bluuebunny/crossref_metadata_2025 huggingface dataset:
Lin-7C/VELI3/MALS-3: An Essential Component in Metastasis of Human Squamous Cell Carcinoma
Authors: Onda Takeshi , Uzawa Katsuhiro , Nakashima Dai , Saito Kengo , Iwadate Yasuo , Seki Naohiko , Shibahara Takahiko , Tanzawa Hideki
Published: October 2007

Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/VELI3/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCC-derived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated β-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P < 0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis. [Cancer Res 2007;67(20):9643–8]
Genetic Determinants of Mitochondrial Response to Arsenic in YeastSaccharomyces cerevisiae
Authors: Vujcic Marija , Shroff Meghna , Singh Keshav K.
Published: October 2007

We have used yeast Saccharomyces cerevisiae as a tool to identify the importance of mitochondrial processes involved in arsenic-induced carcinogenicity in humans. We screened 466 single-gene knockout strains of yeast S. cerevisiae known to be involved in biogenesis of mitochondria for sodium arsenite (AsIII) and sodium arsenate (AsV) sensitivity. We identified 72 arsenite-sensitive and 81 arsenate-sensitive mutants. We categorized the identified mutants based on the various mitochondrial processes, including nucleic acid metabolism, oxidative phosphorylation, protein synthesis, and vacuolar acidification. We have identified 65 human orthologues to proteins involved in arsenite sensitivity and 3 human orthologues to arsenite resistance. Furthermore, 23 human orthologues to arsenate sensitivity and 20 human orthologues to arsenate-resistant proteins, including MSH3, COX10, GCSH, PPOX, and MTHFD1, were also identified. Using PathwayAssist software, we did cellular network analysis between identified mitochondrial proteins. Three types of interactions, (a) protein-protein interactions, (b) common transcriptional regulators, and (c) common target genes, were identified. We found that RTG (retrograde) genes involved in mitochondria-to-nucleus signaling regulate both arsenite sensitivity and resistance. Furthermore, our study revealed that ABF1, a multifunctional transcriptional factor, regulates genes involved in both arsenite and arsenate sensitivity and resistance. However, REB1 and RAP1 transcriptional regulators were common to only arsenate- and arsenite-sensitive genes, respectively. These studies indicate that multiple pathways involved in mitochondrial biogenesis protect yeast S. cerevisiae from arsenic-induced toxicity. Together, our studies suggest that evolutionary conserved mitochondrial networks identified in yeast S. cerevisiae must play an important role in arsenic-induced carcinogenesis in humans. [Cancer Res 2007;67(20):9740–9]
γ-Aminobutyric Acid (GABA) Stimulates Pancreatic Cancer Growth through Overexpressing GABAA Receptor π Subunit
Authors: Takehara Akio , Hosokawa Masayo , Eguchi Hidetoshi , Ohigashi Hiroaki , Ishikawa Osamu , Nakamura Yusuke , Nakagawa Hidewaki
Published: October 2007

γ-Aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor π subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABAA receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca2+ levels and activated the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the up-regulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC. [Cancer Res 2007;67(20):9704–12] [Cancer Res 2007;67(20):9704–12]
Deficiency of NRH:Quinone Oxidoreductase 2 Differentially Regulates TNF Signaling in Keratinocytes: Up-regulation of Apoptosis Correlates with Down-regulation of Cell Survival Kinases
Authors: Ahn Kwang Seok , Gong Xing , Sethi Gautam , Chaturvedi Madan M. , Jaiswal Anil K. , Aggarwal Bharat B.
Published: October 2007

NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (NQO1), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2−/−) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-κB (NF-κB) and IκBα kinase, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2−/− cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH2-terminal kinase, Akt, p38, and p44/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2−/− cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-κB activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis. [Cancer Res 2007;67(20):10004–11]
Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression
Authors: Bunt Stephanie K. , Yang Linglin , Sinha Pratima , Clements Virginia K. , Leips Jeff , Ostrand-Rosenberg Suzanne
Published: October 2007

Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1β promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)–deficient mice which have a reduced potential for inflammation, and IL-1R antagonist–deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonist–deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which down-regulate tumor immunity is one of the mechanisms linking inflammation and cancer. [Cancer Res 2007;67(20):10019–26]
Silent Polymorphisms Speak: How They Affect Pharmacogenomics and the Treatment of Cancer
Authors: Sauna Zuben E. , Kimchi-Sarfaty Chava , Ambudkar Suresh V. , Gottesman Michael M.
Published: October 2007

Polymorphisms in the human genome contribute to wide variations in how individuals respond to medications, either by changing the pharmacokinetics of drugs or by altering the cellular response to therapeutic agents. The goal of the emerging discipline of pharmacogenomics is to personalize therapy based on an individual's genotype. Due to the relatively large frequency of single-nucleotide polymorphisms (SNP) in the human genome, synonymous SNPs are often disregarded in many pharmacogenomic studies based on the assumption that these are silent. We have shown recently that synonymous SNPs in ABCB1 (P-glycoprotein), which is implicated both in determining drug pharmacokinetics and multidrug resistance in human cancer cells, can affect protein conformation and function. We discuss the importance of polymorphisms in drug metabolizing enzymes and transporters in anticancer therapy and suggest that synonymous polymorphisms may play a more significant role than is currently assumed. [Cancer Res 2007;67(20):9609–12]
MicroRNA Let-7a Down-regulates MYC and Reverts MYC-Induced Growth in Burkitt Lymphoma Cells
Authors: Sampson Valerie B. , Rong Nancy H. , Han Jian , Yang Qunying , Aris Virginie , Soteropoulos Patricia , Petrelli Nicholas J. , Dunn Stephen P. , Krueger Leslie J.
Published: October 2007

Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to down-regulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers. [Cancer Res 2007;67(20):9762–70]
Mouse Model of Colonic Adenoma-Carcinoma Progression Based on Somatic Apc Inactivation
Authors: Hinoi Takao , Akyol Aytekin , Theisen Brian K. , Ferguson David O. , Greenson Joel K. , Williams Bart O. , Cho Kathleen R. , Fearon Eric R.
Published: October 2007

Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, β-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Apc allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment. [Cancer Res2007;67(20):9721–30]
The dual role of the contact system in bacterial infectious disease
Authors: Frick Inga-Maria , Björck Lars , Herwald Heiko
Published: October 2007

Hemostasis is a sensitive and tightly regulated process, involving the vascular endothelium and blood cells as well as factors of the coagulation and fibrinolytic cascades. Over the last four decades evidence has accumulated that during infection, inflammatory mediators from the microbe and/or host are capable to modulate the equilibrium between the procoagulant and anticoagulant status of the host. Dependent on the mode of activation, these changes can cause either local or systemic inflammatory reactions that may be beneficial or deleterious to the human host. The present review aims to present the state of the art with respect to the role of the contact system (also known as the intrinsic pathway of coagulation or the kallikrein/kinin system) in innate immunity and systemic inflammatory reactions.
Molecular characterization of four ADAMTS13 mutations responsible for congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome)
Authors: Hommais Antoine , Rayes Julie , Houllier Anne , Obert Bernadette , Legendre Paulette , Veyradier Agnes , Ribba Anne-Sophie , Girma Jean-Pierre
Published: October 2007

ADAMTS13 mutations S203P, R268P, R507Q and A596V were previously identified in French patients with hereditary thrombotic thrombocytopenic purpura (TTP) (Upshaw-Schulman syndrome). Mutated recombinant (r) ADAMTS13 were transiently expressed in COS-7 cells and characterized in comparison with wild-type (WT) rADAMTS13.ADAMTS13 antigen was qualitatively and quantitatively estimated by electrophoretic analysis and ELISA. Enzymatic activity was qualitatively and quantitatively estimated using GST-VWF73,FRETS-VWF73 fragments and full-length rVWF-WT as substrates. The four mutants and rADAMTS13-WT were present within the cells. Secretion level of rADAMTS13-WT reached 1,200 ng/ml. The four mutations strongly altered the secretion and biological activity of rADAMTS13. The percentage secretion was 21, 38 and 17% for rADAMTS13-S203P, -R268P and -A596V compared with rADAMTS13- WT. rADAMTS13-R507Q concentration was under the detection limit of the assay. In the four cases, no enzymatic activity was detected. After concentration, we confirmed that mutations S203P and R268P totally abolished the proteolytic activity of ADAMTS13. Due to the very low protease concentration, activity of rADAMTS13-R507Q was below the threshold of the assays. rADAMTS13-A596V had no proteolytic activity towards the full-length rVWF-WT whereas it exhibited a decreased specific activity of about 30% of that of rADAMTS13- WT towards FRETS-VWF73 fragment. Binding study of mutated rADAMTS13-S203P, -R268P and -A596V showed that the three mutations strongly decreased the interaction of ADAMTS13 with VWF. In conclusion, the four mutations, which led to a secretion defect, a loss of enzymatic activity and a decreased binding to the substrate, are responsible for the hereditary TTP in patients.
Local paclitaxel delivery after coronary stenting in an experimental animal model
Authors: Dommke Christoph , Süselbeck Tim , Streitner Ines , Haghi Dariush , Metz Jürgen , Borggrefe Martin , Herdeg Christian , Haase Karl
Published: October 2007

The goal of this study was to test the safety and efficacy of local paclitaxel delivery via a newly designed application catheter in an experimental animal study. Drug-eluting stents reduce restenosis in comparison to bare-metal stents. The drug-eluting polymer, however, may exert potential thrombogenic and inflammatory effects. A catheter-based local paclitaxel delivery offers further advantages, particularly a homogenous drug transfer into the vessel wall and a pharmacotherapy of the stent edges. In 30 pigs, both bare-metal stent (3.0 × 13mm) implantation and balloon angioplasty were performed. Ten pigs received subsequent local delivery of paclitaxel-solution via a newly designed catheter (Genie™, ACROSTAK corp., Switzerland), 10 animals served as a sham group and received vehicle (0.9% NaCl solution) and 10 animals were used as a control group. All animals were treated with aspirin and clopidogrel to prevent stent thrombosis. After final angiography the vessels were excised 42 days after intervention and prepared for histological and histomorphometric analysis. All coronary arteries showed complete endothelialization 42 days following treatment. Paclitaxel treatment led to a marked reduction of neointimal proliferation either post stent implantation (neointimal area: 1.04 ± 0.10 mm2 vs. 2.37 ± 0.23 mm2, p<0.001) or post balloon dilatation (neontimal area: 0.35 ± 0.14 mm2, vs. 0.68 ± 0.24 mm2, p<0.01).There were no significant angiographic or histomorphometric differences between the control and the sham group. In both paclitaxel groups neither angiographic edge phenomena nor a significant histomorphometric inflammatory response were found in the treated vessel segments. In conclusion, the local application of paclitaxel via the Genie™ catheter is safe and effective to significantly reduce the proliferative response post-stent implantation or balloon dilatation in an experimental animal model.
Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients
Authors: Nisio Marcello Di , Febbo Concetta Di , Moretta Valeria , Guglielmi Maria Domenica , Stuppia Liborio , Cuccurullo Franco , Porreca Ettore
Published: October 2007

Toll-like receptor-4 (TLR-4) gene polymorphisms have been associated with a lower risk of atherosclerosis. High levels of soluble P-selectin (sP-selectin) and von Willebrand factor predict an increased risk for cardiovascular events and correlate to atherosclerotic risk factors. The relationship between these markers and TLR-4 gene polymorphisms was evaluated in a cohort of consecutive hypercholesterolemic outpatients. TLR-4 gene polymorphisms were detected in 48 out of 330 (14%) patients with hypercholesterolemia. Lipid and inflammatory markers, sP-selectin and von Willebrand were evaluated in carriers and in 96 (ratio 2:1 to cases) age- and sex-matched TLR-4 wild-type patients randomly selected from the same population. A cohort of normocholesterolemic outpatients (n=262) served as the control group.sP-selectin was sensibly lower in carriers of TLR-4 variants as compared to wild-types and controls (89 ng/ ml vs. 162 ng/ml and 163 ng/dl, respectively, p=0.0001). Similarly, carriers showed lower von Willebrand factor values (683 mU/ ml) than wild-types (910 mU/ml; p=0.001). In multivariate analysis, TLR-4 gene polymorphisms were positively associated with sP-selectin, whereas the relationship with von Willebrand factor was no longer significant. HMG-CoA reductase inhibitors reduced sP-selectin and von Willebrand factor levels independently of TLR-4 gene variants. Plasma concentrations of these markers, however, remained lower in carriers of TLR-4 gene polymorphisms even after cholesterol lowering. In conclusion, carriership of Asp299 andThr399IleTLR-4 gene polymorphisms is associated with lower levels of sP-selectin and von Willebrand factor among hypercholesterolemic patients. While the underlying mechanisms remain to be investigated, such an association may indicate a protective effect of TLR-4 variants for atherosclerosis.
Fibrinolysis and host response in bacterial infections
Authors: Bergmann Simone , Hammerschmidt Sven
Published: October 2007

The plasminogen activation system is part of the fibrinolysis which is tightly regulated and protected against dysfunction by various activators and inhibitors. However, microorganisms including bacteria, fungi and also parasites have been proven to interact in a specific manner with components of the fibrinolytic pathways. Pathogenic bacteria are capable to subvert the function of proteases, activators or inhibitors for their own benefits including dissemination within the host and evasion of host inflammatory immune response. Here, we provide a state of the art overview of the divers strategies employed by bacteria to interact with components of the fibrinolytic system and to exploit the system for invasion. Moreover, the role of factors of the fibrinolytic cascade in inflammatory host response due to different bacterial infections will be presented.
Exclusion of the α2 subunit of platelet-activating factor acetylhydrolase 1b (PAFAH1B2) as a prothrombotic gene in a protein C-deficient kindred and population-based case-control sample
Authors: Scott Bruce , Rosendaal Frits , Callas Peter , Vossen Carla , Long George , Bovill Edwin , Hasstedt Sandra
Published: October 2007

Protein C deficiency increases the risk of venous thromboembolic disease among members of KindredVermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (107–119Mb, nominal P<0.0001), with weaker support on chromosomes 10p12 (11–25Mb, P<0.0003) and 18p11.2-q11 (12–24Mb, P<0.0007).The 11q23 region contains the α2 subunit (gene name PAFAH1B2) of platelet-activating factor acetylhydrolase 1b, a candidate prothrombotic gene. Re-sequencing of the PAFAH1B2 regulatory region in 137 pedigree members, including 25 thrombosis cases, revealed 12 variants; eight were present in only 0–2 affected individuals; the other four assorted into three haplotypes and included three variants predicted to destroy transcription factor-binding sites. More extensive re-sequencing of the PAFAH1B2 gene in 11 affected and five unaffected pedigree members revealed an additional 13 variants that assorted into the same three haplotypes. We rejected as thrombosis risk factors each of the three presumed destructive variants as well as each of the three haplotypes. We also rejected (odds ratio=1.31 CI: 0.91–1.88) one of the three variants in 469 cases and 472 controls from the Leiden Thrombophilia Study (LETS). Therefore, PAFAH1B2 is not the gene responsible for the linkage evidence on chromosome 11q23.
Coagulation factor V and thrombophilia: Background and mechanisms
Authors: Segers Kenneth , Dahlbäck Björn , Nicolaes Gerry
Published: October 2007

Human coagulation factor V (FV) is an essential coagulation protein with functions in both the pro- and anticoagulant pathways. Failure to express and control FV functions can either lead to bleeding, or to thromboembolic disease. Both events may develop into a life-threatening condition. Since the first description of APC resistance, and in particular the description of the so-called factor VLeiden mutation, in which a prominent activated protein C cleavage site in FV has been abolished through a mutation in the FV gene, FV has been in the center of attention of thrombosis research. In this review we describe how the functions of FV are expressed and regulated and provide an extensive description of the role that FV plays in the etiology of thromboembolic disease.
Invasion mechanisms of Gram-positive pathogenic cocci
Authors: Nitsche-Schmitz Patric , Rohde Manfred , Chhatwal Gursharan
Published: October 2007

Gram-positive cocci are important human pathogens. Streptococci and staphylococci in particular are a major threat to human health,since they cause a variety of serious invasive infections. Their invasion into normally sterile sites of the host depends on elaborated bacterial mechanisms that involve adhesion to the host tissue, its degradation, internalisation by host cells, and passage through epithelia and endothelia. Interactions of bacterial surface proteins with proteins of the host’s extracellular matrix as well as with cell surface receptors are crucial factors in these processes, and some of the key mechanisms are similar in many pathogenic Gram-positive cocci.Therapies that interfere with these mechanisms may become efficient alternatives to today’s antibiotic treatments.
Molecular basis of protein S deficiency
Authors: Fuentes-Prior Pablo , Hurtado Begoña , Frutos Pablo García de , Sala Núria
Published: October 2007

Protein S deficiency (PSD) has been the most difficult to study among the classical inherited thrombophilic factors. This is in part due to the peculiar biology of protein S (PS), which has an anticoagulant role but no enzymatic activity,and because it interacts with plasma components that function in both haemostasis and inflammation.Clinically,it also has been difficult to define and standardise valuable assays to determine PS status and implication in thrombosis. Despite these drawbacks, at present heterozygous PS deficiency is well established as an autosomal dominant trait associated with an increased risk of thrombosis from data on familial and population studies. Almost twohundred mutations have been characterised in PROS1, and approximately 30% of them have been characterised in vitro,clarifying the mechanisms leading to PSD. Furthermore, recent studies on the presence of large deletions in PROS1 have increased the number of PSD associated to PROS1 mutations. Finally, the discovery of new functions for PS, both in the anticoagulant system as well as in the interaction with cellular components through receptor tyrosine kinases, is broadening the importance of this molecule in the context of biomedicine.
Thrombomodulin-mediated catabolism of protein C by pleural mesothelial and vascular endothelial cells
Authors: Rezaie Alireza , Idell Steven , Iakhiaev Alexei
Published: October 2007

Pleural mesothelial and vascular endothelial cells express protein C (PC) pathway components including thrombomodulin (TM) and endothelial protein C receptor (EPCR) and activate PC by the thrombin-TM dependent mechanism.We used these cells as model systems to identify molecules involved in endocytosis and degradation of PC. We find that mesothelial and endothelial cells can bind, internalize and degrade PC.Addition of thrombin markedly induced degradation of PC by these cells in a TM-dependent fashion, implicating the involvement of the thrombin-TM complex in internalization and degradation of PC. This observation defines a novel function for the thrombin-TM complex as a degradation receptor for PC and suggests that PC is degraded concurrent with its activation.A PC Gla-domain mutant, which is unable to bind to the EPCR, was degraded by the cells to a lesser extent than wild-type PC, implicating the PC degradation concurrent with its activation. Consistent with the role of thrombin-TM complex as a degradation receptor, the catalytically inactive thrombin-S195A also induced PC degradation though to a lesser extent than wild-type thrombin.This suggests that generation of activated PC (APC) can contribute to accumulation of degradation products, but is not essential for the thrombin-induced degradation of PC. The thrombin-TMmediated degradation of PC by both cell types suggest a previously unrecognized mechanism, which can contribute to PC consumption.This mechanism may be pathophysiologically relevant and can contribute to an acquired PC deficiency in conditions characterized by sustained thrombin generation.
Fibrinogen-binding proteins of Gram-positive bacteria
Authors: Vannakambadi Ganesh , Höök Magnus , Speziale Pietro , Rivera Jose
Published: October 2007

Fibrinogen (Fg), the major clotting protein in blood plasma, plays key roles in blood coagulation and thrombosis. In addition, this 340 kD glycoprotein is a stress inducible protein; its synthesis is dramatically upregulated during inflammation or under exposure to stress such systemic infections.This regulation of Fg expression indicates that Fg also participates in the host defense system against infections. In fact, a number of reported studies have demonstrated the involvement of both the intrinsic and extrinsic pathways of coagulation; the thrombotic and the fibrinolytic systems in the pathophysiology of infectious diseases. It is, therefore, perhaps not surprising that many pathogenic bacteria can interact with Fg and manipulate its biology.This review focuses on the major Fg-binding proteins (Fgbps) from Gram-positive bacteria with an emphasis on those that are known to have an effect on coagulation and thrombosis
Venous thromboembolism in patients with active cancer
Authors: Seddighzadeh Ali , Shetty Ranjith , Goldhaber Samuel
Published: October 2007

Patients with cancer have an increased risk of venous thromboembolism (VTE).To further define the demographics, comorbidities, and risk factors of VTE in these patients, we analyzed a prospective registry of 5,451 patients with ultrasound confirmed deep vein thrombosis (DVT) from 183 hospitals in the United States. Cancer was reported in 1,768 (39%), of whom 1,096 (62.0%) had active cancer. Of these, 599 (54.7%) were receiving chemotherapy, and 226 (20.6%) had metastases. Lung (18.5%), colorectal (11.8%), and breast cancer (9.0%) were among the most common cancer types. Cancer patients were younger (median age 66 years vs. 70 years; p<0.0001), were more likely to be male (50.4% vs. 44.5%; p=0.0005), and had a lower average body mass index (26.6 kg/m2 vs. 28.9 kg/m2; p<0.0001). Cancer patients less often received VTE prophylaxis prior to development of DVT compared to those with no cancer (308 of 1,096, 28.2% vs. 1,196 of 3,444, 34.6%; p<0.0001). For DVT therapy, low-molecular-weight heparin (LMWH) as monotherapy without warfarin (142 of 1,086, 13.1% vs. 300 of 3,429, 8.7%; p<0.0001) and inferior vena caval filters (234 of 1,086, 21.5% vs. 473 of 3,429, 13.8%; p<0.0001) were utilized more often in cancer patients than in DVT patients without cancer. Cancer patients with DVT and neurological disease were twice as likely to receive inferior vena caval filters than those with no cancer (odds ratio 2.17, p=0.005). In conclusion, cancer patients who develop DVT receive prophylaxis less often and more often receive filters than patients with no cancer who develop DVT. Future studies should focus on ways to improve implementation of prophylaxis in cancer patients and to further define the indications, efficacy, and safety of inferior vena caval filters in this population.
Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORC1 and CYP2C9 alleles
Authors: Bevans Carville , Fregin Andreas , Geisen Christof , Müller-Reible Clemens , Watzka Matthias , Oldenburg Johannes
Published: October 2007

For decades coumarins have been the most commonly prescribed drugs for therapy and prophylaxis of thromboembolic conditions. Despite the limitation of their narrow therapeutic dosage window, the broad variation of intra- and inter-individual drug requirement, and the relatively high incidence of bleeding complications,prescriptions for coumarins are increasing due to the aging populations in industrialised countries.The identification of the molecular target of coumarins,VKORC1, has greatly improved the understanding of coumarin treatment and illuminated new perspectives for a safer and more individualized oral anticoagulation therapy. Mutations and SNPs within the translated and non-translated regions of the VKORC1 gene have been shown to cause coumarin resistance and sensitivity,respectively. Besides the known CYP2C9 variants that affect coumarin metabolism, the haplotype VKORC1*2 representing a frequent SNP within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity,reducingVKORC1 enzyme activity to 50% of wild type. Homozygous carriers of the VKORC1*2 allele are strongly predisposed to coumarin sensitivity. Using individualized dose adaptation, a significant reduction of bleeding complications can be expected, especially in the initial drug saturation phase. Furthermore, concomitant application of low dose vitamin K may significantly reduce intra-individual coumarin dose variation and, thus, may stabilize oral anticoagulation therapy. The use of new pharmacogenetics-based dosing schemes and the concomitant application of low-dose vitamin K with coumarins will decidedly influence the current practice of oral anticoagulation and greatly improve coumarin drug safety.
Studying the Struggle
Authors: Rogers John , Morrell Ernest , Enyedy Noel
Published: October 2007

Activism and organizing can be a fertile subject matter for young people to study. This article presents a case study of a summer seminar in which urban high school students examined the historical struggle for educational justice in their communities. Adopting a “communities of practice” approach to learning, the article documents the changing participation of seminar participants and the changing identities and skills that this entailed. During the seminar, students took on identities as “critical researchers”— skilled investigators who produce and share knowledge relevant to social change. In the process, seminar participants developed and deployed high-level academic skills in language arts, social studies, and mathematics.
Reframing Social Responsibility Within a Technology-Based Youth Activist Program
Authors: Hamilton Carmen , Flanagan Constance
Published: October 2007

The purpose of this qualitative study was to explore the transformation process in a youth group's conception of itself and its role in assuming responsibility for alcohol, tobacco, and other drug use in the community. Building on a technology-based community program, an adult facilitator invited adolescents to collaborate on a youth-produced film that would encourage peers to adopt an ethic of social responsibility for one another. In this article, a framing metaphor is used to discuss the unique potential of film for enabling youth to redefine social issues (in this case, health and responsibility), the importance of an adult facilitator's role in providing alternative frames to the status quo, and the essential role that reframing plays in social change.
Directivity and Freedom
Authors: O'Donoghue Jennifer L. , Strobel Karen R.
Published: October 2007

Community-based youth organizations represent potentially powerful settings for activism among marginalized urban youth. This article uses quantitative and qualitative data collected in one such organization to examine the link between youth—adult relationships and youth activism. Survey data point to adults as contributing to youth's activist development and reveal pathways that lead to this outcome. Interview and observation data clarify youth's perceptions of adult support, highlight the complexity of building egalitarian relationships, and situate youth—adult interactions within broader public action. Analyses direct attention to transformations among youth and convey the challenges inherent in breaking out of conventional patterns of youth—adult interaction.
Sustainable Agriculture and Food Security
Authors: Ramakrishnan P.S.
Published: October 2007

Traditionally scientists have looked at agriculture merely as a production system. It is only in recent times when issues of sustainability have been regularly cropping up, that there is a paradigm shift. There is now an attempt to look at agriculture also as an ecological system. India and China are two large rapidly industrializing countries that have a large and heterogeneous population load to carry. India and China are also very ancient agricultural countries with a long and rich tradition of natural resource conservation linked sustainable management of agriculture. There is a need for linking cultural diversity with biological diversity, so rich in the India-China context, as the basis for sustainable management of natural resources, leading towards human wellbeing, and thus contributing towards human security.
Shaping up the New Countrysides
Authors: Singh Arvinder
Published: October 2007

There has been a tendency in transitional economies, in recent times, marked by faster global integration and the rise of highly visible high-tech industrial sectors of the economy, to see agriculture more as a pre-modern drag than a contributor, right kind of noises and concerns for food security notwithstanding. India, China and Russia, in that order, must realise that agriculture will continue to be around in its present form for a much longer time than they would wish. The manufacturing industrial sector is likely to coexist with a large population persisting in agriculture. Obsession with a certain kind of ‘modern’ industrialisation, mistakenly attributed to the West, and impatience with agriculture will not help. Nor will technocratic solutions to agricultural problems. For instance, large scale mechanised farming may neither be inevitable nor necessarily desirable. Nor may the labour transfer from agriculture to non-agriculture be as quick as expected. It is in this context and on the basis of a far more solid understanding of each other's economy than what the existing state of affairs suggests that cooperation between India, China and Russia needs to build on.
Central Asia in Trilateral Cooperation
Authors: Luzyanin Sergey
Published: October 2007

The region, Central Asia, and the regional organisation, SCO, were of significance for China, India and Russia with respect to dealing with threats to security posed by non-state actors such as terrorists and drug-traffickers. The three could also cooperate with regard to energy resources, transport and investment in the region. However, competition could not be ruled out and hence it was necessary to structure their interaction in terms of ‘cooperative competition’ and well-coordinated trilateral interaction, for example, by each agreeing to specialise in a particular sphere or sector.
A Russian Understanding of China's SCO Policy
Authors: Mohanty A.K.
Published: October 2007

There are three schools of thought among Russian scholars on China and its SCO policy. The first group, referred to as Optimists or Enthusiasts, think that the world needs a strong Russia as a stabilising factor in international affairs. The second group, referred to as Alarmists, assert that there is growing discord between a weak Russia and a fast growing China and that conflict between them is inevitable. Emphasising that China is stronger than Russia for the first time in two centuries, they argue that China's SCO policy is designed to buy time and strengthen itself with Russian assistance within the organisation till it becomes a super power. The third group, referred to as Realists are of the view that China is both a prospective partner and a potential adversary for Russia, and that this should be taken into account while shaping Moscow's SCO policy as well as in judging China's SCO policy.
Recent Developments Relating to North Korea
Authors: Raghunath K.
Published: October 2007

The article seeks to help find common ground, in the Trilateral context, on the approach to current developments relating to North Korea as well as on long-term policy regarding the Koreas. We are aware of the close and long-established interaction between the Koreas, China and Russia, and the particular interests of the latter two in the Korean peninsula. For India, this is by no means a remote area but indeed an integral part of our growing engagement with East and Northeast Asia. The well documented record of trafficking in nuclear weapons and missile technology between North Korea and our immediate South Asian neighbourhood is a matter of utmost concern. The justified anxiety about the proliferation related implications of North Korea's nuclear weapon and missile activity should reinforce purposeful rethinking on the correct ways and means of ensuring non-proliferation and eventual global nuclear disarmament. Also relevant is the larger picture involving North Korea's internal dynamic and development, its reform programme, incipient globalisation, trends in North Korea's relations with Japan and South Korea, especially inter-Korea exchanges and the long term agenda of reunification, and the prospects for the six-party talks and the role of the US.
China-India-Russia
Authors: Bagchi Amiya Kumar
Published: October 2007

At different stages of their history, leaders of China, India and Russia, the most prominent constituents of the Eurasian landmass and home to one-third of the human population of the world, have formulated the aim of breaking out of the ‘backward’ state of their respective countries as a major goal of their movements, their strategies and their policies. Almost in all cases, such a state of backwardness has been perceived in relation to the ‘advanced’ Western countries, and more specifically to the industrialised countries of Europe and North America. All three countries have been caught several times in recent centuries in the cunning passages of history. All of them now see light at the end of the labyrinthine tunnel. A recognition of their common destinies as homes of human beings with complicated histories and of the need for cooperation to protect themselves against the forces of evil, in the shape of market fundamentalism, religious fanaticism and super-hegemonic imperialism can help them to guard themselves against being caught again in Minotaur's lair.
Transport Links in Asia and Their Role in Trilateral Cooperation
Authors: Uyanaev Sergei
Published: October 2007

As growing economic ties necessitates the development of transport routes in Asia, the latter process would in turn facilitate the former one. New transport routes could serve as a strong impulse for the development of adjacent territories. Cooperation between China, India and Russia in this sector could take the form of joint road and pipeline construction, investment projects and measures to safeguard the security of communications.
Privatising the Public Sector
Authors: Chandrashekhar C.P.
Published: October 2007

Privatisation can be defined as the change in ownership of state-owned firms through sale of equity to private individuals or entities and leading to complete private control and management. Means of privatisation are disinvestment through sale of private equity through the stock market; auction or negotiated sale of a controlling block or a majority shareholding to a chosen party; and sale through a voucher system that seeks to provide the ultimate owners (the people) or workers in enterprises an implicit stake in state-owned assets. Progress has been quick and substantial in Russia, slower but now significant in China, and halting and concentrated in profit-making enterprises in India. In all three cases privatisation seems to have been driven in practice by irrational short term considerations or purely ideological motivations. In any event, the acceptability of the process in an accounting sense and its integrity has been brought into question.
Environmental Problems
Authors: Shaumyan Tatiana
Published: October 2007

Through the second half of the twentieth century, the environment has deteriorated throughout the planet in general as well as in China, India and Russia in particular. Russian-Indian cooperation in the ecological sphere works through exchange of experience in resolution of various ecological problems. But it would be very different from the need for Russia and China to make joint efforts to overcome the problems arising in the vast and ecologically unfavourable area across the Russia-China border, particularly with regard to the Amur river basin.
China's Economic Development and Environment Protection
Authors: Gang Zhou
Published: October 2007

There are linkages between the environment and economic development. International cooperation is essential for preserving the environment. China, India and Russia each consist of a large population, a vast territory and a fast growing economy. They could work together to strengthen coordination in the field of environmental protection; establish institutional mechanisms for trilateral cooperation; and start a dialogue, share experiences and jointly train personnel on environment protection. China and Russia could work together in preventing pollution in their border river basin. Important areas for cooperation between China and India would be in research and development of technology for utilising environmentally friendly wind, bio-mass and solar energy, and in improving the energy utilisation ratio.
Potential for Trilateral Cooperation in the Agricultural Sphere
Authors: Portyakov Vladimir
Published: October 2007

An examination of the state of Russia's agrarian sector reveals that at present China and India are not among its leading partners in agricultural and food products trade. The Sino-Indian trade in agrarian products is also insignificant. Factors inhibiting such trade were competition from other countries selling the same type of product; high prices of imported agrarian products; restrictions on the import of such products based on sanitary requirements and quality standards; differences in the perceptions of the three countries regarding their own food security; and different traditions and structures of nutrition in the three countries. If such inhibitions are overcome trade could constitute an important form of cooperation between the three countries in the agrarian sector. Russia and China are also cooperating through the use of Chinese labour for farming on rented land, while Russia and India are interested in sharing of experience of applying microbiology technology for production of biological fertiliser. Coordination between the three countries with regard to the agrarian agenda of the WTO and in the markets of other countries are also possibilities.