bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenesis of Human Papillomaviruses in Differentiating Epithelia
Authors: Longworth Michelle S. , Laimins Laimonis A. 
Published: June 2004

SUMMARY
Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. One-third of HPV types specifically infect the genital tract, and a subset of these are the causative agents of anogenital cancers. Other HPV types that infect the genital tract induce benign hyperproliferative lesions or genital warts. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The L1 and L2 proteins form icosahedral capsids for progeny virion generation. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.
IL-8 Plasma Concentrations and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women
Authors: Boekholdt S. Matthijs , Peters Ron J. G. , Hack C. Erik , Day Nicholas E. , Luben Robert , Bingham Sheila A. , Wareham Nicholas J. , Reitsma Pieter H. , Khaw Kay-Tee 
Published: June 2004

Objective—To study the role of IL-8 in predicting future coronary artery disease (CAD) in apparently healthy men and women.Methods and Results—A nested case-control study was performed in the prospective EPIC-Norfolk population study. We measured baseline IL-8 concentrations among 785 apparently healthy individuals in whom fatal or nonfatal CAD developed during follow-up and 1570 matched controls. Baseline IL-8 concentrations were higher in cases than in matched controls (3.5 pg/mL versus 3.1 pg/mL,P=0.001). The risk of future CAD increased with increasing quartiles of IL-8 (Plinearity <0.0001). Among individuals in the highest IL-8 quartile, the unadjusted odds ratio for future CAD was 1.72 (95% CI, 1.34 to 2.21;P<0.0001). The odds ratio for future CAD was still significant after adjustment for traditional risk factors (OR, 1.58; 95%CI, 1.19 to 2.09;P=0.002) and after additional adjustment for C-reactive protein and white cell count (OR, 1.77; 95% CI, 1.21 to 2.60;P=0.001).Conclusions—We conclude that among apparently healthy men and women, elevated levels of IL-8 are associated with an increased risk of future CAD. These prospective data support a role for IL-8 in the development of CAD events.
Endothelial Overexpression of Fas Ligand Decreases Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Yang Jiang , Sato Kaori , Aprahamian Tamar , Brown Nathaniel J. , Hutcheson Jack , Bialik Ann , Perlman Harris , Walsh Kenneth 
Published: June 2004

Objective—Fas ligand (FasL) can induce apoptosis in cells bearing the Fas receptor. The role of FasL in the vasculature with regard to atherosclerosis is controversial. This study examined the function of endothelial FasL during atherosclerosis.Methods and Results—Transgenic (Tg) mice that specifically overexpress different levels of FasL on vascular endothelial cells were crossed into the apolipoprotein E–knockout background (ApoE-KO) to generate ApoE-KO/FasL–Tg mice. Although plasma cholesterol and triglyceride levels were not different between ApoE-KO/FasL–Tg mice and ApoE-KO mice after 12 weeks of a high-fat diet, overexpression of the FasL transgene significantly reduced atherosclerotic lesion area in aortae by 49%. The reduction of atherosclerotic lesion area was more pronounced in thoracic and abdominal aortae than in the aortic arch, and a 34% reduction in lesion area was observed in aortic root sections from the ApoE-KO/FasL–Tg group compared with the ApoE-KO group. Immunostaining revealed significant decreases in both macrophage and CD8 T-cell accumulation in lesions of ApoE-KO/FasL–Tg mice. ApoE-KO/FasL–Tg mice that express lower levels of endothelial FasL also displayed reduced lesion size, but this reduction was statistically significant at the aortic arch only.Conclusions—Overexpression of endothelial FasL is antiinflammatory and inhibits atherosclerosis under hypercholesterolemic conditions.
Predictors of Hyperacute Clinical Worsening in Ischemic Stroke Patients Receiving Thrombolytic Therapy
Authors: Leigh Richard , Zaidat Osama O. , Suri Muhammad F. , Lynch Gwendolyn , Sundararajan Sophia , Sunshine Jeffrey L. , Tarr Robert , Selman Warren , Landis Dennis M.D. , Suarez Jose I. 
Published: June 2004

Background and Purpose—Although long-term outcome determinants in acute ischemic stroke (AIS) patients have been defined, less is known about those predicting hyperacute worsening after thrombolytic therapy (TT). We investigated predictors of short-term clinical worsening (National Institutes of Health Stroke Scale [NIHSS] change ≥4 within 24 hours of admission).Methods—We studied 201 AIS patients who received TT within 6 hours of symptom onset. We determined baseline demographics, comorbidities, NIHSS at baseline and at 24 hours after TT, head computed tomography scan before and within 24 hours after TT, and angiographic recanalization in patients treated with intra-arterial (IA) thrombolysis. Significance of relationships was evaluated byttest or Wilcoxon signed rank sum test. Logistic regression model (LRM) was fitted to determine independence of significant variables.Results—Of 201 patients, 13% worsened, 39% improved, and 48% remained unchanged 24 hours after TT. Most patients (72%) received IA thrombolysis. Patients who deteriorated, compared with those who improved, were more likely to have complicating intracranial hemorrhage (ICH;P<0.001), absent recanalization (P=0.026), and higher blood glucose (BG;P=0.049). Hyperglycemia (>150 mg/dL) was greater in patients who worsened even in presence of recanalization (P=0.004, odds ratio [OR] 6.47). LRM showed that adjusted OR for increased risk of bad outcome and mortality for an increase of BG by 50 mg/dL is 1.56 and 1.38, respectively.Conclusions—Hyperglycemia and ICH are independent predictors of hyperacute worsening in AIS patients receiving TT. Although recanalization is the purpose of IA thrombolysis, its impact on clinical improvement may not be apparent without strict BG control.
Role of protein kinase Cζ in thrombin-induced endothelial permeability changes: inhibition by angiopoietin-1
Authors: Li Xiaochun , Hahn Christopher N. , Parsons Michelle , Drew Jenny , Vadas Mathew A. , Gamble Jennifer R. 
Published: June 2004

AbstractEndothelial cell leakiness is regulated by mediators such as thrombin, which promotes endothelial permeability, and anti-inflammatory agents, such as angiopoietin-1. Here we define a new pathway involved in thrombin-induced permeability that involves the atypical protein kinase C isoform, PKCζ. Chemical inhibitor studies implicated the involvement of an atypical PKC isoform in thrombin-induced permeability changes in human umbilical vein endothelial cells. Thrombin stimulation resulted in PKCζ, but not the other atypical PKC isoform, PKCλ, translocating to the membrane, an event known to be critical to enzyme activation. The involvement of PKCζ was confirmed by overexpression of constitutively active PKCζ, resulting in enhanced basal permeability. Dominant-negative PKCζ prevented the thrombin-mediated effects on endothelial cell permeability and inhibited thrombin-induced activation of PKCζ. Rho activation does not appear to play a role, either upstream or downstream of PKCζ, as C3 transferase does not block thrombin-induced PKCζ activation and dominant-negative PKCζ does not block thrombin-induced Rho activation. Finally, we show that angiopoietin-1 inhibits thrombin-induced PKCζ activation, Rho activation, and Ca++ flux, thus demonstrating that the powerful antipermeability action of angiopoietin-1 is mediated by its action on a number of signaling pathways induced by thrombin and implicated in permeability changes. (Blood. 2004; 104:1716-1724)
Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene
Authors: Hakobyan Narine , Kazarian Tamara , Jabbar Adnan A. , Jabbar Kausar J. , Valentino Leonard A. 
Published: June 2004

AbstractHemophilia is a genetic disease caused by a deficiency of blood coagulation factor VIII or IX. Bleeding into joints is the most frequent manifestation of hemophilia. Hemarthrosis results in an inflammatory and proliferative disorder termed hemophilic synovitis (HS). In time, a debilitating, crippling arthritis, hemophilic arthropathy, develops. Although the clinical sequence of events from joint bleeding to synovitis to arthropathy is well documented, the component or components in blood and the molecular changes responsible for hemophilic synovitis are not known. Iron has long been suspected to be the culprit but direct evidence has been lacking. Previously, we showed that iron increased human synovial cell proliferation and induced c-myc expression. Here we show that bleeding into a joint in vivo and iron in vitro result in increased expression of the p53-binding protein, mdm2. Iron induced the expression of mdm2 by normal human synovial cells approximately 8-fold. In a murine model of human hemophilia A, hemarthrosis resulted in pathologic changes observed in human hemophilic synovitis and a marked increase in synovial cell proliferation. Iron, in vitro, induced the expression of mdm2. The molecular changes induced by iron in the blood may be the basis of the increase in cell proliferation and the development of hemophilic synovitis. (Blood. 2004;104:2060-2064)
Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator
Authors: Tjin Esther P.M. , Derksen Patrick W.B. , Kataoka Hiroaki , Spaargaren Marcel , Pals Steven T. 
Published: June 2004

AbstractMultiple myeloma (MM) is a common hematologic neoplasm consisting of malignant plasma cells, which expand in the bone marrow. A potential key signal in the evolution of MM is hepatocyte growth factor (HGF), which acts as a potent paracrine and/or autocrine growth factor and survival factor for MM cells. Proteolytic conversion of HGF into its active form is a critical limiting step in HGF/MET signaling. Here, we show that malignant MM plasma cells convert HGF into its active form and secrete HGF-activator (HGFA), a serine protease specific for HGF activation. By using serine protease inhibitors and neutralizing antibodies, we demonstrate that HGFA produced by the MM cells is responsible for their ability to catalyze HGF activation. We, therefore, suggest that autocatalyzation of HGF conversion by MM cells is an important step in HGF/MET-induced myeloma growth and survival, which may have implications for the management of this incurable form of cancer. (Blood. 2004;104:2172-2175)
Activated protein C variants with normal cytoprotective but reduced anticoagulant activity
Authors: Mosnier Laurent O. , Gale Andrew J. , Yegneswaran Subramanian , Griffin John H. 
Published: June 2004

AbstractRecombinant activated protein C (APC), a well-defined anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC's less well-defined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys an increased risk of serious bleeding complications due to APC anticoagulant activity. To generate recombinant APC variants with reduced risk of bleeding due to reduced anticoagulant activity, we dissected APC's anticoagulant activity from its cytoprotective activity by site-directed mutagenesis. Using staurosporine-induced endothelial cell apoptosis assays, we show here that Ala mutations (RR229/230AA and KKK191_ 193AAA) in 2 APC surface loops that severely reduce anticoagulant activity result in 2 APC variants that retain normal antiapoptotic activity that requires protease activated receptor-1 and endothelial cell protein C receptor. Thus, it is possible to reduce anticoagulant activity while preserving antiapoptotic activity of recombinant APC variants. We suggest that therapeutic use of such APC variants may reduce serious bleeding risks while providing the beneficial effects of APC acting directly on cells. (Blood. 2004;104: 1740-1744)
Creation of a mouse expressing defective human factor IX
Authors: Jin Da-Yun , Zhang Tai-Ping , Gui Tong , Stafford Darrel W. , Monahan Paul E. 
Published: June 2004

AbstractThe majority of cases of human hemophilia B are the result of missense mutations in the coagulation factor IX gene and defective circulating factor IX is detectable in most patients. The available mouse factor IX knockout models of hemophilia B (FIXKO mouse) reproduce the bleeding phenotype of human hemophilia B, but because the models produce no factor IX they fail to reproduce the dominant human phenotype. We have created a human factor IX mouse model of hemophilia B (R333Q-hFIX mouse) by homologous recombination in embryonic stem cells. The mouse expresses no mouse factor IX, but instead expresses a missense mutant human factor IX from the mouse FIX promoter. Mutant human factor IX mRNA transcript and circulating human factor IX are detectable throughout development, but factor IX activity is less than 1% and the mouse exhibits the hemophilic phenotype. When R333Q-hFIX mice were challenged by intramuscular injection of adeno-associated virus expressing human factor IX, factor IX expression without the development of antibodies was observed. In contrast, given the same treatment, FIXKO mice consistently develop antibodies. Our R333Q-hFIX mice strain will complement the FIXKO mice for studying factor IX circulating kinetics and gene therapy. (Blood. 2004;104:1733-1739)
Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors
Authors: Dhanji Salim , Teh Soo-Jeet , Oble Darryl , Priatel John J. , Teh Hung-Sia 
Published: June 2004

Abstract
We have recently shown that interleukin-2 (IL-2)-activated CD8+CD44hi cells from normal mice express both adaptive and innate immune system receptors and specifically kill syngeneic tumor cells, particularly those that express NKG2D ligands. Here we show that CD8+ T cells from antigen-expressing H-Y T-cell receptor (TCR) transgenic mice also exhibit characteristics of both T cells and natural killer (NK) cells. Interaction with cognate self-antigen was required for the optimal expansion of these cells in peripheral lymphoid tissues. Although these cells possess a higher activation threshold relative to naive T cells, they can be activated by cytokine alone in vitro. They also undergo bystander proliferation in response to a bacterial infection in vivo. Interestingly, upon activation, the cells express the NKG2D receptor as well as the DNAX activation protein 12 (DAP12) adaptor protein. We provide evidence that NKG2D can act additively with the TCR in the killing of target cells, and it can also function as a directly activating receptor in non-major histocompatibility complex (MHC)-restricted killing of target cells. These properties of CD8+ T cells from H-Y TCR transgenic mice are remarkably similar to CD8+CD44hi cells that are found in normal mice. The H-Y TCR transgenic mice provide a well-defined system for characterizing the developmental biology and function of these cells. (Blood. 2004;104:2116-2123)
Roles of MITF for development of mast cells in mice: effects on both precursors and tissue environments
Authors: Morii Eiichi , Oboki Keisuke , Ishihara Katsuhiko , Jippo Tomoko , Hirano Toshio , Kitamura Yukihiko 
Published: June 2004

AbstractThe mutant tg/tg mice, which do not express mi transcription factor (MITF), lack mast cells in most tissues. Since MITF is expressed in both mast cells and tissues where mast cells develop, there is a possibility that the tg/tg mice may show abnormalities in both mast cell precursors and tissue environments. We examined this possibility by bone marrow and skin transplantation. When bone marrow cells of tg/tg mice were transplanted to W/Wv mice that possess normal tissue environment, mast cells did not develop in all tissues examined. The number of developing mast cells in the skin of W/Wv mice was much lower when grafted to tg/tg recipients than when grafted to normal (+/+) recipients. These results indicated that mast cell precursors of tg/tg mice were defective. When bone marrow cells of +/+ mice were transplanted, the number of developing mast cells was significantly lower in examined tissues of tg/tg recipients than in those of W/Wv recipients, suggesting that the tissue environment for mast cell development was defective in tg/tg mice. MITF appeared essential for the function of both mast cell precursors and tissue environments for their development. (Blood. 2004;104:1656-1661)
FcγRIII discriminates between 2 subsets of Vγ9Vδ2 effector cells with different responses and activation pathways
Authors: Angelini Daniela F. , Borsellino Giovanna , Poupot Mary , Diamantini Adamo , Poupot Rémy , Bernardi Giorgio , Poccia Fabrizio , Fournié Jean-Jacques , Battistini Luca 
Published: June 2004

AbstractUpon recognition of nonpeptidic phosphoantigens, human Vδ2 T lymphocytes enter a lineage differentiation pattern that determines the generation of memory cells with a range of effector functions. Here, we show that within the effector memory Vδ2 population, 2 distinct and complementary subsets with regard to phenotype, mode of activation, and type of responses can be identified: Vδ2 TEMh cells, which express high levels of chemokine receptors, but low levels of perforin and of natural killer receptors (NKRs) and which produce large amounts of interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) in response to T-cell receptor (TCR)–specific stimulation by phosphoantigens; and Vδ2TEMRA cells, which constitutively express several NKRs, high amounts of perforin, but low levels of chemokine receptors and of IFN-γ. These NK-like cells are refractory to phosphoantigen but respond to activation via FcγRIII (CD16) and are highly active against tumoral target cells. Thus, circulating Vδ2T lymphocytes comprise 2 functionally diverse subsets of effector memory cells that may be discriminated on the basis of CD16 expression.
Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity
Authors: Hess David A. , Meyerrose Todd E. , Wirthlin Louisa , Craft Timothy P. , Herrbrich Phillip E. , Creer Michael H. , Nolta Jan A. 
Published: June 2004

AbstractHuman hematopoietic stem cells (HSCs) are commonly purified by the expression of cell surface markers such as CD34. Because cell phenotype can be altered by cell cycle progression or ex vivo culture, purification on the basis of conserved stem cell function may represent a more reliable way to isolate various stem cell populations. We have purified primitive HSCs from human umbilical cord blood (UCB) by lineage depletion (Lin-) followed by selection of cells with high aldehyde dehydrogenase (ALDH) activity. ALDHhiLin- cells contained 22.6% ± 3.0% of the Lin- population and highly coexpressed primitive HSC phenotypes (CD34+ CD38- and CD34+CD133+). In vitro hematopoietic progenitor function was enriched in the ALDHhiLin- population, compared with ALDHloLin- cells. Multilineage human hematopoietic repopulation was observed exclusively after transplantation of ALDHhiLin- cells. Direct comparison of repopulation with use of the nonobese diabetic/severe combined immunodeficient (NOD/SCID) and NOD/SCID β2 microglobulin (β2M) null models demonstrated that 10-fold greater numbers of ALDHhi-Lin- cells were needed to engraft the NOD/SCID mouse as compared with the more permissive NOD/SCID β2M null mouse, suggesting that the ALDHhiLin- population contained committed progenitors as well as primitive repopulating cells. Cell fractionation according to lineage depletion and ALDH activity provides a viable and prospective purification of HSCs on the basis of cell function rather than cell surface phenotype. (Blood. 2004;104:1648-1655)
Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study
Authors: Baker K. Scott , Gurney James G. , Ness Kirsten K. , Bhatia Ravi , Forman Stephen J. , Francisco Liton , McGlave Philip B. , Robison Leslie L. , Snyder David S. , Weisdorf Daniel J. , Bhatia Smita 
Published: June 2004

Abstract
The purpose of this study was to analyze medical late effects among patients with chronic myeloid leukemia (CML) treated with hematopoietic cell transplantation (HCT). Subjects included 248 CML survivors who received an HC transplant (related donors [RDs], n = 150; unrelated donors [URDs], n = 70; or autologous, n = 28) and had survived at least 2 years, and a comparison group of 317 siblings. Subjects completed a 238-item survey on medical late effects. Compared with siblings, survivors were at a higher risk of developing ocular, oral health, endocrine, gastrointestinal, musculoskeletal, neurosensory, and neuromotor impairments. Multivariate analysis limited to RD and URD recipients found that chronic graft-versus-host disease (cGVHD) was associated with a higher risk of hypothyroidism, osteoporosis, cardiopulmonary, neurosensory, and neuromotor impairments. Overall health was reported as excellent, very good, or good in 78% of subjects, although those with cGVHD were more likely to report poor overall health. URD survivors were more likely to report a need for assistance with routine activities and that their current health prevented work or school attendance. This study demonstrates that HCT survivors, regardless of donor type, have a high prevalence of long-term health-related complications. However, adverse medical late effects with significant morbidity were uncommon. Chronic GVHD is the most important predictor of adverse medical late effects and poor overall health.