bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1α) and the HIF-1α target gene DEC1, but not lymph node metastasis in primary human breast carcinomas
Authors: Currie M J , Hanrahan V , Gunningham S P , Morrin H R , Frampton C , Han C , Robinson B A , Fox S B 
Published: July 2004

Background:Vascular endothelial growth factor D (VEGF-D) induces angiogenesis and lymphangiogenesis. Nodal metastasis is recognised as a powerful prognostic marker in breast carcinoma, but the molecular mechanisms underlying this process are unknown. Although it has been suggested that VEGF-D may regulate nodal metastasis, this is based largely on animal models, its role in human disease being unclear.Aims:To measure the pattern and degree of VEGF-D protein expression in normal and neoplastic human breast tissues.Methods:The pattern and degree of VEGF-D expression was measured in normal tissue and invasive carcinomas, and expression was correlated with clinicopathological parameters, hypoxia markers, and survival. Because other VEGF family members are affected by oestrogen, whether VEGF-D is regulated by oestrogen in breast cancer cell lines was also assessed.Results:VEGF-D was significantly positively associated with hypoxia inducible factor (HIF-1α) (p = 0.03) and the HIF-1α regulated gene DEC1 (p = 0.001), but not lymph node status, the number of involved lymph nodes, patient age, tumour size, tumour grade, lymphovascular invasion, oestrogen receptor, progesterone receptor, c-erb-B2, or tumour histology (all p>0.05). There was no significant relation between tumour VEGF-D expression and relapse free (p = 0.78) or overall (p = 0.94) survival. VEGF-D expression was enhanced by oestrogen in MCF-7 and T47D breast cancer cells, and was blocked by hydroxytamoxifen.Conclusion:These findings support a role for hypoxia and oestrogen induced VEGF-D in human breast cancer and also suggest that tamoxifen and related oestrogen antagonists may exert some of their antitumour effects through the abrogation of VEGF-D induced function.
Microvessel density and clinicopathological characteristics in hepatitis C virus and hepatitis B virus related hepatocellular carcinoma
Authors: Messerini L , Novelli L , Comin C E 
Published: July 2004

Aims:To compare intratumorous microvessel density (MVD) and clinicopathological features in two different groups of hepatocellular carcinoma (HCC), namely: hepatitis B virus (HBV) related HCC (B-HCC) and HCV related HCC (C-HCC).Methods:Fifty consecutive cases each of B-HCC and of C-HCC were studied. Microvessel numbers were assessed by staining for the antigen CD34; in each case, three areas with the highest numbers of microvessels were counted in both the intratumorous and the surrounding non-tumorous tissue; the mean value represented the final MVD.Results:Patients with B-HCC were significantly younger than those with C-HCC (mean age, 60.1 (SD, 4.1)v66.4 (4.3) years); no significant differences were seen for sex or Child’s class distribution. The tumour diameter was larger in B-HCCs than in C-HCCs (mean, 5.6 (SD, 1.8)v3.8 (1.8) cm). Tumour microsatellite formation was significantly higher in C-HCCs (12v4 cases). No differences were found for histological subtype, degree of differentiation, tumour encapsulation, and vascular invasion. The mean MVD value was significantly higher in tumorous (mean, 54 (SD, 13.8)v38 (8.9)) and in the surrounding non-tumorous liver tissue (mean, 15 (SD, 4.3)v7 (3.1)) of C-HCCs.Conclusions:C-HCCs present as smaller tumours in older patients, with a higher incidence of tumour microsatellite formation and higher MVD values both in the tumorous and the non-tumorous areas, suggesting a link between HCV infection, angiogenesis, and hepatocarcinogenesis.
Proinflammatory Cytokines Regulate LOX-1 Expression in Vascular Smooth Muscle Cells
Authors: Hofnagel Oliver , Luechtenborg Birgit , Stolle Katrin , Lorkowski Stefan , Eschert Heike , Plenz Gabriele , Robenek Horst 
Published: July 2004

Objective—Atherogenesis represents a type of chronic inflammation and involves elements of the immune response, eg, the expression of proinflammatory cytokines. In advanced atherosclerotic lesions, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs). In vitro, the expression of LOX-1 is induced by inflammatory cytokines like TNF-α and transforming growth factor (TGF)-β. Therefore, LOX-1 is thought to be upregulated locally in response to cytokines in vivo.Methods and Results—We determined by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis whether the mediators of the acute phase response in inflammation, IL-1α, IL-1β, and TNF-α, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor γ (PPARγ). We studied by immunohistochemistry whether these cytokines are spatially correlated with LOX-1 expression in advanced atherosclerotic lesions. We found upregulation of LOX-1 expression in SMC in a dose- and time-dependent manner after incubation with IL-1α, IL-1β, and TNF-α. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPARγ activator, 15d-PGJ2, however, inhibited IL-1β–induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1α, IL-1β, and TNF-α expression corresponded to regions of LOX-1 expression.Conclusion—We suppose that upregulated LOX-1 expression in SMC of advanced atherosclerotic lesions is a response to these proinflammatory cytokines. Moreover, the proinflammatory effects of these cytokines can be decreased by the antiinflammatory effect of PPARγ.
Leukotriene B4Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes
Authors: Huang Li , Zhao Annie , Wong Frederick , Ayala Julia M. , Struthers Mary , Ujjainwalla Feroze , Wright Samuel D. , Springer Marty S. , Evans Jilly , Cui Jisong 
Published: July 2004

Objective—Leukotriene B4(LTB4), a product of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, has been implicated in atherosclerosis. However, the molecular mechanisms for the atherogenic effect of LTB4are not well understood. This study is to determine candidate mechanisms.Method and Results—Primary human monocytes were treated with LTB4and the supernatant was analyzed for cytokine/chemokine production by an immuno-protein array. This analysis revealed a strong increase of the monocyte chemoattractant protein-1 (MCP-1), a proinflammatory cytokine. Follow-up analyses with MCP-1 enzyme-linked immunosorbent assay (for quantitation of MCP-1 protein) and real-time polymerase chain reaction (PCR) (for MCP-1 mRNA) demonstrated that LTB4strongly induced expression of MCP-1 protein and mRNA in a time-dependent and dose-dependent fashion. This induction was effectively abolished by CP-105,696, an antagonist for the LTB4receptor BLT1. Selective inhibitors of ERK1/2 or JNK MAPK effectively blocked the LTB4-induced MCP-1 production. Furthermore, LTB4increased NF-κB DNA binding activity, which was blocked by CP-105,696.Conclusions—LTB4strongly induces MCP-1 production in primary human monocytes. This induction is mediated through the BLT1pathway increasing MCP-1 transcription. Activation of ERK1/2 or JNK MAPK is essential for this induction. The NF-κB activation may be involved in LTB4-increased MCP-1 expression. The LTB4-induced MCP-1 in human monocytes may play a critical role in the atherogenicity of LTB4.
Gene expression profiling of normal and malignant CD34-derived megakaryocytic cells
Authors: Tenedini Elena , Fagioli Maria Elena , Vianelli Nicola , Tazzari Pier Luigi , Ricci Francesca , Tagliafico Enrico , Ricci Paolo , Gugliotta Luigi , Martinelli Giovanni , Tura Sante , Baccarani Michele , Ferrari Sergio , Catani Lucia 
Published: July 2004

Abstract
Gene expression profiles of bone marrow (BM) CD34-derived megakaryocytic cells (MKs) were compared in patients with essential thrombocythemia (ET) and healthy subjects using oligonucleotide microarray analysis to identify differentially expressed genes and disease-specific transcripts. We found that proapoptotic genes such as BAX, BNIP3, and BNIP3L were down-regulated in ET MKs together with genes that are components of the mitochondrial permeability transition pore complex, a system with a pivotal role in apoptosis. Conversely, antiapoptotic genes such as IGF1-R and CFLAR were up-regulated in the malignant cells, as was the SDF1 gene, which favors cell survival. On the basis of the array results, we characterized apoptosis of normal and ET MKs by time-course evaluation of annexin-V and sub-G1 peak DNA stainings of immature and mature MKs after culture in serum-free medium with an optimal thrombopoietin concentration, and annexin-V–positive MKs only, with decreasing thrombopoietin concentrations. ET MKs were more resistant to apoptosis than their normal counterparts. We conclude that imbalance between proliferation and apoptosis seems to be an important step in malignant ET megakaryocytopoiesis.
Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients
Authors: Weiss Laurence , Donkova-Petrini Vladimira , Caccavelli Laure , Balbo Michèle , Carbonneil Cédric , Levy Yves 
Published: July 2004

AbstractThe present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.
Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase, and glucosylceramide synthase
Authors: Taguchi Yoshimitsu , Kondo Tadakazu , Watanabe Mitsumasa , Miyaji Michihiko , Umehara Hisanori , Kozutsumi Yasunori , Okazaki Toshiro 
Published: July 2004

AbstractInterleukin 2 (IL-2) rescued human natural killer (NK) KHYG-1 cells from apoptosis along with a reduction of ceramide. Conversely, an increase of ceramide inhibited IL-2-rescued survival. IL-2 deprivation-induced activation of acid sphingomyelinase (SMase) and inhibition of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) were normalized by IL-2 supplementation. A phosphatidyl inositol-3 (PI-3) kinase inhibitor, LY294002, inhibited IL-2-rescued survival, but a mitogen-activated protein kinase inhibitor, PD98059, and an inhibitor of Janus tyrosine kinase/signal transducer and activator of transcription pathway, AG490, did not. LY294002 inhibited IL-2-induced reduction of ceramide through activation of acid SMase and inhibition of GCS and SMS, suggesting the positive involvement of PI-3 kinase in ceramide reduction through enzymatic regulation. Indeed, a constitutively active PI-3 kinase enhanced growth rate and ceramide reduction through inhibition of acid SMase and activation of GCS and SMS. Further, LY294002 inhibited IL-2-induced changes of transcriptional level as well as mRNA and protein levels in acid SMase and GCS but did not affect the stability of the mRNAs. These results suggest that PI-3 kinase-dependent reduction of ceramide through regulation of acid SMase, GCS, and SMS plays a role in IL-2-rescued survival of NK cells. (Blood. 2004;104:3285-3293)
Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation
Authors: Xystrakis Emmanuel , Dejean Anne S. , Bernard Isabelle , Druet Philippe , Liblau Roland , Gonzalez-Dunia Daniel , Saoudi Abdelhadi 
Published: July 2004

AbstractThe immune system contains natural regulatory T cells that control the magnitude of the immune response during physiologic and pathologic conditions. Although this suppressive function was historically attributed to CD8 T cells, most recent reports have focused on natural regulatory CD4 T cells. In the present study, we describe a new subset of natural CD8 regulatory T cells in normal healthy animals. This subset expresses low levels of CD45RC at its surface (CD45RClow); produces mainly interleukin-4 (IL-4), IL-10, and IL-13 cytokines upon in vitro stimulation; expresses Foxp3 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); and is not cytotoxic against allogeneic targets. This subset suppresses the proliferation and differentiation of autologous CD4 T cells into type-1 cytokines producing T cells after stimulation with allogeneic accessory cells. We also provide evidence that this regulatory subset mediates its suppression by cell-to-cell contact and not through secretion of suppressive cytokines. Finally, the regulatory activity of CD8 CD45RClow cells is also demonstrated in vivo in a rat model of CD4-dependent graft-versus-host disease. Collectively, these data demonstrate for the first time that freshly isolated rat CD8 CD45RClow T cells contain T cells with regulatory properties, a result that enlarges the general picture of T-cell-mediated regulation. (Blood. 2004;104:3294-3301)
Visualization of lymphatic vessels through NF-κB activity
Authors: Saban Marcia R. , Mémet Sylvie , Jackson David G. , Ash John , Roig Aurelio A. , Israël Alain , Saban Ricardo 
Published: July 2004

AbstractThe molecular biology of lymphatics is only rudimentary owing to the long-standing absence of specific markers, and scanty is the information regarding bladder lymphatic vessels. By using mice with a reporter gene for nuclear factor κB (NF-κB) activity (κB-lacZ) in combination with immunohistochemical staining with a specific lymphatic marker (LYVE-1), we show, for the first time, that NF-κB is constitutively active in lymphatic endothelium in the urinary bladder, uterus, intestine, heart, and airways. Tie2-lacZ mice confirmed that the structures observed in κB-lacZ mice were not blood vessels. In addition, acute instillation of lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α) into the κB-lacZ mouse bladder revealed the capacity of this transgenic in reporting inducible NF-κB activity. Our findings demonstrate an overriding constitutive NF-κB activity in the lymphatic system. They also provide a working model for detecting lymphatic vessels and evoke testable hypotheses regarding the role of lymphatic vessels in health and disease.
NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction
Authors: Nwariaku Fiemu E. , Liu Zijuan , Zhu Xudong , Nahari Dorit , Ingle Christine , Wu Ru Feng , Gu Ying , Sarosi George , Terada Lance S. 
Published: July 2004

Abstract
Vascular endothelial activation is an early step during leukocyte/endothelial adhesion and transendothelial leukocyte migration in inflammatory states. Leukocyte transmigration occurs through intercellular gaps between endothelial cells. Vascular endothelial cadherin (VE-cadherin) is a predominant component of endothelial adherens junctions that regulates intercellular gap formation. We found that tumor necrosis factor (TNF) caused tyrosine phosphorylation of VE-cadherin, separation of lateral cell-cell junctions, and intercellular gap formation in human umbilical vein endothelial cell (HUVEC) monolayers. These events appear to be regulated by intracellular oxidant production through endothelial NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase because antioxidants and expression of a transdominant inhibitor of the NADPH oxidase, p67(V204A), effectively blocked the effects of TNF on all 3 parameters of junctional integrity. Antioxidants and p67(V204A) also decreased TNF-induced JNK activation. Dominant-negative JNK abrogated VE-cadherin phosphorylation and junctional separation, suggesting a downstream role for JNK. Finally, adenoviral delivery of the kinase dead PAK1(K298A) decreased TNF-induced JNK activation, VE-cadherin phosphorylation, and lateral junctional separation, consistent with the proposed involvement of PAK1 upstream of the NADPH oxidase. Thus, PAK-1 acts in concert with oxidase during TNF-induced oxidant production and loss of endothelial cell junctional integrity.
Significant receptor affinities of metabolites and a degradation product of mometasone furoate
Authors: Valotis Anagnostis , Högger Petra 
Published: July 2004

AbstractMometasone furoate (MF) is a highly potent glucocorticoid used topically to treat inflammation in the lung, nose and on the skin. However, so far no information has been published on the human glucocorticoid receptor activity of the metabolites or degradation products of MF. We have now determined the relative receptor binding affinities of the known metabolite 6β-OH MF and the degradation product 9,11-epoxy MF to understand their possible contribution to undesirable systemic side effects. In competition experiments with human lung glucocorticoid receptors we have determined the relative receptor affinities (RRA) of these substances with reference to dexamethasone (RRA = 100). We have discovered that 6β-OH MF and 9,11-epoxy MF display RRAs of 206 ± 15 and 220 ± 22, respectively. This level of activity is similar to that of the clinically used inhaled corticosteroid flunisolide (RRA 180 ± 11). Furthermore we observed that 9,11-epoxy MF is a chemically reactive metabolite. In recovery experiments with human plasma and lung tissue we found a time dependent decrease in extractability of the compound. Hence, we provide data that might contribute to the understanding of the pharmacokinetics as well as the clinical effects of MF.
Attentional influences on functional mapping of speech sounds in human auditory cortex
Authors: Obleser Jonas , Elbert Thomas , Eulitz Carsten 
Published: July 2004

Abstract
Background
The speech signal contains both information about phonological features such as place of articulation and non-phonological features such as speaker identity. These are different aspects of the 'what'-processing stream (speaker vs. speech content), and here we show that they can be further segregated as they may occur in parallel but within different neural substrates. Subjects listened to two different vowels, each spoken by two different speakers. During one block, they were asked to identify a given vowel irrespectively of the speaker (phonological categorization), while during the other block the speaker had to be identified irrespectively of the vowel (speaker categorization). Auditory evoked fields were recorded using 148-channel magnetoencephalography (MEG), and magnetic source imaging was obtained for 17 subjects.

Results
During phonological categorization, a vowel-dependent difference of N100m source location perpendicular to the main tonotopic gradient replicated previous findings. In speaker categorization, the relative mapping of vowels remained unchanged but sources were shifted towards more posterior and more superior locations.

Conclusions
These results imply that the N100m reflects the extraction of abstract invariants from the speech signal. This part of the processing is accomplished in auditory areas anterior to AI, which are part of the auditory 'what' system. This network seems to include spatially separable modules for identifying the phonological information and for associating it with a particular speaker that are activated in synchrony but within different regions, suggesting that the 'what' processing can be more adequately modeled by a stream of parallel stages. The relative activation of the parallel processing stages can be modulated by attentional or task demands.
A quantitative analysis of qualitative studies in clinical journals for the 2000 publishing year
Authors: McKibbon Kathleen Ann , Gadd Cynthia S 
Published: July 2004

Abstract
Background
Quantitative studies are becoming more recognized as important to understanding health care with all of its richness and complexities. The purpose of this descriptive survey was to provide a quantitative evaluation of the qualitative studies published in 170 core clinical journals for 2000.

Methods
All identified studies that used qualitative methods were reviewed to ascertain which clinical journals publish qualitative studies and to extract research methods, content (persons and health care issues studied), and whether mixed methods (quantitative and qualitative methods) were used.

Results
60 330 articles were reviewed. 355 reports of original qualitative studies and 12 systematic review articles were identified in 48 journals. Most of the journals were in the discipline of nursing. Only 4 of the most highly cited health care journals, based on ISI Science Citation Index (SCI) Impact Factors, published qualitative studies. 37 of the 355 original reports used both qualitative and quantitative (mixed) methods. Patients and non-health care settings were the most common groups of people studied. Diseases and conditions were cancer, mental health, pregnancy and childbirth, and cerebrovascular disease with many other diseases and conditions represented. Phenomenology and grounded theory were commonly used; substantial ethnography was also present. No substantial differences were noted for content or methods when articles published in all disciplines were compared with articles published in nursing titles or when studies with mixed methods were compared with studies that included only qualitative methods.

Conclusions
The clinical literature includes many qualitative studies although they are often published in nursing journals or journals with low SCI Impact Factor journals. Many qualitative studies incorporate both qualitative and quantitative methods.
World health system performance revisited: the impact of varying the relative importance of health system goals
Authors: Lauer Jeremy A , Lovell CA Knox , Murray Christopher JL , Evans David B 
Published: July 2004

Abstract
Background
In 2002, the World Health Organization published a health system performance ranking for 191 member countries. The ranking was based on five indicators, with fixed weights common to all countries.

Methods
We investigate the feasibility and desirability of using mathematical programming techniques that allow weights to vary across countries to reflect their varying circumstances and objectives.

Results
By global distributional measures, scores and ranks are found to be not very sensitive to changes in weights, although differences can be large for individual countries.

Conclusions
Building the flexibility of variable weights into calculation of the performance index is a useful way to respond to the debates and criticisms appearing since publication of the ranking.