bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo glioblastoma growth is reduced by apyrase activity in a rat glioma model
Authors: Morrone Fernanda B , Oliveira Diogo L , Gamermann Patrícia , Stella Joseli , Wofchuk Suzana , Wink Márcia R , Meurer Luise , Edelweiss Maria Isabel A , Lenz Guido , Battastini Ana Maria O 
Published: September 2006

AbstractBackgroundATP is an important signalling molecule in the peripheral and central nervous system. Both glioma growth and tumor resection induces cell death, thus liberating nucleotides to the extracellular medium. Nucleotides are hydrolyzed very slowly by gliomas when compared with astrocytes and induce neuronal cell death and glioma proliferation. The objective of the present study was to test the involvement of extracellular ATP in glioblastoma growth in a rat glioma model.MethodsTo deplete the extracellular ATP, the enzyme apyrase was tested on the treatment of gliomas implanted in the rats CNS. One million glioma C6 cells in 3 microliters of DMEM/FCS were injected in the right striata of male Wistar rats, 250–270 g. After 20 days, the rats were decapitated and the brain sectioning and stained with hematoxylin and eosine. We performed immunohistochemical experiments with Ki67, CD31 and VEGF. Total RNA was isolated from cultured glioma C6 cells and the cDNA was analyzed by Real Time-PCR with primers for the NTPDase family.ResultsC6 glioma cells effectively have a low expression of all NTPDases investigated, in comparison with normal astrocytes. The implanted glioma co-injected with apyrase had a significant reduction in the tumor size (p < 0.05) when compared with the rats injected only with gliomas or with gliomas plus inactivated apyrase. According to the pathological analysis, the malignant gliomas induced by C6 injection and co-injected with apyrase presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. Reduction of proliferation induced by apyrase co-injection was confirmed by counting the percentage of Ki67 positive glioma cell nuclei. According to counts with CD31, vessel density and neoformation was higher in the C6 group 20 days after implantation. Confirming this observation, rats treated with apyrase presented less VEGF staining in comparison to the control group.ConclusionThese results indicate that the participation of extracellular ATP and the ecto-nucleotidases may be associated with the development of this type of brain tumor in anin vivoglioma model.
A rare case of renal oncocytoma associated with erythrocytosis: case report
Authors: Radopoulos Demetrios , Tzakas Konstantinos , Tahmatzopoulos Anastasios 
Published: September 2006

Abstract

Background
Oncocytomas are benign tumors of the kidney that are usually diagnosed postoperatively due to differential diagnostic problems from renal cell carcinoma. Although the latter are neoplasms that have been associated with erythrocytosis in 3.5% of cases, there are no reports in the literature about a similar occurrence in oncocytomas.

Case presentation
In this case report we present a unique case of a right lower pole oncocytoma associated with erythrocytosis. Erythrocytosis subsided after partial nephrectomy.

Conclusion
Erythrocytosis can sometimes occur in association with renal oncocytomas.
Inhibitors of DNA methylation and histone deacetylation independently relieve AML1/ETO-mediated lysozyme repression
Authors: Claus Rainer , Fliegauf Manfred , Stock Michael , Duque Jesús A , Kolanczyk Mateusz , Lübbert Michael 
Published: September 2006

Abstract
The human lysozyme (LZM) gene is highly methylated in LZM-nonexpressor immature myeloid and in nonmyeloid cells and unmethylated only in LZM-expressing cells. Extended methylation analyses of the CpG-poor 5′ flanking region and of the exon 4 CpG island (both containing Alu elements) of the LZM gene were now performed. Marked demethylation was noted after treatment of AML1/ETO-positive Kasumi-1 cells with the DNA methyltransferase (DNMT) inhibitor 5-aza-2’-deoxycytidine (5-azaCdR), not associated with cellular differentiation. LZM mRNA in Kasumi-1, but not in several AML1/ETO-negative myeloid cell lines, was specifically and independently up-regulated upon treatment with 5-azaCdR and, to a lesser extent, with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Increased chromatin accessibility within the 5′ LZM gene was observed concomitantly with 5-azaCdR-induced demethylation. In contrast, TSA treatment had no effect on chromatin accessibility, but, as shown by chromatin immunoprecipitation, resulted in increased acetylation of histones H3 and H4. Repression of LZM transcription is mediated by conditional AML1/ETO expression in an inducible cell line model (U-937), and is reversed by siRNA “knock-down” of AML1/ETO in Kasumi-1 cells (Dunne et al., Oncogene 25: 2006). Antagonization of LZM repression following conditional expression of AML1/ETO was achieved by TSA. In conclusion, we demonstrate complex interactions between DNA methylation and histone modifications in mediating LZM repression, which implicate AML1/ETO as one component involved in local chromatin remodeling. Interestingly, inhibitors of DNMTs and HDACs independently relieve repression of this CpG-poor gene in AML1/ETO-positive cells.
Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E2
Authors: Tavares Eva , Miñano Francisco J , Maldonado Rosario , Dascombe Michael J 
Published: September 2006

Abstract
PGE2 is a recognized mediator of many fevers, and cyclooxygenase (COX) is the major therapeutic target for antipyretic therapy. The source, as well as the site of action of PGE2, as an endogenous pyrogen, is widely accepted as being central, but PGE2 in the circulation, possibly from leukocytes, may also contribute to the development of fever. However, bacterial infections are important causes of high fever in patients receiving myelosuppressive chemotherapy, and such fevers persist despite the use of COX inhibitors. In the study reported here, the febrile response to bacterial LPS was measured in rats made leukopenic by cyclophosphamide. A striking increase in LPS fever occurred in these granulocytopenic rats when compared with febrile responses in normal animals. Unlike LPS fever in normal rats, fever in granulocytopenic rats was neither accompanied by an increase in blood PGE2 nor inhibited by ibuprofen. Both leukopenic and normal rats showed LPS-induced COX-2-immunoreactivity in cells associated with brain blood vessels. Furthermore, LPS induced an increase of PGE2 in cerebrospinal fluid. Induction of COX-2-expression and PGE2 production was inhibited by ibuprofen in normal but not in leukopenic rats. Although the results presented are, in part, confirmatory, they add new information to this field and open a number of important questions as yet unresolved. Overall, the present results indicate that, in contrast to immunocompetent rats, leukocytes and/or other mechanisms other than PGE2 are implicated in the mechanisms restricting and reducing the enhanced febrile response to endotoxin in immunosuppressed hosts.
In vivo regulation of neutrophil apoptosis by C5a during sepsis
Authors: Guo Ren-Feng , Sun Lei , Gao Hongwei , Shi Kevin X , Rittirsch Daniel , Sarma Vidya J , Zetoune Firas S , Ward Peter A 
Published: September 2006

Abstract
Delayed neutrophil apoptosis is characteristic of sepsis and may accentuate organ injury. It has been shown that PI-3K and MAPK pathways provide survival signaling in neutrophils. In this study, we demonstrate that neutrophils isolated from septic rats are resistant to apoptosis in comparison with the cells from normal animals. In contrast to normal serum, septic sera induced strong phosphorylation of AKT and p44/42 in neutrophils obtained from normal rats, resulting in marked resistance of these cells to apoptosis. Protection from apoptosis by septic sera was abrogated completely by inhibition of PI-3K and partially diminished by MEK inhibition. Increased neutrophil survival in septic rats was associated with increased levels of Bcl-xL in neutrophils and decreased levels of Bim expression. In vivo blockade of C5a in cecal ligation and puncture rats by anti-C5a antibody markedly restored the susceptibility of neutrophils to undergo apoptosis. C5a activated AKT and p44/42 and also enhanced X-linked inhibitor of apoptosis expression in neutrophils. LPS and C5a were able to induce Bcl-xL expression. Thus, neutrophil survival signals derived from effects of septic sera could be linked to activation of ERK1/2 and PI-3K, increased antiapoptotic protein expression, and ultimately, delayed neutrophil apoptosis.
Priming by tumor necrosis factor-α of human neutrophil NADPH-oxidase activity induced by anti-proteinase-3 or anti-myeloperoxidase antibodies
Authors: Reumaux Dominique , Hordijk Peter L , Duthilleul Patrick , Roos Dirk 
Published: September 2006

Abstract
Anti-proteinase-3 (anti-PR3) or anti-myeloperoxidase (anti-MPO) antibodies are capable of activating human neutrophils primed by TNF-α in vitro. We described previously the involvement of FcγRIIa and β2 integrins in this neutrophil activation. In the literature, the requirement of TNF priming has been attributed to an effect of TNF-α on the expression of PR3 or MPO on the cell surface. Under our experimental conditions, TNF-α (2 ng/ml) increased the binding of the antibody against PR3, whereas binding of the antibody against MPO could hardly be detected, not even after TNF-α treatment. The aim of this study was to consider (an)other(s) role(s) for TNF-α in facilitating the NADPH-oxidase activation by these antibodies. We demonstrate the early mobilization of the secretory vesicles as a result of TNF-induced increase in intracellular-free calcium ions, the parallel colocalization of gp91phox, the main component of the NADPH oxidase with β2 integrins and FcγRIIa on the neutrophil surface, and the FcγRIIa clustering upon TNF priming. TNF-α also induced redistribution of FcγRIIa to the cytoskeleton in a dose- and time-dependent manner. Moreover, blocking CD18 MHM23 antibody, cytochalasin B, and D609 (an inhibitor of phosphatidylcholine phospholipase C) inhibited this redistribution and the respiratory burst in TNF-treated neutrophils exposed to anti-PR3 or anti-MPO antibodies. Our results indicate direct effects of TNF-α in facilitating neutrophil activation by these antibodies and further support the importance of cytoskeletal rearrangements in this priming process.
The maturation potential of NK cell clones toward autologous dendritic cells correlates with HMGB1 secretion
Authors: Semino Claudia , Ceccarelli Jenny , Lotti Lavinia V , Torrisi Maria R , Angelini Giovanna , Rubartelli Anna 
Published: September 2006

AbstractInteraction of NK cells with autologous immature dendritic cells (iDCs) results in reciprocal activation. We have previously reported that NK cells trigger iDC to polarize and secrete IL-18; in turn, DC-activated NK cells secrete the nuclear protein/proinflammatory cytokine high mobility group box protein 1 (HMGB1), which induces DC maturation and prevents DC from lysis. However, activated NK cells can also kill iDC. To investigate whether effector and maturative properties may coexist or segregate in different NK subsets, human NK cell clones were generated and analyzed for their effects on iDC. We found that the ability of different NK cell clones to induce iDC maturation is unlinked to their phenotypic and cytolytic features but correlates with the relocation of HMGB1 from nucleus to cytoplasm. “Maturative” NK cell clones secrete HMGB1 spontaneously. It is interesting that secretion is strongly enhanced by engagement of the surface molecule NKp30 but only slightly induced by triggering of the activating NK receptor CD16. However, culturing freshly isolated NK cells for 1 week with low doses of anti-CD16 triggers the relocation of HMGB1 from nucleus to cytoplasm and its spontaneous secretion, resulting in a stronger maturation potential of the NK cells. Together, our data indicate that NK cells comprise functionally different subsets, endowed with different capacities to secrete HMGB1 and to induce maturation of autologous iDC. Nonetheless, maturation properties can be modulated by different stimuli. This suggests that depending on the environmental stimuli, NK/iDC interaction can lead to different outcomes, thus influencing immune response.
Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo
Authors: Smith David F , Deem Tracy L , Bruce Anthony C , Reutershan Jörg , Wu Daniel , Ley Klaus 
Published: September 2006

Abstract
During inflammation, leukocytes roll along the wall of postcapillary venules scanning the surface for immobilized CXCL1, a chemokine that triggers firm adhesion by activating CXCR2 on the neutrophil. PI-3K are signaling molecules important in cellular processes, ranging from cellular differentiation to leukocyte migration. PI-3Kγ can be activated directly by the βγ dimer of heterotrimeric G proteins coupled to CXCR2. Here, we used in vivo and ex vivo intravital microscopy models to test the role of PI-3Kγ in leukocyte arrest. PI-3Kγ null mice showed an 80% decrease in CXCL1-induced leukocyte adhesion in venules of the exteriorized mouse cremaster muscle. In wild-type mice, rolling leukocytes showed rapid and sustained adhesion, but in PI-3Kγ−/− mice, adhesion was not triggered at all or was transient, suggesting that absence of PI-3Kγ interferes with integrin bond strengthening. Wild-type mice reconstituted with PI-3Kγ null bone marrow showed a 50% decrease in CXCL1-induced leukocyte adhesion. In a blood-perfused micro-flow chamber, leukocytes from PI-3Kγ−/− mice showed a defect in adhesion on a P-selectin/ICAM-1/CXCL1 substrate, indicating that leukocyte PI-3Kγ was required for adhesion. The adhesion defect in PI-3Kγ−/− mice was as severe as that in mice lacking LFA-1, the major integrin responsible for neutrophil adhesion. We conclude that the γ isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation.
Depletion of MCP-1 increases development of herpetic stromal keratitis by innate immune modulation
Authors: Kim Bumseok , Sarangi Pranita P , Lee Yunsang , Deshpande Kaistha Shilpa , Lee Sujin , Rouse Barry T 
Published: September 2006

Abstract
Chemokines are important chemoattractant inflammatory molecules, but their interdependent network in disease pathogenesis remains unclear. Studies in mouse models have shown that herpetic stromal keratitis (SK) is produced by the consequence of a tissue-destructive immunoinflammatory reaction involving herpes simplex virus type 1 (HSV) infection. Here we found that ocular HSV infection leads to increased expression of monocyte chemoattractant protein-1 (MCP-1), one of the major chemoattractants for immune cells that express CCR2, in the SK cornea. However, MCP-1 is unlikely to be a chemoattractant for infiltrating Gr-1+, CD11b+ cells in SK, as these cells are found to be CCR2 negative. Nevertheless, infection of MCP-1−/− mice resulted in more severe SK lesion severity compared with WT mice (P&lt;0.01). We demonstrated that the loss of MCP-1 in the SK cornea caused a significant overexpression of macrophage inflammatory protein-2 (MIP-2) (P&lt;0.01) on days 2 and 4 postinfection and increased infiltration of inflammatory cells (Gr-1-high and CD11b+) expressing CXCR2, a receptor for MIP-2, into the cornea. Subsequently, increased infiltration of inflammatory cells accelerated by MIP-2 overexpression might result in the high production of inflammatory molecules, including vascular endothelial growth factor (VEGF) and IL-1β in SK, as well as CpG oligodeoxynucleotide (ODN)-implanted eyes of MCP-1−/− mice. These results indicate that MCP-1 in the SK cornea might regulate the expression of other chemokines, as well as the infiltration of inflammatory cells and control development of SK.
Cytokine-induced killer T cells kill immature dendritic cells by TCR-independent and perforin-dependent mechanisms
Authors: Joshi Pramod S , Liu Jin-Qing , Wang Yin , Chang Xing , Richards John , Assarsson Erika , Shi Fu-Dong , Ljunggren Hans-Gustaf , Bai Xue-Feng 
Published: September 2006

Abstract
Cytokine-induced killer (CIK) cells are ex vivo, expanded T cells with proven anticancer activity in vitro and in vivo. However, their functional properties with the exception of their cancer cell-killing activity are largely unclear. Here, we show that CIK T cells recognize dendritic cells (DC), and although mature DC (mDC) induce CIK T cells to produce IFN-γ, immature DC (iDC) are killed selectively by them. Moreover, CIK T cell activation by mDC and their destruction of iDC are independent of the TCR. The cytotoxicity of CIK T cells to iDC is perforin-dependent. Our data have revealed an important regulatory role of CIK cells.
Monocyte/macrophage infiltration in tumors: modulators of angiogenesis
Authors: Dirkx Anita E M , oude Egbrink Mirjam G A , Wagstaff John , Griffioen Arjan W 
Published: September 2006

AbstractThe role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor’s capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.
Mycobacteria-primed macrophages and dendritic cells induce an up-regulation of complement C5a anaphylatoxin receptor (CD88) in CD3+ murine T cells
Authors: Connelly Mary Anne , Moulton Rachel A , Smith Amanda K , Lindsey Devin R , Sinha Meenal , Wetsel Rick A , Jagannath Chinnaswamy 
Published: September 2006

AbstractComplement C5a anaphylatoxin is a potent activator of macrophages, neutrophils, and dendritic cells (DC) and binds the C5a receptor (C5a-R; CD88). Although C5a is chemotactic for T cells, expression of C5a-R on murine T cells has been disputed. We report here that naïve, Con A-activated, and cytokine (IL-12, IL-18)-stimulated murine CD3+ T cells from three strains of mice [C57Bl/6, B10.nSn (C5+/+), B10.on (C5−/−)] lacked C5a-R, as evaluated by immunophenotyping with an anti-C5a-R mAb. Ligation of CD3 induced a modest up-regulation with 3% of CD3+ T cells expressing cell surface C5a-R. T cells primed by APC differentiate into effector T cells. Activation of mycobacteria [bacillus Calmette-Guerin (BCG)]-sensitized T cells through MHC II and TCR interactions via BCG-infected macrophages enhanced the expression of C5a-R with ∼14% of CD3+ T cells positive for C5a-R. Comparable expression was found in C5+/+ as well as C5−/− strains of mice (14% and 15%, respectively). Furthermore, anti-CD3-activated T cells were primed by BCG-infected DC, and a larger proportion of the primed T cells expressed C5a-R (30–40%). Finally, mice infected with BCG showed significant numbers of CD3+ T cells expressing C5a-R in the spleens during infection. As APC, such as macrophages and DC, can secrete C5 and cleave C5 to C5a and C5b through a peptidase, we suggest that macrophage and DC-T cell interactions can up-regulate C5a-R on T cells through MHC II-TCR and provide a C5a peptide for additional local activation of T cells via C5a-R.
A high-affinity, tryptophan-selective amino acid transport system in human macrophages
Authors: Seymour Robert L , Ganapathy Vadivel , Mellor Andrew L , Munn David H 
Published: September 2006

Abstract
Tryptophan catabolism via the enzyme indoleamine 2,3-dioxygenase (IDO) allows human monocyte-derived macrophages (MDM) and other APC to suppress T cell proliferation. IDO helps protect murine fetuses from rejection by the maternal immune system and can promote tolerance and immunosuppression. For tryptophan to be catabolized by IDO, it must first enter the APC via transmembrane transport. It has been shown that MDM in vitro readily deplete tryptophan present in the extracellular medium to nanomolar levels via IDO activity; yet, no currently known amino acid transport system displays high affinity and specificity sufficiently to permit efficient uptake of tryptophan at these low concentrations. Here, we provide biochemical characterization of a novel transport system with nanomolar affinity and high selectivity for tryptophan. Tryptophan transport in MDM was predominantly sodium-independent and occurred via two distinct systems: one consistent with the known system L transporter and a second system with 100-fold higher affinity for tryptophan (Km&lt;300 nM). Competition studies showed that the high-affinity system did not correspond to any known transporter activity and displayed a marked selectivity for tryptophan over other amino acids and tryptophan analogs. This new system was expressed at low levels in fresh monocytes but underwent selective induction during MDM differentiation. In contrast, resting human T cells expressed only the conventional system L. We speculate that the high-affinity, tryptophan-specific transport system allows MDM to take up tryptophan efficiently under conditions of low substrate concentration, such as may occur during interaction between T cells and IDO-expressing APC.
Phase II Trial Evaluating the Palliative Benefit of Second-Line Zoledronic Acid in Breast Cancer Patients With Either a Skeletal-Related Event or Progressive Bone Metastases Despite First-Line Bisphosphonate Therapy
Authors: Clemons Mark J. , Dranitsaris George , Ooi Wei S. , Yogendran Geetha , Sukovic Tatjana , Wong Betty Y.L. , Verma Sunil , Pritchard Kathleen I. , Trudeau Maureen , Cole David E.C. 
Published: September 2006

Purpose This study evaluated whether additional palliative benefits could be derived from the second-line use of the more potent bisphosphonate zoledronic acid in metastatic breast cancer patients with either progressive bone metastases or skeletal-related events (SRE), despite first-line therapy with either pamidronate or clodronate. Patients and Methods This prospective study evaluated the impact of second-line zoledronic acid on pain, quality of life, and markers of bone turnover (for example, urinary N-telopeptide [NTX]). Patients received monthly zoledronic acid (4mg) for 3 months. Study evaluations were made weekly during the first month and again at week 8. No changes in chemotherapy or endocrine therapy were allowed in the month before or after commencing study treatment. Results Thirty-one women completed this study. By week 8, patients had experienced significant improvements in pain control (P < .001). There was a downward trend in urinary NTX levels over the same time period (P = .008). Overall, there was a trend towards a positive correlation between improvement in pain control and reduction in week one urinary NTX relative to baseline (Spearman's rho r = 0.27; P = .15). Conclusion This is the first study to demonstrate that patients with either progressive bone metastases or SREs while on clodronate or pamidronate can have relevant palliative benefits with a switch to the more potent bisphosphonate zoledronic acid. This is reflected by significant improvements in pain control and bone turnover markers. If confirmed in randomized trials, these findings have major implications to the use of bisphosphonates in both the metastatic and adjuvant settings.