bluuebunny/crossref_metadata_2025 huggingface dataset:
Subtrochanteric Insufficiency Fractures Associated With Bisphosphonate Use: 2 Case Reports and Review
Authors: Kearse J. , Armitage M. , Suk M. , Berrey B. H.
Published: July 2011

Insufficiency fractures are beginning to emerge in case reports of patients on long-term bisphosphonate therapy. The side effects associated with the long-term use of bisphosphonates were once thought to only involve renal and gastrointestinal (GI) toxicity and osteonecrosis of the jaw, but it is becoming clear that the very condition bisphosphonates were meant to treat could be causing another, trading insufficiency fractures for another type of insufficiency fracture. We review the literature concerning this surprising trend in addition to providing 2 case reports and conclude that these fractures do occur, that they can heal uneventfully, and that further research is needed to determine optimum treatment algorithms concerning duration of treatment and to weigh the potential benefits and morbidity of bisphosphonate treatment.
“Feminizing” Middle Management? An Inquiry Into the Gendered Subtexts in University Department Headship
Authors: Martínez José Manuel Lavié
Published: July 2011

This article summarizes a number of issues emerging in a research in progress that is concerned with the analysis of university department headship from a gender perspective. The article interprets the narratives produced by 20 women as they talk about their experience as heads of departments at three different universities in the city of Barcelona (Spain). The three universities, which are all publicly funded, are going through a similar process of change in many different aspects concerning teaching, research, and management. Overall, what these and other changes mean to middle management is an intensification of administrative workload, an increased capacity required to manage and implement external changes, and a displacement of formerly held prerogatives in the hiring and promotion of the staff. All these issues have emerged in some or other way in the narratives of the 20 heads of department that took part in this study as involving multiple tensions and contradictions that have to be sorted out at the department level. They all carry with them, too, a gender subtext that is not always discernible at first sight.
Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells
Authors: Gioia Romain , Leroy Cédric , Drullion Claire , Lagarde Valérie , Etienne Gabriel , Dulucq Stéphanie , Lippert Eric , Roche Serge , Mahon François-Xavier , Pasquet Jean-Max
Published: July 2011

In this study, we have addressed how Lyn kinase signaling mediates nilotinib-resistance by quantitative phospho-proteomics using Stable Isotope Labeling with Amino acid in Cell culture. We have found an increased tyrosine phosphorylation of 2 additional tyrosine kinases in nilotinib-resistant cells: the spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl. This increased tyrosine phosphorylation involved an interaction of these tyrosine kinases with Lyn. Inhibition of Syk by the inhibitors R406 or BAY 61-3606 or by RNA interference restored the capacity of nilotinib to inhibit cell proliferation. Conversely, coexpression of Lyn and Syk were required to fully induce resistance to nilotinib in drug-sensitive cells. Surprisingly, the knockdown of Syk also strongly decreased tyrosine phosphorylation of Lyn and Axl, thus uncovering interplay between Syk and Lyn. We have shown the involvement of the adaptor protein CDCP-1 in resistance to nilotinib. Interestingly, the expression of Axl and CDCP1 were found increased both in a nilotinib-resistant cell line and in nilotinib-resistant CML patients. We conclude that an oncogenic signaling mediated by Lyn and Syk can bypass the need of Bcr-Abl in CML cells. Thus, targeting these kinases may be of therapeutic value to override imatinib or nilotinib resistance in CML.
Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats
Authors: Theurl Igor , Schroll Andrea , Sonnweber Thomas , Nairz Manfred , Theurl Milan , Willenbacher Wolfgang , Eller Kathrin , Wolf Dominik , Seifert Markus , Sun Chia Chi , Babitt Jodie L. , Hong Charles C. , Menhall Tracey , Gearing Patrick , Lin Herbert Y. , Weiss Guenter
Published: July 2011

Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.
Quantitative characterization and analysis of the dynamic NF-κB response in microglia
Authors: Sheppard Patrick W , Sun Xiaoyun , Emery John F , Giffard Rona G , Khammash Mustafa
Published: July 2011

Background

Activation of the NF-κB transcription factor and its associated gene expression in microglia is a key component in the response to brain injury. Its activation is dynamic and is part of a network of biochemical species with multiple feedback regulatory mechanisms. Mathematical modeling, which has been instrumental for understanding the NF-κB response in other cell types, offers a valuable tool to investigate the regulation of NF-κB activation in microglia at a systems level.

Results

We quantify the dynamic response of NF-κB activation and activation of the upstream kinase IKK using ELISA measurements of a microglial cell line following treatment with the pro-inflammatory cytokine TNFα. A new mathematical model is developed based on these data sets using a modular procedure that exploits the feedback structure of the network. We show that the new model requires previously unmodeled dynamics involved in the stimulus-induced degradation of the inhibitor IκBα in order to properly describe microglial NF-κB activation in a statistically consistent manner. This suggests a more prominent role for the ubiquitin-proteasome system in regulating the activation of NF-κB to inflammatory stimuli. We also find that the introduction of nonlinearities in the kinetics of IKK activation and inactivation is essential for proper characterization of transient IKK activity and corresponds to known biological mechanisms. Numerical analyses of the model highlight key regulators of the microglial NF-κB response, as well as those governing IKK activation. Results illustrate the dynamic regulatory mechanisms and the robust yet fragile nature of the negative feedback regulated network.

Conclusions

We have developed a new mathematical model that incorporates previously unmodeled dynamics to characterize the dynamic response of the NF-κB signaling network in microglia. This model is the first of its kind for microglia and provides a tool for the quantitative, systems level study the dynamic cellular response to inflammatory stimuli.
Improving the efficiency of feed utilization in poultry by selection. 1. Genetic parameters of anatomy of the gastro-intestinal tract and digestive efficiency
Authors: de Verdal Hugues , Narcy Agnès , Bastianelli Denis , Chapuis Hervé , Même Nathalie , Urvoix Séverine , Le Bihan-Duval Elisabeth , Mignon-Grasteau Sandrine
Published: July 2011

Background

Feed costs represent about 70% of the costs of raising broilers. The main way to decrease these costs is to improve feed efficiency by modification of diet formulation, but one other possibility would be to use genetic selection. Understanding the genetic architecture of the gastro-intestinal tract (GIT) and the impact of the selection criterion on the GIT would be of particular interest. We therefore studied the genetic parameters of AMEn (Apparent metabolisable energy corrected for zero nitrogen balance), feed efficiency, and GIT traits in chickens.

Genetic parameters were estimated for 630 broiler chickens of the eighth generation of a divergent selection experiment on AMEn. Birds were reared until 23 d of age and fed a wheat-based diet. The traits measured were body weight (BW), feed conversion ratio (FCR), AMEn, weights of crop, liver, gizzard and proventriculus, and weight, length and density of the duodenum, jejunum and ileum.

Results

The heritability estimates of BW, FCR and AMEn were moderate. The heritability estimates were higher for the GIT characteristics except for the weights of the proventriculus and liver. Gizzard weight was negatively correlated with density (weight to length ratio) of duodenum, jejunum and ileum. Proventriculus and gizzard weights were more strongly correlated with AMEn than with FCR, which was not the case for intestine weight and density.

Conclusions

GIT traits were largely dependent on genetics and that selecting on AMEn or FCR would modify them. Phenotypic observations carried out in the divergent lines selected on AMEn were consistent with estimated genetic correlations between AMEn and GIT traits.
Effect of a low fat versus a low carbohydrate weight loss dietary intervention on biomarkers of long term survival in breast cancer patients ('CHOICE'): study protocol
Authors: Sedlacek Scot M , Playdon Mary C , Wolfe Pamela , McGinley John N , Wisthoff Mark R , Daeninck Elizabeth A , Jiang Weiqin , Zhu Zongjian , Thompson Henry J
Published: July 2011

Background

Weight loss in overweight or obese breast cancer patients is associated with an improved prognosis for long term survival. However, it is not clear whether the macronutrient composition of the chosen weight loss dietary plan imparts further prognostic benefit. A study protocol is presented for a dietary intervention to investigate the effects of weight loss dietary patterns that vary markedly in fat and carbohydrate contents on biomarkers of exposure to metabolic processes that may promote tumorigenesis and that are predictive of long term survival. The study will also determine how much weight must be lost for biomarkers to change in a favorable direction.

Methods/Design

Approximately 370 overweight or obese postmenopausal breast cancer survivors (body mass index: 25.0 to 34.9 kg/m2) will be accrued and assigned to one of two weight loss intervention programs or a non-intervention control group. The dietary intervention is implemented in a free living population to test the two extremes of popular weight loss dietary patterns: a high carbohydrate, low fat diet versus a low carbohydrate, high fat diet. The effects of these dietary patterns on biomarkers for glucose homeostasis, chronic inflammation, cellular oxidation, and steroid sex hormone metabolism will be measured. Participants will attend 3 screening and dietary education visits, and 7 monthly one-on-one dietary counseling and clinical data measurement visits in addition to 5 group visits in the intervention arms. Participants in the control arm will attend two clinical data measurement visits at baseline and 6 months. The primary outcome is high sensitivity C-reactive protein. Secondary outcomes include interleukin-6, tumor necrosis factor-α, insulin-like growth factor-1 (IGF), IGF binding protein-3, 8-isoprostane-F2-alpha, estrone, estradiol, progesterone, sex hormone binding globulin, adiponectin, and leptin.

Discussion

While clinical data indicate that excess weight for height is associated with poor prognosis for long term survival, little attention is paid to weight control in the clinical management of breast cancer. This study will provide information that can be used to answer important patient questions about the effects of dietary pattern and magnitude of weight loss on long term survival following breast cancer treatment.

Clinical Trial Registration

CA125243
Lay perceptions of predictive testing for diabetes based on DNA test results versus family history assessment: a focus group study
Authors: Wijdenes-Pijl Miranda , Dondorp Wybo J , Timmermans Danielle RM , Cornel Martina C , Henneman Lidewij
Published: July 2011

Background

This study assessed lay perceptions of issues related to predictive genetic testing for multifactorial diseases. These perceived issues may differ from the "classic" issues, e.g. autonomy, discrimination, and psychological harm that are considered important in predictive testing for monogenic disorders. In this study, type 2 diabetes was used as an example, and perceptions with regard to predictive testing based on DNA test results and family history assessment were compared.

Methods

Eight focus group interviews were held with 45 individuals aged 35-70 years with (n = 3) and without (n = 1) a family history of diabetes, mixed groups of these two (n = 2), and diabetes patients (n = 2). All interviews were transcribed and analysed using Atlas-ti.

Results

Most participants believed in the ability of a predictive test to identify people at risk for diabetes and to motivate preventive behaviour. Different reasons underlying motivation were considered when comparing DNA test results and a family history risk assessment. A perceived drawback of DNA testing was that diabetes was considered not severe enough for this type of risk assessment. In addition, diabetes family history assessment was not considered useful by some participants, since there are also other risk factors involved, not everyone has a diabetes family history or knows their family history, and it might have a negative influence on family relations. Respect for autonomy of individuals was emphasized more with regard to DNA testing than family history assessment. Other issues such as psychological harm, discrimination, and privacy were only briefly mentioned for both tests.

Conclusion

The results suggest that most participants believe a predictive genetic test could be used in the prevention of multifactorial disorders, such as diabetes, but indicate points to consider before both these tests are applied. These considerations differ with regard to the method of assessment (DNA test or obtaining family history) and also differ from monogenic disorders.
Anti-spasmodic action of crude methanolic extract and a new compound isolated from the aerial parts of Myrsine africana
Authors: Azam Sadiq , Bashir Shumaila , Ahmad Bashir
Published: July 2011

Background

Myrsine africana is an herbaceous plant that is traditionally used as appetizer and carminative. Locally, it is used for the treatment of pulmonary tuberculosis, rheumatism and diarrhea by healers. The aims of the current study were to screen the crude methanol extract obtained from the aerial parts (leaves and stem) of M. africana, for antispasmodic actions on isolated tissues and further to subject the ethyl acetate (EtOAc) fraction of plant to column chromatography for isolation of pure compounds.

Methods

The antispasmodic action of the crude methanol extract was measured on the spontaneous rabbit's jejunum preparations at concentration 0.01, 0.03, 0.1, 0.3, 1.0, 5.0 and 10.0 mg/ml. The crude extract was also applied, in similar concentrations, on KCl (80 mM) induced contractions to explain its possible mode of action.

Results

A new compound Myrsigenin was isolated from the EtOAc fraction of M. africana. The structure of the compound was identified with the help of 13C-NMR, 1H-NMR, HMBC, HMQC, NOESY and COSY. The plant crude methanol extract showed a significant antispasmodic action on rabbit jejunum and abolished the tissue contraction completely at concentration of 5.0 mg/ml.

Conclusion

The study concludes that the methanol crude extract of aerial parts of M. africana has antispasmodic action possibly through the calcium channel blocking mechanisms. A new compound Myrsigenin was isolated from the EtOAc fraction of the plant.
Bradykinin promotes migration and invasion of human immortalized trophoblasts
Authors: Erices Rafaela , Corthorn Jenny , Lisboa Francisco , Valdés Gloria
Published: July 2011

Having demonstrated that the bradykinin B2 receptor (B2R) is expressed in cells that participate in trophoblast invasion in humans and guinea-pigs, we investigated the role of bradykinin (BK) on cell migration and invasion in the HTR-8/SVneo trophoblast cell line using wound healing and invasion assays. First, we documented that HTR-8/SVneo cells expressed kallikrein, B2R, B1R, MMP-2 and MMP-9 using immunocytochemistry. Incubation with BK (10.0 microMol/L) for 18 hours increased the migration index 3-fold in comparison to controls or to cells preincubated with the B2R antagonist HOE-140. BK (10.0 microMol/L) incubation yielded a similar number of proliferating and viable cells as controls, therefore the enhanced closure of the wound cannot be attributed to proliferating cells. Incubation with BK (10.0 microMol/L) for 18 hours increased the invasion index 2-fold in comparison to controls or to cells preincubated with the antagonist of the B2R. Neither the B1R ligand Lys-des-Arg9 BK, nor its antagonist Lys-(des-Arg9-Leu8), modified migration and invasion. Further support for the stimulatory effect of B2R activation on migration and invasion is provided by the 3-fold increase in the number of filopodia per cell versus controls or cells preincubated with the B2R antagonist. Bradykinin had no effect on the cellular protein content of the B2R, nor the MMP-9 and MMP-2 gelatinase activity in the culture media varied after incubation with BK. This study adds bradykinin-acting on the B2R-to the stimuli of trophoblast migration and invasion, an effect that should be integrated to other modifications of the kallikrein-kinin system in normal and pathological pregnancies.
Single-step processing of copper-doped titania nanomaterials in a flame aerosol reactor
Authors: Sahu Manoranjan , Biswas Pratim
Published: July 2011

Synthesis and characterization of long wavelength visible-light absorption Cu-doped TiO2 nanomaterials with well-controlled properties such as size, composition, morphology, and crystal phase have been demonstrated in a single-step flame aerosol reactor. This has been feasible by a detailed understanding of the formation and growth of nanoparticles in the high-temperature flame region. The important process parameters controlled were: molar feed ratios of precursors, temperature, and residence time in the high-temperature flame region. The ability to vary the crystal phase of the doped nanomaterials while keeping the primary particle size constant has been demonstrated. Results indicate that increasing the copper dopant concentration promotes an anatase to rutile phase transformation, decreased crystalline nature and primary particle size, and better suspension stability. Annealing the Cu-doped TiO2 nanoparticles increased the crystalline nature and changed the morphology from spherical to hexagonal structure. Measurements indicate a band gap narrowing by 0.8 eV (2.51 eV) was achieved at 15-wt.% copper dopant concentration compared to pristine TiO2 (3.31 eV) synthesized under the same flame conditions. The change in the crystal phase, size, and band gap is attributed to replacement of titanium atoms by copper atoms in the TiO2 crystal.
HuR binding to AU-rich elements present in the 3' untranslated region of Classical swine fever virus
Authors: Nadar Muthukumar , Chan Meng-Yu , Huang Shi-Wei , Huang Chin-Cheng , Tseng Joseph T , Tsai Ching-Hsiu
Published: July 2011

Background

Classical swine fever virus (CSFV) is the member of the genus Pestivirus under the family Flaviviridae. The 5' untranslated region (UTR) of CSFV contains the IRES, which is a highly structured element that recruits the translation machinery. The 3' UTR is usually the recognition site of the viral replicase to initiate minus-strand RNA synthesis. Adenosine-uridine rich elements (ARE) are instability determinants present in the 3' UTR of short-lived mRNAs. However, the presence of AREs in the 3' UTR of CSFV conserved in all known strains has never been reported. This study inspects a possible role of the ARE in the 3' UTR of CSFV.

Results

Using RNA pull-down and LC/MS/MS assays, this study identified at least 32 possible host factors derived from the cytoplasmic extracts of PK-15 cells that bind to the CSFV 3' UTR, one of which is HuR. HuR is known to bind the AREs and protect the mRNA from degradation. Using recombinant GST-HuR, this study demonstrates that HuR binds to the ARE present in the 3' UTR of CSFV in vitro and that the binding ability is conserved in strains irrespective of virulence.

Conclusions

This study identified one of the CSFV 3' UTR binding proteins HuR is specifically binding to in the ARE region.
An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors
Authors: Dean Justin M , Riddle Art , Maire Jennifer , Hansen Kelly D , Preston Marnie , Barnes Anthony P , Sherman Larry S , Back Stephen A
Published: July 2011

Background

CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are noin vitromodels that reproduce these features of myelination failure.

Results

Forebrain coronal slices from postnatal day (P) 0.5/1 rat pups were cultured for 1, 5, or 9 daysin vitro(DIV). Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA), an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2+OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα+and PDGFRα+/Ki67+OPCs were significantly elevated compared to 0 DIV (P< 0.01). Despite this proliferative response, at 9 DIV ~60% of white matter OLs were late progenitors (preOLs), compared to ~7% in the postnatal day 10 rat (P< 0.0001), consistent with preOL maturation arrest. Addition of HA to slices significantly decreased the density of MBP+OLs at 9 DIV compared to controls (217 ± 16vs.328 ± 17 cells/mm2, respectively;P= 0.0003), supporting an inhibitory role of HA in OL lineage progression in chronic lesions.

Conclusions

Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation.
Plasmacytoid dendritic cells and cancer
Authors: Vermi William , Soncini Matias , Melocchi Laura , Sozzani Silvano , Facchetti Fabio
Published: July 2011

Cancer develops in a complex microenvironment comprising cancer cells, stromal cells, and host immune cells with their soluble products. The counteracting host-protective and tumor-promoting roles of different immune cell populations have been elegantly clarified in the last decade by pertinent genetically modified mouse models. Among cells with a potential role in cancer immunity, PDCs might represent important players as a result of their capacity to bring together innate and adaptive immunity. This review summarizes current knowledge about the role of PDCs in cancer immunity. PDCs have been documented in primary and metastatic human neoplasms; however, the clinical significance of this finding is still unknown. Once into the tumor bed, PDCs can be hijacked by the tumor microenvironment and lose their propensity to produce the required amount of endogenous I-IFN. However, when properly reprogrammed (i.e., by TLR agonists), PDCs might mediate tumor rejection in a clinical setting. Tumor rejection, at least partially, is driven by I-IFN and seems to require a cross-talk with other innate immune cells, including IFN DCs. The latter evidence, although still limited to skin cancers, can provide a leading model for developing adjuvant immune therapy for other neoplasms. To this end, the generation of appropriate mouse models to modulate the frequency and activation state of murine PDCs will also be of remarkable importance.
Investigations on the pattern recognition molecule M-ficolin: quantitative aspects of bacterial binding and leukocyte association
Authors: Kjaer Troels R , Hansen Annette G , Sørensen Uffe B S , Nielsen Ole , Thiel Steffen , Jensenius Jens C
Published: July 2011

M-ficolin is a PRM of the innate immune system, found in serum and associated with leukocytes. We used the soluble form to study specificity toward Gram-positive bacteria and characterized and quantified cell-associated M-ficolin. The binding of M-ficolin to capsulated and noncapsulated strains of Streptococcus agalactiae (GBS) and Staphylococcus aureus was investigated. We did not observe binding of M-ficolin to any of 13 serotypes of S. aureus. Dose-dependent binding of M-ficolin was demonstrated for all of the capsulated GBS strains. The binding was abolished by prior treatment of the bacteria with sialidase, indicating that sialic acid is the ligand for M-ficolin on these bacteria. GlcNAc could inhibit the binding, suggesting that M-ficolin binds via its FBG. M-ficolin was found associated with the complement-activating enzyme in serum, and M-ficolin bound to GBS mediated activation of the complement system. M-ficolin expression on leukocytes was evaluated by flow cytometry with anti-M-ficolin mAb. Total M-ficolin of different leukocytes was quantified in detergent extracts. Monocytes and granulocytes showed similar M-ficolin surface expression, 1.1 × 105 and 0.7 × 105 M-ficolin molecules/cell, respectively. The total M-ficolin content of the cells was 1.5 × 106 molecules/monocyte and approximately one-third of this for granulocytes. Lymphocytes contained <1.5% of the amount estimated for monocytes, and none was revealed on the surface of lymphocytes by flow cytometry. Immunohistochemical analysis of the distribution of M-ficolin in 25 tissues revealed staining of only granulocytes and monocytes. Reported M-ficolin expression by type II pneumocytes could not be verified. We demonstrate the specific binding of M-ficolin to sialic acids in the capsule of GBS and give quantitative aspects of the cell-associated M-ficolin.
Heterogeneous Distribution of EGFR Mutations Is Extremely Rare in Lung Adenocarcinoma
Authors: Yatabe Yasushi , Matsuo Keitaro , Mitsudomi Tetsuya
Published: July 2011

Purpose

Some studies have shown that epidermal growth factor receptor (EGFR) mutations can be heterogeneously distributed in individual tumors. In this study, we re-evaluated the distribution of EGFR mutations within tumors.

Patients and Methods

We used multiple approaches, including an analysis of simultaneous dual hot spot mutations, a trans-sectional analysis of individual lung adenocarcinomas, and comparisons of the mutation patterns between primary and metastatic sites and between primary and recurrent tumors.

Results

None of the 862 tumors harboring an EGFR mutation showed simultaneous dual hot spot mutations, although identical EGFR mutations were found throughout individual tumors in a trans-sectional analysis involving 50 tumors divided into three parts and five lung adenocarcinomas divided into 100 parts. In addition, no discordant mutation patterns were detected among 77 paired primary and metastatic site samples or among 54 primary and recurrent tumor pairs.

Conclusion

All of these results suggest that the heterogeneous distribution of EGFR mutations is extremely rare. However, it is possible that pseudoheterogeneity occurs because of a combination of mutant allele–specific imbalance and heterogeneously distributed EGFR amplification, especially when a less sensitive method is used for detection. Specifically, when EGFR amplification occurs, the mutant allele is amplified, and this amplification is involved in invasive growth. Accordingly, invasive growth area significantly over-represents the mutation signal. In contrast, weak EGFR mutation signals in the area without EGFR amplification may not reach the threshold of detection because of the mixture with normal cells. Such unbalanced mutation signals might lead to pseudoheterogeneity.
Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation
Authors: Budde Lihua E. , Guthrie Katherine A. , Till Brian G. , Press Oliver W. , Chauncey Thomas R. , Pagel John M. , Petersdorf Steven H. , Bensinger William I. , Holmberg Leona A. , Shustov Andrei R. , Green Damian J. , Maloney David G. , Gopal Ajay K.
Published: July 2011

Purpose

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown.

Patients and Methods

To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers.

Results

The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT.

Conclusion

An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.
Antenatal Dexamethasone Treatment in Midgestation Reduces System A-Mediated Transport in the Late-Gestation Murine Placenta
Authors: Audette Melanie C. , Challis John R.G. , Jones Rebecca L. , Sibley Colin P. , Matthews Stephen G.
Published: July 2011

Clinically, approximately 30% of women who receive synthetic glucocorticoids (sGC) for risk of preterm labor carry to term. In vitro studies have shown that sGC acutely regulate the placental system A amino acid transporter, but there are no comparable data in vivo. Hence, the objective of our study was to examine the acute [embryonic day (E)15.5] and longer-term (E17.5 and E18.5) consequences of midgestation antenatal sGC [dexamethasone (DEX); 0.1 mg/kg on E13.5 and E14.5] on placental system A-mediated transfer in the mouse (measured in vivo as maternal-fetal unidirectional 14C-methylaminoisobutyric acid transfer per gram of placenta). System A transfer and Slc38a mRNA expression significantly increased from E12.5 to E18.5 (P < 0.05), corresponding to increased fetal growth. DEX treatment had no acute effect at E15.5 or longer-term effect at E17.5 but significantly decreased system A-mediated transfer before term (E18.5; P < 0.05) in placentae of male and female fetuses. There was no effect of DEX on Slc38a gene expression. Administration of DEX in this regime had no effect on birth weight. We conclude that sGC treatment in midgestation leads to a substantial decrease in placental system A-mediated transport in late gestation, suggesting that prenatal sGC therapy may lead to a reduction in availability of neutral amino acids to the fetus if gestation persists to term.
Smooth Muscle Cell-Specific Knockout of Androgen Receptor: A New Model for Prostatic Disease
Authors: Welsh Michelle , Moffat Lindsey , McNeilly Alan , Brownstein David , Saunders Philippa T. K. , Sharpe Richard M. , Smith Lee B.
Published: July 2011

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease.
Cell Phones from Hell
Authors: Bruhm Steven
Published: July 2011

Recently Hollywood has remade a number of movies from the 1970s, movies in which young women are terrorized by a murderer calling from a telephone located elsewhere in the house. In the remakes, the murderer uses a cell phone, which effectively destroys the sense of space and distance on which earlier horror films were predicated. In one way, these films gesture to Jean Baudrillard's idea of “the transparency of evil,” in that they depict the collapse between the speaking self and the technologies of monstrosity against which the self might be defined. In another way, though, the films proliferate sites of desire from which the telephonic subject searches for connection, even if that connection is impossible to establish. This essay reads the original and the remade When a Stranger Calls and Black Christmas through Baudrillard and Georges Bataille. Ultimately, it finds in contemporary telephonic horror a complex deracination of the desiring subject from its own speaking self.
Specters of Biopolitics: Finitude, Eschaton, and Katechon
Authors: Dillon Michael
Published: July 2011

This essay argues that security is not a commodity or value but a generative principle of political formation. Inasmuch as security politics are also politics of the limit, they derive their political rationalities and governing technologies from the vantage point of the end of the temporal order of things. Every politics of security, in the name of which war is waged, is thus also a political eschatology. Modern politics of security are distinguished by the fact that the temporal horizon within which they take place is that of the factical finitude of modern times. Its security politics are katechontic. Said to be an open horizon of the infinite becoming of finite things, happenings or events, the katechontic security politics of modern times are also said to be traversed by intensive relations of procreative force. Including the motif of life as species existence among those of state, nation, society, and people as referent objects through which concrete form is given to factical finitude, modern biopolitics of security and war exemplify the political eschatology of modern times.
The Chora Line: RealD Incorporated
Authors: Benson-Allott Caetlin
Published: July 2011

Using Henry Selick's Coraline (2009) as an exemplum, this essay investigates what sort of desire digital 3-D cinema produces and satisfies in its spectator and how it integrates itself into Western systems of representation. Selick's film manipulates our biocular vision to offer us a new receptacle for the uncanniness of digital verisimilitude, namely, its virtual depth of field. Exploiting biocular vision as binocular vision, it returns our natural stereoscopy to us as mediated spectacle, as uncanny, and as a new standard for cinematic regimes of vision, now that indexical realism faces its obsolescence. However, the film provides a new representational metaphor through both its name and its depiction of three-dimensionality, namely, Plato's chora. The chora's significance as a metaphysical figure—an unintelligible space that gives form to matter—erupts in Coraline as the Beldam, a wicked witch who lives outside yet supports the materialist and gender-normative fantasies of Coraline's world. Evoking this instability through stop-motion animation and digital 3-D cinematography, Coraline invites the spectator to meditate on the psychic dynamics of dimensionality, not to mention the gendered dimensions of materiality. It builds on the uncontrollable animatedness of its stop-motion to capture the tenuous connection between matter and image as well as the cinema's precarious relationship to indexicality and the inherent uncanniness of the body. These it offers back to the spectator as the digital 3-D experience, the pleasure of postindexical spectatorship.
Dirty Brides and Internet Settings: The Affective Pleasures and Troubles with Trash the Dress Photography Sessions
Authors: White Michele
Published: July 2011

Contemporary wedding cultures, in Western heterosexual forms, tend to perpetuate normative femininity, women's visual accessibility, and women's position as clean and mannered bodies. Trash the Dress (TTD) postwedding sessions repeat and trouble these cultural conceptions. Photographers work with married women in TTD sessions and document them wearing white wedding dresses while wandering through the country, posing in dilapidated surroundings, jumping into dirty water, and covering themselves in mud. Many women then discuss and portray these events in Internet wedding forums. In these settings, women pleasurably gaze at erotic images of women; compliment the women who post; imagine how emotionally painful it is to get dresses dirty; and remember the sticky, erotic, and disturbing aspects of being wet and filthy. TTD representations of revolting fluids and soiled bodies, which women incorporate into their sessions, may briefly encourage viewers to look, but they are difficult to gaze at. These women's engagements with TTD images, other women, and dirt are notable because they trouble the bounded body, problematize the ways lens-based media has enabled men to look at women, and offer women a form of pleasure and desire that is not so easily correlated with traditional weddings and femininity.
“The consummation of the swallow's wings”: A Zoo Story
Authors: Ohi Kevin
Published: July 2011

For Robinson Devor's 2000 film Zoo, zoophilia is “digital desire” in ways that go far beyond its thematic fascination with the Internet and with forms of the virtual. Its lavishly excessive visual beauty and its reticence about depicting bestiality make zoophilia a mode of cinematic viewing. Unexpectedly, the film's exploration of zoophilia illuminates an embodied experience of reading that poets and novelists likewise figure in relation to animals; displacements of perspective and voice that literary texts explore in terms of literary meaning as it shades into animal movement in turn help clarify Zoo's understanding of zoophilia. In detailed readings of texts by J. M. Coetzee (Disgrace), William Faulkner (The Hamlet), Wallace Stevens (“Sunday Morning”), and Elizabeth Bishop (“The Armadillo”), the essay finds in them a destitution of the self that—as psychological depth gives way to surface and movement, and literary meaning, to the rapture of mere sound—is experienced as bodily joy and bodily vulnerability. That destitution helps clarify why Zoo does not evade the ethical dilemmas of sex with animals; by linking zoophilia to cinematic absorption, Zoo makes its mode of filming an ethics, and a practice, of desire. If in zoophilia the Internet gives birth to a new sexual identity, that crossing with technology potentially codifies a disappearing subject. Pairing a birth of vision with an unwatchable spectacle, Zoo suggests a birth of vision that is a blindness cleaned, a mode of viewing in which, to the extent that it truly sees, there may be no one there to do the seeing.
The zebrafish embryo as a tool for screening and characterizing pleurocidin host-defense peptides as anti-cancer agents
Authors: Morash Michael G. , Douglas Susan E. , Robotham Anna , Ridley Christina M. , Gallant Jeffrey W. , Soanes Kelly H.
Published: July 2011

The emergence of multidrug-resistant cancers and the lack of targeted therapies for many cancers underscore an unmet need for new therapeutics with novel modes of action towards cancer cells. Host-defense peptides often exhibit selective cytotoxicity towards cancer cells and show potential as anti-cancer therapeutics. Here, we screen 26 naturally occurring variants of the peptide pleurocidin for cytotoxic and anti-cancer activities, and investigate the underlying mechanism of action. Cytotoxicities were assessed in vitro using cell-based assays and in vivo using zebrafish embryos. Morphological changes were assessed by both transmission and scanning electron microscopy, and functional assays were performed on zebrafish embryos to investigate the mechanism of cell death. A total of 14 peptides were virtually inactive against HL60 human leukemia cells, whereas 12 caused >50% death at ≤32 μg/ml. Morphological changes characteristic of oncosis were evident by electron microscopy after only 1 minute of treatment with 32 μg/ml of variant NRC-03. Only two peptides were hemolytic. Four peptides showed no toxicity towards zebrafish embryos at the highest concentration tested (25 μM; ∼64 μg/ml) and one peptide was highly toxic, killing 4-hour-post-fertilization (hpf) embryos immediately after exposure to 1 μM peptide. Four other peptides killed embryos after 24 hours of exposure at 1 μM. Most peptides caused mortality at one or more developmental stages only after continuous exposure (24 hours) with higher lethal doses (≥5 μM). Pleurocidin NRC-03 bound to embryos and induced the release of superoxide, caused an increase in the number of TUNEL-positive nuclei, and caused membrane damage and the loss of embryonic epithelial integrity, marked by the exclusion of cells from the outer epithelium and the appearance of F-actin within the circumferential cells of the repair site. Our results indicate that specific pleurocidin variants are attractive cancer-selective agents that selectively induce cell death in target cells but leave non-target cells such as erythrocytes and non-transformed cells unaffected.
A high level of liver-specific expression of oncogenic KrasV12 drives robust liver tumorigenesis in transgenic zebrafish
Authors: Nguyen Anh Tuan , Emelyanov Alexander , Koh Chor Hui Vivien , Spitsbergen Jan M. , Lam Siew Hong , Mathavan Sinnakaruppan , Parinov Serguei , Gong Zhiyuan
Published: July 2011

Human liver cancer is one of the deadliest cancers worldwide, with hepatocellular carcinoma (HCC) being the most common type. Aberrant Ras signaling has been implicated in the development and progression of human HCC, but a complete understanding of the molecular mechanisms of this protein in hepatocarcinogenesis remains elusive. In this study, a stable in vivo liver cancer model using transgenic zebrafish was generated to elucidate Ras-driven tumorigenesis in HCC. Using the liver-specific fabp10 (fatty acid binding protein 10) promoter, we overexpressed oncogenic krasV12 specifically in the transgenic zebrafish liver. Only a high level of krasV12 expression initiated liver tumorigenesis, which progressed from hyperplasia to benign and malignant tumors with activation of the Ras-Raf-MEK-ERK and Wnt–β-catenin pathways. Histological diagnosis of zebrafish tumors identified HCC as the main lesion. The tumors were invasive and transplantable, indicating malignancy of these HCC cells. Oncogenic krasV12 was also found to trigger p53-dependent senescence as a tumor suppressive barrier in the pre-neoplastic stage. Microarray analysis of zebrafish liver hyperplasia and HCC uncovered the deregulation of several stage-specific and common biological processes and signaling pathways responsible for krasV12-driven liver tumorigenesis that recapitulated the molecular hallmarks of human liver cancer. Cross-species comparisons of cancer transcriptomes further defined a HCC-specific gene signature as well as a liver cancer progression gene signature that are evolutionarily conserved between human and zebrafish. Collectively, our study presents a comprehensive portrait of molecular mechanisms during progressive Ras-induced HCC. These observations indicate the validity of our transgenic zebrafish to model human liver cancer, and this model might act as a useful platform for drug screening and identifying new therapeutic targets.
Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis
Authors: Zhang Yujin , Kao Winston W.-Y. , Pelosi Emanuele , Schlessinger David , Liu Chia-Yang
Published: July 2011

Notch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMCN1-ICD) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced α-SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Müeller muscle formation and normal eyelid development.