bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Activation of Human Gingival Epithelial Cells and Monocytes by
Porphyromonas gingivalis
Fimbriae
Authors: Eskan Mehmet A. , Hajishengallis George , Kinane Denis F. 
Published: November 2006

ABSTRACT

Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR).
Porphyromonas gingivalis
is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by
P. gingivalis
FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that
P. gingivalis
FimA does not readily activate epithelial innate immune responses but rather functions to promote
P. gingivalis
colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion,
P. gingivalis
FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by
P. gingivalis
when interacting with different host cell types or a host strategy to limit inflammation.
Nitroglycerin Treatment May Enhance Chemosensitivity to Docetaxel and Carboplatin in Patients with Lung Adenocarcinoma
Authors: Yasuda Hiroyasu , Nakayama Katsutoshi , Watanabe Mika , Suzuki Satoshi , Fuji Hiromi , Okinaga Shoji , Kanda Akio , Zayasu Kiyoshi , Sasaki Takahiko , Asada Masanori , Suzuki Tomoko , Yoshida Motoki , Yamanda Shinsuke , Inoue Daisuke , Kaneta Tomohiro , Kondo Takashi , Takai Yoshihiro , Sasaki Hidetada , Yanagihara Kazuhiro , Yamaya Mutsuo 
Published: November 2006

AbstractPurpose: Nitroglycerin may improve the response to chemotherapy in advanced non–small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported.Experimental Design: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb.Results: The rates of immunoreactive cells for HIF-1α, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1α in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma.Conclusions: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1α.
SD-1029 Inhibits Signal Transducer and Activator of Transcription 3 Nuclear Translocation
Authors: Duan Zhenfeng , Bradner James E. , Greenberg Edward , Levine Ross , Foster Rosemary , Mahoney Jennifer , Seiden Michael V. 
Published: November 2006

Abstract
Purpose: Signal transducer and activator of transcription 3 (Stat3) proteins have important roles in cancer cell survival and proliferation. Recent studies show that aberrant Stat3 activation promotes tumor growth and survival in several human cancers, and thus, presents an attractive pathway for the development of targeted anticancer therapy. Stat3 is a DNA-binding transcription factor, and thus, its function depends on cytoplasmic to nuclear translocation. To discover novel inhibitors of the Stat3 signaling pathway, we designed a cell-based screening assay capable of identifying compounds that inhibit Stat3 nuclear translocation and activity.
Experimental Design: Cell-based fluorescence microscope screening and quantitative measurement of enhanced green fluorescent protein–Stat3 nuclear translocation assays were used to identify novel Stat3 inhibitors. The effects of identified Stat3 inhibitors on Janus kinase (Jak), Stat3 expression, and activation were determined by Western blotting and kinase in vitro autophosphorylation assay. The effects of identified Stat3 inhibitors on cell growth was evaluated by cell proliferation assay and apoptosis assay.
Results: Among the National Cancer Institute Diversity set, a 2,000-member library of bioactive small molecules, we identified SD-1029 as a micromolar inhibitor of IL-6 or oncostatin-induced Stat3 nuclear translocation. Biochemical analysis shows that SD-1029 inhibits tyrosyl phosphorylation of Stat3 implicating SD-1029 as an inhibitor of Jak. Further analysis shows that this compound inhibits tyrosyl phosphorylation of the Jak2 isoenzyme. The antiapoptotic proteins Bcl-XL and survivin, target proteins of activated Stat3, are down-regulated by SD-1029 resulting in the induction of apoptosis in several human breast and ovarian cancer cell lines. SD-1029 also enhances apoptosis induced by paclitaxel in ovarian cancer cells.
Conclusions: These results show that SD-1029 directly abrogates the Jak-Stat3 signaling pathway in human cancer cells expressing constitutively active Stat, and add to the growing literature that validates this pathway as a viable target for further drug development. Finally, SD-1029 may represent a suitable prototype for structural optimization and exploration as a therapeutic lead.
Arsenic Trioxide Affects Signal Transducer and Activator of Transcription Proteins through Alteration of Protein Tyrosine Kinase Phosphorylation
Authors: Wetzler Meir , Brady Michael T. , Tracy Erin , Li Zhang-Rong , Donohue Kathleen A. , O'Loughlin Kieran L. , Cheng Yijun , Mortazavi Amir , McDonald Amy A. , Kunapuli Padmaja , Wallace Paul K. , Baer Maria R. , Cowell John K. , Baumann Heinz 
Published: November 2006

AbstractPurpose: Arsenic trioxide decreases proliferation of acute myeloid leukemia (AML) cells, but its precise mechanism of action is unknown.Experimental Design: We studied the effect of arsenic trioxide on patient samples and the AML cell line HEL, which, like leukemic blasts from 50% of AML cases, has constitutively activated signal transducer and activator of transcription (STAT) proteins.Results: Arsenic trioxide induced mitotic arrest starting at 24 hours and significant cell death at 48 hours. These events were preceded by an arsenic trioxide dose-dependent down-regulation of activated STAT proteins starting at 6 hours. We hypothesized that arsenic trioxide inhibits protein tyrosine kinases (PTK), which, among others, phosphorylate and activate STATs. We therefore studied arsenic trioxide effects on Janus kinases and on three oncogenic PTKs that are known to activate STATs [FLT3, ZNF198/fibroblast growth factor receptor 1 (FGFR1), and BCR/ABL]. Arsenic trioxide reduced STAT3 activation by Janus kinases, altered phosphorylation and electrophoretic mobility of ZNF198/fibroblast growth factor receptor 1, reduced kinase protein level, and decreased STAT3 protein phosphorylation. Arsenic trioxide also reduced the phosphorylation of BCR/ABL and FLT3 with corresponding decreased STAT5 phosphorylation.Conclusions: These results suggest a selective activity of arsenic trioxide on PTKs and will assist in developing clinical trials in AML.
How molecular imaging is speeding up antiangiogenic drug development
Authors: Cai Weibo , Rao Jianghong , Gambhir Sanjiv S. , Chen Xiaoyuan 
Published: November 2006

Abstract
Drug development is a long process that generally spans about 10 to 15 years. The shift in recent drug discovery to novel agents against specific molecular targets highlights the need for more robust molecular imaging platforms. Using molecular probes, molecular imaging can aid in many steps of the drug development process, such as providing whole body readout in an intact system, decreasing the workload and speeding up drug development/validation, and facilitating individualized anticancer treatment monitoring and dose optimization. The main focus of this review is the recent advances in tumor angiogenesis imaging, and the targets include vascular endothelial growth factor and vascular endothelial growth factor receptor, integrin αvβ3, matrix metalloproteinase, endoglin (CD105), and E-selectin. Through tumor angiogenesis imaging, it is expected that a robust platform for understanding the mechanisms of tumor angiogenesis and evaluating the efficacy of novel antiangiogenic therapies will be developed, which can help antiangiogenic drug development in both the preclinical stage and the clinical settings. Molecular imaging has enormous potential in improving the efficiency of the drug development process, including the specific area of antiangiogenic drugs. [Mol Cancer Ther 2006;5(11):2624–33]
NR0B1 Is Required for the Oncogenic Phenotype Mediated by EWS/FLI in Ewing's Sarcoma
Authors: Kinsey Michelle , Smith Richard , Lessnick Stephen L. 
Published: November 2006

Abstract
A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma, and myxoid liposarcoma, are associated with recurrent translocation events that encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a prototype for this tumor class. Ewing's sarcomas usually harbor the (11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key target genes that are involved in oncogenesis are largely unknown. Although some target genes have been defined, many of these have been identified in heterologous model systems with uncertain relevance to the human disease. To understand the function of EWS/FLI and its targets in a more clinically relevant system, we used retroviral-mediated RNAi to “knock-down” the fusion protein in patient-derived Ewing's sarcoma cell lines. By combining transcriptional profiling data from three of these lines, we identified a conserved transcriptional response to EWS/FLI. The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan nuclear receptor with no previously defined role in oncogenesis. We validated NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary human tumor samples. Functional studies revealed that ongoing NR0B1 expression is required for the transformed phenotype of Ewing's sarcoma. These studies define a new role for NR0B1 in oncogenic transformation and emphasize the utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells. (Mol Cancer Res 2006;4(11):851–7)
Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion
Authors: Wang Feng-qiang , Smicun Yoel , Calluzzo Nicholas , Fishman David A. 
Published: November 2006

AbstractOur previous reports show that matrilysin [matrix metalloproteinase (MMP)-7] is overexpressed in epithelial ovarian cancer (EOC) and recombinant MMP-7 promotes EOC invasion in vitro. In the present study, we further evaluated the correlation of MMP-7 expression to EOC invasiveness and examined its role in lysophosphatidic acid (LPA)-induced invasion. By sense and antisense gene transfection in vitro, we show that overexpression of MMP-7 in all MMP-7 stably transfected DOV13 clones significantly enhanced their invasiveness, although MMP-7 antisense transfection caused a 91% decrease of MMP-7 expression (P &lt; 0.01) and 87% decrease of invasion (P &lt; 0.05) in geneticin (G418)-selected DOV13 clone P47-M7As-3 compared with vector-transfected control. As assessed by MMP-7 ELISA, LPA treatment at 10 to 80 μmol/L significantly stimulated the secretion of total MMP-7 in DOV13 conditioned medium (P &lt; 0.01). In addition, LPA apparently induced the activation of MMP-7 in DOV13 cells as detected by gelatin zymography. In the antisense MMP-7-transfected DOV13 clone (P47-M7As-3), LPA-increased invasion was significantly decreased compared with vector control. Moreover, knocking down of MMP-7 by small interfering RNA also suppressed LPA-induced invasion in two EOC cell lines (DOV13 and R182). Altogether, our results show that MMP-7 expression is correlated with EOC invasiveness and LPA-induced MMP-7 secretion/activation may represent a new mechanism that facilitates ovarian cancer invasion besides the well-known induction of MT1-MMP-mediated proMMP-2 activation by LPA. (Mol Cancer Res 2006;4(11):831–41)
When a Word Is Worth a Thousand Pictures: Mahāyāna Influence on Theravāda Attitudes Towards Writing
Authors: Veidlinger Daniel 
Published: November 2006

AbstractThis article argues that Buddhist attitudes towards the written word in major Theravāda regions of Southeast Asia were strongly influenced by Mahāyāna Buddhism. Writing is not mentioned in the Pāli canon of the Theravāda Buddhists, and no emphasis was put on the idea of worshipping books in authoritative Theravāda literature, save a few words in an eleventh-century sub-commentarial text. The early generations of Theravāda Buddhists, not surprisingly, had an ambivalent relationship to writing and there is little evidence to suggest that they revered it. On the other hand, from the earliest times, seminal Mahāyāna texts have reserved their highest praise for the Dharma-bearing written word, and archeological and iconographic evidence as well as accounts of Chinese travelers suggest that stūpas were indeed made to enshrine texts and that books were the subject of votive cults. From the end of the first millennium CE, however, some Theravāda communities in Southeast Asia did begin to revere the written word in a Buddhist context by constructing beautiful libraries to house the texts, making texts out of gold, enshrining them in stūpas, and even worshipping them outright. In places such as Burma, Sri Lanka and central Thailand, this change of attitude coincided with the height of Mahāyāna influence. Moreover, in the northern Thai kingdom of Lan Na, there does not appear ever to have been any significant Mahāyāna presence and consequently, the more reverential Mahāyāna attitudes towards writing do not seem to have been imbibed by the culture, even though writing was well-known and fairly widely utilized.
Jérémie et les rois de Juda, Sédécias et Joaqim
Authors: Di Pede Elena 
Published: November 2006

AbstractFrom a literary point of view, particularly a narrative one, chapters xxxii-xxxix of Jeremiah, often cut up by the critics into various pericopes, present a beautiful unity of content. An element of this unity is the presence of a repeated scene, namely, the meeting between the king (Zedekia and Joaqim) and the prophet. These repeated scenes reveal that the relationship between king and prophet becomes more and more complicated and conflict-provoking as the story goes on. Moreover, presenting his story in this way, the narrator increases the suspense about the prophet's destiny and the future of his mission : the welcoming of Yhwh's word by the people.
Treatment of Acute Promyelocytic Leukemia
Authors: Sanz Miguel A. 
Published: November 2006

AbstractCure of acute promyelocytic leukemia (APL) is now a possibility for most patients through the use of state-of-the-art treatments, which include simultaneous administration of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction and consolidation, as well as ATRA-based maintenance. Risk-adapted strategies to modulate treatment intensity may be an effective approach to minimize therapy-related morbidity and mortality while maintaining the potential of cure. In this context, there is no role for hematopoietic stem cell transplantation (HSCT) in front-line therapy, except for the small fraction of patients with persistent minimal residual disease at the end of consolidation. However, HSCT plays an important role for patients in second complete remission. In contrast, an increasing role of arsenic trioxide (ATO) is emerging. Given the high antileukemic efficacy observed with ATO in patients relapsing after ATRA-containing regimens, this agent is currently regarded as the best treatment option in this setting. However, until a randomized comparison between the standard therapy and ATO-based regimens in front-line therapy is available, this latter approach should only be recommended for unfit patients for whom chemotherapy is contraindicated. In addition to reviewing current consensus and controversial issues on antileukemic strategies, this review addresses other aspects that can be crucial for the outcome of individual patients. These aspects include supportive care, recognition and treatment of life-threatening complications, evaluation of response, and, finally, management of the disease in special conditions such as older patients, children and pregnant women.
Utility of Positron Emission Tomography (PET) Scanning in Managing Patients with Hodgkin Lymphoma
Authors: Juweid Malik E. 
Published: November 2006

AbstractUse of positron emission tomography (PET) or PET/ computed tomography (CT) in Hodgkin lymphoma (HL) continues to expand worldwide. PET is currently widely utilized for response assessment after completion of therapy and, to a lesser extent, for pretreatment staging and assessment of response during therapy (therapy monitoring). In pretreatment staging, PET cannot replace CT or bone marrow biopsy (BMB); however, it can provide complementary information to both CT and BMB, potentially resulting in a modification of disease stage (usually upstaging) in about 15–20% of patients with impact on management in about 5–15%. PET for response assessment at the conclusion of treatment is substantially more accurate than CT because of its ability to distinguish between viable tumor and necrosis or fibrosis in posttherapy residual mass (es) that are present in about two-thirds of patients with HL without any other clinical or biochemical evidence of disease. PET, therefore, provides more accurate response classifications compared with CT-based assessment. The role of PET for therapy monitoring is still evolving but may prove to be the most exciting with potentially high impact on patient management and outcome. PET evaluation during therapy appears to be at least as accurate for predicting patient outcome as evaluation after completion of therapy and its use is clearly justified if the purpose is to provide an early and yet accurate assessment of response with the clear intent of tailoring therapy according to the information provided by the scan. The role of PET scanning for post-therapy surveillance without clinical, biochemical or radiographic evidence of disease remains controversial, primarily because of the potential for a disproportionate fraction of false-positive findings, potentially resulting in increasing cost without proven benefit from earlier PET detection of disease compared to standard surveillance methods. Large prospective studies are therefore needed to determine whether routine surveillance by PET is both cost-effective and whether it results in meaningful changes in patient management and/or outcome.
Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation
Authors: Orlowski Robert Z. 
Published: November 2006

Abstract
Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient’s disease. Such a risk- and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.
Challenges in the Therapeutic Use of a “So-Called” Universal Hemostatic Agent: Recombinant Factor VIIa
Authors: Hoots W. Keith 
Published: November 2006

Abstract
Recombinant factor VIIa (rFVIIa) was developed in the early 1990s to provide “bypassing” hemostatic therapy for hemophilia A and B patients with inhibitors. More recently, it has been licensed for use in patients with inherited deficiency of factor VII. Since it was licensed for use in hemophilia with inhibitors in the US, Europe, and other countries for these specific indications, it has been used selectively but in a wide array of clinical settings for uncontrolled hemorrhage in individuals without an inherited bleeding disorder. Many of these uses have been described in the medical literature as case reports or small, uncontrolled series. Several randomized clinical trials (RCT) for these “off-label” medical uses have been published in recent months and will serve as the focus of this review. In particular, a review of an RCT for spontaneous intracranial hemorrhage that has demonstrated clinical efficacy in reducing both mortality and volume of central nervous system hemorrhage will be offered. A brief discussion of hypothesized physiologic mechanisms of supraphysiologic doses of rFVIIa will introduce the clinical discussion of these broad off-label uses. Since rFVIIa is a very expensive therapy, possible strategies for optimizing its use in the these settings will be presented.