bluuebunny/crossref_metadata_2025 huggingface dataset:
Stepwise DNA Methylation Changes Are Linked to Escape from Defined Proliferation Barriers and Mammary Epithelial Cell Immortalization
Authors: Novak Petr , Jensen Taylor J. , Garbe James C. , Stampfer Martha R. , Futscher Bernard W.
Published: June 2009

The timing and progression of DNA methylation changes during carcinogenesis are not completely understood. To develop a timeline of aberrant DNA methylation events during malignant transformation, we analyzed genome-wide DNA methylation patterns in an isogenic human mammary epithelial cell (HMEC) culture model of transformation. To acquire immortality and malignancy, the cultured finite lifespan HMEC must overcome two distinct proliferation barriers. The first barrier, stasis, is mediated by the retinoblastoma protein and can be overcome by loss of p16INK4A expression. HMEC that escape stasis and continue to proliferate become genomically unstable before encountering a second more stringent proliferation barrier, telomere dysfunction due to telomere attrition. Rare cells that acquire telomerase expression may escape this barrier, become immortal, and develop further malignant properties. Our analysis of HMEC transitioning from finite lifespan to malignantly transformed showed that aberrant DNA methylation changes occur in a stepwise fashion early in the transformation process. The first aberrant DNA methylation step coincides with overcoming stasis, and results in few to hundreds of changes, depending on how stasis was overcome. A second step coincides with immortalization and results in hundreds of additional DNA methylation changes regardless of the immortalization pathway. A majority of these DNA methylation changes are also found in malignant breast cancer cells. These results show that large-scale epigenetic remodeling occurs in the earliest steps of mammary carcinogenesis, temporally links DNA methylation changes and overcoming cellular proliferation barriers, and provides a bank of potential epigenetic biomarkers that may prove useful in breast cancer risk assessment. [Cancer Res 2009;69(12):5251–8]
Role of Cell Cycle in Epidermal Growth Factor Receptor Inhibitor-Mediated Radiosensitization
Authors: Ahsan Aarif , Hiniker Susan M. , Davis Mary A. , Lawrence Theodore S. , Nyati Mukesh K.
Published: June 2009

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in combination with radiotherapy in the treatment of various EGFR-overexpressing cancers. However, little is known about the effects of cell cycle status on EGFR inhibitor-mediated radiosensitization. Using EGFR-overexpressing A431 and UMSCC-1 cells in culture, we found that radiation activated the EGFR and extracellular signal-regulated kinase pathways in quiescent cells, leading to progression of cells from G1 to S, but this activation and progression did not occur in proliferating cells. Inhibition of this activation blocked S-phase progression and protected quiescent cells from radiation-induced death. To determine if these effects were caused by EGFR expression, we transfected Chinese hamster ovary (CHO) cells, which lack EGFR expression, with EGFR expression vector. EGFR expressed in CHO cells also became activated in quiescent cells but not in proliferating cells after irradiation. Moreover, quiescent cells expressing EGFR underwent increased radiation-induced clonogenic death compared with both proliferating CHO cells expressing EGFR and quiescent wild-type CHO cells. Our data show that radiation-induced enhancement of cell death in quiescent cells involves activation of the EGFR and extracellular signal-regulated kinase pathways. Furthermore, they suggest that EGFR inhibitors may protect quiescent tumor cells, whereas radiosensitization of proliferating cells may be caused by downstream effects such as cell cycle redistribution. These findings emphasize the need for careful scheduling of treatment with the combination of EGFR inhibitors and radiation and suggest that EGFR inhibitors might best be given after radiation in order to optimize clinical outcome. [Cancer Res 2009;69(12):5108–14]
Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma
Authors: Cha Eun Jung , Noh Sang Jae , Kwon Keun Sang , Kim Chan Young , Park Byung-Hyun , Park Ho Sung , Lee Ho , Chung Myoung Ja , Kang Myoung Jae , Lee Dong Geun , Moon Woo Sung , Jang Kyu Yun
Published: June 2009

Purpose: SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients.

Experimental Design: We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray.

Results: Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival.

Conclusion: This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.
GAB2 Amplifications Refine Molecular Classification of Melanoma
Authors: Chernoff Karen A. , Bordone Lindsey , Horst Basil , Simon Katherine , Twadell William , Lee Keagan , Cohen Jason A. , Wang Shuang , Silvers David N. , Brunner Georg , Celebi Julide Tok
Published: June 2009

Purpose: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT.

Experimental Design: A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT.

Results: GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT.

Conclusions: GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.
Activity of panitumumab alone or with chemotherapy in non-small cell lung carcinoma cell lines expressing mutant epidermal growth factor receptor
Authors: Freeman Daniel J. , Bush Tammy , Ogbagabriel Selam , Belmontes Brian , Juan Todd , Plewa Cherylene , Van Gwyneth , Johnson Carol , Radinsky Robert
Published: June 2009

Epidermal growth factor receptor (EGFR) kinase domain mutations cause hyperresponsiveness to ligand and hypersensitivity to small-molecule tyrosine kinase inhibitors. However, little is known about how these mutations respond to antibodies against EGFR. We investigated the activity of panitumumab, a fully human anti-EGFR monoclonal antibody, in vitro in mutant EGFR-expressing non-small cell lung carcinoma (NSCLC) cells and in vivo with chemotherapy in xenograft models. Mutant EGFR-expressing NSCLC cells (NCI-H1975 [L858R+T790M] and NCI-H1650 [Δ746-750]) and CHO cells were treated with panitumumab before EGF stimulation to assess the inhibition of EGFR autophosphorylation. Established tumors were treated with panitumumab (25, 100, or 500 μg/mouse twice a week) alone or with docetaxel (10 or 20 mg/kg once a week) or cisplatin (7.5 mg/kg once a week). Antitumor activity and levels of proliferation markers were analyzed. Treatment of mutant EGFR-expressing CHO and NSCLC cells with panitumumab inhibited ligand-dependent autophosphorylation. In NCI-H1975 and NCI-H1650 xenografts, treatment with panitumumab alone or with cisplatin inhibited tumor growth compared with control (P < 0.0003). With panitumumab plus docetaxel, enhanced antitumor activity was seen in both xenografts versus panitumumab alone. Panitumumab treatment alone decreased Ki-67 and phospho- mitogen-activated protein kinase (pMAPK) staining in both xenografts compared with control. Docetaxel enhanced panitumumab activity in NCI-H1650 xenografts (decreased Ki-67 and pMAPK staining by >60%) when compared with either agent alone. Panitumumab inhibits ligand-induced EGFR phosphorylation, tumor growth, and markers of proliferation alone or with docetaxel in NSCLC cell lines that express clinically observed EGFR kinase domain mutations, including the small-molecule tyrosine kinase inhibitor-resistant T790M mutation. [Mol Cancer Ther 2009;8(6):1536–46]
Orally active α-tocopheryloxyacetic acid suppresses tumor growth and multiplicity of spontaneous murine breast cancer
Authors: Hahn Tobias , Fried Karen , Hurley Laurence H. , Akporiaye Emmanuel T.
Published: June 2009

We recently demonstrated the antitumor efficacy of orally administered α-tocopheryloxyacetic acid (α-TEA), a redox silent and nonhydrolyzable derivative of naturally occurring vitamin E. In order to move α-TEA closer to the clinic to benefit patients with breast cancer, the present study had two goals. First, to determine the minimal effective treatment dose; and second, to test the efficacy of dietary administration of α-TEA in the clinically relevant MMTV-PyMT mouse model of spontaneous breast cancer that more closely resembles human disease. The minimal effective dose of α-TEA was evaluated in the transplantable 4T1 tumor model and we show a dose-dependent decrease of primary tumor growth and reduction of metastatic spread to the lung. Six-week-old MMTV-PyMT mice were treated with oral α-TEA for 9 weeks, with no apparent signs of drug toxicity. The α-TEA treatment delayed tumor development and significantly slowed tumor progression, resulting in a 6-fold reduction of the average cumulative tumor size. In addition, oral α-TEA caused an 80% reduction in spontaneous metastases. In situ analysis of tumor tissue identified apoptosis as an important mechanism of α-TEA–mediated tumor suppression in addition to inhibition of tumor cell proliferation. This study shows, for the first time, the ability of orally administered α-TEA to delay tumor onset and to inhibit the progression and metastatic spread of a clinically relevant model of spontaneous breast cancer. Our finding of the high efficacy in this tumor model highlights the translational potential of oral α-TEA therapy. [Mol Cancer Ther 2009;8(6):1570–78]
Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit
Authors: Bekier Michael E. , Fischbach Robert , Lee Jennifer , Taylor William R.
Published: June 2009

Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosis-inducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death. [Mol Cancer Ther 2009;8(6):1646–54]
Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors
Authors: Baird Richard D. , Kitzen Jos , Clarke Paul A. , Planting Andre , Reade Sarah , Reid Alison , Welsh Lyndsey , López Lázaro Luis , de las Heras Begona , Judson Ian R. , Kaye Stan B. , Eskens Ferry , Workman Paul , deBono Johann S. , Verweij Jaap
Published: June 2009

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m2. Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m2. Two of four patients treated at 256 mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m2 also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m2 died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median Vss at 256 mg/m2 was 2,389 liters; range, 1,615–4,051 liters) and long elimination half life (median t1/2 at 256 mg/m2 was 28 h; range, 21–32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance. [Mol Cancer Ther 2009;8(6):1430–7]
Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells
Authors: Herberger Beata , Berger Walter , Puhalla Harald , Schmid Katharina , Novak Sabine , Brandstetter Anita , Pirker Christine , Gruenberger Thomas , Filipits Martin
Published: June 2009

The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials. [Mol Cancer Ther 2009;8(6):1547–56]
DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation
Authors: Miranda Tina Branscombe , Cortez Connie C. , Yoo Christine B. , Liang Gangning , Abe Masanobu , Kelly Theresa K. , Marquez Victor E. , Jones Peter A.
Published: June 2009

DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their “ground state” after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors. [Mol Cancer Ther 2009;8(6):1579–88]
Blocking Phosphoinositide 3-Kinase Activity in Colorectal Cancer Cells Reduces Proliferation but Does Not Increase Apoptosis Alone or in Combination with Cytotoxic Drugs
Authors: Martin-Fernandez Cristina , Bales Juliana , Hodgkinson Cassandra , Welman Arkadiusz , Welham Melanie J. , Dive Caroline , Morrow Christopher J.
Published: June 2009

In response to growth factors, class IA phosphoinositide 3-kinases (PI3K) phosphorylate phosphatidylinositol-4,5-bisphosphate, converting it to phosphatidylinositol-3,4,5-trisphosphate to activate protein kinase B/Akt. This is widely reported to promote tumorigenesis via increased cell survival, proliferation, migration, and invasion, and many tumor types, including colorectal cancer, exhibit increased PI3K signaling. To investigate the effect of inhibiting PI3K and as an alternative to the use of small molecular inhibitors of PI3K with varying degrees of selectivity, HT29 and HCT116 colorectal cancer cells bearing mutant PIK3CA were generated that could be induced with doxycycline to express synchronously a dominant negative subunit of PI3K, Δp85α. On induction, decreased levels of phosphorylated protein kinase B were detected, confirming PI3K signaling impairment. Induction of Δp85α in vitro reduced cell number via accumulation in G0-G1 phase of the cell cycle in the absence of increased apoptosis. These effects were recapitulated in vivo. HT29 cells expressing Δp85α and grown as tumor xenografts had a significantly slower growth rate on administration of doxycycline with reduced Ki67 staining without increased levels of apoptotic tissue biomarkers. Furthermore, in vitro Δp85α expression did not sensitize HT29 cells to oxaliplatin- or etoposide-induced apoptosis, irrespective of drug treatment schedule. Further analysis comparing isogenic HCT116 cells with and without mutation in PIK3CA showed no effect of the mutation in either proliferative or apoptotic response to PI3K inhibition. These data show in colorectal cancer cells that PI3K inhibition does not provoke apoptosis per se nor enhance oxaliplatin- or etoposide-induced cell death. (Mol Cancer Res 2009;7(6):955–65)
K-Ras Promotes Angiogenesis Mediated by Immortalized Human Pancreatic Epithelial Cells through Mitogen-Activated Protein Kinase Signaling Pathways
Authors: Matsuo Yoichi , Campbell Paul M. , Brekken Rolf A. , Sung Bokyung , Ouellette Michel M. , Fleming Jason B. , Aggarwal Bharat B. , Der Channing J. , Guha Sushovan
Published: June 2009

Activating point mutations in the K-Ras oncogene are among the most common genetic alterations in pancreatic cancer, occurring early in the progression of the disease. However, the function of mutant K-Ras activity in tumor angiogenesis remains poorly understood. Using human pancreatic duct epithelial (HPDE) and K-Ras4BG12V–transformed HPDE (HPDE-KRas) cells, we show that activated K-Ras significantly enhanced the production of angiogenic factors including CXC chemokines and vascular endothelial growth factor (VEGF). Western blot analysis revealed that K-Ras activation promoted the phosphorylation of Raf/mitogen-activated protein kinase kinase-1/2 (MEK1/2) and expression of c-Jun. MEK1/2 inhibitors, U0126 and PD98059, significantly inhibited the secretion of both CXC chemokines and VEGF, whereas the c-Jun NH2-terminal kinase inhibitor SP600125 abrogated only CXC chemokine production. To further elucidate the biological functions of oncogenic K-Ras in promoting angiogenesis, we did in vitro invasion and tube formation assays using human umbilical vein endothelial cells (HUVEC). HUVEC cocultured with HPDE-KRas showed significantly enhanced invasiveness and tube formation as compared with either control (without coculture) or coculture with HPDE. Moreover, SB225002 (a CXCR2 inhibitor) and 2C3 (an anti-VEGF monoclonal antibody) either alone or in a cooperative manner significantly reduced the degree of both Ras-dependent HUVEC invasiveness and tube formation. Similar results were obtained using another pair of immortalized human pancreatic duct–derived cells, E6/E7/st and its oncogenic K-Ras variant, E6/E7/Ras/st. Taken together, our results suggest that angiogenesis is initiated by paracrine epithelial secretion of CXC chemokines and VEGF downstream of activated oncogenic K-Ras, and that this vascular maturation is in part dependent on MEK1/2 and c-Jun signaling. (Mol Cancer Res 2009;7(6):799–808)
Analysis of a Promoter Polymorphism in the SMDF Neuregulin 1 Isoform in Schizophrenia
Authors: Pedrosa Erika , Nolan Karen A. , Stefanescu Radu , Hershcovitz Pnina , Novak Tomas , Zukov Ilja , Stopkova Pavla , Lachman Herbert M.
Published: June 2009

Background/Aims: Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3′ end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. Methods: This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. Results: A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution χ2 = 7.32, p = 0.03) but not in BD (genotype distribution χ2 = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. Conclusion: The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ.
Successful Tracheal Occlusion Using Ultrathin Fetoscopic Equipment Combined with Real-Time Three-Dimensional Ultrasound
Authors: Tchirikov M.
Published: June 2009

Objective: The most common complication of intrauterine tracheal balloon occlusion is the preterm premature rupture of membranes (PPROM) which increases the rate of neonatal morbidity and mortality. Ultrathin fetoscopy may be a method of reducing the risk of PPROM. Materials and Methods: The operation was performed at the 27th week of gestation after sedation and relaxation of a fetus with bilateral congenital diaphragmatic hernia and with the liver lifted upwards into the thorax. An ultrathin sheath with a 1.2-mm fetoscope was used under real-time 3-D ultrasound guidance. The patient delivered in the 38th week of gestation and did not display PPROM after surgery until delivery. Conclusion: Fetal tracheal occlusion using ultrathin fetoscopic equipment in combination with real-time 3-D ultrasound may reduce the risk of PPROM.
Representativeness of a National Heart Failure Quality-of-Care Registry
Authors: Curtis Lesley H. , Greiner Melissa A. , Hammill Bradley G. , DiMartino Lisa D. , Shea Alisa M. , Hernandez Adrian F. , Fonarow Gregg C.
Published: June 2009

Background—

Participation in clinical registries is nonrandom, so participants may differ in important ways from nonparticipants. The extent to which findings from clinical registries can be generalized to broader populations is unclear.

Methods and Results—

We linked data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry with 100% inpatient Medicare fee-for-service claims to identify matched and unmatched patients with heart failure. We evaluated differences in baseline characteristics and mortality, all-cause readmission, and cardiovascular readmission rates. We used Cox proportional hazards models to examine relationships between registry enrollment and outcomes, controlling for baseline characteristics. There were 25 245 OPTIMIZE-HF patients in the Medicare claims data and 929 161 Medicare beneficiaries with heart failure who were not enrolled in OPTIMIZE-HF. Although hospital characteristics differed, patient demographic characteristics and comorbid conditions were similar. In-hospital mortality for OPTIMIZE-HF and non–OPTIMIZE-HF patients was not significantly different (4.7% versus 4.5%;
P
=0.37); however, OPTIMIZE-HF patients had slightly higher 30-day (11.9% versus 11.2%;
P
<0.001) and 1-year unadjusted mortality (37.2% versus 35.7%;
P
<0.001). Controlling for other variables, OPTIMIZE-HF patients were similar to non–OPTIMIZE-HF patients for the hazard of mortality (hazard ratio, 1.02; 95% confidence interval, 0.98 to 1.06). There were small but significant decreases in all-cause (hazard ratio, 0.94; 95% CI, 0.92 to 0.97) and cardiovascular readmission (hazard ratio, 0.94; 95% CI, 0.91 to 0.98).

Conclusions—

Characteristics and outcomes of Medicare beneficiaries enrolled in OPTIMIZE-HF are similar to the broader Medicare population with heart failure, suggesting that findings from this clinical registry may be generalized.
Farming Animals and the Capabilities Approach: Understanding Roles and Responsibilities through Narrative Ethics
Authors: Anthony Raymond
Published: June 2009

In the Proceedings that emerged from the Second International Workshop on the Assessment of Animal Welfare at Farm and Group Level, Sandoe, Christiansen, & Appleby (2003) challenged participants to ponder four fundamental questions:a. What is the baseline standard for morally acceptable animal welfare?b. What is a good animal life?c. What farming purposes are legitimate?d. What kinds of compromises are acceptable in a less-than-perfect world?Continued reflection on those questions warrants examination of the shape of our modern agricultural ethic. It also calls for a reexamination of recent work by Nussbaum (2004) on extending the capabilities approach to animals and the interface of Nussbaum's work with Rollin's scholarship on telos (1995a). The resources of narrative ethics are summoned to navigate the above-mentioned questions and to explore how Nussbaum's approach and Rollin's notion of animals' natures relate to the main storyline associated with developments in agriculture.
Philosophy and Animal Studies: Calarco, Castricano, and Diamond
Authors: Aaltola Elisa
Published: June 2009

Recently, animal studies has started to gain popularity. This interdisciplinary field investigates the human-animal relationship from different perspectives, including philosophy, cultural studies, and biology. In 2008, at least three books explored themes related to animal studies: Matthew Calarco, Zoographies: The Question of the Animal; Jodey Castricano (Ed.), Animal Subjects: An Ethics Reader in a Posthuman World; and Cora Diamond, Cary Wolfe, et al. (Eds.) Philosophy and Animal Life. Each volume approaches animal studies from a different viewpoint (Continental philosophy, interdisciplinary, and Wittgensteinian), but they also share many themes. This review paper discusses the differences and similarities between the volumes and highlights the directions in which animal studies is developing. It is argued that an emphasis on "direct" perception or experience of animality and heterogeneity, and an exploration of otherness, are elements that all these books share, and that are relevant to animal studies.
Sociology and Beyond: Agency, Victimisation and the Ethics of Writing
Authors: Dahl Gudrun
Published: June 2009

During the last decades, development discourse has taken a neo-liberal turn. Parallel to this, the discourse of social science has become more oriented to matters of individual agency. Within the sociological and anthropological literature on development, this emphasis on individual agency is often expressed in terms of an explicit statement taken by the author that s/he wishes to correct an earlier (ethically inferior) emphasis on structure that is assumed to imply that the concerned people are passive victims. Problematising this ethics of scientific writing, this paper will look at various discourses in which the concept of victimhood is used, seeing claims and disclaimers of victimhood as themselves being expressions of agency in a contestation over accountability, responsibility, recognition and possible indemnification or blame.
Sociology, Contingency and Utopia
Authors: Jain Anil
Published: June 2009

On the level of phenomena the observers of society have noticed an increase of polymorphism, of indeterminacy. This contingent society points us — theoretically and through our experience — to possibility and its (outer) limits. Contingency always means limitation, since possibility emerges only from its background and borderline: the impossible is the frame. And the task. The horizon shall be — Utopia: the sphere of imagination which belongs to the impossible but creates possibility. Since there is a greater truth than the truth of the factual and that is the reality of possibility. We are obliged to this reality: conflicting with the dictatorship of the factual.
The Production and Transmission of Knowledge in Colonial Malaya
Authors: Pannu Paula
Published: June 2009

This article aims to highlight how knowledge played an integral role in the cultural reconstruction of the Malay world during the colonial period. The British produced knowledge about the Malays through scholarly writings in history books and the creation of the census report. This knowledge was, for the most part, constructed and did not necessarily correspond to the social reality of the Malays. The education system played a vital role in transmitting this knowledge to the masses, thus beginning a process of internalisation on their part. This led to a rapid disintegration of Malay cultural practices and way of life as they comprehended alien Western concepts, such as history, territory and community. The nationalist movement in present day Malaysia with its emphasis on race and boundaries attests to the degree to which the British has succeeded in transforming the identity of the Malays. The core of this paper is aimed at demonstrating the connection between British administrative procedures and its impact in reconstructing the thought patterns of the people. This permanent invasion upon the minds of the Malays can be said to the most lasting legacy of British colonial rule.
The Sungei Buloh Leper Settlement: Illness and the Technology of Acquiescence
Authors: Chai Choon-Lee
Published: June 2009

The Sungei Buloh Leper Settlement in British Malaya was established in 1930. It served the purposes of housing, controlling, and curing of leprosy patients. In this paper, Foucault's thesis of disciplinary power is employed to examine the settlement's techniques of leper control and to analyse the modus operandi of the leper settlement. The analysis of this paper points to a shift of emphasis in the mid-1920s in the administration of leper settlements in Malaya, from one that exercised predominantly coercive power of control of lepers to one that used primarily persuasive means. The central argument of the paper is that the changing technique of control of lepers was mainly due to the recognition of the leper settlement as being an establishment with an ambiguous identity, hovering between a total and health institution. While resembling a total institution, the leper settlement nevertheless was not a prison, and leprosy patients, like patients in hospitals, needed to be treated as ordinary citizens both on humanitarian and legal grounds. However, the need for mandatory segregation of lepers meant some degree of compulsion was necessary. The challenge to British colonial administrators was how to maintain hegemony over the lepers with minimum use of physical force and the least violation of lepers' civil rights. The investigation of the paper points to the application of a persuasive technique of social control that encouraged the voluntary enrolment and participation of lepers in the leper settlement. To promote the voluntary admission and stay of lepers, the settlement was organised in such a way that it provided a 'natural and fair atmosphere' that was akin to the external social environment. Inmates, as a result, felt comfortably at home in the settlement.
Intersecting Discourses on Tropicality and Disease Causation: Representations of Réunion's Mosquito-borne Epidemics in the Scientific Literature
Authors: Ravi Srilata , Weinstein Philip
Published: June 2009

In this paper we examine whether discourses of tropicality were affected by paradigm shifts in Western thinking about medicine. If tropicalist thinking reflects latent Western assumptions about the 'Other', tropicalism should persist through major shifts in Western thought. Here we explore whether or not such persistence is evident in representations in the scientific literature of mosquito-borne diseases on the Indian Ocean island of Réunion and where discrete epidemics occurred before, during and after a paradigm shift in Western thinking about disease causation. Late in the 19th Century, miasma theory (epidemics caused by unhealthy air) was replaced by microbial theory (epidemics caused by transmission of microbes) as the dominant scientific understanding of disease causation. We analyse representations of mosquito-borne epidemics in the contemporaneous scientific literature about Réunion for evidence of both tropicalism and a shift in the scientific paradigm. In pre-microbial representations, the unhealthy tropical environments thought to be responsible for miasmatic disease transmission are associated predominantly with the non-white population; in microbial representations non-whites are directly blamed for the spread of tropical infections. The paper argues that the persistence of tropicalist thinking through a major paradigm shift in the Western understanding of disease causation supports Said's (1979) contention that 'Othering' is a generalisable ahistorical phenomenon, and discusses issues of economic exigency that may have supported an ongoing tropicalist influence on public health practice in French overseas departments.
Thèmes bédouins dans la poésie descriptive andalouse classique : transformation et adaptation
Authors: Foulon Brigitte
Published: June 2009

La présence récurrente de la thématique bédouine dans la poésie andalouse est généralement attribuée à l'importation de motifs orientaux. En effet, comment expliquer autrement que les Andalous, sans aucune expérience du désert, aient, dans leur production, multiplié les allusions aux espaces désolés et arides, et accordé une place de premier choix à la flore et au bestiaire arabiques? Si le caractère exogène de ces thèmes et motifs ne fait guère de doute, cela ne signifie pas pour autant que les auteurs andalous aient intégré ceux-ci en l'état dans leurs compositions. Nous tenterons de déterminer, dans cette étude, comment ils ont procédé pour se les approprier et les faire fonctionner dans leur réseau de représentations. Vu l'ampleur de la question, nous nous bornerons ici à explorer cette problématique dans deux contextes particuliers:– celui, d'abord, des poèmes évoquant la Fitna berbère, et en particulier la destruction de Cordoue, qui réactualisent le thème des vestiges des campements (atlāl). Nous nous focaliserons sur les textes d'Ibn Šuhayd (382/992-426/1035) et d'Ibn Hazm (384/994-456/1064), les deux auteurs phares de cette période.– celui, ensuite, des vers dédiés au thème du voyage nocturne (surā) au Ve/XIe siècle, en nous appuyant sur le corpus poétique d'Ibn Hafağa (450/1058-533/1139).
La géographie andalouse : l'autre versant d'une même écriture
Authors: du Mesnil Emmanuelle Tixier
Published: June 2009

Si dans l'Antiquité la géographie est grecque, au Moyen Âge, elle est arabe. Dans la Bagdad abbasside des IXe et Xe siècles, de vastes traités de géographie universelle livrèrent une imago mundi qui permet tout à la fois de faire l'histoire de cette discipline et de comprendre la façon dont les hommes de l'époque médiévale concevaient le monde. À partir des environs de l'An Mil cependant, le genre périclita, ne livrant plus, à quelques exceptions près, que des monographies régionales, des journaux de voyages et des encyclopédies généralistes résumant « la science des pays ». La géographie universelle n'avait cependant pas disparu ; le lieu de son écriture s'était translaté en une terre excentrée et bien éloignée du cœur oriental de l'Islam : al-Andalus. Loin de reconnaître le mérite de ce qu'il convient d'appeler une continuation, les historiens n'ont généralement vu dans cette différence chronologique que le signe évident de la reprise et de l'imitation. Or les traités andalous, dont l'écriture s'échelonne entre le Xe et le XIVe siècle, sont bien plus que cela. À la fois fidèles aux canons de la géographie orientale et originaux dans le traitement de certains thèmes, ils réservent un sort particulier à al-Andalus tout en l'arrimant fermement au domaine de l'Islam. La peinture qu'ils brossent de la Péninsule et du reste du monde est bien l'autre versant d'une même écriture. Une écriture dont il convient d'analyser les évolutions et les inflexions sur le temps long.
Ungrateful or Honorable: A Re-examination of the Word Kanūd in Qur'ān 100 (al-'Ādiyāt)
Authors: Younes Munther
Published: June 2009

In a previous study, and building on the work of Günter Lüling and Christoph Luxenberg, I argued that the first five verses of Q100 were either misunderstood or deliberately modified by the Qur'an editors from an original text that can be characterized as a pre-Islamic hymn. Instead of the traditional Muslim interpretation of horses charging into battle and striking at the enemy, the "reconstructed" version presents an image of maidens going out in the morning and lighting a flame to benefit others.This paper focuses on the second half of the sūra, vv. 6-11. Starting with a reexamination of the word kanūd in v. 6, which is a hapax legomenon in the Qur'an and which is virtually non-existent in the language in general, I argue for a radically different interpretation of these verses. Evidence is provided from the sūra itself, from other parts of the Qur'an, and from a comparison with a related form in Hebrew, a language which is known to have influenced the Qur'an. Just as the reconstruction of vv. 1-5 results in an image of peace and sharing in place of war and destruction, the reconstruction of vv. 6-12 results in an image of man honoring and glorifying his Lord and loving to do good deeds rather than a selfish and ungrateful creature whose selfishness and ingratitude cannot be hidden from God.One of the problems with the traditional interpretation of Q100 is the lack of thematic unity: vv. 1-5 portray horses charging into battle, while vv. 6-11 condemn man as being an ingrate. My reconstruction of the sūra gives it a high degree of coherence. The first half shows women doing good deeds in worship, while the second confirms that mankind loves to do good deeds in the service of God and that God knows all about such deeds.
Encountering Globalization
Authors: Allsop Judith , Bourgeault Ivy Lynn , Evetts Julia , Le Bianic Thomas , Jones Kathryn , Wrede Sirpa
Published: June 2009

The market for professional services is increasingly international but comparisons have not been made between different professions nor on how state policies affect opportunities for mobility. This article considers three professions: engineers, physicians and psychologists and explores the similarities and differences in international labour market demand for occupations. It examines how state policies in four countries, Canada, Finland, France and the UK, aim to promote and control professional labour mobility and migration, and the differences across the three professions. Engineering is an international profession and the extent to which states encourage inward migration differs. Medicine is highly regulated in all four countries but inward migration of physicians varies depending on national policy. Psychologists are less mobile, and the extent of state sponsorship and regulation varies across countries. In all three professions, international organizations are a force encouraging global standards. The conclusion is that state policies reflect state interests and have a strong influence on patterns of mobility.
English Educational Policy for High Schools in Japan
Authors: Kikuchi Keita , Browne Charles
Published: June 2009

■ The Japanese Ministry of Education, Culture, Sports, Science and Technology issues a document known as the Course of Study Guidelines on average once every ten years. This document states the overall and specific goals for English education in Japanese junior and senior high schools including specifying the contents of ministry approved textbooks. This study looks at the influence these guidelines have had on classroom pedagogy from the point of view of the student. For this study 112 college freshmen were surveyed shortly after they had been admitted into several private universities in the Tokyo area, responding to both closed-response and open-response questions about their perceptions of classroom practice in each of the six English courses defined in the guidelines. In the closed-response questionnaire, students were asked to rate various items related to teaching. In the open-response questionnaire, students were asked to describe the teaching practice of their English teachers. Standard descriptive statistics were used to analyse the quantitative data. The study gives insights into the successes and failures of the guideline's curriculum revisions. It is a response to call for the further study by Nunan (2003) and helps to show the complicated gap between educational policies and actual teaching practice in Japan.
Do Fairness and Equity Matter?
Authors: Taxman Faye S. , Gordon Jill A.
Published: June 2009

The concepts of justice and fairness are commonly examined in the literature on criminal justice, except for the issues affecting organizational justice in the workplace. Organizational justice has two properties: distributive justice (the focus on the outcome of a decision) and procedural justice (the decision-making process that leads to the outcome). The authors surveyed 1,200 correctional officers across one state's prison system. Both organizational justice dimensions were leading predictors of job stress and variants of organizational commitment (i.e., climate for learning and type of organizational climate). Procedural justice was related to individual perceptions of fear and perceived risk of inmate victimization. A positive work environment was more likely to occur when employees had a moderate to high sense of equity, which influenced factors related to acceptance of change, stronger commitment to the organization, and better understanding and agreement with organizational goals. Study findings reaffirm the need for administrators to support organizational justice through expanded use of work team processes whereby staff are involved in assessing organizational functionality and recommending improvements.
Reducing Teacher Burnout by Increasing Student Engagement
Authors: Covell Katherine , McNeil Justin K. , Howe R. Brian
Published: June 2009

Teacher burnout has long been understood to have significant negative effects on teaching efficacy. Research has indicated that student misbehaviour, often a result of disengagement, is a major predictor of teacher burnout. In part to address student disengagement, Hampshire County in England has undertaken a whole-school rights-based reform initiative called Rights, Respect and Responsibility (RRR). This study was designed to examine the effects of RRR on student engagement and teacher burnout over a three-year period. The sample initially comprised a total of 15 schools (four infant, five primary and six junior) and 127 teachers. At the second time of measure, one year later, the sample was reduced to 69 teachers from 13 of the schools. At both times teachers completed the following measures: the Maslach Burnout Inventory, the perceived effect of RRR on teaching, and student engagement. In the third year of the study we obtained data on the Maslach Burnout Inventory from 100 teachers at 12 of the schools. Findings suggest that RRR can improve student engagement and reduce teacher burnout. Of particular note was the predictive power of student participation in the classroom and school in reducing teacher burnout.