bluuebunny/crossref_metadata_2025 huggingface dataset:
Acquired Resistance of Non–Small Cell Lung Cancer Cells to MET Kinase Inhibition Is Mediated by a Switch to Epidermal Growth Factor Receptor Dependency
Authors: McDermott Ultan , Pusapati Raju V. , Christensen James G. , Gray Nathanael S. , Settleman Jeff
Published: February 2010

Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non–small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones. Cancer Res; 70(4); 1625–34
Hormonal Regulation and Distinct Functions of Semaphorin-3B and Semaphorin-3F in Ovarian Cancer
Authors: Joseph Doina , Ho Shuk-Mei , Syed Viqar
Published: February 2010

Semaphorins comprise a family of molecules that influence neuronal growth and guidance. Class-3 semaphorins, semaphorin-3B (SEMA3B) and semaphorin-3F (SEMA3F), illustrate their effects by forming a complex with neuropilins (NP-1 or NP-2) and plexins. We examined the status and regulation of semaphorins and their receptors in human ovarian cancer cells. A significantly reduced expression of SEMA3B (83 kDa), SEMA3F (90 kDa), and plexin-A3 was observed in ovarian cancer cell lines when compared with normal human ovarian surface epithelial cells. The expression of NP-1, NP-2, and plexin-A1 was not altered in human ovarian surface epithelial and ovarian cancer cells. The decreased expression of SEMA3B, SEMA3F, and plexin-A3 was confirmed in stage 3 ovarian tumors. The treatment of ovarian cancer cells with luteinizing hormone, follicle-stimulating hormone, and estrogen induced a significant upregulation of SEMA3B, whereas SEMA3F was upregulated only by estrogen. Cotreatment of cell lines with a hormone and its specific antagonist blocked the effect of the hormone. Ectopic expression of SEMA3B or SEMA3F reduced soft-agar colony formation, adhesion, and cell invasion of ovarian cancer cell cultures. Forced expression of SEMA3B, but not SEMA3F, inhibited viability of ovarian cancer cells. Overexpression of SEMA3B and SEMA3F reduced focal adhesion kinase phosphorylation and matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in ovarian cancer cells. Forced expression of SEMA3F, but not SEMA3B in ovarian cancer cells, significantly inhibited endothelial cell tube formation. Collectively, our results suggest that the loss of SEMA3 expression could be a hallmark of cancer progression. Furthermore, gonadotropin- and/or estrogen-mediated maintenance of SEMA3 expression could control ovarian cancer angiogenesis and metastasis. Mol Cancer Ther; 9(2); 499–509
Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set
Authors: Park Eun Sung , Rabinovsky Rosalia , Carey Mark , Hennessy Bryan T. , Agarwal Roshan , Liu Wenbin , Ju Zhenlin , Deng Wanleng , Lu Yiling , Woo Hyun Goo , Kim Sang-Bae , Cheong Jae-Ho , Garraway Levi A. , Weinstein John N. , Mills Gordon B. , Lee Ju-Seog , Davies Michael A.
Published: February 2010

Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257–67
Aurora Kinase Inhibitors - Rising Stars in Cancer Therapeutics?
Authors: Dar Altaf A. , Goff Laura W. , Majid Shahana , Berlin Jordan , El-Rifai Wael
Published: February 2010

Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy. Mol Cancer Ther; 9(2); 268–78
Resistance to ErbB2 Tyrosine Kinase Inhibitors in Breast Cancer Is Mediated by Calcium-Dependent Activation of RelA
Authors: Xia Wenle , Bacus Sarah , Husain Intisar , Liu Leihua , Zhao Sumin , Liu Zuguo , Moseley M. Arthur , Thompson J. Will , Chen Franklin L. , Koch Kevin M. , Spector Neil L.
Published: February 2010

The widespread clinical use of therapies targeting the ErbB2 receptor tyrosine kinase oncogene represents a significant advance in breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that lapatinib (GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2+ breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2+ breast cancer cell lines, which was mediated by the calcium-dependent activation of RelA, the prosurvival subunit of NF-κB. Abrogation of lapatinib-induced RelA activation using either small interfering RNA constructs or an intracellular calcium chelator enhanced the apoptotic effects of lapatinib in parental ErbB2+ breast cancer cells and overcame therapeutic resistance to lapatinib in ErbB2+ breast cancer lines that had been rendered resistant to lapatinib through chronic exposure to the drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2+ breast cancers treated with lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by lapatinib in ErbB2+ breast cancers, and showing its role in the development of therapeutic resistance to lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to lapatinib in some women with ErbB2+ breast cancers. Mol Cancer Ther; 9(2); 292–9
ASCL1 Regulates the Expression of the CHRNA5/A3/B4 Lung Cancer Susceptibility Locus
Authors: Improgo Ma. Reina D. , Schlichting Nicolette A. , Cortes Roxana Y. , Zhao-Shea Rubing , Tapper Andrew R. , Gardner Paul D.
Published: February 2010

Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the α3 and β4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis. Mol Cancer Res; 8(2); 194–203
Tryptophan Hydroxylase as Novel Target for the Treatment of Depressive Disorders
Authors: Matthes Susann , Mosienko Valentina , Bashammakh Saleh , Alenina Natalia , Bader Michael
Published: February 2010

Serotonin (5-HT) is a monoamine implicated in a variety of physiological processes that functions either as a neurotransmitter or as a peripheral hormone. Pharmacological and genetic studies in humans and experimental animals have shown that 5-HT is important for the pathophysiology of depressive disorders. The 5-HT system is thus already a main target for the therapy of these diseases. The peripheral and cerebral biosynthesis of 5-HT is initiated by two distinct tryptophan hydroxylases: TPH1 and TPH2. This duality of the serotonergic system and the existence of a brain-specific TPH isoform provide a promising new target for pharmacological intervention with higher selectivity and specificity and, therefore, possibly with reduced side effects and increased efficiency. This paper summarizes the data which support TPH2 as novel drug target and discusses strategies for its pharmacological exploitation.
Applications of Nanobiotechnology in Ophthalmology – Part I
Authors: Nguyen Pho , Meyyappan M. , Yiu Samuel C.
Published: February 2010

Much progress has been achieved in the field of nanotechnology and its applications in ophthalmology. It is evident that drug delivery, gene therapy, implantable devices and regenerative medicine are some of the key areas of active research. To the best of our knowledge, there is limited review work on this subject area in the current literature. To assist the interested clinicians and scientists, this bipartite commentary will focus the discussion on emerging researches in nano-ophthalmology and other enabling technologies that soon may be available in the clinician’s armamentarium to maintain and restore eye sight. This installment will focus on recent discoveries in drug delivery, gene therapy, imaging and visual prostheses; the second installment will discuss the impact of nanotechnology on artificial environment, cell-nanostructure interaction, other enabling nano-ophthalmic technologies, and safety and biocompatibility of nanostructures. We will take this opportunity to introduce some exciting nano-ophthalmic applications under investigation in our laboratory. The accomplishments by the scientific community are tremendous and the future prospects are wide open.
Electrophysiological Retinal Pigment Epithelium Changes Observed with Indocyanine Green, Trypan Blue and Triamcinolone
Authors: Arndt Carl , Meunier Isabelle , Rebollo Olivier , Martinenq Catherine , Hamel Christian , Hattenbach Lars-Olof
Published: February 2010

Background: Intravitreal application of indocyanine green (ICG), trypan blue (TB) or triamcinolone (TA) during vitreoretinal surgery has been associated with severe damage to the retinal pigment epithelium (RPE). However, the physiological background of these findings remains to be assessed. Methods: In bovine RPE choroid preparations maintained in Ussing chambers, the effect of apical application of ICG, TA (filtered and not filtered) and TB at different concentrations was evaluated. The electrophysiological parameters (transepithelial potential, tissular resistance and short-circuit current) were continuously monitored. The experiments were conducted either in daylight or in dark-adapted conditions. Results: After apical application of ICG and TA (purified and not purified), all bioelectrical parameters were affected in a dose-dependent manner. No significant changes were observed when the preparations were exposed to daylight. No changes were observed with TB. Conclusions: The electrophysiological results of apical application may explain the toxic effects observed after intraoperative use of ICG and TA. In this RPE study, TB appears to be the safest visualization aid for vitreoretinal surgery.
Non-Injection Drug Use Patterns and History of Injection among Street Youth
Authors: Hadland Scott E. , Kerr Thomas , Marshall Brandon D.L. , Small William , Lai Calvin , Montaner Julio S. , Wood Evan
Published: February 2010

Aims: Efforts to prevent youth from initiating injection drug use require an understanding of the drug use patterns that predispose to injecting. Here we identify such patterns and describe the circumstances of first injection among street youth. Methods: From October 2005 to November 2007, data were collected for the At Risk Youth Study, a prospective cohort of 560 street-recruited youth aged 14–26 in Vancouver, Canada. Non-injection drug use behaviors were compared between those with and without a history of injection through multiple logistic regression. The circumstances of first injection were also examined in gender-stratified analyses. Results: Youth who had previously injected were more likely to have engaged in non-injection use of heroin or of crystal methamphetamine. Daily users of marijuana were less likely to have injected. Among prior injectors, the median age of first injection was lower among females. Females were also more likely to have had a sexual partner present at first injection and to have become a regular injector within one week of initiation. Conclusion: Preventing transition to injection among street youth may require special attention to predisposing drug use patterns and should acknowledge gender differences in the circumstances of first injection.
Differences between Newborn and Adult Mice in Their Response to Immune Thrombocytopenia
Authors: Hu Zhongbo , Slayton William B. , Rimsza Lisa M. , Bailey Matthew , Sallmon Hannes , Sola-Visner Martha C.
Published: February 2010

Background: Sick neonates frequently develop severe thrombocytopenia. Objective and Methods: In order to test the ability of fetal mice to increase their megakaryocyte size and ploidy in response to thrombocytopenia, we injected an antiplatelet antibody (MWReg30) into pregnant mice daily for 7 days, and into nonpregnant adult mice to serve as controls. After that time, platelet counts were obtained and megakaryocytes in the bone marrow, liver, and spleen were stained with anti-von Willebrand factor antibody, individually measured, and quantified. Results: Our study demonstrated that megakaryocytopoiesis in newborn mice shares many features of human fetal/neonatal megakaryocytopoiesis, including the small size of megakaryocytes. In response to thrombocytopenia, adult mice increased megakaryocyte volume and concentration, primarily in the spleen. Newborn mice, in contrast, increased the megakaryocyte concentration in the spleen, but exhibited no increase in megakaryocyte volume in any of the organs studied. In fact, the megakaryocyte mass was significantly lower in the bone marrow of thrombocytopenic neonates than in age-matched controls. Conclusions: We concluded that fetuses have a limited ability to increase their megakaryocyte mass in response to consumptive thrombocytopenia, compared to adult mice. These observations provide further evidence for the existence of biological differences between fetal/neonatal and adult megakaryocytopoiesis.
Effect of Chordin-Like 1 on MC3T3-E1 and Human Mesenchymal Stem Cells
Authors: Fernandes Hugo , Dechering Koen , van Someren Eugene , Steeghs Ilse , Apotheker Marion , Mentink Anouk , van Blitterswijk Clemens , de Boer Jan
Published: February 2010

Since the discovery that bone morphogenetic proteins (BMPs) are able to induce ectopic bone formation, considerable effort has been devoted to apply it for bone regeneration. BMP activity needs to be temporally and spatially controlled and the organism has devised ways to achieve it. Here we show that the BMP inhibitor chordin-like 1 can interfere with BMP2 signalling thereby affecting the osteogenic differentiation of MC3T3-E1 cells. Besides its function as a BMP antagonist, chordin-like 1 enhanced the proliferation of human mesenchymal stem cells (hMSCs) in a BMP2-independent manner. When MC3T3-E1 cells were exposed to recombinant chordin-like 1 there was an inhibition of alkaline phosphatase (ALP) expression, whereas in the case of hMSCs no effect was observed. However, chordin-like 1 dose-dependently increased the proliferation of hMSCs. This effect is probably BMP2 independent because the chordin-like 1 concentration that stimulates proliferation does not interfere with BMP signalling monitored by a Smad-dependent reporter gene. Our data point towards a novel, BMP-independent role of chordin-like 1 in hMSC proliferation.
Common Variants in
HSPB7
and
FRMD4B
Associated With Advanced Heart Failure
Authors: Cappola Thomas P. , Li Mingyao , He Jing , Ky Bonnie , Gilmore Joan , Qu Liming , Keating Brendan , Reilly Muredach , Kim Cecelia E. , Glessner Joseph , Frackelton Edward , Hakonarson Hakon , Syed Faisel , Hindes Anna , Matkovich Scot J. , Cresci Sharon , Dorn Gerald W.
Published: February 2010

Background—

Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk.

Methods and Results—

We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in ≈2000 genes of predicted importance to cardiovascular biology. Our design was a 2-stage case-control study. In stage 1, genotypes in Caucasian patients with heart failure (n=1590; ejection fraction, 32�16%) were compared with those in unaffected controls (n=577; ejection fraction, 67�8%) who were recruited from the same referral centers. Associations were tested for independent replication in stage 2 (308 cases and 2314 controls). Two intronic single-nucleotide polymorphisms showed replicated associations with all-cause heart failure as follows: rs1739843 in
HSPB7
(combined
P
=3.09�10
−6
) and rs6787362 in
FRMD4B
(
P
=6.09�10
−6
). For both single-nucleotide polymorphisms, the minor allele was protective. In subgroup analyses, rs1739843 associated with both ischemic and nonischemic heart failure, whereas rs6787362 associated principally with ischemic heart failure. Linkage disequilibrium surrounding rs1739843 suggested that the causal variant resides in a region containing
HSPB7
and a neighboring gene,
CLCNKA
, whereas the causal variant near rs6787362 is probably within
FRMD4B
. Allele frequencies for these single-nucleotide polymorphisms were substantially different in African Americans (635 cases and 714 controls) and showed no association with heart failure in this population.

Conclusions—

Our findings identify regions containing
HSPB7
and
FRMD4B
as novel susceptibility loci for advanced heart failure. More broadly, in an era of genome-wide association studies, we demonstrate how knowledge of candidate genes can be leveraged as a complementary strategy to discern the genetics of complex disorders.
Heart Failure–Associated Changes in RNA Splicing of Sarcomere Genes
Authors: Kong Sek Won , Hu Yong Wu , Ho Joshua W.K. , Ikeda Sadakatsu , Polster Sean , John Ranjit , Hall Jennifer L. , Bisping Egbert , Pieske Burkert , dos Remedios Cristobal G. , Pu William T.
Published: February 2010

Background—

Alternative mRNA splicing is an important mechanism for regulation of gene expression. Altered mRNA splicing occurs in association with several types of cancer, and a small number of disease-associated changes in splicing have been reported in heart disease. However, genome-wide approaches have not been used to study splicing changes in heart disease. We hypothesized that mRNA splicing is different in diseased hearts compared with control hearts.

Methods and Results—

We used the Affymetrix Exon array to globally evaluate mRNA splicing in left ventricular myocardial RNA from controls (n=15) and patients with ischemic cardiomyopathy (n=15). We observed a broad and significant decrease in mRNA splicing efficiency in heart failure, which affected some introns to a greater extent than others. The profile of mRNA splicing separately clustered ischemic cardiomyopathy and control samples, suggesting distinct changes in mRNA splicing between groups. Reverse transcription–polymerase chain reaction validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that splicing of 4 key sarcomere genes,
cardiac troponin T
(
TNNT2
),
cardiac troponin I
(
TNNI3
),
myosin heavy chain 7
(
MYH7
), and
filamin C, gamma
(
FLNC
), was significantly altered in ischemic cardiomyopathy and in dilated cardiomyopathy and aortic stenosis. In aortic stenosis samples, these differences preceded the onset of heart failure. Remarkably, the ratio of minor to major splice variants of
TNNT2
,
MYH7
, and
FLNC
classified independent test samples as control or disease with >98% accuracy.

Conclusions—

Our data indicate that mRNA splicing is broadly altered in human heart disease and that patterns of aberrant RNA splicing accurately assign samples to control or disease classes.
Chylomicronemia With Low Postheparin Lipoprotein Lipase Levels in the Setting of GPIHBP1 Defects
Authors: Franssen Remco , Young Stephen G. , Peelman Frank , Hertecant Jozef , Sierts Jeroen A. , Schimmel Alinda W.M. , Bensadoun André , Kastelein John J.P. , Fong Loren G. , Dallinga-Thie Geesje M. , Beigneux Anne P.
Published: February 2010

Background—

Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins.

Methods and Results—

We report the discovery of a homozygous missense mutation in
GPIHBP1
in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL.

Conclusions—

We identified a novel
GPIHBP1
missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans.
Role of Orally Available Antagonists of Factor Xa in the Treatment and Prevention of Thromboembolic Disease: Focus on Rivaroxaban
Authors: Morell Jason , Sullivan Bridgette , Khalabuda Marina , McBride Brian F.
Published: February 2010

Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half‐life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.
Latino Migrations to the U.S. Heartland
Authors: Allegro Linda
Published: February 2010

Reexamination of the notion of “illegality” reveals the important role of state in crafting an “illegal” class and opens the way for a structural interpretation of recent Latin American migratory flows to the United States heartland. A case study of the effects of anti-immigrant legislation passed in Oklahoma in 2007 reveals that “getting tough on illegals” can have unintended consequences, causing both illegal and legal migrants to leave the state and diverting attention from issues of wages, organizing rights, and health and safety standards that affect all workers, Latino and other. Extending labor protections to all workers could reduce the incentive to prefer undocumented migrants over U.S. workers.
Where Is Latin America Going? FTAA or “Twenty-first-Century Socialism”?
Authors: Grinberg Nicolas
Published: February 2010

The current political and economic situation in Latin America is characterized by a marked difference between South American countries, on one side, and Mexico, Central America, and the Caribbean, on the other. While the former have seen the resuscitation of pseudo-import-substitution-industrialization policies by neopopulist governments, the latter are increasingly attached to the neoliberal project. This difference was apparent at the Fourth Summit of the Americas in 2005 with regard to the declaration of support for the Free Trade Area of the Americas pushed forward by Mexico. It is an expression of the distinct forms of integration of the two regions into the new international division of labor and therefore of the different specific forms of development of their national processes of capital accumulation. In South America, capital still accumulates through the appropriation/recovery of a portion of its abundant ground rent. In Mexico and most of the Caribbean Basin, capital accumulates through the production, exploiting a relatively cheap and disciplined labor force, of industrial goods for the world market.
The Emergence and Entrenchment of a New Political Regime in Mexico
Authors: Rodríguez Araujo Octavio
Published: February 2010

Mexico in the eighties was torn between two political systems: one statist, populist, and authoritarian and the other neoliberal, technocratic, and no less authoritarian. Large and powerful business groups, both Mexican and foreign, that had adopted neoliberal dogma managed to impose the latter through the fraudulent election of Carlos Salinas de Gortari as President of the Republic in 1988. The technocracy, first under the Partido Revolucionario Institucional (Institutional Revolutionary Party— PRI) and then under the Partido Acción Nacional (National Action Party—PAN), became entrenched in power and did not hesitate to conduct a preemptive coup to prevent Andrés Manuel López Obrador of the Partido de la Revolución Democrática (Democratic Revolution Party—PRD) from winning the presidency in 2006. The reason is not hard to understand: López Obrador represented something that the ruling class was unable and unwilling to concede: the need to dismantle the new regime and return to greater state intervention and the safeguarding of national sovereignty, especially with regard to natural resources. The dilemma of two overlapping political regimes was resolved, by trickery and fraud, in favor of neoliberal technocracy in 2000, with the victory of the right-wing PAN. The problem is that the center-left party, with Cuauhtémoc Cárdenas and López Obrador, does not seem up to the historic challenge that it confronts.
Organizational Theory Development: Displacement of Ends?
Authors: McKinley William
Published: February 2010

In this essay I argue that organization theory has witnessed a significant displacement of ends over the last 30 years. Whereas in the 1960s and 1970s the dominant goal of the discipline was achieving consensus on the validity status of theories, today the overriding goal appears to be development of new theory. Formerly new theory development was considered a means to the end of attaining consensus on theory validity, but was not the only activity deemed necessary to accomplish that goal. In addition, instrumental standardization and replication were viewed as important. The contemporary displacement of ends toward new theory development creates the paradox that organization theory today is both epistemologically simpler (in terms of the intellectual activity deemed desirable) and more complex theoretically than it was 30 years ago. I discuss the advantages and disadvantages of the displacement of ends toward new theory development in organization theory, and offer some possible remedies that are designed to reallocate priorities and resources toward the instrumentation, theory testing, and replication components of the research process. I also propose an agenda of future research in the history and sociology of organization science that would study the displacement of ends hypothesized here, with a view to improving our understanding of how organization theory has evolved and how its knowledge could be made more useful to managers.
Initial Insights Regarding the Role of p53 in Maintaining Sperm DNA Integrity Following Treatment of Mice with Ethylnitrosourea or Cyclophosphamide
Authors: Sue Marty M. , Singh Narendra P. , Stebbins Kenneth E. , Ann Linscombe V. , Passage Julie , Bhaskar Gollapudi B.
Published: February 2010

If p53 is essential to eliminate damaged spermatogenic cells, then mutagen exposure in the absence of p53 would increase sperm containing damaged DNA. p53 knockout (−/−, NULL) and wild-type (+/+, WT) mice (five/group) were exposed to ethylnitrosourea (ENU) or cyclophosphamide (CP). In phase I, mice were exposed by gavage to 0 or 60 mg/kg/day ENU or CP for four days and examined on test day (TD) 4, and in phase II, mice were exposed to 0, 6, 20, or 60 mg/kg/day ENU or CP for four days and evaluated on TD 36 when exposed spermatocytes matured. In phase I, mutagens were not directly cytotoxic to mature sperm. In phase II, WT mice were more sensitive to decreases in reproductive organ weights, whereas both genotypes had decreased sperm counts. Testicular histology revealed similar CP responses, but genotype-specific ENU responses (WT mice had depletion of elongating spermatids; NULL mice had late-stage spermatocyte/early stage spermatid loss). Ethylnitrosourea increased DNA strand breaks in WT mice. Thus, mice responded similarly to CP, suggesting a primarily p53-independent response, whereas the ENU response differed by zygosity, suggesting a role for p53. As DNA damage increased at higher ENU doses, compensatory repair pathways may operate in NULL mice.
Age-Related Lesions in the Cerebrum in Middle-Aged Female Cynomolgus Monkeys
Authors: Kodama Rinya , Yang Xiuying , Saski Yuji , Iwashige Shuichiro , Tanigawa Yohei , Yoshikawa Tsuyoshi , Nagaoka Takaharu , Kamimura Yasuhiro , Maeda Hiroshi
Published: February 2010

Alzheimer’s disease (AD) in humans is a progressive neurogenic disease that can be linked with such characteristic pathological findings in the cerebrum as senile plaques (SPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA), and neuronal loss. In the present study, the authors investigated the age-related morphological changes in 12 middle-aged and 12 young cynomolgus monkeys. Low numbers of neurons and astrocytes in the hippocampal region in cynomolgus monkeys accompanied ageing, and there was a high number of microglial cells; however, no clearly neurotoxic abnormalities due to β-amyloid were noted before the age of 20 years. The onset of SPs and CAA in the cerebrum in cynomolgus monkeys can occur before the age of 20 years. SPs were almost all categorized as diffuse plaques (DPs); they did not have amyloid cores and were unaccompanied by neuritic degeneration. In cynomolgus monkeys, SPs (DPs) occur before the appearance of CAA. From the above, it was concluded that cynomolgus monkeys showed pathological changes due to ageing similar to those related to Alzheimer’s disease in humans, even before they were 20 years old.
Spontaneous Poorly Differentiated Carcinoma with Cells Positive for Vimentin in a Salivary Gland of a Young Rat
Authors: Nishikawa Satomi , Sano Fumiko , Takagi Kan , Okada Miyoko , Sugimoto Jiro , Takagi Shiro
Published: February 2010

Spontaneous salivary gland tumors in rats are rare. The authors report a poorly differentiated carcinoma of a submandibular gland in a ten-week-old rat that was positive for vimentin. Microscopically, the neoplastic cells showed a diffuse growth pattern in most areas of the tumor mass and a nestlike structure in a part of the peripheral area. Immunohistochemically, the cells were positive for keratin and vimentin but not for α-smooth muscle actin. Ultrastructurally, desmosome-like structures were observed. Based on these findings, the tumor was diagnosed as a poorly differentiated carcinoma. The origin of the neoplastic cells would be either acinar or ductal cells. This suggests that acinar or ductal cells have the potential to transform into vimentin-expressing cells.
Revisiting Alternative Approaches to the Assessment of Carcinogenic Risk
Authors: Downes Noel
Published: February 2010

The rodent bioassay has been a mainstay of carcinogenic risk assessment for close to half a century; not that it has been without criticism in that time. As early as the 1990s, there were clearly established shortcomings with regard to relevance and extrapolation, but despite these concerns, this test continues relatively unchanged. As our understanding of the mechanisms of carcinogenesis and the availability of investigative techniques improve, there seems less reason than ever to persist with this exercise that provides little meaningful scientific data at great cost in terms of animal usage and pathologist time. This article highlights possible ways to gather and present data pertinent to carcinogenesis in man and suggests that it is the toxicological pathology community that should take the lead here in persuading regulators that there is great room for improvement in this particular aspect of regulatory pathology.
Stack emissions tests in a brick manufacturing Hoffmann kiln: firing of municipal solid waste
Authors: García Ubaque C.A. , Gonzales Hässig A. , Acosta Mendoza C.
Published: February 2010

This article reviews the results obtained from stack emissions analysis during the co-firing process of municipal solid waste (MSW) from the municipality of Tabio, Colombia, in a Hoffmann-type brick kiln. MSW (2 tonne) was incinerated and about 18.5 tonnes of clay were processed into brick using one and four kiln chambers, respectively. During the process, the following emissions were investigated: particulate emissions, emissions of SO2, SO3, NO X, metals (Sb, As, Cd, Co, Sn, Cr, Cu, Mn, Ni, Hg), hydrofluoric and hydrochloric acid, hydrocarbons (such as methane) and emission of polychlorinated dioxins and furans. Also, CO emissions were monitored during each test to evaluate the influence of MSW co-firing on that parameter. The observed emissions concentrations proved to be below the threshold values issued by MAVDT, the environmental authority in Colombia, indicating that the emissions were under control during the proposed process. In addition, statistical analysis showed that the emissions were 10—40% below the regulation limit with a confidence of 95%.
Effective utilization of incinerated municipal solid waste incineration ash: zeolitic material synthesis and silica extraction
Authors: Bui Hoang Bac  , Yungoo Song  , Yonghee Moon  , Myung Hun Kim  , Il Mo Kang
Published: February 2010

In this study the effective utilization of two types of municipal solid waste incinerator (MSWI) ashes, namely air-cooled ash (ACS) and water-cooled ash (WCS) samples obtained from a municipal solid waste incineration plant, was examined by applying zeolitic material synthesis and silica extraction. The influence of the experimental conditions including the ratio of sample : NaOH solution, the reaction temperature and time, and the concentration of NaOH solution were investigated. The results for the 25 experimental trials can be summarized as: (1) the formation of tobermorite and/or pectolite-1A as a major component in most conditions; (2) the synthesis of hydroxycancrinite as a major phase at 200 °C; (3) a dramatic increase in the extracted SiO2 yield at 1 : 30 value of sample : NaOH ratio and 200 °C, even at short reaction times; and (4) relatively high SiO2 yields for WCS ashes rather than ACS ashes. An increase in the reaction time improved the quantity of synthesized zeolitic materials. The reaction temperature determined the type of zeolite. An increase in the NaOH concentration can be an essential factor to improve zeolitic material synthesis, but it significantly reduced the yield of SiO2 extraction. In conclusion, suitable conditions for obtaining both SiO2 extraction and synthesized zeolites from the ashes of the incinerated solid waste materials should be: 200 °C reaction temperature; a 1 : 30 (g : mL) value for the sample : NaOH ratio; 2 mol L—1 NaOH concentration; and a reaction time of more than 24 h.
Understanding the Role of Nutrition and Wound Healing
Authors: Stechmiller Joyce K.
Published: February 2010

Optimal wound healing requires adequate nutrition. Nutrition deficiencies impede the normal processes that allow progression through stages of wound healing. Malnutrition has also been related to decreased wound tensile strength and increased infection rates. Malnourished patients can develop pressure ulcers, infections, and delayed wound healing that result in chronic nonhealing wounds. Chronic wounds are a significant cause of morbidity and mortality for many patients and therefore constitute a serious clinical concern. Because most patients with chronic skin ulcers suffer micronutrient status alterations and malnutrition to some degree, current nutrition therapies are aimed at correcting nutrition deficiencies responsible for delayed wound healing. This review provides current information on nutrition management for simple acute wounds and complex nonhealing wounds and offers some insights into innovative future treatments.
An analysis of knowledge management mechanisms in healthcare portals
Authors: Chei Sian Lee  , Goh Dion Hoe-Lian , Chua Alton Y.K.
Published: February 2010

Healthcare portals are becoming increasingly popular with Internet users since they play an important role in supporting interaction between individuals and healthcare organizations with a Web presence. Additionally, many of these organizations make use of knowledge management mechanisms on their healthcare portals to manage the abundance of health-related information, and exchange and share information with their users. Hence, the objective of this study is to evaluate the extent to which knowledge management mechanisms can be supported by healthcare portals. This paper presents a comprehensive analysis of knowledge management mechanisms used by 60 healthcare portals to access, create and transfer knowledge. We selected healthcare portals from two geographical regions (i.e. North America and Asia) and three healthcare portal provider categories (i.e. hospital, government, non-government). We found that healthcare portals from different geographical regions and portal provider categories differed significantly on how they used their portals to access, create and transfer knowledge. The results of this study can be used by healthcare portal providers to enhance their knowledge management practices and improve their customer service relationships.
Development and Security: Origins and Future
Authors: Hettne Björn
Published: February 2010

The problems of development and security have historically formed distinct discourses. More recently, they have been inextricably linked both in discourse and in much policy, thus creating the so-called development—security nexus that pervades much of today’s international development assistance. The empirical basis for attention to this nexus has been quite obvious given the many humanitarian emergencies occurring in the 1990s. It is less clear what, in terms of linkages, went before and what will come after. This article discusses the putative nexus in different historical geopolitical contexts, probing into its origins and speculating about the shape it may take in the future. It consists of three parts. The first deals with conceptual issues and the overall theoretical framework. The second describes four historical discourses, consecutively prevalent from about 1750 to 1980. The third concerns the current discourse on globalization and its possible future shape: global development.
Developing reading fluency and comprehension using repeated reading: Evidence from longitudinal student reports
Authors: Gorsuch Greta , Taguchi Etsuo
Published: February 2010

In recent years, interest in reading fluency development in first language, and second and foreign language (L2/FL) settings has increased. Reading fluency, in which readers decode and comprehend at the same time, is critical to successful reading. Fluent readers are accurate and fast in their ability to recognize words, and in their use of prosodic and syntactic knowledge to better comprehend text. Reading is a significant and viable means of developing L2/FL ability, particularly in FL settings in which L2 input sources are limited, such as Vietnam or Japan (for English as a foreign language), or the USA (for Japanese or Russian as a foreign language).Yet many L2/FL learners read slowly and laboriously, likely because of poor word recognition skills. Repeated reading (RR) is one method of fluency-building long used in first language (L1) settings and more recently in L2/FL settings, and seems successful in increasing the reading fluency and comprehension of both L1 and L2/FL learners. Nonetheless, it is likely that teachers and learners in L2/FL settings may be unaware of or unconvinced of the role increased reading fluency plays in reading comprehension and, as a result, may not see the utility of devoting class or personal time to repeated reading or, indeed, any reading fluency activity. Because quantitative evidence for positive effects of RR has already been offered (see Taguchi, Sasamoto, & Gorsuch, 2006; Gorsuch & Taguchi, 2008), we offer additional evidence in the form of open-ended, post-reading student reports written over the length of an 11-week RR treatment for 30 young adult EFL learners in Vietnam. Iterative analyses of over 200 pages of student reports provided nuanced evidence of the positive effects RR has on FL learners’ reading fluency and comprehension development, and general language development. Learners’ comments revealed information that suggested a meaningful role for extended experience with RR to increasing use of learner metacognition in reading strategy use, and growing awarenesses on the part of learners of (1) the relationship between fluency and comprehension, (2) the utility of developing fluency as a stand-alone skill, and (3) RR as a causal agent in the development of listening, writing, and speaking skills.
A task-based needs analysis: Putting principles into practice
Authors: Lambert Craig
Published: February 2010

This study triangulates multiple data sources and methods to build a consensus on the English-language tasks faced by graduates in their lives and careers as a practical basis for L2 program development. It addresses a problem similar to what West (1994) refers to as TENOR (Teaching English for No Obvious Reason). TENOR is problematic in that it frequently results in unfocused instruction, lower than normal learner motivation, and graduates who have no clear idea of what they have learned or who do not have the ability to use it for any functional purpose. Employment records, interviews and a sequence of surveys were used to build consensus on the L2 tasks faced by graduates over the 25-year period preceding the study. Results demonstrate that it was possible to identify and build consensus on task types common across workplace domains, and that, given adequate support, graduates could specify target tasks as a basis for organizing focused, goal-oriented instruction in a context where TENOR was the norm. The study is intended to provide a heuristic framework and procedures for future task-based needs analyses.