bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

Purpose: 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

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

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

Our 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 < 0.01) and 87% decrease of invasion (P < 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 < 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)
Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor δ Agonist
Authors: Sprecher Dennis L. , Massien Christine , Pearce Greg , Billin Andrew N. , Perlstein Itay , Willson Timothy M. , Hassall David G. , Ancellin Nicolas , Patterson Scott D. , Lobe David C. , Johnson Tony G.
Published: November 2006

Objectives—

Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)δ expression. In parallel, PPARδ agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models.

Methods and Results—

Healthy volunteers were allocated placebo (n=6) or PPARδ agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (
P
=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (
P
=0.02). HDLc was enhanced in both treatment groups (2.5 mg
P
=0.004, 10 mg
P
<0.001) when compared with the decrease in the placebo group (−11.5±1.6%,
P
=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (
P
=0.002). However, LpL expression remained unchanged.

Conclusions—

This is the first report of a PPARδ agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.
GPVI Potentiation of Platelet Activation by Thrombin and Adhesion Molecules Independent of Src Kinases and Syk
Authors: Hughan Sascha C. , Hughes Craig E. , McCarty Owen J.T. , Schweighoffer Edina , Soultanova Izoumroud , Ware Jerry , Tybulewicz Victor L.J. , Watson Steve P.
Published: November 2006

Objective—

The present study investigates the role of Src and Syk tyrosine kinases in signaling by G-protein coupled and platelet adhesion receptors.

Methods and Results—

Using Syk
−/−
platelets or the Src kinase inhibitor PP2, we demonstrate a critical role for Src and Syk kinases in mediating lamellipodia formation on VWF, collagen, CRP, fibrinogen, and fibronectin. In all cases, the spreading defect was overcome by addition of thrombin. Conversely, platelet aggregation and α
IIb
β
3
activation induced by thrombin was similar to controls, arguing against a functional role for Src and Syk in α
IIb
β
3
activation. Unexpectedly, CRP potentiated integrin α
IIb
β
3
activation and platelet aggregation induced by subthreshold concentrations of thrombin in Syk
−/−
platelets or in the presence of the Src kinase inhibitor PP2. Potentiation in the presence of PP2 was lost in the absence of FcRγ-chain or GPVI confirming that it was mediated through the immunoglobulin receptor. Further delineation of this PP2-resistant synergy revealed that PAR4 could trigger the enhanced response in combination with CRP.

Conclusions—

We show that Syk is critical for lamellipodia formation on a range of immobilized proteins but that this can be overcome by addition of thrombin. Further, we reveal a novel role for GPVI in supporting thrombin-induced activation, independent of Syk and Src kinases.
Hypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2
Authors: Li Weimin , Petrimpol Marco , Molle Klaus D. , Hall Michael N. , Battegay Edouard J. , Humar Rok
Published: November 2006

A central regulator of cell growth that has been implicated in responses to stress such as hypoxia is mTOR (
m
ammalian
T
arget
O
f
R
apamycin). We have shown previously that mTOR is required for angiogenesis in vitro and endothelial cell proliferation in response to hypoxia. Here we have investigated mTOR-associated signaling components under hypoxia and their effects on cell proliferation in rat aortic endothelial cells (RAECs). Hypoxia (1% O
2
) rapidly (>30 minutes) and in a concentration-dependent manner promoted rapamycin-sensitive and sustained phosphorylation of mTOR-Ser2448 followed by nuclear translocation in RAECs. Similarly, hypoxia induced phosphorylation of the mTORC2 substrate Akt-Ser473 (3 to 6 hours at 1% O
2
) and a brief phosphorylation peak of the mTORC1 substrate S6 kinase–Thr389 (10 to 60 minutes). Phosphorylation of Akt was inhibited by mTOR knockdown and partially with rapamycin. mTOR knockdown, rapamycin, or Akt inhibition specifically and significantly inhibited proliferation of serum-starved RAECs under hypoxia (
P
<0.05; n≥4). Similarly, hypoxia induced Akt-dependent and rapamycin-sensitive proliferation in mouse embryonic fibroblasts. This response was partially blunted by hypoxia-inducible factor-1α knockdown and not affected by TSC2 knockout. Finally, mTORC2 inhibition by rictor silencing, especially (
P
<0.001; n=7), and mTORC1 inhibition by raptor silencing, partially (
P
<0.05; n=7), inhibited hypoxia-induced RAEC proliferation. Thus, mTOR mediates an early response to hypoxia via mTORC1 followed by mTORC2, promoting endothelial proliferation mainly via Akt signaling. mTORC1 and especially mTORC2 might therefore play important roles in diseases associated with hypoxia and altered angiogenesis.
When a Word Is Worth a Thousand Pictures: Mahāyāna Influence on Theravāda Attitudes Towards Writing
Authors: Veidlinger Daniel
Published: November 2006

This 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

From 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.
Speech-cycles in the book of Job: a response to James E. Patrick
Authors: van der Lugt Pieter
Published: November 2006

This short note challenges the idea that fourfold structures determine the composition of the book of Job. Instead, it is demonstrated that it is the numbers three and eleven that are the major structural keys for the poetic section of the book.
The Making of a Radical Economist
Authors: Sherman Howard J.
Published: November 2006

This article is about the process by which I became a radical, my early political activism, my struggle in the army during McCarthyism, and the long fight for a political economy program at the University of California, Riverside. The point of the article is to convey to readers as clearly as possible information on the ways that people become radicals, the radical fight against McCarthyism, and the building of a political economy program.
Perishable Money in a Threefold Commonwealth: Rudolf Steiner and the Social Economics of an Anarchist Utopia
Authors: Preparata Guido Giacomo
Published: November 2006

Austrian mystic Rudolf Steiner (1861-1925) devoted significant portions of speculative activity to social and economic questions; during the fateful interwar period, he delivered remarkable lectures on the nature of economics and the physiology of the social order. He fashioned analyses consonant with the intuitions of monetary reformer Silvio Gesell and kindred to institutional narratives of the old German school, providing penetrating insight into the (perishable) nature of money, distribution, and the fundamental notion of the gift. His blueprint for social Utopia was the threefold social order, whereby three independent systems of collective life (economy, state, and arts and sciences) are conceived to function as a harmonious whole. Steiner's contribution to the social sciences, naturally obliterated in our opportunistic times of “ultra-economism,” would deservedly occupy a preeminent place among heterodox thought that awaits impatiently the demise of modern capitalism's unreasoning appetites with a view to refashioning an alternative, more humane economy.
The Evolution of Organizations and Natural Environment Discourse
Authors: Kallio Tomi J. , Nordberg Piia
Published: November 2006

In this article, the authors analyze some of the developments and weaknesses in organizational environmental studies and make an effort to evaluate the field's current status, role, and future prospects. During recent years, the field of management and organizational studies has witnessed environmental research gaining a secure foothold, especially in quantitative terms. It is questionable, however, whether it is actually organizational environmental studies that has arrived or whether the discourse is in fact only a minor annex or a slight modification of the same old themes in management and organizational studies. This is because of the fact that it is still too early to say that organizations and natural-environment-related research would have been able to develop its own theory base and legitimate posture in relation to the management and organizational studies.
Pursuing Gender Diversity in Police Organizations in the 1990s: A Longitudinal Analysis of Factors Associated With the Hiring of Female Officers
Authors: Zhao Jihong “Solomon” , He Ni , Lovrich Nicholas P.
Published: November 2006

This article examines the relevance of a number of factors presumed to be associated with the employment of female police officers in U.S. municipal law enforcement agencies. Female officer representation is investigated with respect to three primary race/ethnic groups in mind: Caucasians, African Americans, and Hispanics. This study utilizespanel data collected during the period from 1993 to 2000 on a representative sample of police departments serving populations of 25,000+ residents distributed across the United States. A noteworthy increase in the number of female officers did occur during the decade of the 1990s, and both internal departmental and external environmental influences on the hiring of female police officers were investigated. The major finding observed is that different sets of external and internal features have an influence on the hiring of women officers in each race/ethnic group.
Treatment of Acute Promyelocytic Leukemia
Authors: Sanz Miguel A.
Published: November 2006

Cure 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

Use 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

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

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.
Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells
Authors: Garín Marina I. , Chu Chung-Ching , Golshayan Dela , Cernuda-Morollón Eva , Wait Robin , Lechler Robert I.
Published: November 2006

The naturally occurring population of dedicated regulatory T cells that coexpress CD4 and CD25 is known to play a key role in the maintenance of peripheral T-cell tolerance; however, their mechanism of action has remained obscure. Here we report that a member of the family of β-galactoside–binding proteins, galectin-1, is overexpressed in regulatory T cells, and that expression is increased after activation. Most importantly, blockade of galectin-1 binding significantly reduced the inhibitory effects of human and mouse CD4+CD25+ T cells. Reduced regulatory activity was observed in CD4+CD25+ T cells obtained from galectin-1–homozygous null mutant mice. These results suggest that galectin-1 is a key effector of the regulation mediated by these cells.
Hypoxia-inducible transcription factor–1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib
Authors: Veschini Lorenzo , Belloni Daniela , Foglieni Chiara , Cangi Maria Giulia , Ferrarini Marina , Caligaris-Cappio Federico , Ferrero Elisabetta
Published: November 2006

Angiogenesis is a complex, orchestrated process that plays a critical role in several conditions and has special relevance in the progression of cancer. Hypoxia is the major stimulus for angiogenesis, and hypoxia-inducible transcription factor–1 alpha (HIF-1α) is its key mediator. We set up a novel in vitro model of HIF-1α up-regulation by treating human umbilical vein endothelial cells (HUVECs) with the hypoxia-mimicking deferoxamine (DFO) and found that this condition was sufficient to promote angiogenesis, like the well-known HUVEC model cultured under low pO2. The proteasome inhibitor bortezomib, which induces strong apoptosis in cancer cells, abrogated proliferation and angiogenesis of HUVECs when used at a high concentration (100 nM), yet promoted both functions at a low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of bortezomib on 2 master regulators of tumor-associated angiogenesis, HIF-1α and nuclear factor kappa B (NF-kB). Significantly, when HUVECs were induced to express HIF-1α prior to bortezomib treatment, proliferative and angiogenic responses were abolished, and a greatly enhanced proapoptotic effect was promoted with both concentrations of the drug. These findings indicate that HIF-1α up-regulation may sensitize endothelial cells to the antiangiogenic and proapoptotic effects of bortezomib and might be exploited to target tumor-associated vessels in the course of antiangiogenic therapies.
Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412
Authors: Aichberger Karl J. , Mayerhofer Matthias , Gleixner Karoline V. , Krauth Maria-Theresa , Gruze Alexander , Pickl Winfried F. , Wacheck Volker , Selzer Edgar , Müllauer Leonhard , Agis Hermine , Sillaber Christian , Valent Peter
Published: November 2006

MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expression and functional role of MCL-1 in neoplastic MCs and sought to determine whether MCL-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemical examination, primary neoplastic MCs expressed MCL-1 mRNA and the MCL-1 protein in all SM patients examined. Moreover, MCL-1 was detectable in both subclones of the MC line HMC-1—HMC-1.1 cells, which lack the SM-related KIT mutation D816V, and HMC-1.2 cells, which carry KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to MCL-1–specific antisense oligonucleotides (ASOs) or MCL-1–specific siRNA resulted in reduced survival and increased apoptosis compared with untreated cells. Moreover, MCL-1 ASOs were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MCs, with synergistic effects observed with PKC412, AMN107, and imatinib in HMC-1.1 cells and with PKC412 in HMC-1.2 cells. Together, these data show that MCL-1 is a novel survival factor and an attractive target in neoplastic MCs.
The cytoprotective protein C pathway
Authors: Mosnier Laurent O. , Zlokovic Berislav V. , Griffin John H.
Published: November 2006

Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status
Authors: Carobbio Alessandra , Finazzi Guido , Guerini Vittoria , Spinelli Orietta , Delaini Federica , Marchioli Roberto , Borrelli Giovanna , Rambaldi Alessandro , Barbui Tiziano
Published: November 2006

Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up (“baseline analysis,” relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P = .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis (“time-dependent analysis,” RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P = .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies.
Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin
Authors: Sconce Elizabeth , Avery Peter , Wynne Hilary , Kamali Farhad
Published: November 2006

Patients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 μg oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (−0.24 ± 0.14 vs −0.11 ± 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% ± 20% vs 15% ± 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.
Visual setup of logical models of signaling and regulatory networks with ProMoT
Authors: Saez-Rodriguez Julio , Mirschel Sebastian , Hemenway Rebecca , Klamt Steffen , Gilles Ernst Dieter , Ginkel Martin
Published: November 2006

Background

The analysis of biochemical networks using a logical (Boolean) description is an important approach in Systems Biology. Recently, new methods have been proposed to analyze large signaling and regulatory networks using this formalism. Even though there is a large number of tools to set up models describing biological networks using a biochemical (kinetic) formalism, however, they do not support logical models.

Results

Herein we present a flexible framework for setting up large logical models in a visual manner with the software tool ProMoT. An easily extendible library, ProMoT's inherent modularity and object-oriented concept as well as adaptive visualization techniques provide a versatile environment. Both the graphical and the textual description of the logical model can be exported to different formats.

Conclusion

New features of ProMoT facilitate an efficient set-up of large Boolean models of biochemical interaction networks. The modeling environment is flexible; it can easily be adapted to specific requirements, and new extensions can be introduced. ProMoT is freely available from http://www.mpi-magdeburg.mpg.de/projects/promot/.
Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study
Authors: Burwinkel Barbara , Shanmugam Kalai S , Hemminki Kari , Meindl Alfons , Schmutzler Rita K , Sutter Christian , Wappenschmidt Barbara , Kiechle Marion , Bartram Claus R , Frank Bernd
Published: November 2006

Background

The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/β-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes.

Methods

We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals.

Results

The T allele of rs12255372 showed an association with borderline significance (OR = 1.19, 95% C.I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk (P
trend = 0.04).

Conclusion

Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC.
The CENP-B homolog, Abp1, interacts with the initiation protein Cdc23 (MCM10) and is required for efficient DNA replication in fission yeast
Authors: Locovei Alexandra M , Spiga Maria-Grazia , Tanaka Katsunori , Murakami Yota , D'Urso Gennaro
Published: November 2006

Abp1, and the closely related Cbh1 and Cbh2 are homologous to the human centromere-binding protein CENP-B that has been implicated in the assembly of centromeric heterochromatin. Fission yeast cells lacking Abp1 show an increase in mini-chromosome instability suggesting that Abp1 is important for chromosome segregation and/or DNA synthesis. Here we show that Abp1 interacts with the DNA replication protein Cdc23 (MCM10) in a two-hybrid assay, and that the Δabp1 mutant displays a synthetic phenotype with a cdc23 temperature-sensitive mutant. Moreover, genetic interactions were also observed between abp1
+ and four additional DNA replication initiation genes cdc18
+, cdc21
+, orc1
+, and orc2
+. Interestingly, we find that S phase is delayed in cells deleted for abp1
+ when released from a G1 block. However, no delay is observed when cells are released from an early S phase arrest induced by hydroxyurea suggesting that Abp1 functions prior to, or coincident with, the initiation of DNA replication.
Real-time ultrasound-guided catheterisation of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients
Authors: Karakitsos Dimitrios , Labropoulos Nicolaos , De Groot Eric , Patrianakos Alexandros P , Kouraklis Gregorios , Poularas John , Samonis George , Tsoutsos Dimosthenis A , Konstadoulakis Manousos M , Karabinis Andreas
Published: November 2006

Introduction

Central venous cannulation is crucial in the management of the critical care patient. This study was designed to evaluate whether real-time ultrasound-guided cannulation of the internal jugular vein is superior to the standard landmark method.

Methods

In this randomised study, 450 critical care patients who underwent real-time ultrasound-guided cannulation of the internal jugular vein were prospectively compared with 450 critical care patients in whom the landmark technique was used. Randomisation was performed by means of a computer-generated random-numbers table, and patients were stratified with regard to age, gender, and body mass index.

Results

There were no significant differences in gender, age, body mass index, or side of cannulation (left or right) or in the presence of risk factors for difficult venous cannulation such as prior catheterisation, limited sites for access attempts, previous difficulties during catheterisation, previous mechanical complication, known vascular abnormality, untreated coagulopathy, skeletal deformity, and cannulation during cardiac arrest between the two groups of patients. Furthermore, the physicians who performed the procedures had comparable experience in the placement of central venous catheters (p = non-significant). Cannulation of the internal jugular vein was achieved in all patients by using ultrasound and in 425 of the patients (94.4%) by using the landmark technique (p < 0.001). Average access time (skin to vein) and number of attempts were significantly reduced in the ultrasound group of patients compared with the landmark group (p < 0.001). In the landmark group, puncture of the carotid artery occurred in 10.6% of patients, haematoma in 8.4%, haemothorax in 1.7%, pneumothorax in 2.4%, and central venous catheter-associated blood stream infection in 16%, which were all significantly increased compared with the ultrasound group (p < 0.001).

Conclusion

The present data suggest that ultrasound-guided catheterisation of the internal jugular vein in critical care patients is superior to the landmark technique and therefore should be the method of choice in these patients.
Calcitonin gene-related peptide inhibits early B cell development in vivo
Authors: Schlomer Jerome J , Storey Benjamin B , Ciornei Radu-Tudor , McGillis Joseph P
Published: November 2006

Recent in vitro studies suggest that calcitonin gene-related peptide (CGRP) inhibits early B cell differentiation; however, there is no evidence in the intact animal for a role for CGRP in B cell development. Here, we show that in vivo treatment of mice with CGRP reduces the number of IL-7 responsive B cell progenitors in bone marrow. A single CGRP treatment reduces IL-7-responsive B cell progenitors by up to 40% for up to 72 h. The reduction is dose-dependent and can be blocked by a CGRP receptor antagonist, CGRP8–37. CGRP in serum following injection is highly elevated at 30 min but returns to basal levels by 4 h, suggesting that a single injection of CGRP has long-lasting effects on B cell development. This report provides the first direct in vivo evidence that CGRP, a neuropeptide with multiple effects on mature lymphocytes, also plays a regulatory role in early B cell development in the bone marrow.
Effect of Microgravity and Magnetic Field on the Metallic and Crystalline Structure of Magnetostrictive SmFe2 Synthesized by Unidirectional Solidification
Authors: OKUTANI TAKESHI , NAGAI HIDEAKI , MAMIYA MIKITO , SHIBUYA MASACHIKA , CASTILLO MARTIN
Published: November 2006

Abstract:  The Sm‐2Fe molten alloy with 1:2 molar ratio was unidirectionally solidified in both microgravity and normal gravity in concurrence with a magnetic flux (0–0.12 T). The compound SmFe2 was produced by the unidirectional solidification in microgravity with a magnetic flux of 0T and exhibited a lamellar microstructure. The average lamellar thickness was 30 μm and each lamella possessed a <111> crystallographic alignment along major axis aligned in the direction of cooling. Unidirectional solidification in microgravity with a magnetic field of 0.04 T produced crystalline SmFe2 and Fe phases. The microstructure of this product was lamellar with an average lamellar thickness of 17 μm and no crystalline alignment. Unidirectional solidification in microgravity with a magnetic flux ranging from 0.06 to 0.12 T and in normal gravity with a magnetic flux ranging from 0 to 0.12 T produced crystalline Sm2Fe17 and Fe. During unidirectional solidification in microgravity without a magnetic flux, few nucleation sites were formed and rapid crystal growth occurred, consequently forming large‐grain SmFe2. The produced SmFe2 had a lamellar structure with a dominant <111> crystallographic alignment in the direction of cooling. Convection in the molten state and where a magnetic flux was present caused homogeneous nucleation, forming Sm2Fe17 with a disordered structure and crystalline alignment coinciding with the formation of the dendritic Fe.