers are needed to refine stratification of patients for chemotherapy but validated biomarkers are not yet available. Recently, a SNP in a lethal-7 (let-7) miRNA complementary site (LCS6) in the KRAS 3′untranslated region was suggested to affect survival in metastatic CRC. Effects in early-stage CRC are however unknown. We studied KRAS-LCS6 genotype, hypothesizing that it might identify early-stage cases with a poor prognosis, and could potentially be used in therapy decision-making.
Experimental Design: We studied 409 early stage, 182 stage III, and 69 stage IV cases, and 1,886 subcohort members from the Netherlands Cohort Study. KRAS-LCS6 genotype was assessed with TaqMan PCR. Kaplan–Meier analyses or Cox regression were used to assess associations between genotype and CRC risk or cause-specific survival.
Results: Early-stage cases with the KRAS-LCS6 variant had a lower CRC risk (incidence-rate ratio 0.68; 95% CI: 0.49–0.94) and a better survival (log-rank P = 0.038; HR 0.46; 95% CI: 0.18–1.14). In patients with KRAS-mutated CRC carrying the KRAS-LCS6 variant, the better outcome was enhanced as no patients died of CRC (log-rank P = 0.017). In advanced patients, no clear association between genotype and CRC risk or survival was observed.
Conclusions: Our results indicate that early-stage CRC cases with the KRAS-LCS6 variant have a better outcome. In advanced disease, the better outcome no longer exists. For early-stage patients, KRAS-LCS6 genotype combined with KRAS mutations merits validation as a prognostic biomarker and consideration in therapy decision-making. Clin Cancer Res; 17(24); 7723–31. ©2011 AACR.
Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner
Authors: Chen Peiwen , Huang Yujie , Bong Rosabel , Ding Yanping , Song Nan , Wang Xiaofeng , Song Xiaomin , Luo Yongzhang 
Published: October 2011

AbstractPurpose: Elevated numbers of tumor-associated macrophages (TAM) in the tumor microenvironment are often correlated with poor prognosis in melanoma. However, the mechanisms by which TAMs modulate melanoma growth are still poorly understood. This study was aimed at examining the function and mechanism of TAM-derived adrenomedullin (ADM) in angiogenesis and melanoma growth.Experimental Design: We established in vitro and in vivo models to investigate the relationship between TAMs and ADM in melanoma, the role and mechanism of ADM in TAM-induced angiogenesis and melanoma growth. The clinical significance of ADM and its receptors was evaluated using melanoma tissue microarrays.Results: ADM was expressed by infiltrating TAMs in human melanoma, and its secretion from macrophages was upregulated upon coculture with melanoma cells, or with melanoma cells conditioned media. Meanwhile, TAMs enhanced endothelial cell migration and tubule formation and also increased B16/F10 tumor growth. Neutralizing ADM antibody and ADM receptor antagonist, AMA, attenuated TAM-induced angiogenesis in vitro and melanoma growth in vivo, respectively. Furthermore, ADM promoted angiogenesis and melanoma growth via both the paracrine effect, mediated by the endothelial nitric oxide synthase signaling pathway, and the autocrine effect, which stimulated the polarization of macrophages toward an alternatively activated (M2) phenotype. Finally, immunofluorescence analysis on human melanomas showed that the expression of ADM in TAMs and its receptors was greatly increased compared with adjacent normal skins.Conclusion: Our study reveals a novel mechanism that TAMs enhance angiogenesis and melanoma growth via ADM and provides potential targets for melanoma therapies. Clin Cancer Res; 17(23); 7230–9. ©2011 AACR.
Mapping of Chromosome 1p Deletions in Myeloma Identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as Being Genes in Regions Associated with Adverse Survival
Authors: Boyd Kevin D. , Ross Fiona M. , Walker Brian A. , Wardell Christopher P. , Tapper William J. , Chiecchio Laura , Dagrada GianPaolo , Konn Zoe J. , Gregory Walter M. , Jackson Graham H. , Child J. Anthony , Davies Faith E. , Morgan Gareth J. 
Published: October 2011

Abstract
Purpose: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact.
Experimental Design: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data.
Results: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting.
Conclusion: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations. Clin Cancer Res; 17(24); 7776–84. ©2011 AACR.
The Novel Bcl-2 Inhibitor ABT-737 Is More Effective in Hypoxia and Is Able to Reverse Hypoxia-Induced Drug Resistance in Neuroblastoma Cells
Authors: Klymenko Tetyana , Brandenburg Martin , Morrow Christopher , Dive Caroline , Makin Guy 
Published: October 2011

Abstract
Neuroblastoma is a common solid tumor of childhood and advanced disease carries a poor prognosis despite intensive multimodality therapy. Hypoxia is a common feature of solid tumors because of poorly organized tumor-induced neovasculature. Hypoxia is associated with advanced stage and poor outcome in a range of tumor types, and leads to resistance to clinically relevant cytotoxic agents in neuroblastoma and other pediatric tumors in vitro. Resistance to apoptosis is a common feature of tumor cells and leads to pleiotropic drug resistance, mediated by Bcl-2 family proteins. ABT-737 is a novel small-molecule inhibitor of Bcl-2 and Bcl-xL that is able to induce apoptosis in a range of tumor types. Neuroblastoma cell lines are relatively resistant to ABT-737–induced apoptosis in normoxia, but in contrast to the situation with conventional cytotoxic agents are more sensitive in hypoxia. This sensitization is because of an increase in ABT-737–induced apoptosis and is variably dependent upon the presence of functional hypoxia-inducible factor 1 (HIF-1) α. In contrast to the situation in colon carcinoma and non–small cell lung cancer cells, hypoxia does not result in downregulation of the known ABT-737 resistance factor, Mcl-1, nor any other Bcl-2 family proteins. ABT-737 sensitizes neuroblastoma cells to clinically relevant cytotoxic agents under normal levels of oxygen, and importantly, this sensitization is maintained under hypoxia when neuroblastoma cells are resistant to these agents. Thus rational combinations of ABT-737 and conventional cytotoxics offer a novel approach to overcoming hypoxia-induced drug resistance in neuroblastoma. Mol Cancer Ther; 10(12); 2373–83. ©2011 AACR.
Notch Signaling Contributes to Lung Cancer Clonogenic Capacity In Vitro but May Be Circumvented in Tumorigenesis In Vivo
Authors: Osanyingbemi-Obidi Joyce , Dobromilskaya Irina , Illei Peter B. , Hann Christine L. , Rudin Charles M. 
Published: October 2011

Abstract
The Notch signaling pathway is a critical embryonic developmental regulatory pathway that has been implicated in oncogenesis. In non–small cell lung cancer (NSCLC), recent evidence suggests that Notch signaling may contribute to maintenance of a cancer stem or progenitor cell compartment required for tumorigenesis. We explored whether intact Notch signaling is required for NSCLC clonogenic and tumorigenic potential in vitro and in vivo using a series of genetically modified model systems. In keeping with previous observations, we find that Notch3 in particular is upregulated in human lung cancer lines and that downregulation of Notch signaling using a selective γ-secretase inhibitor (MRK-003) is associated with decreased proliferation and clonogenic capacity in vitro. We show that this phenotype is rescued with the expression of NICD3, a constitutively active cleaved form of Notch3 not affected by γ-secretase inhibition. Using an inducible LSL-KRASG12D model of lung cancer in vivo, we show a transient upregulation of Notch pathway activity in early tumor precursor lesions. However, a more rigorous test of the requirement for Notch signaling in lung oncogenesis, crossing the LSL-KRASG12D mouse model with a transgenic with a similarly inducible global dominant-negative suppressor of Notch activity, LSL-DNMAML (dominant-negative mastermind-like), reveals no evidence of Notch pathway requirement for lung tumor initiation or growth in vivo. Distinct Notch family members may have different and potentially opposing activities in oncogenesis, and targeted inhibition of individual Notch family members may be a more effective anticancer strategy than global pathway suppression. Mol Cancer Res; 9(12); 1746–54. ©2011 AACR.
Plasma levels of potassium and magnessium after modified ultrafiltration in pediatric cardiac surgery with cardiopulmonary bypass
Authors: López R , Lema G , González A , Carvajal C , Canessa R , Carrasco P , Lazo V , Hudson C , Gonzalez R , Frangini P 
Published: October 2011

Objective: Modified ultrafiltration (MUF) reduces some of the complications associated with cardiopulmonary bypass (CPB) in pediatric cardiac surgery. However, we have observed hypokalemia and hypomagnesemia in children when MUF is used. Such alterations may elicit severe arrhythmias in the postoperative period. To date, no studies have focused on the effects MUF may have in plasma levels of potassium (K) and magnesium (Mg). The objective of our study was to determine if there is any variation in plasma levels of K (plK) and Mg (plMg) after MUF in children undergoing cardiac surgery with CPB. Patients: Sixteen children scheduled for cardiac surgery with CBP and MUF were prospectively studied. Anesthetic, CPB and MUF management were standardized for all patients, the latter lasting for 10 minutes. Results: Plasma K average levels before and after MUF were 4.16 mmol/L and 3.58 mmol/L, respectively. The average plasma Mg levels before and after MUF were 4.82 mmol/L and 4.81 mmol/L, respectively. Conclusions: The plasma level of K is reduced by 13.7% after MUF (p<0.0001). The reduction in Mg at the same period of time was not statistically significant (p<0.970).
Applications of instrumented indentation testing for the characterization of polypropylene materials
Authors: Koch T , Seidler S 
Published: October 2011

In this study, instrumented indentation testing, or so-called depth-sensing indentation testing, was used to characterize polypropylene (PP) materials. The influence of molecular weight and cooling rate on the hardness was investigated showing that low cooling rates and relatively low molecular weight lead to higher hardness values. In random copolymers of propene with butene and hexene, the correlation between hardness and degree of crystallinity is linear and the conversion to the amorphous state could be detected. Blends of PP with ethylene–propylene elastomer show a strong negative deviation of indentation modulus from linear rule of mixture. This behaviour can be described by Kerner’s model in the case of particulate arrangement and by Davies’ model in the phase inversion region. The addition of high-density polyethylene to PP results in a synergistic behaviour of modulus which can be attributed to nucleation effects. Furthermore, the application of indentation testing to detect physical ageing of a surface of an injection-moulded specimen and heterogeneity of weld lines was shown. Orientations in a biaxially oriented film could be detected using Knoop indenter.