bluuebunny/crossref_metadata_2025 huggingface dataset:
Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia
Authors: Bies Juraj , Sramko Marek , Fares Joanna , Rosu-Myles Michael , Zhang Steven , Koller Richard , Wolff Linda
Published: May 2010

Inactivation of p15INK4b, an inhibitor of cyclin-dependent kinases, through DNA methylation is one of the most common epigenetic abnormalities in myeloid leukemia. Although this suggests a key role for this protein in myeloid disease suppression, experimental evidence to support this has not been reported. To address whether this event is critical for premalignant myeloid disorders and leukemia development, mice were generated that have loss of p15Ink4b specifically in myeloid cells. The p15Ink4bfl/fl-LysMcre mice develop nonreactive monocytosis in the peripheral blood accompanied by increased numbers of myeloid and monocytic cells in the bone marrow resembling the myeloproliferative form of chronic myelomonocytic leukemia. Spontaneous progression from chronic disease to acute leukemia was not observed. Nevertheless, MOL4070LTR retrovirus integrations provided cooperative genetic mutations resulting in a high frequency of myeloid leukemia in knockout mice. Two common retrovirus insertion sites near c-myb and Sox4 genes were identified, and their transcript up-regulated in leukemia, suggesting a collaborative role of their protein products with p15Ink4b-deficiency in promoting malignant disease. This new animal model demonstrates experimentally that p15Ink4b is a tumor suppressor for myeloid leukemia, and its loss may play an active role in the establishment of preleukemic conditions.
A central role of GPIb-IX in the procoagulant function of platelets that is independent of the 45-kDa GPIbα N-terminal extracellular domain
Authors: Ravanat Catherine , Strassel Catherine , Hechler Béatrice , Schuhler Simone , Chicanne Gaëtan , Payrastre Bernard , Gachet Christian , Lanza François
Published: May 2010

Activated platelets become procoagulant and efficiently promote the conversion of prothrombin to thrombin. A role of the GPIb-V-IX complex has long been postulated in view of the decreased prothrombin consumption in Bernard-Soulier patients. We evaluated the impact of GPIb-V-IX deficiency and the requirement for the GPIbα extracellular domain. In GPIbβ−/− mice, thrombin generation was profoundly decreased in tissue factor– or collagen-related peptide (CRP)–activated platelet-rich plasma and in washed platelets supplemented with normal plasma or with FVa, FXa, and prothrombin. Phosphatidylserine (PS) exposure was similarly decreased in response to thrombin, CRP, or CRP + PAR4 peptide despite a normal platelet phospholipid composition. The hypothesis that these defects originate from lack of the GPIbα N-terminal domain was evaluated after its removal from normal mouse and human platelets with Nk protease or O-sialoglycoprotein endopeptidase. Unexpectedly, the treated platelets exhibited normal thrombin generation and PS exposure, indicating that GPIb-V-IX regulates procoagulant activity independently of its GPIbα-binding region. These results suggested a more general structuring role through intracellular cytoskeleton-anchoring portions regulating responses leading to PS exposure. This hypothesis was supported by the decreased calcium mobilization observed in GPIbβ−/− platelets in response to several agonists, some acting independently of GPIb, in contrast to the normal calcium responses in Nk protease–treated platelets.
Computational prediction of the osmoregulation network in Synechococcus sp. WH8102
Authors: Mao Xizeng , Olman Victor , Stuart Rhona , Paulsen Ian T , Palenik Brian , Xu Ying
Published: May 2010

Background

Osmotic stress is caused by sudden changes in the impermeable solute concentration around a cell, which induces instantaneous water flow in or out of the cell to balance the concentration. Very little is known about the detailed response mechanism to osmotic stress in marine Synechococcus, one of the major oxygenic phototrophic cyanobacterial genera that contribute greatly to the global CO2 fixation.

Results

We present here a computational study of the osmoregulation network in response to hyperosmotic stress of Synechococcus sp strain WH8102 using comparative genome analyses and computational prediction. In this study, we identified the key transporters, synthetases, signal sensor proteins and transcriptional regulator proteins, and found experimentally that of these proteins, 15 genes showed significantly changed expression levels under a mild hyperosmotic stress.

Conclusions

From the predicted network model, we have made a number of interesting observations about WH8102. Specifically, we found that (i) the organism likely uses glycine betaine as the major osmolyte, and others such as glucosylglycerol, glucosylglycerate, trehalose, sucrose and arginine as the minor osmolytes, making it efficient and adaptable to its changing environment; and (ii) σ38, one of the seven types of σ factors, probably serves as a global regulator coordinating the osmoregulation network and the other relevant networks.
Functional analysis of an intergenic non-coding sequence within mce1 operon of M.tuberculosis
Authors: Joon Monika , Bhatia Shipra , Pasricha Rashmi , Bose Mridula , Brahmachari Vani
Published: May 2010

Background

The mce operons play an important role in the entry of M. tuberculosis into macrophages and non-phagocytic cells. Their non-redundant function as well as complex regulation is implied by the phenotype of mce mutants. Recently, mce1 operon was found to extend over 13 genes, fadD5 (Rv0166) being the first gene of the operon. The presence of a non-coding sequence of 200 base pairs between Rv0166 and Rv0167 is peculiar to mce1 among the four mce operons of M.tuberculosis. We have examined the function of this region.

Results

We predicted putative promoter activity of the 200 base pairs of non-coding, intergenic region between Rv0166 and Rv0167 in silico using MEME software and designate it as intergenic promoter, IGPr. We demonstrate both promoter activity and a putative negative regulatory function of this fragment by reporter assays carried out in the surrogate host M.smegmatis. We find that the repressive elements not only control the native promoter but also repress a heterologous promoter of M.smegmatis. The higher activity of the intergenic promoter in a clinical isolate in comparison with the wild type sequence from M.tuberculosis H37Rv could be correlated with a point mutation within the negative element. We have mapped two transcription start sites for mce1 operon both of which are utilized in M.tuberculosis H37Rv as well as the clinical isolate VPCI591. Our studies show that the promoter activity in the non-coding region is relevant not only in reporter gene expression but also in the expression of mce1 operon in M. tuberculosis cells grown in synthetic medium.

Conclusion

The mce operon of M.tuberculosis H37Rv potentially can be transcribed from two promoters P1 and P2, former mapping upstream of Rv0166 and the latter in the non-coding intergenic region between Rv0166 and Rv0167. The transcription initiation from P1 results in a transcript with Rv0166 while that from P2 will be without it. The sequences between the translation start site of Rv0167 and the promoter P2 have a negative regulatory role, as point mutation within the sequence leads to enhanced activity of P2 as well as a heterologous promoter from M.smegmatis. The mutation detected in the clinical isolate VPCI591 therefore behaves like a gain-of-function mutation.
Expression and activity profiles of DPP IV/CD26 and NEP/CD10 glycoproteins in the human renal cancer are tumor-type dependent
Authors: Varona Adolfo , Blanco Lorena , Perez Itxaro , Gil Javier , Irazusta Jon , López José I , Candenas M Luz , Pinto Francisco M , Larrinaga Gorka
Published: May 2010

Background

Cell-surface glycoproteins play critical roles in cell-to-cell recognition, signal transduction and regulation, thus being crucial in cell proliferation and cancer etiogenesis and development. DPP IV and NEP are ubiquitous glycopeptidases closely linked to tumor pathogenesis and development, and they are used as markers in some cancers. In the present study, the activity and protein and mRNA expression of these glycoproteins were analysed in a subset of clear-cell (CCRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytomas (RO).

Methods

Peptidase activities were measured by conventional enzymatic assays with fluorogen-derived substrates. Gene expression was quantitatively determined by qRT-PCR and membrane-bound protein expression and distribution analysis was performed by specific immunostaining.

Results

The activity of both glycoproteins was sharply decreased in the three histological types of renal tumors. Protein and mRNA expression was strongly downregulated in tumors from distal nephron (ChRCC and RO). Moreover, soluble DPP IV activity positively correlated with the aggressiveness of CCRCCs (higher activities in high grade tumors).

Conclusions

These results support the pivotal role for DPP IV and NEP in the malignant transformation pathways and point to these peptidases as potential diagnostic markers.
Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc
Authors: Luo Haitao , Daddysman Matthew K , Rankin Gary O , Jiang Bing-Hua , Chen Yi C
Published: May 2010

Background

Ovarian cancer is one of the most significant malignancies in the western world. Studies showed that Ovarian cancers tend to grow resistance to cisplatin treatment. Therefore, new approaches are needed in ovarian cancer treatment. Kaempferol is a dietary flavonoid that is widely distributed in fruits and vegetables, and epidemiology studies have revealed a protective effect of kaempferol against ovarian cancer risk. Our early studies also found that kaempferol is effective in reducing vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. In this study, we investigated kaempferol's effects on sensitizing ovarian cancer cell growth in response to cisplatin treatment.

Results

Ten chemicals were screened for sensitizing OVCAR-3 ovarian cancer cell growth in response to cisplatin treatment. For kaempferol, which shows a significant synergistic interaction with cisplatin, expression of ABCC1, ABCC5, ABCC6, NFkB1, cMyc, and CDKN1A genes was further examined. For cisplatin/kaempferol treatments on OVCAR-3 cancer cells, the mRNA levels of ABCC1, ABCC5, and NFkB1 did not change. However, significant inhibition of ABCC6 and cMyc mRNA levels was observed for the cisplatin/kaempferol combined treatment. The CDKN1A mRNA levels were significantly up-regulated by cisplatin/kaempferol treatment. A plot of CDKN1A mRNA levels against that of cMyc gene further revealed a reverse, linear relationship, proving cMyc's regulation on CDKN1A gene expressions. Our work found that kaempferol works synergistically with cisplatin in inhibiting ovarian cancer cell viability, and their inhibition on cell viabilities was induced through inhibiting ABCC6 and cMyc gene transcription. Apoptosis assay showed the addition of 20 μM kaempferol to the cisplatin treatment induces the apoptosis of the cancer cells.

Conclusions

Kaempferol enhances the effect of cisplatin through down regulation of cMyc in promoting apoptosis of ovarian cancer cells. As a dietary component, kaempferol sensitizes ovarian cancer cells to cisplatin treatment and deserves further studies for possible applications in chemotherapy of ovarian cancers.
Diabetes prediction, lipid accumulation product, and adiposity measures; 6-year follow-up: Tehran lipid and glucose study
Authors: Bozorgmanesh Mohammadreza , Hadaegh Farzad , Azizi Fereidoun
Published: May 2010

Background

The body mass index (BMI) is the most commonly used marker for evaluating obesity related risks, however, central obesity measures have been proposed to be more informative. Lipid accumulation product (LAP) is an alternative continuous index of lipid accumulation, which is computed from waist circumference (WC, cm) and triglycerides (TGs, mmol/l): (WC-65) ×TG (men) and (WC-58) ×TG (women). We sought in this study to assess if LAP can outperform BMI, waist-to-height-ratio (WHtR), or waist-to-hip-ratio (WHpR) in identifying prevalent and predicting incident diabetes.

Results

The cross-sectional analyses were performed on a sample included 3,682 men and 4,989 women who were not pregnant, aged ≥ 20 years. According to the age (≥ 50 and <50 years) - and sex-specific analyses, odds ratios (ORs) of LAP for prevalent diabetes were higher than those of BMI, WHpR, or WHtR among women, after adjustment for mean arterial pressure and family history of diabetes. The OR of LAP in old men was lower than those of other adiposity measures; in young men, however, LAP was superior to BMI but identical to WHpR and WHtR in identifying prevalent diabetes. Except in young men, LAP showed highest area under the receiver operating characteristic curves (AROC) for prevalent diabetes (P for trend ≤ 0.005).

For longitudinal analyses, a total of 5,018 non-diabetic subjects were followed for ~6 years. The ORs of BMI, WHpR, and WHtR were the same as those of LAP in both sexes and across age groups; except in young men where LAP was superior to the BMI. AROCs of LAP were relatively the same as anthropometric adiposity measures.

Conclusions

LAP was a strong predictor of diabetes and in young individuals had better predictability than did BMI; it was, however, similar to WHpR and WHtR in prediction of incident diabetes.
Controlled spatial and conformational display of immobilised bone morphogenetic protein-2 and osteopontin signalling motifs regulates osteoblast adhesion and differentiation in vitro
Authors: Mitchell Elizabeth A , Chaffey Benjamin T , McCaskie Andrew W , Lakey Jeremy H , Birch Mark A
Published: May 2010

Background

The interfacial molecular mechanisms that regulate mammalian cell growth and differentiation have important implications for biotechnology (production of cells and cell products) and medicine (tissue engineering, prosthetic implants, cancer and developmental biology). We demonstrate here that engineered protein motifs can be robustly displayed to mammalian cells in vitro in a highly controlled manner using a soluble protein scaffold designed to self assemble on a gold surface.

Results

A protein was engineered to contain a C-terminal cysteine that would allow chemisorption to gold, followed by 12 amino acids that form a water soluble coil that could switch to a hydrophobic helix in the presence of alkane thiols. Bioactive motifs from either bone morphogenetic protein-2 or osteopontin were added to this scaffold protein and when assembled on a gold surface assessed for their ability to influence cell function. Data demonstrate that osteoblast adhesion and short-term responsiveness to bone morphogenetic protein-2 is dependent on the surface density of a cell adhesive motif derived from osteopontin. Furthermore an immobilised cell interaction motif from bone morphogenetic protein supported bone formation in vitro over 28 days (in the complete absence of other osteogenic supplements). In addition, two-dimensional patterning of this ligand using a soft lithography approach resulted in the spatial control of osteogenesis.

Conclusion

These data describe an approach that allows the influence of immobilised protein ligands on cell behaviour to be dissected at the molecular level. This approach presents a durable surface that allows both short (hours or days) and long term (weeks) effects on cell activity to be assessed. This widely applicable approach can provide mechanistic insight into the contribution of immobilised ligands in the control of cell activity.
Live cell visualization of the interactions between HIV-1 Gag and the cellular RNA-binding protein Staufen1
Authors: Milev Miroslav P , Brown Chris M , Mouland Andrew J
Published: May 2010

Background

Human immunodeficiency virus type 1 (HIV-1) uses cellular proteins and machinery to ensure transmission to uninfected cells. Although the host proteins involved in the transport of viral components toward the plasma membrane have been investigated, the dynamics of this process remain incompletely described. Previously we showed that the double-stranded (ds)RNA-binding protein, Staufen1 is found in the HIV-1 ribonucleoprotein (RNP) that contains the HIV-1 genomic RNA (vRNA), Gag and other host RNA-binding proteins in HIV-1-producing cells. Staufen1 interacts with the nucleocapsid domain (NC) domain of Gag and regulates Gag multimerization on membranes thereby modulating HIV-1 assembly. The formation of the HIV-1 RNP is dynamic and likely central to the fate of the vRNA during the late phase of the HIV-1 replication cycle.

Results

Detailed molecular imaging of both the intracellular trafficking of virus components and of virus-host protein complexes is critical to enhance our understanding of factors that contribute to HIV-1 pathogenesis. In this work, we visualized the interactions between Gag and host proteins using bimolecular and trimolecular fluorescence complementation (BiFC and TriFC) analyses. These methods allow for the direct visualization of the localization of protein-protein and protein-protein-RNA interactions in live cells. We identified where the virus-host interactions between Gag and Staufen1 and Gag and IMP1 (also known as VICKZ1, IGF2BP1 and ZBP1) occur in cells. These virus-host interactions were not only detected in the cytoplasm, but were also found at cholesterol-enriched GM1-containing lipid raft plasma membrane domains. Importantly, Gag specifically recruited Staufen1 to the detergent insoluble membranes supporting a key function for this host factor during virus assembly. Notably, the TriFC experiments showed that Gag and Staufen1 actively recruited protein partners when tethered to mRNA.

Conclusions

The present work characterizes the interaction sites of key components of the HIV-1 RNP (Gag, Staufen1 and IMP1), thereby bringing to light where HIV-1 recruits and co-opts RNA-binding proteins during virus assembly.
Propensity scores in the presence of effect modification: A case study using the comparison of mortality on hemodialysis versus peritoneal dialysis
Authors: Liem Ylian S , Wong John B , Hunink MG Myriam , de Charro Frank Th , Winkelmayer Wolfgang C
Published: May 2010

Purpose

To control for confounding bias from non-random treatment assignment in observational data, both traditional multivariable models and more recently propensity score approaches have been applied. Our aim was to compare a propensity score-stratified model with a traditional multivariable-adjusted model, specifically in estimating survival of hemodialysis (HD) versus peritoneal dialysis (PD) patients.

Methods

Using the Dutch End-Stage Renal Disease Registry, we constructed a propensity score, predicting PD assignment from age, gender, primary renal disease, center of dialysis, and year of first renal replacement therapy. We developed two Cox proportional hazards regression models to estimate survival on PD relative to HD, a propensity score-stratified model stratifying on the propensity score and a multivariable-adjusted model, and tested several interaction terms in both models.

Results

The propensity score performed well: it showed a reasonable fit, had a good c-statistic, calibrated well and balanced the covariates. The main-effects multivariable-adjusted model and the propensity score-stratified univariable Cox model resulted in similar relative mortality risk estimates of PD compared with HD (0.99 and 0.97, respectively) with fewer significant covariates in the propensity model. After introducing the missing interaction variables for effect modification in both models, the mortality risk estimates for both main effects and interactions remained comparable, but the propensity score model had nearly as many covariates because of the additional interaction variables.

Conclusion

Although the propensity score performed well, it did not alter the treatment effect in the outcome model and lost its advantage of parsimony in the presence of effect modification.
Diametrically opposed effects of hypoxia and oxidative stress on two viral transactivators
Authors: Washington Amber T , Singh Gyanendra , Aiyar Ashok
Published: May 2010

Background

Many pathogens exist in multiple physiological niches within the host. Differences between aerobic and anaerobic conditions are known to alter the expression of bacterial virulence factors, typically through the conditional activity of transactivators that modulate their expression. More recently, changes in physiological niches have been shown to affect the expression of viral genes. For many viruses, differences in oxygen tension between hypoxia and normoxia alter gene expression or function. Oxygen tension also affects many mammalian transactivators including AP-1, NFkB, and p53 by affecting the reduced state of critical cysteines in these proteins. We have recently determined that an essential cys-x-x-cys motif in the EBNA1 transactivator of Epstein-Barr virus is redox-regulated, such that transactivation is favoured under reducing conditions. The crucial Tat transactivator of human immunodeficiency virus (HIV) has an essential cysteine-rich region, and is also regulated by redox. Contrary to EBNA1, it is reported that Tat's activity is increased by oxidative stress. Here we have compared the effects of hypoxia, oxidative stress, and cellular redox modulators on EBNA1 and Tat.

Results

Our results indicate that unlike EBNA1, Tat is less active during hypoxia. Agents that generate hydroxyl and superoxide radicals reduce EBNA1's activity but increase transactivation by Tat. The cellular redox modulator, APE1/Ref-1, increases EBNA1's activity, without any effect on Tat. Conversely, thioredoxin reductase 1 (TRR1) reduces Tat's function without any effect on EBNA1.

Conclusions

We conclude that oxygen partial pressure and oxidative stress affects the functions of EBNA1 and Tat in a dramatically opposed fashion. Tat is more active during oxidative stress, whereas EBNA1's activity is compromised under these conditions. The two proteins respond to differing cellular redox modulators, suggesting that the oxidized cysteine adduct is a disulfide bond(s) in Tat, but sulfenic acid in EBNA1. The effect of oxygen partial pressure on transactivator function suggests that changes in redox may underlie differences in virus-infected cells dependent upon the physiological niches they traffic to.
Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats
Authors: Jeng Yow-Jiun , Kochukov Mikhail , Nauduri Dhananjaya , Kaphalia Bhupendra S , Watson Cheryl S
Published: May 2010

Background

Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as "safer" estrogen replacements. However, it is unknown if they might themselves establish or exacerbate the growth of estrogen-responsive cancers, such as in pituitary.

Methods

We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, ortrans-resveratrol, in the presence or absence of DES. We examined pituitary and other organ weights, blood levels of prolactin (PRL) and growth hormone (GH), body weights, and pituitary tissue histology.

Results

Blood level measurements of the administered phytoestrogens confirmed successful exposure of the animals to high levels of these compounds. By themselves, no phytoestrogen increased pituitary weights or serum PRL levels after 10 weeks of treatment. DES, genistein, and resveratrol increased GH levels during this time. Phytoestrogens neither changed any wet organ weight (uterus, ovary, cervix, liver, and kidney) after 10 weeks of treatment, nor reversed the adverse effects of DES on pituitaries, GH and PRL levels, or body weight gain after 8 weeks of co-treatment. However, they did reverse the DES-induced weight increase on the ovary and cervix. Morphometric examination of pituitaries revealed that treatment with DES, either alone or in combination with phytoestrogens, caused gross structural changes that included decreases in tissue cell density, increases in vascularity, and multiple hemorrhagic areas. DES, especially in combination with phytoestrogens, caused the development of larger and more heterogeneous nuclear sizes in pituitary.

Conclusions

High levels of phytoestrogens by themselves did not cause pituitary precancerous growth or change weights of other estrogen-sensitive organs, though when combined with DES, they counteracted the growth effects of DES on reproductive organs. In the pituitary, phytoestrogens did not reverse the effects of DES, but they did increase the sizes and size heterogeneity of nuclei. Therefore, phytoestrogens may oppose some but not all estrogen-responsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes.
Evaluation of the fullerene compound DF-1 as a radiation protector
Authors: Brown Aaron P , Chung Eun Joo , Urick Mary Ellen , Shield William P , Sowers Anastasia L , Thetford Angela , Shankavaram Uma T , Mitchell James B , Citrin Deborah E
Published: May 2010

Background

Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells.

Methods

In vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for γH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry.

Results

DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer γH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls.

Conclusions

DF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.
Enterobacter cloacae infection of an expanded polytetrafluoroethylene femoral-popliteal bypass graft: a case report
Authors: Musil Ian , Jensen Vanessa , Schilling Jolyon , Ashdown Boyd , Kent Tyler
Published: May 2010

Introduction

Enterobacter cloacae infections are common among burn victims, immunocompromised patients, and patients with malignancy. Most commonly these infections are manifested as nosocomial urinary tract or pulmonary infections. Nosocomial outbreaks have also been associated with colonization of certain surgical equipment and operative cleaning solutions. Infections of an aortobifemoral prosthesis, an aortic graft, and arteriovenous fistulae are noted in the literature. To our knowledge, this is the first isolated account of an E. cloacae infection of a femoral-popliteal expanded polytetrafluoroethylene bypass graft.

Case presentation

A 68-year-old Caucasian man presented with fever and rest pain in the right lower extremity five months after the placement of a vascular expanded polytetrafluoroethylene graft for femoral-popliteal bypass. Computed tomography angiography demonstrated peri-graft fluid that was aspirated percutaneously with image guidance and cultured to reveal E. cloacae. The graft was revised and then removed. The patient completed a six-week course of ceftazidime and is currently without signs of infection. There were no other reports of E. cloacae graft infections in any patients receiving treatment in the same surgical suite within a month of this report.

Conclusion

Isolated cases of E. cloacae infection of surgical bypass grafts are rare (unique in this setting). Clinicians should have a high index of suspicion for device contamination in such cases and should consider testing for possible microbial reservoirs. Graft removal is required due to the formation of biofilm and the recent emergence of Enterobacteriaceae producing extended-spectrum beta-lactamase in community acquired infections.
Enhancement of ATRA-induced differentiation of neuroblastoma cells with LOX/COX inhibitors: an expression profiling study
Authors: Chlapek Petr , Redova Martina , Zitterbart Karel , Hermanova Marketa , Sterba Jaroslav , Veselska Renata
Published: May 2010

Background

We performed expression profiling of two neuroblastoma cell lines, SK-N-BE(2) and SH-SY5Y, after combined treatment with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). This study is a continuation of our previous work confirming the possibility of enhancing ATRA-induced cell differentiation in these cell lines by the application of LOX/COX inhibitors and brings more detailed information concerning the mechanisms of the enhancement of ATRA-induced differentiation of neuroblastoma cells.

Methods

Caffeic acid, as an inhibitor of 5-lipoxygenase, and celecoxib, as an inhibitor on cyclooxygenase-2, were used in this study. Expression profiling was performed using Human Cancer Oligo GEArray membranes that cover 440 cancer-related genes.

Results

Cluster analyses of the changes in gene expression showed the concentration-dependent increase in genes known to be involved in the process of retinoid-induced neuronal differentiation, especially in cytoskeleton remodeling. These changes were detected in both cell lines, and they were independent of the type of specific inhibitors, suggesting a common mechanism of ATRA-induced differentiation enhancement. Furthermore, we also found overexpression of some genes in the same cell line (SK-N-BE(2) or SH-SY5Y) after combined treatment with both ATRA and CA, or ATRA and CX. Finally, we also detected that gene expression was changed after treatment with the same inhibitor (CA or CX) in combination with ATRA in both cell lines.

Conclusions

Obtained results confirmed our initial hypothesis of the common mechanism of enhancement in ATRA-induced cell differentiation via inhibition of arachidonic acid metabolic pathway.
Altered microRNA expression profile with miR-146a upregulation in CD4+T cells from patients with rheumatoid arthritis
Authors: Li Jingyi , Wan Ying , Guo Qiuye , Zou Liyun , Zhang Jinyu , Fang Yongfei , Zhang Jingbo , Zhang Jinjun , Fu Xiaolan , Liu Hongli , Lu Liwei , Wu Yuzhang
Published: May 2010

Introduction

Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).

Methods

The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.

Results

miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.

Conclusions

We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.
Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study
Authors: Gor Priya P , Su H Irene , Gray Robert J , Gimotty Phyllis A , Horn Michelle , Aplenc Richard , Vaughan William P , Tallman Martin S , Rebbeck Timothy R , DeMichele Angela
Published: May 2010

Introduction

Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes.

Methods

We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables.

Results

In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen.

Conclusions

These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.
Spectral Clustering of Microarray Data Elucidates the Roles of Microenvironment Remodeling and Immune Responses in Survival of Head and Neck Squamous Cell Carcinoma
Authors: Thurlow Johanna K. , Peña Murillo Claudia L. , Hunter Keith D. , Buffa Francesca M. , Patiar Shalini , Betts Guy , West Catharine M.L. , Harris Adrian L. , Parkinson Eric K. , Harrison Paul R. , Ozanne Bradford W. , Partridge Max , Kalna Gabriela
Published: May 2010

Purpose

To identify functionally related prognostic gene sets for head and neck squamous cell carcinoma (HNSCC) by unsupervised statistical analysis of microarray data.

Patients and Methods

Microarray analysis was performed on 14 normal oral epithelium and 71 HNSCCs from patients with outcome data. Spectral clustering (SC) analysis of the data set identified multiple vectors representing distinct aspects of gene expression heterogeneity between samples. Gene ontology (GO) analysis of vector gene lists identified gene sets significantly enriched within defined biologic pathways. The prognostic significance of these was established by Cox survival analysis.

Results

The most influential SC vectors were V2 and V3. V2 separated normal from tumor samples. GO analysis of V2 gene lists identified pathways with heterogeneous expression between HNSCCs, notably focal adhesion (FA)/extracellular matrix remodeling and cytokine-cytokine receptor (CR) interactions. Similar analysis of V3 gene lists identified further heterogeneity in CR pathways. V2CR genes represent an innate immune response, whereas high expression of V3CR genes represented an adaptive immune response that was not dependent on human papillomavirus status. Survival analysis demonstrated that the FA gene set was prognostic of poor outcome, whereas classification for adaptive immune response by the CR gene set was prognostic of good outcome. A combined FA&CR model dramatically exceeded the performance of current clinical classifiers (P < .001 in our cohort and, importantly, P = .007 in an independent cohort of 60 HNSCCs).

Conclusion

The application of SC and GO algorithms to HNSCC microarray data identified gene sets highly significant for predicting patient outcome. Further large-scale studies will establish the usefulness of these gene sets in the clinical management of HNSCC.
Patient Decisions About Breast Cancer Chemoprevention: A Systematic Review and Meta-Analysis
Authors: Ropka Mary E. , Keim Jess , Philbrick John T.
Published: May 2010

Purpose

Women at high risk of breast cancer face the complex decision of whether to take tamoxifen or raloxifene for breast cancer chemoprevention. We investigated what is known about decisions of women regarding chemoprevention.

Methods

Using MEDLINE, CINAHL, and PSYCINFO, plus reviewing reference lists of relevant articles, in December 2009 we identified 13 studies that addressed patient decisions about breast cancer chemoprevention, were published in 1995 or later, were peer-reviewed primary clinical studies, and reported rates at which participants showed interest in (hypothetical uptake) or accepted (real uptake) chemoprevention medications.

Results

Nine studies provided information about hypothetical breast cancer chemoprevention decisions (mean uptake rate, 24.7%) and five provided information about real decisions (mean uptake rate, 14.8%). The range of rates was wide, and each of the hypothetical uptake studies assessed interest differently. A logistic regression model found significant correlation with uptake of decision type (hypothetical versus real, odds ratio [OR] = 1.65; 95% CI, 1.26 to 2.16), educational or decision support intervention (provided v not, OR = 0.21; 95% CI, 0.17 to 0.27), and cohort risk for breast cancer (high-risk v general population, OR = 0.65; 95% CI, 0.56 to 0.75). Perceived vulnerability to breast cancer was consistently correlated with increased uptake, and concern for adverse effects was correlated with reduced uptake. All studies used a correlational/descriptive design, and most studies used convenience sampling strategies.

Conclusion

Breast cancer chemoprevention uptake rates are low and variation is wide. Hypothetical uptake rates are higher than real uptake, and interventions markedly reduce uptake. Research is needed that uses reproducible sampling methods and examines decision support strategies that lead to quality decisions.
Cyclophosphamide, Vincristine, and Prednisone Followed by Tositumomab and Iodine-131–Tositumomab in Patients With Untreated Low-Grade Follicular Lymphoma: Eight-Year Follow-Up of a Multicenter Phase II Study
Authors: Link Brian K. , Martin Peter , Kaminski Mark S. , Goldsmith Stanley J. , Coleman Morton , Leonard John P.
Published: May 2010

Purpose

The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 (131I) –tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma.

Patients and Methods

Patients received six cycles of CVP followed by one cycle of tositumomab and 131I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety.

Results

All 30 patients enrolled completed CVP as well as tositumomab and 131I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (≥ 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade ≥ 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia.

Conclusion

These mature data demonstrate that sequential therapy with a non-anthracycline–containing regimen comprising CVP followed by one cycle of tositumomab and 131I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.
Contraband Singing: Poems and Songs in Circulation during the Civil War
Authors: Cohen Michael C.
Published: May 2010

Cohen excavates the social history of the contraband song, a genre of poetry and music popular during the American Civil War. Written in the voices of “contrabands,” former slaves living under the protection of the Union army, contraband songs emerged in the intersections of diverse discourses and institutions of the 1860s: unionist nationalism, blackface minstrelsy, abolitionism, emancipation, antiwar satire, and the study of slave culture that began under the Port Royal experiment. The mobility and mutability of the contraband song allowed it to serve competing political agendas, and therefore Cohen argues that the contraband song offers a particularly rich opportunity to map the contested terrain of wartime culture. Ultimately, the article suggests that wartime poetry and music were crucial to the mediation of the war and must be taken more seriously in the historiography of wartime culture. Cohen analyzes a series of contraband works: abolitionist poems by John Greenleaf Whittier; African American spirituals like “O Let My People Go”; minstrel songs like “Kingdom Coming”; and an assortment of anonymous poems published as broadsides and in periodicals such as the Liberator. In addition, the article examines the use of these works in performances, quotations, recitations, and individual acts of reading. By combining close reading with an archival history of these poems and songs, Cohen proposes that “circulation” and “genre” offer valuable categories of analysis for the study of nineteenth-century poetry.
Melville in the Customhouse Attic
Authors: Hager Christopher
Published: May 2010

In a standard narrative of Herman Melville's career, the author's initial tendency toward cultural nationalism—most famously displayed in his 1850 essay “Hawthorne and His Mosses”—gave way during the early 1850s to political misgivings and increasingly dark novels. The Democratic Party and the “Young America” movement seemed to take a sinister turn with the 1850 Fugitive Slave Law, and Melville grew disillusioned with Young America's literary side following the poor reception of Moby-Dick (1851). Melville's fourth novel, Redburn (1849), though regarded as one of his secondary works, merits greater attention as a counternationalist meditation on the origins of U.S. culture. Because it was written before the political events of the early 1850s and Melville's falling-out with the New York literary establishment, Redburn focuses our attention on a different context for the deepening and darkening of Melville's work: the apparent realization of U.S. “Manifest Destiny” in 1848, with a massive territorial conquest from Mexico. Hager explores the political implications of Redburn's spatial tropes, paying special attention to the architectural history of the New York customhouse and the way Melville expanded the novel itself. As this essay argues, Redburn suggests that excesses of space—architectural, textual, and territorial—obscure the origins and founding principles of the nation.
From Sympathy to Empathy: Anzia Yezierska and the Transformation of the American Subject
Authors: Mikkelsen Ann
Published: May 2010

The work of Anzia Yezierska presents a challenge to early-twentieth-century models of personhood, citizenship, and reading based on common assumptions regarding the nature of sympathy. Yezierska's deployment of what Mikkelsen terms “aesthetic empathy” draws on an emergent discourse about empathy that defined this concept quite differently from current usages. Rather than designating an interpersonal dynamic, this discourse considered empathy as a relation among bodies, objects, and desire within capitalism. Yezierska's fashion-conscious characters reveal a United States constituted by economically, socially, and culturally mobile, not to mention aesthetically pleasing, bodies. Both Jewish and American, these bodies serve as touchpoints for their own desiring gazes, positing a model of assimilative empathy for “native” and immigrant alike in which “looks” refer to both an act and its object, the agent blurred with the process of her continual self-invention as a hybrid of multiple cultures.

Meditating on relations between subject and object, viewer and vision, consumer and commodity, Yezierska makes plain the role of citizen as consumer. Her work crystallizes the dominance of technologies that infused the public sphere with art and beautiful images of human forms, leading the modern spectator to see others as potential reflections of herself. Mikkelsen's examination begins with a reading of the short story “Wings”; continues with a discussion of Jewish American involvement with the garment industry and high fashion as imagined in Salome of the Tenements (1922); and concludes with early theorizations of aesthetic empathy's role in motion pictures such as Hungry Hearts (1922), the film made of Yezierska's short stories.
The Technê Whim: Lin Yutang and the Invention of the Chinese Typewriter
Authors: Williams R. John
Published: May 2010

Despite his enormous popularity as a native interpreter of Chinese culture for Western readers, Lin Yutang's literary career has been largely ignored in American studies and only selectively attended to in Asian and Asian American studies. This essay argues that much of this inattention and misreading has been a result of failing to see how Lin's engagement with the discourse on technology (and especially his decades-long attempt to invent an electric Chinese typewriter) was central to both his literary work and its transnational circulation. Whereas some scholars have argued that Lin simply internalized the basic tenets of Euro-American orientalism, Williams contends that Lin's typewriter demonstrates an aggressive attempt to modify and subvert those discursive practices for Asia's benefit. Recasting Lin's career in the context of a discourse he calls “Asia-as-technê” not only provides a more accurate picture of Lin's transnational literary development; it also opens a space for a reading of Lin's novel Chinatown Family that dramatically alters the typical Asian American understanding of his work and offers an important contribution to the larger critical discourse on the place of technology in American studies.