bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Macrophages to Target Therapeutic Adenovirus to Human Prostate Tumors
Authors: Muthana Munitta , Giannoudis Athina , Scott Simon D. , Fang Hsin-Yu , Coffelt Seth B. , Morrow Fiona J. , Murdoch Craig , Burton Julian , Cross Neil , Burke Bernard , Mistry Roshna , Hamdy Freddie , Brown Nicola J. , Georgopoulos Lindsay , Hoskin Peter , Essand Magnus , Lewis Claire E. , Maitland Norman J. 
Published: January 2011

Abstract
New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural “homing” of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells. Cancer Res; 71(5); 1805–15. ©2011 AACR.
Therapeutic Inhibition of MAP Kinase Interacting Kinase Blocks Eukaryotic Initiation Factor 4E Phosphorylation and Suppresses Outgrowth of Experimental Lung Metastases
Authors: Konicek Bruce W. , Stephens Jennifer R. , McNulty Ann M. , Robichaud Nathaniel , Peery Robert B. , Dumstorf Chad A. , Dowless Michele S. , Iversen Philip W. , Parsons Stephen , Ellis Karen E. , McCann Denis J. , Pelletier Jerry , Furic Luc , Yingling Jonathan M. , Stancato Louis F. , Sonenberg Nahum , Graff Jeremy R. 
Published: January 2011

Abstract
Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach. Cancer Res; 71(5); 1849–57. ©2011 AACR.
CpG Blocks Immunosuppression by Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice
Authors: Zoglmeier Christine , Bauer Helen , Nörenberg Daniel , Wedekind Georg , Bittner Philipp , Sandholzer Nadja , Rapp Moritz , Anz David , Endres Stefan , Bourquin Carole 
Published: January 2011

AbstractPurpose: The Toll-like receptor (TLR) 9 ligand CpG has been used successfully for the immunotherapy of cancer. Chronic CpG application in tumor-free hosts leads, however, to the expansion of myeloid-derived suppressor cells (MDSC), which can cause T-cell suppression and may thus hamper the development of an effective immune response. Here, we investigated the effect of TLR9 activation on the function of MDSC in tumor-bearing mice.Experimental Design: We investigated the effect of CpG treatment on the number, phenotype, and function of MDSC in mice bearing subcutaneous C26 tumors and in CEA424-TAg mice bearing autochthonous gastric tumors.Results: CpG treatment blocks the suppressive activity of MDSC on T-cell proliferation in both tumor models. Inhibition of MDSC function by CpG was particularly pronounced for a highly suppressive Ly6Ghi polymorphonuclear subset of MDSC. We further show that TLR9 activation by CpG promotes maturation and differentiation of MDSC and strongly decreases the proportion of Ly6Ghi MDSC in both tumor-bearing and tumor-free mice. We demonstrate that IFN-α produced by plasmacytoid dendritic cells upon CpG stimulation is a key effector for the induction of MDSC maturation in vitro and show that treatment of mice with recombinant IFN-α is sufficient to block MDSC suppressivity.Conclusions: We show here for the first time that TLR9 activation inhibits the regulatory function of MDSC in tumor-bearing mice and define a role for the antitumoral cytokine IFN-α in this process. Clin Cancer Res; 17(7); 1765–75. ©2011 AACR.
Collateral Flow Predicts Response to Endovascular Therapy for Acute Ischemic Stroke
Authors: Bang Oh Young , Saver Jeffrey L. , Kim Suk Jae , Kim Gyeong-Moon , Chung Chin-Sang , Ovbiagele Bruce , Lee Kwang Ho , Liebeskind David S. 
Published: January 2011

Background and Purpose—
Collaterals sustain the penumbra before recanalization and offset infarct growth, yet the influence of baseline collateral flow on recanalization after endovascular therapy remains relatively unexplored.

Methods—
We analyzed consecutive patients who received endovascular therapy for acute cerebral ischemia from 2 distinct study populations. We assessed the relationship between pretreatment collateral grade and vascular recanalization (Thrombolysis In Myocardial Ischemia [TIMI] scale). In addition, we assessed infarct growth on serial MRI.

Results—

A total of 222 patients was included, 138 from the United States and 84 from South Korea. Complete revascularization occurred in 14.1% (11 of 78) patients with poor pretreatment collateral grades, whereas it was observed in 25.2% (26 of 103) patients with good collaterals and 41.5% (17 of 41) patients with excellent collaterals (
P
<0.001). This relationship was consistently observed in both study populations, although the mode of endovascular therapy was different between them. After adjustment for other factors, including mode of endovascular therapy, prior use of intravenous tissue plasminogen activator, and site of occlusion, pretreatment collateral grade was independently associated with recanalization. When revascularization was achieved, greater infarct growth occurred in patients with poor collaterals than in those with good collaterals (
P
=0.012).

Conclusions—
Our data indicate that angiographic collateral grade determines the recanalization rate after endovascular revascularization therapy. When therapeutic revascularization was achieved, beneficial effects were not observed in patients with poor collaterals. Angiographic collateral grade may therefore help guide treatment decision-making in acute cerebral ischemia.
A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation
Authors: Tichelli André , Schrezenmeier Hubert , Socié Gérard , Marsh Judith , Bacigalupo Andrea , Dührsen Ulrich , Franzke Anke , Hallek Michael , Thiel Eckhard , Wilhelm Martin , Höchsmann Britta , Barrois Alain , Champion Kim , Passweg Jakob R. 
Published: January 2011

Abstract
We evaluated the role of granulocyte colony-stimulating factor (G-CSF) in patients with severe aplastic anemia (SAA) treated with antithymocyte globulin (ATG) and cyclosporine (CSA). Between January 2002 and July 2008, 192 patients with newly diagnosed SAA not eligible for transplantation were entered into this multicenter, randomized study to receive ATG/CSA with or without G-CSF. Overall survival (OS) at 6 years was 76% ± 4%, and event-free survival (EFS) was 42% ± 4%. No difference in OS/EFS was seen between patients randomly assigned to receive or not to receive G-CSF, neither for the entire cohort nor in subgroups stratified by age and disease severity. Patients treated with G-CSF had fewer infectious episodes (24%) and hospitalization days (82%) compared with patients without G-CSF (36%; P = .006; 87%; P = .0003). In a post hoc analysis of patients receiving G-CSF, the lack of a neutrophil response by day 30 was associated with significantly lower response rate (56% vs 81%; P = .048) and survival (65% vs 87%; P = .031). G-CSF added to standard ATG and CSA reduces the rate of early infectious episodes and days of hospitalization in very SAA patients and might allow early identification of nonresponders but has no effect on OS, EFS, remission, relapse rates, and mortality. This study was registered at www.clinicaltrials.gov as NCT01163942.
Relationship between parental lung function and their children’s lung function early in life
Authors: van Putte-Katier N. , Koopmans M. , Uiterwaal C.S.P.M. , de Jong B.M. , Kimpen J.L.L. , Verheij T.J.M. , Numans M.E. , van der Ent C.K. 
Published: January 2011

This study investigated the relationship between parental lung function and their children’s lung function measured early in life.Infants were participants in the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function was measured before the age of 2 months using the single occlusion technique. Parental data on lung function (spirometry), medical history and environmental factors were obtained from the linked database of the Utrecht Health Project.Parental data on pulmonary function and covariates were available in 546 infants. Univariate linear regression analysis demonstrated a significant positive relationship between the infant's respiratory compliance and parental forced expiratory flow at 25–75% of forced vital capacity (FEF25–75%),forced expiratory volume in 1 s (FEV1) and forced vital capacity. A significant negative relationship was found between the infant's respiratory resistance and parental FEF25–75%and FEV1. No significant relationship was found between the infant's respiratory time constant and parental lung function. Adjusting for body size partially reduced the significance of the observed relationship; adjusting for shared environmental factors did not change the observed results.Parental lung function levels are predictors of the respiratory mechanics of their newborn infants, which can only partially be explained by familial aggregation of body size. This suggests genetic mechanisms in familial aggregation of lung function, which are already detectable early in life.
Identification of craniofacial risk factors for obstructive sleep apnoea using three-dimensional MRI
Authors: Chi L. , Comyn F-L. , Mitra N. , Reilly M.P. , Wan F. , Maislin G. , Chmiewski L. , Thorne-FitzGerald M.D. , Victor U.N. , Pack A.I. , Schwab R.J. 
Published: January 2011

The alteration of craniofacial structures has been associated with obstructive sleep apnoea (OSA). We hypothesised that: 1) a smaller mandible is a risk factor for OSA; and 2) the previously observed inferiorly positioned hyoid bone in apnoeics is associated with enlarged tongue volume.This is a case–control study using three-dimensional magnetic resonance imaging cephalometry. 55 apneics and 55 controls were matched for age, sex and race. The analysis was stratified by sex and controlled for age, race, height, neck visceral fat, skeletal type and tongue volume.We found that a 1-sdincrease in mandibular length and depth were associated with decreased risk of sleep apnoea (OR 0.52, 95% CI 0.28–0.99 and OR 0.46, 95% CI 0.23–0.91, respectively) in males but not in females. Greater hyoid-to-nasion (OR 2.64, 95% CI 1.19–5.89 in males and OR 5.01, 95% CI 2.00–12.52 in females) and supramentale-to-hyoid (OR 2.39, 95% CI 1.12–5.14) in males and OR 3.38, 95% CI 1.49–7.68 in females) distances were associated with increased risk of OSA. The difference for hyoid position between apnoeics and controls was lost after controlling for tongue volume.Enlargement of tongue is likely to be the pathogenic factor for inferior–posterior positioning of hyoid. A small and shallow mandible is an independent risk factor for OSA in males but not in females.
Cytohesin-1 regulates fMLF-mediated activation and functions of the β2 integrin Mac-1 in human neutrophils
Authors: El Azreq Mohammed-Amine , Garceau Valérie , Bourgoin Sylvain G 
Published: January 2011

ABSTRACTThe nucleotide exchange factor cytohesin-1 was previously reported to interact with the cytoplasmic domains of the integrin β-chain common to all β2 integrins such as LFA-1 and Mac-1. We show here that cytohesin-1, which contributes to fMLF-induced functional responses in PMNs through activation of Arf6, restrains the activation of the β2 integrin Mac-1 (αMβ2) in PMNs or dcAMP-differentiated PLB-985 cells. We found that the cytohesin-1 inhibitor SecinH3 or siRNA increased cell adhesion to immobilized fibrinogen and fMLF-mediated conformational changes of Mac-1, monitored using mAb CBRM1/5, specific for the activation epitope of the αM subunit. In contrast, PLB-985 cells overexpressing cytohesin-1 showed little adhesion to fibrinogen. The use of SecinH3 and siRNA also revealed that interference with cytohesin-1 signaling also enhanced phagocytosis of zymosan particles and chemotaxis toward fMLF in transwell migration assays. These increments of phagocytosis and chemotaxis in cells treated with SecinH3 and cytohesin-1 siRNA were reversed by a blocking mAb to the integrin-αM subunit. We provide evidence for increased polymerized cortical actin in cells treated with SecinH3 and that altered signaling through cytohesin-1 increased cell surface expression of FPRL-1 and impairs the late calcium mobilization response elicited by fMLF. The data provide evidence that stimulation with fMLF initiates a signaling cascade that restrains Mac-1 activation in PMNs. Such crosstalk between FPRL-1 and Mac-1 involves cytohesin-1. We suggest that cytohesin-1 may coordinate activation of the β2 integrins to regulate PMN adhesion, phagocytosis, and chemotaxis.
Statins inhibit T-acute lymphoblastic leukemia cell adhesion and migration through Rap1b
Authors: Infante Elvira , Heasman Sarah J , Ridley Anne J 
Published: January 2011

ABSTRACTStatins are known to inhibit signaling of Ras superfamily GTPases and reduce T cell adhesion to ICAM-1. Here, we address the hypothesis that statins affect T cell adhesion and migration by modulating the function of specific GTPases. Statins inhibit the synthesis of mevalonic acid, which is required for farnesyl and geranylgeranyl isoprenoid synthesis. Ras superfamily GTPases are post-translationally isoprenylated to facilitate their anchorage to membranes, where they function to stimulate signal transduction processes. We demonstrate that 1 μM statin inhibits the adhesion, migration, and chemotaxis of the T-ALL cell line CCRF-CEM and TEM of CCRF-CEM and PEER T-ALL cells, but higher statin concentrations are needed to inhibit adhesion of primary T cells. Similar effects are observed following treatment with GGTI-298 or RNA interference-mediated knockdown of Rap1b but not Rap1a, Rac1, Rac2, RhoA, or Cdc42. Statins also alter Rap1 activity and Rap1b localization. Rap1 levels are higher in primary T cells than T-ALL cells, which could explain their reduced sensitivity to statins. These results demonstrate for the first time that the closely related Rap1a and Rap1b isoforms have different functions and suggest that statins or Rap1b depletion could be used to reduce tissue invasion in T-ALL.
IFN-α produced by human plasmacytoid dendritic cells enhances T cell-dependent naïve B cell differentiation
Authors: Gujer Cornelia , Sandgren Kerrie J , Douagi Iyadh , Adams William C , Sundling Christopher , Smed-Sörensen Anna , Seder Robert A , Hedestam Gunilla B Karlsson , Loré Karin 
Published: January 2011

ABSTRACTThe development and quality of a humoral immune response are largely influenced by the environment that supports the activation of naïve B cells. Human PDCs, through their unique capacity to produce high levels of IFN-α, have been shown earlier to enhance B cell responses stimulated by selected TLR ligands. In this study, we investigated whether PDCs also promote B cell activation induced by Th cell interactions and BCR ligation. Sorted human naive CD19+ CD27– B cells were activated in vitro with anti-Ig and irradiated CD4+ T cells. Under these conditions, the presence of supernatants from TLR-stimulated PDCs increased B cell proliferation, the frequency of B cells that differentiated to CD27high CD38high cells, and secretion of IgM. Similar results were observed when the B cells were activated in the presence of purified IFN-α. In contrast, supernatants from stimulated MDCs did not augment these functions. Also, IFN-α treatment of B cells up-regulated the expression of costimulatory molecule CD86 but not CD40, CD80, MHC class II, or CD25. Although direct IFN-α exposure of T cells suppressed their proliferative capacity, IFN-α treatment of B cells led to a small increase in their capacity to induce superantigen-driven activation of autologous CD4+ T cells. In summary, PDCs, via their production of IFN-α, may render B cells more responsive to T cell contact, which in turn, facilitates B cell proliferation and differentiation to antibody-producing cells.
Unilateral leg swelling: deep vein thrombosis?
Authors: Bekou V , Galis D , Traber J 
Published: January 2011

Objective We present two cases of a unilateral leg swelling of unusual aetiology as a reminder to the physician to consider causes of unilateral leg swelling other than deep vein thrombosis, lymphoedema and infectious diseases. Case reports Both of our patients developed progressive leg swelling. Subsequent investigation revealed a lesion compressing the femoral vein. At exploration this was found to be a ganglion cyst. In one patient surgical removal of the cyst and in the other puncture of the cyst and instillation of steroid resulted in prompt resolution of the swelling. Conclusion Venous compression due to external cystic lesions, although rare, is recognized. In strange cases this differential diagnosis should also be taken into account. Therapeutic options are the surgical removal or puncture of the cyst.
MMP-9 expression in peripheral blood mononuclear cells and the association with clinicopathological features and prognosis of nasopharyngeal carcinoma
Authors: He Jian-Rong , Qin Han , Ren Ze-Feng , Cui Cui , Zhang Ying , Ranatunga Dharshana , Zeng Yi-Xin , Jia Wei-Hua 
Published: January 2011

Abstract

Background: Matrix metalloproteinase-9 (MMP-9) shows significant involvement with cancer invasion and therefore has prognostic significance. Tumor tissues from nasopharyngeal carcinoma (NPC) patients are not easy to access, and peripheral blood mononuclear cells (PBMC) are a valuable alternative. This study compared the expression levels of MMP-9 in PBMCs from NPC patients and healthy controls and evaluated the potential as a prognostic biomarker for NPC patients.

Methods:
MMP-9 mRNA concentrations in PBMCs from 146 NPC patients and 110 healthy controls were measured using quantitative real-time PCR. Differences in MMP-9 expression between NPC patients and controls were evaluated using non-parametric tests, and the effects of different clinical characteristics on MMP-9 expression were also analyzed. The Kaplan-Meier test and Cox regression model were used to explore the association between MMP-9 expression and overall survival of NPC patients.

Results:
MMP-9 mRNA levels in PBMCs were significantly higher in NPC patients than in healthy controls (p<0.001). Increased MMP-9 expression was associated with the following clinical characteristics: advanced clinical stage (p<0.001), T stage (p=0.016), N stage (p=0.002), histology type (p=0.037), and poor overall survival (p=0.049).

Conclusions:
MMP-9 mRNA expression in PBMCs from NPC patients is increased and associated with the clinical characteristics and overall survival. It supports the belief that MMP-9 may contribute to the progression of NPC.
The pragmatics of humor reception: Young people's responses to a newspaper cartoon
Authors: El Refaie Elisabeth 
Published: January 2011

AbstractThis paper uses the example of 25 young people's responses to a Daily Mail cartoon on the subject of gay marriage in order to explore the pragmatics of humor reception. The results indicate that the enjoyment of a multimodal joke depends to a large extent on the background knowledge, values and attitudes of the individual. If, for instance, a cartoon is too threatening to someone's core sense of identity, it is likely to create anger and alienation rather than amusement. Humor appreciation is also shown to depend on the broader socio-cultural context in which the cartoon is encountered.
Salivary Interleukin‐1β Levels in Patients With Chronic Periodontitis Before and After Periodontal Phase I Therapy and Healthy Controls: A Case‐Control Study
Authors: Kaushik Rachna , Yeltiwar Ramreddy K. , Pushpanshu Kumar 
Published: January 2011

Background: The role of interleukin (IL)‐1β in periodontal disease pathogenesis is well researched. This study aimed to assess and compare the salivary IL‐1β levels in patients with chronic periodontitis before and after periodontal phase I therapy and periodontally healthy controls. Further, relationships between IL‐1β levels and various clinical parameters were explored.Methods: Twenty‐eight patients with moderate‐to‐severe generalized chronic periodontitis and 24 age‐, race‐, and ethnicity‐matched controls participated in this study. Saliva samples were obtained from all patients. The clinical parameters recorded were clinical attachment loss (AL), probing depth, bleeding on probing, periodontal index, and gingival index. Clinical evaluation and sample collection were repeated 1 month after periodontal phase I therapy in patients with periodontitis. IL‐1β levels were assessed using enzyme‐linked immunosorbent assay.Results: Mean IL‐1β levels in patients with periodontitis at baseline (1,312.75 pg/mL) were significantly higher (P <0.0001; eight‐fold) than in controls (161.51 pg/mL). Although treatment in patients with periodontitis resulted in significant reduction in IL‐1β levels (mean: 674.34 pg/mL; P = 0.001), they remained significantly higher (P <0.0001; four‐fold) than control levels. There were significant correlations between IL‐1β levels and all clinical parameters (P <0.01) except percentage sites with clinical AL >2 mm (P >0.05).Conclusions: The data indicate that IL‐1β levels are raised in the saliva of patients with chronic periodontitis, which are reduced after phase I therapy, suggesting a close association between salivary IL‐1β and periodontitis. Additional longitudinal studies are needed to validate salivary IL‐1β as a marker for periodontal disease.