bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor–independent urokinase-type plasminogen activator inhibition
Authors: Oh Seung-Hyun , Lee Ok-Hee , Schroeder Claudia P. , Oh Yun W. , Ke Shi , Cha Hee-Jae , Park Rang-Woon , Onn Amir , Herbst Roy S. , Li Chun , Lee Ho-Young 
Published: November 2006

Abstract
Insulin-like growth factor binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates the growth of non–small cell lung cancer (NSCLC) cells through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in lung cancer metastasis is not well known. In the present study, we showed that noncytotoxic doses of adenoviral or recombinant IGFBP-3 significantly decreased the migration and invasion of H1299 and A549 NSCLC cells. Furthermore, treatment of human lung fibroblasts with recombinant IGFBP-3 suppressed their ability to stimulate the invasion of H1299 cells. Overexpression of IGFBP-3 markedly reduced lung metastasis of A549 cells in an experimental animal model system and prolonged the survival time of the animals. Urokinase-type plasminogen activator (uPA) inhibitor treatment or uPA small interfering RNA transfection of A549 and H1299 cells resulted in a significant decrease in invasion. Corresponding ELISA, Western blot, gelatin zymogram, and semiquantitative reverse transcription-PCR analyses revealed that IGFBP-3 reduced the expression of uPA mRNA through IGF-independent mechanisms. The specific role of uPA in anti-invasive activity of IGFBP-3 was further confirmed in NSCLC cells, in which uPA expression/activity was suppressed by the transfection with synthetic small interfering RNA or by the treatment with uPA inhibitor or induced by the infection with an adenoviral vector. IGFBP-3 also decreased the expression/activity of matrix metalloproteinase-2 through IGF-dependent but uPA-independent pathways. Taken together, our data suggest that IGFPB-3 effectively block uPA- and matrix metalloproteinase-2–stimulated invasion pathways, ultimately reducing lung cancer cell metastasis. Our findings indicate that IGFBP-3 may be a promising anti-invasive and antimetastatic therapeutic agent in lung cancer. [Mol Cancer Ther 2006;5(11):2685–95]
Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-κB activation
Authors: Bu Pengcheng , Gao Lizeng , Zhuang Jie , Feng Jing , Yang Dongling , Yan Xiyun 
Published: November 2006

Abstract
Our previous study showed that an anti-CD146 monoclonal antibody (mAb), AA98, which was raised against the vascular endothelial cells stimulated by a conditioned medium from hepatocarcinoma SMMC 7721 cells (SMMC 7721-CM), inhibited cell migration, angiogenesis, and tumor growth. However, the underlying mechanism was not elucidated. The objective of this study was to understand the mechanism by which mAb AA98 inhibits the endothelial cell migration and angiogenesis that is induced by SMMC 7721-CM. Using confocal imaging and biochemical studies, we found that SMMC 7721-CM induced nuclear factor κB (NF-κB) activation through the upstream p38 mitogen-activated protein kinase pathway, leading to the up-regulation of matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression. Interestingly, all these activities stimulated by SMMC 7721-CM could be effectively inhibited by mAb AA98 in a dose- and time-dependent manner. Our data showed that the engagement of mAb AA98 with membrane protein CD146 inhibited p38 mitogen-activated protein kinase phosphorylation, suppressed NF-κB activation, and down-regulated matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression, suggesting that the suppression of NF-κB is a critical point for the inhibitory function of mAb AA98 on endothelial cell migration, angiogenesis, and tumor metastasis. These results will provide clues for a better understanding of the mechanisms underlying tumor angiogenesis as well as antiangiogenesis therapy. [Mol Cancer Ther 2006;5(11):2872–8]
Pretherapy nuclear factor-κB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma
Authors: Izzo Julie G. , Correa Arlene M. , Wu Tsung-Teh , Malhotra Usha , Chao Clifford K.S. , Luthra Rajyalakshmi , Ensor Joe , Dekovich Alexander , Liao Zhongxing , Hittelman Walter N. , Aggarwal Bharat B. , Ajani Jaffer A. 
Published: November 2006

Abstract
Background: Transcriptional factor nuclear factor-κB (NF-κB) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-κB would define clinical biology irrespective of the type of chemotherapy or sequence administered. Methods: Pretherapy and/or posttherapy cancer specimens were examined for activated NF-κB and correlated with pathologic response to chemoradiation, metastatic potential, overall survival, disease-free survival, and type of chemotherapy or sequence used. Findings: Eighty patients undergoing chemotherapy and concurrent radiation were studied. Activated NF-κB prior to any therapy was associated with the lack of complete pathologic response (pathCR, P = 0.006). Forty-five (78%) of 58 patients achieving &lt;pathCR had activated NF-κB in pretherapy and/or posttherapy cancer specimens versus 2 (9%) of 22 patients with pathCR (P = 0.001). Twenty-four (51%) of 47 patients with activated NF-κB in cancer developed metastases versus 7 (21%) of 22 patients with negative NF-κB in cancer (P = 0.01). At a median follow-up of 32 months, 25 (53%) of 47 patients with activated NF-κB cancer had died versus 3 (9%) of 33 patients with negative NF-κB cancer. NF-κB activation was the only independent predictor of disease-free survival (P = 0.01) and overall survival (P = 0.007) in a multivariate model. The class of chemotherapy or its sequence had no effect on NF-κB expression or patient outcome. Conclusions: Our data are the first to show that pretreatment-activated NF-κB significantly correlates with clinical biology of esophageal cancer, and most importantly, with pathCR. To therapeutically exploit NF-κB-regulated genes and their pathways, further research is warranted. [Mol Cancer Ther 2006;5(11):2844–50]
Benzyl isothiocyanate–induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak
Authors: Xiao Dong , Vogel Victor , Singh Shivendra V. 
Published: November 2006

AbstractEpidemiologic studies have revealed an inverse correlation between dietary intake of cruciferous vegetables and the risk of breast cancer. We now show that cruciferous vegetable constituent benzyl isothiocyanate (BITC) effectively suppresses growth of cultured human breast cancer cells (MDA-MB-231 and MCF-7) by causing G2-M phase cell cycle arrest and apoptosis induction. On the other hand, a normal mammary epithelial cell line (MCF-10A) is significantly more resistant to growth arrest and apoptosis by BITC compared with breast cancer cells. The BITC-mediated cell cycle arrest was associated with a decrease in levels of proteins involved in regulation of G2-M transition, including cyclin B1, cyclin-dependent kinase 1, and cell division cycle 25C. The BITC-induced apoptosis correlated with induction of proapoptotic proteins Bax (MCF-7) and Bak (MDA-MB-231 and MCF-7) and down-regulation of antiapoptotic proteins Bcl-2 and Bcl-xL (MDA-MB-231). The SV40-immortalized mouse embryonic fibroblasts derived from Bax and Bak double knockout mice were significantly more resistant to BITC-induced DNA fragmentation compared with wild-type mouse embryonic fibroblasts. The BITC treatment caused rapid disruption of the mitochondrial membrane potential, leading to cytosolic release of apoptogenic molecules, which was accompanied by formation of autophagosome-like structures as revealed by transmission electron microscopy. The BITC-mediated apoptosis was associated with generation of reactive oxygen species and cleavage of caspase-9, caspase-8, and caspase-3. Apoptosis induction by BITC was significantly attenuated in the presence of a combined superoxide dismutase and catalase mimetic EUK134 as well as caspase inhibitors. In conclusion, the present study reveals a complex signaling leading to growth arrest and apoptosis induction by BITC. [Mol Cancer Ther 2006;5(11):2931–45]
Huqūq Allāh and Huqūq al-'Ibād: A Legal Heuristic for a Natural Rights Regime
Authors: Emon Anver 
Published: November 2006

AbstractThis article shows that early Muslim jurists often created rules that had no foundation in the Qur'ān or Sunna. Their successors adopted these views as authoritative precedent, but not without further justifying them. Their justificatory reasons reflected background values concerning inherent qualities of the individual and the goods society must uphold in order to give substantive content to their legal determinations. Recourse to these values, whether implicit or explicit, illustrates how Muslim jurists incorporated naturalistic reasoning in their juridical analyses. To prove their implicit naturalism, this article focuses on how Sunnī Muslim jurists primarily from the 2nd/8th-10th/16th centuries used the conceptual heuristic of "rights of God" and "rights of individuals" (huqūq Allāh, huqūq al-i'ibād) as an interpretive mechanism to frame their naturalistic assumptions and apply them in legal analysis to create and distribute rights, duties, and public commitments.
Nature Seen through the Eyes of Faith: Understandings among Seminarians
Authors: Groenendyk Kathi , Curry Janel 
Published: November 2006

AbstractAttitudes toward nature were surveyed among male and female seminary students at three seminaries, all of which were located in West Michigan. Mixed methodologies were used in the study, including questionnaires, visualization, and content analysis of discussion transcripts. The seminaries represented theological traditions that were either "communal" or "individualistic" in their perceptions of society. Previous research has confirmed that individualistic, fundamentalist belief systems hold together in such a way as to lead to a utilitarian view of nature. Beyond this fundamentalist social group, environmental attitudes were much more complex. Gender differences were present but not substantial. The results of this study began to clarify the elusive concept of stewardship. The participants from the seminary who most closely reflected this position rejected the general concept of rights, whether for humans or nature, and held neither a utilitarian nor a biocentric view of nature. However, they believed that God's sustaining power was present in nature, and that the human community was embedded in nature.
The Efforts to Limit the International Criminal Court's Jurisdiction Over Nationals of Non-Party States: A Comparative Study
Authors: Roscini Marco 
Published: November 2006

AbstractThe purpose of this article is to discuss and compare the multilateral and bilateral efforts to prevent the ICC from exercising its jurisdiction over nationals of states non-parties to the Rome Statute. In particular, the US secured the adoption of Security Council resolutions no. 1422 (2002), 1487 (2003), 1497 (2003), 1593 (2005) and launched a campaign for the conclusion of bilateral non-surrender agreements: the differences between the resolutions and between them and the agreements are analysed. None of the resolutions above can be qualified as an exercise of the Security Council's power to request the ICC not to commence or proceed with investigations or prosecutions under Article 16 of the Rome Statute, as this provision was not conceived to cover future and hypothetical cases. Furthermore, by adopting resolutions 1422 and 1487 and by including the paragraphs on the exclusive jurisdiction of the contributing state in resolutions 1497 and 1593, the Security Council acted ultra vires, since no threat to the peace can be found in order to justify the exercise of Chapter VII powers. The resolutions are also in contrast with the principles and purposes of the UN. As to the bilateral non-surrender agreements, they cannot be qualified as "international agreements pursuant to which the consent of the sending State is required to surrender a person of that State to the Court" as required by Article 98 (2) of the Statute, since they prohibit the surrender to the ICC of any individual who is "present" on the territory of the other party and they do not require the state to which the accused has been transferred to investigate and prosecute the case. Should Italy conclude a non-surrender agreement with the US, it would incur international responsibility. The law giving effect to such an agreement in the Italian legal order would also be in contrast with Articles 10 (1) and 11 of the Constitution.
Ex iure manum conserere: Symbolic violence in early Roman property disputes
Authors: Platschek Johannes 
Published: November 2006

AbstractThe technical term ex iure manum conserere known from the formulas of the old Roman procedure concerning ownership (legis actio sacramento in rem) means – exactly as in the words' common use – 'to come to blows according to the law'. It signifies an act of mutual violence regarding the thing in dispute for the purpose to prepare a trial. The judicial decision about who was entitled to use force is indirectly an acknowledgment of ownership. The terminology is in line with other institutes of Roman law, and there are parallels in Greek law. In contrast, Gellius interprets ex iure in opposition to in iure and therefore as 'out of court'. He explains manum conserere with reference to the procedure as it had already developed, viz. 'to seize the object jointly and claim it with the prescribed wording'. But his reconstruction is neither consistent nor supported by any other evidence.
Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet?
Authors: Davies Stella M. 
Published: November 2006

Abstract
The genetic basis of a differential response to drugs has been understood for a limited number of agents for over 30 years. This knowledge has generated hope that the individual basis for response to a wide range of drugs would be quickly known, and individualized drug selection and dosing would be possible for many or all disorders. Understanding the variable response to drugs seems particularly pressing in the field of oncology, in which the stakes are high (failure to cure cancer usually leads to death), drugs commonly have a narrow therapeutic index, and toxicities can be severe (a significant frequency of toxic death is a feature of most acute myeloid leukemia protocols, for example). However, in common with many new technologies, the generalizability and clinical application of pharmacogenetics has proved more challenging than expected. Difficulties include, in many examples, a modest clinical effect relative to genotype, therapy-specific, not broad, applicability and the very major challenge of unraveling the complexity of gene-gene interactions. In addition, ethical and economic challenges to the application of pharmacogenetics have moved to the fore in recent years, particularly in the context of racial differences in outcome of therapy. Genomic, rather than candidate gene approaches to identification of relevant loci are increasingly being explored, and significant progress is being made. However, greater understanding of the complexities of multiple gene modifiers of outcome, and the statistical challenge of understanding such data, will be needed before individualized therapy can be applied on a routine basis.
Deeper Insights into Hematological Oncology Disorders via Single-Cell Phospho-Signaling Analysis
Authors: Nolan Garry P. 
Published: November 2006

Abstract
An understanding of hematological cancer cell signaling processes poses one of the most complex and intractable problems in modern biomedical inquiry. While we understand some of the fundamental players that contribute to oncogenic processes, significant effort is focused upon determining how these individual players relay information to each other to create the composite functions of a cancer cell. Efforts designed to understand these processes at the single cell level will undoubtedly allow for understanding of the heterogeneity of hematological tumors as well as, simultaneously, the function of the ‘responding’ immune system. I will relate some of the insights our laboratory has developed over the last several years applying single-cell phospho-flow cytometry to the study of signaling in primary patient material and murine models. While it is clear that this analysis now allows us to accomplish phospho-signaling biochemistry at the single cell level with primary cell material, we are only beginning to develop some of the bioinformatics tools to appropriately display the vast amount of information collected by such approaches. These approaches, however, have already allowed us to develop approaches that prognosticate patient outcomes based on signaling status, prior to any treatment, as well as subgroup patient subtypes according to signaling states. The modest efforts to date presage a time where it should be possible to provide far more tailored therapies specific to the varied diseases represented by the hematological malignancies.
ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring
Authors: Hughes Timothy 
Published: November 2006

AbstractFor chronic phase chronic myeloid leukemia (CML) patients treated with imatinib, the essential pre-therapy assessments include bone marrow morphology and cytogenetics as well as a baseline real-time quantitative PCR (RQ-PCR) for BCR-ABL. Baseline assessments of clinical relevance include Sokal and Hasford prognostic scores. Several other baseline assays are likely to be predictive of response, including IC50imatinib, organic cation transporter-1 (OCT-1) mRNA level, and gene expression profiles, but further confirmation is required. RQ-PCR assays of blood at least every 3 months once patients have commenced imatinib is recommended. This will facilitate early identification of suboptimal responders who may benefit from higher doses of imatinib or alternative therapy, and identify at an early stage patients with acquired resistance. Management of the latter group can be further guided by the findings from cytogenetics and BCR-ABL kinase domain mutation screening. Bone marrow cytogenetics is indicated at least every 6 months until the patient achieves major molecular response. RQ-PCR is only clinically useful if it is conducted under a rigorous quality control regimen so that fluctuations in the BCR-ABL level can be confidently attributed to a biological cause rather than assay variation. To further improve the clinical value of RQ-PCR monitoring, expression of results on an international scale is needed. This will facilitate a more uniform and rational approach to management of suboptimal response and loss of response.
New Insights into Paroxysmal Nocturnal Hemoglobinuria
Authors: Brodsky Robert A. 
Published: November 2006

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is an uncommon intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A. PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis. Intravascular hemolysis leads to release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm, erectile dysfunction and possibly thrombosis. Interestingly, rare PIG-A mutations can be found in virtually all healthy control subjects, leading to speculation that PIG-A mutations in hematopoietic stem cells are common benign events. However, negative selection of PIG-A mutant colony-forming cells with proaerolysin, a toxin that targets GPI-anchored proteins, reveals that most of these mutations are not derived from stem cells. Recently, a humanized monoclonal antibody directed against the terminal complement protein C5 has been shown to reduce hemolysis and greatly improve symptoms and quality of life for PNH patients.
Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era
Authors: Tefferi Ayalew 
Published: November 2006

Abstract
JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL− MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
Myeloproliferative Disease in Pregnancy and Other Management Issues
Authors: Barbui Tiziano , Finazzi Guido 
Published: November 2006

AbstractThe goal of this review is to assess the current treatment and outcomes of special clinical situations in patients with myeloproliferative disease (MPD) such as pregnancy, major thrombotic and bleeding complications and surgical interventions. However, only a limited literature to support optimal management strategies is available. Many of the proposed strategies are the results of common sense or derive from the extrapolation of data from other studies not specifically designed to solve these problems. Therefore, practical recommendations to guide clinical decisions in these settings still remain largely empirical.