bluuebunny/crossref_metadata_2025_split huggingface dataset:
Production and Release of Antimicrobial and Immune Defense Proteins by Mammary Epithelial Cells following Streptococcus uberis Infection of Sheep
Authors: Addis Maria Filippa , Pisanu Salvatore , Marogna Gavino , Cubeddu Tiziana , Pagnozzi Daniela , Cacciotto Carla , Campesi Franca , Schianchi Giuseppe , Rocca Stefano , Uzzau Sergio 
Published: June 2013

ABSTRACTInvestigating the innate immune response mediators released in milk has manifold implications, spanning from elucidation of the role played by mammary epithelial cells (MECs) in fighting microbial infections to the discovery of novel diagnostic markers for monitoring udder health in dairy animals. Here, we investigated the mammary gland response following a two-step experimental infection of lactating sheep with the mastitis-associated bacteriumStreptococcus uberis. The establishment of infection was confirmed both clinically and by molecular methods, including PCR and fluorescentin situhybridization of mammary tissues. Proteomic investigation of the milk fat globule (MFG), a complex vesicle released by lactating MECs, enabled detection of enrichment of several proteins involved in inflammation, chemotaxis of immune cells, and antimicrobial defense, including cathelicidins and calprotectin (S100A8/S100A9), in infected animals, suggesting the consistent involvement of MECs in the innate immune response to pathogens. The ability of MECs to produce and release antimicrobial and immune defense proteins was then demonstrated by immunohistochemistry and confocal immunomicroscopy of cathelicidin and the calprotectin subunit S100A9 on mammary tissues. The time course of their release in milk was also assessed by Western immunoblotting along the course of the experimental infection, revealing the rapid increase of these proteins in the MFG fraction in response to the presence of bacteria. Our results support an active role of MECs in the innate immune response of the mammary gland and provide new potential for the development of novel and more sensitive tools for monitoring mastitis in dairy animals.
Systemic CD14 Inhibition Attenuates Organ Inflammation in Porcine Escherichia coli Sepsis
Authors: Thorgersen Ebbe Billmann , Pischke Søren Erik , Barratt-Due Andreas , Fure Hilde , Lindstad Julie Katrine , Pharo Anne , Hellerud Bernt Christian , Mollnes Tom Eirik 
Published: June 2013

ABSTRACT

Sepsis is an infection-induced systemic inflammatory response syndrome. Upstream recognition molecules, like CD14, play key roles in the pathogenesis. The aim of the present study was to investigate the effect of systemic CD14 inhibition on local inflammatory responses in organs from septic pigs. Pigs (
n
= 34) receiving
Escherichia coli
-bacteria or
E. coli
-lipopolysaccharide (LPS) were treated with an anti-CD14 monoclonal antibody or an isotype-matched control. Lungs, liver, spleen, and kidneys were examined for bacteria and inflammatory biomarkers.
E. coli
and LPS were found in large amounts in the lungs compared to the liver, spleen, and kidneys. Notably, the bacterial load did not predict the respective organ inflammatory response. There was a marked variation in biomarker induction in the organs and in the effect of anti-CD14. Generally, the spleen produced the most cytokines per weight unit, whereas the liver contributed the most to the total load. All cytokines were significantly inhibited in the spleen. Interleukin-6 (IL-6) was significantly inhibited in all organs, IL-1β and IP-10 were significantly inhibited in liver, spleen, and kidneys, and tumor necrosis factor, IL-8, and PAI-1 were inhibited only in the spleen. ICAM-1 and VCAM-1 was significantly inhibited in the kidneys. Systemic CD14-inhibition efficiently, though organ dependent, attenuated local inflammatory responses. Detailed knowledge on how the different organs respond to systemic inflammation
in vivo
, beyond the information gained by blood examination, is important for our understanding of the nature of systemic inflammation and is required for future mediator-directed therapy in sepsis. Inhibition of CD14 seems to be a good candidate for such treatment.
The Intracellular Environment of Human Macrophages That Produce Nitric Oxide Promotes Growth of Mycobacteria
Authors: Jung Joo-Yong , Madan-Lala Ranjna , Georgieva Maria , Rengarajan Jyothi , Sohaskey Charles D. , Bange Franz-Christoph , Robinson Cory M. 
Published: June 2013

ABSTRACT

Nitric oxide (NO) is a diffusible radical gas produced from the activity of nitric oxide synthase (NOS). NOS activity in murine macrophages has a protective role against mycobacteria through generation of reactive nitrogen intermediates (RNIs). However, the production of NO by human macrophages has remained unclear due to the lack of sensitive reagents to detect NO directly. The purpose of this study was to investigate NO production and the consequence to mycobacteria in primary human macrophages. We found that
Mycobacterium bovis
BCG or
Mycobacterium tuberculosis
infection of human macrophages induced expression of NOS2 and NOS3 that resulted in detectable production of NO. Treatment with gamma interferon (IFN-γ),
l
-arginine, and tetrahydrobiopterin enhanced expression of NOS2 and NOS3 isoforms, as well as NO production. Both of these enzymes were shown to contribute to NO production. The maximal level of NO produced by human macrophages was not bactericidal or bacteriostatic to
M. tuberculosis
or BCG. The number of viable mycobacteria was increased in macrophages that produced NO, and this requires expression of nitrate reductase. An
narG
mutant of
M. tuberculosis
persisted but was unable to grow in human macrophages. Taken together, these data (i) enhance our understanding of primary human macrophage potential to produce NO, (ii) demonstrate that the level of RNIs produced in response to IFN-γ
in vitro
is not sufficient to limit intracellular mycobacterial growth, and (iii) suggest that mycobacteria may use RNIs to enhance their survival in human macrophages.
Review of the utility of infrared remote sensing for detecting and monitoring volcanic activity with the case study of shortwave infrared data for Lascar Volcano from 2001–2005
Authors: Blackett Matthew 
Published: June 2013

Abstract
This chapter provides a historical review of the use of infrared remote sensing for the monitoring of volcanic activity. It (1) examines the theoretical basis for infrared observations of thermally anomalous volcanic features, (2) presents the various sensors that have been used and are currently available and (3) describes the techniques that have been developed to analyse such data. The chapter ends with a case study of data derived from Advanced Spaceborne Thermal Emission and Reflection Radiometer shortwave infrared observations of Lascar Volcano in Chile. This case study aims to highlight the utility of infrared observations in volcanological studies, assessing the various techniques that can be used and examining the different factors which influence these analyses. The chapter ends discussing future prospects for volcanic infrared remote sensing.
The Value of CA 125 and CA72‐4 in Management of Patients with Epithelial Ovarian Cancer
Authors: Fayed Salah T. , Ahmad Samira M. , Kassim Samar K. , Khalifa Ali 
Published: June 2013

The role of the tumor markers CA125 and CA72‐4 has been evaluated in the diagnosis and management of ovarian cancer. Both markers were measured in 30 patients with proven epithelial ovarian cancer, 30 patients with benign pelvic masses and 30 normal women. CA125 and CA72‐4 were measured using the luminometric immunoassay and immuno‐radiometric assay respectively. All patients with ovarian cancer were submitted to surgical staging and cytoreduction followed by adjuvant platinum based chemotherapy for 3–6 courses. Fixing the specificity at 95%, CA125 had a sensitivity of 76.7% at a cut‐off 85u/ml while CA72‐4 had a sensitivity of 70% at a cut‐off 8.5 u/ml. The combination of CA72‐4 with CA125 increased the sensitivity to 95% while fixing the specificity at 95%. Among seven cases with stage I and II ovarian cancer five cases had CA125 level below 85 U/ml, three patients out of them had CA72‐4 above 8.5 U/ml. CA 72‐4 could reflect the residual disease following cytoreduction and could improve the detection of relapse by CA125.Conclusion: CA72‐4 could complement the standard tumor marker CA125 both in diagnosis and follow up of patients with epithelial ovarian cancer.
The Genetics of Signal Transduction and the Feto‐Maternal Relationship. A Study of Cytosolic Low Molecular Weight Phosphotyrosine Phosphatase
Authors: Bottini E. , Cosmi E. , Nicotra M. , Santeusanio G. , La Torre M. , Bottini N. , Lucarini N. 
Published: June 2013

Intracellular kinases mediate positive signalling from surface receptors by phosphorylating critical target proteins whereas phosphatases inhibit this process. Differential phosphatase activity at the feto‐maternal interface could determine the appropriate relative growth and development on each side of the placenta.The highly polymorphic cytosolic low molecular weight phosphotyrosine‐phosphatase (ACP1‐cLMWPTPase) has been studied in 170 women who had at least two consecutive spontaneous abortions along with their husbands and in 352 normal puerperae along with their newborn babies.Symmetry analysis of joint wife/husband and mother/infant distribution suggests that when ACP1 activity is lower in the mother than in either her aborted fetus or her child, the probability of abortion is higher and the survival to term is lower as compared to pairs in which the ACP1 activity is higher in the mother than in her fetus. Further analysis has shown that the effect is due to S isoform: i.e. a high mother/fetus S isoform ratio favours intrauterine survival.Analysis of gestational duration and birth weight suggests that a high ACP1 maternal activity coupled with a low or moderate fetal activity favour fetal growth and developmental maturation.The present data indicate that maternal‐fetal genetic differences in signal transduction could contribute significantly to variability of intrauterine developmental parameters and to pathological manifestation of pregnancy.
Screening of the FcεRI‐β‐Gene in a Swiss Population of Asthmatic Children: No Association with E237G and Identification of New Sequence Variations
Authors: Rohrbach M. , Kraemer R. , Liechti-Gallati S. 
Published: June 2013

Background: The gene of the beta subunit of the high affinity receptor for IgE (FcεRI‐β) encoded on chromosome 11q13 has recently been identified as a candidate gene for asthma and atopy. Two coding variations, E237G and I181L have been described as being associated with asthma and atopy. Our aim was to investigate a Swiss population of atopic and asthmatic children for variations in this gene.Methods: We screened all 7 exons of the FcεRI‐β‐ gene in 224 atopic/asthmatic, 68 relatives and 159 control subjects using exon amplification by PCR and single strand conformation polymorphism (SSCP) analysis followed by fluorescence based DNA sequencing.Results: The sequence variant E237G was found in 3.7% in atopics and in 2.6% in the control population. None of the samples carried the I181L mutation. In addition, we characterised nine novel mutations (1 nonsense mutation, 2 missense mutations, mutation, 2 silent mutations, 4 intronic mutations).Conclusions: Our results suggest that the E237G does not have a primary effect on the development of atopy and asthma, and thus excludes the FcεRI‐β locus from being a candidate gene directly involved in these diseases.
LIN28Expression in Malignant Germ Cell Tumors Downregulateslet-7and Increases Oncogene Levels
Authors: Murray Matthew J. , Saini Harpreet K. , Siegler Charlotte A. , Hanning Jennifer E. , Barker Emily M. , van Dongen Stijn , Ward Dawn M. , Raby Katie L. , Groves Ian J. , Scarpini Cinzia G. , Pett Mark R. , Thornton Claire M. , Enright Anton J. , Nicholson James C. , Coleman Nicholas 
Published: June 2013

AbstractDespite their clinicopathologic heterogeneity, malignant germ cell tumors (GCT) share molecular abnormalities that are likely to be functionally important. In this study, we investigated the potential significance of downregulation of the let-7 family of tumor suppressor microRNAs in malignant GCTs. Microarray results from pediatric and adult samples (n = 45) showed that LIN28, the negative regulator of let-7 biogenesis, was abundant in malignant GCTs, regardless of patient age, tumor site, or histologic subtype. Indeed, a strong negative correlation existed between LIN28 and let-7 levels in specimens with matched datasets. Low let-7 levels were biologically significant, as the sequence complementary to the 2 to 7 nt common let-7 seed “GAGGUA” was enriched in the 3′ untranslated regions of mRNAs upregulated in pediatric and adult malignant GCTs, compared with normal gonads (a mixture of germ cells and somatic cells). We identified 27 mRNA targets of let-7 that were upregulated in malignant GCT cells, confirming significant negative correlations with let-7 levels. Among 16 mRNAs examined in a largely independent set of specimens by quantitative reverse transcription PCR, we defined negative-associations with let-7e levels for six oncogenes, including MYCN, AURKB, CCNF, RRM2, MKI67, and C12orf5 (when including normal control tissues). Importantly, LIN28 depletion in malignant GCT cells restored let-7 levels and repressed all of these oncogenic let-7 mRNA targets, with LIN28 levels correlating with cell proliferation and MYCN levels. Conversely, ectopic expression of let-7e was sufficient to reduce proliferation and downregulate MYCN, AURKB, and LIN28, the latter via a double-negative feedback loop. We conclude that the LIN28/let-7 pathway has a critical pathobiologic role in malignant GCTs and therefore offers a promising target for therapeutic intervention. Cancer Res; 73(15); 4872–84. ©2013 AACR.
CTEN Prolongs Signaling by EGFR through Reducing Its Ligand-Induced Degradation
Authors: Hong Shiao-Ya , Shih Yi-Ping , Li Tianhong , Carraway Kermit L. , Lo Su Hao 
Published: June 2013

Abstract
Activation of EGF receptor (EGFR) triggers signaling pathways regulating various cellular events that contribute to tissue development and function. Aberrant activation of EGFR contributes to tumor progression as well as therapeutic resistance in patients with cancer. C-terminal tensin-like (CTEN; TNS4) is a focal adhesion molecule that is a member of the tensin family. Its expression is upregulated by EGF and elevated CTEN mediates EGF-induced cell migration. In the presence of CTEN, we found that EGF treatment elevated the level of EGFR protein but not mRNA. The extended half-life of activated EGFR sustained its signaling cascades. CTEN reduced ligand-induced EGFR degradation by binding to the E3 ubiquitin ligase c-Cbl and decreasing the ubiquitination of EGFR. The Src homology 2 domain of CTEN is not only required for binding to the phosphorylated tyrosine residue at codon 774 of c-Cbl, but is also essential for the tumorigenicity observed in the presence of CTEN. Public database analyses indicated that CTEN mRNA levels are elevated in breast, colon, lung, and pancreas cancers, but not correlated with EGFR mRNA levels in these cancers. In contrast, immunohistochemistry analyses of lung cancer specimens showed that CTEN and EGFR protein levels were positively associated, in support of our finding that CTEN regulates EGFR protein levels through a posttranslational mechanism. Overall, this work defines a function for CTEN in prolonging signaling from EGFR by reducing its ligand-induced degradation. Cancer Res; 73(16); 5266–76. ©2013 AACR.
Pivotal Role of the Lipid Raft SK3–Orai1 Complex in Human Cancer Cell Migration and Bone Metastases
Authors: Chantôme Aurélie , Potier-Cartereau Marie , Clarysse Lucie , Fromont Gaëlle , Marionneau-Lambot Séverine , Guéguinou Maxime , Pagès Jean-Christophe , Collin Christine , Oullier Thibauld , Girault Alban , Arbion Flavie , Haelters Jean-Pierre , Jaffrès Paul-Alain , Pinault Michelle , Besson Pierre , Joulin Virginie , Bougnoux Philippe , Vandier Christophe 
Published: June 2013

Abstract
The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca2+ entry and cancer cell migration through an interaction with the Ca2+ channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3–Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3–Orai1 lipid raft localization. Upon Ohmline treatment, the SK3–Orai1 complex moved away from lipid rafts, and SK3-dependent Ca2+ entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3–Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases. Cancer Res; 73(15); 4852–61. ©2013 AACR.
A Functional Variant at 19q13.3, rs967591G&gt;A, Is Associated with Shorter Survival of Early-Stage Lung Cancer
Authors: Jeon Hyo-Sung , Jin Guang , Kang Hyo-Gyoung , Choi Yi Young , Lee Won Kee , Choi Jin Eun , Bae Eun Young , Yoo Seung Soo , Lee Shin Yup , Lee Eung Bae , Kim Young Tae , Lee Jaehee , Cha Seung-Ick , Kim Chang Ho , Jheon Sanghoon , Kim In San , Park Jae Yong 
Published: June 2013

Abstract
Purpose: This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) in 19q13.3 and survival of patients with early-stage non–small cell lung cancer (NSCLC), and to define the causative functional SNP of the association.
Experimental Design: A two-stage study design was used to evaluate five SNPs in relation to survival outcomes in 328 patients and then to validate the results in an independent patient population (n = 483). Luciferase assay and real-time PCR were conducted to examine functional relevance of a potentially functional SNP.
Results: Of the five SNPs, three SNPs (rs105165C&gt;T, rs967591G&gt;A, and rs735482A&gt;C) were significantly associated with survival outcomes in a stage I study. The rs967591A allele had significantly higher activity of the CD3EAP promoter compared with the rs967591G allele (P = 0.002), but the SNP did not have an effect on the activity of PPP1R13L promoter. The rs967591G&gt;A was associated with the level of CD3EAP mRNA expression in lung tissues (P = 0.01). The rs967591G&gt;A exhibited consistent associations in a stage II study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted HR = 1.69; 95% confidence interval = 1.29–2.20; P = 0.0001).
Conclusion: The rs967591G&gt;A affects CD3EAP expression and thus influences survival in early-stage NSCLC. The analysis of the rs967591G&gt;A polymorphism can help identify patients at high risk of a poor disease outcome. Clin Cancer Res; 19(15); 4185–95. ©2013 AACR.
U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma
Authors: Herndon Thomas M. , Deisseroth Albert , Kaminskas Edvardas , Kane Robert C. , Koti Kallappa M. , Rothmann Mark D. , Habtemariam Bahru , Bullock Julie , Bray Jeffrey D. , Hawes Jessica , Palmby Todd R. , Jee Josephine , Adams William , Mahayni Houda , Brown Janice , Dorantes Angelica , Sridhara Rajeshwari , Farrell Ann T. , Pazdur Richard 
Published: June 2013

Abstract
The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy. Clin Cancer Res; 19(17); 4559–63. ©2013 AACR.
ZNF365 Promotes Stability of Fragile Sites and Telomeres
Authors: Zhang Yuqing , Shin Sandra J. , Liu Debra , Ivanova Elena , Foerster Friedrich , Ying Haoqiang , Zheng Hongwu , Xiao Yonghong , Chen Zhengming , Protopopov Alexei , DePinho Ronald A. , Paik Ji-Hye 
Published: June 2013

Abstract
Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites, including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange and formation of anaphase DNA bridges, including ultra-fine DNA bridges, and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53–ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction.
Significance: The contribution of the p53–ZNF365–telomere axis in the suppression of genomic instability illuminates how alterations in this pathway may confer increased cancer risk for individuals harboring germline alterations in the ZNF365 locus. Cancer Discov; 3(7); 798–811. ©2013 AACR.
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