bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Endothelial Growth Factor Polymorphisms and Esophageal Cancer Prognosis
Authors: Bradbury Penelope A. , Zhai Rihong , Ma Clement , Xu Wei , Hopkins Jessica , Kulke Matthew J. , Asomaning Kofi , Wang Zhaoxi , Su Li , Heist Rebecca S. , Lynch Thomas J. , Wain John C. , Christiani David , Liu Geoffrey
Published: July 2009

Purpose: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The VEGF gene is polymorphic. We investigated the prognostic significance of three VEGF single nucleotide polymorphisms (SNP) in esophageal cancer.

Experimental Design: Three hundred sixty-one patients were genotyped for three VEGF SNPs (−460T/C, 405G/C, and 936C/T) using DNA extracted from prospectively collected blood samples. The association of each individual SNP, and haplotypes of the three SNPs, on overall survival (OS) was investigated.

Results: The variant allele of 936C/T was associated with improved OS compared with the wild-type genotype (log-rank P < 0.001). This association remained significant for OS after adjustments for age, gender, performance status, and disease stage [VEGF 936C/T: adjusted hazard ratio (AHR), 0.70; 95% confidence interval (95% CI), 0.49-0.99; P = 0.04; VEGF 936T/T: AHR, 0.11; 95% CI, 0.02-0.82; P = 0.03]. No independent associations were found for VEGF −460T/C and VEGF 405G/C. The CGC haplotype of the three VEGF SNPs (−460T/C, 405G/C, and 936C/T) combined was associated with reduced OS compared with all other patients (CGC/CGC: AHR, 1.51; 95% CI, 1.00-2.30; P = 0.05).

Conclusions: VEGF 936C/T, and a haplotype of 460T/C, 405G/C, and 936C/T combined, has potential prognostic significance in esophageal cancer.
Relationship of CDX2 Loss with Molecular Features and Prognosis in Colorectal Cancer
Authors: Baba Yoshifumi , Nosho Katsuhiko , Shima Kaori , Freed Ellen , Irahara Natsumi , Philips Juliet , Meyerhardt Jeffrey A. , Hornick Jason L. , Shivdasani Ramesh A. , Fuchs Charles S. , Ogino Shuji
Published: July 2009

Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma. However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).

Experimental Design: Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by immunohistochemistry.

Results: In multivariate logistic regression analysis, CDX2 loss was associated with female gender [odds ratio (OR), 3.32; P < 0.0001], CIMP-high (OR, 4.42; P = 0.0003), high tumor grade (OR, 2.69; P = 0.0085), stage IV disease (OR, 2.03; P = 0.019), and inversely with LINE-1 hypomethylation (for a 30% decline; OR, 0.33; P = 0.0031), p53 expression (OR, 0.55; P = 0.011), and β-catenin activation (OR, 0.60; P = 0.037), but not with body mass index, tumor location, microsatellite instability, BRAF, KRAS, PIK3CA, p21, or cyclooxygenase-2. CDX2 loss was not independently associated with patient survival. However, the prognostic effect of CDX2 loss seemed to differ according to family history of colorectal cancer (Pinteraction = 0.0094). CDX2 loss was associated with high overall mortality (multivariate hazard ratio, 2.40; 95% CI, 1.28-4.51) among patients with a family history of colorectal cancer; no such association was present (multivariate hazard ratio, 0.97; 95% CI, 0.66-1.41) among patients without a family history of colorectal cancer.

Conclusions: CDX2 loss in colorectal cancer is independently associated with female gender, CIMP-high, high-level LINE-1 methylation, high tumor grade, and advanced stage. CDX2 loss may be associated with poor prognosis among patients with a family history of colorectal cancer.
Prevention of Radiation-Induced Oral Mucositis after Adenoviral Vector–Mediated Transfer of the Keratinocyte Growth Factor cDNA to Mouse Submandibular Glands
Authors: Zheng Changyu , Cotrim Ana P. , Sunshine Abraham N. , Sugito Takayuki , Liu Lina , Sowers Anastasia , Mitchell James B. , Baum Bruce J.
Published: July 2009

Purpose: The study aims to evaluate if human keratinocyte growth factor (hKGF), secreted after transduction of murine salivary glands with adenoviral vectors, can prevent oral mucositis resulting from radiation.

Experimental Design: Two serotype 5 adenoviral vectors encoding hKGF were constructed: AdEF1α-hKGF and AdLTR2EF1α-hKGF. Female C3H mice, 8 weeks old, were irradiated by single (22.5 Gy) or fractionated (5 × 8 Gy for 5 days) doses to induce oral mucositis (ulcers on tongue). One day before irradiation, the above viral vectors or an empty vector, Adcontrol, was given (1010 particles per gland) to both submandibular glands by retrograde ductal instillation. Each experiment included five groups: no irradiation and irradiation (±Adcontrol, AdEF1α-hKGF, or AdLTR2EF1α-hKGF). Blood, saliva, submandibular glands, and tongue were collected on day 7 for single-dose studies or day 10 for fractionated dosing. hKGF levels were measured by ELISA.

Results: In three separate single-dose irradiation experiments, lingual ulcers were dramatically reduced after either KGF-expressing vector. Similarly, in two separate fractionated irradiation experiments, the hKGF-expressing vectors completely prevented ulcer formation. QPCR data indicated that ∼107 to 108 particles of each vector remained in the targeted submandibular glands at the terminal time. Transgenic hKGF protein was found at high levels in saliva, serum, and submandibular gland extracts.

Conclusions: hKGF gene transfer to salivary glands prevented radiation-induced oral mucositis in mice. This proof of concept study suggests that transgenic hKGF secreted from transduced salivary glands may be useful clinically to prevent oral mucositis caused by radiation.
Response prediction to a multitargeted kinase inhibitor in cancer cell lines and xenograft tumors using high-content tyrosine peptide arrays with a kinetic readout
Authors: Versele Matthias , Talloen Willem , Rockx Cindy , Geerts Tamara , Janssen Boud , Lavrijssen Tom , King Peter , Göhlmann Hinrich W.H. , Page Martin , Perera Tim
Published: July 2009

Multitargeted kinase inhibitors have shown clinical efficacy in a range of cancer types. However, two major problems associated with these drugs are the low fraction of patients for which these treatments provide initial clinical benefit and the occurrence of resistance during prolonged therapy. Several types of predictive biomarkers have been suggested, such as expression level and phosphorylation status of the major targeted kinase(s), mutational status of the kinases involved and of key components of the downstream signaling cascades, and gene expression signatures. In this work, we describe the development of a response prediction platform that does not require prior knowledge of the relevant kinases targeted by the inhibitor; instead, a phosphotyrosine peptide profile using peptide arrays with a kinetic readout is derived in lysates in the presence and absence of a kinase inhibitor. We show in a range of cell lines and in xenograft tumors that this approach allows for the stratification of responders and nonresponders to a multitargeted kinase inhibitor. [Mol Cancer Ther 2009;8(7):1846–55]
Elevated Poly-(ADP-Ribose)-Polymerase Activity Sensitizes Retinoblastoma-Deficient Cells to DNA Damage–Induced Necrosis
Authors: Liu Huiping , Knabb James R. , Spike Benjamin T. , Macleod Kay F.
Published: July 2009

The retinoblastoma (Rb) tumor suppressor is a key regulator of cell cycle checkpoints but also protects against cell death induced by stresses such as DNA damage and death receptor ligation. We report here that cell death of Rb-deficient cells exposed to key genotoxic agents was associated with increased expression of S phase–specific E2F target genes and cell death consistently occurred in the S phase of the cell cycle. Cell cycle arrest induced by serum starvation prevented S phase entry, attenuated DNA damage, and promoted survival, suggesting that Rb-null cells die due to a failure to prevent S phase entry. DNA damage–induced death of Rb-null cells was associated with nucleotide depletion, higher activity of poly-ADP-ribose-polymerase (Parp), and cell death that was primarily necrotic. Knockdown of Parp-1 or chemical inhibition of Parp activity prevented nucleotide depletion and restored the viability of Rb-deficient cells to wild-type levels. Furthermore, chemical inhibition of Parp activity in vivo attenuated the cytotoxic effects of cisplatin against Rb-deficient tumors, arguing that Parp inhibitors should not be used therapeutically in combination with genotoxic drugs against tumors that are inactivated for the Rb tumor suppressor.(Mol Cancer Res 2009;7(7):1099–109)
p21 Expression Is Induced by Activation of Nuclear Nerve Growth Factor–Induced Bα (Nur77) in Pancreatic Cancer Cells
Authors: Lee Syng-Ook , Chintharlapalli Sudhakar , Liu Shengxi , Papineni Sabitha , Cho Sung Dae , Yoon Kyungsil , Safe Stephen
Published: July 2009

1,1-Bis(3′-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor–induced Bα (Nur77) in cancer cells, and in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0-G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies showed that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77 dependent but did not depend on Krüppel-like factor 4, which was also induced by DIM-C-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21, which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter. [Mol Cancer Res 2009;7(7):1169–78]
Bleeding with anticoagulation therapy – Who is at risk, and how best to identify such patients
Authors: Cosmi Benilde , Palareti Gualtiero
Published: July 2009

Anticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person- associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.
Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases
Authors: Matsuyama Tomomi , Kuwana Masataka , Matsumoto Masanori , Isonishi Ayami , Inokuma Shigeko , Fujimura Yoshihiro
Published: July 2009

To clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs.70.3%,p<0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.
Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence
Authors: Petersen Lars , Mousa Shaker
Published: July 2009

Malignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis.Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations.The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH.The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients.The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.
Novel evaluation method for densitometric curves of von Willebrand Factor multimers and a new parameter (MMW) to describe the degree of multimersation
Authors: Udvardy Miklós , Szekeres-Csiki Katalin , Hársfalvi Jolán
Published: July 2009

Von Willebrand factor (VWF) is built up from a varying number of subunits, of which the larger molecules have higher haemostatic activity. Von Willebrand disease (VWD) and thrombotic thrombocytopenic purpura are the best known disorders with pathognomonic changes of the highly multimerised VWF forms. There is an established method to calculate the relative amount of large oligomers. Our aim is to quantify the degree of VWF multimerisation as well, to complete the densitometric analysis of VWF electrophoresis. After optimisation, we have defined this new parameter (MMW) as the molecular weight corresponding to the lower boundary of the largest 25% of VWF protein. MMW was significantly different (p<.0001) in platelet lysate, normal samples and VWD type 2 samples (10.4, 6.3, 2.1, respectively). There was strong correlation between the MMW and the amount of large multimers in normal samples (r2=0.98) and in platelet lysate. However MMW was higher in latelet lysate, in which VWF is not cleaved by ADAMTS-13, than in healthy samples with the same amount of large multimers. Comparison of the new parameter and the collagen binding and ristocetin cofactor activity of VWF, showed that the functional tests are at least partially determined by the multimerisation; however, about 15% of VWD samples had normal activity to antigen ratios. The quantification of multimerisation aids the classification in these cases, especially at low antigen concentrations, and also might help in the detection of thrombotic conditions.
Venous thromboembolic events in hospitalised medical patients
Authors: Fanikos John , Zayaruzny Maksim , Goldhaber Samuel Z. , Piazza Gregory
Published: July 2009

The number of acutely ill hospitalised medical patients at risk for acute venous thromboembolism (VTE) has not been well defined. Therefore, we used the 2003 United States Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample database to estimate VTE events among hospitalised medical patients. We then modeled the potential reduction in VTE with universal utilisation of appropriate pharmacological thromboprophylaxis. We calculated that 8,077,919 acutely ill hospitalised medical patients were at risk for VTE. Heart failure, respiratory failure, pneumonia, and cancer were the most common medical diagnoses. We estimated that 196,134 VTE-related events occurred in 2003, afflicting two out of every 100 acutely ill hospitalised medical patients. These VTE-related events were comprised of 122,235 symptomatic deep venous thromboses, 32,654 symptomatic episodes of pulmonary embolism, and 41,245 deaths due to VTE. In our model, rates of pharmacological thromboprophylaxis prescription were low for various acute medical illnesses, ranging from 15.3% to 49.2%. However, with universal thromboprophylaxis, 114,174 VTE-related events would have been prevented. In conclusion, acutely ill medical patients represent a large population vulnerable to the development of VTE during hospitalisation. The number of VTE-related events would be halved with universal thromboprophylaxis. Further efforts focused on improving VTE prevention strategies in hospitalised medical patients are warranted.
Function of β1 Integrin in Oral Epithelia and Tooth Bud Morphogenesis
Authors: Chen B. , Goodman E. , Lu Z. , Bandyopadhyay A. , Magraw C. , He T. , Raghavan S.
Published: July 2009

Integrin β1 is critical for basement membrane organization and hair follicle morphogenesis in the skin epidermis; however, less is known about its function in the developing oral epithelium. Since the skin and oral epithelia share structural similarity, we hypothesized that β1 integrin function would be critical for the normal development of oral epithelium and tooth buds. The conditional (oral mucosa-specific) β1 integrin knockout (KO) mice displayed severe disruption of the basement membrane of the tongue epithelium and developing tooth buds. Interestingly, unlike the developing hair follicles, early morphological development of the KO molar tooth buds was normal. However, subsequent morphogenetic events, such as cusp formation, cervical loop down-growth, and ameloblast polarization, did not occur normally. Primary KO oral keratinocytes showed defective cell spreading and robust focal adhesions. Our studies indicate that β1 integrin plays an essential role in the normal development of the oral epithelium and its appendages.
Novel Golgi Protein, GoPro49, Is a Specific Dental Follicle Marker
Authors: Takatalo M.S. , Tummers M. , Thesleff I. , Rönnholm R.
Published: July 2009

GoPro49 is a recently identified, novel Golgi protein that is expressed in embryonic mesenchymal tissues, including dental follicle. In the present study, we have tested the hypothesis that the gene is a specific marker for the dental follicle, and examined its expression during the development of mouse incisors and molars. In situ hybridization showed that GoPro49 is expressed in dental follicles from bud to post-eruption stages. The expression is intense throughout the dental follicle during crown development, and persists in the root follicle during root development. In the forming periodontal ligament, GoPro49 expression is down-regulated upon differentiation of the follicle cells to cementoblasts and osteoblasts marked by Bsp1. In cultured dental follicle cells, the GoPro49 protein co-localizes with β-COP, suggesting that GoPro49 may function in the secretory pathway. We conclude that GoPro49 is a novel, specific marker for the dental follicle and can be used to identify this tissue. Abbreviations: Bsp1, bone sialoprotein 1; GoPro49, Golgi protein 49 kDa; E16, embryonic day 16; HERS, Hertwig’s epithelial root sheath; PDL, periodontal ligament; dpn, day post-natal.
Smoking Cessation Alters Subgingival Microbial Recolonization
Authors: Fullmer S.C. , Preshaw P.M. , Heasman P.A. , Kumar P.S.
Published: July 2009

Smoking cessation improves the clinical manifestations of periodontitis; however, its effect on the subgingival biofilm, the primary etiological agent of periodontitis, is unclear. The purpose of this study was to investigate, longitudinally, if smoking cessation altered the composition of the subgingival microbial community, by means of a quantitative, cultivation-independent assay for bacterial profiling. Subgingival plaque was collected at baseline, and 3, 6, and 12 months post-treatment from smokers who received root planing and smoking cessation counseling. The plaque was analyzed by terminal restriction fragment length polymorphism (t-RFLP). Microbial profiles differed significantly between smokers and quitters at 6 and 12 months following smoking cessation. The microbial community in smokers was similar to baseline, while quitters demonstrated significantly divergent profiles. Changes in bacterial levels contributed to this shift. These findings reveal a critical role for smoking cessation in altering the subgingival biofilm and suggest a mechanism for improved periodontal health associated with smoking cessation.
Youths’ Caretaking of Their Adolescent Sisters’ Children
Authors: East Patricia L. , Weisner Thomas S. , Slonim Ashley
Published: July 2009

The extent and experiences of youths’ caretaking of their adolescent sisters’ children have been assessed in two longitudinal studies. The first study examines the caretaking patterns of 132 Latino and African American youth during middle and late adolescence. The second study involves 110 Latino youth whose teenage sister has recently given birth. Youth are studied at 6 weeks and 6 months postpartum. In both studies, girls provide more hours of care than boys, and in Study 1, girls’ hours of care significantly increase with age whereas boys’ hours of caretaking decrease. Girls provide more care when their sisters are older and when their mothers provide many hours of care, whereas boys provide less care when their mothers provide more care and when they have many siblings. Results of both studies reveal age, gender, and across-time differences in the extent of care, type of caretaking activities, and experiences in providing care.
The Impact of Protective Factors in Desistance From Violent Reoffending
Authors: Lodewijks Henny P. B. , de Ruiter Corine , Doreleijers Theo A. H.
Published: July 2009

This study examined the impact of protective factors, assessed by means of the Structured Assessment of Violence Risk in Youth (SAVRY), on desistance from violent reoffending in adolescents. Three samples included male adolescents in different stages of the judicial process: pre-trial ( n = 111); during residential treatment ( n = 66); and after release from a juvenile justice facility ( n = 47). The results lend support to the hypothesis that protective factors buffer or mitigate the risk of violent reoffending. Using regression analyses, in all samples, the addition of protective factors yielded a significant increment in the amount of variance explained by dynamic risk factors alone. Furthermore, in medium to high risk subgroups, the violent reoffending rate was significantly higher when protective factors were absent, compared to when protective factors were present. These findings are discussed in terms of their implications for risk assessment and risk management practice with adolescent offenders.
Psychosocial Correlates of Physical Dating Violence Victimization Among Latino Early Adolescents
Authors: Yan Fang A. , Howard Donna E. , Beck Kenneth H. , Shattuck Teresa , Hallmark-Kerr Melissa
Published: July 2009

This study examined the association between dating violence victimization and psychosocial risk and protective factors among Latino early adolescents. An anonymous, cross-sectional, self-reported survey was administered to a convenience sample of Latino youth ( n = 322) aged 11 to 13 residing in suburban Washington, D.C. The dependent variable was physical dating violence; the independent variables included violence, substance use, emotional well-being, prosocial behaviors, and parenting practices. Multivariate logistic regression models were constructed and adjusted odds ratio and 95% confidence interval were examined. Overall, 13.5% ( n = 43) of Latino early adolescents reported being a victim of physical dating violence within the past year. The prevalence was 14.4% for girls and 12.9% for boys. Among the girls, binge drinking was the sole risk behavior associated with dating violence. Gun carrying, alcohol consumption, and having considered suicide were associated with dating violence among the boys. Physical dating violence appears to affect a small but significant proportion of Latino early adolescents and is associated with other risk behaviors. Healthy dating relationship programs are warranted for middle school youth with some tailoring to reflect gender differences in risk profiles.
Art Installation as Method
Authors: Mandlis Lane R.
Published: July 2009

This article discusses the use of art mediums as methods to enhance the theoretical and political intentions of an academic work. More specifically, it traces the author’s moving from one artistic method to another, in order to show how the engagement with the theory that is afforded by each is different. Taking performance ethnography as a methodology, the author argues that two different artistic mediums (performance text and art installation) function as significant tools of method that inform his research on various forms of transphobic violence. The author discusses the ways in which the author’s experience as a transsexed (transsexual) researcher and artist informed the move into this methodology, and the ways in which the chosen method of art installation allows the work to perform and be performative more effectively than the original paper-based performance text method.
Extending Social Security to the Excluded
Authors: Leisering Lutz
Published: July 2009

Formal social security in developing countries has long been centred on employees in the formal sector of the economy. The majority of the population has been excluded. Since the 2000s international organizations have called for extending the coverage of social security. This article analyses a recent strategy of extending social security, social cash transfers (SCT) to the poor. The article traces the rise of SCT as a global issue, then describes and classifies SCT in the global South, and inquires into the `appropriateness' (J. Midgley) of SCT in a development context. We find that SCT have spread to all world regions and that SCT covers a highly diverse institutional landscape. Evidence on appropriateness is inconclusive at this early stage of SCT. As yet, the call for social security for all is largely `decoupled' (J.W. Meyer) from the realities of developing countries. But the semantics of `SCT' has opened up a new arena of consensus and conflict in global social policy.
Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome
Authors: Roumenina Lubka T. , Jablonski Mathieu , Hue Christophe , Blouin Jacques , Dimitrov Jordan D. , Dragon-Durey Marie-Agnes , Cayla Mathieu , Fridman Wolf H. , Macher Marie-Alice , Ribes David , Moulonguet Luc , Rostaing Lionel , Satchell Simon C. , Mathieson Peter W. , Sautes-Fridman Catherine , Loirat Chantal , Regnier Catherine H. , Halbwachs-Mecarelli Lise , Fremeaux-Bacchi Veronique
Published: July 2009

Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase.
Coagulation and innate immune responses: can we view them separately?
Authors: Delvaeye Mieke , Conway Edward M.
Published: July 2009

The horseshoe crab is often referred to as a “living fossil,” representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated—indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by identifying recently established paradigms that will hopefully result in the emergence of new strategies to treat a range of inflammatory and hemostatic disorders.
Non-SMC condensin I complex proteins control chromosome segregation and survival of proliferating cells in the zebrafish neural retina
Authors: Seipold Sabine , Priller Florian C , Goldsmith Paul , Harris William A , Baier Herwig , Abdelilah-Seyfried Salim
Published: July 2009

Background

The condensation of chromosomes and correct sister chromatid segregation during cell division is an essential feature of all proliferative cells. Structural maintenance of chromosomes (SMC) and non-SMC proteins form the condensin I complex and regulate chromosome condensation and segregation during mitosis. However, due to the lack of appropriate mutants, the function of the condensin I complex during vertebrate development has not been described.

Results

Here, we report the positional cloning and detailed characterization of retinal phenotypes of a zebrafish mutation at the cap-g locus. High resolution live imaging reveals that the progression of mitosis between prometa- to telophase is delayed and that sister chromatid segregation is impaired upon loss of CAP-G. CAP-G associates with chromosomes between prometa- and telophase of the cell cycle. Loss of the interaction partners CAP-H and CAP-D2 causes cytoplasmic mislocalization of CAP-G throughout mitosis. DNA content analysis reveals increased genomic imbalances upon loss of non-SMC condensin I subunits. Within the retina, loss of condensin I function causes increased rates of apoptosis among cells within the proliferative ciliary marginal zone (CMZ) whereas postmitotic retinal cells are viable. Inhibition of p53-mediated apoptosis partially rescues cell numbers in cap-g mutant retinae and allows normal layering of retinal cell types without alleviating their aberrant nuclear sizes.

Conclusion

Our findings indicate that the condensin I complex is particularly important within rapidly amplifying progenitor cell populations to ensure faithful chromosome segregation. In contrast, differentiation of postmitotic retinal cells is not impaired upon polyploidization.
Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia
Authors: Bass Nicholas J , Datta Susmita R , McQuillin Andrew , Puri Vinay , Choudhury Khalid , Thirumalai Srinivasa , Lawrence Jacob , Quested Digby , Pimm Jonathan , Curtis David , Gurling Hugh MD
Published: July 2009

Background

Previous linkage and association studies have implicated the D-amino acid oxidase activator gene (DAOA)/G30 locus or neighbouring region of chromosome 13q33.2 in the genetic susceptibility to both schizophrenia and bipolar disorder. Four single nucleotide polymorphisms (SNPs) within the D-amino acid oxidase (DAO) gene located at 12q24.11 have also been found to show allelic association with schizophrenia.

Methods

We used the case control method to test for genetic association with variants at these loci in a sample of 431 patients with schizophrenia, 303 patients with bipolar disorder and 442 ancestrally matched supernormal controls all selected from the UK population.

Results

Ten SNPs spanning the DAOA locus were genotyped in these samples. In addition three SNPs were genotyped at the DAO locus in the schizophrenia sample. Allelic association was detected between the marker rs3918342 (M23), 3' to the DAOA gene and both schizophrenia (χ2 = 5.824 p = 0.016) and bipolar disorder (χ2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, χ2 = 3.675 p = 0.055) and rs1421292 (M24; χ2 = 3.499 p = 0.062). A test of association between a three marker haplotype comprising of the SNPs rs778293 (M22), rs3918342 (M23) and rs1421292 (M24) and schizophrenia gave a global empirical significance of p = 0.015. No evidence was found to confirm the association of genetic markers at the DAO gene with schizophrenia.

Conclusion

Our results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder.
Experimental evaluation of insecticidal paints against Triatoma infestans (Hemiptera: Reduviidae), under natural climatic conditions
Authors: Amelotti Ivana , Catalá Silvia S , Gorla David E
Published: July 2009

Background

Triatoma infestans is the main vector of Chagas disease in the Gran Chaco region of South America. The traditional spraying technique used for the application of pyrethroid insecticides has shown low efficiency in the elimination of the vector species populations occupying peridomestic structures of rural houses in the endemic area of Argentina. As part of studies looking for better alternatives, we evaluated the residual effect of insecticidal paints on the mortality of fourth instar nymphs of T. infestans.

Results

The study was based on an experimental design that included two groups treated with an organophosphate (Inesfly 5A IGR™) and a pyrethroid (Inesfly 5A IGR NG™) formulations of the paint, that were applied on wood, cement blocks and adobe bricks under natural climatic conditions. A third group was an untreated control. Both paint formulations showed very long residual activity, producing mortality of 84% and 98% (pyrethroid and organophosphate formulations, respectively) after 12 months of the paint application. After eight months, nymphs exposed during 6 hours to the painted surfaces with the pyrethroid and organophosphate formulations showed 81.33% and 100% mortality, respectively.

Conclusion

The organophosphate- and pyrethroid-based insecticidal paints showed a very long residual activity on the mortality of fourth instar nymphs of T infestans, compared with the traditional spraying technique used for the application of pyrethroid insecticides in peridomestic structures of rural houses in the endemic region for Chagas disease in the Gran Chaco of Argentina. The application of the paints by trained personnel of the vector control programmes could be considered as an alternative control tool in areas where the traditional methods have failed or showed low efficacy.
Ethyl pyruvate administration inhibits hepatic tumor growth
Authors: Liang Xiaoyan , Romo de Vivar Chavez Antonio , Schapiro Nicole E , Loughran Patricia , Thorne Stephen H , Amoscato Andrew A , Zeh Herbert J , Beer–Stolz Donna , Lotze Michael T , de Vera Michael E
Published: July 2009

The first demonstration of ethyl pyruvate inhibition of liver tumor growth associated with induction of tumor apoptosis, diminished HMGB1 release, and decreased inflammation is reported.

EP is a potent inhibitor of HMGB1 release that has significant anti–inflammatory activities and exerts a protective effect in animal models of inflammation. As inflammation is linked to cancer growth, we hypothesized that EP would have anti–tumor activity and explored its effects in a liver tumor model. Mice injected intraportally with MC38 colorectal cancer cells led to the growth of visible hepatic tumors within 2 weeks. Pretreatment with EP 30 min prior to infusion of tumor cells and continuing daily for 9 days inhibited tumor growth significantly in a dose–dependent manner, with 80 mg/kg EP achieving >70% reduction in the number of tumor nodules when compared with untreated animals. Delayed treatment with EP also suppressed tumor growth significantly, although to a lesser extent. Tumors had early, marked leukocytic infiltrates, and EP administration decreased innate (NK cells, monocytes) and adaptive (T and B cell lymphocytic) immune cell infiltrates acutely and significantly in the liver. Serum IL–6 and HMGB1 levels, which were elevated following tumor injection, were decreased significantly in EP–treated animals. Tumors showed an increase in apoptosis in EP–treated mice, and tumor cells treated in vitro with EP had marked increases in LC3–II and cleaved PARP, consistent with enhanced autophagic flux and apoptosis. Thus, EP inhibition of tumor growth in the liver was mediated by tumor (induction of apoptosis) and host (decreased inflammation) effects. EP administration may have a therapeutic role in the treatment of cancer in conjunction with other therapeutic agents.
Effects of Teriparatide in Postmenopausal Women with Osteoporosis on Prior Alendronate or Raloxifene: Differences between Stopping and Continuing the Antiresorptive Agent
Authors: Cosman Felicia , Wermers Robert A. , Recknor Christopher , Mauck Karen F. , Xie Li , Glass Emmett V. , Krege John H.
Published: July 2009

Objective: The aim of the study was to assess adding vs. switching to teriparatide 20μg/d in patients on alendronate or raloxifene.

Design: We conducted a randomized, open-label trial.

Patients and Interventions: Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months added teriparatide (Add groups) or switched to teriparatide (Switch groups) for 18 months.

Main Outcome Measures: We measured bone turnover markers (BTM) and bone mineral density (BMD).

Results: In the alendronate stratum, increases in BTM were smaller in the Add vs. Switch group [6-month PINP (64 vs. 401%); bone ALP (15 vs. 71%); βCTX (27 vs. 250%); all P < 0.001]. However, at 6 months, total hip BMD increased more in the Add vs. Switch group (1.4 vs. −0.8%; P = 0.002). In the Add vs. Switch group, 18-month BMD increments were higher in lumbar spine (8.4 vs. 4.8%; P = 0.003) and total hip (3.2 vs. 0.9%; P = 0.02), but not in femoral neck (2.7 vs. 2.3%; P = 0.75). In the raloxifene stratum, increases in BTM were also smaller in the Add vs. Switch group [6-month PINP (131 vs. 259%; P < 0.001), bone ALP (31 vs. 44%; P = 0.035), and βCTX (67 vs. 144%; P = 0.001)]. At 6 months, total hip BMD increase was greater in the Add vs. Switch group (1.8 vs. 0.5%; P = 0.028). At 18 months, increases in lumbar spine (9.2 vs. 8.1%), total hip (2.8 vs. 1.8%), and femoral neck (3.8 vs. 2.2%) were not significantly different between groups.

Conclusions: In women with osteoporosis treated with antiresorptives, greater bone turnover increases were achieved by switching to teriparatide, whereas greater BMD increases were achieved by adding teriparatide.

In patients treated with alendronate or raloxifene, adding teriparatide results in a greater bone mineral density response, and appears to be at least as safe as switching to teriparatide.
Humanity Adrift: Race, Materiality, and Allegory in Alfonso Cuarón's Children of Men
Authors: Chaudhary Zahid R.
Published: July 2009

This article aims for an account of materiality that helps apprehend race as a material reality while attending to its semiotic, aesthetic, and cultural signification. Through a close reading of Alfonso Cuarón's film, Children of Men (UK, 2006), the author argues that allegory is a figure for recasting the problematic of racial alterity as a materialist concern. Relying on Walter Benjamin's formulations on allegory as a privileged mode of representation under conditions of modernity, the author argues that alterity straddles the boundary between the corporeal and the ideational. Cuarón's film deploys certain cinematic strategies to represent difference: from disjunctures between sound and image and a cinematic obsession with lingering on “incidental” details that lends them allegorical significance to an extended chase sequence. The place of race and biopolitics in this film cannot be understood without examining how allegory produces meaning, and what saves allegory from a nihilistic surplus of meaning in the film is the figure of alterity, which in this film has become an allegorical emblem. The cinematic logic of this film, which stages racial and biopolitical issues as ones about visibility, suggests that alterity itself is what grounds the circulation of all the other signs. Allegory's claims are transhistorical, and when alterity is caught in its system of signs, it marks the transience of our own historical embeddedness, a double recognition that categories of difference regulating human organization and politics are as temporary and as transient as all historical artifacts. Alterity-as-biopolitics is also, however, a kind of traumatic sign that persists across history, and its meaning is often concealed. The article concludes with speculation about cinema's unique means of producing the truth about race.
Paranoid Empire: Specters from Guantánamo and Abu Ghraib
Authors: McClintock Anne
Published: July 2009

The question is still open: what is the purpose of Guantanamo Bay? Why torture people whom the government and the interrogators know are innocent? What kind of U.S. empire now extends its filaments throughout the global gulag of interrogation prisons, torture-ships and internment camps? The U.S. state, I argue, has entered the domain of paranoia, for it is only in paranoia that one finds simultaneously both deliriums of omnipotence and forebodings of perpetual threat. I trace the flashpoints of paranoid violence into the labyrinths of torture to explore three crises: the crisis of violence and the visible; the crisis of imperial legitimacy; and what I call `the enemy deficit. What is the relation between photography and forgetting? What accounts for the persistent presence of photography in the scene of torture? I critique the `pornography-made-them do-it” narrative and explore the torture photographs not for what they reveal, but for what they conceal and what they allow us to forget about the now established but concealed circuits of global imperial violence.
Locating the Transnational in Postwar African American History
Authors: Gaines Kevin
Published: July 2009

A discussion of Left of Karl Marx: The Political Life of Black Communist Claudia Jones.
Integrins mediate their unconventional, mechanical-stress-induced secretion via RhoA and PINCH inDrosophila
Authors: Schotman Hans , Karhinen Leena , Rabouille Catherine
Published: July 2009

During the epithelium remodelling such as the flattening of the Drosophila follicular epithelium, the α-integrin subunits are unconventionally secreted through a dGRASP-dependent route that is built de novo. The biogenetic process starts with the upregulation of a small subset of targeted mRNAs, including dgrasp. Here, we show that dgrasp mRNA upregulation is triggered by the tension of the underlying oocyte and by applied external forces at the basal side of the follicular epithelium. We show that integrins are also involved in dgrasp mRNA upregulation and the epithelium remodelling. Tension leads to the recruitment of RhoA to the plasma membrane, where it participates in its remodelling. The LIM protein PINCH can cycle to the nucleus and is involved in dgrasp mRNA upregulation. We propose that integrins are involved in triggering the biogenesis of their own unconventional secretion route that they use to strengthen adhesion and ensure epithelial integrity at the next stages of development, perhaps by acting as mechanosensors of the underlying tension through RhoA and PINCH.
Dynamic localization of G proteins in Dictyostelium discoideum
Authors: Elzie Carrie A. , Colby Jennifer , Sammons Morgan A. , Janetopoulos Chris
Published: July 2009

Extracellular stimuli exert their effects on eukaryotic cells via serpentine G-protein-coupled receptors and mediate a vast number of physiological responses. Activated receptors stimulate heterotrimeric G-proteins, consisting of three subunits, α, β and γ. In Dictyostelium discoideum, cAMP binds to the cAMP receptor cAR1, which is coupled to the heterotrimer containing the Gα2 subunit. These studies provide in vivo evidence as to how receptors influence the localization of the G-protein complex prior to and after ligand binding. Previous work has shown that the state of the heterotrimer could be monitored by changes in fluorescence (or Förster) resonance energy transfer (FRET) between the α2- and β-subunits of D. discoideum. We now report the kinetics of G-protein activation as a loss of FRET prior to and after cAMP addition by using total internal reflection fluorescence microscopy (TIRFM). We also performed photobleaching experiments to measure G-protein recovery times. Our data show that inactive and active G-proteins cycle between the cytosol and plasma membrane. These data suggest that cAR1 activation slows the membrane dissociation (`off') rate of the α2 subunit, while simultaneously promoting βγ-subunit dissociation.
4,5-Bis(diarylmethylene)-1,3-dithiole: A Novel Helical Electron Donor Exhibiting Electrochromic Behavior
Authors: Suzuki Takanori , Mikuni Shintaro , Ishigaki Yusuke , Higuchi Hiroki , Kawai Hidetoshi , Fujiwara Kenshu
Published: July 2009

Vivid color change from intense yellow to deep purple was observed upon electrochemcal oxidation of the title donor 1 to bis(Michler’s hydrol blue)-type dication 12+. Since the interconversion was also accompanied by drastic geometric changes, configurational stability of the helical π-arrangement is modified upon redox reactions.