bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Foxp3 regulatory gene expression with graft-versus-host disease
Authors: Miura Yuji , Thoburn Christopher J. , Bright Emilie C. , Phelps Michele L. , Shin Tahiro , Matsui Elizabeth C. , Matsui William H. , Arai Sally , Fuchs Ephraim J. , Vogelsang Georgia B. , Jones Richard J. , Hess Allan D. 
Published: June 2004

AbstractGraft-versus-host disease (GVHD) is characterized by an impairment of mechanisms that underlie the development of immunologic tolerance. Although the cytokine storm associated with GVHD leads to expression of cell surface markers on both effector and regulatory T cells, regulatory CD4+ T cells that play an instrumental role in the maintenance of tolerance appear to uniquely express the Foxp3 transcriptional repressor. Foxp3 mRNA expression was significantly decreased in peripheral blood mononuclear cells from patients with either allogeneic GVHD or autologous GVHD compared with patients without GVHD. Expression of Foxp3 negatively correlated with the severity of GVHD but positively correlated with recent thymic emigrants. The results suggest that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms following transplantation. The decrease in regulatory mechanisms after transplantation appears to provide an environment permissive to the development of GVHD. (Blood. 2004;104:2187-2193)
Heparin-activated antithrombin interacts with the autolysis loop of target coagulation proteases
Authors: Yang Likui , Manithody Chandrashekhara , Rezaie Alireza R. 
Published: June 2004

AbstractA unique pentasaccharide fragment of heparin can enhance the reactivity of antithrombin with coagulation proteases factors IXa and Xa by 300- to 600-fold through a conformational activation of the serpin, without having a significant effect on the reactivity of antithrombin with thrombin. In this study, it was hypothesized that differences in the structure of the autolysis loop of coagulation proteases (residues 143-154 in chymotrypsin numbering) may be responsible for their differential reactivity with the native and heparin-activated antithrombin. To test this hypothesis, the autolysis loops of both thrombin and the anticoagulant serine protease-activated protein C were replaced with the corresponding loop of factor Xa. Inhibition studies revealed that in contrast to the approximately 1.5-fold difference in the reactivity of thrombin with antithrombin in the absence and presence of pentasaccharide, the difference in reactivity was increased to approximately 37-fold for the mutant thrombin. In the case of the activated protein C mutant, similar to factor Xa, pentasaccharide accelerated the reaction 375-fold. These results suggest that structural differences in the autolysis loop of coagulation proteases play a key role in their differential reactivity with the native and heparin-activated conformations of antithrombin. (Blood. 2004;104:1753-1759)
Immobilization of rolling NK cells on platelet-borne P-selectin under flow by proinflammatory stimuli, interleukin-12, and leukotriene B4
Authors: Sheikh S , Parhar R S , Bakheet R , Saleh S , Collison K , Al-Mohanna F 
Published: June 2004

AbstractRecruitment of leukocytes from bloodstream to extrahematic sites is tightly regulated by a variety of adhesion molecules that are expressed on the leukocytes and the vessel walls. In this manuscript, wedescribe the interactions between natural killer (NK) cells and activated, autologous platelets under physiologic flow. We found that surface-adherent human platelets are capable of recruiting human NK cells from flow and that this recruitment is characterized by an initial tethering followed by a rolling phase. Both phases were dependent on the adhesion molecule P-selectin and its counter-ligand on the NK cells (P-selectin glycoprotein ligand 1). Activation of rolling NK cells with inflammatory mediators commonly found in atherosclerotic plaques (interleukin-12 and leukotriene B4) causes immediate cessation of the rolling process and conversion to stationary adhesion. Blocking antibodies to the adhesion molecules membrane-activated complex-1 and leukocyte function antigen-1 inhibited this conversion. Our data suggest that platelets deposited at sites of vascular injury may provide an alternative substrate to endothelial cells for initial recruitment of NK cells to the vessel wall. This may result in extravasation of the NK cells if the appropriate chemotactic signal is applied. These data implicate the P-selectin and integrin family of adhesion molecules in the recruitment of NK cells to atherosclerotic sites.
Endogenous ligands of Toll-like receptors
Authors: Tsan Min-Fu , Gao Baochong 
Published: June 2004

AbstractExtensive work has suggested that a number of endogenous molecules such as heat shock proteins (hsp) may be potent activators of the innate immune system capable of inducing proinflammatory cytokine production by the monocyte-macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via the Toll-like receptor (TLR) signal-transduction pathways in a manner similar to lipopolysaccharide (LPS; via TLR4) and bacterial lipoproteins (via TLR2). However, recent evidence suggests that the reported cytokine effects of hsp may be a result of the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) being responsible for the putative TLR ligands of hsp include failure to use highly purified hsp free o LPS contamination; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Whether other reported putative endogenous ligands of TLR2 and TLR4 are a result of contamination of pathogen-associated molecular patterns is not clear. It is essential that efforts should be directed to conclusively determine whether the reported putative endogenous ligands of TLRs are a result of the endogenous molecules or of contaminant(s), before exploring further the implication and therapeutic potential of these putative TLR ligands.
Human epidermal Langerhans cells differ from monocyte-derived Langerhans cells in CD80 expression and in secretion of IL-12 after CD40 cross-linking
Authors: Peiser Matthias , Wanner Reinhard , Kolde Gerhard 
Published: June 2004

AbstractLangerhans cells (LCs) represent an immature population of myeloid dendritic cells (DCs). As a result of their unique Birbeck granules (BGs), langerin expression, and heterogeneous maturation process, they differ from other immature DCs. Monocyte-derived LCs (MoLCs) mimic epidermal LCs. MoLCs with characteristic BGs are generated by culturing blood-derived monocytes with granulocyte macrophage-colony stimulating factor, interleukin (IL)-4, and transforming growth factor-β1. Here, we compare maturation-induced antigen expression and cytokine release of LCs with MoLCs. To achieve comparable cell populations, LCs and MoLCs were isolated by CD1c cell sorting, resulting in high purity. In unstimulated cells, CD40 was expressed at equal levels. After stimulation with CD40 ligand (CD40L), LCs and MoLCs acquired CD83 and increased CD86. High CD80 expression was exclusively detected in CD1c-sorted MoLCs. Human leukocyte antigen-DR and CD54 expression was found in all cell populations, however, at different intensities. CD40 triggering increased the potency of LCs and MoLCs to stimulate CD4+ T cell proliferation. Activated MoLCs released IL-12p70 and simultaneously, anti-inflammatory IL-10. The application of the Toll-like receptor ligands peptidoglycan, flagellin, and in particular, lipoplysaccharide (LPS) increased the corelease of these cytokines. LCs secreted IL-10 at a comparable level with MoLCs but failed to produce high amounts of IL-12p70 after application of danger signals. These data indicate that MoLCs as well as LCs display no maturation arrest concerning CD83 and CD86 expression. In difference to MoLCs, LCs resisted activation by CD40L and LPS in terms of IL-12 production. This shows that natural and generated LCs share similar features but differ in relevant functions.
Human neutrophils synthesize IL-8 in an IgE-mediated activation
Authors: Monteseirín Javier , Chacón Pedro , Vega Antonio , El Bekay Rajaa , Alvarez Moisés , Alba Gonzalo , Conde Manuel , Jiménez Juan , Asturias Juan A , Martínez Alberto , Conde José , Pintado Elizabeth , Bedoya Francisco J , Sobrino Francisco 
Published: June 2004

AbstractIt has been demonstrated that neutrophils are responsible for the release of large amounts of the inflammatory chemokine interleukin-8 (IL-8), associated with inflammation. To further define the mechanisms implicated, we have analyzed the response of human neutrophils from allergic patients to specific antigens or challenge with anti-immunoglobulin (Ig)E antibodies. Neutrophils showed a dose- and time-dependent production of IL-8. The release of the cytokine was parallel to expression of IL-8 mRNA analyzed by the polymerase chain reaction. This expression was transient—it occurred after 3 h of anti-IgE treatment and was maintained for 18 h. Trifluoperazine, EGTA, reduced nicotinamide adenine dinucleotide phosphate-oxidase inhibitors, and reactive oxygen species (ROS) scavengers inhibited IL-8 production, indicating a critical dependence of calcium and oxidative stress. Moreover, an inhibitory effect of cyclosporin A, an immunosuppressor that inhibits calcineurin activity, on IL-8 release and IL-8 mRNA expression was observed. This is the first evidence of the involvement of ROS and calcium/calcineurin in IgE-dependent IL-8 production. These findings open new perspectives into the functional role of neutrophils in IgE-associated diseases.
IFN-α regulates IL-21 and IL-21R expression in human NK and T cells
Authors: Strengell Mari , Julkunen Ilkka , Matikainen Sampsa 
Published: June 2004

AbstractInterleukin (IL)-21 is a T cell-derived cytokine that regulates innate and adaptive immune responses. IL-21 receptor (IL-21R), which is expressed in natural killer (NK) and T cells, is structurally homologous to IL-2Rβ and IL-15Rα. These receptors also share a common cytokine receptor γ-chain with IL-4, IL-7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-α/β is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN-γ gene expression, IFN-α/β and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN-α/β enhanced T cell receptor stimulation-induced IL-21 and IFN-γ gene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFN-γ activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN-α/β-stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN-α/β down-regulated IL-21R mRNA expression in NK and T cells. IFN-α/β-induced down-regulation of IL-21R expression resulted in reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. In conclusion, our results suggest a novel role for IFN-α/β in the regulation of IL-21 response.
Lysophosphatidylcholine up-regulates CXCR4 chemokine receptor expression in human CD4 T cells
Authors: Han Ki Hoon , Hong Kyung Hee , Ko Jesang , Rhee Kyong Suk , Hong Myeong Ki , Kim Jae Joong , Kim You Ho , Park Seung Jung 
Published: June 2004

AbstractOxidized low-density lipoprotein (OxLDL) is an inflammatory modulator in the atherosclerotic plaque. We examined the effect of lysophosphatidylcholine (lysoPC), a main phospholipid component of OxLDL, on inflammatory responses in human CD4 T cells. We found that lysoPC dose- and time-dependently increased expression of CXCR4, the chemokine receptor on CD4 T cells. This increase was inhibited by caffeic acid phenethyl ester or SN50, nuclear factor-κB inhibitors, and also by suppression of G2A expression, the specific receptor for lysoPC, using antisense oligonucleotide. lysoPC enhanced CD4 T cell chemotaxis in response to stromal cell-derived factor-1 (SDF-1), the exclusive ligand for CXCR4. lysoPC also enhanced SDF-1-stimulated production of inflammatory cytokines interleukin-2 and interferon-γ by CD4 T cells activated by anti-CD3 immunoglobulin G. In conclusion, this study demonstrates that lysoPC directly modulates inflammatory responses in human CD4 T cells. The data suggest that the presence of lysoPC and SDF-1 in atherosclerotic lesions may trigger inflammatory responses mediated by CD4 T cells, which may play an important role in progression of atherosclerosis.
Insulin cell mass is altered inCsf1op/Csf1opmacrophage-deficient mice
Authors: Banaei-Bouchareb Linda , Gouon-Evans Valerie , Samara-Boustani Dinane , Castellotti Marie Claire , Czernichow Paul , Pollard Jeffrey W , Polak Michel 
Published: June 2004

AbstractMacrophages play an important role in organ development, tissue homeostasis, and remodeling. Thus, we monitored the presence of F4/80-positive macrophages in the pancreas of wild-type mice, and some developmental features of this complex tissue were compared throughout life in wild-type and macrophage-deficient Csf1op/Csf1op (op/op) mice. The combined use of immunohistochemistry, morphometry, and cell quantification allows us to evaluate insulin and glucagon cell mass, total and insulin cell proliferation, and apoptosis in fetuses (E18.5), weanings (postnatal day 21), nonpregnant adults, and adults in late pregnancy (18.5 days). F4/80-positive macrophages were found in pancreases recovered from Csf1op/Csf1+ (op/+) mice but were extremely scarce or absent in pancreas recovered from op/op ones at all studied time-points. The macrophage-deficient op/op phenotype was clearly associated with a major insulin mass deficit in fetuses and adults, abnormal postnatal islet morphogenesis, and impaired pancreatic cell proliferation at weaning and late pregnancy. We also obtained indirect evidence of increased neogenesis in this model at time-points when pancreatic remodeling does occur. The demonstration of the colony-stimulating factor 1-dependent macrophage involvement in life-time pancreas development/remodeling allows us to pinpoint the tissue-modeling and remodeling functions of this leukocyte lineage.
Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression through p38 MAPK activation
Authors: Ma Penglin , Cui Xiaolin , Wang Shuibang , Zhang Jianhua , Nishanian Ervant V , Wang Weihan , Wesley Robert A , Danner Robert L 
Published: June 2004

AbstractNitric oxide (NO·) contributes to vascular collapse in septic shock and regulates inflammation. Here, we demonstrate in lipopolysaccharide (LPS)-stimulated human THP-1 cells and monocytes that NO· regulates interleukin (IL)-8 and tumor necrosis factor α (TNF-α) by distinct mechanisms. Dibutyryl-cyclic guanosine 5′-monophosphate (cGMP) failed to simulate NO·-induced increases in TNF-α or IL-8 production. In contrast, dibutyryl-cyclic adenosine monophosphate blocked NO·-induced production of TNF-α (P=0.009) but not IL-8. NO· increased IL-8 (5.7-fold at 4 h; P=0.04) and TNF-α mRNA levels (2.2-fold at 4 h; P=0.037). However, nuclear run-on assays demonstrated that IL-8 transcription was slightly decreased by NO· (P=0.08), and TNF-α was increased (P=0.012). Likewise, NO· had no effect on IL-8 promoter activity (P=0.84) as measured by reporter gene assay. In THP-1 cells and human primary monocytes treated with actinomycin D, NO· had no effect on TNF-α mRNA stability (P&gt;0.3 for both cell types) but significantly stabilized IL-8 mRNA (P=0.001 for both cell types). Because of its role in mRNA stabilization, the p38 mitogen-activated protein kinase (MAPK) pathway was examined and found to be activated by NO· in LPS-treated THP-1 cells and human monocytes. Further, SB202190, a p38 MAPK inhibitor, was shown to block NO·-induced stabilization of IL-8 mRNA (P&lt;0.02 for both cell types). Thus, NO· regulates IL-8 but not TNF-α post-transcriptionally. IL-8 mRNA stabilization by NO· is independent of cGMP and at least partially dependent on p38 MAPK activation.
Benefits and Costs of Interventions to Improve Breast Cancer Outcomes in African American Women
Authors: Mandelblatt Jeanne S. , Schechter Clyde B. , Yabroff K. Robin , Lawrence William , Dignam James , Muennig Peter , Chavez Yoko , Cullen Jennifer , Fahs Marianne 
Published: June 2004

PurposeHistorically, African American women have experienced higher breast cancer mortality than white women, despite lower incidence. Our objective was to evaluate whether costs of increasing rates of screening or application of intensive treatment will be off-set by survival benefits for African American women.MethodsWe use a stochastic simulation model of the natural history of breast cancer to evaluate the incremental societal costs and benefits of status quo versus targeted biennial screening or treatment improvements among African Americans 40 years of age and older. Main outcome measures were number of mammograms, stage, all-cause mortality, and discounted costs per life year saved (LYS).ResultsAt the current screening rate of 76%, there is little incremental benefit associated with further increasing screening, and the costs are high: $124,053 and $124,217 per LYS for lay health worker and patient reminder interventions, respectively, compared with the status quo. Using reminders would cost $51,537 per LYS if targeted to virtually unscreened women or $78,130 per LYS if targeted to women with a two-fold increase in baseline risk. If all patients received the most intensive treatment recommended, costs increase but deaths decrease, for a cost of $52,678 per LYS. Investments of up to $6,000 per breast cancer patient could be used to enhance treatment and still yield cost-effectiveness ratios of less than $75,000 per LYS.ConclusionExcept in pockets of unscreened or high-risk women, further investments in interventions to increase screening are unlikely to be an efficient use of resources. Ensuring that African American women receive intensive treatment seems to be the most cost-effective approach to decreasing the disproportionate mortality experienced by this population.
XPD and XRCC1 Genetic Polymorphisms Are Prognostic Factors in Advanced Non—Small-Cell Lung Cancer Patients Treated With Platinum Chemotherapy
Authors: Gurubhagavatula Sarada , Liu Geoffrey , Park Sohee , Zhou Wei , Su Li , Wain John C. , Lynch Thomas J. , Neuberg Donna S. , Christiani David C. 
Published: June 2004

Purpose Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents for non–small-cell lung cancer (NSCLC). Methods We used polymerase chain reaction–restriction fragment length polymorphism to evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with platinum-based chemotherapy. Results Median age was 58 years (range, 32 to 77 years), 49% were females, and there were 86 deaths. Median follow-up period was 61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6 months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival (P = .003 and P = .07, respectively, by log-rank test). Similarly, when we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing overall survival (P = .009, log-rank test). These polymorphisms independently predicted overall survival even after taking into account stage, performance status, and chemotherapy regimen. Conclusion Genetic polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum-treated patients with advanced NSCLC.
Phase I Trial of Yttrium-90—Labeled Anti—Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate Cancer
Authors: Milowsky Matthew I. , Nanus David M. , Kostakoglu Lale , Vallabhajosula Shankar , Goldsmith Stanley J. , Bander Neil H. 
Published: June 2004

Purpose To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90–labeled anti–prostate-specific membrane antigen monoclonal antibody J591 (90Y-J591) in patients with androgen-independent prostate cancer (PC). Patients and Methods Patients with androgen-independent PC and evidence of disease progression received indium-111–J591 for pharmacokinetic and biodistribution determinations followed 1 week later by 90Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m2. Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. Results Twenty-nine patients with androgen-independent PC received 90Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m2, with two patients experiencing thrombocytopenia with non–life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m2 dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. Conclusion The recommended dose for 90Y-J591 is 17.5 mCi/m2. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of 90Y-J591 in the treatment of patients with PC.
Prediction of inter-segment stability and osteophyte formation on the multi-segment C2-C7 after unilateral and bilateral facetectomy
Authors: Hong-Wan Ng , Ee-Chon Teo , Qing-Hang Zhang 
Published: June 2004

The objective of this study was to determine the intersegment stability, disc degeneration, and osteophytes formation on the multisegment cervical spine (C2-C7) after unilateral and bilateral facetectomy. A geometrically accurate non-linear three-dimensional model of the intact human cervical spine was created from the digitized coordinates of the dry vertebrae. The intact model was validated against the published results under physiological loading conditions. Eight surgically altered models were created from the intact model. The intact and surgical altered models were subjected to physiological loading. The inclusion of five levels in the present model allowed accurate determination of the intersegment responses and internal cortical bone and disc annulus stress in the adjacent spinal components. Results indicated that facetectomy performed on C5-C6 significantly affects the corresponding stress and intersegment motions at the corresponding C5-C6 levels. The maximum increases were 18 per cent for bilateral facetectomy and 7 per cent for unilateral facetectomy under lateral bending. Combined flexion-extension and axial rotation caused an approximately similar amount of increases after total facetectomy. In addition, adjacent segments (C4-C5 and C6-7) also experience a slight increase in the intersegment responses and internal stress after facetectomy. It has been shown that facetectomy of greater than 50 per cent resulted in segment hypermobility and substantial increase in the disc annulus and cortical bone stress. Increase in the stress may lead to osteophytes formation. This study revealed important information that will help clinicians identify the critical intersegment stability and to decide on the amount of facets resection.